Interactions between THC and cannabidiol in mouse models of cannabinoid activity.

PubMed

Varvel, S A; Wiley, J L; Yang, R; Bridgen, D T; Long, K; Lichtman, A H; Martin, B R

2006-06-01

Interest persists in characterizing potential interactions between Delta(9)-tetrahydocannabinol (THC) and other marijuana constituents such as cannabidiol (CBD). Such interactions may have important implications for understanding the long-term health consequences of chronic marijuana use as well as for attempts to develop therapeutic uses for THC and other CB(1) agonists. We investigated whether CBD may modulate the pharmacological effects of intravenously administered THC or inhaled marijuana smoke on hypoactivity, antinociception, catalepsy, and hypothermia, the well characterized models of cannabinoid activity. Intravenously administered CBD possessed very little activity on its own and, at a dose equal to a maximally effective dose of THC (3 mg/kg), failed to alter THC's effects on any measure. However, higher doses of CBD (ED(50)=7.4 mg/kg) dose-dependently potentiated the antinociceptive effects of a low dose of THC (0.3 mg/kg). Pretreatment with 30 mg/kg CBD, but not 3 mg/kg, significantly elevated THC blood and brain levels. No interactions between THC and CBD were observed in several variations of a marijuana smoke exposure model. Either quantities of CBD were applied directly to marijuana, CBD and THC were both applied to placebo plant material, or mice were pretreated intravenously with 30 mg/kg CBD before being exposed to marijuana smoke. As the amount of CBD found in most marijuana strains in the US is considerably less than that of THC, these results suggest that CBD concentrations relevant to what is normally found in marijuana exert very little, if any, modulatory effects on CB(1)-receptor-mediated pharmacological effects of marijuana smoke.

Quantitative Assessment of the CCMC's Experimental Real-time SWMF-Geospace Results

NASA Astrophysics Data System (ADS)

Liemohn, Michael; Ganushkina, Natalia; De Zeeuw, Darren; Welling, Daniel; Toth, Gabor; Ilie, Raluca; Gombosi, Tamas; van der Holst, Bart; Kuznetsova, Maria; Maddox, Marlo; Rastaetter, Lutz

2016-04-01

Experimental real-time simulations of the Space Weather Modeling Framework (SWMF) are conducted at the Community Coordinated Modeling Center (CCMC), with results available there (http://ccmc.gsfc.nasa.gov/realtime.php), through the CCMC Integrated Space Weather Analysis (iSWA) site (http://iswa.ccmc.gsfc.nasa.gov/IswaSystemWebApp/), and the Michigan SWMF site (http://csem.engin.umich.edu/realtime). Presently, two configurations of the SWMF are running in real time at CCMC, both focusing on the geospace modules, using the BATS-R-US magnetohydrodynamic model, the Ridley Ionosphere Model, and with and without the Rice Convection Model for inner magnetospheric drift physics. While both have been running for several years, nearly continuous results are available since July 2015. Dst from the model output is compared against the Kyoto real-time Dst, in particular the daily minimum value of Dst to quantify the ability of the model to capture storms. Contingency tables are presented, showing that the run with the inner magnetosphere model is much better at reproducing storm-time values. For disturbances with a minimum Dst lower than -50 nT, this version yields a probability of event detection of 0.86 and a Heidke Skill Score of 0.60. In the other version of the SWMF, without the inner magnetospheric module included, the modeled Dst never dropped below -50 nT during the examined epoch.

The effects of cannabidiol (CBD) on Δ⁹-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats.

PubMed

Wakeford, Alison G P; Wetzell, Bradley B; Pomfrey, Rebecca L; Clasen, Matthew M; Taylor, William W; Hempel, Briana J; Riley, Anthony L

2017-08-01

Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ⁹-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Geomagnetic storms, the Dst ring-current myth and lognormal distributions

USGS Publications Warehouse

Campbell, W.H.

1996-01-01

The definition of geomagnetic storms dates back to the turn of the century when researchers recognized the unique shape of the H-component field change upon averaging storms recorded at low latitude observatories. A generally accepted modeling of the storm field sources as a magnetospheric ring current was settled about 30 years ago at the start of space exploration and the discovery of the Van Allen belt of particles encircling the Earth. The Dst global 'ring-current' index of geomagnetic disturbances, formulated in that period, is still taken to be the definitive representation for geomagnetic storms. Dst indices, or data from many world observatories processed in a fashion paralleling the index, are used widely by researchers relying on the assumption of such a magnetospheric current-ring depiction. Recent in situ measurements by satellites passing through the ring-current region and computations with disturbed magnetosphere models show that the Dst storm is not solely a main-phase to decay-phase, growth to disintegration, of a massive current encircling the Earth. Although a ring current certainly exists during a storm, there are many other field contributions at the middle-and low-latitude observatories that are summed to show the 'storm' characteristic behavior in Dst at these observatories. One characteristic of the storm field form at middle and low latitudes is that Dst exhibits a lognormal distribution shape when plotted as the hourly value amplitude in each time range. Such distributions, common in nature, arise when there are many contributors to a measurement or when the measurement is a result of a connected series of statistical processes. The amplitude-time displays of Dst are thought to occur because the many time-series processes that are added to form Dst all have their own characteristic distribution in time. By transforming the Dst time display into the equivalent normal distribution, it is shown that a storm recovery can be predicted with remarkable accuracy from measurements made during the Dst growth phase. In the lognormal formulation, the mean, standard deviation and field count within standard deviation limits become definitive Dst storm parameters.

Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats.

PubMed

Klein, Charlotte; Karanges, Emily; Spiro, Adena; Wong, Alexander; Spencer, Jarrah; Huynh, Thanh; Gunasekaran, Nathan; Karl, Tim; Long, Leonora E; Huang, Xu-Feng; Liu, Kelly; Arnold, Jonathon C; McGregor, Iain S

2011-11-01

The interactions between Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.

Dependence of efficiency of magnetic storm generation on the types of interplanetary drivers.

NASA Astrophysics Data System (ADS)

Yermolaev, Yuri; Nikolaeva, Nadezhda; Lodkina, Irina

2015-04-01

To compare the coupling coefficients between the solar-wind electric field Ey and Dst (and corrected Dst*) index during the magnetic storms generated by different types of interplanetary drivers, we use the Kyoto Dst-index data, the OMNI data of solar wind plasma and magnetic field measurements, and our "Catalog of large scale phenomena during 1976-2000" (published in [1] and presented on websites: ftp://ftp.iki.rssi.ru/pub/omni/). Both indexes at the main phase of magnetic storms are approximated by the linear dependence on the following solar wind parameters: integrated electric field of solar wind (sumEy), solar wind dynamic pressure (Pd), and the level of magnetic field fluctuations (sB), and the fitting coefficients are determined by the technique of least squares. We present the results of the main phase modelling for magnetic storms with Dst<-50 nT induced by 4 types of the solar wind streams: MC (10 events), CIR (41), Sheath (26), Ejecta (45). Our analysis [2, 3] shows that the coefficients of coupling between Dst and Dst* indexes and integral electric field are significantly higher for Sheath (for Dst*and Dst they are -3.4 and -3.3 nT/V m-1 h, respectively) and CIR (-3.0 and -2.8) than for MC (-2.0 and -2.5) and Ejecta (-2.1 and -2.3). Thus we obtained additional confirmation of experimental fact that Sheath and CIR have higher efficiency in generation of magnetic storms than MC and Ejecta. This work was supported by the RFBR, project 13-02-00158a, and by the Program 9 of Presidium of Russian Academy of Sciences. References 1. Yu. I. Yermolaev, N. S. Nikolaeva, I. G. Lodkina, and M. Yu. Yermolaev, Catalog of Large-Scale Solar Wind Phenomena during 1976-2000, Cosmic Research, 2009, Vol. 47, No. 2, pp. 81-94. 2. N.S. Nikolaeva, Yu.I. Yermolaev, I.G. Lodkina, Modeling of Dst-index temporal profile on the main phase of the magnetic storms generated by different types of solar wind, Cosmic Research, 2013, Vol. 51, No. 6, pp. 401-412 3. Nikolaeva N.S., Yermolaev Yu.I., Lodkina I.G., Modeling of corrected Dst-index temporal profile on the main phase of the magnetic storms generated by different types of solar wind, Cosmic Research, 2015, Vol.53, No. 2, 81, DOI: 10.7868/S0023420615020077

New insights into soil temperature time series modeling: linear or nonlinear?

NASA Astrophysics Data System (ADS)

Bonakdari, Hossein; Moeeni, Hamid; Ebtehaj, Isa; Zeynoddin, Mohammad; Mahoammadian, Abdolmajid; Gharabaghi, Bahram

2018-03-01

Soil temperature (ST) is an important dynamic parameter, whose prediction is a major research topic in various fields including agriculture because ST has a critical role in hydrological processes at the soil surface. In this study, a new linear methodology is proposed based on stochastic methods for modeling daily soil temperature (DST). With this approach, the ST series components are determined to carry out modeling and spectral analysis. The results of this process are compared with two linear methods based on seasonal standardization and seasonal differencing in terms of four DST series. The series used in this study were measured at two stations, Champaign and Springfield, at depths of 10 and 20 cm. The results indicate that in all ST series reviewed, the periodic term is the most robust among all components. According to a comparison of the three methods applied to analyze the various series components, it appears that spectral analysis combined with stochastic methods outperformed the seasonal standardization and seasonal differencing methods. In addition to comparing the proposed methodology with linear methods, the ST modeling results were compared with the two nonlinear methods in two forms: considering hydrological variables (HV) as input variables and DST modeling as a time series. In a previous study at the mentioned sites, Kim and Singh Theor Appl Climatol 118:465-479, (2014) applied the popular Multilayer Perceptron (MLP) neural network and Adaptive Neuro-Fuzzy Inference System (ANFIS) nonlinear methods and considered HV as input variables. The comparison results signify that the relative error projected in estimating DST by the proposed methodology was about 6%, while this value with MLP and ANFIS was over 15%. Moreover, MLP and ANFIS models were employed for DST time series modeling. Due to these models' relatively inferior performance to the proposed methodology, two hybrid models were implemented: the weights and membership function of MLP and ANFIS (respectively) were optimized with the particle swarm optimization (PSO) algorithm in conjunction with the wavelet transform and nonlinear methods (Wavelet-MLP & Wavelet-ANFIS). A comparison of the proposed methodology with individual and hybrid nonlinear models in predicting DST time series indicates the lowest Akaike Information Criterion (AIC) index value, which considers model simplicity and accuracy simultaneously at different depths and stations. The methodology presented in this study can thus serve as an excellent alternative to complex nonlinear methods that are normally employed to examine DST.

CRCM + BATS-R-US two-way coupling

NASA Astrophysics Data System (ADS)

Glocer, A.; Fok, M.; Meng, X.; Toth, G.; Buzulukova, N.; Chen, S.; Lin, K.

2013-04-01

We present the coupling methodology and validation of a fully coupled inner and global magnetosphere code using the infrastructure provided by the Space Weather Modeling Framework (SWMF). In this model, the Comprehensive Ring Current Model (CRCM) represents the inner magnetosphere, while the Block-Adaptive-Tree Solar-Wind Roe-Type Upwind Scheme (BATS-R-US) represents the global magnetosphere. The combined model is a global magnetospheric code with a realistic ring current and consistent electric and magnetic fields. The computational performance of the model was improved to surpass real-time execution by the use of the Message Passing Interface (MPI) to parallelize the CRCM. Initial simulations under steady driving found that the coupled model resulted in a higher pressure in the inner magnetosphere and an inflated closed field-line region as compared to simulations without inner-magnetosphere coupling. Our validation effort was split into two studies. The first study examined the ability of the model to reproduce Dst for a range of events from the Geospace Environment Modeling (GEM) Dst Challenge. It also investigated the possibility of a baseline shift and compared two approaches to calculating Dst from the model. We found that the model did a reasonable job predicting Dst and Sym-H according to our two metrics of prediction efficiency and predicted yield. The second study focused on the specific case of the 22 July 2009 moderate geomagnetic storm. In this study, we directly compare model predictions and observations for Dst, THEMIS energy spectragrams, TWINS ENA images, and GOES 11 and 12 magnetometer data. The model did an adequate job reproducing trends in the data. Moreover, we found that composition can have a large effect on the result.

Verification of short lead time forecast models: applied to Kp and Dst forecasting

NASA Astrophysics Data System (ADS)

Wintoft, Peter; Wik, Magnus

2016-04-01

In the ongoing EU/H2020 project PROGRESS models that predicts Kp, Dst, and AE from L1 solar wind data will be used as inputs to radiation belt models. The possible lead times from L1 measurements are shorter (10s of minutes to hours) than the typical duration of the physical phenomena that should be forecast. Under these circumstances several metrics fail to single out trivial cases, such as persistence. In this work we explore metrics and approaches for short lead time forecasts. We apply these to current Kp and Dst forecast models. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 637302.

Effect of combined oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models.

PubMed

Rock, Erin M; Connolly, Cassidy; Limebeer, Cheryl L; Parker, Linda A

2016-09-01

The purpose of this study was to evaluate the potential of oral combined cannabis constituents to reduce nausea. The objective of this study was to determine the effect of combining subthreshold oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models of conditioned gaping. The potential of intragastric (i.g.) administration of THC, CBDA, or combined doses, to interfere with acute nausea-induced conditioned gaping (acute nausea) or the expression of contextually elicited conditioned gaping (anticipatory nausea), was evaluated. For acute nausea, i.g. administration of subthreshold doses of THC (0.5 and 1 mg/kg) or CBDA (0.5 and 1 μg/kg) significantly suppressed acute nausea-induced gaping, whereas higher individual doses of both THC and CBDA were maximally effective. Combined i.g. administration of higher doses of THC and CBDA (2.5 mg/kg THC-2.5 μg/kg CBDA; 10 mg/kg THC-10 μg/kg CBDA; 20 mg/kg THC-20 μg/kg CBDA) also enhanced positive hedonic reactions elicited by saccharin solution during conditioning. For anticipatory nausea, combined subthreshold i.g. doses of THC (0.1 mg/kg) and CBDA (0.1 μg/kg) suppressed contextually elicited conditioned gaping. When administered i.g., THC was effective on its own at doses ranging from 1 to 10 mg/kg, but CBDA was only effective at 10 μg/kg. THC alone was equally effective by intraperitoneal (i.p.) and i.g. administration, whereas CBDA alone was more effective by i.p. administration (Rock et al. in Psychopharmacol (Berl) 232:4445-4454, 2015) than by i.g. administration. Oral administration of subthreshold doses of THC and CBDA may be an effective new treatment for acute nausea and anticipatory nausea and appetite enhancement in chemotherapy patients.

Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability

PubMed Central

Adelli, Goutham R.; Bhagav, Prakash; Taskar, Pranjal; Hingorani, Tushar; Pettaway, Sara; Gul, Waseem; ElSohly, Mahmoud A.; Repka, Michael A.; Majumdar, Soumyajit

2017-01-01

Purpose The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls. Methods THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops. Results THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased by at least 50%. A similar trend was observed in the retina-choroid tissues. Conclusions A combination of prodrug derivatization and formulation development approaches significantly improved the penetration of THC into the anterior segment of the eye following topical application. Enhanced ocular penetration resulted in significantly improved IOP-lowering activity. PMID:28399267

The digital storytelling process: A comparative analysis from various experts

NASA Astrophysics Data System (ADS)

Hussain, Hashiroh; Shiratuddin, Norshuhada

2016-08-01

Digital Storytelling (DST) is a method of delivering information to the audience. It combines narrative and digital media content infused with the multimedia elements. In order for the educators (i.e the designers) to create a compelling digital story, there are sets of processes introduced by experts. Nevertheless, the experts suggest varieties of processes to guide them; of which some are redundant. The main aim of this study is to propose a single guide process for the creation of DST. A comparative analysis is employed where ten DST models from various experts are analysed. The process can also be implemented in other multimedia materials that used the concept of DST.

Delta-9-tetrahydrocannabinol (THC) history fails to affect THC's ability to induce place preferences in rats.

PubMed

Hempel, Briana J; Wakeford, Alison G P; Clasen, Matthew M; Friar, Mary A; Riley, Anthony L

2016-05-01

In pre-clinical models of marijuana abuse, there is relatively limited evidence of delta-9-tetrahydrocannabinol's (THC) rewarding effects, as indexed by its general inability to induce a place preference. One explanation for this failure is that its rewarding effects are masked by its concurrently occurring aversive properties. Consistent with this explanation, THC pre-exposure, which presumably weakens its aversive effects, induces place preferences. Such demonstrations are limited to mice and given reported species differences in THC reactivity, it is unknown to what extent the same shift in affective properties would be evident in rats. The present experiment examined the effect of THC history (3.2mg/kg) on THC (1 or 3.2mg/kg) induced place preference conditioning in rats. An assessment of taste avoidance was also run to independently characterize THC's aversive effects and any changes that occurred with drug pre-exposure. These assessments were made in a combined taste avoidance/place preference procedure in which a novel saccharin solution and environment were paired with THC (0, 1 or 3.2mg/kg). THC did not induce place conditioning, and a history of THC was ineffective in increasing THC's ability to do so, despite the fact that this same history significantly attenuated the aversive effects of THC. The failure of THC to consistently induce place preferences has been argued to be a function of its concurrently occurring aversive effects masking its rewarding properties. The fact that pre-exposure to THC significantly reduced its aversive effects without impacting THC's ability to induce place preferences suggests that THC has weak rewarding effects and/or its residual aversive affects may have still masked its rewarding properties. An important area for future work will be characterizing under what conditions THC is rewarding and whether its overall reinforcing effects are impacted by the relationship between its affective properties. Copyright © 2016 Elsevier Inc. All rights reserved.

MOUNTAIN-SCALE COUPLED PROCESSES (TH/THC/THM)MODELS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Y.S. Wu

This report documents the development and validation of the mountain-scale thermal-hydrologic (TH), thermal-hydrologic-chemical (THC), and thermal-hydrologic-mechanical (THM) models. These models provide technical support for screening of features, events, and processes (FEPs) related to the effects of coupled TH/THC/THM processes on mountain-scale unsaturated zone (UZ) and saturated zone (SZ) flow at Yucca Mountain, Nevada (BSC 2005 [DIRS 174842], Section 2.1.1.1). The purpose and validation criteria for these models are specified in ''Technical Work Plan for: Near-Field Environment and Transport: Coupled Processes (Mountain-Scale TH/THC/THM, Drift-Scale THC Seepage, and Drift-Scale Abstraction) Model Report Integration'' (BSC 2005 [DIRS 174842]). Model results are used tomore » support exclusion of certain FEPs from the total system performance assessment for the license application (TSPA-LA) model on the basis of low consequence, consistent with the requirements of 10 CFR 63.342 [DIRS 173273]. Outputs from this report are not direct feeds to the TSPA-LA. All the FEPs related to the effects of coupled TH/THC/THM processes on mountain-scale UZ and SZ flow are discussed in Sections 6 and 7 of this report. The mountain-scale coupled TH/THC/THM processes models numerically simulate the impact of nuclear waste heat release on the natural hydrogeological system, including a representation of heat-driven processes occurring in the far field. The mountain-scale TH simulations provide predictions for thermally affected liquid saturation, gas- and liquid-phase fluxes, and water and rock temperature (together called the flow fields). The main focus of the TH model is to predict the changes in water flux driven by evaporation/condensation processes, and drainage between drifts. The TH model captures mountain-scale three-dimensional flow effects, including lateral diversion and mountain-scale flow patterns. The mountain-scale THC model evaluates TH effects on water and gas chemistry, mineral dissolution/precipitation, and the resulting impact to UZ hydrologic properties, flow and transport. The mountain-scale THM model addresses changes in permeability due to mechanical and thermal disturbances in stratigraphic units above and below the repository host rock. The THM model focuses on evaluating the changes in UZ flow fields arising out of thermal stress and rock deformation during and after the thermal period (the period during which temperatures in the mountain are significantly higher than ambient temperatures).« less

Acquisition of Turbulence Data Using the DST Group Constant-Temperature Hot-Wire Anemometer System

DTIC Science & Technology

2015-10-01

fluctuations in the low-speed wind tunnel at DST Group. The use of both single- wire and crossed- wire (2 wire ) probes is described. Areas covered include a...fluid-flow studies, including testing of models of aircraft, ships and submarines in wind and water tunnels. Hot- wire anemometers and associated hot...spectra of velocity fluctuations in the low-speed wind tunnel at DST Group. The use of both single- wire and crossed- wire (2 wires ) probes is

Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

PubMed Central

Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María del Rosario; Molpeceres, Jesús

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970

Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

PubMed

Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Geospace environment modeling 2008--2009 challenge: Dst index

USGS Publications Warehouse

Rastätter, L.; Kuznetsova, M.M.; Glocer, A.; Welling, D.; Meng, X.; Raeder, J.; Wittberger, M.; Jordanova, V.K.; Yu, Y.; Zaharia, S.; Weigel, R.S.; Sazykin, S.; Boynton, R.; Wei, H.; Eccles, V.; Horton, W.; Mays, M.L.; Gannon, J.

2013-01-01

This paper reports the metrics-based results of the Dst index part of the 2008–2009 GEM Metrics Challenge. The 2008–2009 GEM Metrics Challenge asked modelers to submit results for four geomagnetic storm events and five different types of observations that can be modeled by statistical, climatological or physics-based models of the magnetosphere-ionosphere system. We present the results of 30 model settings that were run at the Community Coordinated Modeling Center and at the institutions of various modelers for these events. To measure the performance of each of the models against the observations, we use comparisons of 1 hour averaged model data with the Dst index issued by the World Data Center for Geomagnetism, Kyoto, Japan, and direct comparison of 1 minute model data with the 1 minute Dst index calculated by the United States Geological Survey. The latter index can be used to calculate spectral variability of model outputs in comparison to the index. We find that model rankings vary widely by skill score used. None of the models consistently perform best for all events. We find that empirical models perform well in general. Magnetohydrodynamics-based models of the global magnetosphere with inner magnetosphere physics (ring current model) included and stand-alone ring current models with properly defined boundary conditions perform well and are able to match or surpass results from empirical models. Unlike in similar studies, the statistical models used in this study found their challenge in the weakest events rather than the strongest events.

Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice

PubMed Central

Ferrier, Andrew; De Repentigny, Yves; Lynch-Godrei, Anisha; Gibeault, Sabrina; Eid, Walaa; Kuo, Daniel; Zha, Xiaohui; Kothary, Rashmi

2015-01-01

A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dstdt) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dstdt-Tg4 mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, Dstdt-Tg4 sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dstdt-Tg4 mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dstdt-Tg4 mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dstdt-Tg4 dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dstdt pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis. PMID:26043942

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease.

PubMed

Carroll, C B; Zeissler, M-L; Hanemann, C O; Zajicek, J P

2012-10-01

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC. Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Lattice dynamics and lattice thermal conductivity of thorium dicarbide

NASA Astrophysics Data System (ADS)

Liao, Zongmeng; Huai, Ping; Qiu, Wujie; Ke, Xuezhi; Zhang, Wenqing; Zhu, Zhiyuan

2014-11-01

The elastic and thermodynamic properties of ThC2 with a monoclinic symmetry have been studied by means of density functional theory and direct force-constant method. The calculated properties including the thermal expansion, the heat capacity and the elastic constants are in a good agreement with experiment. Our results show that the vibrational property of the C2 dimer in ThC2 is similar to that of a free standing C2 dimer. This indicates that the C2 dimer in ThC2 is not strongly bonded to Th atoms. The lattice thermal conductivity for ThC2 was calculated by means of the Debye-Callaway model. As a comparison, the conductivity of ThC was also calculated. Our results show that the ThC and ThC2 contributions of the lattice thermal conductivity to the total conductivity are 29% and 17%, respectively.

Longitudinal observation of [11C]4DST uptake in turpentine-induced inflammatory tissue.

PubMed

Toyohara, Jun; Sakata, Muneyuki; Oda, Keiichi; Ishii, Kenji; Ishiwata, Kiichi

2013-02-01

Longitudinal changes of 4'-[methyl-(11)C]thiothymidine ([(11)C]4DST) uptake were evaluated in turpentine-induced inflammation. Turpentine (0.1 ml) was injected intramuscularly into the right hind leg of male Wistar rats. Longitudinal [(11)C]4DST uptake was evaluated by the tissue dissection method at 1, 2, 4, 7, and 14 days after turpentine injection (n=5). The tumor selectivity index was calculated using the previously published biodistribution data in C6 glioma-bearing rats. Dynamic PET scan was performed on day 4 when maximum [(11)C]4DST uptake was observed during the longitudinal study. Histopathological analysis and Ki-67 immunostaining were also performed. The uptake of [(11)C]4DST in inflammatory tissue was significantly increased on days 2-4 after turpentine injection, and then decreased. On day 14, tracer uptake returned to the day 1 level. The maximum SUV of inflamed muscle was 0.6 and was 3 times higher than that of the contralateral healthy muscle on days 2-4 after turpentine injection. However, tumor selectivity index remains very high (>10) because of the low inflammation uptake. A dynamic PET scan showed that the radioactivity in inflammatory tissues peaked at 5 min after [(11)C]4DST injection, and then washed out until 20 min. At intervals >20 min, radioactivity levels were constant and double that of healthy muscle. The changes in Ki-67 index were paralleled with those of [(11)C]4DST uptake, indicating cell proliferation-dependent uptake of [(11)C]4DST in inflammatory tissues. In our animal model, low but significant levels of [(11)C]4DST uptake were observed in subacute inflammation. Copyright © 2013 Elsevier Inc. All rights reserved.

GMD Coupling to Power Systems and Disturbance Mitigation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rivera, Michael Kelly; Bent, Russell Whitford

Presentation includes slides on Geomagnetic Disturbance: Ground Fields; Geomagnetic Disturbance: Coupling to Bulk Electric System; Geomagnetic Disturbance: Transformers; GMD Assessment Workflow (TPL-007-1); FERC order 830; Goals; SuperMag (1 min data) Nov. 20-21, 2003 Storm (DST = -422); Spherical Harmonics; Spherical Harmonics Nov. 20-21, 2003 Storm (DST = -422); DST vs HN0,0; Fluctuations vs. DST; Fluctuations; Conclusions and Next Steps; GMD Assessment Workflow (TPL-007-1); EMP E3 Coupling to Texas 2000 Bus Model; E3 Coupling Comparison (total GIC) Varying Ground Zero; E3 Coupling Comparison (total MVAR) Varying Ground Zero; E3 Coupling Comparison (GIC) at Peak Ground Zero; E3 Coupling Comparison (GIC) atmore » Peak Ground Zero; and Conclusion.« less

Development of a decision support tool for seasonal water supply management incorporating system uncertainties and operational constraints

NASA Astrophysics Data System (ADS)

Wang, H.; Asefa, T.

2017-12-01

A real-time decision support tool (DST) for water supply system would consider system uncertainties, e.g., uncertain streamflow and demand, as well as operational constraints and infrastructure outage (e.g., pump station shutdown, an offline reservoir due to maintenance). Such DST is often used by water managers for resource allocation and delivery for customers. Although most seasonal DST used by water managers recognize those system uncertainties and operational constraints, most use only historical information or assume deterministic outlook of water supply systems. This study presents a seasonal DST that incorporates rainfall/streamflow uncertainties, seasonal demand outlook and system operational constraints. Large scale climate-information is captured through a rainfall simulator driven by a Bayesian non-homogeneous Markov Chain Monte Carlo model that allows non-stationary transition probabilities contingent on Nino 3.4 index. An ad-hoc seasonal demand forecasting model considers weather conditions explicitly and socio-economic factors implicitly. Latin Hypercube sampling is employed to effectively sample probability density functions of flow and demand. Seasonal system operation is modelled as a mixed-integer optimization problem that aims at minimizing operational costs. It embeds the flexibility of modifying operational rules at different components, e.g., surface water treatment plants, desalination facilities, and groundwater pumping stations. The proposed framework is illustrated at a wholesale water supplier in Southeastern United States, Tampa Bay Water. The use of the tool is demonstrated in proving operational guidance in a typical drawdown and refill cycle of a regional reservoir. The DST provided: 1) probabilistic outlook of reservoir storage and chance of a successful refill by the end of rainy season; 2) operational expectations for large infrastructures (e.g., high service pumps and booster stations) throughout the season. Other potential use of such DST is also discussed.

Crustal structure along the DESERT 2000 Transect inferred from 3-D gravity modelling

NASA Astrophysics Data System (ADS)

El-Kelani, R.; Goetze, H.; Rybakov, M.; Hassouneh, M.; Schmidt, S.

2003-12-01

A three-dimensional interpretation of the newly compiled Bouguer anomaly map is part of the DESERT 2000 Transect. That is multi-disciplinary and multinational project studying for first time the Dead Sea Transform (DST) fault system (DST) from the Mediterranean Sea to Saudi Arabia across the international border in the NW-SE direction. The negative Bouguer anomalies (with magnitude reached "C130 mGal), located into transform valley, are caused by the internal sedimentary basins filled by the light density young sediments (­Y10 km). A high-resolution 3-D model constrained with the seismic results reveals a possible crustal thickness and density distribution beneath the DST valley. The inferred zone of intrusion coincides with the maximum gravity anomaly over the eastern flank of the DST. The intrusion is displaced at different sectors along the NW-SE direction. The zone of the maximum crustal thinning (­30 km) is attained in the western sector at the Mediterranean. The southeastern plateau, on the other hand, shows by far the largest crustal thickness in the region (38-42 km). Linked to the left lateral movement of ~ 105 km at the boundary between the African and Arabian plate, and constrained with the DESERT 2000 seismic data, a small asymmetric topography of the Moho beneath the DST was modelled. The thickness and density of the crust suggest that a continental crust underlies the DST. The deep basins, the relatively large nature of the intrusion and the asymmetric topography of the Moho lead to the conclusion that a small-scale asthenospheric upwelling(?) might be responsible for the thinning of the crust and subsequent rifting of the Dead Sea graben during the left lateral movement.

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

PubMed Central

Vann, Robert E.; Gamage, Thomas F.; Warner, Jonathan A.; Marshall, Ericka M.; Taylor, Nathan L.; Martin, Billy R.; Wiley, Jenny L.

2008-01-01

Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Δ9-tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC’s effects by these other cannabinoids [e.g., cannabidiol (CBD)] has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC’s abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10 mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC’s discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios. PMID:18206320

Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monnet-Tschudi, Florianne; Hazekamp, Arno; Perret, Nicolas

Despite the widespread use of Cannabis as recreational drug or as medicine, little is known about its toxicity. The accumulation, metabolism and toxicity of THC were analyzed 10 days after a single treatment, and after repeated exposures during 10 days. Mixed-cell aggregate cultures of fetal rat telencephalon were used as in vitro model, as well as aggregates enriched either in neurons or in glial cells. It was found that THC accumulated preferentially in neurons, and that glia-neuron interactions decreased THC accumulation. The quantification of 11-OH-THC and of THC-COOH showed that brain aggregates were capable of THC metabolism. No cell-type differencemore » was found for the metabolite 11-OH-THC, whereas the THC-COOH content was higher in mixed-cell cultures. No cell death was found at THC concentrations of 2 {mu}M in single treatment and of 1 {mu}M and 2 {mu}M in repeated treatments. Neurons, and particularly GABAergic neurons, were most sensitive to THC. Only the GABAergic marker was affected after the single treatment, whereas the GABAergic, cholinergic and astrocytic markers were decreased after the repeated treatments. JWH 015, a CB2 receptor agonist, showed effects similar to THC, whereas ACEA, a CB1 receptor agonist, had no effect. The expression of the cytokine IL-6 was upregulated 48 h after the single treatment with 5 {mu}M of THC or JWH 015, whereas the expression of TNF-{alpha} remained unchanged. These results suggest that the adverse effects of THC were related either to THC accumulation or to cannabinoid receptor activation and associated with IL-6 upregulation.« less

Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague- Dawley) models of conditioned gaping.

PubMed

Rock, Erin M; Limebeer, Cheryl L; Parker, Linda A

2015-12-01

Δ(9)-Tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) found in cannabis both reduce the distressing symptom of nausea, but their combined effects are not understood. The potential of combined doses of THC and CBDA to reduce acute nausea and anticipatory nausea in rodent models was assessed. For acute nausea, the potential of cannabinoid pretreatment(s) to reduce LiCl-induced nausea paired with saccharin was evaluated in a subsequent drug free taste reactivity test, followed by a taste avoidance test. For anticipatory nausea, the potential of the cannabinoid pretreatment(s) to reduce the expression of LiCl-induced contextually elicited conditioned gaping was evaluated. Combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) reduced acute nausea. Higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses also reduced acute nausea. THC (10 mg/kg) interfered with conditioned taste avoidance, an effect attenuated by CBDA (10 μg/kg). On the other hand, combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) did not suppress contextually elicited conditioned gaping in a test for anticipatory nausea. However, higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses, also reduced anticipatory nausea. Only at the highest dose (10 mg/kg) did THC impair locomotor activity, but CBDA did not at any dose. Combined subthreshold doses of THC:CBDA are particularly effective as a treatment for acute nausea. At higher doses, CBDA may attenuate THC-induced interference with learning.

Co-expression of tetanus toxin fragment C in Escherichia coli with thioredoxin and its evaluation as an effective subunit vaccine candidate.

PubMed

Yu, Yun-Zhou; Gong, Zheng-Wei; Ma, Yao; Zhang, Shu-Ming; Zhu, Heng-Qi; Wang, Wen-Bing; Du, Yun; Wang, Shuang; Yu, Wei-Yuan; Sun, Zhi-Wei

2011-08-11

The receptor-binding domain of tetanus toxin (THc), which mediates the binding of the toxin to the nerve cells, is a candidate subunit vaccine against tetanus. In this study one synthetic gene encoding the THc was constructed and highly expressed in Escherichia coli by co-expression with thioredoxin (Trx). The purified THc-vaccinated mice were completely protected against an active toxin challenge in mouse models of disease and the potency of two doses of THc was comparable to that of three doses of toxoid vaccine. And a solid-phase assay showed that the anti-THc sera inhibited the binding of THc or toxoid to the ganglioside GT1b as the anti-tetanus toxoid sera. Furthermore, mice were vaccinated once or twice at four different dosages of THc and a dose-response was observed in both the antibody titer and protective efficacy with increasing dosage of THc and number of vaccinations. The data presented in the report showed that the recombinant THc expressed in E. coli is efficacious in protecting mice against challenge with tetanus toxin suggesting that the THc protein may be developed into a human subunit vaccine candidate designed for the prevention of tetanus. Copyright © 2011 Elsevier Ltd. All rights reserved.

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

Accident rates and the impact of daylight saving time transitions.

PubMed

Robb, David; Barnes, Thomas

2018-02-01

One-third of nations have adopted some form of Daylight Saving Time (DST). Associated costs and benefits include impacts on accident rates. Using data from 12.6 million accident claims in New Zealand during 2005-2016, we model accident rates as a function of various date-based predictors including days before/after the start and end of DST, holidays, day of week, and month of year. This is the first study to consider multiple accident categories (Road, Work, Falls and Home & Community), and the first in the southern hemisphere. The start of DST is associated with significantly higher rates of road accidents (first day +16% and second day +12%). Evidence that accident rates for Falls and Home & Community decline (increase) prior to the start (end) of DST suggest potential behavioural adaption from anticipating the change. While Work accidents show limited impact from DST changes, they exhibit a significant decline over the course of the week (Friday 13% lower than Monday), whereas Road accidents exhibit a significant increase (Friday 19% higher than Monday). Our results have implications for both DST implementation and policy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of Prevalent Phytocannabinoids in the Acetic Acid Model of Visceral Nociception

PubMed Central

Booker, Lamont; Naidu, Pattipati S.; Razdan, Raj K.; Mahadevan, Anu; Lichtman, Aron H.

2009-01-01

Considerable preclinical research has demonstrated the efficacy of Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Δ9-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Δ9-THC and CBN bound to the CB1 receptor and produced antinociceptive effects. The CB1 receptor antagonist, rimonabant, but not the CB2 receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB1 receptor with similar affinity as Δ9-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Δ9-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Δ9-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Δ9-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Δ9-THC. PMID:19679411

Lithosphere structure across the Dead Sea Transform as constrained by Rayleigh waves observed during the DESERT experiment

NASA Astrophysics Data System (ADS)

Laske, G.; Weber, M.

2008-05-01

The interdisciplinary Dead Sea Rift Transect (DESERT) project that was conducted in Israel, the Palestine Territories and Jordan has provided a rich palette of data sets to examine the crust and uppermost mantle beneath one of Earth's most prominent fault systems, the Dead Sea Transform (DST). As part of the passive seismic component, thirty broad-band sensors were deployed in 2000 across the DST for roughly one year. During this deployment, we recorded 115 teleseismic earthquakes that are suitable for a fundamental mode Rayleigh wave analysis at intermediate periods (35-150s). Our initial analysis reveals overall shear velocities that are reduced by up to 4 per cent with respect to reference Earth model PREM. To the west of the DST, we find a seismically relatively fast but thin lid that is about 80 km thick. Towards the east, shallow seismic velocities are low while a deeper low velocity zone is not detected. This contradicts the currently favoured thermomechanical model for the DST that predicts lithospheric thinning through mechanical erosion by an intruding plume from the Red Sea. On the other hand, our current results are somewhat inconclusive regarding asthenosphere velocities east of the DST due to the band limitation of the recording equipment in Jordan.

A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part I: development and validation of a pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents.

PubMed

Manwell, Laurie A; Charchoglyan, Armen; Brewer, Dyanne; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

2014-01-01

Most studies evaluating the effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in animal models administer it via a parenteral route (e.g., intraperitoneal (IP) or intravenous injection (IV)), however, the common route of administration for human users is pulmonary (e.g., smoking or vapourizing marijuana). A vapourized Δ(9)-THC delivery system for rodents was developed and used to compare the effects of pulmonary and parenteral Δ(9)-THC administration on blood cannabinoid levels and behaviour. Sprague-Dawley rats were exposed to pulmonary Δ(9)-THC (1, 5, and 10mg of inhaled vapour) delivered via a Volcano® vapourizing device (Storz and Bickel, Germany) or to parenteral Δ(9)-THC (0.25, 0.5, 1.0, and 1.5mg/kg injected IP). Quantification of Δ(9)-THC and its psychoactive metabolite, 11-hydroxy-Δ(9)-THC (11-OH-Δ(9)-THC), in blood was determined by liquid chromatography/mass spectrometry (LC/MS). In order to verify the potential for the vapourization procedure to produce a robust conditioned place preference (CPP) or conditioned place avoidance CPA, classical conditioning procedures were systematically varied by altering the exposure time (10 or 20min) and number of exposed rats (1 or 2) while maintaining the same vapourization dose (10mg). Blood collected at 20min intervals showed similar dose-dependent and time-dependent changes in Δ(9)-THC and 11-OH-Δ(9)-THC for both pulmonary and parenteral administration of Δ(9)-THC. However, vapourized Δ(9)-THC induced CPP under certain conditions whereas IP-administered Δ(9)-THC induced CPA. These results support and extend the limited evidence (e.g., in humans, Naef et al., 2004; in rodents, Niyuhire et al., 2007) that Δ(9)-THC produces qualitatively different effects on behaviour depending upon the route of administration. Copyright © 2014 Elsevier Inc. All rights reserved.

Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.

PubMed

Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L

2015-06-01

A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184). Copyright © 2015 Elsevier Ltd. All rights reserved.

Anticoagulant effects of a Cannabis extract in an obese rat model.

PubMed

Coetzee, C; Levendal, R-A; van de Venter, M; Frost, C L

2007-05-01

Blood coagulation studies were conducted to determine the possible anti-/prothrombotic effect of an organic cannabis extract and the three major cannabinoids, THC, CBD and CBN. The in vitro effect of the cannabis extract on thrombin activity produced an IC50 value of 9.89 mg/ml, compared to THC at 1.79 mg/ml. It was also found that the extract, THC and CBN showed considerable inhibition of thrombin-induced clot formation in vitro with IC50 values of 600, 87 and 83 microg/ml for the extract, THC and CBN respectively. In an in vivo model used to determine clotting times of lean and obese rats treated with a cannabis extract, 50% clotting times were found to be 1.5 and 2 fold greater than their respective control groups, supporting the results obtained in the in vitro model. The study thus shows that Cannabis sativa and the cannabinoids, THC and CBN, display anticoagulant activity and may be useful in the treatment of diseases such as type 2 diabetes in which a hypercoagulable state exists.

Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant.

PubMed

Justinova, Zuzana; Munzar, Patrik; Panlilio, Leigh V; Yasar, Sevil; Redhi, Godfrey H; Tanda, Gianluigi; Goldberg, Steven R

2008-11-01

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.

Tetrahydrocurcumin induces mesenchymal-epithelial transition and suppresses angiogenesis by targeting HIF-1α and autophagy in human osteosarcoma

PubMed Central

Zhang, Yan; Liu, Ying; Zou, Jilong; Yan, Lixin; Du, Wei; Zhang, Yafeng; Sun, Hanliang; Lu, Peng; Geng, Shuo; Gu, Rui; Zhang, Hongyue; Bi, Zhenggang

2017-01-01

Human osteosarcoma is considered a malignant tumor with poor prognosis that readily metastasizes. Tetrahydrocurcumin (THC) has been reported to have anti-tumor activity in numerous tumors. In addition, hypoxia-inducible factor-1α (HIF-1α) has been demonstrated to be associated with tumor metastasis by regulating epithelial-mesenchymal transition (EMT). However, the role of THC in osteosarcoma remains uncertain. Therefore, this study aimed to elucidate the potential mechanisms. We found that THC significantly reduced the growth of osteosarcoma cells and suppressed migration and invasion, as tested in a nude mouse lung metastasis model. Additionally, the mesenchymal-epithelial transition (MET) process was facilitated by THC. Mechanistically, our study showed that HIF-1α had a pivotal role in the anti-metastatic effect of THC. Importantly, HIF-1α expression was downregulated by THC by inhibiting Akt/mTOR and p38 MAPK pathways. Moreover, THC exhibited a remarkable inhibitory effect on HIF-1α expression and angiogenesis under hypoxic conditions. Furthermore, THC activated autophagy and induced MET and suppressed angiogenesis in a HIF-1α-related manner. Taken together, our findings suggest that THC suppresses metastasis and invasion and this may be associated with HIF-1α and autophagy, which would potentially provide therapeutic strategies for human osteosarcoma. PMID:29207631

Decarboxylation of Δ 9-tetrahydrocannabinol: Kinetics and molecular modeling

NASA Astrophysics Data System (ADS)

Perrotin-Brunel, Helene; Buijs, Wim; van Spronsen, Jaap; van Roosmalen, Maaike J. E.; Peters, Cor J.; Verpoorte, Rob; Witkamp, Geert-Jan

2011-02-01

Efficient tetrahydrocannabinol (Δ 9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ 9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ 9-THC-acid naturally present in the plant into the psychoactive Δ 9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol -1 and a pre-exponential factor of 3.7 × 10 8 s -1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ 9-THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ 9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ 9-THC from the plant.

Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

PubMed

Nguyen, Jacques D; Aarde, Shawn M; Vandewater, Sophia A; Grant, Yanabel; Stouffer, David G; Parsons, Loren H; Cole, Maury; Taffe, Michael A

2016-10-01

Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC.

PubMed

Ménétrey, Annick; Augsburger, Marc; Favrat, Bernard; Pin, Marie A; Rothuizen, Laura E; Appenzeller, Monique; Buclin, Thierry; Mangin, Patrice; Giroud, Christian

2005-01-01

Delta(9)-Tetrahydrocannabinol (THC) is frequently found in the blood of drivers suspected of driving under the influence of cannabis or involved in traffic crashes. The present study used a double-blind crossover design to compare the effects of medium (16.5 mg THC) and high doses (45.7 mg THC) of hemp milk decoctions or of a medium dose of dronabinol (20 mg synthetic THC, Marinol on several skills required for safe driving. Forensic interpretation of cannabinoids blood concentrations were attempted using the models proposed by Daldrup (cannabis influencing factor or CIF) and Huestis and coworkers. First, the time concentration-profiles of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) (active metabolite of THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in whole blood were determined by gas chromatography-mass spectrometry-negative ion chemical ionization. Compared to smoking studies, relatively low concentrations were measured in blood. The highest mean THC concentration (8.4 ng/mL) was achieved 1 h after ingestion of the strongest decoction. Mean maximum 11-OH-THC level (12.3 ng/mL) slightly exceeded that of THC. THCCOOH reached its highest mean concentration (66.2 ng/mL) 2.5-5.5 h after intake. Individual blood levels showed considerable intersubject variability. The willingness to drive was influenced by the importance of the requested task. Under significant cannabinoids influence, the participants refused to drive when they were asked whether they would agree to accomplish several unimportant tasks, (e.g., driving a friend to a party). Most of the participants reported a significant feeling of intoxication and did not appreciate the effects, notably those felt after drinking the strongest decoction. Road sign and tracking testing revealed obvious and statistically significant differences between placebo and treatments. A marked impairment was detected after ingestion of the strongest decoction. A CIF value, which relies on the molar ratio of main active to inactive cannabinoids, greater than 10 was found to correlate with a strong feeling of intoxication. It also matched with a significant decrease in the willingness to drive, and it matched also with a significant impairment in tracking performances. The mathematic model II proposed by Huestis et al. (1992) provided at best a rough estimate of the time of oral administration with 27% of actual values being out of range of the 95% confidence interval. The sum of THC and 11-OH-THC blood concentrations provided a better estimate of impairment than THC alone. This controlled clinical study points out the negative influence on fitness to drive after medium or high dose oral THC or dronabinol.

The yin and yang of cannabis-induced psychosis: the actions of Δ(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia.

PubMed

Arnold, J C; Boucher, A A; Karl, T

2012-01-01

The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein).

A DST Model of Multilingualism and the Role of Metalinguistic Awareness

ERIC Educational Resources Information Center

Jessner, Ulrike

2008-01-01

This paper suggests that a dynamic systems theory (DST) provides an adequate conceptual metaphor for discussing multilingual development. Multilingual acquisition is a nonlinear and complex dynamic process depending on a number of interacting factors. Variability plays a crucial role in the multilingual system as it changes over time (Herdina &…

Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Δ(9) -tetrahydrocannabinol in Sprague-Dawley rats.

PubMed

Taffe, Michael A; Creehan, Kevin M; Vandewater, Sophia A

2015-04-01

Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ(9) -tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10-30 mg·kg(-1) , i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model. There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats. © 2014 The British Pharmacological Society.

Effects of Uncertainties in Electric Field Boundary Conditions for Ring Current Simulations

NASA Astrophysics Data System (ADS)

Chen, Margaret W.; O'Brien, T. Paul; Lemon, Colby L.; Guild, Timothy B.

2018-01-01

Physics-based simulation results can vary widely depending on the applied boundary conditions. As a first step toward assessing the effect of boundary conditions on ring current simulations, we analyze the uncertainty of cross-polar cap potentials (CPCP) on electric field boundary conditions applied to the Rice Convection Model-Equilibrium (RCM-E). The empirical Weimer model of CPCP is chosen as the reference model and Defense Meteorological Satellite Program CPCP measurements as the reference data. Using temporal correlations from a statistical analysis of the "errors" between the reference model and data, we construct a Monte Carlo CPCP discrete time series model that can be generalized to other model boundary conditions. RCM-E simulations using electric field boundary conditions from the reference model and from 20 randomly generated Monte Carlo discrete time series of CPCP are performed for two large storms. During the 10 August 2000 storm main phase, the proton density at 10 RE at midnight was observed to be low (< 1.4 cm-3) and the observed disturbance Dst index is bounded by the simulated Dst values. In contrast, the simulated Dst values during the recovery phases of the 10 August 2000 and 31 August 2005 storms tend to underestimate systematically the observed late Dst recovery. This suggests a need to improve the accuracy of particle loss calculations in the RCM-E model. Application of this technique can aid modelers to make efficient choices on either investing more effort on improving specification of boundary conditions or on improving descriptions of physical processes.

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2013 CFR

2013-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2011 CFR

2011-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2012 CFR

2012-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2014 CFR

2014-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2010 CFR

2010-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

Empirical Characterization of Low-Altitude Ion Flux Derived from TWINS

NASA Astrophysics Data System (ADS)

Goldstein, J.; LLera, K.; McComas, D. J.; Redfern, J.; Valek, P. W.

2018-05-01

In this study we analyze ion differential flux from 10 events between 2008 and 2015. The ion fluxes are derived from low-altitude emissions (LAEs) in energetic neutral atom (ENA) images obtained by Two Wide-angle Imaging Neutral-atom Spectrometers (TWINS). The data set comprises 119.44 hr of observations, including 4,284 per energy images with 128,277 values of differential ENA flux from pixels near Earth's limb. Limb pixel data are extracted and mapped to a common polar ionospheric grid and associated with values of the Dst index. Statistical analysis is restricted to pixels within 10% of the LAE emissivity peak. For weak Dst conditions we find a premidnight peak in the average ion precipitation, whose flux and location are relatively insensitive to energy. For moderate Dst, elevated flux levels appear over a wider magnetic local time (MLT) range, with a separation of peak locations by energy. Strong disturbances bring a dramatic flux increase across the entire nightside at all energies but strongest for low energies in the postmidnight sector. The arrival of low-energy ions can lower the average energy for strong Dst, even as it raises the total integral number flux. TWINS-derived ion fluxes provide a macroscale measurement of the average precipitating ion distribution and confirm that convection, either quasi-steady or bursty, is an important process controlling the spatial and spectral properties of precipitating ions. The premidnight peak (weak Dst), MLT widening and energy-versus-MLT dependence (moderate Dst), and postmidnight low-energy ion enhancement (strong Dst) are consistent with observations and models of steady or bursty convective transport.

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

PubMed

Javadi-Paydar, Mehrak; Nguyen, Jacques D; Kerr, Tony M; Grant, Yanabel; Vandewater, Sophia A; Cole, Maury; Taffe, Michael A

2018-06-16

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. To compare thermoregulatory and locomotor responses to inhaled ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

PubMed

King, Kirsten M; Myers, Alyssa M; Soroka-Monzo, Ariele J; Tuma, Ronald F; Tallarida, Ronald J; Walker, Ellen A; Ward, Sara Jane

2017-09-01

The non-psychoactive phytocannabinoid cannabidiol (CBD) can affect the pharmacological effects of Δ 9 -tetrahydrocannabinol (THC). We tested the possible synergy between CBD and THC in decreasing mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain. We also tested the effects of CBD on oxaliplatin- and vincristine-induced mechanical sensitivity. Paclitaxel-treated mice (8.0 mg·kg -1 i.p., days 1, 3, 5 and 7) were pretreated with CBD (0.625-20.0 mg·kg -1 i.p.), THC (0.625-20.0 mg·kg -1 i.p.) or CBD + THC (0.04 + 0.04-20.0 + 20.0 mg·kg -1 i.p.), and mechanical sensitivity was assessed on days 9, 14 and 21. Oxaliplatin-treated (6.0 mg·kg -1 i.p., day 1) or vincristine-treated mice (0.1 mg·kg -1 i.p. days 1-7) were pretreated with CBD (1.25-10.0 mg·kg -1 i.p.), THC (10.0 mg·kg -1 i.p.) or THC + CBD (0.16 mg·kg -1 THC + 0.16 mg·kg -1 CBD i.p.). Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity. CBD may be potent and effective at preventing the development of chemotherapy-induced peripheral neuropathy, and its clinical use may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of cannabis-based pharmacotherapies. © 2017 The British Pharmacological Society.

Daylight saving time can decrease the frequency of wildlife–vehicle collisions

PubMed Central

Ellis, William A.; FitzGibbon, Sean I.; Barth, Benjamin J.; Niehaus, Amanda C.; David, Gwendolyn K.; Taylor, Brendan D.; Matsushige, Helena; Melzer, Alistair; Bercovitch, Fred B.; Carrick, Frank; Jones, Darryl N.; Dexter, Cathryn; Gillett, Amber; Predavec, Martin; Lunney, Dan

2016-01-01

Daylight saving time (DST) could reduce collisions with wildlife by changing the timing of commuter traffic relative to the behaviour of nocturnal animals. To test this idea, we tracked wild koalas (Phascolarctos cinereus) in southeast Queensland, where koalas have declined by 80% in the last 20 years, and compared their movements with traffic patterns along roads where they are often killed. Using a simple model, we found that DST could decrease collisions with koalas by 8% on weekdays and 11% at weekends, simply by shifting the timing of traffic relative to darkness. Wildlife conservation and road safety should become part of the debate on DST. PMID:27881767

Application of fuzzy set and Dempster-Shafer theory to organic geochemistry interpretation

NASA Technical Reports Server (NTRS)

Kim, C. S.; Isaksen, G. H.

1993-01-01

An application of fuzzy sets and Dempster Shafter Theory (DST) in modeling the interpretational process of organic geochemistry data for predicting the level of maturities of oil and source rock samples is presented. This was accomplished by (1) representing linguistic imprecision and imprecision associated with experience by a fuzzy set theory, (2) capturing the probabilistic nature of imperfect evidences by a DST, and (3) combining multiple evidences by utilizing John Yen's generalized Dempster-Shafter Theory (GDST), which allows DST to deal with fuzzy information. The current prototype provides collective beliefs on the predicted levels of maturity by combining multiple evidences through GDST's rule of combination.

Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Ù9-tetrahydrocannabinol in Sprague-Dawley rats

PubMed Central

Taffe, Michael A; Creehan, Kevin M; Vandewater, Sophia A

2015-01-01

Background and Purpose Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ9-tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Experimental Approaches Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10–30 mg·kg−1, i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). Key Results CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model. Conclusions and Implications There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats. PMID:25425111

A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis.

PubMed

Gras, Adrien; Broughton, Julie

2016-12-01

Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales. A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone. At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at £3,836/patient (ICER: £10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -£33,609/patient (ICER: -£95,423/QALY). The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity.

An empirical probability density distribution of planetary ionosphere storms with geomagnetic precursors

NASA Astrophysics Data System (ADS)

Gulyaeva, Tamara; Stanislawska, Iwona; Arikan, Feza; Arikan, Orhan

The probability of occurrence of the positive and negative planetary ionosphere storms is evaluated using the W index maps produced from Global Ionospheric Maps of Total Electron Content, GIM-TEC, provided by Jet Propulsion Laboratory, and transformed from geographic coordinates to magnetic coordinates frame. The auroral electrojet AE index and the equatorial disturbance storm time Dst index are investigated as precursors of the global ionosphere storm. The superposed epoch analysis is performed for 77 intense storms (Dst≤-100 nT) and 227 moderate storms (-100

Chronic Adolescent Δ9-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment.

PubMed

Murphy, Michelle; Mills, Sierra; Winstone, Joanna; Leishman, Emma; Wager-Miller, Jim; Bradshaw, Heather; Mackie, Ken

2017-01-01

Introduction: The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ 9 -tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between CBD and THC in the neurodevelopmental effects of THC is also important. The current study examined the immediate and long-term behavioral consequences of THC, CBD, and their combination in a mouse model of adolescent cannabis use. Materials and Methods: Male CD1 mice received daily injections of THC (3 mg/kg), CBD (3 mg/kg), CBD+THC (3 mg/kg each), vehicle, or remained undisturbed in their home cage (no handling/injections), either during adolescence (postnatal day [PND] 28-48) or during early adulthood (PND 69-89). Animals were then evaluated with a battery of behavioral tests 1 day after drug treatment, and again after 42 drug-free days. The tests included the following: open field (day 1), novel object recognition (NOR; day 2), marble burying (day 3), elevated plus maze (EPM; day 4), and Nestlet shredding (day 5). Results: Chronic administration of THC during adolescence led to immediate and long-term impairments in object recognition/working memory, as measured by the NOR task. In contrast, adult administration of THC caused immediate, but not long term, impairment of object/working memory. Adolescent chronic exposure to THC increased repetitive and compulsive-like behaviors, as measured by the Nestlet shredding task. Chronic administration of THC, either during adolescence or during adulthood, led to a delayed increase in anxiety as measured by the EPM. All THC-induced behavioral abnormalities were prevented by the coadministration of CBD+THC, whereas CBD alone did not influence behavioral outcomes. Conclusion: These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits.

Chronic Adolescent Δ9-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment

PubMed Central

Murphy, Michelle; Mills, Sierra; Winstone, Joanna; Leishman, Emma; Wager-Miller, Jim; Bradshaw, Heather; Mackie, Ken

2017-01-01

Abstract Introduction: The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ9-tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between CBD and THC in the neurodevelopmental effects of THC is also important. The current study examined the immediate and long-term behavioral consequences of THC, CBD, and their combination in a mouse model of adolescent cannabis use. Materials and Methods: Male CD1 mice received daily injections of THC (3 mg/kg), CBD (3 mg/kg), CBD+THC (3 mg/kg each), vehicle, or remained undisturbed in their home cage (no handling/injections), either during adolescence (postnatal day [PND] 28–48) or during early adulthood (PND 69–89). Animals were then evaluated with a battery of behavioral tests 1 day after drug treatment, and again after 42 drug-free days. The tests included the following: open field (day 1), novel object recognition (NOR; day 2), marble burying (day 3), elevated plus maze (EPM; day 4), and Nestlet shredding (day 5). Results: Chronic administration of THC during adolescence led to immediate and long-term impairments in object recognition/working memory, as measured by the NOR task. In contrast, adult administration of THC caused immediate, but not long term, impairment of object/working memory. Adolescent chronic exposure to THC increased repetitive and compulsive-like behaviors, as measured by the Nestlet shredding task. Chronic administration of THC, either during adolescence or during adulthood, led to a delayed increase in anxiety as measured by the EPM. All THC-induced behavioral abnormalities were prevented by the coadministration of CBD+THC, whereas CBD alone did not influence behavioral outcomes. Conclusion: These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits. PMID:29098186

An empirical model for prediction of geomagnetic storms using initially observed CME parameters at the Sun

NASA Astrophysics Data System (ADS)

Kim, R.-S.; Cho, K.-S.; Moon, Y.-J.; Dryer, M.; Lee, J.; Yi, Y.; Kim, K.-H.; Wang, H.; Park, Y.-D.; Kim, Yong Ha

2010-12-01

In this study, we discuss the general behaviors of geomagnetic storm strength associated with observed parameters of coronal mass ejection (CME) such as speed (V) and earthward direction (D) of CMEs as well as the longitude (L) and magnetic field orientation (M) of overlaying potential fields of the CME source region, and we develop an empirical model to predict geomagnetic storm occurrence with its strength (gauged by the Dst index) in terms of these CME parameters. For this we select 66 halo or partial halo CMEs associated with M-class and X-class solar flares, which have clearly identifiable source regions, from 1997 to 2003. After examining how each of these CME parameters correlates with the geoeffectiveness of the CMEs, we find several properties as follows: (1) Parameter D best correlates with storm strength Dst; (2) the majority of geoeffective CMEs have been originated from solar longitude 15°W, and CMEs originated away from this longitude tend to produce weaker storms; (3) correlations between Dst and the CME parameters improve if CMEs are separated into two groups depending on whether their magnetic fields are oriented southward or northward in their source regions. Based on these observations, we present two empirical expressions for Dst in terms of L, V, and D for two groups of CMEs, respectively. This is a new attempt to predict not only the occurrence of geomagnetic storms, but also the storm strength (Dst) solely based on the CME parameters.

Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with Δ-9-tetrahydrocannabinol

PubMed Central

Hutcheson, Daniel M; Th. Tzavara, Eleni; Smadja, Claire; Valjent, Emmanuel; Roques, Bernard P; Hanoune, Jacques; Maldonado, Rafael

1998-01-01

Tolerance and dependence induced by chronic Δ-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg−1 THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration.The selective CB-1 receptor antagonist SR 141716A (10 mg kg−1) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome.Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice.The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg−1), without observing place preference at any of the doses used.This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence. PMID:9884086

Circulation and oxygen cycling in the Mediterranean Sea: Sensitivity to future climate change

NASA Astrophysics Data System (ADS)

Powley, Helen R.; Krom, Michael D.; Van Cappellen, Philippe

2016-11-01

Climate change is expected to increase temperatures and decrease precipitation in the Mediterranean Sea (MS) basin, causing substantial changes in the thermohaline circulation (THC) of both the Western Mediterranean Sea (WMS) and Eastern Mediterranean Sea (EMS). The exact nature of future circulation changes remains highly uncertain, however, with forecasts varying from a weakening to a strengthening of the THC. Here we assess the sensitivity of dissolved oxygen (O2) distributions in the WMS and EMS to THC changes using a mass balance model, which represents the exchanges of O2 between surface, intermediate, and deep water reservoirs, and through the Straits of Sicily and Gibraltar. Perturbations spanning the ranges in O2 solubility, aerobic respiration kinetics, and THC changes projected for the year 2100 are imposed to the O2 model. In all scenarios tested, the entire MS remains fully oxygenated after 100 years; depending on the THC regime, average deep water O2 concentrations fall in the ranges 151-205 and 160-219 µM in the WMS and EMS, respectively. On longer timescales (>1000 years), the scenario with the largest (>74%) decline in deep water formation rate leads to deep water hypoxia in the EMS but, even then, the WMS deep water remains oxygenated. In addition, a weakening of THC may result in a negative feedback on O2 consumption as supply of labile dissolved organic carbon to deep water decreases. Thus, it appears unlikely that climate-driven changes in THC will cause severe O2 depletion of the deep water masses of the MS in the foreseeable future.

Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

PubMed

de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

2015-11-03

The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

40 CFR 86.097-9 - Emission standards for 1997 and later model year light-duty trucks.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO NOX PM Gasoline 0-3750 0... LVW (lbs) THC 1 NMHC THCE 1 NMHCE CO NOX PM Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10 Gasoline 3751-5750...—Intermediate Useful Life Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO...

Daylight saving time can decrease the frequency of wildlife-vehicle collisions.

PubMed

Ellis, William A; FitzGibbon, Sean I; Barth, Benjamin J; Niehaus, Amanda C; David, Gwendolyn K; Taylor, Brendan D; Matsushige, Helena; Melzer, Alistair; Bercovitch, Fred B; Carrick, Frank; Jones, Darryl N; Dexter, Cathryn; Gillett, Amber; Predavec, Martin; Lunney, Dan; Wilson, Robbie S

2016-11-01

Daylight saving time (DST) could reduce collisions with wildlife by changing the timing of commuter traffic relative to the behaviour of nocturnal animals. To test this idea, we tracked wild koalas (Phascolarctos cinereus) in southeast Queensland, where koalas have declined by 80% in the last 20 years, and compared their movements with traffic patterns along roads where they are often killed. Using a simple model, we found that DST could decrease collisions with koalas by 8% on weekdays and 11% at weekends, simply by shifting the timing of traffic relative to darkness. Wildlife conservation and road safety should become part of the debate on DST. © 2016 The Author(s).

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model

PubMed Central

Wray, Louise; Stott, Colin; Jones, Nicholas; Wright, Stephen

2017-01-01

Abstract Introduction: Cannabidiol (CBD) can convert to Δ9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N=3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations (Cmax) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean Cmax CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h·ng/mL) and 5 (881 h·ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function. PMID:29285522

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model.

PubMed

Wray, Louise; Stott, Colin; Jones, Nicholas; Wright, Stephen

2017-01-01

Introduction: Cannabidiol (CBD) can convert to Δ 9 -tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo . Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs ( N =3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations ( C max ) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean C max CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h·ng/mL) and 5 (881 h·ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.

A statistical analysis of the energy policy act of 2005, its changes to the daylight saving program, and impact on residential energy consumption

NASA Astrophysics Data System (ADS)

Murray, Patrick L.

Government programs designed to decrease resource consumption, improve productivity and capitalize on extended daylight hours in the summer have been developed and implemented throughout the world for nearly three hundred years. In 2005, The United States government adopted an extended daylight savings program that increases the number of weeks where the country observes Daylight Saving Time (DST) from 31 to 35 weeks. The program took effect in March 2007. Arguments in support of DST programs highlight the portion of electricity consumption attributed to residential lighting in the evening hours. Adjusting clocks forward by one hour in summer months is believed to reduce electricity consumption due to lighting and therefore significantly reduce residential energy consumption during the period of DST. This paper evaluates the efficacy of the changes to DST resulting from the Energy Policy Act of 2005. The study focuses on changes to household electricity consumption during the extended four weeks of DST. Arizona, one of two states that continue to opt out of DST serves as the study's control for a comparison with neighboring states, Colorado, Nebraska, Nevada, New Mexico, Oklahoma, Texas and Utah. Results from the regression analysis of a Difference in Difference model indicate that contrary to evaluations by Congress and the Department of Energy, the four week period of Extended Daylight Saving Time does not produce a significant decrease in per capita electricity consumption in Southwestern states.

USGS 1-min Dst index

USGS Publications Warehouse

Gannon, J.L.; Love, J.J.

2011-01-01

We produce a 1-min time resolution storm-time disturbance index, the USGS Dst, called Dst8507-4SM. This index is based on minute resolution horizontal magnetic field intensity from low-latitude observatories in Honolulu, Kakioka, San Juan and Hermanus, for the years 1985-2007. The method used to produce the index uses a combination of time- and frequency-domain techniques, which more clearly identifies and excises solar-quiet variation from the horizontal intensity time series of an individual station than the strictly time-domain method used in the Kyoto Dst index. The USGS 1-min Dst is compared against the Kyoto Dst, Kyoto Sym-H, and the USGS 1-h Dst (Dst5807-4SH). In a time series comparison, Sym-H is found to produce more extreme values during both sudden impulses and main phase maximum deviation, possibly due to the latitude of its contributing observatories. Both Kyoto indices are shown to have a peak in their distributions below zero, while the USGS indices have a peak near zero. The USGS 1-min Dst is shown to have the higher time resolution benefits of Sym-H, while using the more typical low-latitude observatories of Kyoto Dst. ?? 2010.

Generation of Look-Up Tables for Dynamic Job Shop Scheduling Decision Support Tool

NASA Astrophysics Data System (ADS)

Oktaviandri, Muchamad; Hassan, Adnan; Mohd Shaharoun, Awaluddin

2016-02-01

Majority of existing scheduling techniques are based on static demand and deterministic processing time, while most job shop scheduling problem are concerned with dynamic demand and stochastic processing time. As a consequence, the solutions obtained from the traditional scheduling technique are ineffective wherever changes occur to the system. Therefore, this research intends to develop a decision support tool (DST) based on promising artificial intelligent that is able to accommodate the dynamics that regularly occur in job shop scheduling problem. The DST was designed through three phases, i.e. (i) the look-up table generation, (ii) inverse model development and (iii) integration of DST components. This paper reports the generation of look-up tables for various scenarios as a part in development of the DST. A discrete event simulation model was used to compare the performance among SPT, EDD, FCFS, S/OPN and Slack rules; the best performances measures (mean flow time, mean tardiness and mean lateness) and the job order requirement (inter-arrival time, due dates tightness and setup time ratio) which were compiled into look-up tables. The well-known 6/6/J/Cmax Problem from Muth and Thompson (1963) was used as a case study. In the future, the performance measure of various scheduling scenarios and the job order requirement will be mapped using ANN inverse model.

Post-dexamethasone Cortisol, Self-inflicted Injury, and Suicidal Ideation among Depressed Adolescent Girls

PubMed Central

Beauchaine, Theodore P.; Crowell, Sheila E.; Hsiao, Ray C.

2014-01-01

Although the dexamethasone suppression test (DST) has limited use as a marker of depression given inadequate sensitivity and specificity, it marks prospective risk for suicide among adults. However, few studies have examined associations between the DST, suicidal ideation, and self-inflicted injury (SII) among adolescents, even though SII is the single best predictor of eventual suicide. We evaluated the DST as a correlate of suicidal ideation and retrospective reports of self-inflicted injury (SII) among adolescent girls, ages 13–17, with histories of depression (n=28) or depression/self-harm (n=29). Lower post-DST cortisol was associated with suicidal ideation and SII, over-and-above parent-reports and combined parent-/self-reports of internalizing and externalizing behavior. These findings are consistent with recent acquired capacity models of stress-related psychopathology in which hypothalamic-pituitary adrenal (HPA) axis function is altered through epigenetic/allostatic mechanisms among vulnerable individuals who incur adversity early in life. PMID:25208812

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2012 CFR

2012-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2011 CFR

2011-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2013 CFR

2013-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2010 CFR

2010-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents.

PubMed

Manwell, Laurie A; Ford, Brittany; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

2014-01-01

Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Δ(9)-THC and directly compared to parenteral (intraperitoneal, IP) administration of Δ(9)-THC. Sprague-Dawley rats were exposed to pure Δ(9)-THC vapour (1, 2, 5, 10, and 20mg/pad), using a Volcano® vapourizing device (Storz and Bickel, Germany) or IP-administered Δ(9)-THC (0.1, 0.3, 0.5, 1.0mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5mg/kg) were measured. Vapourized Δ(9)-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Δ(9)-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10mg of vapourized Δ(9)-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7days of repeated exposure; this chronic exposure to 10mg of vapourized Δ(9)-THC did not induce behavioural sensitization to morphine. These results suggest vapourized Δ(9)-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Δ(9)-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal and human cannabinoid studies may be related to pharmacokinetic differences associated with route of administration. Copyright © 2014 Elsevier Inc. All rights reserved.

Use of an automated decision support tool optimizes clinicians' ability to interpret and appropriately respond to structured self-monitoring of blood glucose data.

PubMed

Rodbard, Helena W; Schnell, Oliver; Unger, Jeffrey; Rees, Christen; Amstutz, Linda; Parkin, Christopher G; Jelsovsky, Zhihong; Wegmann, Nathan; Axel-Schweitzer, Matthias; Wagner, Robin S

2012-04-01

We evaluated the impact of an automated decision support tool (DST) on clinicians' ability to identify glycemic abnormalities in structured self-monitoring of blood glucose (SMBG) data and then make appropriate therapeutic changes based on the glycemic patterns observed. In this prospective, randomized, controlled, multicenter study, 288 clinicians (39.6% family practice physicians, 37.9% general internal medicine physicians, and 22.6% nurse practitioners) were randomized to structured SMBG alone (STG; n = 72); structured SMBG with DST (DST; n = 72); structured SMBG with an educational DVD (DVD; n = 72); and structured SMBG with DST and the educational DVD (DST+DVD; n = 72). Clinicians analyzed 30 patient cases (type 2 diabetes), identified the primary abnormality, and selected the most appropriate therapy. A total of 222 clinicians completed all 30 patient cases with no major protocol deviations. Significantly more DST, DVD, and DST+DVD clinicians correctly identified the glycemic abnormality and selected the most appropriate therapeutic option compared with STG clinicians: 49, 51, and 55%, respectively, vs. 33% (all P < 0.0001) with no significant differences among DST, DVD, and DST+DVD clinicians. Use of structured SMBG, combined with the DST, the educational DVD, or both, enhances clinicians' ability to correctly identify significant glycemic patterns and make appropriate therapeutic decisions to address those patterns. Structured testing interventions using either the educational DVD or the DST are equally effective in improving data interpretation and utilization. The DST provides a viable alternative when comprehensive education is not feasible, and it may be integrated into medical practices with minimal training.

Validated method for the simultaneous determination of Delta9-THC and Delta9-THC-COOH in oral fluid, urine and whole blood using solid-phase extraction and liquid chromatography-mass spectrometry with electrospray ionization.

PubMed

Teixeira, Helena; Verstraete, Alain; Proença, Paula; Corte-Real, Francisco; Monsanto, Paula; Vieira, Duarte Nuno

2007-08-06

A fully validated, sensitive and specific method for the extraction and quantification of Delta(9)-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Delta(9)-THC (THC-COOH) and for the detection of 11-hydroxy-Delta(9)-THC (11-OH THC) in oral fluid, urine and whole blood is presented. Solid-phase extraction and liquid chromatography-mass spectrometry (LC-MS) technique were used, with electrospray ionization. Three ions were monitored for THC and THC-COOH and two for 11-OH THC. The compounds were quantified by selected ion recording of m/z 315.31, 329.18 and 343.16 for THC, 11-OH THC and THC-COOH, respectively, and m/z 318.27 and 346.26 for the deuterated internal standards, THC-d(3) and THC-COOH-d(3), respectively. The method proved to be precise for THC and THC-COOH both in terms of intra-day and inter-day analysis, with intra-day coefficients of variation (CV) less than 6.3, 6.6 and 6.5% for THC in saliva, urine and blood, respectively, and 6.8 and 7.7% for THC-COOH in urine and blood, respectively. Day-to-day CVs were less than 3.5, 4.9 and 11.3% for THC in saliva, urine and blood, respectively, and 6.2 and 6.4% for THC-COOH in urine and blood, respectively. Limits of detection (LOD) were 2 ng/mL for THC in oral fluid and 0.5 ng/mL for THC and THC-COOH and 20 ng/mL for 11-OH THC, in urine and blood. Calibration curves showed a linear relationship for THC and THC-COOH in all samples (r(2)>0.999) within the range investigated. The procedure presented here has high specificity, selectivity and sensitivity. It can be regarded as an alternative method to GC-MS for the confirmation of positive immunoassay test results, and can be used as a suitable analytical tool for the quantification of THC and THC-COOH in oral fluid, urine and/or blood samples.

Thermal-hydrodynamic-chemical (THC) modeling based on geothermal field data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiryukhin, Alexey; Xu, Tianfu; Pruess, Karsten

Data on fluid chemistry and rock mineralogy are evaluated for a number of geothermal fields located in the volcanic arc of Japan and Kamchatka, Russia, Common chemical characteristics are identified and used to define scenarios for detailed numerical modeling of coupled thermal hydrodynamic chemical (THC) processes. The following scenarios of parental geothermal fluid upflow were studied: (1) single-phase conditions, 260 C at the bottom ( Ogiri type); (2) two-phase conditions, 300 C at the bottom ( Hatchobaru type); and (3) heat pipe conditions, 260 C at the bottom ( Matsukawa type). THC modeling for the single-phase upflow scenario shows wairakite,more » quartz, K-feld spar and chlorite formed as the principal secondary minerals in the production zone, and illite-smectite formed below 230 C. THC modeling of the two-phase upflow shows that quartz, K-feldspar (microcline), wairakite and calcite precipitate in the model as principal secondary minerals in the production zone. THC modeling of heat pipe conditions shows no significant secondary deposition of minerals (quartz, K-feldspar, zeolites) in the production zone. The influence of thermodynamic and kinetic parameters of chemical interaction, and of mass fluxes on mineral phase changes, was found to be significant, depending on the upflow regime. It was found that no parental geothermal fluid inflow is needed for zeolite precipitation, which occurs above 140 C in saturated andesite, provided that the porosity is greater than 0.001. In contrast, quartz and K-feldspar precipitation may result in a significant porosity reduction over a hundred-year time scale under mass flux conditions, and complete fracture sealing will occur given sufficient time under either single-phase or two-phase upflow scenarios. A heat pipe scenario shows no significant porosity reduction due to lack of secondary mineral phase deposition.« less

BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

PubMed

Segal-Gavish, Hadar; Gazit, Neta; Barhum, Yael; Ben-Zur, Tali; Taler, Michal; Hornfeld, Shay Henry; Gil-Ad, Irit; Weizman, Abraham; Slutsky, Inna; Niwa, Minae; Kamiya, Atsushi; Sawa, Akira; Offen, Daniel; Barzilay, Ran

2017-07-01

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.

PubMed

Milman, Garry; Bergamaschi, Mateus M; Lee, Dayong; Mendu, Damodara R; Barnes, Allan J; Vandrey, Ryan; Huestis, Marilyn A

2014-04-01

Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high-dose oral THC pharmacotherapy and later a smoked cannabis challenge. Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. During placebo dosing, THC, 11-OH-THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake.

Plasma Cannabinoid Concentrations during Dronabinol Pharmacotherapy for Cannabis Dependence

PubMed Central

Milman, Garry; Bergamaschi, Mateus M.; Lee, Dayong; Mendu, Damodara R.; Barnes, Allan J.; Vandrey, Ryan; Huestis, Marilyn A.

2013-01-01

Background Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic daily cannabis smokers who received high-dose oral THC pharmacotherapy and later, a smoked cannabis challenge. Methods 11 daily cannabis smokers received 0, 30, 60, or 120 mg/day THC for four 5-day medication sessions, each separated by 9-days of ad-libitum cannabis smoking. On the 5th day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the 1st and 5th days was quantified by GC-GC-MS for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5–100 for THC, 1–50 11-OH-THC, and 0.5–200 THCCOOH. Results During placebo dosing, THC, 11-OH-THC and THCCOOH concentrations consistently decreased, while all cannabinoids increased dose-dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during 60 and 120 mg/day doses, and THCCOOH increased significantly only during the 120 mg/day dose. THC and 11-OH-THC, and THCCOOH concentrations peaked within 0.25 h after cannabis smoking, except after 120 mg/day THC when THCCOOH peaked 0.5 h before smoking. Conclusions The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 h, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 h after overnight oral dronabinol abstinence, but cannot distinguish oral THC dosing from smoked cannabis intake. PMID:24067260

Validation of microscopic observation drug susceptibility testing for rapid, direct rifampicin and isoniazid drug susceptibility testing in patients receiving tuberculosis treatment

PubMed Central

Coronel, J; Roper, M H; Herrera, C; Bonilla, C; Jave, O; Gianella, C; Sabogal, I; Huancaré, V; Leo, E; Tyas, A; Mendoza-Ticona, A; Caviedes, L; Moore, D A J; Drancourt, M

2014-01-01

Drug susceptibility testing (DST) is often needed in patients clinically failing tuberculosis (TB) therapy. Most studies of phenotypic direct drug susceptibility tests, such as microscopic observation drug susceptibility (MODS) tests, have been performed in patients not receiving TB treatment. The effect of ongoing TB treatment on the performance of MODS direct DST has not been previously explored, but patients failing such therapy constitute an important target group. The aim of this study was to determine the performance of MODS direct rifampicin and isoniazid DST in patients clinically failing first-line TB treatment, and to compare MODS direct DST with indirect proportion method DST. Sputa from 264 TB patients were cultured in parallel in Lowenstein–Jensen (LJ) and MODS assays; strains were tested for rifampicin and isoniazid susceptibility by the proportion method at the national reference laboratory. Ninety-three samples were culture-positive by LJ and MODS (concordance of 96%; kappa 0.92). With conventional MODS plate DST reading (performed on the same day as the sample is classified as culture-positive), the isoniazid DST concordance was 96.8% (kappa 0.89), and the concordance for rifampicin susceptibility testing was 92.6% (kappa 0.80). Reading of MODS DST plates 1 week after cultures had been determined to be culture-positive improved overall performance marginally—the isoniazid DST concordance was 95.7% (kappa 0.85); and the rifampicin DST concordance was 96.8% (kappa 0.91). Sensitivity for detection of multidrug-resistant TB was 95.8%. MODS testing provided reliable rifampicin and isoniazid DST results for samples obtained from patients receiving TB therapy. A modified DST reading schedule for such samples, with a final reading 1 week after a MODS culture turns positive, marginally improves the concordance with reference DST. PMID:24107197

Using natural laboratories and modeling to decipher lithospheric rheology

NASA Astrophysics Data System (ADS)

Sobolev, Stephan

2013-04-01

Rheology is obviously important for geodynamic modeling but at the same time rheological parameters appear to be least constrained. Laboratory experiments give rather large ranges of rheological parameters and their scaling to nature is not entirely clear. Therefore finding rheological proxies in nature is very important. One way to do that is finding appropriate values of rheological parameter by fitting models to the lithospheric structure in the highly deformed regions where lithospheric structure and geologic evolution is well constrained. Here I will present two examples of such studies at plate boundaries. One case is the Dead Sea Transform (DST) that comprises a boundary between African and Arabian plates. During the last 15- 20 Myr more than 100 km of left lateral transform displacement has been accumulated on the DST and about 10 km thick Dead Sea Basin (DSB) was formed in the central part of the DST. Lithospheric structure and geological evolution of DST and DSB is rather well constrained by a number of interdisciplinary projects including DESERT and DESIRE projects leaded by the GFZ Potsdam. Detailed observations reveal apparently contradictory picture. From one hand widespread igneous activity, especially in the last 5 Myr, thin (60-80 km) lithosphere constrained from seismic data and absence of seismicity below the Moho, seem to be quite natural for this tectonically active plate boundary. However, surface heat flow of less than 50-60mW/m2 and deep seismicity in the lower crust ( deeper than 20 km) reported for this region are apparently inconsistent with the tectonic settings specific for an active continental plate boundary and with the crustal structure of the DSB. To address these inconsistencies which comprise what I call the "DST heat-flow paradox", a 3D numerical thermo-mechanical model was developed operating with non-linear elasto-visco-plastic rheology of the lithosphere. Results of the numerical experiments show that the entire set of observations for the DSB can be explained within the classical pull-apart model assuming that (1) the lithosphere has been thermally eroded at about 20 Ma, just before the active faulting at the DST, and (2) the uppermost mantle in the region have relatively weak rheology consistent with the experimental data for wet olivine or pyroxenite. Another example is modeling of the collision of India and Eurasia in Tibet. Our recent thermo-mechanical model (see abstract by Tympel et al) reproduce well many important features of this orogeny, including observed convergence and distance of underthrusting of Indian lithosphere beneath Tibet, if long-term friction at India-Eurasia interface is about 0.04- 0.05, which is typical for oceanic subduction zones, but is unexpected low for continental setting.

Idle emissions from heavy-duty diesel and natural gas vehicles at high altitude.

PubMed

McCormick, R L; Graboski, M S; Alleman, T L; Yanowitz, J

2000-11-01

Idle emissions of total hydrocarbon (THC), CO, NOx, and particulate matter (PM) were measured from 24 heavy-duty diesel-fueled (12 trucks and 12 buses) and 4 heavy-duty compressed natural gas (CNG)-fueled vehicles. The volatile organic fraction (VOF) of PM and aldehyde emissions were also measured for many of the diesel vehicles. Experiments were conducted at 1609 m above sea level using a full exhaust flow dilution tunnel method identical to that used for heavy-duty engine Federal Test Procedure (FTP) testing. Diesel trucks averaged 0.170 g/min THC, 1.183 g/min CO, 1.416 g/min NOx, and 0.030 g/min PM. Diesel buses averaged 0.137 g/min THC, 1.326 g/min CO, 2.015 g/min NOx, and 0.048 g/min PM. Results are compared to idle emission factors from the MOBILE5 and PART5 inventory models. The models significantly (45-75%) overestimate emissions of THC and CO in comparison with results measured from the fleet of vehicles examined in this study. Measured NOx emissions were significantly higher (30-100%) than model predictions. For the pre-1999 (pre-consent decree) truck engines examined in this study, idle NOx emissions increased with model year with a linear fit (r2 = 0.6). PART5 nationwide fleet average emissions are within 1 order of magnitude of emissions for the group of vehicles tested in this study. Aldehyde emissions for bus idling averaged 6 mg/min. The VOF averaged 19% of total PM for buses and 49% for trucks. CNG vehicle idle emissions averaged 1.435 g/min for THC, 1.119 g/min for CO, 0.267 g/min for NOx, and 0.003 g/min for PM. The g/min PM emissions are only a small fraction of g/min PM emissions during vehicle driving. However, idle emissions of NOx, CO, and THC are significant in comparison with driving emissions.

A Study on the Optimal Duration of Daylight Saving Time (DST) in Korea

NASA Astrophysics Data System (ADS)

Mihn, Byeong-Hee; Ahn, Young Sook; Kim, Dong-Bin; Yang, Hong-Jin

2009-09-01

Daylight saving time aims at spending effective daylight in summer season. Korea had enforced daylight saving time twelve times from 1948 to 1988. Since 1988, it is not executed, but it is recently discussed the resumption of DST. In this paper, we investigate the trend of DST in other countries, review the history of DST in Korea, and suggest the optimal DST duration in terms of astronomical aspects (times of sunrise and sunset). We find that the starting day of DST in Korea is apt for the second Sunday in May or the second Sunday in April according to the time of sunrise or to the difference between Korean standard meridian and observer's, respectively. We also discuss time friction that might be caused by time difference between DST and Korea Standard Time (KST).

Real-time SWMF-Geospace at CCMC: assessing the quality of output from continuous operational simulations

NASA Astrophysics Data System (ADS)

Liemohn, M. W.; Welling, D. T.; De Zeeuw, D.; Kuznetsova, M. M.; Rastaetter, L.; Ganushkina, N. Y.; Ilie, R.; Toth, G.; Gombosi, T. I.; van der Holst, B.

2016-12-01

The ground-based magnetometer index Dst is a decent measure of the near-Earth current systems, in particular those in the storm-time inner magnetosphere. The ability of a large-scale, physics-based model to reproduce, or even predict, this index is therefore a tangible measure of the overall validity of the code for space weather research and space weather operational usage. Experimental real-time simulations of the Space Weather Modeling Framework (SWMF) are conducted at the Community Coordinated Modeling Center (CCMC), with results available there (http://ccmc.gsfc.nasa.gov/realtime.php), through the CCMC Integrated Space Weather Analysis (iSWA) site (http://iswa.ccmc.gsfc.nasa.gov/IswaSystemWebApp/), and the Michigan SWMF site (http://csem.engin.umich.edu/realtime). Presently, two configurations of the SWMF are running in real time at CCMC, both focusing on the geospace modules, using the BATS-R-US magnetohydrodynamic model, the Ridley Ionosphere Model, and with and without the Rice Convection Model for inner magnetospheric drift physics. While both have been running for several years, nearly continuous results are available since July 2015. Dst from the model output is compared against the Kyoto real-time Dst. Various quantitative measures are presented to assess the goodness of fit between the models and observations. In particular, correlation coefficients, RMSE and prediction efficiency are calculated and discussed. In addition, contingency tables are presented, demonstrating the ability of the model to predict "disturbed times" as defined by Dst values below some critical threshold. It is shown that the SWMF run with the inner magnetosphere model is significantly better at reproducing storm-time values, with prediction efficiencies above 0.25 and Heidke skill scores above 0.5. This work was funded by NASA and NSF grants, and the European Union's Horizon 2020 research and innovation programme under grant agreement 637302 PROGRESS.

Prior exposure to THC increases the addictive effects of nicotine in rats.

PubMed

Panlilio, Leigh V; Zanettini, Claudio; Barnes, Chanel; Solinas, Marcelo; Goldberg, Steven R

2013-06-01

Although it is more common for drug abuse to progress from tobacco to cannabis, in many cases cannabis use develops before tobacco use. Epidemiological evidence indicates that prior cannabis use increases the likelihood of becoming dependent on tobacco. To determine whether this effect might be due to cannabis exposure per se, in addition to any genetic, social, or environmental factors that might contribute, we extended our series of studies on 'gateway drug' effects in animal models of drug abuse. Rats were exposed to THC, the main psychoactive constituent of cannabis, for 3 days (two intraperitoneal injections/day). Then, starting 1 week later, they were allowed to self-administer nicotine intravenously. THC exposure increased the likelihood of acquiring the nicotine self-administration response from 65% in vehicle-exposed rats to 94% in THC-exposed rats. When the price of nicotine was manipulated by increasing the response requirement, THC-exposed rats maintained higher levels of intake than vehicle-exposed rats, indicating that THC exposure increased the value of nicotine reward. These results contrast sharply with our earlier findings that prior THC exposure did not increase the likelihood of rats acquiring either heroin or cocaine self-administration, nor did it increase the reward value of these drugs. The findings obtained here suggest that a history of cannabis exposure might have lasting effects that increase the risk of becoming addicted to nicotine.

Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Huang, Huimin; Niu, Xiaofeng, E-mail: niuxf@mail.xjtu.edu.cn

Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increasedmore » pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. - Highlights: • THC decreased ethanol-induced pro-inflammatory cytokine release. • THC inhibited the production of NO in serum and gastric tissue. • THC reduced NF-κB expression and MPO accumulation in ethanol-induced gastric tissue.« less

Prognostics of lithium-ion batteries based on Dempster-Shafer theory and the Bayesian Monte Carlo method

NASA Astrophysics Data System (ADS)

He, Wei; Williard, Nicholas; Osterman, Michael; Pecht, Michael

A new method for state of health (SOH) and remaining useful life (RUL) estimations for lithium-ion batteries using Dempster-Shafer theory (DST) and the Bayesian Monte Carlo (BMC) method is proposed. In this work, an empirical model based on the physical degradation behavior of lithium-ion batteries is developed. Model parameters are initialized by combining sets of training data based on DST. BMC is then used to update the model parameters and predict the RUL based on available data through battery capacity monitoring. As more data become available, the accuracy of the model in predicting RUL improves. Two case studies demonstrating this approach are presented.

Cannabis constituents modulate δ9-tetrahydrocannabinol-induced hyperphagia in rats.

PubMed

Farrimond, Jonathan A; Hill, Andrew J; Whalley, Benjamin J; Williams, Claire M

2010-05-01

The hyperphagic effect of Delta9-tetrahydrocannabinol (Delta9THC) in humans and rodents is well known. However, no studies have investigated the importance of Delta9THC composition and any influence other non-Delta9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified Delta9THC, synthetic Delta9THC (dronabinol), and Delta9THC botanical drug substance (Delta9THC-BDS), a Delta9THC-rich standardized extract comparable in composition to recreationally used cannabis. Adult male rats were orally dosed with purified Delta9THC, synthetic Delta9THC, or Delta9THC-BDS, matched for Delta9THC content (0.34-2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following Delta9THC administration. Data were then analyzed in terms of hourly intake and meal patterns. All three Delta9THC substances tested induced significant hyperphagic effects at doses >or=0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified Delta9THC and Delta9THC-BDS. All Delta9THC compounds displayed classical Delta9THC effects on feeding, significantly increasing shortterm intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified Delta9THC and Delta9THC-BDS are due to non-Delta9THC cannabinoids present in Delta9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate Delta9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.

Differential effects of cannabis extracts and pure plant cannabinoids on hippocampal neurones and glia.

PubMed

Ryan, Duncan; Drysdale, Alison J; Pertwee, Roger G; Platt, Bettina

2006-11-20

We have shown previously that the plant cannabinoid cannabidiol (CBD) elevates intracellular calcium levels in both cultured hippocampal neurones and glia. Here, we investigated whether the main psychotropic constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC) alone or in combination with other cannabis constituents can cause similar responses, and whether THC affects the responses induced by CBD. Our experiments were performed with 1 microM pure THC (pTHC), with 1 microM pure CBD (pCBD), with a high-THC, low CBD cannabis extract (eTHC), with a high-CBD, low THC cannabis extract (eCBD), with a mixture of eTHC and eCBD (THC:CBD=1:1) or with corresponding 'mock extracts' that contained only pTHC and pCBD mixed in the same proportion as in eTHC, eCBD or the 1:1 mixture of eTHC and eCBD. We detected significant differences in neurones both between the effects of pTHC and eTHC and between the effects of pCBD and eCBD. There were also differences between the Ca(2+) responses evoked in both neurones and glia by eTHC and mock eTHC, but not between eCBD and mock eCBD. A particularly striking observation was the much increased response size and maximal responder rates induced by the mixture of eTHC and eCBD than by the corresponding 1:1 mixture of pTHC and pCBD. Our data suggest that THC shares the ability of CBD to elevate Ca(2+) levels in neurones and glia, that THC and CBD interact synergistically and that the cannabis extracts have other constituents yet to be identified that can significantly modulate the ability of THC and CBD to raise Ca(2+) levels.

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed

Lee, Dayong; Karschner, Erin L; Milman, Garry; Barnes, Allan J; Goodwin, Robert S; Huestis, Marilyn A

2013-06-01

We characterize cannabinoid disposition in oral fluid (OF) after dronabinol, synthetic oral Δ(9)-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5 h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25-1 h. Median CBD/THC and CBN/THC ratios were 0.82-1.34 and 0.04-0.06, respectively, reflecting cannabinoids' composition in Sativex. THCCOOH/THC ratios within 4.5 h post Sativex were ≤ 1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. Published by Elsevier Ireland Ltd.

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed Central

Lee, Dayong; Karschner, Erin L.; Milman, Garry; Barnes, Allan J.; Goodwin, Robert S.; Huestis, Marilyn A.

2012-01-01

OBJECTIVES We characterize cannabinoid disposition in oral fluid (OF) after Dronabinol, synthetic oral Δ9-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. METHODS 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25–1h. Median CBD/THC and CBN/THC ratios were 0.82–1.34 and 0.04–0.06, respectively, reflecting cannabinoids’ composition in Sativex. THCCOOH/THC ratios within 4.5h post Sativex were ≤1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. CONCLUSIONS Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. PMID:23146820

Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity.

PubMed

Britch, Stevie C; Wiley, Jenny L; Yu, Zhihao; Clowers, Brian H; Craft, Rebecca M

2017-06-01

Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ 9 -tetrahydrocannabinol's (THC) effects. The current study examined sex differences in CBD modulation of THC-induced antinociception, hypolocomotion, and metabolism. In Experiment 1, CBD (0, 10 or 30mg/kg) was administered 15min before THC (0, 1.8, 3.2, 5.6 or 10mg/kg), and rats were tested for antinociception and locomotion 15-360min post-THC injection. In Experiments 2 and 3, CBD (30mg/kg) was administered 13h or 15min before THC (1.8mg/kg); rats were tested for antinociception and locomotion 30-480min post-THC injection (Experiment 2), or serum samples were taken 30-360min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3). In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4-6h post-THC injection. CBD alone increased locomotor activity at 6h post-injection, but enhanced THC-induced hypolocomotion 4-6h post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC's effects when CBD was administered 13h or 15min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males. These results suggest that CBD may enhance THC's antinociceptive and hypolocomotive effects, primarily prolonging THC's duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

A Dempster-Shafer Method for Multi-Sensor Fusion

DTIC Science & Technology

2012-03-01

position results for DST Mean Mod (or DST Mean for Case 1) to follow the same general path as the true aircraft . Also, if the points diverged from the true...of the aircraft . Its results were similar to those for DST True and Kalman. Also DST Mean had the same clustering of points as the others specifically...DST Mean values increasingly diverged as time t increased. Then Run 27 was very similar to Case 2 Run 5. Instead of following the true aircraft path

Provisional hourly values of equatorial Dst for 1971

NASA Technical Reports Server (NTRS)

Sugiura, M.; Poros, D. J.

1972-01-01

Tables and plots of provisional hourly values of the equatorial Dst index for 1971 are given, a table of daily mean Dst values for 1971 is also provided. The base line values for the four observatories, Hermanus, Kakioka, Honolulu, and San Juan, were obtained from extrapolations using the coefficients for the secular variations determined for the previous years. Examining the Dst values for quiet days, the base lines so determined appear to be slightly low, so that the Dst index for quiet periods tends to be high.

Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.

PubMed

ElSohly, M A; Harland, E C; Benigni, D A; Waller, C W

1984-06-01

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

Overexpression of a Chimeric Gene, OsDST-SRDX, Improved Salt Tolerance of Perennial Ryegrass

PubMed Central

Cen, Huifang; Ye, Wenxing; Liu, Yanrong; Li, Dayong; Wang, Kexin; Zhang, Wanjun

2016-01-01

The Drought and Salt Tolerance gene (DST) encodes a C2H2 zinc finger transcription factor, which negatively regulates salt tolerance in rice (Oryza sativa). Phylogenetic analysis of six homologues of DST genes in different plant species revealed that DST genes were conserved evolutionarily. Here, the rice DST gene was linked to an SRDX domain for gene expression repression based on the Chimeric REpressor gene-Silencing Technology (CRES-T) to make a chimeric gene (OsDST-SRDX) construct and introduced into perennial ryegrass by Agrobacterium-mediated transformation. Integration and expression of the OsDST-SRDX in transgenic plants were tested by PCR and RT-PCR, respectively. Transgenic lines overexpressing the OsDST-SRDX fusion gene showed obvious phenotypic differences and clear resistance to salt-shock and to continuous salt stresses compared to non-transgenic plants. Physiological analyses including relative leaf water content, electrolyte leakage, proline content, malondialdehyde (MDA) content, H2O2 content and sodium and potassium accumulation indicated that the OsDST-SRDX fusion gene enhanced salt tolerance in transgenic perennial ryegrass by altering a wide range of physiological responses. To our best knowledge this study is the first report of utilizing Chimeric Repressor gene-Silencing Technology (CRES-T) in turfgrass and forage species for salt-tolerance improvement. PMID:27251327

Modeling Coupled Thermal-Hydrological-Chemical Processes in the Unsaturated Fractured Rock of Yucca Mountain, Nevada: Heterogeneity and Seepage

DOE Office of Scientific and Technical Information (OSTI.GOV)

S. Mukhopadhyay; E.L. Donnenthal; N. Spycher

An understanding of processes affecting seepage into emplacement tunnels is needed for correctly predicting the performance of underground radioactive waste repositories. It has been previously estimated that the capillary and vaporization barriers in the unsaturated fractured rock of Yucca Mountain are enough to prevent seepage under present day infiltration conditions. It has also been thought that a substantially elevated infiltration flux will be required to cause seepage after the thermal period is over. While coupled thermal-hydrological-chemical (THC) changes in Yucca Mountain host rock due to repository heating has been previously investigated, those THC models did not incorporate elements of themore » seepage model. In this paper, we combine the THC processes in unsaturated fractured rock with the processes affecting seepage. We observe that the THC processes alter the hydrological properties of the fractured rock through mineral precipitation and dissolution. We show that such alteration in the hydrological properties of the rock often leads to local flow channeling. We conclude that such local flow channeling may result in seepage under certain conditions, even with nonelevated infiltration fluxes.« less

Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC.

PubMed

Hunault, Claudine C; Mensinga, Tjeert T; de Vries, Irma; Kelholt-Dijkman, Hermien H; Hoek, Jani; Kruidenier, Maaike; Leenders, Marianne E C; Meulenbelt, Jan

2008-12-01

Delta9-Tetrahydrocannabinol (THC) is the main active constituent of cannabis. In recent years, the average THC content of some cannabis cigarettes has increased up to approximately 60 mg per cigarette (20% THC cigarettes). The pharmacokinetics of THC after smoking cannabis cigarettes containing more than approximately 35 mg THC (3.55% THC cigarettes) is unknown. To be able to perform suitable exposure risk analysis, it is important to know if there is a linear relation at higher doses. The present study aimed to characterise the pharmacokinetics of THC, the active metabolite 11-OH-THC and the inactive metabolite THC-COOH after smoking a combination of tobacco and cannabis containing high THC doses. This double-blind, placebo-controlled, four-way, cross-over study included 24 male non-daily cannabis users (two to nine joints per month). Participants were randomly assigned to smoke cannabis cigarettes containing 29.3, 49.1 and 69.4 mg THC and a placebo. Serial serum samples collected over a period of 0-8 h were analysed by liquid chromatography electrospray tandem mass spectrometry. Effects on heart rate, blood pressure and 'high' feeling were also measured. Mean maximal concentrations (Cmax) were 135.1, 202.9 and 231.0 microg/L for THC and 9.2, 16.4 and 15.8 microg/L for 11-OH-THC after smoking a 29.3-, 49.1- and 69.4-mg THC cigarette, respectively. A large inter-individual variability in Cmax was observed. Heart rate and 'high' feeling significantly increased with increasing THC dose. This study demonstrates that the known linear association between THC dose and THC serum concentration also applies for high THC doses.

A Continuous Long-Term Record of Magnetic-Storm Occurrence and Intensity

NASA Astrophysics Data System (ADS)

Love, J. J.

2007-05-01

Hourly magnetometer data have been produced by ground-based magnetic observatories for over a century. These data are used for a wide variety of applications, including many for space physics. In particular, hourly data from a longitudinal necklace of mid-latitude observatories can be used to construct a time series recording the storm-time disturbance index Dst, one of the most useful scalar summaries of magnetic storm intensity which is generally interpreted in terms of an equivalent equatorial magnetospheric ring current. Dst has been routinely calculated in a temporally piece-wise fashion since the IGY using a subset of the available observatories: four or five stations, typically including Honolulu (HON), San Juan (SJG), Kakioka Japan (KAK), Hermanus South Africa (HER), and Alibag India (ABG). In this presentation we discuss a single continuous Dst time series made using a denser and more uniform distribution of observatories than that which is standard: including, additionally, Watheroo Australia (WAT), Apia Samoa (API), and Vassouras Brazil (VSS). Starting first with the data from each individual observatory, we subtract the geomagnetic secular variation, caused primarily by the core dynamo, and the solar-quiet (Sq) variation, caused primarily by the ionospheric dynamo. The latter requires careful spectral analysis, and those intermediate results are, themselves, of scientific interest. Following this, we combine the disturbance residuals from each station to form the continuous Dst time series. Statistics deduced from this model allow us to quantify the likelihood of storm occurrence and intensity, both of which are modulated in time by the solar cycle. This analysis is accomplished using a 50 year Dst time series. The prospects for constructing a longer continuous Dst time series are discussed.

Calibration of the Flow in the Test Section of the Research Wind Tunnel at DST Group

DTIC Science & Technology

2015-10-01

calibration of the flow in the test section of the Research Wind Tunnel at DST Group. The calibration was performed to establish the flow quality and to...of the Flow in the Test Section of the Research Wind Tunnel at DST Group Executive Summary The Defence Science and Technology Group (DST

76 FR 32227 - DST Systems, Inc., Including On-Site Leased Workers From Comsys Information Technology Services...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-03

... Technologies, a wholly owned subsidiary of DSI Systems, Inc., Boston, Massachusetts operated in conjunction... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-74,649; TA-W-74,649a] DST Systems... Kelly Services Kansas City, MO; DST Technologies, a Wholly Owned Subsidiary of DST Systems, Inc., Boston...

HANFORD DOUBLE SHELL TANK (DST) THERMAL & SEISMIC PROJECT SEISMIC ANALYSIS IN SUPPORT OF INCREASED LIQUID LEVEL IN 241-AP TANK FARMS

DOE Office of Scientific and Technical Information (OSTI.GOV)

MACKEY TC; ABBOTT FG; CARPENTER BG

2007-02-16

The overall scope of the project is to complete an up-to-date comprehensive analysis of record of the DST System at Hanford. The "Double-Shell Tank (DST) Integrity Project - DST Thermal and Seismic Project" is in support of Tri-Party Agreement Milestone M-48-14.

Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity

PubMed Central

Britch, Stevie C.; Wiley, Jenny L.; Yu, Zhihao; Clowers, Brian H.; Craft, Rebecca M.

2017-01-01

Background Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ9-tetrahydrocannabinol’s (THC) effects. The current study examined sex differences in CBD-THC interactions on antinociception, locomotion, and THC metabolism. Methods In Experiment 1, CBD (0, 10 or 30 mg/kg) was administered 15 min before THC (0, 1.8, 3.2, 5.6 or10 mg/kg), and rats were tested for antinociception and locomotion 15–360 min post-THC injection. In Experiments 2 and 3, CBD (30 mg/kg) was administered 13 hr or 15 min before THC (1.8 mg/kg); rats were tested for antinociception and locomotion 30–480 min post-THC injection (Experiment 2), or serum samples were taken 30–360 min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3). Results In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4–6 hr post-THC injection. CBD alone increased locomotor activity at 6 hr post-injection, but enhanced THC-induced hypolocomotion 4–6 hr post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC’s effects when CBD was administered 13 hr or 15 min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males. Conclusions These results suggest that CBD may enhance THC’s antinociceptive and hypolocomotive effects, primarily prolonging THC’s duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior. PMID:28445853

Mountain-Scale Coupled Processes (TH/THC/THM)

DOE Office of Scientific and Technical Information (OSTI.GOV)

P. Dixon

The purpose of this Model Report is to document the development of the Mountain-Scale Thermal-Hydrological (TH), Thermal-Hydrological-Chemical (THC), and Thermal-Hydrological-Mechanical (THM) Models and evaluate the effects of coupled TH/THC/THM processes on mountain-scale UZ flow at Yucca Mountain, Nevada. This Model Report was planned in ''Technical Work Plan (TWP) for: Performance Assessment Unsaturated Zone'' (BSC 2002 [160819], Section 1.12.7), and was developed in accordance with AP-SIII.10Q, Models. In this Model Report, any reference to ''repository'' means the nuclear waste repository at Yucca Mountain, and any reference to ''drifts'' means the emplacement drifts at the repository horizon. This Model Report provides themore » necessary framework to test conceptual hypotheses for analyzing mountain-scale hydrological/chemical/mechanical changes and predict flow behavior in response to heat release by radioactive decay from the nuclear waste repository at the Yucca Mountain site. The mountain-scale coupled TH/THC/THM processes models numerically simulate the impact of nuclear waste heat release on the natural hydrogeological system, including a representation of heat-driven processes occurring in the far field. The TH simulations provide predictions for thermally affected liquid saturation, gas- and liquid-phase fluxes, and water and rock temperature (together called the flow fields). The main focus of the TH Model is to predict the changes in water flux driven by evaporation/condensation processes, and drainage between drifts. The TH Model captures mountain-scale three dimensional (3-D) flow effects, including lateral diversion at the PTn/TSw interface and mountain-scale flow patterns. The Mountain-Scale THC Model evaluates TH effects on water and gas chemistry, mineral dissolution/precipitation, and the resulting impact to UZ hydrological properties, flow and transport. The THM Model addresses changes in permeability due to mechanical and thermal disturbances in stratigraphic units above and below the repository host rock. The Mountain-Scale THM Model focuses on evaluating the changes in 3-D UZ flow fields arising out of thermal stress and rock deformation during and after the thermal periods.« less

Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls.

PubMed

Lamers, C T J; Bechara, A; Rizzo, M; Ramaekers, J G

2006-03-01

Repeated ecstasy (MDMA) use is reported to impair cognition and cause increased feelings of depression and anxiety. Yet, many relevant studies have failed to control for use of drugs other than MDMA, especially marijuana (THC). To address these confounding effects we compared behavioural performance of 11 MDMA/THC users, 15 THC users and 15 non-drug users matched for age and intellect. We tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment (memory, executive function and decision making) are more severe in MDMA/THC users than in THC users. MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users. Memory function was impaired in both groups of drug users. MDMA/THC users showed slower psychomotor speed and less mental flexibility than non-drug users. THC users exhibited less mental flexibility and performed worse on the decision making task compared to non-drug users but these functions were similar to those in MDMA/THC users. It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users. THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users, suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

PubMed

Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

2017-08-01

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid analysis of Δ-9-tetrahydrocannabinol in hair using direct analysis in real time ambient ionization orbitrap mass spectrometry.

PubMed

Duvivier, Wilco F; van Beek, Teris A; Pennings, Ed J M; Nielen, Michel W F

2014-04-15

Forensic hair analysis methods are laborious, time-consuming and provide only a rough retrospective estimate of the time of drug intake. Recently, hair imaging methods using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were reported, but these methods require the application of MALDI matrix and are performed under vacuum. Direct analysis of entire locks of hair without any sample pretreatment and with improved spatial resolution would thus address a need. Hair samples were attached to stainless steel mesh screens and scanned in the X-direction using direct analysis in real time (DART) ambient ionization orbitrap MS. The DART gas temperature and the accuracy of the probed hair zone were optimized using Δ-9-tetrahydrocannabinol (THC) as a model compound. Since external contamination is a major issue in forensic hair analysis, sub-samples were measured before and after dichloromethane decontamination. The relative intensity of the THC signal in spiked blank hair versus that of quinine as the internal standard showed good reproducibility (26% RSD) and linearity of the method (R(2)  = 0.991). With the DART hair scan THC could be detected in hair samples from different chronic cannabis users. The presence of THC was confirmed by quantitative liquid chromatography/tandem mass spectrometry. Zones with different THC content could be clearly distinguished, indicating that the method might be used for retrospective timeline assessments. Detection of THC in decontaminated drug user hair showed that the DART hair scan not only probes THC on the surface of hair, but penetrates deeply enough to measure incorporated THC. A new approach in forensic hair analysis has been developed by probing complete locks of hair using DART-MS. Longitudinal scanning enables detection of incorporated compounds and can be used as pre-screening for THC without sample preparation. The method could also be adjusted for the analysis of other drugs of abuse. Copyright © 2014 John Wiley & Sons, Ltd.

The Yucca Mountain Project drift scale test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Finley, R.E.; Blair, S.C.; Boyle, W.J.

The Yucca Mountain Project is currently evaluating the coupled thermal-mechanical-hydrological-chemical (TMHC) response of the potential repository host rock through an in situ thermal testing program. A drift scale test (DST) was constructed during 1997 and heaters were turned on in December 1997. The DST includes nine canister-sized containers with thirty operating heaters each located within the heated drift (HD) and fifty wing heaters located in boreholes in both ribs with a total power output of nominally 210kW. A total of 147 boreholes (combined length of 3.3 km) houses most of the over 3700 TMHC sensors connected with 201 km ofmore » cabling to a central data acquisition system. The DST is located in the Exploratory Studies Facility in a 5-m diameter drift approximately 50 m in length. Heating will last up to four years and cooling will last another four years. The rock mass surrounding the DST will experience a harsh thermal environment with rock surface temperatures expected to reach a maximum of about 200 C. This paper describes the process of designing the DST. The first 38 m of the 50-m long Heated Drift (HD) is dedicated to collection of data that will lead to a better understanding of the complex coupled TMHC processes in the host rock of the proposed repository. The final 12 m is dedicated to evaluating the interactions between the heated rock mass and cast-in-place (CIP) concrete ground support systems at elevated temperatures. In addition to a description of the DST design, data from site characterization, and a general description of the analyses and analysis approach used to design the test and make pretest predictions are presented. Test-scoping and pretest numerical predictions of one way thermal-hydrologic, thermal-mechanical, and thermal-chemical behaviors have been completed (TRW, 1997a). These analyses suggest that a dry-out zone will be created around the DST and a 10,000 m{sup 3} volume of rock will experience temperatures above 100 C. The HD will experience large stress increases, particularly in the crown of the drift. Thermoelastic displacements of up to about 16 mm are predicted for some thermomechanical gages. Additional analyses using more complex models will be performed during the conduct of the DST and the results compared with measured data.« less

Oral fluid cannabinoids in chronic cannabis smokers during oral Δ9-tetrahydrocannabinol therapy and smoked cannabis challenge

PubMed Central

Lee, Dayong; Vandrey, Ryan; Mendu, Damodara R.; Anizan, Sebastien; Milman, Garry; Murray, Jeannie A.; Barnes, Allan J.; Huestis, Marilyn A.

2014-01-01

BACKGROUND Oral Δ9-tetrahydrocannabinol (THC) is effective for attenuating cannabis withdrawal and may benefit treatment of cannabis use disorders. Oral fluid (OF) cannabinoid testing, increasing in forensic and workplace settings, could be valuable for monitoring during cannabis treatment. METHODS Eleven cannabis smokers resided on a closed research unit for 51 days, and received daily 0, 30, 60, and 120 mg oral THC in divided doses for 5 days. There was a 5-puff smoked cannabis challenge on the 5th day. Each medication session was separated by 9 days of ad libitum cannabis smoking. OF was collected the evening prior to and throughout oral THC sessions and analyzed by 2-dimensional GC-MS for THC, cannabidiol (CBD), cannabinol (CBN), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS During all oral THC administrations, THC OF concentrations decreased to ≤78.2, 33.2, and 1.4 μg/L by 24, 48, and 72h, respectively. CBN also decreased over time with concentrations 10-fold lower than THC, with none detected beyond 69h. CBD and 11-OH-THC were rarely detected, only within 19 and 1.6h post smoking, respectively. THCCOOH OF concentrations were dose-dependent and increased over time during 120 mg THC dosing. After cannabis smoking, THC, CBN, and THCCOOH concentrations showed a significant dose-effect and decreased significantly over time. CONCLUSIONS Oral THC dosing significantly affected OF THCCOOH but minimally contributed to THC OF concentrations; prior ad libitum smoking was the primary source of THC, CBD and CBN. Higher cannabinoid concentrations following active oral THC administrations versus placebo suggest a compensatory effect of THC tolerance on smoking topography. PMID:23938457

Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC.

PubMed

Hložek, Tomáš; Uttl, Libor; Kadeřábek, Lukáš; Balíková, Marie; Lhotková, Eva; Horsley, Rachel R; Nováková, Pavlína; Šíchová, Klára; Štefková, Kristýna; Tylš, Filip; Kuchař, Martin; Páleníček, Tomáš

2017-12-01

Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract.

PubMed

Nadulski, Thomas; Pragst, Fritz; Weinberg, Gordon; Roser, Patrik; Schnelle, Martin; Fronk, Eva-Maria; Stadelmann, Andreas Michael

2005-12-01

Cannabidiol (CBD) is known to modify the effects of Delta-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.

Nonlinear ARMA models for the D(st) index and their physical interpretation

NASA Technical Reports Server (NTRS)

Vassiliadis, D.; Klimas, A. J.; Baker, D. N.

1996-01-01

Time series models successfully reproduce or predict geomagnetic activity indices from solar wind parameters. A method is presented that converts a type of nonlinear filter, the nonlinear Autoregressive Moving Average (ARMA) model to the nonlinear damped oscillator physical model. The oscillator parameters, the growth and decay, the oscillation frequencies and the coupling strength to the input are derived from the filter coefficients. Mathematical methods are derived to obtain unique and consistent filter coefficients while keeping the prediction error low. These methods are applied to an oscillator model for the Dst geomagnetic index driven by the solar wind input. A data set is examined in two ways: the model parameters are calculated as averages over short time intervals, and a nonlinear ARMA model is calculated and the model parameters are derived as a function of the phase space.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease.

PubMed

Laprairie, Robert B; Bagher, Amina M; Kelly, Melanie E M; Denovan-Wright, Eileen M

2016-03-01

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh(Q7/Q7)) or mutant huntingtin protein (STHdh(Q111/Q111)). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gαi/o, Gαs, Gαq, Gβγ, and β-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The Emax of Gαi/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gαi/o/Gβγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-arrestin-biased--such as THC found at high levels in modern varieties of marijuana--may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15.

PubMed

Niesink, Raymond J M; Rigter, Sander; Koeter, Maarten W; Brunt, Tibor M

2015-12-01

Between 2000 and 2005 the average percentage of Δ(9) -tetrahydrocannabinol (THC) in marijuana as sold in Dutch coffeeshops has increased substantially; the potency of domestic products (Nederwiet and Nederhasj) has particularly increased. In contrast with imported marijuana, Nederwiet hardly contained any cannabidiol (CBD), a cannabinoid that is thought to offset some of the adverse effects of THC. In 2005, the THC content in Nederwiet was significantly lower than in 2004. This study investigates the further decrease or increase of cannabinoids in these cannabis products. From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected randomly each year from all coffeeshops in the Netherlands. A total of 2126 cannabis samples were bought, consisting of 664 Nederwiet samples (most popular), 537 Nederwiet samples (supposed strongest varieties), 183 imported herbal cannabis samples, 140 samples of cannabis resin made of Nederwiet and 602 samples of imported cannabis resin. All samples were analysed chemically for their THC, CBD and cannabinol (CBN) content. Between 2005 and 2015, the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0±4.0%, 17.0±3,9% and 16.5±6.3%, respectively. Imported herbal cannabis (6.5±3.5%) and cannabis resin made from Nederwiet (30.2±16.4%) contained, respectively, less (β=-10.0, P<0.001) and more (β=13.7, P<0.001) THC than imported cannabis resin. Linear regression models were used to study the trends in THC of the different cannabis products over time. A marginal, but significant (P<0.001), overall decline of THC per year of 0.22% was found in all cannabis products. However, no significant difference was found between the five products in the THC linear trajectories across time. Of all the cannabis products, only imported cannabis resin contained a relatively high CBD/THC ratio (median 0.42). The average tetrahydrocannabinol (THC) content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005. The popular Nederwiet type still has a relatively high THC to cannabidiol ratio. © 2015 Society for the Study of Addiction.

Gonadal hormone modulation of Δ9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats

PubMed Central

Craft, R.M.; Haas, A.E.; Wiley, J.L.; Yu, Z.; Clowers, B.H.

2016-01-01

The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of Δ9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100 g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25 mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; one h later, vehicle or THC (3 mg/kg females, 5 mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240 min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males’ and females’ behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC's behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats. PMID:27670094

Design and analysis of low-loss linear analog phase modulator for deep space spacecraft X-band transponder (DST) application

NASA Technical Reports Server (NTRS)

Mysoor, Narayan R.; Mueller, Robert O.

1991-01-01

This paper summarizes the design concepts, analyses, and the development of an X-band transponder low-loss linear phase modulator for deep space spacecraft applications. A single section breadboard circulator-coupled reflection phase modulator has been analyzed, fabricated, and evaluated. Two- and three-cascaded sections have been modeled and simulations performed to provide an X-band DST phase modulator with +/- 2.5 radians of peak phase deviation to accommodate down-link signal modulation with composite telemetry data and ranging with a deviation linearity tolerance +/- 8 percent and insertion loss of less than 10 +/- 0.5 dB. A two-section phase modulator using constant gamma hyperabrupt varactors and an efficient modulator driver circuit was breadboarded. The measured results satisfy the DST phase modulator requirements, and excellent agreement with the predicted results.

Subjective and physiological effects of oromucosal sprays containing cannabinoids (nabiximols): potentials and limitations for psychosis research.

PubMed

Schoedel, Kerri A; Harrison, Sarah Jane

2012-01-01

Cannabis use is associated with a spectrum of effects including euphoria, relaxation, anxiety, perceptual alterations, paranoia, and impairments in attention and memory. Cannabis is made up of approximately 80 different cannabinoid compounds, which have synergistic or antagonistic effects on the principle active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC). The net overall effect of cannabis is thought to be related to the ratio of its composite constituents; in particular, the ratio of THC to cannabidiol (CBD). Since cannabinoids induce subjective and cognitive changes that share qualitative similarities with schizophrenia, cannabinoids have been used to model psychosis. Some limitations of cannabinoid models of psychosis include the relatively high variability in experiences between different individuals, the potential for inducing unwanted effects, such as toxic psychosis in study subjects, and the lack of data showing that effective anti-psychotic treatments can reverse the behavioural and cognitive/motor effects of cannabinoids. Nabiximols (Sativex®) is an oromucosal spray containing THC and CBD in an approximate 1:1 ratio. While not extensively studied, most studies confirm that nabiximols, despite the different route of administration and presence of CBD, have similar or slightly reduced subjective/cognitive effects compared to similar doses of oral THC. While the presence of CBD may have utility in some models, it is likely that the concentrations are not high enough to meaningfully affect those aspects important for psychosis research. This review suggests that while it may present an alternative to the use of oral THC, oromucosal nabiximols may not present substantial advantages for use in psychosis research.

Crustal structure of the southern Dead Sea basin derived from project DESIRE wide-angle seismic data

NASA Astrophysics Data System (ADS)

Mechie, J.; Abu-Ayyash, K.; Ben-Avraham, Z.; El-Kelani, R.; Qabbani, I.; Weber, M.

2009-07-01

As part of the DEad Sea Integrated REsearch project (DESIRE) a 235 km long seismic wide-angle reflection/refraction (WRR) profile was completed in spring 2006 across the Dead Sea Transform (DST) in the region of the southern Dead Sea basin (DSB). The DST with a total of about 107 km multi-stage left-lateral shear since about 18 Ma ago, accommodates the movement between the Arabian and African plates. It connects the spreading centre in the Red Sea with the Taurus collision zone in Turkey over a length of about 1100 km. With a sedimentary infill of about 10 km in places, the southern DSB is the largest pull-apart basin along the DST and one of the largest pull-apart basins on Earth. The WRR measurements comprised 11 shots recorded by 200 three-component and 400 one-component instruments spaced 300 m to 1.2 km apart along the whole length of the E-W trending profile. Models of the P-wave velocity structure derived from the WRR data show that the sedimentary infill associated with the formation of the southern DSB is about 8.5 km thick beneath the profile. With around an additional 2 km of older sediments, the depth to the seismic basement beneath the southern DSB is about 11 km below sea level beneath the profile. Seismic refraction data from an earlier experiment suggest that the seismic basement continues to deepen to a maximum depth of about 14 km, about 10 km south of the DESIRE profile. In contrast, the interfaces below about 20 km depth, including the top of the lower crust and the Moho, probably show less than 3 km variation in depth beneath the profile as it crosses the southern DSB. Thus the Dead Sea pull-apart basin may be essentially an upper crustal feature with upper crustal extension associated with the left-lateral motion along the DST. The boundary between the upper and lower crust at about 20 km depth might act as a decoupling zone. Below this boundary the two plates move past each other in what is essentially a shearing motion. Thermo-mechanical modelling of the DSB supports such a scenario. As the DESIRE seismic profile crosses the DST about 100 km north of where the DESERT seismic profile crosses the DST, it has been possible to construct a crustal cross-section of the region before the 107 km left-lateral shear on the DST occurred.

Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops.

PubMed

Pijlman, F T A; Rigter, S M; Hoek, J; Goldschmidt, H M J; Niesink, R J M

2005-06-01

The total concentration of THC has been monitored in cannabis preparations sold in Dutch coffee shops since 1999. This annual monitoring was issued by the Ministry of Health after reports of increased potency. The level of the main psychoactive compound, Delta9-tetrahydrocannabinol (THC), is measured in marijuana and hashish. A comparison is made between imported and Dutch preparations, and between seasons. Samples of cannabis preparations from randomly selected coffee shops were analyzed using gas chromatography (GC-FID) for THC, CBD and CBN. In 2004, the average THC level of Dutch home-grown marijuana (Nederwiet) (20.4% THC) was significantly higher than that of imported marijuana (7.0% THC). Hashish derived from Dutch marijuana (Nederhasj) contained 39.3% THC in 2004, compared with 18.2% THC in imported hashish. The average THC percentage of Dutch marijuana, Dutch hashish and imported hashish was significantly higher than in previous years. It nearly doubled over 5 years. During this period, the THC percentage in imported marijuana remained unchanged. A higher price had to be paid for cannabis with higher levels of THC. Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use, abuse liability, bioavailability and levels of THC in the brain.

Determination of ∆-9-Tetrahydrocannabinol (THC), 11-hydroxy-THC, 11-nor-9-carboxy-THC and Cannabidiol in Human Plasma using Gas Chromatography-Tandem Mass Spectrometry.

PubMed

Andrenyak, David M; Moody, David E; Slawson, Matthew H; O'Leary, Daniel S; Haney, Margaret

2017-05-01

Two marijuana compounds of particular medical interest are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A gas chromatography-tandem mass spectrometry (GC-MS-MS) method was developed to test for CBD, THC, hydroxy-THC (OH-THC) and carboxy-THC (COOH-THC) in human plasma. Calibrators (THC and OH-THC, 0.1 to 100; CBD, 0.25 to 100; COOH-THC, 0.5-500 ng/mL) and controls (0.3, 5 and 80 ng/mL, except COOH-THC at 1.5, 25 and 400 ng/mL) were prepared in blank matrix. Deuterated (d3) internal standards were added to 1-mL samples. Preparation involved acetonitrile precipitation, liquid-liquid extraction (hexane:ethyl acetate, 9:1), and MSTFA derivatization. An Agilent 7890 A GC was interfaced with an Agilent 7000 MS Triple Quadrupole. Selected reaction monitoring was employed. Blood samples were provided from a marijuana smoking study (two participants) and a CBD ingestion study (eight participants). Three analytes with the same transitions (THC, OH-THC and COOH-THC) were chromatographically separated. Matrix selectivity studies showed endogenous chromatographic peak area ratios (PAR) at the analyte retention times were <20% of the analyte limit of quantitation PAR. The intra-assay accuracy ranged from 83.5% to 118% of target and the intra-run imprecision ranged from 2.0% to 19.1%. The inter-assay accuracy ranged from 90.3% to 104% of target and the inter-run imprecision ranged from 6.5% to 12.0%. Stability was established for 25 hours at room temperature, 207 days at -20°C, after three freeze-thaw cycles and for 26 days for rederivatized processed samples. After smoking marijuana predictable concentrations of THC, OH-THC and COOH-THC were seen; low concentrations of CBD were detected at early time points. In moderate users who had not smoked for at least 9 hours before ingesting an 800 mg oral dose of CBD, the method was sensitive enough to follow residual concentrations of THC and OH-THC; sustained COOH-THC concentrations over 50 ng/mL validated its higher analytical range. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Determination of ∆-9-Tetrahydrocannabinol (THC), 11-hydroxy-THC, 11-nor-9-carboxy-THC and Cannabidiol in Human Plasma using Gas Chromatography–Tandem Mass Spectrometry

PubMed Central

Andrenyak, David M.; Slawson, Matthew H.; O'Leary, Daniel S.; Haney, Margaret

2017-01-01

Abstract Two marijuana compounds of particular medical interest are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A gas chromatography–tandem mass spectrometry (GC–MS-MS) method was developed to test for CBD, THC, hydroxy-THC (OH-THC) and carboxy-THC (COOH-THC) in human plasma. Calibrators (THC and OH-THC, 0.1 to 100; CBD, 0.25 to 100; COOH-THC, 0.5–500 ng/mL) and controls (0.3, 5 and 80 ng/mL, except COOH-THC at 1.5, 25 and 400 ng/mL) were prepared in blank matrix. Deuterated (d3) internal standards were added to 1-mL samples. Preparation involved acetonitrile precipitation, liquid–liquid extraction (hexane:ethyl acetate, 9:1), and MSTFA derivatization. An Agilent 7890 A GC was interfaced with an Agilent 7000 MS Triple Quadrupole. Selected reaction monitoring was employed. Blood samples were provided from a marijuana smoking study (two participants) and a CBD ingestion study (eight participants). Three analytes with the same transitions (THC, OH-THC and COOH-THC) were chromatographically separated. Matrix selectivity studies showed endogenous chromatographic peak area ratios (PAR) at the analyte retention times were <20% of the analyte limit of quantitation PAR. The intra-assay accuracy ranged from 83.5% to 118% of target and the intra-run imprecision ranged from 2.0% to 19.1%. The inter-assay accuracy ranged from 90.3% to 104% of target and the inter-run imprecision ranged from 6.5% to 12.0%. Stability was established for 25 hours at room temperature, 207 days at −20°C, after three freeze-thaw cycles and for 26 days for rederivatized processed samples. After smoking marijuana predictable concentrations of THC, OH-THC and COOH-THC were seen; low concentrations of CBD were detected at early time points. In moderate users who had not smoked for at least 9 hours before ingesting an 800 mg oral dose of CBD, the method was sensitive enough to follow residual concentrations of THC and OH-THC; sustained COOH-THC concentrations over 50 ng/mL validated its higher analytical range. PMID:28069869

Adverse Effects of Daylight Saving Time on Adolescents' Sleep and Vigilance

PubMed Central

Medina, Diana; Ebben, Matthew; Milrad, Sara; Atkinson, Brianna; Krieger, Ana C.

2015-01-01

Study Objectives: Daylight saving time (DST) has been established with the intent to reduce energy expenditure, however unintentional effects on sleep and vigilance have not been consistently measured. The objective of this study was to test the hypothesis that DST adversely affects high school students' sleep and vigilance on the school days following its implementation. Methods: A natural experiment design was used to assess baseline and post-DST differences in objective and subjective measures of sleep and vigilance by actigraphy, sleep diary, sleepiness scale, and psychomotor vigilance testing (PVT). Students were tested during school days immediately preceding and following DST. Results: A total of 40 high school students were enrolled in this study; 35 completed the protocol. Sleep duration declined by an average of 32 minutes on the weeknights post-DST, reflecting a cumulative sleep loss of 2 h 42 min as compared to the baseline week (p = 0.001). This finding was confirmed by sleep diary analyses, reflecting an average sleep loss of 27 min/night (p = 0.004) post-DST. Vigilance significantly deteriorated, with a decline in PVT performance post-DST, resulting in longer reaction times (p < 0.001) and increased lapses (p < 0.001). Increased daytime sleepiness was also demonstrated (p < 0.001). Conclusions: The early March DST onset adversely affected sleep and vigilance in high school students resulting in increased daytime sleepiness. Larger scale evaluations of sleep impairments related to DST are needed to further quantify this problem in the population. If confirmed, measures to attenuate sleep loss post-DST should be implemented. Citation: Medina D, Ebben M, Milrad S, Atkinson B, Krieger AC. Adverse effects of daylight saving time on adolescents' sleep and vigilance. J Clin Sleep Med 2015;11(8):879–884. PMID:25979095

Architectural constructs of Ampex DST

NASA Technical Reports Server (NTRS)

Johnson, Clay

1993-01-01

The DST 800 automated library is a high performance, automated tape storage system, developed by AMPEX, providing mass storage to host systems. Physical Volume Manager (PVM) is a volume server which supports either a DST 800, DST 600 stand alone tape drive, or a combination of DST 800 and DST 600 subsystems. The objective of the PVM is to provide the foundation support to allow automated and operator assisted access to the DST cartridges with continuous operation. A second objective is to create a data base about the media, its location, and its usage so that the quality and utilization of the media on which specific data is recorded and the performance of the storage system may be managed. The DST tape drive architecture and media provides several unique functions that enhance the ability to achieve high media space utilization and fast access. Access times are enhanced through the implementation of multiple areas (called system zones) on the media where the media may be unloaded. This reduces positioning time in loading and unloading the cartridge. Access times are also reduced through high speed positioning in excess of 800 megabytes per second. A DST cartridge can be partitioned into fixed size units which can be reclaimed for rewriting without invalidating other recorded data on the tape cartridge. Most tape management systems achieve space reclamation by deleting an entire tape volume, then allowing users to request a 'scratch tape' or 'nonspecific' volume when they wish to record data to tape. Physical cartridge sizes of 25, 75, or 165 gigabytes will make this existing process inefficient or unusable. The DST cartridge partitioning capability provides an efficient mechanism for addressing the tape space utilization problem.

U.S. Geological Survey Near Real-Time Dst Index

USGS Publications Warehouse

Gannon, J.L.; Love, J.J.; Friberg, P.A.; Stewart, D.C.; Lisowski, S.W.

2011-01-01

The operational version of the United States Geological Survey one-minute Dst index (a global geomagnetic disturbance-intensity index for scientific studies and definition of space-weather effects) uses either four- or three-station input (including Honolulu, Hawaii; San Juan, Puerto Rico; Hermanus, South Africa; and Kakioka, Japan; or Honolulu, San Juan and Guam) and a method based on the U.S. Geological Survey definitive Dst index, in which Dst is more rigorously calculated. The method uses a combination of time-domain techniques and frequency-space filtering to produce the disturbance time series at an individual observatory. The operational output is compared to the U.S. Geological Survey one-minute Dst index (definitive version) and to the Kyoto (Japan) Final Dst to show that the U.S. Geological Survey operational output matches both definitive indices well.

Does the transition into daylight saving time really cause partial sleep deprivation?

PubMed

Toth Quintilham, Manoel Carlos; Adamowicz, Taísa; Pereira, Erico Felden; Pedrazzoli, Mario; Louzada, Fernando Mazzilli

2014-01-01

To identify possible changes in the sleep patterns according to chronotype in undergraduate students during the daylight saving time (DST) transition. A total of 378 students answered the Morningness-Eveningness Questionnaire (MEQ) to determine their chronotype and kept a diary about sleep-wake schedules 1 week before and after the DST transition. Oral mucosal cell samples were collected for genetic analysis. After the DST transition, intermediate types (I-types) delayed bedtime and increased their time in bed and all groups delayed their wake-up time. All groups presented a shorter phase angle between sunset and the bedtime after the DST transition. On the other hand, only E-types showed a tendency to reduce the phase angle between sunrise and wake-up time, while I-types and M-types kept the same phase angles between sunrise and wake-up time after the DST transition. The polymorphisms in the human genes CLOCK and PER3 were not associated with individual differences in sleep patterns, nor were they associated with an adjustment to the DST transition. Under the new set of social times determined by DST, the adjustment was only partial. I-types delayed bedtime and all groups delayed their wake-up times after the beginning of DST. Consequently, the time in bed after the DST transition was not reduced; Morning (M-types) and Evening-types (E-types) kept the same time in bed and I-types showed an increase on it.

Reintoxication: the release of fat-stored delta(9)-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure.

PubMed

Gunasekaran, N; Long, L E; Dawson, B L; Hansen, G H; Richardson, D P; Li, K M; Arnold, J C; McGregor, I S

2009-11-01

Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC. In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg.kg(-1)) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels. ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections. The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of 'reintoxication' whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or 'flashbacks'.

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

PubMed

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2016-02-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the sub-chronic PCP model of schizophrenia

PubMed Central

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2017-01-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the CSF levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared to THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID:26510449

Thermohaline circulation at three key sections in the North Atlantic over 1985-2002

NASA Astrophysics Data System (ADS)

Marsh, Robert; de Cuevas, Beverly A.; Coward, Andrew C.; Bryden, Harry L.; Álvarez, Marta

2005-05-01

Efforts are presently underway to monitor the Thermohaline Circulation (THC) in the North Atlantic. A measuring strategy has been designed to monitor both the Meridional Overturning Circulation (MOC) in the subtropics and dense outflows at higher latitudes. To provide a historical context for these new observations, we diagnose an eddy-permitting ocean model simulation of the period 1985-2002. We present time series of the THC, MOC and heat transport, at key hydrographic sections in the subtropics, the northeast Atlantic and the Labrador Sea. The simulated THC compares well with observations. We find considerable variability in the THC on each section, most strikingly in the Labrador Sea during the early 1990's, consistent with observed changes. Overturning in the northeast Atlantic declines by ~20% over the 1990's, coincident with an increase in the subtropics. We speculate that MOC weakening may soon be detected in the subtropics, if the decline continues in mid-latitudes.

Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract.

PubMed

Nadulski, Thomas; Sporkert, Frank; Schnelle, Martin; Stadelmann, Andreas M; Roser, Patrik; Schefter, Tom; Pragst, Fritz

2005-01-01

Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

Chronic Administration of Δ9-Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

PubMed Central

Chandra, Lawrance C.; Kumar, Vinay; Torben, Workineh; Stouwe, Curtis Vande; Winsauer, Peter; Amedee, Angela; Molina, Patricia E.

2014-01-01

ABSTRACT Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n = 3) and SIV-infected macaques administered either vehicle (VEH/SIV; n = 4) or THC (THC/SIV; n = 4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with Δ9-tetrahydrocannabinol (Δ9-THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4+ epithelial cells in the intestines of THC-treated SIV-infected macaques. Overall, our results show that selective upregulation of anti-inflammatory miRNA expression contributes to THC-mediated suppression of gastrointestinal inflammation and maintenance of intestinal homeostasis. PMID:25378491

Subjective and physiological effects after controlled Sativex and oral THC administration.

PubMed

Karschner, E L; Darwin, W D; McMahon, R P; Liu, F; Wright, S; Goodwin, R S; Huestis, M A

2011-03-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.

Subjective and Physiological Effects After Controlled Sativex and Oral THC Administration

PubMed Central

Karschner, EL; Darwin, WD; McMahon, RP; Liu, F; Wright, S; Goodwin, RS; Huestis, MA

2013-01-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and “good drug effects” with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses. PMID:21289620

Thermohaline circulation and its box models simulation

NASA Astrophysics Data System (ADS)

Bazyura, Kateryna; Polonsky, Alexander; Sannikov, Viktor

2014-05-01

Ocean Thermochaline circulation (THC) is the part of large-scale World Ocean circulation and one of the main climate system components. It is generated by global meridional density gradients, which are controlled by surface heat and freshwater fluxes. THC regulates climate variability on different timescales (from decades to thousands years) [Stocker (2000), Clark (2002)]. Study of paleoclimatic evidences of abrupt and dramatic changes in ocean-atmosphere system in the past (such as, Dansgaard-Oeschger and Heinrich events or Younger Dryas, see e.g., [Rahmstorf (2002), Alley & Clark(1999)]) shows that these events are connected with THC regimes. At different times during last 120,000 years, three THC modes have prevailed in the Atlantic. They can be labeled as stadial, interstadial and Heinrich modes or as cold, warm and off mode. THC collapse (or thermohaline catastrophe) can be one of the consequences of global warming (including modern anthropogenic climate changes occurring at the moment). The ideas underlying different box-model studies, possibility of thermochaline catastrophe in present and past are discussed in this presentation. Response of generalized four box model of North Atlantic thermohaline circulation [developing the model of Griffies & Tzippermann (1995)] on periodic, stochastic and linear forcing is studied in details. To estimate climatic parameters of the box model we used monthly salinity and temperature data of ECMWF operational Ocean Reanalysis System 3 (ORA-S3) and data from atmospheric NCEP/NCAR reanalysis on precipitation, and heat fluxes for 1959-2011. Mean values, amplitude of seasonal cycle, amplitudes and periods of typical interdecadal oscillations, white noise level, linear trend coefficients and their significance level were estimated for every hydrophysical parameter. In response to intense freshwater or heat forcing, THC regime can change resulting in thermohaline catastrophe. We analyze relevant thresholds of external forcing in cases of using linear and nonlinear seawater state equation. In the frame of four-box model it is shown that: 1) The occurrence of the thermohaline catastrophe, which is likely happened at Younger Dryas period or developed as Heinrich events in the past, is improbable in modern climate epoch. 2) Choice of nonlinear seawater equitation of state leads to stabilization of warm mode of THC, which corresponds to modern climate state. 3) Typical white noise in heat and freshwater fluxes leads to generation of multidecadal oscillations of volume transport. Time-scale of these oscillations coincides with Atlantic Multidecadal oscillation periodicity. So, it is shown that that recent climate is characterized by quasi-periodical stable multidecadal THC warm regime. Stocker, T. F., 2000: Past and future reorganisations in the climate system. Quat. Sci.Rev, Vol. 19, P.301-319. Clark U., 2002: The role of the thermohaline circulation in abrupt climate change. Nature. Vol. 415, P.863-869. Rahmstorf S., 2002: Ocean circulation and climate during the past 120000 years. Nature. Vol. 419, P.207-214. Alley, R. B. & Clark, P. U., 1999: The deglaciation of the Northern Hemisphere: a global perspective. Annu.Rev. Earth Planet. Sci. Vol. 27, P.149-182. Griffies S.M., Tziperman E., 1995: A linear thermohaline oscillator driven by stochastic atmospheric forcing. Journal of Climate. Vol. 8. P. 2440-2453.

Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imaging.

PubMed

Toyota, Yasunori; Miyake, Keisuke; Kawai, Nobuyuki; Hatakeyama, Tetsuhiro; Yamamoto, Yuka; Toyohara, Jun; Nishiyama, Yoshihiro; Tamiya, Takashi

2015-01-01

3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, (18)F-FLT has several limitations in clinical use. Recently, (11)C-labeled thymidine analogue, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of (11)C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of (18)F-FLT PET. Twenty patients with primary and recurrent brain gliomas underwent (18)F-FLT and (11)C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of (11)C-4DST and (18)F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual (18)F-FLT and (11)C-4DST uptake values in the tumors was also examined. (11)C-4DST uptake was significantly higher than that of (18)F-FLT in the normal brain. The uptake values of (11)C-4DST in the tumor were similar to those of (18)F-FLT resulting in better visualization with (18)F-FLT. No significant differences in the uptake values of (18)F-FLT and (11)C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of (11)C-4DST (r = 0.50, P < 0.05) and (18)F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of (11)C-4DST (r = 0.52, P < 0.05) and (18)F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of (11)C-4DST and (18)F-FLT in the tumor (r = 0.79, P = 0.0001). The present study demonstrates that (11)C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of (11)C-4DST in the normal brain compared to (18)F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in (11)C-4DST over (18)F-FLT in the evaluation of cell proliferation.

[Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

PubMed

Goullé, Jean-Perre; Guerbet, Michel

2014-03-01

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

Reintoxication: the release of fat-stored Δ9-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure

PubMed Central

Gunasekaran, N; Long, LE; Dawson, BL; Hansen, GH; Richardson, DP; Li, KM; Arnold, JC; McGregor, IS

2009-01-01

Background and purpose: Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC. Experimental approach: In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg·kg−1) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels. Key results: ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections. Conclusions and implications: The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of ‘reintoxication’ whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or ‘flashbacks’. PMID:19681888

Modeling of coupled heat transfer and reactive transport processesin porous media: Application to seepage studies at Yucca Mountain, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mukhopadhyay, Sumit; Sonnenthal, Eric L.; Spycher, Nicolas

When hot radioactive waste is placed in subsurface tunnels, a series of complex changes occurs in the surrounding medium. The water in the pore space of the medium undergoes vaporization and boiling. Subsequently, vapor migrates out of the matrix pore space, moving away from the tunnel through the permeable fracture network. This migration is propelled by buoyancy, by the increased vapor pressure caused by heating and boiling, and through local convection. In cooler regions, the vapor condenses on fracture walls, where it drains through the fracture network. Slow imbibition of water thereafter leads to gradual rewetting of the rock matrix.more » These thermal and hydrological processes also bring about chemical changes in the medium. Amorphous silica precipitates from boiling and evaporation, and calcite from heating and CO2 volatilization. The precipitation of amorphous silica, and to a much lesser extent calcite, results in long-term permeability reduction. Evaporative concentration also results in the precipitation of gypsum (or anhydrite), halite, fluorite and other salts. These evaporative minerals eventually redissolve after the boiling period is over, however, their precipitation results in a significant temporary decrease in permeability. Reduction of permeability is also associated with changes in fracture capillary characteristics. In short, the coupled thermal-hydrological-chemical (THC) processes dynamically alter the hydrological properties of the rock. A model based on the TOUGHREACT reactive transport software is presented here to investigate the impact of THC processes on flow near an emplacement tunnel at Yucca Mountain, Nevada. We show how transient changes in hydrological properties caused by THC processes often lead to local flow channeling and saturation increases above the tunnel. For models that include only permeability changes to fractures, such local flow channeling may lead to seepage relative to models where THC effects are ignored. However, coupled THC seepage models that include both permeability and capillary changes to fractures may not show this additional seepage.« less

Modeling of coupled heat transfer and reactive transport processesin porous media: Application to seepage studies at Yucca Mountain, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mukhopadhyay, S.; Sonnenthal, E.L.; Spycher, N.

When hot radioactive waste is placed in subsurface tunnels, a series of complex changes occurs in the surrounding medium. The water in the pore space of the medium undergoes vaporization and boiling. Subsequently, vapor migrates out of the matrix pore space, moving away from the tunnel through the permeable fracture network. This migration is propelled by buoyancy, by the increased vapor pressure caused by heating and boiling, and through local convection. In cooler regions, the vapor condenses on fracture walls, where it drains through the fracture network. Slow imbibition of water thereafter leads to gradual rewetting of the rock matrix.more » These thermal and hydrological processes also bring about chemical changes in the medium. Amorphous silica precipitates from boiling and evaporation, and calcite from heating and CO{sub 2} volatilization. The precipitation of amorphous silica, and to a much lesser extent calcite, results in long-term permeability reduction. Evaporative concentration also results in the precipitation of gypsum (or anhydrite), halite, fluorite and other salts. These evaporative minerals eventually redissolve after the boiling period is over, however, their precipitation results in a significant temporary decrease in permeability. Reduction of permeability is also associated with changes in fracture capillary characteristics. In short, the coupled thermal-hydrological-chemical (THC) processes dynamically alter the hydrological properties of the rock. A model based on the TOUGHREACT reactive transport software is presented here to investigate the impact of THC processes on flow near an emplacement tunnel at Yucca Mountain, Nevada. We show how transient changes in hydrological properties caused by THC processes often lead to local flow channeling and saturation increases above the tunnel. For models that include only permeability changes to fractures, such local flow channeling may lead to seepage relative to models where THC effects are ignored. However, coupled THC seepage models that include both permeability and capillary changes to fractures may not show this additional seepage.« less

An efficient motion-resistant method for wearable pulse oximeter.

PubMed

Yan, Yong-Sheng; Zhang, Yuan-Ting

2008-05-01

Reduction of motion artifact and power saving are crucial in designing a wearable pulse oximeter for long-term telemedicine application. In this paper, a novel algorithm, minimum correlation discrete saturation transform (MCDST) has been developed for the estimation of arterial oxygen saturation (SaO2), based on an optical model derived from photon diffusion analysis. The simulation shows that the new algorithm MCDST is more robust under low SNRs than the clinically verified motion-resistant algorithm discrete saturation transform (DST). Further, the experiment with different severity of motions demonstrates that MCDST has a slightly better performance than DST algorithm. Moreover, MCDST is more computationally efficient than DST because the former uses linear algebra instead of the time-consuming adaptive filter used by latter, which indicates that MCDST can reduce the required power consumption and circuit complexity of the implementation. This is vital for wearable devices, where the physical size and long battery life are crucial.

A novel single-step GC-MS/MS method for cannabinoids and 11-OH-THC metabolite analysis in hair.

PubMed

Angeli, Ilaria; Casati, Sara; Ravelli, Alessandro; Minoli, Mauro; Orioli, Marica

2018-06-05

THC, CBD, CBN, THC-COOH and 11-OH-THC are the most popular markers of cannabis consumption and abuse. The use of this drug is a serious social problem worldwide. In this study, a method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) operated in electron ionization (EI) with simple and rapid liquid-liquid extraction (LLE) and derivatization was developed and validated for the simultaneous determination of THC, CBD, CBN and 11-OH-THC in hair samples. The detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The most important advantage of this method is the single-step, quick, easy and effective sample extraction procedure for THC, CBD, CBN and 11-OH-THC. The method showed a good linearity with a correlation coefficient (r 2 ) between 0.997 and 0.999 for all substances. The variation coefficient (%CV) was <5% for THC, 11-OH-THC and CBD and <13% for CBN. The limit of detection (LOD) was 0.03 pg/mg for 11-OH-THC and it ranged from 0.3 to 1.4 pg/mg for THC, CBD and CBN. The limit of quantification was 0.1 pg/mg for 11-OH-THC and it ranged from 0.9 to 4.7 pg/mg for THC, CBD and CBN. Analytical recovery was higher than 88% for 11-OH-THC and it ranged between 68 and 97% for THC, CBD and CBN. Intra- and inter-assay precision and accuracy were always lower than 9-14% and 5-9%, respectively. In parallel, we have quantified the THC-COOH level, following the methods previously set-up by us. The whole procedure was successfully applied to more than 200 different hair samples from cannabis consumers, disclosing the presence of 11-OH-THC in a range between 0.2 pg/mg and 27 pg/mg, and the presence of THC-COOH in a range between 0.05 pg/mg and 42.05 pg/mg. These data provided a good start towards the use of 11-THC-OH as alternative hair biomarker of cannabis consumption. Copyright © 2018 Elsevier B.V. All rights reserved.

Delayed and Unreported Drug-Susceptibility Testing Results in the US National Tuberculosis Surveillance System, 1993-2014.

PubMed

Jones, Jefferson Michael; Armstrong, Lori R

Drug-susceptibility testing (DST) of Mycobacterium tuberculosis is necessary for identifying drug-resistant tuberculosis, administering effective treatment regimens, and preventing the spread of drug-resistant tuberculosis. DST is recommended for all culture-confirmed cases of tuberculosis. We examined trends in delayed and unreported DST results in the Centers for Disease Control and Prevention's National Tuberculosis Surveillance System. We analyzed culture-confirmed tuberculosis cases reported to the National Tuberculosis Surveillance System during 1993-2014 for annual trends in initial DST reporting for first-line antituberculosis drugs and trends in on-time, delayed, and unreported results. We defined on-time reporting as DST results received during the same calendar year in which the patient's case was reported or ≤4 months after the calendar year ended and delayed reporting as DST results received after the calendar year. We compared cases with on-time, delayed, and unreported DST results by patient and tuberculosis program characteristics. The proportion of cases with reported results for all first-line antituberculosis drugs increased during 1993-2011. Reporting of pyrazinamide results was lower than reporting of other drugs. However, during 2000-2012, of 134 787 tuberculosis cases reported to the National Tuberculosis Surveillance System, reporting was on time for 125 855 (93.4%) cases, delayed for 5332 (4.0%) cases, and unreported for 3600 (2.7%) cases. Despite increases in the proportion of cases with on-time DST results, delayed and unreported results persisted. Carefully assessing causes for delayed and unreported DST results should lead to more timely reporting of drug-resistant tuberculosis.

On the Freshwater Sensitivity of the Arctic-Atlantic Thermohaline Circulation

NASA Astrophysics Data System (ADS)

Lambert, E.; Eldevik, T.; Haugan, P.

2016-02-01

The North Atlantic thermohaline circulation (THC) carries heat and salt toward the Arctic. This circulation is generally believed to be inhibited by northern freshwater input as indicated by the `box-model' of Stommel (1961). The inferred freshwater-sensitivity of the THC, however, varies considerably between studies, both quantitatively and qualitatively. The northernmost branch of the Atlantic THC, which forms a double estuarine circulation in the Arctic Mediterranean, is one example where both strengthening and weakening of the circulation may occur due to increased freshwater input. We have accordingly built on Stommel's original concept to accomodate a THC similar to that in the Arctic Mediterranean. This model consists of three idealized basins, or boxes, connected by two coupled branches of circulation - the double estuary. The net transport of these two branches represents the extension of the Gulf Stream toward the Arctic. Its sensitivity to a change in freshwater forcing depends largely on the distribution of freshwater over the two northern basins. Varying this distribution opens a spectrum of qualitative behaviours ranging from Stommel's original freshwater-inhibited overturning circulation to a freshwater-facilitated estuarine circulation. Between these limiting cases, a Hopf and a cusp bifurcation divide the spectrum into three qualitative regions. In the first region, the circulation behaves similarly to Stommel's circulation, and sufficient freshwater input can induce an abrupt transition into a reversed flow; in the second, a similar transition can be found, although it does not reverse the circulation; in the third, no transition can occur and the circulation is generally facilitated by the northern freshwater input. Overall, the northern THC appears more stable than what would be inferred based on Stommel's model; it requires a larger amount and more localized freshwater input to `collapse' it, and a double estuary circulation is less prone to flow reversal.

A Two-Year Study of Δ 9 Tetrahydrocannabinol Concentrations in Drivers; Part 2: Physiological Signs on Drug Recognition Expert (DRE) and non-DRE Examinations,.

PubMed

Declues, Kari; Perez, Shelli; Figueroa, Ariana

2018-03-01

Whole blood samples were examined for ∆ 9 -Tetrahydrocannabinol (THC) over 2 years in drivers suspected of driving under the influence. Part one of the study examined the link between [THC] and performance on field sobriety tests. This portion examined objective signs, eye examinations and physiological indicators; and their relationship to the presence of THC. Several objective signs were excellent indicators of the presence of THC: red eyes (94%), droopy eyelids (85.6%), affected speech (87.6%), tongue coating (96.2%), and odor of marijuana (82.4%). About 63.6% of THC positive subjects had dialted pupils (room light). THC positive subjects had either rebound dilation or hippus in 88.8% of cases. Pulse and blood pressure (BP) were evaluated to determine any correlation with [THC]. An increased pulse rate correlated well to the presence of THC (88.5%), but not [THC]. BP did not correlate to [THC] and was also a poor indicator of THC in the blood (50% high). © 2017 American Academy of Forensic Sciences.

40 CFR 86.143-96 - Calculations; evaporative emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

....1005(f): ER28AP14.005 Where: m THCE = the sum of the mass of THCE in the SHED. m THC = the mass of THC and all oxygenated hydrocarbons in the SHED, as measured by the FID. Calculate THC mass based on ρ THC. ρ THC = the effective C1-equivalent density of THC as specified in 40 CFR 1066.1005(f). m OHCi = the...

Simple, direct drug susceptibility testing technique for diagnosis of drug-resistant tuberculosis in resource-poor settings.

PubMed

Kim, C-K; Joo, Y-T; Lee, E P; Park, Y K; Kim, H-J; Kim, S J

2013-09-01

The Korean Institute of Tuberculosis, Seoul, Republic of Korea. To develop a simple, direct drug susceptibility testing (DST) technique using Kudoh-modified Ogawa (KMO) medium. The critical concentrations of isoniazid (INH), rifampicin (RMP), kanamycin (KM) and ofloxacin (OFX) for KMO medium were calibrated by comparing the minimal inhibitory concentrations (MICs) against clinical isolates of Mycobacterium tuberculosis on KMO with those on Löwenstein-Jensen (LJ). The performance of the direct KMO DST technique was evaluated on 186 smear-positive sputum specimens and compared with indirect LJ DST. Agreement of MICs on direct vs. indirect DST was high for INH, RMP and OFX. KM MICs on KMO were ∼10 g/ml higher than those on LJ. The critical concentrations of INH, RMP, OFX and KM for KMO were therefore set at 0.2, 40.0, 2.0, and 40.0 g/ml. The evaluation of direct DST of smear-positive sputum specimens showed 100% agreement with indirect LJ DST for INH and RMP. However, the respective susceptible and resistant predictive values were 98.8% and 100% for OFX, and 100% and 80% for KM. Direct DST using KMO is useful, with clear advantages of a shorter turnaround time, procedural simplicity and low cost compared to indirect DST. It may be most indicated in resource-poor settings for programmatic management of drug-resistant tuberculosis.

On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).

PubMed

Costa, Barbara

2007-08-01

Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.

Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

PubMed

Castelli, M Paola; Madeddu, Camilla; Casti, Alberto; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M Grazia

2014-01-01

Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively.

Postmortem redistribution of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH)

PubMed Central

Holland, Michael G.; Schwope, David M.; Stoppacher, Robert; Gillen, Shane B.; Huestis, Marilyn A.

2012-01-01

Introduction Postmortem redistribution (PMR), a well-described phenomenon in forensic toxicology for certain drugs, can result in increased central blood concentrations relative to peripheral blood concentrations. Δ9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis or marijuana, is the illicit substance most commonly implicated in driving under the influence of drugs (DUID) cases and fatally-injured drivers. No investigation of PMR of THC in human blood has been reported to date. Methods Matched heart and iliac postmortem blood specimens were collected from 19 medical examiner cases (16 Males, 3 Females) with positive cannabinoid urine immunoassay screens. THC, its equipotent metabolite 11-hydroxy-THC (11-OH-THC) and non-psychoactive metabolite 11-nor-9-carboxy-THC (THCCOOH) were quantified by two-dimensional gas chromatography-mass spectrometry with cryofocusing, with 0.5 ng/mL limits of quantification (LOQ) for all analytes. Results 10 cases had quantifiable THC and 11-OH-THC; THCCOOH was present in all 19. Median (range) heart:iliac blood ratios were 1.5 for THC (range: 0.3–3.1); 1.6 for 11-OH-THC (range: 0.3–2.7); and 1.8 for THCCOOH (range: 0.5–3.0). Discussion Cannabinoids, in general, exhibited a mean and median central: peripheral (C: P) concentration ratio of less than 2 following death. A trend was observed for greater PMR with increasing postmortem interval between death and sampling. To our knowledge, these are the first data on THC PMR in humans, providing important scientific data to aid in the interpretation of postmortem cannabinoid concentrations in medico-legal investigations. PMID:21764230

A decision support tool to prioritize risk management options for contaminated sites.

PubMed

Sorvari, Jaana; Seppälä, Jyri

2010-03-15

The decisions on risk management (RM) of contaminated sites in Finland have typically been driven by practical factors such as time and money. However, RM is a multifaceted task that generally involves several additional determinants, e.g. performance and environmental effects of remediation methods, psychological and social factors. Therefore, we adopted a multi-criteria decision analysis approach and developed a decision support tool (DST) that is viable in decision-making in such a complex situation. The basic components of the DST are based on the Dutch REC system. However, our DST is more case-specific and allows the consideration of the type, magnitude and scale of contamination, land use, environmental conditions and socio-cultural aspects (e.g. loss of cultural heritage, image aspects). The construction of the DST was started by structuring the decision problem using a value tree. Based on this work we adopted the Multi-Attribute Value Theory (MAVT) for data aggregation. The final DST was demonstrated by two model sites for which the RM alternatives and site-specific data were created on the basis of factual remediation projects and by interviewing experts. The demonstration of the DST was carried out in a workshop where representatives of different stakeholders were requested to rank and weight the decision criteria involved. To get information on the consistency of the ranking of the RM alternatives, we used different weighting techniques (ratio estimation and pair-wise weighting) and alternative ways to treat individual respondents' weights in calculating the preference scores for each RM alternative. These dissimilar approaches resulted in some differences in the preference order of the RM alternatives. The demonstration showed that attention has to be paid to the proper description of the site, the principles of the procedure and the decision criteria. Nevertheless, the procedure proved to enable efficient communication between different stakeholders and the identification of the preferred RM option.

Combined effects of THC and caffeine on working memory in rats

PubMed Central

Panlilio, Leigh V; Ferré, Sergi; Yasar, Sevil; Thorndike, Eric B; Schindler, Charles W; Goldberg, Steven R

2012-01-01

BACKGROUND AND PURPOSE Cannabis and caffeine are two of the most widely used psychoactive substances. Δ9-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory. EXPERIMENTAL APPROACH Rats were given THC (0, 1 and 3 mg·kg−1, i.p.) along with caffeine (0, 1, 3 and 10 mg·kg−1, i.p.), the selective adenosine A1-receptor antagonist CPT (0, 3 and 10 mg·kg−1) or the selective adenosine A2A-receptor antagonist SCH58261 (0 and 5 mg·kg−1) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal. KEY RESULTS THC alone produced memory deficits at 3 mg·kg−1. The initial exposure to caffeine (10 mg·kg−1) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg−1) was combined with caffeine (10 mg·kg−1) or CPT (10 mg·kg−1), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered. CONCLUSION AND IMPLICATIONS Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A1 receptors modulate cannabinoid signalling in the hippocampus. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21699509

Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC).

PubMed

Mayer, Tzur Alexander; Matar, Michael Alex; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

2014-07-01

The therapeutic value of Delta-9-tetrahydrocannabinol (Δ9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24 h or 7 days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with "extreme," "minimal" or "intermediate" (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Δ9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated. In the short term (1-6 h), 5 mg/kg of Δ9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7 days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Δ9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1 h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis. The demonstrated lack of preventive efficacy of early Δ9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences. Copyright © 2014 Elsevier Inc. All rights reserved.

The potential use of unmanned aircraft systems (drones) in mountain search and rescue operations.

PubMed

Karaca, Yunus; Cicek, Mustafa; Tatli, Ozgur; Sahin, Aynur; Pasli, Sinan; Beser, Muhammed Fatih; Turedi, Suleyman

2018-04-01

This study explores the potential use of drones in searching for and locating victims and of motorized transportation of search and rescue providers in a mountain environment using a simulation model. This prospective randomized simulation study was performed in order to compare two different search and rescue techniques in searching for an unconscious victim on snow-covered ground. In the control arm, the Classical Line Search Technique (CLT) was used, in which the search is performed on foot and the victim is reached on foot. In the intervention arm, the Drone-snowmobile Technique (DST) was used, the search being performed by drone and the victim reached by snowmobile. The primary outcome of the study was the comparison of the two search and rescue techniques in terms of first human contact time. Twenty search and rescue operations were conducted in this study. Median time to arrival at the mannequin was 57.3min for CLT, compared to 8.9min for DST. The median value of the total searched area was 88,322.0m 2 for CLT and 228,613.0m 2 for DST. The median area searched per minute was 1489.6m 2 for CLT and 32,979.9m 2 for DST (p<0.01 for all comparisons). In conclusion, a wider area can be searched faster by drone using DST compared to the classical technique, and the victim can be located faster and reached earlier with rescuers transported by snowmobile. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute and chronic effects of cannabidiol on Δ⁹-tetrahydrocannabinol (Δ⁹-THC)-induced disruption in stop signal task performance.

PubMed

Jacobs, David S; Kohut, Stephen J; Jiang, Shan; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack

2016-10-01

Recent clinical and preclinical research has suggested that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized. To address this, we investigated the effects of Δ9-THC and CBD independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys (n = 6) performing a stop signal task (SST). Additionally, the development of tolerance to the effects of Δ9-THC on SST performance was evaluated by determining the effects of acutely administered Δ9-THC (0.1-3.2 mg/kg), during a 24-day chronic Δ9-THC treatment period with Δ9-THC alone or in combination with CBD. Results indicate that Δ9-THC (0.032-0.32 mg/kg) dose-dependently decreased go success but did not alter go reaction time (RT) or stop signal RT (SSRT); CBD (0.1-1.0 mg/kg) was without effect on all measures and, when coadministered in a 1:1 dose ratio, did not exacerbate or attenuate the effects of Δ9-THC. When coadministered in a 1:3 dose ratio, CBD (1.0 mg/kg) attenuated the disruptive effects of 0.32 mg/kg Δ9-THC but did not alter the effects of other Δ9-THC doses. Increases in ED50 values for the effects of Δ9-THC on SST performance were apparent during chronic Δ9-THC treatment, with little evidence for modification of changes in sensitivity by CBD. These results indicate that CBD, when combined with Δ9-THC in clinically available dose ratios, does not exacerbate and, under restricted conditions may even attenuate, Δ9-THC's behavioral effects. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

In Vitro Stability of Free and Glucuronidated Cannabinoids in Blood and Plasma Following Controlled Smoked Cannabis

PubMed Central

Karschner, Erin L.; Desrosiers, Nathalie A.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. METHODS Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (±2) weeks at 4 °C; and 1, 2, 4, 12, 26 (±2), and 52 (±4) weeks at −20 °C. Stability was assessed by Friedman test. RESULTS Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 °C and 12, 12, 26, 26, and 52 weeks at −20 °C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 °C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at −20 °C. CONCLUSIONS Blood and plasma samples should be stored at −20 °C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results. PMID:23519966

Large Eddy Simulations using oodlesDST

DTIC Science & Technology

2016-01-01

Research Agency DST-Group-TR-3205 ABSTRACT The oodlesDST code is based on OpenFOAM software and performs Large Eddy Simulations of......maritime platforms using a variety of simulation techniques. He is currently using OpenFOAM software to perform both Reynolds Averaged Navier-Stokes

Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption

PubMed Central

Llorente-Berzal, Alvaro; Puighermanal, Emma; Burokas, Aurelijus; Ozaita, Andrés; Maldonado, Rafael; Marco, Eva M.; Viveros, Maria-Paz

2013-01-01

Ecstasy is a drug that is usually consumed by young people at the weekends and frequently, in combination with cannabis. In the present study we have investigated the long-term effects of administering increasing doses of delta-9-tetrahydrocannabinol [THC; 2.5, 5, 10 mg/kg; i.p.] from postnatal day (pnd) 28 to 45, alone and/or in conjunction with 3,4-methylenedioxymethamphetamine [MDMA; two daily doses of 10 mg/kg every 5 days; s.c.] from pnd 30 to 45, in both male and female Wistar rats. When tested one day after the end of the pharmacological treatment (pnd 46), MDMA administration induced a reduction in directed exploration in the holeboard test and an increase in open-arm exploration in an elevated plus maze. In the long-term, cognitive functions in the novel object test were seen to be disrupted by THC administration to female but not male rats. In the prepulse inhibition test, MDMA-treated animals showed a decrease in prepulse inhibition at the most intense prepulse studied (80 dB), whereas in combination with THC it induced a similar decrease at 75 dB. THC decreased hippocampal Arc expression in both sexes, while in the frontal cortex this reduction was only evident in females. MDMA induced a reduction in ERK1/2 immunoreactivity in the frontal cortex of male but not female animals, and THC decreased prepro-orexin mRNA levels in the hypothalamus of males, although this effect was prevented when the animals also received MDMA. The results presented indicate that adolescent exposure to THC and/or MDMA induces long-term, sex-dependent psychophysiological alterations and they reveal functional interactions between the two drugs. PMID:24223797

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury.

PubMed

Hochhauser, Edith; Lahat, Eylon; Sultan, Maya; Pappo, Orit; Waldman, Maayan; Sarne, Yosef; Shainberg, Asher; Gutman, Mordechai; Safran, Michal; Ben Ari, Ziv

2015-01-01

Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC), a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg) in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. C57Bl Mice were studied in in vivo model of hepatic segmental (70%) ischemia for 60min followed by reperfusion for 6 hours. THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway), the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation). This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL) after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma. © 2015 S. Karger AG, Basel.

Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test.

PubMed

Ueland, Grethe Å; Methlie, Paal; Kellmann, Ralf; Bjørgaas, Marit; Åsvold, Bjørn O; Thorstensen, Ketil; Kelp, Oskar; Thordarson, Hrafnkell B; Mellgren, Gunnar; Løvås, Kristian; Husebye, Eystein S

2017-06-01

The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) ( n  = 49), incidentaloma ( n  = 152) and healthy controls ( n  = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST ( n  = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort ( n  = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol. Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS. © 2017 European Society of Endocrinology.

40 CFR 1065.303 - Summary of required calibration and verifications

Code of Federal Regulations, 2010 CFR

2010-07-01

.... THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: Upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers.... For THC FID analyzers: Upon initial installation, after major maintenance, and after FID optimization...

40 CFR 1065.660 - THC and NMHC determination.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 32 2010-07-01 2010-07-01 false THC and NMHC determination. 1065.660... CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC and NMHC determination. (a) THC determination and THC/CH 4 initial contamination corrections. (1) If we require you to...

40 CFR 1065.303 - Summary of required calibration and verifications

Code of Federal Regulations, 2011 CFR

2011-07-01

.... THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: Upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers.... For THC FID analyzers: Upon initial installation, after major maintenance, and after FID optimization...

The Coast Artillery Journal. Volume 71, Number 2, 1929

DTIC Science & Technology

1929-08-01

Although airplancs had bcen used in the minor Balkan -Wars in thc pcriod just pre- ceding thc ,Yorld \\\\’ar and had becn tcntatiycly fired on by...wedges or pins. Incidcntally all loose pieces arc fastencd to thc caniagc with chains. 1\\. targct moying at thc spced of an airplanc has a widc...rangc of possiblc mancU\\’cr <lUt’jng thc timc of flight of thc projectilc .. \

Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys.

PubMed

ElSohly, M A; Stanford, D F; Harland, E C; Hikal, A H; Walker, L A; Little, T L; Rider, J N; Jones, A B

1991-10-01

Oral administration of delta-9-tetrahydrocannabinal (delta 9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. delta 9-THC-Hemisuccinate was formulated as a prodrug for delta 9-THC in suppositories using Witepsol H15 base. The bioavailability of delta 9-THC from this formulation was evaluated in monkeys. The plasma levels of delta 9-THC and its metabolite 11-nor-delta 9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of delta 9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for delta 9-THC in the body to be 3 h following iv administration of delta 9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the delta 9-THC hemisuccinate. The observed rectal bioavailability of delta 9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

Separate and combined effects of gabapentin and Δ9-THC in humans discriminating Δ9-THC

PubMed Central

Lile, Joshua A.; Wesley, Michael J.; Kelly, Thomas H.; Hays, Lon R.

2015-01-01

The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating Δ9-THC using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received gabapentin (600 and 1200 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ9-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate and impaired psychomotor performance. Both doses of gabapentin substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of Δ9-THC leftward/upward, and combinations of Δ9-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to Δ9-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids. PMID:26313650

Thermohaline circulation: a missing equation and its climate-change implications

NASA Astrophysics Data System (ADS)

Ou, Hsien-Wang

2018-01-01

We formulate a box model of coupled ocean-atmosphere to examine the differential fields interactive with the thermohaline circulation (THC) and their response to global warming. We discern a robust convective bound on the atmospheric heat transport, which would divide the climate regime into warm and cold branches; but unlike the saline mode of previous box models, the cold state, if allowed, has the same-signed—though weaker—density contrast and THC as the present climate, which may explain its emergence from coupled general circulation models. We underscore the nondeterminacy of the THC due to random eddy shedding and apply the fluctuation theorem to constrain the shedding rate, thus closing the problem. The derivation reveals an ocean propelled toward the maximum entropy production (MEP) on millennial timescale (termed "MEP-adjustment"), the long timescale arising from the compounding effect of microscopic fluctuations in the shedding rate and their slight probability bias. Global warming may induce hysteresis between the two branches, like that seen in GCMs, but the cold transition is far more sensitive to the moistening than the heating effects as the latter would be countered by the hydrological feedback. The uni- or bi-modality of the current state—hence whether the THC may recover after the cold transition—depends on the global-mean convective flux and may not be easily assessed due to its observed uncertainty.

Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

PubMed

Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O

Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28years, body weight: 62.5-91.0kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V 1 ). Normal ALT concentration (6.0 to 45.0IU/l) demonstrated a statistically significant correlation with k 10 . The mean values (%Relative Standard Error (RSE)) for k 10 , k 12 , k 21 , k 23 , k 32 and V 1 were 0.408h -1 (48.8%), 4.070h -1 (21.4%), 0.022h -1 (27.0%), 1.070h -1 (14.3%), 1.060h -1 (16.7%) and 19.10L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k 10 has been described and request further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Does Daylight Savings Time encourage physical activity?

PubMed

Zick, Cathleen D

2014-07-01

Extending Daylight Savings Time (DST) has been identified as a policy intervention that may encourage physical activity. However, there has been little research on the question of if DST encourages adults to be more physically active. Data from residents of Arizona, Colorado, New Mexico, and Utah ages 18-64 who participated in the 2003-2009 American Time Use Survey are used to assess whether DST is associated with increased time spent in moderate-to-vigorous physical activity (MVPA). The analysis capitalizes on the natural experiment created because Arizona does not observe DST. Both bivariate and multivariate analyses indicate that shifting 1 hour of daylight from morning to evening does not impact MVPA of Americans living in the southwest. While DST may affect the choices people make about the timing and location of their sports/recreational activities, the potential for DST to serve as a broad-based intervention that encourages greater sports/recreation participation is not supported by this analysis. Whether this null effect would persist in other climate situations is an open question.

Time Delay Between Dst Index and Magnetic Storm Related Structure in the Solar Wind

NASA Technical Reports Server (NTRS)

Osherovich, Vladimir A.; Fainberg, Joseph

2015-01-01

Benson et al. (2015, this volume) selected 10 large magnetic storms, with associated Dst minimum values less than or equal to -100 nT, for which high-latitude topside ionospheric electron density profiles are available from topside-sounder satellites. For these 10 storms, we performed a superposition of Dst and interplanetary parameters B, v, N(sub p) and T(sub p). We have found that two interplanetary parameters, namely B and v, are sufficient to reproduce Dst with correlation coefficient cc approximately 0.96 provided that the interplanetary parameter times are taken 0.15 days earlier than the associated Dst times. Thus we have found which part of the solar wind is responsible for each phase of the magnetic storm. This result is also verified for individual storms as well. The total duration of SRS (storm related structure in the solar wind) is 4 - 5 days which is the same as the associated Dst interval of the magnetic storm.

Bond energies of ThO+ and ThC+: A guided ion beam and quantum chemical investigation of the reactions of thorium cation with O2 and CO

NASA Astrophysics Data System (ADS)

Cox, Richard M.; Citir, Murat; Armentrout, P. B.; Battey, Samuel R.; Peterson, Kirk A.

2016-05-01

Kinetic energy dependent reactions of Th+ with O2 and CO are studied using a guided ion beam tandem mass spectrometer. The formation of ThO+ in the reaction of Th+ with O2 is observed to be exothermic and barrierless with a reaction efficiency at low energies of k/kLGS = 1.21 ± 0.24 similar to the efficiency observed in ion cyclotron resonance experiments. Formation of ThO+ and ThC+ in the reaction of Th+ with CO is endothermic in both cases. The kinetic energy dependent cross sections for formation of these product ions were evaluated to determine 0 K bond dissociation energies (BDEs) of D0(Th+-O) = 8.57 ± 0.14 eV and D0(Th+-C) = 4.82 ± 0.29 eV. The present value of D0 (Th+-O) is within experimental uncertainty of previously reported experimental values, whereas this is the first report of D0 (Th+-C). Both BDEs are observed to be larger than those of their transition metal congeners, TiL+, ZrL+, and HfL+ (L = O and C), believed to be a result of lanthanide contraction. Additionally, the reactions were explored by quantum chemical calculations, including a full Feller-Peterson-Dixon composite approach with correlation contributions up to coupled-cluster singles and doubles with iterative triples and quadruples (CCSDTQ) for ThC, ThC+, ThO, and ThO+, as well as more approximate CCSD with perturbative (triples) [CCSD(T)] calculations where a semi-empirical model was used to estimate spin-orbit energy contributions. Finally, the ThO+ BDE is compared to other actinide (An) oxide cation BDEs and a simple model utilizing An+ promotion energies to the reactive state is used to estimate AnO+ and AnC+ BDEs. For AnO+, this model yields predictions that are typically within experimental uncertainty and performs better than density functional theory calculations presented previously.

Daylight savings time and myocardial infarction.

PubMed

Sandhu, Amneet; Seth, Milan; Gurm, Hitinder S

2014-01-01

Prior research has shown a transient increase in the incidence of acute myocardial infarction (AMI) after daylight savings time (DST) in the spring as well as a decrease in AMI after returning to standard time in the fall. These findings have not been verified in a broader population and if extant, may have significant public health and policy implications. We assessed changes in admissions for AMI undergoing percutaneous coronary intervention (PCI) in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) database for the weeks following the four spring and three fall DST changes between March 2010 and September 2013. A negative binomial regression model was used to adjust for trend and seasonal variation. There was no difference in the total weekly number of PCIs performed for AMI for either the fall or spring time changes in the time period analysed. After adjustment for trend and seasonal effects, the Monday following spring time changes was associated with a 24% increase in daily AMI counts (p=0.011), and the Tuesday following fall changes was conversely associated with a 21% reduction (p=0.044). No other weekdays in the weeks following DST changes demonstrated significant associations. In the week following the seasonal time change, DST impacts the timing of presentations for AMI but does not influence the overall incidence of this disease.

[Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

PubMed

Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

2014-03-01

To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography Study

PubMed Central

Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M. A.; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

2013-01-01

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID:23936196

Tetrahydrocannabinols in clinical and forensic toxicology.

PubMed

Kochanowski, Maciej; Kała, Maria

2005-01-01

Cannabinoids are the natural constituents of marihuana (cannabis). The main of them are delta9-tetrahydrocannabinol (9THC)--psychoactive agent, cannabinol (CBN) and cannabidiol (CBD). Cannabis is administered either by smoking or orally. 9THC potency and duration of action as well as its and two of its major metabolites concentrations in organism highly depend on the route of administration. A single active dose of 9THC is estimated on 520 mg. 9THC is rapidly metabolised. It is hydroxylated to an active metabolite, I1 -hydroxy-delta9-tetrahydro-cannabinol (11-OH-THC), then oxidised to an inactive 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THCCOOH), which is conjugated with glucuronic acid and predominantly excreted in the urine. The maximum psychological effect persists for 4-6 h after administration despite of very low 9THC blood concentrations. 9THC plasma concentration declined to values of 2-3 ng/ml during 3-4 h after smoking. Such a low concentration of the active compound in human organism create a demand for use of sensitive analytical methods for detection and determination of 9THC and its metabolites. The most effective techniques for 9THC and related compounds determination in biological material are chromatographic ones (gas and liquid) with mass spectrometric detection and different ionization modes. 9THC and its two metabolites (11-OH-THC and THCCOOH) are present in blood and hair, 9THC in saliva, and THCCOOH in urine. 9THC and related compounds are determined in autopsy material, although deaths by overdose of cannabis are exceptionally rare. Fatalities happen most often after intravenous injection of hashish oil. 9THC and its metabolites determination in different biological materials gives the basis for a wide interpretation of analytical results for clinical and forensic toxicology purposes.

Blood levels do not predict behavioral or physiological effects of Δ9-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure

PubMed Central

Ginsburg, Brett C.; Hruba, Lenka; Zaki, Armia; Javors, Martin; McMahon, Lance R.

2014-01-01

Background Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ9-tetrahydrocannabinol (THC) or its metabolites could be used to substantiate impairment, particularly related to behavioral tasks such as driving. However, because marked tolerance develops to behavioral effects of THC, the applicability of a particular threshold of blood THC as an index of impairment in people with different patterns of use remains unclear. Studies relevant to this issue are difficult to accomplish in humans, as prior drug exposure is difficult to control. Methods Here, effects of THC to decrease rectal temperature and operant response rate compared to levels of THC and its metabolites were studied in blood in two groups of monkeys: one received intermittent treatment with THC (0.1 mg/kg i.v.) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. Results In monkeys with intermittent THC exposure, a single dose of THC (3.2 mg/kg s.c.) decreased rectal temperature and response rate. The same dose did not affect response rate or rectal temperature in chronically exposed monkeys, indicative of greater tolerance. In both groups, blood levels of THC peaked 20–60 min post-injection and had a similar half life of elimination, indicating no tolerance to the pharmacokinetics of THC. Notably, in both groups, the behavioral effects of THC were not apparent when blood levels were maximal (20-min post-administration). Conclusion These data indicate that thresholds for blood levels of THC do not provide a consistent index of behavioral impairment across individuals with different patterns of THC exposure. PMID:24703610

Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.

PubMed

Todd, Stephanie M; Zhou, Cilla; Clarke, David J; Chohan, Tariq W; Bahceci, Dilara; Arnold, Jonathon C

2017-02-01

The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 33 2014-07-01 2014-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 34 2012-07-01 2012-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 34 2013-07-01 2013-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 33 2011-07-01 2011-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and THC/CH 4 initial contamination corrections. (1) If we...

Analysis of the Variable Pressure Growth Chamber using the CASE/A simulation package

NASA Technical Reports Server (NTRS)

Mcfadden, Carl D.; Edeen, Marybeth A.

1992-01-01

A computer simulation of the Variable Pressure Growth Chamber (VPGC), located at the NASA Johnson Space Center, has been developed using the Computer Aided Systems Engineering and Analysis (CASE/A) package. The model has been used to perform several analyses of the VPGC. The analyses consisted of a study of the effects of a human metabolic load on the VPGC and a study of two new configurations for the temperature and humidity control (THC) subsystem in the VPGC. The objective of the human load analysis was to study the effects of a human metabolic load on the air revitalization and THC subsystems. This included the effects on the quantity of carbon dioxide injected and oxygen removed from the chamber and the effects of the additional sensible and latent heat loads. The objective of the configuration analysis was to compare the two new THC configurations against the current THC configuration to determine which had the best performance.

Total hydrocarbon content (THC) testing in liquid oxygen (LOX) systems

NASA Astrophysics Data System (ADS)

Meneghelli, B. J.; Obregon, R. E.; Ross, H. R.; Hebert, B. J.; Sass, J. P.; Dirschka, G. E.

2015-12-01

The measured Total Hydrocarbon Content (THC) levels in liquid oxygen (LOX) systems at Stennis Space Center (SSC) have shown wide variations. Examples of these variations include the following: 1) differences between vendor-supplied THC values and those obtained using standard SSC analysis procedures; and 2) increasing THC values over time at an active SSC test stand in both storage and run vessels. A detailed analysis of LOX sampling techniques, analytical instrumentation, and sampling procedures will be presented. Additional data obtained on LOX system operations and LOX delivery trailer THC values during the past 12-24 months will also be discussed. Field test results showing THC levels and the distribution of the THC's in the test stand run tank, modified for THC analysis via dip tubes, will be presented.

Total Hydrocarbon Content (THC) Testing in Liquid Oxygen (LOX)

NASA Technical Reports Server (NTRS)

Meneghelli, B. J.; Obregon, R. E.; Ross, H. R.; Hebert, B. J.; Sass, J. P.; Dirschka, G. E.

2016-01-01

The measured Total Hydrocarbon Content (THC) levels in liquid oxygen (LOX) systems at Stennis Space Center (SSC) have shown wide variations. Examples of these variations include the following: 1) differences between vendor-supplied THC values and those obtained using standard SSC analysis procedures; and 2) increasing THC values over time at an active SSC test stand in both storage and run vessels. A detailed analysis of LOX sampling techniques, analytical instrumentation, and sampling procedures will be presented. Additional data obtained on LOX system operations and LOX delivery trailer THC values during the past 12-24 months will also be discussed. Field test results showing THC levels and the distribution of the THC's in the test stand run tank, modified for THC analysis via dip tubes, will be presented.

Comparison of Cannabinoid Concentrations in Plasma, Oral Fluid and Urine in Occasional Cannabis Smokers After Smoking Cannabis Cigarette.

PubMed

Marsot, Amélie; Audebert, Christine; Attolini, Laurence; Lacarelle, Bruno; Micallef, Joelle; Blin, Olivier

A randomized cross-over, double blind placebo controlled study of smoked cannabis was carried out on occasional cannabis smokers. The objective of this research was to describe the pharmacokinetic parameters of THC and its metabolites in plasma, oral fluid and urine, from samples obtained simultaneously to provide estimations of THC and metabolites concentrations after smoking a cannabis cigarette. Blood, oral fluid and urine samples were collected until up to 72 h after smoking the cannabis cigarette (4% of delta-9-tetrathydrocannabinol (THC)). THC, 11-OH-THC and THC-COOH were analyzed by gas-chromatography-mass spectrometry. Pharmacokinetic parameters were estimated from these data. Eighteen male healthy adults participated in the study. In total, 560 plasma, 288 oral fluid and 448 urine samples were quantified for cannabinoids. Plasma, oral fluid and urine pharmacokinetic parameters were calculated. A wide range of median THC Cmax (1.6-160.0 µg/L and 55.4-123120.0 µg/L in plasma and oral fluid, respectively), 11-OH-THC Cmax (0-11.1 µg/L in plasma) and THC-COOH Cmax (1.0-56.3 µg/L in plasma) was observed. When expressed as a percentage of the total available THC dose, and corrected for molar equivalents, mean percentage of total THC dose excreted was 1.9 +/-2.5 % with range of 0.2-7.5%. This high inter-individual variability was also observed on other calculated pharmacokinetic parameters. Prediction of plasma THC concentration from THC oral fluid concentration or from THC-COOH urinary concentrations is not feasible due to the large variations observed. The results from this study support the assumption that a positive oral fluid THC result or a positive urine fluid result are indicative of a recent cannabis exposure. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Acute and chronic effects of cannabidiol on Δ9-tetrahydrocannabinol (Δ9-THC)-induced disruption in stop signal task performance

PubMed Central

Jacobs, David S.; Kohut, Stephen J.; Jiang, Shan; Nikas, Spyros P.; Makriyannis, Alexandros; Bergman, Jack

2016-01-01

Recent clinical and preclinical research suggests that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized. To address this, the effects of Δ9-THC and CBD were investigated independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys (n=6) performing a stop signal task (SST). Additionally, the development of tolerance to the effects of THC on SST performance was evaluated by determining the effects of acutely administered Δ9-THC (0.1-3.2 mg/kg), during a 24-day chronic Δ9-THC treatment period with Δ9-THC alone or with CBD. Results indicate that Δ9-THC (0.032 - 0.32 mg/kg) dose-dependently decreased ‘go’ success but did not alter ‘go’ reaction time or stop signal reaction time (SSRT); CBD (0.1-1.0 mg/kg) was without effect on all measures and, when co-administered in a 1:1 dose-ratio, did not exacerbate or attenuate the effects of Δ9-THC. When co-administered in a 1:3 dose-ratio, CBD (1.0 mg/kg) attenuated the disruptive effects of 0.32 mg/kg Δ9-THC but did not alter the effects of other Δ9-THC doses. Increases in ED50 values for the effects of Δ9-THC on SST performance were apparent during chronic Δ9-THC treatment, with little evidence for modification of changes in sensitivity by CBD. These results indicate that CBD, when combined with THC in clinically available dose-ratios does not exacerbate and, under restricted conditions, may even attenuate Δ9-THC’s behavioral effects. PMID:27690502

THC and CBD in blood samples and seizures in Norway: Does CBD affect THC-induced impairment in apprehended subjects?

PubMed

Havig, Stine Marie; Høiseth, Gudrun; Strand, Maren Cecilie; Karinen, Ritva Anneli; Brochmann, Gerd-Wenche; Strand, Dag Helge; Bachs, Liliana; Vindenes, Vigdis

2017-07-01

Several publications have suggested increasing cannabis potency over the last decade, which, together with lower amounts of cannabidiol (CBD), could contribute to an increase in adverse effects after cannabis smoking. Naturalistic studies on tetrahydrocannabinol (THC) and CBD in blood samples are, however, missing. This study aimed to investigate the relationship between THC- and CBD concentrations in blood samples among cannabis users, and to compare cannabinoid concentrations with the outcome of a clinical test of impairment (CTI) and between traffic accidents and non-accident driving under the influence of drugs (DUID)-cases. Assessment of THC- and CBD contents in cannabis seizures was also included. THC- and CBD concentrations in blood samples from subjects apprehended in Norway from April 2013-April 2015 were included (n=6134). A CTI result was compared with analytical findings in cases where only THC and/or CBD were detected (n=705). THC- and CBD content was measured in 41 cannabis seizures. Among THC-positive blood samples, 76% also tested positive for CBD. There was a strong correlation between THC- and CBD concentrations in blood samples (Pearson's r=0.714, p<0.0005). Subjects judged as impaired by a CTI had significantly higher THC- (p<0.001) and CBD (p=0.008) concentrations compared with not impaired subjects, but after multivariate analyses, impairment could only be related to THC concentration (p=0.004). Analyzing seizures revealed THC/CBD ratios of 2:1 for hashish and 200:1 for marijuana. More than ¾ of the blood samples testing positive for THC, among subjects apprehended in Norway, also tested positive for CBD, suggesting frequent consumption of high CBD cannabis products. The simultaneous presence of CBD in blood does, however, not appear to affect THC-induced impairment on a CTI. Seizure sample analysis did not reveal high potency cannabis products, and while CBD content appeared high in hashish, it was almost absent in marijuana. Copyright © 2017. Published by Elsevier B.V.

Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

PubMed

Keating, Gillian M

2017-04-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex ® , nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Twelve weeks' therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial. Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice. Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD. THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized. THC/CBD has low abuse potential and a low risk of psychoactive effects. In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.

Second-line drug susceptibility breakpoints for Mycobacterium tuberculosis using the MODS assay.

PubMed

Trollip, A P; Moore, D; Coronel, J; Caviedes, L; Klages, S; Victor, T; Romancenco, E; Crudu, V; Ajbani, K; Vineet, V P; Rodrigues, C; Jackson, R L; Eisenach, K; Garfein, R S; Rodwell, T C; Desmond, E; Groessl, E J; Ganiats, T G; Catanzaro, A

2014-02-01

To establish breakpoint concentrations for the fluoroquinolones (moxifloxacin [MFX] and ofloxacin [OFX]) and injectable second-line drugs (amikacin [AMK], kanamycin [KM] and capreomycin [CPM]) using the microscopic observation drug susceptibility (MODS) assay. A multinational study conducted between February 2011 and August 2012 in Peru, India, Moldova and South Africa. In the first phase, breakpoints for the fluoroquinolones and injectable second-line drugs (n = 58) were determined. In the second phase, MODS second-line drug susceptibility testing (DST) as an indirect test was compared to MGIT™ DST (n = 89). In the third (n = 30) and fourth (n = 156) phases, we determined the reproducibility and concordance of MODS second-line DST directly from sputum. Breakpoints for MFX (0.5 μg/ml), OFX (1 μg/ml), AMK (2 μg/ml), KM (5 μg/ml) and CPM (2.5 μg/ml) were determined. In all phases, MODS results were highly concordant with MGIT DST. The few discrepancies suggest that the MODS breakpoint concentrations for some drugs may be too low. MODS second-line DST yielded comparable results to MGIT second-line DST, and is thus a promising alternative. Further studies are needed to confirm the accuracy of the drug breakpoints and the reliability of MODS second-line DST as a direct test.

Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study.

PubMed

Swords, Ronan T; Azzam, Diana; Al-Ali, Hassan; Lohse, Ines; Volmar, Claude-Henry; Watts, Justin M; Perez, Aymee; Rodriguez, Ana; Vargas, Fernando; Elias, Roy; Vega, Francisco; Zelent, Arthur; Brothers, Shaun P; Abbasi, Taher; Trent, Jonathan; Rangwala, Shaukat; Deutsch, Yehuda; Conneally, Eibhlin; Drusbosky, Leylah; Cogle, Christopher R; Wahlestedt, Claes

2018-01-01

A precision medicine approach is appealing for use in AML due to ease of access to tumor samples and the significant variability in the patients' response to treatment. Attempts to establish a precision medicine platform for AML, however, have been unsuccessful, at least in part due to the use of small compound panels and having relatively slow turn over rates, which restricts the scope of treatment and delays its onset. For this pilot study, we evaluated a cohort of 12 patients with refractory AML using an ex vivo drug sensitivity testing (DST) platform. Purified AML blasts were screened with a panel of 215 FDA-approved compounds and treatment response was evaluated after 72h of exposure. Drug sensitivity scoring was reported to the treating physician, and patients were then treated with either DST- or non-DST guided therapy. We observed survival benefit of DST-guided therapy as compared to the survival of patients treated according to physician recommendation. Three out of four DST-treated patients displayed treatment response, while all of the non-DST-guided patients progressed during treatment. DST rapidly and effectively provides personalized treatment recommendations for patients with refractory AML. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2014 CFR

2014-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C = THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC = THC concentration (uncorrected...

Environmental modelling of use of treated organic waste on agricultural land: a comparison of existing models for life cycle assessment of waste systems.

PubMed

Hansen, Trine Lund; Christensen, Thomas Højlund; Schmidt, Sonia

2006-04-01

Modelling of environmental impacts from the application of treated organic municipal solid waste (MSW) in agriculture differs widely between different models for environmental assessment of waste systems. In this comparative study five models were examined concerning quantification and impact assessment of environmental effects from land application of treated organic MSW: DST (Decision Support Tool, USA), IWM (Integrated Waste Management, U.K.), THE IFEU PROJECT (Germany), ORWARE (ORganic WAste REsearch, Sweden) and EASEWASTE (Environmental Assessment of Solid Waste Systems and Technologies, Denmark). DST and IWM are life cycle inventory (LCI) models, thus not performing actual impact assessment. The DST model includes only one water emission (biological oxygen demand) from compost leaching in the results and IWM considers only air emissions from avoided production of commercial fertilizers. THE IFEU PROJECT, ORWARE and EASEWASTE are life cycle assessment (LCA) models containing more detailed land application modules. A case study estimating the environmental impacts from land application of 1 ton of composted source sorted organic household waste was performed to compare the results from the different models and investigate the origin of any difference in type or magnitude of the results. The contributions from the LCI models were limited and did not depend on waste composition or local agricultural conditions. The three LCA models use the same overall approach for quantifying the impacts of the system. However, due to slightly different assumptions, quantification methods and environmental impact assessment, the obtained results varied clearly between the models. Furthermore, local conditions (e.g. soil type, farm type, climate and legal regulation) and waste composition strongly influenced the results of the environmental assessment.

Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns.

PubMed

Kampa-Schittenhelm, Kerstin Maria; Salitzky, Olaf; Akmut, Figen; Illing, Barbara; Kanz, Lothar; Salih, Helmut Rainer; Schittenhelm, Marcus Matthias

2016-01-16

It has been previously demonstrated in several cancer models, that Dronabinol (THC) may have anti-tumor activity--however, controversial data exists for acute leukemia. We have anecdotal evidence that THC may have contributed to disease control in a patient with acute undifferentiated leukemia. To test this hypothesis, we evaluated the antileukemic efficacy of THC in several leukemia cell lines and native leukemia blasts cultured ex vivo. Expression analysis for the CB1/2 receptors was performed by Western immunoblotting and flow cytometry. CB-receptor antagonists as well as a CRISPR double nickase knockdown approach were used to evaluate for receptor specificity of the observed proapoptotic effects. Meaningful antiproliferative as well as proapoptotic effects were demonstrated in a subset of cases--with a preference of leukemia cells from the lymphatic lineage or acute myeloid leukemia cells expressing lymphatic markers. Induction of apoptosis was mediated via CB1 as well as CB2, and expression of CB receptors was a prerequisite for therapy response in our models. Importantly, we demonstrate that antileukemic concentrations are achievable in vivo. Our study provides rigorous data to support clinical evaluation of THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.

The effects of Δ9-Tetrahydrocannabinole treatment on gonadal micro-vascularization and affected fertility examined by SEM and 3D-morphometry

NASA Astrophysics Data System (ADS)

Erlbacher, K. M. T.; Minnich, B.

2015-10-01

The present study focuses on the effects of Δ9-tetrahydrocannabinol (THC) on the reproductive system in nude rats with special emphasis on how Δ9-THC impacts the vascularization of testes which in turn indirectly influences fertility. Basically, Δ9-tetrahydrocannabinol (THC) causes not only negative (psychoactive) effects in the human body as cannabinole administration in medical use (dose-dependent) offers multiple new treatment opportunities such as pain relief or containment of various cancers. Concerning the reproductive system it strongly influences CB-receptors along the hypothalamic-pituitary-gonadal axis resulting in reduced plasma testosterone levels. There is also altered sperm quality parameters reported such as sperm motility or sperm count. On the other hand Δ9-THC effects endothelial growth factors (VEGF, Ang-1 etc.) respectively acts on their specific receptors which in turn modify angiogenesis and vascularization of tissues and organs (e.g. tumorous tissues). This leads to new therapeutical strategies in the suppression of various cancers by inhibiting (neo-)vascularization and in turn famishment of tumorous tissues (lack of nutrition supply). Here we studied the micro-vascularization of gonads in a long-term THC-treated nude rat model by vascular corrosion casting, SEM and 3D-morphometry.

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2012 CFR

2012-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2013 CFR

2013-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2011 CFR

2011-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2010 CFR

2010-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

Radioimmunoanalysis of delta-9-THC in blood by means of an /sup 125/I tracer. [Delta-9-Tetrahydrocannabinol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Owens, S.M.; McBay, A.J.; Reisner, H.M.

A radioimmunoassay for delta-9-THC in plasma, whole blood, or hemolyzed blood specimens has been presented. Samples and standards were diluted with methanol and centrifuged. An aliquot of the supernatant fluid was incubated with RIA buffer, /sup 125/I-labeled delta-8-THC and rabbit anti-THC serum. Solid phase goat anti-rabbit immunoglobulins were added to separate bound from free THC. After centrifugation the supernatant fluid was aspirated and the radioactivity of the precipitate was counted in a gamma counter. The concentration of THC was calculated from a standard curve using the logit-log transformation of the average counts of duplicate tubes. The assay had several advantages.more » Methanol dilution gave better results than direct analysis. The /sup 125/I-labeled THC had high specific activity and could be counted in a gamma counter. The immunological separation of antibody-bound THC from free THC was better than separation techniques using ammonium sulfate and activated charcoal. THC was determined in 0.1 ml of sample with a sensitivity of 1.5 ng/ml in plasma and 3.0 ng/ml in hemolyzed blood.« less

Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.

PubMed

Karschner, Erin L; Darwin, W David; Goodwin, Robert S; Wright, Stephen; Huestis, Marilyn A

2011-01-01

Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Enzymatic Degradation of Aromatic and Aliphatic Polyesters by P. pastoris Expressed Cutinase 1 from Thermobifida cellulosilytica

PubMed Central

Gamerith, Caroline; Vastano, Marco; Ghorbanpour, Sahar M.; Zitzenbacher, Sabine; Ribitsch, Doris; Zumstein, Michael T.; Sander, Michael; Herrero Acero, Enrique; Pellis, Alessandro; Guebitz, Georg M.

2017-01-01

To study hydrolysis of aromatic and aliphatic polyesters cutinase 1 from Thermobifida cellulosilytica (Thc_Cut1) was expressed in P. pastoris. No significant differences between the expression of native Thc_Cut1 and of two glycosylation site knock out mutants (Thc_Cut1_koAsn and Thc_Cut1_koST) concerning the total extracellular protein concentration and volumetric activity were observed. Hydrolysis of poly(ethylene terephthalate) (PET) was shown for all three enzymes based on quantification of released products by HPLC and similar concentrations of released terephthalic acid (TPA) and mono(2-hydroxyethyl) terephthalate (MHET) were detected for all enzymes. Both tested aliphatic polyesters poly(butylene succinate) (PBS) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) were hydrolyzed by Thc_Cut1 and Thc_Cut1_koST, although PBS was hydrolyzed to significantly higher extent than PHBV. These findings were also confirmed via quartz crystal microbalance (QCM) analysis; for PHBV only a small mass change was observed while the mass of PBS thin films decreased by 93% upon enzymatic hydrolysis with Thc_Cut1. Although both enzymes led to similar concentrations of released products upon hydrolysis of PET and PHBV, Thc_Cut1_koST was found to be significantly more active on PBS than the native Thc_Cut1. Hydrolysis of PBS films by Thc_Cut1 and Thc_Cut1_koST was followed by weight loss and scanning electron microscopy (SEM). Within 96 h of hydrolysis up to 92 and 41% of weight loss were detected with Thc_Cut1_koST and Thc_Cut1, respectively. Furthermore, SEM characterization of PBS films clearly showed that enzyme tretment resulted in morphological changes of the film surface. PMID:28596765

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences.

PubMed

Wong, Alexander; Keats, Kirily; Rooney, Kieron; Hicks, Callum; Allsop, David J; Arnold, Jonathon C; McGregor, Iain S

2014-10-01

Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences. Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation. Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THC-COOH) also measured. Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise. These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.

Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers.

PubMed

Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schroeder, Jennifer R; Schwope, David M; Kelly, Deanna L; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

2013-01-01

Δ9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence. Human laboratory studies of oral THC have not shown consistent effects on sleep. We prospectively evaluated self-reported sleep parameters during controlled oral THC administration to research volunteers. Thirteen male chronic daily cannabis smokers (mean ± SD age 24.6± 3.7 years, self-reported smoking frequency of 5.5 ± 5.9 (range 1-24) joint-equivalents daily at study entry) were administered oral THC doses (20 mg) around-the-clock for 7 days (40-120 mg daily) starting the afternoon after admission. The St. Mary's Hospital Sleep Questionnaire was completed every morning. Plasma THC and 11-OH-THC (active metabolite) concentrations were measured in venous blood samples collected every evening. Changes in sleep characteristics over time and associations between sleep characteristics and plasma cannabinoid concentrations were evaluated with repeated measures mixed linear regression. Higher evening THC and 11-OH-THC concentrations were significantly associated with shorter sleep latency, less difficulty falling asleep, and more daytime sleep the following day. In contrast, the duration of calculated and self-reported nighttime sleep decreased slightly (3.54 and 5.34 minutes per night, respectively) but significantly during the study. These findings suggest that tolerance to the somnolent effects of THC may have occurred, but results should be considered preliminary due to design limitations. Somnolence from oral THC may dissipate with chronic, high-dose use. This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment. (Am J Addict 2013;22:510-514). Copyright © American Academy of Addiction Psychiatry.

Identification of Recent Cannabis Use: Whole-Blood and Plasma Free and Glucuronidated Cannabinoid Pharmacokinetics following Controlled Smoked Cannabis Administration

PubMed Central

Schwope, David M.; Karschner, Erin L.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Δ9-Tetrahydrocannabinol (THC) is the most frequently observed illicit drug in investigations of accidents and driving under the influence of drugs. THC-glucuronide has been suggested as a marker of recent cannabis use, but there are no blood data following controlled THC administration to test this hypothesis. Furthermore, there are no studies directly examining whole-blood cannabinoid pharmacokinetics, although this matrix is often the only available specimen. METHODS Participants (9 men, 1 woman) resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. We quantified THC, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide and THCCOOH-glucuronide directly in whole blood and plasma by liquid chromatography/ tandem mass spectrometry within 24 h of collection to obviate stability issues. RESULTS Median whole blood (plasma) observed maximum concentrations (Cmax) were 50 (76), 6.4 (10), 41 (67), 1.3 (2.0), 2.4 (3.6), 89 (190), and 0.7 (1.4) μg/L 0.25 h after starting smoking for THC, 11-OH-THC, THCCOOH, CBD, CBN, and THCCOOH-glucuronide, respectively, and 0.5 h for THC-glucuronide. At observed Cmax, whole-blood (plasma) detection rates were 60% (80%), 80% (90%), and 50% (80%) for CBD, CBN, and THC-glucuronide, respectively. CBD and CBN were not detectable after 1 h in either matrix (LOQ 1.0 μg/L). CONCLUSIONS Human whole-blood cannabinoid data following cannabis smoking will assist whole blood and plasma cannabinoid interpretation, while furthering identification of recent cannabis intake. PMID:21836075

Neural correlates of interactions between cannabidiol and Δ(9) -tetrahydrocannabinol in mice: implications for medical cannabis.

PubMed

Todd, S M; Arnold, J C

2016-01-01

It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ(9) -tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study was to investigate whether CBD modulated the functional effects and c-Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Male C57BL/6 mice were treated with vehicle, CBD, THC or a combination of CBD and THC (10 mg·kg(-1) i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety-related behaviour, body temperature and brain c-Fos expression (a marker of neuronal activation). CBD potentiated THC-induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c-Fos expression in 11 of the 35 brain regions studied. CBD co-administration suppressed THC-induced c-Fos expression in six of these brain regions. This effect was most pronounced in the medial preoptic nucleus and lateral periaqueductal gray. Treatment with CBD alone diminished c-Fos expression only in the central nucleus of the amygdala compared with vehicle. These data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC. © 2015 The British Pharmacological Society.

Cortisol responses on the dexamethasone suppression test among women with Bulimia-spectrum eating disorders: associations with clinical symptoms.

PubMed

Bruce, Kenneth R; Steiger, Howard; Israël, Mimi; Groleau, Patricia; Ng Ying Kin, N M K; Ouellette, Anne-Sophie; Sycz, Lindsay; Badawi, Ghislaine

2012-08-07

Evidence associates Bulimia Nervosa (BN) with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis, but the clinical implications of such alterations need to be better understood. We contrasted cortisol responses to the dexamethasone suppression test (DST) in bulimic and non-eating disordered women and examined relationships among DST cortisol responses, eating symptoms and co-morbid disturbances. Sixty women with Bulimia Spectrum (BS) Disorders (either BN or normal weight Eating Disorder NOS with regular binge eating or purging) and 54 non-eating disordered women of similar age and body mass index participated in a 0.5 mg DST, and completed interviews and questionnaires assessing eating symptoms and co-morbid psychopathology. Compared with the normal-eater group, the BS women demonstrated significantly less DST suppression. Among BS women, DST non-suppression was associated with more severe depression, anxiety and eating preoccupations. Our findings show BS women to show less DST suppression compared to normal eater women, and results link extent of non-suppression, in BS individuals, to severity of depression, anxiety and eating preoccupations. Copyright © 2012 Elsevier Inc. All rights reserved.

Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration.

PubMed

Milman, Garry; Barnes, Allan J; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deana L; Gorelick, David A; Huestis, Marilyn A

2011-08-01

Oral fluid (OF) is an increasingly accepted matrix for drug testing programs, but questions remain about its usefulness for monitoring cannabinoids. Expectorated OF specimens (n = 360) were obtained from 10 adult daily cannabis smokers before, during, and after 37 20-mg oral Δ(9)-tetrahydrocannabinol (THC) doses over 9 days to characterize cannabinoid disposition in this matrix. Specimens were extracted and analyzed by gas chromatography-mass spectrometry with electron-impact ionization for THC, 11-hydroxy-THC, cannabidiol, and cannabinol, and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges for THC, 11-hydroxy-THC, and cannabidiol were 0.25-50 ng/mL; cannabinol 1-50 ng/mL; and THCCOOH 5-500 pg/mL. THCCOOH was the most prevalent analyte in 344 specimens (96.9%), with concentrations up to 1,390.3 pg/mL. 11-hydroxy-THC, cannabidiol, and cannabinol were detected in 1, 1, and 3 specimens, respectively. THC was detected in only 13.8% of specimens. The highest THC concentrations were obtained at admission (median 1.4 ng/mL, range 0.3-113.6) from previously self-administered smoked cannabis. A total of 2.5 and 3.7% of specimens were THC-positive at the recommended Substance Abuse and Mental Health Services Administration (2 ng/mL) and Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) (1 ng/mL) confirmation cutoffs, respectively. THC is currently the only analyte for monitoring cannabis exposure in OF; however, these data indicate chronic therapeutic oral THC administration and illicit oral THC use are unlikely to be identified with current guidelines. Measurement of THCCOOH may improve the detection and interpretation of OF cannabinoid tests and minimize the possibility of OF contamination from passive inhalation of cannabis smoke.

Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration

PubMed Central

Milman, Garry; Barnes, Allan J.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deana L.; Gorelick, David A.

2013-01-01

Oral fluid (OF) is an increasingly accepted matrix for drug testing programs, but questions remain about its usefulness for monitoring cannabinoids. Expectorated OF specimens (n=360) were obtained from 10 adult daily cannabis smokers before, during, and after 37 20-mg oral Δ9-tetrahydrocannabinol (THC) doses over 9 days to characterize cannabinoid disposition in this matrix. Specimens were extracted and analyzed by gas chromatography– mass spectrometry with electron-impact ionization for THC, 11-hydroxy-THC, cannabidiol, and cannabinol, and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges for THC, 11-hydroxy-THC, and cannabidiol were 0.25–50 ng/mL; cannabinol 1–50 ng/mL; and THCCOOH 5–500 pg/mL. THCCOOH was the most prevalent analyte in 344 specimens (96.9%), with concentrations up to 1,390.3 pg/mL. 11-hydroxy-THC, cannabidiol, and cannabinol were detected in 1, 1, and 3 specimens, respectively. THC was detected in only 13.8% of specimens. The highest THC concentrations were obtained at admission (median 1.4 ng/mL, range 0.3–113.6) from previously self-administered smoked cannabis. A total of 2.5 and 3.7% of specimens were THC-positive at the recommended Substance Abuse and Mental Health Services Administration (2 ng/mL) and Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) (1 ng/mL) confirmation cutoffs, respectively. THC is currently the only analyte for monitoring cannabis exposure in OF; however, these data indicate chronic therapeutic oral THC administration and illicit oral THC use are unlikely to be identified with current guidelines. Measurement of THCCOOH may improve the detection and interpretation of OF cannabinoid tests and minimize the possibility of OF contamination from passive inhalation of cannabis smoke. PMID:21637933

Oral Fluid and Plasma Cannabinoid Ratios after Around-the-Clock Controlled Oral Δ9-Tetrahydrocannabinol Administration

PubMed Central

Milman, Garry; Schwope, David M.; Schwilke, Eugene W.; Darwin, William D.; Kelly, Deanna L.; Goodwin, Robert S.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ9-tetrahydrocannabinol (THC, dronabinol) doses (40–120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-μg/L, 0.5-μg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 μg/L for THC and THCCOOH, and 0.5 μg/L for 11-hydroxy-THC. RESULTS Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = −0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high inter-individual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations. PMID:21875944

Disposition of Cannabichromene, Cannabidiol, and Δ9-Tetrahydrocannabinol and its Metabolites in Mouse Brain following Marijuana Inhalation Determined by High-Performance Liquid Chromatography–Tandem Mass Spectrometry

PubMed Central

Poklis, Justin L.; Thompson, Candace C.; Long, Kelly A.; Lichtman, Aron H.; Poklis, Alphonse

2011-01-01

A liquid chromatography–tandem mass spectrometry (LC–MS–MS) method was developed for the analysis of marijuana cannabinoids in mouse brain tissue using an Applied Biosystems 3200 Q trap with a turbo V source for TurbolonSpray attached to a Shimadzu SCL HPLC system. The method included cannabichromene (CBC), cannabidiol (CBD), D9-tetrahydrocannabinol (THC), 11-hydroxytetrahydrocannabinol (11-OH-THC), and 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). These compounds were isolated by liquid-liquid extraction using cold acetonitrile. The following transition ions were monitored by multiple reaction monitoring (MRM): m/z 315>193, 315>259 for THC/CBD/CBC; m/z 331>193, 331>105 for 11-OH-THC; m/z 345>299, 345>193 for THC-COOH;c m/z 318>196 for THC-d3; m/z 334>196 for 11-OH-THC-d3, and m/z 348>302 for THCCOOH-d3. Linearity for THC, 1-OH-THC, and THC-COOH was 1-200 ng/g; for CBC and CBD, it was 0.5–20 ng/g. Within-run and between-run precisions for all the analytes yielded coefficients of variation of < 20%. Four C57BL6 mice were sacrificed 20 min after nose-only exposure to the smoke of 200 mg of marijuana containing 0.44 mg CBC, 0.93 mg CBD, and 8.81 mg THC. The mean brain concentrations were 3.9 ± 1.5 ng/g CBC, 21 ± 3.9 ng/g CBD, 364 ± 74 ng/g THC, and 28 ± 5.9 ng/g 11-OH-THC. THCCOOH was not detected. The relative mean brain cannabinoid concentrations correlated to the amounts of the cannabinoids in the inhaled marijuana. PMID:21258613

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

PubMed Central

Castelli, M. Paola; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M. Grazia

2014-01-01

Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4×10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (−19% and −28% for 1 mg/kg pre- and post-treated animals; −25% and −21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (−50%) and by pre-treatment with 3 mg/kg Δ9-THC (−53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (−34% and −47% for 1 mg/kg pre- and post-treated animals; −37% and −29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively. PMID:24844285

The radiation belts and ring current: the relationship between Dst and relativistic electron phase space density

NASA Astrophysics Data System (ADS)

Grande, M.; Carter, M.; Perry, C. H.

2002-03-01

We briefly review the radiation belts, before moving on to a more detailed examination of the relationship between the Disturbance Storm Time Index (Dst) and relativistic electron flux. We show that there is a strong correlation between the growth phase of storms, as represented by Dst, and dropouts in electron flux. Recovery is accompanied by growth of the electron flux. We calculate Electron Phase Space Density (PSD) as a function of adiabatic invariants using electron particle mesurements from the Imaging Electron Sensor (IES) and the High Sensitivity Telescope (HIST) on the CEPPAD experiment onboard POLAR. We present the time history of the phase space density through the year 1998 as L-sorted plots and look in detail at the May 98 storm. Comparison with the Tsyganenko 96 magnetic field model prediction for the last closed field line suggests that the loss of electrons may be directly caused by the opening of drift shells.

Simultaneous quantification of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in human plasma using two-dimensional gas chromatography, cryofocusing, and electron impact-mass spectrometry

PubMed Central

Lowe, Ross H.; Karschner, Erin L.; Schwilke, Eugene W.; Barnes, Allan J.; Huestis, Marilyn A.

2009-01-01

A two-dimensional (2D) gas chromatography/electron impact-mass spectrometry (GC/EI-MS) method for simultaneous quantification of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in human plasma was developed and validated. The method employs 2D capillary GC and cryofocusing for enhanced resolution and sensitivity. THC, 11-OH-THC, and THCCOOH were extracted by precipitation with acetonitrile followed by solid-phase extraction. GC separation of trimethylsilyl derivatives of analytes was accomplished with two capillary columns in series coupled via a pneumatic Deans switch system. Detection and quantification were accomplished with a bench-top single quadrupole mass spectrometer operated in electron impact-selected ion monitoring mode. Limits of quantification (LOQ) were 0.125, 0.25 and 0.125 ng/mL for THC, 11-OH-THC, and THCCOOH, respectively. Accuracy ranged from 86.0 to 113.0% for all analytes. Intra- and inter-assay precision, as percent relative standard deviation, was less than 14.1% for THC, 11-OH-THC, and THCCOOH. The method was successfully applied to quantification of THC and its 11-OH-THC and THCCOOH metabolites in plasma specimens following controlled administration of THC. PMID:17640656

Opioid antagonism of cannabinoid effects: differences between marijuana smokers and nonmarijuana smokers.

PubMed

Haney, Margaret

2007-06-01

In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of Delta(9)-tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min before oral THC (0-40 mg) or methadone (0-10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (Study 1; n=22) and in nonmarijuana smoking (Study 2; n=21) men and women. The results show that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg), while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history.

The inheritance of chemical phenotype in Cannabis sativa L.

PubMed Central

de Meijer, Etienne P M; Bagatta, Manuela; Carboni, Andrea; Crucitti, Paola; Moliterni, V M Cristiana; Ranalli, Paolo; Mandolino, Giuseppe

2003-01-01

Four crosses were made between inbred Cannabis sativa plants with pure cannabidiol (CBD) and pure Delta-9-tetrahydrocannabinol (THC) chemotypes. All the plants belonging to the F(1)'s were analyzed by gas chromatography for cannabinoid composition and constantly found to have a mixed CBD-THC chemotype. Ten individual F(1) plants were self-fertilized, and 10 inbred F(2) offspring were collected and analyzed. In all cases, a segregation of the three chemotypes (pure CBD, mixed CBD-THC, and pure THC) fitting a 1:2:1 proportion was observed. The CBD/THC ratio was found to be significantly progeny specific and transmitted from each F(1) to the F(2)'s derived from it. A model involving one locus, B, with two alleles, B(D) and B(T), is proposed, with the two alleles being codominant. The mixed chemotypes are interpreted as due to the genotype B(D)/B(T) at the B locus, while the pure-chemotype plants are due to homozygosity at the B locus (either B(D)/B(D) or B(T)/B(T)). It is suggested that such codominance is due to the codification by the two alleles for different isoforms of the same synthase, having different specificity for the conversion of the common precursor cannabigerol into CBD or THC, respectively. The F(2) segregating groups were used in a bulk segregant analysis of the pooled DNAs for screening RAPD primers; three chemotype-associated markers are described, one of which has been transformed in a sequence-characterized amplified region (SCAR) marker and shows tight linkage to the chemotype and codominance. PMID:12586720

Acute administration of THC impairs spatial but not associative memory function in zebrafish.

PubMed

Ruhl, Tim; Prinz, Nicole; Oellers, Nadine; Seidel, Nathan Ian; Jonas, Annika; Albayram, Onder; Bilkei-Gorzo, Andras; von der Emde, Gerhard

2014-10-01

The present study examined the effect of acute administration of endocannabinoid receptor CB1 ligand ∆-9-tetrahydrocannabinol (THC) on intracellular signalling in the brain and retrieval from two different memory systems in the zebrafish (Danio rerio). First, fish were treated with THC and changes in the phosphorylation level of mitogen-activated protein (MAP) kinases Akt and Erk in the brain were determined 1 h after drug treatment. Next, animals of a second group learned in a two-alternative choice paradigm to discriminate between two colours, whereas a third group solved a spatial cognition task in an open-field maze by use of an ego-allocentric strategy. After memory acquisition and consolidation, animals were pharmacologically treated using the treatment regime as in the first group and then tested again for memory retrieval. We found an enhanced Erk but not Akt phosphorylation suggesting that THC treatment specifically activated Erk signalling in the zebrafish telencephalon. While CB1 agonist THC did not affect behavioural performance of animals in the colour discrimination paradigm, spatial memory was significantly impaired. The effect of THC on spatial learning is probably specific, since neither motor activity nor anxiety-related behaviour was influenced by the drug treatment. That indicates a striking influence of the endocannabinoid system (ECS) on spatial cognition in zebrafish. The results are very coincident with reports on mammals, demonstrating that the ECS is functional highly conserved during vertebrate evolution. We further conclude that the zebrafish provides a promising model organism for ongoing research on the ECS.

Exposure to marijuana smoke impairs memory retrieval in mice.

PubMed

Niyuhire, Floride; Varvel, Stephen A; Martin, Billy R; Lichtman, Aron H

2007-09-01

Marijuana (Cannabis sativa) and its primary psychoactive component, delta-9-tetrahydrocannabinol (Delta(9)-THC), have long been known to disrupt cognition in humans. Although Delta(9)-THC and other cannabinoids disrupt performance in a wide range of animal models of learning and memory, few studies have investigated the effects of smoked marijuana in these paradigms. Moreover, in preclinical studies, cannabinoids are generally administered before acquisition, and because retention is generally evaluated soon afterward, it is difficult to distinguish between processes related to acquisition and retrieval. In the present study, we investigated the specific effects of marijuana smoke and injected Delta(9)-THC on acquisition versus memory retrieval in a mouse repeated acquisition Morris water-maze task. To distinguish between these processes, subjects were administered Delta(9)-THC or they were exposed to marijuana smoke either 30 min before acquisition or 30 min before the retention test. Inhalation of marijuana smoke or injected Delta(9)-THC impaired the ability of the mice to learn the location of the hidden platform and to recall the platform location once learning had already taken place. In contrast, neither drug impaired performance in a cued task in which the platform was made visible. Finally, the cannabinoid-1 (CB(1)) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (rimonabant) blocked the memory disruptive effects of both Delta(9)-THC and marijuana. These data represent the first evidence demonstrating that marijuana impairs memory retrieval through a CB(1) receptor mechanism of action and independently of its effects on sensorimotor performance, motivation, and initial acquisition.

Effect of hydrolysis on identifying prenatal cannabis exposure

PubMed Central

Gray, Teresa R.; Barnes, Allan J.

2011-01-01

Identification of prenatal cannabis exposure is important due to potential cognitive and behavioral consequences. A two-dimensional gas chromatography–mass spectrometry method for cannabinol, Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 8β,11-dihydroxy-THC, and 11-nor-9-carboxy-THC (THCCOOH) quantification in human meconium was developed and validated. Alkaline, enzymatic, and enzyme–alkaline tandem hydrolysis conditions were optimized with THC- and THCCOOH-glucuronide reference standards. Limits of quantification ranged from 10 to 15 ng/g, and calibration curves were linear to 500 ng/g. Bias and intra-day and inter-day imprecision were <12.3%. Hydrolysis efficiencies were analyte-dependent; THC-glucuronide was effectively cleaved by enzyme, but not base. Conversely, THCCOOH-glucuronide was most sensitive to alkaline hydrolysis. Enzyme–alkaline tandem hydrolysis maximized efficiency for both glucuronides. Identification of cannabinoid-positive meconium specimens nearly doubled following alkaline and enzyme–alkaline hydrolysis. Although no 11-OH-THC glucuronide standard is available, enzymatic hydrolysis improved 11-OH-THC detection in authentic specimens. Maximal identification of cannabis-exposed neonates and the widest range of cannabis biomarkers are achieved with enzyme–alkaline tandem hydrolysis. PMID:20517601

The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model.

PubMed

Cherniakov, Irina; Izgelov, Dvora; Domb, Abraham J; Hoffman, Amnon

2017-11-15

The lipophilic phytocannabinoids cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally. Copyright © 2017. Published by Elsevier B.V.

Dynamic surface tension measurement for the screening of biosurfactants produced by Lactobacillus plantarum subsp. plantarum PTCC 1896.

PubMed

Bakhshi, Nafiseh; Soleimanian-Zad, Sabihe; Sheikh-Zeinoddin, Mahmoud

2017-06-01

Currently, screening of microbial biosurfactants (BSs) is based on their equilibrium surface tension values obtained using static surface tension measurement. However, a good surfactant should not only have a low equilibrium surface tension, but its dynamic surface tension (DST) should also decrease rapidly with time. In this study, screening of BSs produced by Lactobacillus plantarum subsp. plantarum PTCC 1896 (probiotic) was performed based on their DST values measured by Wilhelmy plate tensiometry. The relationship between DST and structural and functional properties (anti-adhesive activity) of the BSs was investigated. The results showed that the changes in the yield, productivity and structure of the BSs were growth medium and incubation time dependent (p<0.05). Structurally different BSs produced exhibited identical equilibrium surface tension values. However, differences among the structure/yield of the BSs were observed through the measurement of their DST. The considerable dependence of DST on the concentration and composition of the BS proteins was observed (p<0.05). Moreover, the anti-adhesive activity of the BS was found to be positively correlated with its DST. The results suggest that the DST measurement could serve as an efficient method for the clever screening of BSs producer/production condition, and consequently, for the investigation of probiotic features of bacteria, since the anti-adhesive activity is an important criterion of probiotics. Copyright © 2017 Elsevier Inc. All rights reserved.

Initial geomagnetic field model from Magsat vector data

NASA Technical Reports Server (NTRS)

Langel, R. A.; Mead, G. D.; Lancaster, E. R.; Estes, R. H.; Fabiano, E. B.

1980-01-01

Magsat data from the magnetically quiet days of November 5-6, 1979, were used to derive a thirteenth degree and order spherical harmonic geomagnetic field model, MGST(6/80). The model utilized both scalar and high-accuracy vector data and fit that data with root-mean-square deviations of 8.2, 6.9, 7.6 and 7.4 nT for the scalar magnitude, B(r), B(theta), and B(phi), respectively. The model includes the three first-order coefficients of the external field. Comparison with averaged Dst indicates that zero Dst corresponds with 25 nT of horizontal field from external sources. When compared with earlier models, the earth's dipole moment continues to decrease at a rate of about 26 nT/yr. Evaluation of earlier models with Magsat data shows that the scalar field at the Magsat epoch is best predicted by the POGO(2/72) model but that the WC80, AWC/75 and IGS/75 are better for predicting vector fields.

Combined effects of THC and caffeine on working memory in rats.

PubMed

Panlilio, Leigh V; Ferré, Sergi; Yasar, Sevil; Thorndike, Eric B; Schindler, Charles W; Goldberg, Steven R

2012-04-01

Cannabis and caffeine are two of the most widely used psychoactive substances. Δ(9) -Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory. Rats were given THC (0, 1 and 3 mg·kg(-1) , i.p.) along with caffeine (0, 1, 3 and 10 mg·kg(-1) , i.p.), the selective adenosine A(1) -receptor antagonist CPT (0, 3 and 10 mg·kg(-1) ) or the selective adenosine A(2A) -receptor antagonist SCH58261 (0 and 5 mg·kg(-1) ) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal. THC alone produced memory deficits at 3 mg·kg(-1) . The initial exposure to caffeine (10 mg·kg(-1) ) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg(-1) ) was combined with caffeine (10 mg·kg(-1) ) or CPT (10 mg·kg(-1) ), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered. Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A(1) receptors modulate cannabinoid signalling in the hippocampus. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Are daylight saving time transitions associated with changes in myocardial infarction incidence? Results from the German MONICA/KORA Myocardial Infarction Registry.

PubMed

Kirchberger, Inge; Wolf, Kathrin; Heier, Margit; Kuch, Bernhard; von Scheidt, Wolfgang; Peters, Annette; Meisinger, Christa

2015-08-14

Some studies suggest that transitions to and from daylight saving time (DST) have an influence on acute myocardial infarction (AMI) incidence. However, the available publications have a number of limitations e.g. regarding sample size, exclusion of fatal AMI cases, precise assessment of AMI onset, and consideration of possible confounders, and they were conducted in countries with different geographical location. The objective of this study was to examine the association of DST transitions with AMI incidence recorded in the population-based German MONICA/KORA Myocardial Infarction Registry. The study sample consisted of 25,499 coronary deaths and non-fatal AMI cases aged 25-74 years. We used Poisson regression with indicator variables for the 3 days or the week after the spring and the autumn transition and adjusted for potential confounders to model the association between DST transitions and AMI incidence. In addition, we built an excess model by calculating observed over expected events per day. Overall, no significant changes of AMI risk during the first 3 days or 1 week after the transition to and from DST were found. However, subgroup analyses on the spring transition revealed significantly increased risks for men in the first 3 days after transition (RR 1.155, 95 % CI 1.000-1.334) and for persons who took angiotensine converting enzyme (ACE) inhibitors prior to the AMI (3 days: RR 1.489, 95 % CI 1.151-1.927; 1 week: RR 1.297, 95 % CI 1.063-1.582). After the clock shift in autumn, patients with a prior infarction had an increased risk to have a re-infarction (3 days: RR 1.319, 95 % CI 1.029-1.691; 1 week: RR 1.270, 95 % CI 1.048-1.539). Specific subgroups such as men and persons with a history of AMI or prior treatment with ACE inhibitors, may have a higher risk for AMI during DST. Further studies which include data on chronotype and sleep duration are needed in order to confirm these results.

The DESIRE Airborne gravity project in the Dead Sea Basin and 3D numerical gravity modeling

NASA Astrophysics Data System (ADS)

Choi, S.; Goetze, H.; Meyer, U.; Group, D.

2008-12-01

This geo-scientific research focuses on the geological setting of the Dead Sea Transform (DST) and the Dead Sea Basin (DSB) and its resulting pull-apart basins. Since the late 1970s, crustal scale geophysical experiments have been carried out in this region. However, the nature of the crust underlying the eastern and western shoulders of the DSB and underneath the DST itself is still a hotly debated topic among researchers. To address one of the central questions of plate tectonics - How do large transform systems work and what are their typical features? - An international geoscientific Dead Sea Integrated Research project (DESIRE) is being conducted by colleagues from Germany, Israel, Palestine, and Jordan. In order to provide a high resolution gravity database that support 3D numerical modeling and hence a more comprehensive understanding of the nature and segmentation of the DST, an airborne gravity survey as a part of the DESIRE project has been carried out from February to March 2007. The airborne gravity survey covered the DST from Elat/Aqaba in the South to the northern rim of the Dead Sea. The low speed and terrain-following helicopter gravity flights were performed to acquire the highest possible data quality. In total, 32 north-south profiles and 16 west-east profiles crossing the DST have been measured. Most of the profiles concentrated in areas that lacked terrestrial gravity data coverage, e. g. over the shoulders of the DSB. The airborne gravity data are merged with existing conventional (terrestrial) data sets to provide a seamless gravity map of the area of interest. Using that combined gravity dataset and DESIRE wide angle refractions seismic interpretation we modified density structures in the DSB. As results we estimated that (1) the Moho depth varies from 26 km in the Israel side to 34 km in the Jordan side. (2) The maximum thickness of the Dead Sea sediment Basin is about 15 km. (3) The salt rock with an average thickness of about 5 km is present not only in the southern part of the DSB but also in northern part underlying the entire Dead Sea.

Personal Voices in Higher Education: A Digital Storytelling Experience for Pre-Service Teachers

ERIC Educational Resources Information Center

Kocaman-Karoglu, Aslihan

2016-01-01

Digital storytelling (DST) has recently emerged as a new tool in instructional environments. DST involves the combination of media and technology with traditional storytelling to help students learn. This paper examines the use of DST in a university course and pre-service teachers' perceptions of their learning experiences using this tool.…

Simulation of Theoretical Most-Extreme Geomagnetic Sudden Commencements

NASA Astrophysics Data System (ADS)

Welling, D. T.; Love, J. J.; Wiltberger, M. J.; Rigler, E. J.

2016-12-01

We report results from a numerical simulation of geomagnetic sudden commencements driven by solar wind conditions given by theoretical-limit extreme coronal-mass ejections (CMEs) estimated by Tsurutani and Lakhina [2014]. The CME characteristics at Earth are a step function that jumps from typical quiet values to 2700 km/s flow speed and a magnetic field magnitude of 127 nT. These values are used to drive three coupled models: a global magnetohydrodynamic (MHD) magnetospheric model (BATS-R-US), a ring current model (the Rice Convection Model, RCM), and a height-integrated ionospheric electrodynamics model (the Ridley Ionosphere Model, RIM), all coupled together using the Space Weather Modeling Framework (SWMF). Additionally, simulations from the Lyon-Fedder-Mobarry MHD model are performed for comparison. The commencement is simulated with both purely northward and southward IMF orientations. Low-latitude ground-level geomagnetic variations, both B and dB/dt, are estimated in response to the storm sudden commencement. For a northward interplanetary magnetic field (IMF) storm, the combined models predict a maximum sudden commencement response, Dst-equivalent of +200 nT and a maximum local dB/dt of 200nT/s. While this positive Dst response is driven mainly by magnetopause currents, complicated and dynamic Birkeland current patterns also develop, which drive the strong dB/dt responses at high latitude. For southward IMF conditions, erosion of dayside magnetic flux allows magnetopause currents to approach much closer to the Earth, leading to a stronger terrestrial response (Dst-equivalent of +250 nT). Further, high latitude signals from Region 1 Birkeland currents move to lower latitudes during the southward IMF case, increasing the risk to populated areas around the globe. Results inform fundamental understanding of solar-terrestrial interaction and benchmark estimates for induction hazards of interest to the electric-power grid industry.

Daylight savings time and myocardial infarction

PubMed Central

Sandhu, Amneet; Seth, Milan; Gurm, Hitinder S

2014-01-01

Background Prior research has shown a transient increase in the incidence of acute myocardial infarction (AMI) after daylight savings time (DST) in the spring as well as a decrease in AMI after returning to standard time in the fall. These findings have not been verified in a broader population and if extant, may have significant public health and policy implications. Methods We assessed changes in admissions for AMI undergoing percutaneous coronary intervention (PCI) in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) database for the weeks following the four spring and three fall DST changes between March 2010 and September 2013. A negative binomial regression model was used to adjust for trend and seasonal variation. Results There was no difference in the total weekly number of PCIs performed for AMI for either the fall or spring time changes in the time period analysed. After adjustment for trend and seasonal effects, the Monday following spring time changes was associated with a 24% increase in daily AMI counts (p=0.011), and the Tuesday following fall changes was conversely associated with a 21% reduction (p=0.044). No other weekdays in the weeks following DST changes demonstrated significant associations. Conclusions In the week following the seasonal time change, DST impacts the timing of presentations for AMI but does not influence the overall incidence of this disease. PMID:25332784

Revised Dst and the epicycles of magnetic disturbance: 1958-2007

USGS Publications Warehouse

Love, J.J.; Gannon, J.L.

2009-01-01

A revised version of the storm-time disturbance index Dst is calculated using hourly-mean magnetic-observatory data from four standard observatories and collected over the years 1958-2007. The calculation algorithm is a revision of that established by Sugiura et al., and which is now used by the Kyoto World Data Center for routine production of Dst. The most important new development is for the removal of solar-quiet variation. This is done through time and frequency-domain band-stop filtering - selectively removing specific Fourier terms approximating stationary periodic variation driven by the Earth's rotation, the Moon's orbit, the Earth's orbit around the Sun, and their mutual coupling. The resulting non-stationary disturbance time series are weighted by observatory-site geomagnetic latitude and then averaged together across longitudes to give what we call Dst5807-4SH. Comparisons are made with the standard Kyoto D st. Various biases, especially for residual solar-quiet variation, are identified in the Kyoto Dst, and occasional storm-time errors in the Kyoto Dst are noted. Using Dst5807-4SH, storms are ranked for maximum storm-time intensity, and we show that storm-occurrence frequency follows a power-law distribution with an exponential cutoff. The epicycles of magnetic disturbance are explored: we (1) map low-latitude local-time disturbance asymmetry, (2) confirm the 27-day storm-recurrence phenomenon using autocorrelation, (3) investigate the coupled semi-annual-diurnal variation of magnetic activity and the proposed explanatory equinoctial and Russell-McPherron hypotheses, and (4) illustrate the well-known solar-cycle modulation of storm-occurrence likelihood. Since Dst5807-4SH is useful for a variety of space physics and solid-Earth applications, it is made freely available to the scientific community.

Influence of the substorm current wedge on the Dst index

NASA Astrophysics Data System (ADS)

Friedrich, Erena; Rostoker, Gordon; Connors, Martin G.; McPherron, R. L.

1999-03-01

One of the major questions confronting researchers studying the nature of the solar-terrestrial interaction centers around whether or not the substorm expansive phase has any causal effect on the growth of the storm time ring current. This question is often addressed by using the Dst index as a proxy for the storm time ring current and inspecting the main phase growth of Dst in the context of the substorm expansive phases which occur in the same time frame as the ring current growth. In the past it has been assumed that the magnetic effects of the substorm current wedge have little influence on the Dst index because the current wedge is an asymmetric current system, while Dst is supposed to reflect changes in the symmetric component of the ring current. In this paper we shall shown that the substorm current wedge can have a significant effect on the present Dst index, primarily as a consequence of the fact that only four stations are presently used to formulate the index. Calculations are made assuming the instantaneous magnitude of the wedge current is constant at 1 MA. Hourly values of Dst may be as much as 50° smaller than those presented here because of variation of the wedge current over the hour. We shall show how the effect of the current wedge depends on the UT of the expansive phase onset, the angular extent of the current wedge, and the locale of the closure current in the magnetosphere. The fact that the substorm current wedge is a conjugate phenomenon has an important influence on the magnitude of the expansive phase effect in the Dst index.

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Satta, Valentina; Ramos, José A; Pertwee, Roger G; Fernández-Ruiz, Javier

2011-09-01

We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. Copyright © 2011 Wiley-Liss, Inc.

Metabolic patterns of JWH-210, RCS-4, and THC in pig urine elucidated using LC-HR-MS/MS: Do they reflect patterns in humans?

PubMed

Schaefer, Nadine; Helfer, Andreas G; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Ewald, Andreas H; Meyer, Markus R; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2017-04-01

The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ 9 -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC.

PubMed

Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

2014-10-01

Our previous research suggested the involvement of γ-aminobutyric acid (GABA), in particular the GABAB receptor subtype, in the interoceptive effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC). The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ(9)-THC using pharmacologically selective drug-discrimination procedures. Ten cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received diazepam (5 and 10mg), Δ(9)-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ(9)-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug) and elevated heart rate. Diazepam alone impaired performance on psychomotor performance tasks and increased ratings on a limited number of self-report questionnaire items (e.g., Any Effect, Sedated), but did not substitute for the Δ(9)-THC discriminative stimulus or alter the Δ(9)-THC discrimination dose-response function. Similarly, diazepam had limited impact on the other behavioral effects of Δ(9)-THC. These results suggest that the GABAA receptor subtype has minimal involvement in the interoceptive effects of Δ(9)-THC, and by extension cannabis, in humans. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Storm time global thermosphere: A driven-dissipative thermodynamic system

NASA Astrophysics Data System (ADS)

Burke, W. J.; Lin, C. S.; Hagan, M. P.; Huang, C. Y.; Weimer, D. R.; Wise, J. O.; Gentile, L. C.; Marcos, F. A.

2009-06-01

Orbit-averaged mass densities $\\overline{\\rho and exospheric temperatures $\\overline{T ∞ inferred from measurements by accelerometers on the Gravity Recovery and Climate Experiment (GRACE) satellites are used to investigate global energy Eth and power Πth inputs to the thermosphere during two complex magnetic storms. Measurements show $\\overline{\\rho, $\\overline{T ∞, and Eth rising from and returning to prevailing baselines as the magnetospheric electric field $\\varepsilon$ VS and the Dst index wax and wane. Observed responses of Eth and $\\overline{T ∞ to $\\varepsilon$ VS driving suggest that the storm time thermosphere evolves as a driven-but-dissipative thermodynamic system, described by a first-order differential equation that is identical in form to that governing the behavior of Dst. Coupling and relaxation coefficients of the Eth, $\\overline{T ∞, and Dst equations are established empirically. Numerical solutions of the equations for $\\overline{T ∞ and Eth are shown to agree with GRACE data during large magnetic storms. Since $\\overline{T ∞ and Dst have the same $\\varepsilon$ VS driver, it is possible to combine their governing equations to obtain estimates of storm time thermospheric parameters, even when lacking information about interplanetary conditions. This approach has the potential for significantly improving the performance of operational models used to calculate trajectories of satellites and space debris and is also useful for developing forensic reconstructions of past magnetic storms. The essential correctness of the approach is supported by agreement between thermospheric power inputs calculated from both GRACE-based estimates of Eth and the Weimer Poynting flux model originally derived from electric and magnetic field measurements acquired by the Dynamics Explorer 2 satellite.

A decision support tool for adaptive management of native prairie ecosystems

USGS Publications Warehouse

Hunt, Victoria M.; Jacobi, Sarah; Gannon, Jill J.; Zorn, Jennifer E.; Moore, Clinton; Lonsdorf, Eric V.

2016-01-01

The Native Prairie Adaptive Management initiative is a decision support framework that provides cooperators with management-action recommendations to help them conserve native species and suppress invasive species on prairie lands. We developed a Web-based decision support tool (DST) for the U.S. Fish and Wildlife Service and the U.S. Geological Survey initiative. The DST facilitates cross-organizational data sharing, performs analyses to improve conservation delivery, and requires no technical expertise to operate. Each year since 2012, the DST has used monitoring data to update ecological knowledge that it translates into situation-specific management-action recommendations (e.g., controlled burn or prescribed graze). The DST provides annual recommendations for more than 10,000 acres on 20 refuge complexes in four U.S. states. We describe how the DST promotes the long-term implementation of the program for which it was designed and may facilitate decision support and improve ecological outcomes of other conservation efforts.

Modeling coupled thermal-hydrological-chemical processes in theunsaturated fractured rock of Yucca Mountain, Nevada: Heterogeneity andseepage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mukhopadhyay, Sumit; Sonnenthal, Eric L.; Spycher, Nicolas

An understanding of processes affecting seepage intoemplacement tunnels is needed for correctly predicting the performance ofunderground radioactive waste repositories. It has been previouslyestimated that the capillary and vaporization barriers in the unsaturatedfractured rock of Yucca Mountain are enough to prevent seepage underpresent day infiltration conditions. It has also been thought that asubstantially elevated infiltration flux will be required to causeseepage after the thermal period is over. While coupledthermal-hydrological-chemical (THC) changes in Yucca Mountain host rockdue to repository heating has been previously investigated, those THCmodels did not incorporate elements of the seepage model. In this paper,we combine the THC processes inmore » unsaturated fractured rock with theprocesses affecting seepage. We observe that the THC processes alter thehydrological properties of the fractured rock through mineralprecipitation and dissolution. We show that such alteration in thehydrological properties of the rock often leads to local flow channeling.We conclude that such local flow channeling may result in seepage undercertain conditions, even with nonelevated infiltrationfluxes.« less

Predicting Coupled Ocean-Atmosphere Modes with a Climate Modeling Hierarchy -- Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michael Ghil, UCLA; Andrew W. Robertson, IRI, Columbia Univ.; Sergey Kravtsov, U. of Wisconsin, Milwaukee

The goal of the project was to determine midlatitude climate predictability associated with tropical-extratropical interactions on interannual-to-interdecadal time scales. Our strategy was to develop and test a hierarchy of climate models, bringing together large GCM-based climate models with simple fluid-dynamical coupled ocean-ice-atmosphere models, through the use of advanced probabilistic network (PN) models. PN models were used to develop a new diagnostic methodology for analyzing coupled ocean-atmosphere interactions in large climate simulations made with the NCAR Parallel Climate Model (PCM), and to make these tools user-friendly and available to other researchers. We focused on interactions between the tropics and extratropics throughmore » atmospheric teleconnections (the Hadley cell, Rossby waves and nonlinear circulation regimes) over both the North Atlantic and North Pacific, and the ocean’s thermohaline circulation (THC) in the Atlantic. We tested the hypothesis that variations in the strength of the THC alter sea surface temperatures in the tropical Atlantic, and that the latter influence the atmosphere in high latitudes through an atmospheric teleconnection, feeding back onto the THC. The PN model framework was used to mediate between the understanding gained with simplified primitive equations models and multi-century simulations made with the PCM. The project team is interdisciplinary and built on an existing synergy between atmospheric and ocean scientists at UCLA, computer scientists at UCI, and climate researchers at the IRI.« less

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells*

PubMed Central

Kozela, Ewa; Pietr, Maciej; Juknat, Ana; Rimmerman, Neta; Levy, Rivka; Vogel, Zvi

2010-01-01

Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1β, interleukin-6, and interferon (IFN)β, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-κB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNβ-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-κB and IFNβ-dependent pathways. PMID:19910459

Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes.

PubMed

Keeley, R J; Trow, J; McDonald, R J

2015-10-01

The use of recreational marijuana is widespread and frequently begins and persists through adolescence. Some research has shown negative consequences of adolescent marijuana use, but this is not seen across studies, and certain factors, like genetic background and sex, may influence the results. It is critical to identify which characteristics predispose an individual to be susceptible to the negative consequences of chronic exposure to marijuana in adolescence on brain health and behavior. To this end, using males and females of two strains of rats, Long-Evans hooded (LER) and Wistar (WR) rats, we explored whether these anatomically and behaviorally dimorphic strains demonstrated differences in puberty onset and strain-specific effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. Daily 5 mg/kg treatment began on the day of puberty onset and continued for 14 days. Of particular interest were metrics of growth and volumetric estimates of brain areas involved in cognition that contain high densities of cannabinoid receptors, including the hippocampus and its subregions, the amygdala, and the frontal cortex. Brain volumetrics were analyzed immediately following the treatment period. LER and WR females started puberty at different ages, but no strain differences were observed in brain volumes. THC decreased weight gain throughout the treatment period for all groups. Only the hippocampus and some of its subregions were affected by THC, and increased volumes with THC administration was observed exclusively in females, regardless of strain. Long-term treatment of THC did not affect all individuals equally, and females displayed evidence of increased sensitivity to the effects of THC, and by extension, marijuana. Identifying differences in adolescent physiology of WR and LER rats could help determine the cause for strain and sex differences in brain and behavior of adults and help to refine the use of animal models in marijuana research. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

PubMed Central

Wakley, Alexa A.; Wiley, Jenny L.; Craft, Rebecca M.

2014-01-01

Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure. PMID:25131716

Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects.

PubMed

Eichler, Martin; Spinedi, Luca; Unfer-Grauwiler, Sandra; Bodmer, Michael; Surber, Christian; Luedi, Markus; Drewe, Juergen

2012-05-01

The most important psychoactive constituent of CANNABIS SATIVA L. is Δ (9)-tetrahydrocannabinol (THC). Cannabidiol (CBD), another important constituent, is able to modulate the distinct unwanted psychotropic effect of THC. In natural plant extracts of C. SATIVA, large amounts of THC and CBD appear in the form of THCA-A (THC-acid-A) and CBDA (cannabidiolic acid), which can be transformed to THC and CBD by heating. Previous reports of medicinal use of cannabis or cannabis preparations with higher CBD/THC ratios and use in its natural, unheated form have demonstrated that pharmacological effects were often accompanied with a lower rate of adverse effects. Therefore, in the present study, the pharmacokinetics and metabolic profiles of two different C. SATIVA extracts (heated and unheated) with a CBD/THC ratio > 1 were compared to synthetic THC (dronabinol) in a double-blind, randomized, single center, three-period cross-over study involving 9 healthy male volunteers. The pharmacokinetics of the cannabinoids was highly variable. The metabolic pattern was significantly different after administration of the different forms: the heated extract showed a lower median THC plasma AUC (24 h) than the unheated extract of 2.84 vs. 6.59 pmol h/mL, respectively. The later was slightly higher than that of dronabinol (4.58 pmol h/mL). On the other hand, the median sum of the metabolites (THC, 11-OH-THC, THC-COOH, CBN) plasma AUC (24 h) was higher for the heated than for the unheated extract. The median CBD plasma AUC (24 h) was almost 2-fold higher for the unheated than for the heated extract. These results indicate that use of unheated extracts may lead to a beneficial change in metabolic pattern and possibly better tolerability. © Georg Thieme Verlag KG Stuttgart · New York.

Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users.

PubMed

Curran, H Valerie; Brignell, Catherine; Fletcher, Sally; Middleton, Paul; Henry, John

2002-10-01

Although some aspects of memory functions are known to be acutely impaired by delta(9)-tetrahydrocannabinol (delta(9)-THC; the main active constituent of marijuana), effects on other aspects of memory are not known and the time course of functional impairments is unclear. The present study aimed to detail the acute and residual cognitive effects of delta(9)-THC in infrequent cannabis users. A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg delta(9)-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact. The higher dose of delta(9)-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by delta(9)-THC. In several tasks, delta(9)-THC increased both speed and error rates, reflecting "riskier" speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as "stoned" for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal. These data demonstrate that oral delta(9)-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory.

Tolerance to Chronic Delta-9-Tetrahydrocannabinol (Δ9-THC) in Rhesus Macaques Infected With Simian Immunodeficiency Virus

PubMed Central

Winsauer, Peter J.; Molina, Patricia E.; Amedee, Angela M.; Filipeanu, Catalin M.; McGoey, Robin R.; Troxclair, Dana A.; Walker, Edith M.; Birke, Leslie L.; Stouwe, Curtis Vande; Howard, Jessica M.; Leonard, Stuart T.; Moerschbaecher, Joseph M.; Lewis, Peter B.

2011-01-01

Although Δ9-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Δ9-THC before and after inoculation with simian immunodeficiency virus(SIVmac251, 100 TCID50/ml, i.v.). Prior to chronic Δ9-THC and SIV inoculation, 0.032– 0.32 mg/kg of Δ9-THC produced dose-dependent rate-decreasing effects and small, sporadic error-increasing effects in the acquisition and performance components in each subject. Following 28 days of chronic Δ9-THC (0.32 mg/kg, i.m.) or vehicle twice daily, delta-9-THC-treated subjects developed tolerance to the rate-decreasing effects, and this tolerance was maintained during the initial 7–12 months irrespective of SIV infection (i.e., +THC/−SIV, +THC/+SIV). Full necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation, with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in delta-9-THC-treated subjects. Chronic Δ9-THC also significantly reduced CB-1 and CB-2 receptor levels in the hippocampus, attenuated the expression of a proinflammatory cytokine (MCP-1), and did not increase viral load in plasma, cerebrospinal fluid, or brain tissue compared to vehicle-treated subjects with SIV. Together, these data indicate that chronic Δ9-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection. PMID:21463073

Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC

PubMed Central

Lile, Joshua A.; Kelly, Thomas H.; Hays, Lon R.

2012-01-01

Background Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABAB receptor subtype by assessing the separate and combined effects of the GABAB-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. Methods Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. Conclusions These results suggest that the GABAB receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABAB receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABAA) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans. PMID:22699093

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats.

PubMed

Wiley, Jenny L; Lefever, Timothy W; Marusich, Julie A; Craft, Rebecca M

2017-03-01

Women report greater sensitivity to the subjective effects of Δ 9 -tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure. Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes. This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC's effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology. Copyright © 2017 Elsevier B.V. All rights reserved.

Delta-9-tetrahydrocannabinol (THC) affects forelimb motor map expression but has little effect on skilled and unskilled behavior.

PubMed

Scullion, K; Guy, A R; Singleton, A; Spanswick, S C; Hill, M N; Teskey, G C

2016-04-05

It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.

PubMed

Englund, Amir; Atakan, Zerrin; Kralj, Aleksandra; Tunstall, Nigel; Murray, Robin; Morrison, Paul

2016-02-01

Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers. Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day. THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (χ(2)=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031). In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose. © The Author(s) 2015.

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2012 CFR

2012-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2013 CFR

2013-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2014 CFR

2014-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

Application of a New Integrated Decision Support Tool (i-DST) for Urban Water Infrastructure: Analyzing Water Quality Compliance Pathways for Three Los Angeles Watersheds

NASA Astrophysics Data System (ADS)

Gallo, E. M.; Hogue, T. S.; Bell, C. D.; Spahr, K.; McCray, J. E.

2017-12-01

The water quality of receiving streams and waterbodies in urban watersheds are increasingly polluted from stormwater runoff. The implementation of Green Infrastructure (GI), which includes Low Impact Developments (LIDs) and Best Management Practices (BMPs), within a watershed aim to mitigate the effects of urbanization by reducing pollutant loads, runoff volume, and storm peak flow. Stormwater modeling is generally used to assess the impact of GIs implemented within a watershed. These modeling tools are useful for determining the optimal suite of GIs to maximize pollutant load reduction and minimize cost. However, stormwater management for most resource managers and communities also includes the implementation of grey and hybrid stormwater infrastructure. An integrated decision support tool, called i-DST, that allows for the optimization and comprehensive life-cycle cost assessment of grey, green, and hybrid stormwater infrastructure, is currently being developed. The i-DST tool will evaluate optimal stormwater runoff management by taking into account the diverse economic, environmental, and societal needs associated with watersheds across the United States. Three watersheds from southern California will act as a test site and assist in the development and initial application of the i-DST tool. The Ballona Creek, Dominguez Channel, and Los Angeles River Watersheds are located in highly urbanized Los Angeles County. The water quality of the river channels flowing through each are impaired by heavy metals, including copper, lead, and zinc. However, despite being adjacent to one another within the same county, modeling results, using EPA System for Urban Stormwater Treatment and Analysis INtegration (SUSTAIN), found that the optimal path to compliance in each watershed differs significantly. The differences include varied costs, suites of BMPs, and ancillary benefits. This research analyzes how the economic, physical, and hydrological differences between the three watersheds shape the optimal plan for stormwater management.

New theoretical framework for designing nonionic surfactant mixtures that exhibit a desired adsorption kinetics behavior.

PubMed

Moorkanikkara, Srinivas Nageswaran; Blankschtein, Daniel

2010-12-21

How does one design a surfactant mixture using a set of available surfactants such that it exhibits a desired adsorption kinetics behavior? The traditional approach used to address this design problem involves conducting trial-and-error experiments with specific surfactant mixtures. This approach is typically time-consuming and resource-intensive and becomes increasingly challenging when the number of surfactants that can be mixed increases. In this article, we propose a new theoretical framework to identify a surfactant mixture that most closely meets a desired adsorption kinetics behavior. Specifically, the new theoretical framework involves (a) formulating the surfactant mixture design problem as an optimization problem using an adsorption kinetics model and (b) solving the optimization problem using a commercial optimization package. The proposed framework aims to identify the surfactant mixture that most closely satisfies the desired adsorption kinetics behavior subject to the predictive capabilities of the chosen adsorption kinetics model. Experiments can then be conducted at the identified surfactant mixture condition to validate the predictions. We demonstrate the reliability and effectiveness of the proposed theoretical framework through a realistic case study by identifying a nonionic surfactant mixture consisting of up to four alkyl poly(ethylene oxide) surfactants (C(10)E(4), C(12)E(5), C(12)E(6), and C(10)E(8)) such that it most closely exhibits a desired dynamic surface tension (DST) profile. Specifically, we use the Mulqueen-Stebe-Blankschtein (MSB) adsorption kinetics model (Mulqueen, M.; Stebe, K. J.; Blankschtein, D. Langmuir 2001, 17, 5196-5207) to formulate the optimization problem as well as the SNOPT commercial optimization solver to identify a surfactant mixture consisting of these four surfactants that most closely exhibits the desired DST profile. Finally, we compare the experimental DST profile measured at the surfactant mixture condition identified by the new theoretical framework with the desired DST profile and find good agreement between the two profiles.

Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats.

PubMed

Winsauer, Peter J; Sutton, Jessie L

2014-02-01

This study examined whether chronic Δ(9)-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ(9)-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ(9)-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ(9)-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ(9)-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ(9)-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ(9)-THC than the OVX groups irrespective of chronic Δ(9)-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ(9)-THC) and the dose of Δ(9)-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ(9)-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence. Copyright © 2013 Elsevier Inc. All rights reserved.

Ocular disposition of the hemiglutarate ester prodrug of ∆⁹-Tetrahydrocannabinol from various ophthalmic formulations.

PubMed

Hingorani, Tushar; Adelli, Goutham R; Punyamurthula, Nagendra; Gul, Waseem; Elsohly, Mahmoud A; Repka, Michael A; Majumdar, Soumyajit

2013-08-01

The overall goal of this project is to enhance ocular delivery of ∆(9)-Tetrahydrocannabinol (THC) through the topical route. Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.

Alteration in the level of endogenous hypothalamic prostaglandins induced by delta 9-tetrahydrocannabinol in the rat.

PubMed Central

Coupar, I. M.; Taylor, D. A.

1982-01-01

1 Whole brain and regional brain levels of prostaglandin E2 (PGE2)-like material have been determined following administration of delta 9-tetrahydrocannabinol (delta 9 -THC) in rats. 2 Intravenous administration of delta 9-THC 2 mg/kg, resulted in marked behavioural changes and hypothermia. The behavioural changes consisted mainly of catatonia (most apparent at 30 min after administration of delta 9-THC), followed by sedation (most evident at 60 min). Hypothermia was marked from 30 min after administration of delta 9-THC. 3 delta 9-THC did not after the whole brain levels of PGE2-like material 30, 60 or 120 min after administration. 4 delta 9-THC did not alter the levels of PGE2-like material in the medulla oblongata/pons, midbrain, cortex and cerebellum, 30 min after administration. However, there was a significant reduction of PGE2-like material in the hypothalamus, 30 min after delta 9-THC. 5 It is suggested that the delta 9-THC-induced decrease in hypothalamic PGE2-like material may contribute to the hypothermia observed following delta 9-THC administration. PMID:6282371

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2012 CFR

2012-07-01

... initial installation and after major maintenance. THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon initial installation, within 185 days before...

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2013 CFR

2013-07-01

... initial installation and after major maintenance. THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon initial installation, within 185 days before...

A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.

PubMed

Stott, Colin; White, Linda; Wright, Stephen; Wilbraham, Darren; Guy, Geoffrey

2013-12-01

This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. NCT01323465.

Cost of Incremental Expansion of an Existing Family Medicine Residency Program.

PubMed

Ashkin, Evan A; Newton, Warren P; Toomey, Brian; Lingley, Ronald; Page, Cristen P

2017-07-01

Expanding residency training programs to address shortages in the primary care workforce is challenged by the present graduate medical education (GME) environment. The Medicare funding cap on new GME positions and reductions in the Health Resources and Services Administration (HRSA) Teaching Health Center (THC) GME program require innovative solutions to support primary care residency expansion. Sparse literature exists to assist in predicting the actual cost of incremental expansion of a family medicine residency program without federal or state GME support. In 2011 a collaboration to develop a community health center (CHC) academic medical partnership (CHAMP), was formed and created a THC as a training site for expansion of an existing family medicine residency program. The cost of expansion was a critical factor as no Federal GME funding or HRSA THC GME program support was available. Initial start-up costs were supported by a federal grant and local foundations. Careful financial analysis of the expansion has provided actual costs per resident of the incremental expansion of the residencyRESULTS: The CHAMP created a new THC and expanded the residency from eight to ten residents per year. The cost of expansion was approximately $72,000 per resident per year. The cost of incremental expansion of our residency program in the CHAMP model was more than 50% less than that of the recently reported cost of training in the HRSA THC GME program.

Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats.

PubMed

Malone, Daniel Thomas; Jongejan, Dennis; Taylor, David Alan

2009-08-01

While Delta(9)-tetrahydrocannabinol (THC) is the main psychoactive constituent of the cannabis plant, a non-psychoactive constituent is cannabidiol (CBD). CBD has been implicated as a potential treatment of a number of disorders including schizophrenia and epilepsy and has been included with THC in a 1:1 combination for the treatment of conditions such as neuropathic pain. This study investigated the effect of THC and CBD, alone or in combination, on some objective behaviours of rats in the open field. Pairs of rats were injected with CBD or vehicle followed by THC or vehicle and behaviour in the open field was assessed for 10 min. In vehicle pretreated rats THC (1 mg/kg) significantly reduced social interaction between rat pairs. Treatment with CBD had no significant effect alone, but pretreatment with CBD (20 mg/kg) reversed the THC-induced decreases in social interaction. A higher dose of THC (10 mg/kg) produced no significant effect on social interaction. However, the combination of high dose CBD and high dose THC significantly reduced social interaction between rat pairs, as well as producing a significant decrease in locomotor activity. This data suggests that CBD can reverse social withdrawal induced by low dose THC, but the combination of high dose THC and CBD impairs social interaction, possibly by decreasing locomotor activity.

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.

PubMed

Silveira, Mason M; Adams, Wendy K; Morena, Maria; Hill, Matthew N; Winstanley, Catharine A

2017-03-01

Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ 9 -Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. Male Long-Evans rats ( n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. We found that THC decreased choice of hard trials without impairing the animals' ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex - an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in "slacker" rats. Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.

Global Warming In A Regional Model of The Atlantic Ocean - Echam4/opyc3 In Flame 4/3

NASA Astrophysics Data System (ADS)

Schweckendiek, U.; Willebrand, J.

The reaction of the Thermohaline Circulation (THC) in most climate models on global warming scenarios is a weakening of the THC. An exception is the ECHAM4/OPYC3 simulation whose stable behaviour is traced back to a strongly enhanced evaporation and as a consequence to a development of a salt anomaly in the tropics and subtropics of the Atlantic Ocean (Latif et al.,2000). This salt signal is advected into convection regions and compensates the reduction of surface density due to surface heating and freshening. To examine this scenario for a more realistic ocean model, data from this model is used to drive a reginal model of the Atlantic Ocean. In order to test the crucial mechanisms for the maintainance of the meridional overturning, we have performed sensitivity studies by focussing on different combinations of the anomalous freshwater and heat fluxes. The results demonstrate that for the stabilising effect to become effective the salt sig- nal has to enter the GIN-Seas and subsequently the overflow waters, underlining the importance of the overflows for the THC. The Labrador Sea Convection is however uneffected by this stabilising salt signal and its convection ultimatly breaks down un- der surface warming and freshening.

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2014 CFR

2014-07-01

...: FID calibrationTHC FID optimization, and THC FID verification Calibrate all FID analyzers: upon initial installation and after major maintenance.Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon...

Humanoids Learning to Walk: A Natural CPG-Actor-Critic Architecture.

PubMed

Li, Cai; Lowe, Robert; Ziemke, Tom

2013-01-01

The identification of learning mechanisms for locomotion has been the subject of much research for some time but many challenges remain. Dynamic systems theory (DST) offers a novel approach to humanoid learning through environmental interaction. Reinforcement learning (RL) has offered a promising method to adaptively link the dynamic system to the environment it interacts with via a reward-based value system. In this paper, we propose a model that integrates the above perspectives and applies it to the case of a humanoid (NAO) robot learning to walk the ability of which emerges from its value-based interaction with the environment. In the model, a simplified central pattern generator (CPG) architecture inspired by neuroscientific research and DST is integrated with an actor-critic approach to RL (cpg-actor-critic). In the cpg-actor-critic architecture, least-square-temporal-difference based learning converges to the optimal solution quickly by using natural gradient learning and balancing exploration and exploitation. Futhermore, rather than using a traditional (designer-specified) reward it uses a dynamic value function as a stability indicator that adapts to the environment. The results obtained are analyzed using a novel DST-based embodied cognition approach. Learning to walk, from this perspective, is a process of integrating levels of sensorimotor activity and value.

Humanoids Learning to Walk: A Natural CPG-Actor-Critic Architecture

PubMed Central

Li, Cai; Lowe, Robert; Ziemke, Tom

2013-01-01

The identification of learning mechanisms for locomotion has been the subject of much research for some time but many challenges remain. Dynamic systems theory (DST) offers a novel approach to humanoid learning through environmental interaction. Reinforcement learning (RL) has offered a promising method to adaptively link the dynamic system to the environment it interacts with via a reward-based value system. In this paper, we propose a model that integrates the above perspectives and applies it to the case of a humanoid (NAO) robot learning to walk the ability of which emerges from its value-based interaction with the environment. In the model, a simplified central pattern generator (CPG) architecture inspired by neuroscientific research and DST is integrated with an actor-critic approach to RL (cpg-actor-critic). In the cpg-actor-critic architecture, least-square-temporal-difference based learning converges to the optimal solution quickly by using natural gradient learning and balancing exploration and exploitation. Futhermore, rather than using a traditional (designer-specified) reward it uses a dynamic value function as a stability indicator that adapts to the environment. The results obtained are analyzed using a novel DST-based embodied cognition approach. Learning to walk, from this perspective, is a process of integrating levels of sensorimotor activity and value. PMID:23675345

Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential

PubMed Central

Tai, Sherrica; Fantegrossi, William E.

2015-01-01

Cannabis has been used throughout the world for centuries. The psychoactive effects of cannabis are largely attributable to Δ9-tetrahydrocannabinol (Δ9-THC), the prototypical cannabinoid that occurs naturally in the plant. More recently, chemically- and pharmacologically-distinct synthetic cannabinoids (SCBs) have emerged as drugs of abuse. As compared to Δ9-THC, the distinct structures of these compounds allow them to avoid legal restrictions (at least initially) and detection in standard drug screens. This has contributed to the popularity of SCBs among drug users who seek to avoid positive drug screens. Importantly, the distinct structures of the SCBs also typically result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be responsible for the psychoactive effects of Δ9-THC and its analogues. Accordingly, it seems likely that these more powerful cannabimimetic effects could result in increased adverse reactions and toxicities not elicited by Δ9-THC in cannabis. Animal models useful for the study of emerging SCBs include the cannabinoid tetrad, drug discrimination, and assays of tolerance, dependence, and withdrawal. However, these in vivo procedures have not been particularly informative with regards to drug efficacy, where the majority of SCB effects are comparable to those of Δ9-THC. In contrast, essentially all in vitro measures of drug efficacy confirm Δ9-THC as a relatively weak CB1 partial agonist, while the majority of the SCBs detected in commercial preparations are full agonists at the CB1 receptor. As use of these emerging SCBs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds. PMID:26413452

Species-specific susceptibility to cannabis-induced convulsions.

PubMed

Whalley, Benjamin J; Lin, Hong; Bell, Lynne; Hill, Thomas; Patel, Amesha; Gray, Roy A; Elizabeth Roberts, C; Devinsky, Orrin; Bazelot, Michael; Williams, Claire M; Stephens, Gary J

2018-02-19

Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ 9 -tetrahydrocannabinol (THC), variously reported to be pro- and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats and treatment-naïve rat, mouse, chicken, dog and human tissue. Prolonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11-hydroxy-THC (11-OH-THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB 1 receptor)-mediated signalling. Profiling CB 1 receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than one that did not (dog). Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models. © 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

A Field Evaluation of the Hardy TB MODS Kit™ for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis

PubMed Central

Martin, Laura; Coronel, Jorge; Faulx, Dunia; Valdez, Melissa; Metzler, Mutsumi; Crudder, Chris; Castillo, Edith; Caviedes, Luz; Grandjean, Louis; Rodriguez, Mitzi; Friedland, Jon S.; Gilman, Robert H.; Moore, David A. J.

2014-01-01

Background Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory. Methods & Findings 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3–99.8%), 98.3% (97.5–98.8%), 95.8% (94.0–97.1%), and 99.7% (99.3–99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9–13) days for conventional MODS and 8.5 (7–11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples). Conclusions MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest. PMID:25225802

A field evaluation of the Hardy TB MODS Kit™ for the rapid phenotypic diagnosis of tuberculosis and multi-drug resistant tuberculosis.

PubMed

Martin, Laura; Coronel, Jorge; Faulx, Dunia; Valdez, Melissa; Metzler, Mutsumi; Crudder, Chris; Castillo, Edith; Caviedes, Luz; Grandjean, Louis; Rodriguez, Mitzi; Friedland, Jon S; Gilman, Robert H; Moore, David A J

2014-01-01

Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory. 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples). MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.

Suppression of human macrophage function in vitro by delta 9-tetrahydrocannabinol.

PubMed

Specter, S; Lancz, G; Goodfellow, D

1991-11-01

The ability of macrophages to function in the presence of delta 9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, was evaluated. THC added to macrophage cultures prepared from human peripheral blood inhibited macrophage spreading and phagocytosis of yeast. The effects of THC were concentration dependent, with inhibitory effects observed from 10 to 1 micrograms/ml or lower. These results suggest that macrophages are more sensitive to THC than are lymphocytes because macrophage functions were inhibited by THC at concentrations that did not affect lymphocyte function. Thus, inhibition of lymphocyte function(s) by THC could be attributed to a direct effect of the drug on macrophages which indirectly results in lowered lymphoid cell activity.

Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis.

PubMed

Morgan, Celia J A; Curran, H Valerie

2008-04-01

Cannabis contains various cannabinoids, two of which have almost opposing actions: Delta9-tetrahydrocannabinol (Delta9-THC) is psychotomimetic, whereas cannabidiol (CBD) has antipsychotic effects. Hair samples were analysed to examine levels of Delta9-THC and CBD in 140 individuals. Three clear groups emerged: ;THC only', ;THC+CBD' and those with no cannabinoid in hair. The THC only group showed higher levels of positive schizophrenia-like symptoms compared with the no cannabinoid and THC+CBD groups, and higher levels of delusions compared with the no cannabinoid group. This provides evidence of the divergent properties of cannabinoids and has important implications for research into the link between cannabis use and psychosis.

Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.

PubMed

Schaefer, Nadine; Wojtyniak, Jan-Georg; Kettner, Mattias; Schlote, Julia; Laschke, Matthias W; Ewald, Andreas H; Lehr, Thorsten; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2016-06-24

Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Reasons for Synthetic THC Use among College Students

ERIC Educational Resources Information Center

Vidourek, Rebecca A.; King, Keith A.; Burbage, Michelle L.

2013-01-01

Synthetic THC, also known as fake marijuana, is used by college students in the United States. The present study examined reasons for recent synthetic THC use among college students (N = 339). Students completed a 3-page survey during regularly scheduled class times. Results indicated students reported using synthetic THC for curiosity, to get…

40 CFR 63.6620 - What performance tests and other procedures must I use?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Where: Ci = concentration of carbon monoxide (CO), total hydrocarbons (THC), or formaldehyde at the control device inlet, Co = concentration of CO, THC, or formaldehyde at the control device outlet, and R = percent reduction of CO, THC, or formaldehyde emissions. (2) You must normalize the CO, THC, or...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2010 CFR

2010-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2011 CFR

2011-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2012 CFR

2012-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

32 CFR 161.16 - Benefits for transitional health care members and dependents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... members and dependents. This section shows the benefits for THC members and their eligible dependents. THC... Defense Authorization Act of for Fiscal Year 2005” made the THC program permanent and made the medical... years' commissary and exchange benefits to THC members. Section 734 of Public Law 110-417, “National...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2012 CFR

2012-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR 63.6620 - What performance tests and other procedures must I use?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Where: Ci = concentration of carbon monoxide (CO), total hydrocarbons (THC), or formaldehyde at the control device inlet, Co = concentration of CO, THC, or formaldehyde at the control device outlet, and R = percent reduction of CO, THC, or formaldehyde emissions. (2) You must normalize the CO, THC, or...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2011 CFR

2011-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2010 CFR

2010-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a b

Code of Federal Regulations, 2014 CFR

2014-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR 86.137-94 - Dynamometer test run, gaseous and particulate emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., if applicable), the temperature recorder, the vehicle cooling fan, and the heated THC analysis... diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and... measuring devices to zero. (i) For gaseous bag samples (except THC samples), the minimum flow rate is 0.17...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2010 CFR

2010-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2011 CFR

2011-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2014 CFR

2014-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2013 CFR

2013-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

...)(1). (4)(i) THC CEMS relative accuracy test. (A) If you are subject to limitations on THC emissions... CEMS, the THC span value (as propane) is 50 ppmvd. You demonstrate compliance with a RATA when the... conducting the performance test for total organic HAP, you must also determine THC emissions by operating a...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

...)(1). (4)(i) THC CEMS relative accuracy test. (A) If you are subject to limitations on THC emissions... CEMS, the THC span value (as propane) is 50 ppmvd. You demonstrate compliance with a RATA when the... conducting the performance test for total organic HAP, you must also determine THC emissions by operating a...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2012 CFR

2012-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2013 CFR

2013-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2013 CFR

2013-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR 86.137-94 - Dynamometer test run, gaseous and particulate emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., if applicable), the temperature recorder, the vehicle cooling fan, and the heated THC analysis... diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and... measuring devices to zero. (i) For gaseous bag samples (except THC samples), the minimum flow rate is 0.17...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2014 CFR

2014-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

Properties of the Only Thorium Fullerene, Th@C84, Uncovered.

PubMed

Kaminský, Jakub; Vícha, Jan; Bouř, Petr; Straka, Michal

2017-04-27

Only a single thorium fullerene, Th@C 84 , has been reported to date (Akiyama, K.; et al. J. Nucl. Radiochem. Sci. 2002, 3, 151-154). Although the system was characterized by UV-vis and XANES (X-ray absorption near edge structure) spectra, its structure and properties remain unknown. In this work we used the density functional calculations to identify molecular and electronic structure of the Th@C 84 . Series of molecular structures satisfying the ThC 84 stoichiometric formula were studied comprising 24 IPR and 110 non-IPR Th@C 84 isomers as well as 9 ThC 2 @C 82 IPR isomers. The lowest energy structure is Th@C 84 -C s (10) with the singlet ground state. Its predicted electronic absorption spectra are in agreement with the experimentally observed ones. The bonding between the cage and Th was characterized as polar covalent with Th in formal oxidation state IV. The NMR chemical shifts of Th@C 84 -C s (10) were predicted to guide the future experimental efforts in identification of this compound.

Effects of delta-9-tetrahydrocannabinol on evaluation of emotional images

PubMed Central

Ballard, Michael E; Bedi, Gillinder; de Wit, Harriet

2013-01-01

There is growing evidence that drugs of abuse alter processing of emotional information in ways that could be attractive to users. Our recent report that Δ9-tetrahydrocannabinol (THC) diminishes amygdalar activation in response to threat-related faces suggests that THC may modify evaluation of emotionally-salient, particularly negative or threatening, stimuli. In this study, we examined the effects of acute THC on evaluation of emotional images. Healthy volunteers received two doses of THC (7.5 and 15 mg; p.o.) and placebo across separate sessions before performing tasks assessing facial emotion recognition and emotional responses to pictures of emotional scenes. THC significantly impaired recognition of facial fear and anger, but it only marginally impaired recognition of sadness and happiness. The drug did not consistently affect ratings of emotional scenes. THC' effects on emotional evaluation were not clearly related to its mood-altering effects. These results support our previous work, and show that THC reduces perception of facial threat. Nevertheless, THC does not appear to positively bias evaluation of emotional stimuli in general PMID:22585232

Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in adult male rats.

PubMed

Wakeford, Alison G P; Flax, Shaun M; Pomfrey, Rebecca L; Riley, Anthony L

2016-01-01

Adolescent initiation of drug use has been linked to problematic drug taking later in life and may represent an important variable that changes the balance of the rewarding and/or aversive effects of abused drugs which may contribute to abuse vulnerability. The current study examined the effects of adolescent THC exposure on THC-induced place preference (rewarding effects) and taste avoidance (aversive effects) conditioning in adulthood. Forty-six male Sprague-Dawley adolescent rats received eight injections of an intermediate dose of THC (3.2mg/kg) or vehicle. After these injections, animals were allowed to mature and then trained in a combined CTA/CPP procedure in adulthood (PND ~90). Animals were given four trials of conditioning with intervening water-recovery days, a final CPP test and then a one-bottle taste avoidance test. THC induced dose-dependent taste avoidance but did not produce place conditioning. None of these effects was impacted by adolescent THC exposure. Adolescent exposure to THC had no effect on THC taste and place conditioning in adulthood. The failure to see an effect of adolescent exposure was addressed in the context of other research that has assessed exposure of drugs of abuse during adolescence on drug reactivity in adulthood. Copyright © 2015 Elsevier Inc. All rights reserved.

Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction.

PubMed

Chang, Xinwen; Bian, Yiding; He, Qizhi; Yao, Julei; Zhu, Jingping; Wu, Jinting; Wang, Kai; Duan, Tao

2017-01-01

Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction. © 2017 The Author(s). Published by S. Karger AG, Basel.

Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.

PubMed

Tunbridge, Elizabeth M; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Stumpenhorst, Katharina; Harrison, Paul J; Morrison, Paul D; Freeman, Daniel

2015-11-01

Cannabis use can induce cognitive impairments and psychotic experiences. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val(158)Met) appears to influence the immediate cognitive and psychotic effects of cannabis, or ∆(9)-tetrahydrocannabinol (THC), its primary psychoactive ingredient. This study investigated the moderation of the impact of experimentally administered THC by COMT. Cognitive performance and psychotic experiences were studied in participants without a psychiatric diagnosis, using a between-subjects design (THC vs. placebo). The effect of COMT Val(158)Met genotype on the cognitive and psychotic effects of THC, administered intravenously in a double-blind, placebo-controlled manner to 78 participants who were vulnerable to paranoia, was examined. The results showed interactive effects of genotype and drug group (THC or placebo) on working memory, assayed using the Digit Span Backwards task. Specifically, THC impaired performance in COMT Val/Val, but not Met, carriers. In contrast, the effect of THC on psychotic experiences, measured using the Community Assessment of Psychic Experiences (CAPE) positive dimension, was unaffected by COMT genotype. This study is the largest to date examining the impact of COMT genotype on response to experimentally administered THC, and the first using a purely non-clinical cohort. The data suggest that COMT genotype moderates the cognitive, but not the psychotic, effects of acutely administered THC. © The Author(s) 2015.

Δ9-Tetrahydrocannabinol (Δ9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques.

PubMed

Simon, Liz; Song, Keijing; Vande Stouwe, Curtis; Hollenbach, Andrew; Amedee, Angela; Mohan, Mahesh; Winsauer, Peter; Molina, Patricia

2016-03-01

Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing. Among the 24 miRs that were differentially expressed among the four groups, 16 miRs were modulated by THC in the presence of SIV. These 16 miRs were classified into four categories and the biological processes enriched by the target genes determined. Our results indicate that Δ9-THC modulates miRs that regulate mRNAs of proteins involved in 1) neurotrophin signaling, 2) MAPK signaling, and 3) cell cycle and immune response thus promoting an overall neuroprotective environment in the striatum of SIV-infected macaques. This is also reflected by increased Brain Derived Neurotrophic Factor (BDNF) and decreased proinflammatory cytokine expression compared to the VEH/SIV group. Whether Δ9-THC-mediated modulation of epigenetic mechanisms provides neuroprotection in other regions of the brain and during chronic SIV-infection remains to be determined.

Two-Step Forecast of Geomagnetic Storm Using Coronal Mass Ejection and Solar Wind Condition

NASA Technical Reports Server (NTRS)

Kim, R.-S.; Moon, Y.-J.; Gopalswamy, N.; Park, Y.-D.; Kim, Y.-H.

2014-01-01

To forecast geomagnetic storms, we had examined initially observed parameters of coronal mass ejections (CMEs) and introduced an empirical storm forecast model in a previous study. Now we suggest a two-step forecast considering not only CME parameters observed in the solar vicinity but also solar wind conditions near Earth to improve the forecast capability. We consider the empirical solar wind criteria derived in this study (Bz = -5 nT or Ey = 3 mV/m for t = 2 h for moderate storms with minimum Dst less than -50 nT) (i.e. Magnetic Field Magnitude, B (sub z) less than or equal to -5 nanoTeslas or duskward Electrical Field, E (sub y) greater than or equal to 3 millivolts per meter for time greater than or equal to 2 hours for moderate storms with Minimum Disturbance Storm Time, Dst less than -50 nanoTeslas) and a Dst model developed by Temerin and Li (2002, 2006) (TL [i.e. Temerin Li] model). Using 55 CME-Dst pairs during 1997 to 2003, our solar wind criteria produce slightly better forecasts for 31 storm events (90 percent) than the forecasts based on the TL model (87 percent). However, the latter produces better forecasts for 24 nonstorm events (88 percent), while the former correctly forecasts only 71 percent of them. We then performed the two-step forecast. The results are as follows: (i) for 15 events that are incorrectly forecasted using CME parameters, 12 cases (80 percent) can be properly predicted based on solar wind conditions; (ii) if we forecast a storm when both CME and solar wind conditions are satisfied (n, i.e. cap operator - the intersection set that is comprised of all the elements that are common to both), the critical success index becomes higher than that from the forecast using CME parameters alone, however, only 25 storm events (81 percent) are correctly forecasted; and (iii) if we forecast a storm when either set of these conditions is satisfied (?, i.e. cup operator - the union set that is comprised of all the elements of either or both), all geomagnetic storms are correctly forecasted.

In Vitro Stability of Free and Glucuronidated Cannabinoids in Urine Following Controlled Smoked Cannabis

PubMed Central

Desrosiers, Nathalie A.; Lee, Dayong; Scheidweiler, Karl B.; Concheiro-Guisan, Marta; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24h at room temperature (RT), 4°C and −20°C. Stability at RT, 4°C and −20°C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than −20°C, but not 4°C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH+THCCOOH-glucuronide) was significantly lower after 1 week. At 4°C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4°C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after one week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4°C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required. PMID:24292435

Validation of an Enzyme Immunoassay for Detection and Semiquantification of Cannabinoids in Oral Fluid

PubMed Central

Schwope, David M.; Milman, Garry; Huestis, Marilyn A.

2011-01-01

BACKGROUND Oral fluid (OF) is gaining prominence as an alternative matrix for monitoring drugs of abuse in the workplace, criminal justice, and driving under the influence of drugs programs. It is important to characterize assay performance and limitations of screening techniques for Δ9-tetrahydrocannabinol (THC) in OF. METHODS We collected OF specimens by use of the Quantisal™ OF collection device from 13 daily cannabis users after controlled oral cannabinoid administration. All specimens were tested with the Immunalysis Sweat/OF THC Direct ELISA and confirmed by 2-dimensional GC-MS. RESULTS The limit of detection was <1 µg/L THC equivalent, and the assay demonstrated linearity from 1 to 50 µg/L, with semiquantification to 200 µg/L. Intraplate imprecision (n = 7) ranged from 2.9% to 7.7% CV, and interplate imprecision (n = 20) was 3.0%–9.1%. Cross-reactivities at 4 µg/L were as follows: 11-hydroxy-THC, 198%; Δ8-tetrahydrocannabinol (Δ8-THC), 128%; 11-nor-9-carboxy-THC (THCCOOH), 121%; THC (target), 98%; cannabinol, 87%; THCCOOH-glucuronide, 11%; THC-glucuronide, 10%; and cannabidiol, 2.4%. Of 499 tested OF specimens, 52 confirmed positive (THC 2.0–290 µg/L), with 100% diagnostic sensitivity at the proposed Substance Abuse and Mental Health Services Administration screening cutoff of 4 µg/L cannabinoids and GC-MS cutoff of 2 µg/L THC. Forty-seven specimens screened positive but were not confirmed by 2D-GC-MS, yielding 89.5% diagnostic specificity and 90.6% diagnostic efficiency. Thirty-one of 47 unconfirmed immunoassay positive specimens were from 1 individual and contained >400 ng/L THCCOOH, potentially contributing to cross-reactivity. CONCLUSIONS The Immunalysis Sweat/OF THC Direct ELISA is an effective screening procedure for detecting cannabinoids in OF. PMID:20360126

Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats*

PubMed Central

Wiley, Jenny L.; Lefever, Timothy W.; Marusich, Julie A.; Craft, Rebecca M.

2017-01-01

Background Women report greater sensitivity to the subjective effects of Δ9-tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. Methods A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure. Results Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes. Conclusions This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC’s effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology. PMID:28130989

Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats

PubMed Central

Silveira, Mason M.; Adams, Wendy K.; Morena, Maria; Hill, Matthew N.; Winstanley, Catharine A.

2017-01-01

Background Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ9-Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. Methods Male Long–Evans rats (n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. Results We found that THC decreased choice of hard trials without impairing the animals’ ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex — an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in “slacker” rats. Limitations Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. Conclusion These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction. PMID:28245177

Neural correlates of interactions between cannabidiol and Δ9‐tetrahydrocannabinol in mice: implications for medical cannabis

PubMed Central

Todd, S M

2015-01-01

Background and Purpose It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ9‐tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study was to investigate whether CBD modulated the functional effects and c‐Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Experimental Approach Male C57BL/6 mice were treated with vehicle, CBD, THC or a combination of CBD and THC (10 mg·kg−1 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety‐related behaviour, body temperature and brain c‐Fos expression (a marker of neuronal activation). Key Results CBD potentiated THC‐induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c‐Fos expression in 11 of the 35 brain regions studied. CBD co‐administration suppressed THC‐induced c‐Fos expression in six of these brain regions. This effect was most pronounced in the medial preoptic nucleus and lateral periaqueductal gray. Treatment with CBD alone diminished c‐Fos expression only in the central nucleus of the amygdala compared with vehicle. Conclusions and Implications These data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC. PMID:26377899

Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis.

PubMed

Syed, Yahiya Y; McKeage, Kate; Scott, Lesley J

2014-04-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.

Plasma Cannabinoid Pharmacokinetics following Controlled Oral Δ9-Tetrahydrocannabinol and Oromucosal Cannabis Extract Administration

PubMed Central

Karschner, Erin L.; Darwin, W. David; Goodwin, Robert S.; Wright, Stephen; Huestis, Marilyn A.

2013-01-01

BACKGROUND Sativex®, a cannabis extract oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC’s effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board–approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (Cmax) and areas under the curve from 0–10.5 h postdose (AUC0→10.5) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in Cmax, time to maximum concentration or in the AUC0→10.5 between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION These data suggest that CBD modulation of THC’s effects is not due to a pharmacokinetic interaction at these therapeutic doses. PMID:21078841

Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro.

PubMed

Medveczky, Maria M; Sherwood, Tracy A; Klein, Thomas W; Friedman, Herman; Medveczky, Peter G

2004-09-15

The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication. Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV) and Epstein-Barr virus (EBV) replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS) of monkeys, murine gamma herpesvirus 68 (MHV 68), and herpes simplex type 1 (HSV-1) was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method. Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68. THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC. These studies may also provide the foundation for the development of antiviral strategies utilizing non-psychoactive derivatives of THC.

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

PubMed Central

Merrick, John; Lane, Brian; Sebree, Terri; Yaksh, Tony; O'Neill, Carol; Banks, Stan L.

2016-01-01

Abstract Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of −0.031 min−1 (R2=0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic reference standards. Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored. PMID:28861485

A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-04-01

To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans

PubMed Central

Braley, Gabriel; Blaise, Rebecca; Vendetti, Michael; Oliver, Stephen; Pittman, Brian; Ranganathan, Mohini; Bhakta, Savita; Zimolo, Zoran; Cooper, Thomas; Perry, Edward

2010-01-01

Introduction Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Δ-9-tetrahydrocannabinol (Δ-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Δ-9-THC in humans. Materials and methods In a 2-test-day double-blind study, 28 subjects including healthy subjects (n=17) and frequent users of cannabis (n=11) were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Δ-9-THC, respectively. Results Consistent with previous reports, intravenous Δ-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including “high.” Δ-9-THC also impaired verbal recall and attention. Haloperidol pretreatment did not reduce any of the behavioral effects of Δ-9-THC. Haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Δ-9-THC. Haloperidol and Δ-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Δ-9-THC induced memory impairments. Conclusions The deleterious effects of haloperidol pretreatment on the cognitive effects of Δ-9-THC are consistent with the preclinical literature in suggesting crosstalk between DAergic and CBergic systems. However, it is unlikely that DA D2 receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Δ-9-THC. Further investigation is warranted to understand the basis of the psychotomimetic effects of Δ-9-THC and to better understand the crosstalk between DAergic and CBergic systems. PMID:18228005

Work place drug testing of police officers after THC exposure during large volume cannabis seizures.

PubMed

Doran, Gregory S; Deans, Ralph; De Filippis, Carlo; Kostakis, Chris; Howitt, Julia A

2017-06-01

Police officers responsible for the seizure and removal of illegally grown cannabis plants from indoor and outdoor growing operations face the prospect of THC exposure while performing their work duties. As a result, a study investigating the amount of THC on hands and uniforms of officers during raids on cannabis growing houses (CGHs) and forest cannabis plantations (FCPs) and in the air at these sites was conducted. Swabs of gloves/hands, chests, and heads/necks were collected and analysed for THC. Results of hand swabs indicated that officers removing plants from FCPs were exposed to THC concentrations up to 20 times those involved in raids at CGHs, which was mainly associated with the number and size of plants seized. Air samples collected inside cannabis houses showed no detectable THC. Air samples collected inside the cargo area of the storage trucks used during FCP raids indicated that THC can be volatilised when lush plants are compressed by other seized plants loaded on top of them in the truck over a period of several days, allowing composting of plants at the bottom of the load to commence. The elevated temperature and humidity inside the truck may assist the decarboxylation of THCA to THC, as well as increasing the rate of volatilisation of THC. More than 100 urine samples were collected from officers in raids on both CGHs and FCPs and all tested negative for THC. Removal of cannabis plants by officers often resulted in cuts, abrasions and ruptured blisters on exposed skin surfaces, particularly at FCPs. The results in this study suggest that even when small areas of damaged skin are directly exposed to THC by contact transfer, the likelihood of showing a positive THC urine test is low. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

A Novel Observational Method for Assessing Acute Responses to Cannabis: Preliminary Validation Using Legal Market Strains.

PubMed

Bidwell, L Cinnamon; Mueller, Raeghan; YorkWilliams, Sophie L; Hagerty, Sarah; Bryan, Angela D; Hutchison, Kent E

2018-01-01

Background: The development of novel cannabis research methods that are compatible with current federal regulations is imperative to conduct studies of the effects of legal market cannabis. There is very little research on higher strength, higher Δ9-tetrahydrocannabinol (THC), which has become increasingly available since legalization. Research on strains containing cannabidiol (CBD), a second primary, but nonpsychotomimetic, cannabinoid, is very limited. Materials and Methods: Using a novel observational methodology, regular cannabis users were asked to use one of two legal market cannabis strains that they purchased from a local dispensary (one strain containing 8% THC and 16% CBD (THC+CBD) and one containing a 17% THC concentration, but no CBD (THC). After using their suggested cannabis strain as they typically would for a 3-day period, participants returned to the laboratory immediately after their final use. Measures included a blood draw to measure cannabinoid blood levels and circulating cytokines, self-reported subjective drug effects, and verbal recall memory. Results: Analysis of CBD/THC concentration levels in the blood following the 3-day strain manipulation suggests that all, but one participant ( n =23/24) followed instructions and used their assigned strain. Individuals in the THC group ( n =11) smoked no more than their usual amount, and participants who used the THC+CBD ( n =12) strain smoked more than their reported usual amount, but did not have significantly different THC+metabolite blood levels from the THC group. The THC+CBD strain was also associated with less desire to smoke, lower levels of subjective drug effects, and lower levels of circulating cytokines (TNF-α, IL-6, and IL-1β) immediately after use. Conclusions: Initial results support the feasibility of this novel observational methodology involving brief manipulation of strain use. Preliminary findings indicate that participants may self-titrate cannabis use based on cannabinoid concentration and the THC+CBD strain was associated with lower levels of cannabis craving, subjective intoxication, and circulating cytokines.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

Validation of a two-dimensional gas chromatography mass spectrometry method for the simultaneous quantification of cannabidiol, Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC in plasma.

PubMed

Karschner, Erin L; Barnes, Allan J; Lowe, Ross H; Scheidweiler, Karl B; Huestis, Marilyn A

2010-05-01

A sensitive analytical method for simultaneous quantification of sub-nanogram concentrations of cannabidiol (CBD), Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in plasma is presented for monitoring cannabinoid pharmacotherapy and illicit cannabis use. Analytes were extracted from 1 mL plasma by solid-phase extraction, derivatized with N,O-bis(trimethylsilyl) trifluoroacetamide with 1% trimethylchlorosilane, and analyzed by two-dimensional gas chromatography mass spectrometry (2D-GCMS) with cryofocusing. The lower calibration curve was linear from 0.25-25 ng/mL for CBD and THC, 0.125-25 ng/mL for 11-OH-THC and 0.25-50 ng/mL for THCCOOH. A second higher linear range from 5-100 ng/mL, achieved through modification of injection parameters, was validated for THC, 11-OH-THC, and THCCOOH and was only implemented if concentrations exceeded the lower curve upper limit of linearity. This procedure prevented laborious re-extraction by allowing the same specimen to be re-injected for quantification on the high calibration curve. Intra- and inter-assay imprecision, determined at four quality control concentrations, were or=72.9% for all analytes. Analytes were stable when stored at 22 degrees C for 16 h, 4 degrees C for 48 h, after three freeze-thaw cycles at -20 degrees C and when stored on the autosampler for 48 h. This sensitive and specific 2D-GCMS assay provides a new means of simultaneously quantifying CBD, THC and metabolite biomarkers in clinical medicine, forensic toxicology, workplace drug testing, and driving under the influence of drugs programs.

Frequency and irregularity of heart rate in drivers suspected of driving under the influence of cannabis.

PubMed

Khiabani, Hassan Z; Mørland, Jørg; Bramness, Jørgen G

2008-12-01

Delta 9-tetrahydrocannabinol (THC) is the major active component of cannabis. Cardiovascular effects of THC have previously been reported: tachycardia after intake, but also bradycardia at higher doses. The purpose of this study was, firstly, to investigate the frequency and irregularity of heart rate in a group of cannabis users in their natural surroundings. We also compared THC-positive drivers with a regular pulse with THC-positive drivers with an irregular pulse. The division of Forensic Toxicology and Drug Abuse (DFTDA) at the Norwegian Institute of Public Heath analyzes blood samples from all drivers suspected of driving under the influence of drugs. We studied pulse rate and regularity in 502 THC-positive drivers who tested negative for other substances. As a control group, we randomly selected 125 drug-negative cases from the database of the DFTDA; no alcohol, narcotics, or medicinal drugs of abuse were detected. The Delta9-THC-positive drivers had a higher mean pulse rate than the control group [82.8 beats/min (SD 16.3) versus 75.6 beats/min (SD 9.2)] and more cases with tachycardia were detected in the Delta9-THC-positive group (19.4% versus 1.6%). There was only one driver with an irregular heart beat in the control group, while there were nine among the Delta9-THC-positive drivers. The drivers with an irregular pulse were over-represented amongst those with the lowest blood Delta9-THC concentrations. This report represents a large study of subjects in a real-life situation and includes observations on pulse frequency, regularity, and blood Delta9-THC concentration. A substantial fraction of Delta9-THC-positive drivers had tachycardia, but there was no correlation between blood Delta9-THC concentration and pulse rate in the present study. We had no further diagnostic information on the cause of the pulse irregularities, but our results indicate that occasional users of cannabis tend to have irregular heart rates at low THC concentrations and at low pulse rates.

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

PubMed

Weinstein, A; Brickner, O; Lerman, H; Greemland, M; Bloch, M; Lester, H; Chisin, R; Sarne, Y; Mechoulam, R; Bar-Hamburger, R; Freedman, N; Even-Sapir, E

2008-06-01

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

Hair analysis for delta(9)-THC, delta(9)-THC-COOH, CBN and CBD, by GC/MS-EI. Comparison with GC/MS-NCI for delta(9)-THC-COOH.

PubMed

Baptista, Maria João; Monsanto, Paula Verâncio; Pinho Marques, Estela Gouveia; Bermejo, Ana; Avila, Sofia; Castanheira, Alice Martelo; Margalho, Cláudia; Barroso, Mário; Vieira, Duarte Nuno

2002-08-14

A sensitive analytical method was developed for quantitative analysis of delta(9)-tetrahydrocannabinol (delta(9)-THC), 11-nor-delta(9)-tetrahydrocannabinol-carboxylic acid (delta(9)-THC-COOH), cannabinol (CBN) and cannabidiol (CBD) in human hair. The identification of delta(9)-THC-COOH in hair would document Cannabis use more effectively than the detection of parent drug (delta(9)-THC) which might have come from environmental exposure. Ketamine was added to hair samples as internal standard for CBN and CBD. Ketoprofen was added to hair samples as internal standard for the other compounds. Samples were hydrolyzed with beta-glucuronidase/arylsulfatase for 2h at 40 degrees C. After cooling, samples were extracted with a liquid-liquid extraction procedure (with chloroform/isopropyl alcohol, after alkalinization, and n-hexane/ethyl acetate, after acidification), which was developed in our laboratory. The extracts were analysed before and after derivatization with pentafluoropropionic anhydride (PFPA) and pentafluoropropanol (PFPOH) using a Hewlett Packard gas chromatographer/mass spectrometer detector, in electron impact mode (GC/MS-EI). Derivatized delta(9)-THC-COOH was also analysed using a Hewlett Packard gas chromatographer/mass spectrometer detector, in negative ion chemical ionization mode (GC/MS-NCI) using methane as the reagent gas. Responses were linear ranging from 0.10 to 5.00 ng/mg hair for delta(9)-THC and CBN, 0.10-10.00 ng/mg hair for CBD, 0.01-5.00 ng/mg for delta(9)-THC-COOH (r(2)>0.99). The intra-assay precisions ranged from <0.01 to 12.40%. Extraction recoveries ranged from 80.9 to 104.0% for delta(9)-THC, 85.9-100.0% for delta(9)-THC-COOH, 76.7-95.8% for CBN and 71.0-94.0% for CBD. The analytical method was applied to 87 human hair samples, obtained from individuals who testified in court of having committed drug related crimes. Quantification of delta(9)-THC-COOH using GC/MS-NCI was found to be more convenient than GC/MS-EI. The latter may give rise to false negatives due to the detection limit.

Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.

PubMed

Johnson, Jeremy R; Burnell-Nugent, Mary; Lossignol, Dominique; Ganae-Motan, Elena Doina; Potts, Richard; Fallon, Marie T

2010-02-01

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of -1.37 vs. -0.69), whereas the THC group showed a nonsignificant change (-1.01 vs. -0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids. Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Plasma and urine profiles of Delta9-tetrahydrocannabinol and its metabolites 11-hydroxy-Delta9-tetrahydrocannabinol and 11-nor-9-carboxy-Delta9-tetrahydrocannabinol after cannabis smoking by male volunteers to estimate recent consumption by athletes.

PubMed

Brenneisen, Rudolf; Meyer, Pascale; Chtioui, Haithem; Saugy, Martial; Kamber, Matthias

2010-04-01

Since 2004, cannabis has been prohibited by the World Anti-Doping Agency for all sports competitions. In the years since then, about half of all positive doping cases in Switzerland have been related to cannabis consumption. In doping urine analysis, the target analyte is 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), the cutoff being 15 ng/mL. However, the wide urinary detection window of the long-term metabolite of Delta(9)-tetrahydrocannabinol (THC) does not allow a conclusion to be drawn regarding the time of consumption or the impact on the physical performance. The purpose of the present study on light cannabis smokers was to evaluate target analytes with shorter urinary excretion times. Twelve male volunteers smoked a cannabis cigarette standardized to 70 mg THC per cigarette. Plasma and urine were collected up to 8 h and 11 days, respectively. Total THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (THC-OH), and THC-COOH were determined after hydrolysis followed by solid-phase extraction and gas chromatography/mass spectrometry. The limits of quantitation were 0.1-1.0 ng/mL. Eight puffs delivered a mean THC dose of 45 mg. Plasma levels of total THC, THC-OH, and THC-COOH were measured in the ranges 0.2-59.1, 0.1-3.9, and 0.4-16.4 ng/mL, respectively. Peak concentrations were observed at 5, 5-20, and 20-180 min. Urine levels were measured in the ranges 0.1-1.3, 0.1-14.4, and 0.5-38.2 ng/mL, peaking at 2, 2, and 6-24 h, respectively. The times of the last detectable levels were 2-8, 6-96, and 48-120 h. Besides high to very high THC-COOH levels (245 +/- 1,111 ng/mL), THC (3 +/- 8 ng/mL) and THC-OH (51 +/- 246 ng/mL) were found in 65 and 98% of cannabis-positive athletes' urine samples, respectively. In conclusion, in addition to THC-COOH, the pharmacologically active THC and THC-OH should be used as target analytes for doping urine analysis. In the case of light cannabis use, this may allow the estimation of more recent consumption, probably influencing performance during competitions. However, it is not possible to discriminate the intention of cannabis use, i.e., for recreational or doping purposes. Additionally, pharmacokinetic data of female volunteers are needed to interpret cannabis-positive doping cases of female athletes.

Development and validation of an automated liquid-liquid extraction GC/MS method for the determination of THC, 11-OH-THC, and free THC-carboxylic acid (THC-COOH) from blood serum.

PubMed

Purschke, Kirsten; Heinl, Sonja; Lerch, Oliver; Erdmann, Freidoon; Veit, Florian

2016-06-01

The analysis of Δ(9)-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-Δ(9)-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THC-COOH) from blood serum is a routine task in forensic toxicology laboratories. For examination of consumption habits, the concentration of the phase I metabolite THC-COOH is used. Recommendations for interpretation of analysis values in medical-psychological assessments (regranting of driver's licenses, Germany) include threshold values for the free, unconjugated THC-COOH. Using a fully automated two-step liquid-liquid extraction, THC, 11-OH-THC, and free, unconjugated THC-COOH were extracted from blood serum, silylated with N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA), and analyzed by GC/MS. The automation was carried out by an x-y-z sample robot equipped with modules for shaking, centrifugation, and solvent evaporation. This method was based on a previously developed manual sample preparation method. Validation guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh) were fulfilled for both methods, at which the focus of this article is the automated one. Limits of detection and quantification for THC were 0.3 and 0.6 μg/L, for 11-OH-THC were 0.1 and 0.8 μg/L, and for THC-COOH were 0.3 and 1.1 μg/L, when extracting only 0.5 mL of blood serum. Therefore, the required limit of quantification for THC of 1 μg/L in driving under the influence of cannabis cases in Germany (and other countries) can be reached and the method can be employed in that context. Real and external control samples were analyzed, and a round robin test was passed successfully. To date, the method is employed in the Institute of Legal Medicine in Giessen, Germany, in daily routine. Automation helps in avoiding errors during sample preparation and reduces the workload of the laboratory personnel. Due to its flexibility, the analysis system can be employed for other liquid-liquid extractions as well. To the best of our knowledge, this is the first publication on a comprehensively automated classical liquid-liquid extraction workflow in the field of forensic toxicological analysis. Graphical abstract GC/MS with MPS Dual Head at the Institute of Legal Medicine, Giessen, Germany. Modules from left to right: (quick) Mix (for LLE), wash station, tray 1 (vials for extracts), solvent reservoir, (m) VAP (for extract evaporation), Solvent Filling Station (solvent supply), cooled tray 2 (vials for serum samples), and centrifuge (for phase separation).

Analysis and Management of Rectal Gas with Kampo Formulas During Intensity-Modulated Radiotherapy of Prostate Cancer: A Case Series Study.

PubMed

Nagai, Aiko; Shibamoto, Yuta; Ogawa, Keiko; Inoda, Koji; Yoshida, Masanori; Kikuchi, Yuzo

2016-06-01

During intensity-modulated radiation therapy (IMRT) for prostate cancer, the target, bladder, and rectum positions should be kept constant to reduce adverse events, such as radiation proctitis, and to increase local tumor control. For this purpose, decreasing the rectal contents as much as possible is important. Daisaikoto (DST) and bukuryoingohangekobokuto (BIHKT) are traditional Japanese herbal (Kampo) formulas that have been used to treat patients with abdominal bloating or constipation. This study investigated the effect of DST and BIHKT on the rectal gas volume during prostate IMRT according to Kampo diagnosis. Five patients were treated with DST or BIHKT at a dose of 5.0 or 7.5 g/d. The volume of rectal gas in 189 megavoltage computed tomographic images taken before each treatment session and the frequency of rectal gas drainage were evaluated before and after DST or BIHKT administration. After DST or BIHKT treatment, the mean volume of rectal gas was reduced from 6.4 to 2.1 mL, and the mean frequency of gas drainage decreased from 43% to 9%. DST and BIHKT appear to be useful in reducing rectal gas, which would help prevent radiation proctitis and improve the local control of prostate cancer with IMRT.

The correlation between perceived social support, cortisol and brain derived neurotrophic factor levels in healthy women.

PubMed

Ma, Doy Yung; Chang, Wei Hung; Chi, Mei Hung; Tsai, Hsin Chun; Yang, Yen Kuang; Chen, Po See

2016-05-30

In this study, the role of brain derived neurotrophic factor (BDNF) in stress resilience was investigated. With a focus on healthy subjects, we explored whether plasma BDNF levels are correlated with the dexamethasone suppression test (DST) and subjectively perceived social support status. Moreover, we examined the possible interacting effect of DST status and perceived social support on BDNF levels. Seventy-two healthy volunteers, 44 females and 28 males, were recruited from the community and completed the perceived routine support subscale of Measurement of Support Function (PRS_MSF) questionnaire. Plasma BDNF levels and DST suppression rate with the low dose DST were measured. There was a significant positive correlation between BDNF and DST suppression rate in the female subjects. This was also true for the plasma BDNF levels and PRS_MSF in the female subjects. The positive correlation between BDNF and PRS_MSF was significant only in female subjects with low DST suppression rates. Plasma BDNF levels were associated with stress resilience in a sex-specific manner. Subjects' belief in social support might buffer the biological stress reactions. Differences in social perception and the biological stress response between men and women merits further investigation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prediction of MeV electron fluxes throughout the outer radiation belt using multivariate autoregressive models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakaguchi, Kaori; Nagatsuma, Tsutomu; Reeves, Geoffrey D.

The Van Allen radiation belts surrounding the Earth are filled with MeV-energy electrons. This region poses ionizing radiation risks for spacecraft that operate within it, including those in geostationary orbit (GEO) and medium Earth orbit. In order to provide alerts of electron flux enhancements, 16 prediction models of the electron log-flux variation throughout the equatorial outer radiation belt as a function of the McIlwain L parameter were developed using the multivariate autoregressive model and Kalman filter. Measurements of omnidirectional 2.3 MeV electron flux from the Van Allen Probes mission as well as >2 MeV electrons from the GOES 15 spacecraftmore » were used as the predictors. Furthermore, we selected model explanatory parameters from solar wind parameters, the electron log-flux at GEO, and geomagnetic indices. For the innermost region of the outer radiation belt, the electron flux is best predicted by using the Dst index as the sole input parameter. For the central to outermost regions, at L≥4.8 and L ≥5.6, the electron flux is predicted most accurately by including also the solar wind velocity and then the dynamic pressure, respectively. The Dst index is the best overall single parameter for predicting at 3 ≤ L ≤ 6, while for the GEO flux prediction, the K P index is better than Dst. Finally, a test calculation demonstrates that the model successfully predicts the timing and location of the flux maximum as much as 2 days in advance and that the electron flux decreases faster with time at higher L values, both model features consistent with the actually observed behavior.« less

Prediction of MeV electron fluxes throughout the outer radiation belt using multivariate autoregressive models

DOE PAGES

Sakaguchi, Kaori; Nagatsuma, Tsutomu; Reeves, Geoffrey D.; ...

2015-12-22

The Van Allen radiation belts surrounding the Earth are filled with MeV-energy electrons. This region poses ionizing radiation risks for spacecraft that operate within it, including those in geostationary orbit (GEO) and medium Earth orbit. In order to provide alerts of electron flux enhancements, 16 prediction models of the electron log-flux variation throughout the equatorial outer radiation belt as a function of the McIlwain L parameter were developed using the multivariate autoregressive model and Kalman filter. Measurements of omnidirectional 2.3 MeV electron flux from the Van Allen Probes mission as well as >2 MeV electrons from the GOES 15 spacecraftmore » were used as the predictors. Furthermore, we selected model explanatory parameters from solar wind parameters, the electron log-flux at GEO, and geomagnetic indices. For the innermost region of the outer radiation belt, the electron flux is best predicted by using the Dst index as the sole input parameter. For the central to outermost regions, at L≥4.8 and L ≥5.6, the electron flux is predicted most accurately by including also the solar wind velocity and then the dynamic pressure, respectively. The Dst index is the best overall single parameter for predicting at 3 ≤ L ≤ 6, while for the GEO flux prediction, the K P index is better than Dst. Finally, a test calculation demonstrates that the model successfully predicts the timing and location of the flux maximum as much as 2 days in advance and that the electron flux decreases faster with time at higher L values, both model features consistent with the actually observed behavior.« less

Prediction of MeV electron fluxes throughout the outer radiation belt using multivariate autoregressive models

NASA Astrophysics Data System (ADS)

Sakaguchi, Kaori; Nagatsuma, Tsutomu; Reeves, Geoffrey D.; Spence, Harlan E.

2015-12-01

The Van Allen radiation belts surrounding the Earth are filled with MeV-energy electrons. This region poses ionizing radiation risks for spacecraft that operate within it, including those in geostationary orbit (GEO) and medium Earth orbit. To provide alerts of electron flux enhancements, 16 prediction models of the electron log-flux variation throughout the equatorial outer radiation belt as a function of the McIlwain L parameter were developed using the multivariate autoregressive model and Kalman filter. Measurements of omnidirectional 2.3 MeV electron flux from the Van Allen Probes mission as well as >2 MeV electrons from the GOES 15 spacecraft were used as the predictors. Model explanatory parameters were selected from solar wind parameters, the electron log-flux at GEO, and geomagnetic indices. For the innermost region of the outer radiation belt, the electron flux is best predicted by using the Dst index as the sole input parameter. For the central to outermost regions, at L ≧ 4.8 and L ≧ 5.6, the electron flux is predicted most accurately by including also the solar wind velocity and then the dynamic pressure, respectively. The Dst index is the best overall single parameter for predicting at 3 ≦ L ≦ 6, while for the GEO flux prediction, the KP index is better than Dst. A test calculation demonstrates that the model successfully predicts the timing and location of the flux maximum as much as 2 days in advance and that the electron flux decreases faster with time at higher L values, both model features consistent with the actually observed behavior.

Effects of Geomagnetic Storms on the Postsunset Vertical Plasma Drift in the Equatorial Ionosphere

NASA Astrophysics Data System (ADS)

Huang, Chao-Song

2018-05-01

It has been observed that geomagnetic storms cause suppression of the occurrence of equatorial spread F or plasma bubbles in the evening sector. In this study, we use ion drift data measured by the Communication/Navigation Outage Forecasting System satellite over 6 years (2008-2014) to derive the dependence of the vertical ion drift at the prereversal enhancement peak on the strength of magnetic storms (the Dst index). It is found that the average vertical ion drift does not change much for Dst in the range between 0 and -60 nT but decreases approximately linearly with the increasing magnitude of Dst for Dst < -60 nT. The net decrease in the average vertical ion drift is 30 m/s when Dst changes from -60 to -90 nT. This result is derived when the ion drift data during the storm main phase are excluded, so the decrease of the vertical ion drift is caused by storm time disturbance dynamo. A possible interpretation of this phenomenon is that geomagnetic activity must be strong enough (e.g., Dst < -60 nT) so disturbance winds can reach the equatorial region and change plasma drifts there. The storm time disturbance dynamo becomes dominant in the equatorial ionospheric dynamics near the end of the storm main phase, 4.7 hr after the storm onset. The postsunset vertical ion drift is significantly decreased during the early stage of the storm recovery phase but becomes almost fully recovered when Dst increases close to -60 nT.

Evaluation of the BACTEC MGIT 960 SL DST Kit and the GenoType MTBDRsl Test for Detecting Extensively Drug-resistant Tuberculosis Cases

PubMed Central

Tekin, Kemal; Albay, Ali; Simsek, Hulya; Sig, Ali Korhan; Guney, Mustafa

2017-01-01

Objective: The present study aimed to evaluate the performances of the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test for detecting second-line antituberculosis drug resistance in Multidrug-resistant TB (MDR-TB) cases. Materials and Methods: Forty-six MDR-TB strains were studied. Second-line antituberculosis drug resistances were detected using the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test. The Middlebrook 7H10 agar proportion method was used as the reference test. Results: The sensitivity and specificity values for the BACTEC MGIT 960 SL DST kit were both 100% for amikacin, kanamycin, capreomycin (4 µg/mL), and ofloxacin; 100% and 95.3%, respectively, for capreomycin (10 µg/mL); and 85.7% and 100%, respectively, for moxifloxacin (0.5 µg/mL). The sensitivity and specificity values for the GenoType MTBDRsl test to detect fluoroquinolone and aminoglycoside/cyclic peptide resistance were 88.9% and 100%, respectively, for ofloxacin and 85.7% and 94.9%, respectively, for moxifloxacin (0.5 µg/mL). The accuracy of the GenoType MTBDRsl assay for kanamycin, capreomycin, ofloxacin, and moxifloxacin was lower than that of the BACTEC MGIT 960 SL DST. Conclusion: The BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl were successful in detecting second-line antituberculosis drug resistance. Preliminary results of the GenoType MTBDRsl are very valuable for early treatment decisions, but we still recommend additional BACTEC MGIT 960 SL DST kit usage in the routine evaluation of drug-resistant tuberculosis. PMID:29123441

A comparison of quality of present-day heat flow obtained from BHTs, Horner Plots of Malay Basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waples, D.W.; Mahadir, R.

1994-07-01

Reconciling temperature data obtained from measurement of single BHT, multiple BHT at a single depth, RFTs, and DSTs, is very difficult. Quality of data varied widely, however DST data were assumed to be most reliable. Data from 87 wells was used in this study, but only 47 wells have DST data. BASINMOD program was used to calculate the present-day heat flow, using measured thermal conductivity and calibrated against the DST data. The heat flows obtained from the DST data were assumed to be correct and representative throughout the basin. Then, heat flows using (1) uncorrected RFT data, (2) multiple BHTmore » data corrected by the Horner plot method, and (3) single BHT values corrected upward by a standard 10% were calculated. All of these three heat-flow populations had identically standard deviations to that for the DST data, but with significantly lower mean values. Correction factors were calculated to give each of the three erroneous populations the same mean value as the DST population. Heat flows calculated from RFT data had to be corrected upward by a factor of 1.12 to be equivalent to DST data; Horner plot data corrected by a factor of 1.18, and single BHT data by a factor of 1.2. These results suggest that present-day subsurface temperatures using RFT, Horner plot, and BHT data are considerably lower than they should be. The authors suspect qualitatively similar results would be found in other areas. Hence, they recommend significant corrections be routinely made until local calibration factors are established.« less

Evaluation of the BACTEC MGIT 960 SL DST Kit and the GenoType MTBDRsl Test for Detecting Extensively Drug-resistant Tuberculosis Cases.

PubMed

Tekin, Kemal; Albay, Ali; Simsek, Hulya; Sig, Ali Korhan; Guney, Mustafa

2017-10-01

The present study aimed to evaluate the performances of the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test for detecting second-line antituberculosis drug resistance in Multidrug-resistant TB (MDR-TB) cases. Forty-six MDR-TB strains were studied. Second-line antituberculosis drug resistances were detected using the BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl test. The Middlebrook 7H10 agar proportion method was used as the reference test. The sensitivity and specificity values for the BACTEC MGIT 960 SL DST kit were both 100% for amikacin, kanamycin, capreomycin (4 µg/mL), and ofloxacin; 100% and 95.3%, respectively, for capreomycin (10 µg/mL); and 85.7% and 100%, respectively, for moxifloxacin (0.5 µg/mL). The sensitivity and specificity values for the GenoType MTBDRsl test to detect fluoroquinolone and aminoglycoside/cyclic peptide resistance were 88.9% and 100%, respectively, for ofloxacin and 85.7% and 94.9%, respectively, for moxifloxacin (0.5 µg/mL). The accuracy of the GenoType MTBDRsl assay for kanamycin, capreomycin, ofloxacin, and moxifloxacin was lower than that of the BACTEC MGIT 960 SL DST. The BACTEC MGIT 960 SL DST kit and the GenoType MTBDRsl were successful in detecting second-line antituberculosis drug resistance. Preliminary results of the GenoType MTBDRsl are very valuable for early treatment decisions, but we still recommend additional BACTEC MGIT 960 SL DST kit usage in the routine evaluation of drug-resistant tuberculosis.

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2010 CFR

2010-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2012 CFR

2012-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2014 CFR

2014-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2012 CFR

2012-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) THC emissions test. (i) If you are subject to limitations on THC emissions, you must operate a CEMS in... assurance evaluations for CEMS, the THC span value (as propane) is 50 ppmvd and the reference method (RM) is Method 25A of appendix A to part 60 of this chapter. (ii) Use the THC CEMS to conduct the initial...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2010 CFR

2010-07-01

... THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR part 60... the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2013 CFR

2013-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2014 CFR

2014-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2013 CFR

2013-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2011 CFR

2011-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2011 CFR

2011-07-01

... THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR part 60... the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

Descending and Local Network Interactions Control Adaptive Locomotion

DTIC Science & Technology

2014-12-04

segment). The thorax-coxa ( ThC ) joint swings dramatically in the front leg, but hardly moves at all in the middle and hind legs. These observations...changes in the three degree of freedom thorax-coxa joint ( ThC ) (Fig. 1). Indeed we were able to describe which of the three degrees of freedom were...these actions are distinct. The T1 leg relies heavily on actions of the second and third degree of freedom of the ThC joint ( ThC 2 and ThC3) whereas in

Decay of the Dst field of geomagnetic disturbance after substorm onset and its implication to storm-substorm relation

NASA Astrophysics Data System (ADS)

Iyemori, T.; Rao, D. R. K.

1996-06-01

In order to investigate the causal relationship between magnetic storms and substorms, variations of the mid-latitude geomagnetic indices, ASY (asymmetric part) and SYM (symmetric part), at substorm onsets are examined. Substorm onsets are defined by three different phenomena; (1) a rapid increase in the mid-latitude asymmetric-disturbance indices, ASY-D and ASY-H, with a shape of so-called `mid-latitude positive bay\\'; (2) a sharp decrease in the AL index; (3) an onset of Pi2 geomagnetic pulsation. The positive bays are selected using eye inspection and a pattern-matching technique. The 1-min-resolution SYM-H index, which is essentially the same as the hourly Dst index except in terms of the time resolution, does not show any statistically significant development after the onset of substorms; it tends to decay after the onset rather than to develop. It is suggested by a simple model calculation that the decay of the magnetospheric tail current after substorm onset is responsible for the decay of the Dst field. The relation between the IMF southward turning and the development of the Dst field is re-examined. The results support the idea that the geomagnetic storms and substorms are independent processes; that is, the ring-current development is not the result of the frequent occurrence of substorms, but that of enhanced convection caused by the large southward IMF. A substorm is the process of energy dissipation in the magnetosphere, and its contribution to the storm-time ring-current formation seems to be negligible. The decay of the Dst field after a substorm onset is explained by a magnetospheric energy theorem. Acknowledgements. This study is supported in part by the Ministry of Education, Science, Sports, and Culture in Japan, under a Grant-in-Aid for Scientific Research (Category B). Topical Editor D. Alcaydé thanks M. Lockwood and N. J. Fox for their help in evaluating this paper.-> Correspondence to: Y. Kamide->

The DESIRE Airborne gravity project in the Dead Sea Basin and 3D numerical gravity modeling

NASA Astrophysics Data System (ADS)

Choi, Sungchan; Götze, Hans-Jürgen; Meyer, Uwe; Desire-Group

2010-05-01

This geo-scientific research focuses on the geological setting of the Dead Sea Transform (DST) and the Dead Sea Basin (DSB) and its resulting pull-apart basins. Since the late 1970s, crustal scale geophysical experiments have been carried out in this region. However, the nature of the crust underlying the eastern and western shoulders of the DSB and underneath the DST itself is still a hotly debated topic among researchers. To address one of the central questions of plate tectonics - How do large transform systems work and what are their typical features? - An international geoscientific Dead Sea Integrated Research project (DESIRE) is being conducted by colleagues from Germany, Israel, Palestine, and Jordan. In order to provide a high resolution gravity database that support 3D numerical modeling and hence a more comprehensive understanding of the nature and segmentation of the DST, an airborne gravity survey as a part of the DESIRE project has been carried out from February to March 2007. The airborne gravity survey covered the DST from Elat/Aqaba in the South to the northern rim of the Dead Sea. The low speed and terrain-following helicopter gravity flights were performed to acquire the highest possible data quality. In total, 32 north-south profiles and 16 west-east profiles crossing the DST have been measured. Most of the profiles concentrated in areas that lacked terrestrial gravity data coverage, e. g. over the shoulders of the DSB. The airborne gravity data are merged with existing conventional (terrestrial) data sets to provide a seamless gravity map of the area of interest. The results of the 3D gravity modelling based the GPS analysis, magnetic field characters, seismic researches and analysis of earthquake data allow us to propose that (1) the DSB is divided into two tectonic blocks by the region between the Lisan peninsula and the southern margin of the northern DSB and (2) the tectonic system in the DSB is defined as a counter-clockwise rotating pull apart basin due to the ‘Riedel flaking', by which the northern DSB is rotated counter-clockwise from the region and the southern DSB to the opposite direction. The salt diapir below the Dead Sea is suspected to be migrated from the Lisan peninsula to present region by the rotation of the northern DSB, while the Sedom diapir is extended to the SE direction. The Almacik flake along the North Anatolian fault, Turkey is probably another example of such basin.

Effect of Norbinaltorphimine on Δ9-Tetrahydrocannabinol (THC)-Induced Taste Avoidance in Adolescent and Adult Sprague-Dawley Rats

PubMed Central

Flax, Shaun M.; Wakeford, Alison G.P.; Cheng, Kejun; Rice, Kenner C.; Riley, Anthony L.

2017-01-01

Rationale The aversive effects of Δ9-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. Objectives The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. Methods Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8 and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague Dawley rats. Results The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. Conclusions That norBNI had no significant effect on THC-induced avoidance in adults and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague Dawley rats. PMID:26025420

Effect of norbinaltorphimine on ∆⁹-tetrahydrocannabinol (THC)-induced taste avoidance in adolescent and adult Sprague-Dawley rats.

PubMed

Flax, Shaun M; Wakeford, Alison G P; Cheng, Kejun; Rice, Kenner C; Riley, Anthony L

2015-09-01

The aversive effects of ∆(9)-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8, and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague-Dawley rats. The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. That norBNI had no significant effect on THC-induced avoidance in adults, and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague-Dawley rats.

Two-step forecast of geomagnetic storm using coronal mass ejection and solar wind condition

PubMed Central

Kim, R-S; Moon, Y-J; Gopalswamy, N; Park, Y-D; Kim, Y-H

2014-01-01

To forecast geomagnetic storms, we had examined initially observed parameters of coronal mass ejections (CMEs) and introduced an empirical storm forecast model in a previous study. Now we suggest a two-step forecast considering not only CME parameters observed in the solar vicinity but also solar wind conditions near Earth to improve the forecast capability. We consider the empirical solar wind criteria derived in this study (Bz ≤ −5 nT or Ey ≥ 3 mV/m for t≥ 2 h for moderate storms with minimum Dst less than −50 nT) and a Dst model developed by Temerin and Li (2002, 2006) (TL model). Using 55 CME-Dst pairs during 1997 to 2003, our solar wind criteria produce slightly better forecasts for 31 storm events (90%) than the forecasts based on the TL model (87%). However, the latter produces better forecasts for 24 nonstorm events (88%), while the former correctly forecasts only 71% of them. We then performed the two-step forecast. The results are as follows: (i) for 15 events that are incorrectly forecasted using CME parameters, 12 cases (80%) can be properly predicted based on solar wind conditions; (ii) if we forecast a storm when both CME and solar wind conditions are satisfied (∩), the critical success index becomes higher than that from the forecast using CME parameters alone, however, only 25 storm events (81%) are correctly forecasted; and (iii) if we forecast a storm when either set of these conditions is satisfied (∪), all geomagnetic storms are correctly forecasted. PMID:26213515

Two-step forecast of geomagnetic storm using coronal mass ejection and solar wind condition.

PubMed

Kim, R-S; Moon, Y-J; Gopalswamy, N; Park, Y-D; Kim, Y-H

2014-04-01

To forecast geomagnetic storms, we had examined initially observed parameters of coronal mass ejections (CMEs) and introduced an empirical storm forecast model in a previous study. Now we suggest a two-step forecast considering not only CME parameters observed in the solar vicinity but also solar wind conditions near Earth to improve the forecast capability. We consider the empirical solar wind criteria derived in this study ( B z  ≤ -5 nT or E y  ≥ 3 mV/m for t ≥ 2 h for moderate storms with minimum Dst less than -50 nT) and a Dst model developed by Temerin and Li (2002, 2006) (TL model). Using 55 CME- Dst pairs during 1997 to 2003, our solar wind criteria produce slightly better forecasts for 31 storm events (90%) than the forecasts based on the TL model (87%). However, the latter produces better forecasts for 24 nonstorm events (88%), while the former correctly forecasts only 71% of them. We then performed the two-step forecast. The results are as follows: (i) for 15 events that are incorrectly forecasted using CME parameters, 12 cases (80%) can be properly predicted based on solar wind conditions; (ii) if we forecast a storm when both CME and solar wind conditions are satisfied (∩), the critical success index becomes higher than that from the forecast using CME parameters alone, however, only 25 storm events (81%) are correctly forecasted; and (iii) if we forecast a storm when either set of these conditions is satisfied (∪), all geomagnetic storms are correctly forecasted.

Residual cannabis levels in blood, urine and oral fluid following heavy cannabis use.

PubMed

Odell, Morris S; Frei, Matthew Y; Gerostamoulos, Dimitri; Chu, Mark; Lubman, Dan I

2015-04-01

An understanding of tetrahydrocannabinol (THC) kinetics and residual levels after cannabis use is essential in interpreting toxicology tests in body fluids from live subjects, particularly when used in forensic settings for drug abuse, traffic and interpersonal violence cases. However the current literature is largely based on laboratory studies using controlled cannabis dosages in experienced users, with limited research investigating the kinetics of residual THC concentrations in regular high dose cannabis users. Twenty-one dependent cannabis users were recruited at admission to two residential detoxification units in Melbourne, Australia. After being provided with information about, and consenting to, the study, subjects volunteered to provide once-daily blood, urine and oral fluid (saliva) samples for seven consecutive days following admission, involving cessation and abstinence from all cannabis use. Blood and oral fluid specimens were analysed for THC and urine specimens for the metabolite THC-COOH. In some subjects THC was detectable in blood for at least 7 days and oral fluid specimens were positive for THC up to 78 h after admission to the unit. Urinary THC-COOH concentrations exceeded 1000 ng/mL for some subjects 129 h after last use. The presented blood THC levels are higher and persist longer in some individuals than previously described, our understanding and interpretation of THC levels in long term heavy cannabis users may need to be reconsidered. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A low-Δ9 tetrahydrocannabinol cannabis extract induces hyperphagia in rats.

PubMed

Farrimond, Jonathan A; Whalley, Benjamin J; Williams, Claire M

2010-12-01

Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Δtetrahydrocannabinol (ΔTHC) is well documented and can be modulated by non-ΔTHC phytocannabinoids. ΔTHC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little ΔTHC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-ΔTHC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses ≥1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-ΔTHC phytocannabinoids in the extract rather than ΔTHC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-ΔTHC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of ΔTHC.

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2010 CFR

2010-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2013 CFR

2013-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2010 CFR

2010-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2011 CFR

2011-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2012 CFR

2012-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2011 CFR

2011-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2014 CFR

2014-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2013 CFR

2013-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2012 CFR

2012-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2012 CFR

2012-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2013 CFR

2013-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2014 CFR

2014-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2014 CFR

2014-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

Impact of daylight savings time on spontaneous pregnancy loss in in vitro fertilization patients.

PubMed

Liu, Constance; Politch, Joseph A; Cullerton, Evan; Go, Kathryn; Pang, Samuel; Kuohung, Wendy

2017-01-01

Transition into daylight savings time (DST) has studied negative impacts on health, but little is known regarding impact on fertility. This retrospective cohort study evaluates DST impact on pregnancy and pregnancy loss rates in 1,654 autologous in vitro fertilization cycles (2009 to 2012). Study groups were identified based on the relationship of DST to embryo transfer. Pregnancy rates were similar in Spring and Fall (41.4%, 42.2%). Pregnancy loss rates were also comparable between Spring and Fall (15.5%, 17.1%), but rates of loss were significantly higher in Spring when DST occurred after embryo transfer (24.3%). Loss was marked in patients with a history of prior spontaneous pregnancy loss (60.5%).

11C-4DST PET/CT Imaging of Cardiac Sarcoidosis: Comparison With 18F-FDG and Cardiac MRI.

PubMed

Hotta, Masatoshi; Minamimoto, Ryogo; Kubota, Shuji; Awaya, Toru; Hiroi, Yukio

2018-06-01

A 75-year-old woman with a history of sarcoidosis presenting with low cardiac output and complete right bundle-branch block underwent 4'-[methyl-C]-thiothymidine (4DST) PET/CT after cardiac MRI and FDG PET/CT for the evaluation of suspected cardiac sarcoidosis (CS) before treatment. Cardiac MRI revealed late gadolinium enhancement on the anterior-to-lateral and posterior wall, indicating CS. FDG uptake was shown on the anterior-to-lateral wall, but not on the posterior wall. In contrast, 4DST uptake was demonstrated on both anterior-to-lateral and posterior walls. Use of 4DST appears promising for detecting CS without dietary restriction, due to the lack of physiological uptake in myocardium.

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.

PubMed

Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie

2017-09-01

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse. © 2016 Society for the Study of Addiction.

Tetrahydrocannabinol-induced suppression of macrophage spreading and phagocytic activity in vitro.

PubMed

Lopez-Cepero, M; Friedman, M; Klein, T; Friedman, H

1986-06-01

The effects of tetrahydrocannabinol (THC) on several parameters of macrophage function in vitro were assessed. Delta 9 THC added to cultures of normal mouse peritoneal cells in vitro affected the ability of the cells to spread on glass surfaces and also had some effect on their ability to phagocytize yeast. These effects were dose related. A concentration of 20 micrograms of THC almost completely inhibited macrophage spreading, but it also decreased viability and the total number of these cells. Doses of 10 or 5 micrograms of THC also inhibited spreading but had little effect on cell viability or number. A dose of 1.0 microgram of THC had some inhibitory effect on spreading and the lowest dose affecting spreading appeared to be about 0.05 micrograms per culture. Higher doses of THC were necessary to inhibit phagocytosis of yeast particles as determined by direct microscopic examination or use of radiolabeled yeast as the test particles. These results indicate that several readily measured functions of macrophages may be suppressed by THC.

Brain imaging study of the acute effects of Delta9-tetrahydrocannabinol (THC) on attention and motor coordination in regular users of marijuana.

PubMed

Weinstein, Aviv; Brickner, Orit; Lerman, Hedva; Greemland, Mazal; Bloch, Miki; Lester, Hava; Chisin, Roland; Mechoulam, Raphael; Bar-Hamburger, Rachel; Freedman, Nanette; Even-Sapir, Einat

2008-01-01

Twelve regular users of marijuana underwent two positron emission tomography (PET) scans using [18F] Fluorodeoxyglucose (FDG), one while subject to the effects of 17 mg THC, the other without THC. In both sessions, a virtual reality maze task was performed during the FDG uptake period. When subject to the effects of 17 mg THC, regular marijuana smokers hit the walls more often on the virtual maze task than without THC. Compared to results without THC, 17 mg THC increased brain metabolism during task performance in areas that are associated with motor coordination and attention in the middle and medial frontal cortices and anterior cingulate, and reduced metabolism in areas that are related to visual integration of motion in the occipital lobes. These findings suggest that in regular marijuana users, the immediate effects of marijuana may impact on cognitive-motor skills and brain mechanisms that modulate coordinated movement and driving.

Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis

PubMed Central

Hilliard, A.; Stott, C.; Wright, S.; Guy, G.; Pryce, G.; Al-Izki, S.; Bolton, C.; Giovannoni, G.

2012-01-01

This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the “stiffness” of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS. PMID:22928118

A THC Simulator for Modeling Fluid-Rock Interactions

NASA Astrophysics Data System (ADS)

Hamidi, Sahar; Galvan, Boris; Heinze, Thomas; Miller, Stephen

2014-05-01

Fluid-rock interactions play an essential role in many earth processes, from a likely influence on earthquake nucleation and aftershocks, to enhanced geothermal system, carbon capture and storage (CCS), and underground nuclear waste repositories. In THC models, two-way interactions between different processes (thermal, hydraulic and chemical) are present. Fluid flow influences the permeability of the rock especially if chemical reactions are taken into account. On one hand solute concentration influences fluid properties while, on the other hand, heat can affect further chemical reactions. Estimating heat production from a naturally fractured geothermal systems remains a complex problem. Previous works are typically based on a local thermal equilibrium assumption and rarely consider the salinity. The dissolved salt in fluid affects the hydro- and thermodynamical behavior of the system by changing the hydraulic properties of the circulating fluid. Coupled thermal-hydraulic-chemical models (THC) are important for investigating these processes, but what is needed is a coupling to mechanics to result in THMC models. Although similar models currently exist (e.g. PFLOTRAN), our objective here is to develop algorithms for implementation using the Graphics Processing Unit (GPU) computer architecture to be run on GPU clusters. To that aim, we present a two-dimensional numerical simulation of a fully coupled non-isothermal non-reactive solute flow. The thermal part of the simulation models heat transfer processes for either local thermal equilibrium or nonequilibrium cases, and coupled to a non-reactive mass transfer described by a non-linear diffusion/dispersion model. The flow process of the model includes a non-linear Darcian flow for either saturated or unsaturated scenarios. For the unsaturated case, we use the Richards' approximation for a mixture of liquid and gas phases. Relative permeability and capillary pressure are determined by the van Genuchten relations. Permeability of rock is controlled by porosity, which is itself related to effective stress. The theoretical model is solved using explicit finite differences, and runs in parallel mode with OpenMP. The code is fully modular so that any combination of current THC processes, one- and two-phase, can be chosen. Future developments will include dissolution and precipitation of chemical components in addition to chemical erosion.

40 CFR 1066.15 - Overview of test procedures.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ways: (i) Total hydrocarbons, THC. (ii) Nonmethane hydrocarbons, NMHC, which results from subtracting methane (CH4) from THC. (iii) Total hydrocarbon-equivalent, THCE, which results from adjusting THC...

40 CFR 1066.15 - Overview of test procedures.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ways: (i) Total hydrocarbons, THC. (ii) Nonmethane hydrocarbons, NMHC, which results from subtracting methane (CH4) from THC. (iii) Total hydrocarbon-equivalent, THCE, which results from adjusting THC...

Statistical modeling of Earth's plasmasphere

NASA Astrophysics Data System (ADS)

Veibell, Victoir

The behavior of plasma near Earth's geosynchronous orbit is of vital importance to both satellite operators and magnetosphere modelers because it also has a significant influence on energy transport, ion composition, and induced currents. The system is highly complex in both time and space, making the forecasting of extreme space weather events difficult. This dissertation examines the behavior and statistical properties of plasma mass density near geosynchronous orbit by using both linear and nonlinear models, as well as epoch analyses, in an attempt to better understand the physical processes that precipitates and drives its variations. It is shown that while equatorial mass density does vary significantly on an hourly timescale when a drop in the disturbance time scale index ( Dst) was observed, it does not vary significantly between the day of a Dst event onset and the day immediately following. It is also shown that increases in equatorial mass density were not, on average, preceded or followed by any significant change in the examined solar wind or geomagnetic variables, including Dst, despite prior results that considered a few selected events and found a notable influence. It is verified that equatorial mass density and and solar activity via the F10.7 index have a strong correlation, which is stronger over longer timescales such as 27 days than it is over an hourly timescale. It is then shown that this connection seems to affect the behavior of equatorial mass density most during periods of strong solar activity leading to large mass density reactions to Dst drops for high values of F10.7. It is also shown that equatorial mass density behaves differently before and after events based on the value of F10.7 at the onset of an equatorial mass density event or a Dst event, and that a southward interplanetary magnetic field at onset leads to slowed mass density growth after event onset. These behavioral differences provide insight into how solar and geomagnetic conditions impact mass density at geosynchronous orbit, enabling operators to better anticipate the response to space weather events and magnetosphere models to include mass density effects in magnetosphere simulations. It is shown that it is possible to classify an equatorial mass density event onset as being distinct from the three hours preceding it, indicating that there are distinguishing characteristics of solar wind and geomagnetic conditions surrounding an event. It is also been shown that given four days of solar and geomagnetic conditions, an event can be forecasted a day in advance with reasonable accuracy, but also with a number of false positives. These false positives have similarly distributed values as the true positives, though, indicating more data are needed to distinguish impending events.

[Time profile of serum THC levels in occasional and chronic marihuana smokers after acute drog use - implication for drivind motor vehicles].

PubMed

Balíková, Marie; Hložek, Tomáš; Páleníček, Tomáš; Tylš, Filip; Viktorinová, Michaela; Melicher, Tomáš; Androvičová, Renáta; Tomíček, Pavel; Roman, Michal; Horáček, Jiří

2014-01-01

Cannabis consumption has individual influence to cognitive and psychomotor functions of drivers and it has been generally accepted that driving under influence is risky in the perspective of traffic safety. However, rules how to assess fitness to drive are not quite clear. The psychoactive compound delta-9-tetrahydrocannabinol (THC) impairs cognition, psychomotor behaviour and driving performance in a dose-related manner approximately. After a single drug dose, THC blood concentration peaks within minutes, before the end of smoking, with a subsequent rapid decrease to the analytical limit of detection. Peak euphoria is delayed compared to THC peak blood concentration and physiological and behavioural effects return to baseline within 3-5 hours. In chronic users, the lipophilic THC accumulates in fat tissues, where its slow redistribution into blood is the rate limiting process in its terminal elimination. In our experimental study we have attempted to contribute to this discussion with results obtained from human volunteers - cannabis consumers in Czech Republic. Aim of our study was to document the time profile of serum THC level in occasional and chronic cannabis users. The observational interval covered the time immediately after the drug consumption (an own cigarette/joint) till 24 hours after. Our preliminary results have shown that in occasional users, THC serum levels cannot be detected already 4 hours after usual cannabis dose, whereas in chronic users measurable THC concentrations in serum persist longer. Moreover, some chronic consumers were practically with permanent THC detection during our observation period and also the chronic users consumed higher THC doses significantly related to doses in occasional ones. Presented results of the experimental study with human volunteers confirm a great individual variability of the kinetic profile of THC in blood due to complicated redistribution. The practical forensic question is how long the psychotropic effects of THC can persist after the last drug dose. In chronic users there are well documented indications of long term adverse effects to neurocognitive functions. THC blood level itself can not directly document the intensity of impairment of a driver. Moreover, the concentration of THC in blood at the time of driving is probably substantially higher than at the time of blood sampling. Therefore due to the prevention of traffic risk, some countries adopted per se traffic legislation based on analytical principle with minimum tolerance to illegal drugs in blood of drivers at driving. Low blood concentrations of THC close to the limit of detection of a specific toxicological method (GC-MS or LC-MS) are justified in an effective traffic legislation.

A tale of two theories: How the adiabatic response and ULF waves affect relativistic electrons

NASA Astrophysics Data System (ADS)

Green, J. C.; Kivelson, M. G.

2001-11-01

Using data from the Comprehensive Energetic Particle and Pitch Angle Distribution (CEPPAD)-High Sensitivity Telescope (HIST) instrument on the Polar spacecraft and ground magnetometer data from the 210 meridian magnetometer chain, we test the ULF wave drift resonance theory proposed to explain relativistic electron phase space density enhancements. We begin by investigating changes in electron flux due to the ``Dst effect.'' The Dst effect refers to the adiabatic response of relativistic electrons to changes in the magnetic field characterized by the Dst index. The Dst effect, assuming no loss or addition of new electrons, produces reversible order of magnitude changes in relativistic electrons flux measured at fixed energy, but it cannot account for the flux enhancement that occurs in the recovery phase of most storms. Liouville's theorem states that phase space density expressed in terms of constant adiabatic invariants is unaffected by adiabatic field changes and thus is insensitive to the Dst effect. It is therefore useful to express flux measurements in terms of phase space densities at constant first, second and third adiabatic invariants. The phase space density is determined from the CEPPAD-HIST electron detector that measures differential directional flux of electrons from 0.7 to 9 MeV and the Tsyganenko 96 field model. The analysis is done for January to June 1997. The ULF wave drift resonance theory that we test proposes that relativistic electrons are accelerated by an m=2 toroidal or poloidal mode wave whose frequency equals the drift frequency of the electron. The theory is tested by comparing the relativistic electron phase space densities to wave power determined at three ground stations with L* values of 4.0, 5.7 and 6.2. Comparison of the wave data to the phase space densities shows that five out of nine storm events are consistent with the ULF wave drift resonance mechanism, three out of nine give ambiguous support to the model, and one event has high ULF wave power at the drift frequency of the electrons but no corresponding phase space density enhancement suggesting that ULF wave power alone is not sufficient to cause an electron response. Two explanations of the anomalous event are investigated including excessive loss of electrons to the magnetopause and wave duration.

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.

PubMed

Rowland, Laura M; Summerfelt, Ann; Wijtenburg, S Andrea; Du, Xiaoming; Chiappelli, Joshua J; Krishna, Nithin; West, Jeffrey; Muellerklein, Florian; Kochunov, Peter; Hong, L Elliot

2016-02-01

Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia. The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia.

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

PubMed Central

Rowland, Laura M.; Summerfelt, Ann; Wijtenburg, S. Andrea; Du, Xiaoming; Chiappelli, Joshua J.; Krishna, Nithin; West, Jeffrey; Muellerklein, Florian; Kochunov, Peter; Hong, L. Elliot

2016-01-01

IMPORTANCE Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. OBJECTIVE To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. MAIN OUTCOMES AND MEASURES Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. RESULTS The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia. CONCLUSIONS AND RELEVANCE The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia. PMID:26720179

Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ⁹-THC.

PubMed

Coskun, Zeynep Mine; Bolkent, Sema

2014-10-01

The objectives of study were (a) to determine alteration of feeding, glucose level and oxidative stress and (b) to investigate expression and localization of cannabinoid receptors in type-2 diabetic rat pancreas treated with Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Rats were randomly divided into four groups: control, Δ(9)-THC, diabetes and diabetes + Δ(9)-THC groups. Diabetic rats were treated with a single dose of nicotinamide (85 mg/kg) 15 min before injection of streptozotocin (65 mg/kg). Δ(9)-THC was administered intraperitoneally at 3 mg/kg/day for 7 days. Body weights and blood glucose level of rats in all groups were measured on days 0, 7, 14 and 21. On day 15 after the Δ(9)-THC injections, pancreatic tissues were removed. Blood glucose levels and body weights of diabetic rats treated with Δ(9)-THC did not show statistically significant changes when compared with the diabetic animals on days 7, 14 and 21. Treatment with Δ(9)-THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non-treatment diabetes group. The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic. We can suggest that Δ(9) -THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti-hyperglycaemic agents. Furthermore, the present study for the first time emphasizes that Δ(9)-THC may improve pancreatic cells via cannabinoid receptors in diabetes. The aim of present study was to elucidate the effects of Δ(9)-THC, a natural cannabinoid receptor agonist, on the expression and localization of cannabinoid receptors, and oxidative stress statue in type-2 diabetic rat pancreas. Results demonstrate that the cannabinoid receptors are presented in both Langerhans islets and duct regions. The curative effects of Δ(9)-THC can be occurred via activation of cannabinoid receptors in diabetic rat pancreas. Moreover, it may provide a protective effect against oxidative damage induced by diabetes. Thus, it is suggested that Δ(9)-THC can be a candidate for therapeutic alternatives of diabetes symptoms. Copyright © 2014 John Wiley & Sons, Ltd.

Simultaneous quantification of cannabinoids and metabolites in oral fluid by two-dimensional gas chromatography mass spectrometry

PubMed Central

Milman, Garry; Barnes, Allan J.; Lowe, Ross H.; Huestis, Marilyn A.

2010-01-01

Development and validation of a method for simultaneous identification and quantification of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and metabolites 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) in oral fluid. Simultaneous analysis was problematic due to different physicochemical characteristics and concentration ranges. Neutral analytes, such as THC and CBD, are present in ng/mL, rather than pg/mL concentrations, as observed for the acidic THCCOOH biomarker in oral fluid. THCCOOH is not present in cannabis smoke, definitively differentiating cannabis use from passive smoke exposure. THC, 11-OH-THC, THCCOOH, CBD, and CBN quantification was achieved in a single oral fluid specimen collected with the Quantisal™ device. One mL oral fluid/buffer solution (0.25mL oral fluid and 0.75mL buffer) was applied to conditioned CEREX® Polycrom™ THC solid phase extraction (SPE) columns. After washing, THC, 11-OH-THC, CBD, and CBN were eluted with hexane/acetone/ethyl acetate (60:30:20, v/v/v), derivatized with N, O-bis-(trimethylsilyl) trifluoroacetamide and quantified by two-dimensional gas chromatography electron ionization mass spectrometry (2D-GCMS) with cold trapping. Acidic THCCOOH was separately eluted with hexane/ethyl acetate/acetic acid (75:25:2.5, v/v/v), derivatized with trifluoroacetic anhydride and hexafluoroisopropanol, and quantified by the more sensitive 2D-GCMS–electron capture negative chemical ionization (NCI-MS). Linearity was 0.5-50ng/mL for THC, 11-OH-THC, CBD and 1-50ng/mL for CBN. The linear dynamic range for THCCOOH was 7.5–500pg/mL. Intra-and inter-assay imprecision as percent RSD at three concentrations across the linear dynamic range were 0.3%-6.6%. Analytical recovery was within 13.8% of target. This new SPE 2D-GCMS assay achieved efficient quantification of five cannabinoids in oral fluid, including pg/mL concentrations of THCCOOH by combining differential elution, 2D-GCMS with electron ionization and negative chemical ionization. This method will be applied to quantification of cannabinoids in oral fluid specimens from individuals participating in controlled cannabis and Sativex® (50% THC and 50% CBD) administration studies, and during cannabis withdrawal. PMID:20083251

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 12 2010-07-01 2010-07-01 true How do I determine the outlet THC.../outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and add-on control... section to determine either the outlet THC emissions or add-on control device emission destruction or...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 13 2013-07-01 2012-07-01 true How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 13 2014-07-01 2014-07-01 false How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 12 2011-07-01 2009-07-01 true How do I determine the outlet THC.../outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and add-on control... section to determine either the outlet THC emissions or add-on control device emission destruction or...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 13 2012-07-01 2012-07-01 false How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2011 CFR

2011-07-01

... on THC CEMS data Collecting and recording the THC monitoring data listed in Table 2 to this subpart... according to calculations in § 63.2269(d); AND maintaining the 3-hour block average THC concentration in the exhaust gases less than or equal to the THC concentration established according to § 63.2262. (3) Each...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2010 CFR

2010-07-01

... on THC CEMS data Collecting and recording the THC monitoring data listed in Table 2 to this subpart... according to calculations in § 63.2269(d); AND maintaining the 3-hour block average THC concentration in the exhaust gases less than or equal to the THC concentration established according to § 63.2262. (3) Each...

An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.

PubMed

Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T

2013-08-01

Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Comparison of intracorporeal single-stapled and double-stapled anastomosis in laparoscopic low anterior resection for rectal cancer: a case-control study.

PubMed

Kim, Hye Jin; Choi, Gyu-Seog; Park, Jun Seok; Park, Soo Yeun

2013-01-01

Recently, a single-stapled technique (SST) was performed instead of the conventional double-stapled technique (DST) in laparoscopic low anterior resection for anastomosis, by placement of intracorporeal purse-string sutures on the distal rectum with transanal specimen extraction. This study aimed to compare the short-term outcomes between the two anastomotic techniques. Between July 2007 and April 2010, 60 patients underwent SST by laparoscopic or robotic procedure. These patients were matched 1:2 by age, gender, date of surgery, and tumor stage with 120 patients who underwent conventional DST in laparoscopic low anterior resection. The robotic-assisted operative approach was used more frequently in the SST group than in the DST group (61.7 % vs. 3.3 %, p < 0.001). The mean operative time was 203.9 (range, 120-400) min for the SST group and 167.6 (range, 90-300) min for the DST group (p < 0.001). For specimen removal, the transanal approach was used in the SST group, while the transabdominal approach was used for the DST group. The pain score (visual analogue scale) of the SST group was lower (4.5 vs. 5.6, p < 0.001), although postoperative recovery was similar. Pathological examination revealed that the distal resection margin was significantly longer in the SST group (3.1 vs. 2.5 cm, p = 0.018). Postoperative morbidity including anastomotic leakage was similar in both groups. SST yielded equivalent short-term outcomes when compared to conventional DST and provided the advantages of minimal access and a longer distal resection margin. Therefore, SST in lower anterior resection may be a useful alternative to conventional DST.

CSF 5-HIAA and DST non-suppression--orthogonal biologic risk factors for suicide in male mood disorder inpatients.

PubMed

Jokinen, Jussi; Nordström, Anna-Lena; Nordström, Peter

2009-01-30

Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims (n=6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims (n=5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.

New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.

PubMed

Yanase, Toshihiko; Oki, Yutaka; Katabami, Takuyuki; Otsuki, Michio; Kageyama, Kazunori; Tanaka, Tomoaki; Kawate, Hisaya; Tanabe, Makito; Doi, Masaru; Akehi, Yuko; Ichijo, Takamasa

2018-04-26

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 μg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 μg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance.

PubMed

Karschner, Erin L; Swortwood, Madeleine J; Hirvonen, Jussi; Goodwin, Robert S; Bosker, Wendy M; Ramaekers, Johannes G; Huestis, Marilyn A

2016-07-01

Cannabis smoking increases motor vehicle accident risk. Empirically defined cannabinoid detection windows are important to drugged driving legislation. Our aims were to establish plasma cannabinoid detection windows in frequent cannabis smokers and to determine if residual cannabinoid concentrations were correlated with psychomotor performance. Twenty-eight male chronic frequent cannabis smokers resided on a secure research unit for up to 33 days with daily blood collection. Plasma specimens were analyzed for Δ(9) -tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) by gas chromatography-mass spectrometry. Critical tracking and divided attention tasks were administered at baseline (after overnight stay to ensure lack of acute intoxication) and after 1, 2, and 3 weeks of cannabis abstinence. Twenty-seven of the twenty-eight participants were THC-positive at admission (median 4.2 µg/L). THC concentrations significantly decreased 24 h after admission, but were still ≥2 µg/L in 16 of the 28 participants 48 h after admission. THC was detected in 3 of 5 specimens on day 30. The last positive 11-OH-THC specimen was 15 days after admission. THCCOOH was measureable in 4 of 5 participants after 30 days of abstinence. Years of prior cannabis use significantly correlated with THC concentrations on admission, and days 7 and 14. Tracking error, evaluated by the Divided Attention Task, was the only evaluated psychomotor assessment significantly correlated with cannabinoid concentrations at baseline and day 8 (11-OH-THC only). Median THC was 0.3 µg/L in 5 chronic frequent cannabis smokers' plasma samples after 30 days of sustained abstinence. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

A novel fast method for aqueous derivatization of THC, OH-THC and THC-COOH in human whole blood and urine samples for routine forensic analyses.

PubMed

Stefanelli, Fabio; Pesci, Federica Giorgia; Giusiani, Mario; Chericoni, Silvio

2018-04-01

A novel aqueous in situ derivatization procedure with propyl chloroformate (PCF) for the simultaneous, quantitative analysis of Δ 9 -tetrahydrocannabinol (THC), 11-hydroxy-Δ 9 -tetrahydrocannabinol (OH-THC) and 11-nor-Δ 9 -tetrahydrocannabinol-carboxylic acid (THC-COOH) in human blood and urine is proposed. Unlike current methods based on the silylating agent [N,O-bis(trimethylsilyl)trifluoroacetamide] added in an anhydrous environment, this new proposed method allows the addition of the derivatizing agent (propyl chloroformate, PCF) directly to the deproteinized blood and recovery of the derivatives by liquid-liquid extraction. This novel method can be also used for hydrolyzed urine samples. It is faster than the traditional method involving a derivatization with trimethyloxonium tetrafluoroborate. The analytes are separated, detected and quantified by gas chromatography-mass spectrometry in selected ion monitoring mode (SIM). The method was validated in terms of selectivity, capacity of identification, limits of detection (LOD) and quantification (LOQ), carryover, linearity, intra-assay precision, inter-assay precision and accuracy. The LOD and LOQ in hydrolyzed urine were 0.5 and 1.3 ng/mL for THC and 1.2 and 2.6 ng/mL for THC-COOH, respectively. In blood, the LOD and LOQ were 0.2 and 0.5 ng/mL for THC, 0.2 and 0.6 ng/mL for OH-THC, and 0.9 and 2.4 ng/mL for THC-COOH, respectively. This method was applied to 35 urine samples and 50 blood samples resulting to be equivalent to the previously used ones with the advantage of a simpler method and faster sample processing time. We believe that this method will be a more convenient option for the routine analysis of cannabinoids in toxicological and forensic laboratories. Copyright © 2017 John Wiley & Sons, Ltd.

Recovery of spiked Δ9-tetrahydrocannabinol in oral fluid from polypropylene containers.

PubMed

Molnar, Anna; Lewis, John; Fu, Shanlin

2013-04-10

Oral fluid is currently used by Australian and international law enforcement agencies and employers to detect recent use of cannabis and other drugs of abuse. The main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol (THC), is highly lipophilic and losses occur when in contact with plastic, possibly due to its adsorption onto the plastic surface. This study aims to investigate factors governing the interaction of THC with plastic and search for ways of overcoming such interaction so to improve THC recovery. As polypropylene is one of the most common types of plastic used in collection devices, it was the focus of this study. All experiments were done by preparing neat oral fluid samples spiked with THC in 2-mL polypropylene centrifuge tubes. Samples were transferred with or without prior addition of Triton(®) X-100 (0.25%) to glass tubes containing d3-THC as internal standard and 0.1M phosphate buffer was then added. Samples were extracted by liquid-liquid extraction using hexane/ethyl acetate (9:1, v/v), dried and analysed by gas chromatography-mass spectrometry (GC-MS) after derivatisation. No significant difference was found in terms of THC loss to plastic when the concentration ranged from 25 to 1000 ng/mL in the same volume of oral fluid. Varying the oral fluid volume (0.5-1.5 mL) while keeping THC at a constant concentration showed an upward trend with more loss associated with lower volumes. The use of Triton(®) X-100 significantly decreased the adherence of THC to the plastic tubes and increased the THC transfer (>96%) at all volumes tested. Degradation of THC during storage was also studied over a 4-week period and it was found that azide did not seem to play a significant role in preserving THC in oral fluid. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats

PubMed Central

Shen, Erica Y.; Ali, Syed F.; Meyer, Jerrold S.

2011-01-01

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ9-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5 mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. PMID:21763331

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats.

PubMed

Shen, Erica Y; Ali, Syed F; Meyer, Jerrold S

2011-12-01

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or "ecstasy") also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ(9)-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. Published by Elsevier Ltd.

Association between posttest dexamethasone and cortisol concentrations in the 1 mg overnight dexamethasone suppression test.

PubMed

Asvold, Bjørn O; Grill, Valdemar; Thorstensen, Ketil; Bjørgaas, Marit R

2012-11-01

It has been suggested that comparison of posttest dexamethasone and cortisol concentrations may improve the evaluation of the dexamethasone suppression test (DST) for Cushing's syndrome. In particular, this would be reasonable if posttest cortisol differs by dexamethasone levels within the range that is usually attained in the DST. Using fractional polynomial regression, we therefore studied the association between posttest 0800 h dexamethasone and cortisol levels in 53 subjects without Cushing's syndrome who were tested with the 1 mg overnight DST. Plasma dexamethasone was associated with plasma cortisol (P<0.001), and the regression line suggested a strong negative association related to dexamethasone levels <5 nmol/l. However, among the 94% of subjects with plasma dexamethasone >5.0 nmol/l, there was no association between dexamethasone and cortisol levels (P=0.55). In conclusion, subjects tested with the 1 mg overnight DST usually attain an 0800 h plasma dexamethasone >5 nmol/l, and plasma cortisol does not differ by plasma dexamethasone in these subjects. This suggests that routine comparison of dexamethasone and cortisol levels may not be a useful approach to improve the performance of the 1 mg DST. However, dexamethasone measurements may identify subjects with inadequately low plasma dexamethasone and may therefore be of value when retesting subjects with possibly false-positive DST results.

A rapid culture system uninfluenced by an inoculum effect increases reliability and convenience for drug susceptibility testing of Mycobacterium tuberculosis.

PubMed

Jung, Yong-Gyun; Kim, Hyejin; Lee, Sangyeop; Kim, Suyeoun; Jo, EunJi; Kim, Eun-Geun; Choi, Jungil; Kim, Hyun Jung; Yoo, Jungheon; Lee, Hye-Jeong; Kim, Haeun; Jung, Hyunju; Ryoo, Sungweon; Kwon, Sunghoon

2018-06-05

The Disc Agarose Channel (DAC) system utilizes microfluidics and imaging technologies and is fully automated and capable of tracking single cell growth to produce Mycobacterium tuberculosis (MTB) drug susceptibility testing (DST) results within 3~7 days. In particular, this system can be easily used to perform DSTs without the fastidious preparation of the inoculum of MTB cells. Inoculum effect is one of the major problems that causes DST errors. The DAC system was not influenced by the inoculum effect and produced reliable DST results. In this system, the minimum inhibitory concentration (MIC) values of the first-line drugs were consistent regardless of inoculum sizes ranging from ~10 3 to ~10 8 CFU/mL. The consistent MIC results enabled us to determine the critical concentrations for 12 anti-tuberculosis drugs. Based on the determined critical concentrations, further DSTs were performed with 254 MTB clinical isolates without measuring an inoculum size. There were high agreement rates (96.3%) between the DAC system and the absolute concentration method using Löwenstein-Jensen medium. According to these results, the DAC system is the first DST system that is not affected by the inoculum effect. It can thus increase reliability and convenience for DST of MTB. We expect that this system will be a potential substitute for conventional DST systems.

A critical examination of the dual system theory in Ostrinia nubilalis.

PubMed

Skopik, S D; Takeda, M; Holyoke, C W

1981-11-01

Beck's dual system theory (DST) is examined theoretically and experimentally by investigating the oviposition rhythm of Ostrinia nubilalis and its entrainment by light cycles. Several well-known circadian phenomena are not accounted for by the DST. 1) It does not generate transient cycles when light pulses fall during the advance portion of the circadian cycle. This is also reflected in DST-predicted phase-response curves (PRC's) for both Drosophila pseudoobscura and O. nubilalis. Steady-state phase advances are predicted to occur on day 1 after the light pulses by the DST, not several cycles later as has been observed in many cases. 2) It does not account for the observation that the magnitude of a phase shift (delta phi) is often a function of pulse duration of both delays and advances. The DST predicts the same + delta phi, for example, for a 0.5-h and a 6.0-h light pulse beginning 5.0 h after dusk. 3) The DST does not accurately predict steady-state phase relationships between the light cycle and the gating oscillation (P-system) in non-24-h light cycles. 4) The driver (S-system) is given the property of being temperature sensitive whereas the driven rhythm (P-system) is temperature compensated. This is contrary to accumulated data suggesting that the circadian pacemaker is temperature compensated.

Probability of occurrence of planetary ionosphere storms associated with the magnetosphere disturbance storm time events

NASA Astrophysics Data System (ADS)

Gulyaeva, T. L.; Arikan, F.; Stanislawska, I.

2014-11-01

The ionospheric W index allows to distinguish state of the ionosphere and plasmasphere from quiet conditions (W = 0 or ±1) to intense storm (W = ±4) ranging the plasma density enhancements (positive phase) or plasma density depletions (negative phase) regarding the quiet ionosphere. The global W index maps are produced for a period 1999-2014 from Global Ionospheric Maps of Total Electron Content, GIM-TEC, designed by Jet Propulson Laboratory, converted from geographic frame (-87.5:2.5:87.5° in latitude, -180:5:180° in longitude) to geomagnetic frame (-85:5:85° in magnetic latitude, -180:5:180° in magnetic longitude). The probability of occurrence of planetary ionosphere storm during the magnetic disturbance storm time, Dst, event is evaluated with the superposed epoch analysis for 77 intense storms (Dst ≤ -100 nT) and 230 moderate storms (-100 < Dst ≤ -50 nT) with start time, t0, defined at Dst storm main phase onset. It is found that the intensity of negative storm, iW-, exceeds the intensity of positive storm, iW+, by 1.5-2 times. An empirical formula of iW+ and iW- in terms of peak Dst is deduced exhibiting an opposite trends of relation of intensity of ionosphere-plasmasphere storm with regard to intensity of Dst storm.

Association between posttest dexamethasone and cortisol concentrations in the 1 mg overnight dexamethasone suppression test

PubMed Central

Åsvold, Bjørn O; Grill, Valdemar; Thorstensen, Ketil; Bjørgaas, Marit R

2012-01-01

It has been suggested that comparison of posttest dexamethasone and cortisol concentrations may improve the evaluation of the dexamethasone suppression test (DST) for Cushing's syndrome. In particular, this would be reasonable if posttest cortisol differs by dexamethasone levels within the range that is usually attained in the DST. Using fractional polynomial regression, we therefore studied the association between posttest 0800 h dexamethasone and cortisol levels in 53 subjects without Cushing's syndrome who were tested with the 1 mg overnight DST. Plasma dexamethasone was associated with plasma cortisol (P<0.001), and the regression line suggested a strong negative association related to dexamethasone levels <5 nmol/l. However, among the 94% of subjects with plasma dexamethasone >5.0 nmol/l, there was no association between dexamethasone and cortisol levels (P=0.55). In conclusion, subjects tested with the 1 mg overnight DST usually attain an 0800 h plasma dexamethasone >5 nmol/l, and plasma cortisol does not differ by plasma dexamethasone in these subjects. This suggests that routine comparison of dexamethasone and cortisol levels may not be a useful approach to improve the performance of the 1 mg DST. However, dexamethasone measurements may identify subjects with inadequately low plasma dexamethasone and may therefore be of value when retesting subjects with possibly false-positive DST results. PMID:23781306

Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

PubMed

Miederer, I; Uebbing, K; Röhrich, J; Maus, S; Bausbacher, N; Krauter, K; Weyer-Elberich, V; Lutz, B; Schreckenberger, M; Urban, R

2017-05-01

Δ 9 -Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain. The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain. 21 male Sprague Dawley rats (12-13 w) were examined and received five different doses of THC ranging from 0.01 to 1 mg/kg. For data acquisition a Focus 120 small animal PET scanner was used and 24.1-28.0 MBq of [ 18 F]-fluoro-2-deoxy-d-glucose were injected. The data were acquired for 70 min and arterial blood samples were collected throughout the scan. THC, THC-OH and THC-COOH were determined at 55 min p.i. Nine volumes of interest were defined, and the cerebral glucose uptake was calculated for each brain region. Low blood THC levels of < 1 ng/ml (injected dose: ≤ 0.01 mg/kg) corresponded to an increased glucose uptake (6-30 %), particularly in the hypothalamus (p = 0.007), while blood THC levels > 10 ng/ml (injected dose: ≥ 0.05 mg/kg) coincided with a decreased glucose uptake (-2 to -22 %), especially in the cerebellar cortex (p = 0.008). The effective concentration in this region was estimated 2.4 ng/ml. This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose - an effect that may be of relevance in behavioural studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

PubMed

Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

2015-01-01

Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. Copyright © 2014 Elsevier Inc. All rights reserved.

Chronic Δ9-Tetrahydrocannabinol Administration May Not Attenuate Simian Immunodeficiency Virus Disease Progression in Female Rhesus Macaques

PubMed Central

Amedee, Angela M.; Nichols, Whitney A.; LeCapitaine, Nicole J.; Stouwe, Curtis Vande; Birke, Leslie L.; Lacour, Nedra; Winsauer, Peter J.

2014-01-01

Abstract Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; Δ9-THC dronabinol). Previously, we demonstrated that chronic Δ9-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either Δ9-THC (0.18–0.32 mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic Δ9-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4+/CD8+ ratio, were not altered by Δ9-THC compared to control females; however, females that received chronic Δ9-THC did not gain as much weight as control animals. In addition, Δ9-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4+ and CD8+ T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic Δ9-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic Δ9-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of Δ9-THC and other cannabinoids on the HIV disease course and their implications for virus transmission. PMID:25113915

Separate and combined effects of the cannabinoid agonists nabilone and Δ⁹-THC in humans discriminating Δ⁹-THC.

PubMed

Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

2011-07-01

Agonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ⁹-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment. Six cannabis users learned to discriminate 30 mg oral Δ⁹-THC from placebo and then received nabilone (0, 1 and 3mg) and Δ⁹-THC (0, 5, 15 and 30 mg), alone and in combination. Subjects completed the multiple-choice procedure to assess drug reinforcement, and self-report, task performance and physiological measures were collected. Δ⁹-THC and nabilone alone shared discriminative-stimulus effects with the training dose of Δ⁹-THC, increased crossover point on the multiple-choice procedure, produced overlapping subject ratings and decreased skin temperature. Nabilone alone also elevated heart rate. In combination, nabilone shifted the discriminative-stimulus effects of Δ⁹-THC leftward/upward and enhanced Δ⁹-THC effects on the other outcome measures. These results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors.

PubMed

Gaffal, E; Cron, M; Glodde, N; Tüting, T

2013-08-01

∆(9) -Tetrahydrocannabinol (THC), the active constituent of Cannabis sativa, exerts its biological effects in part through the G-protein-coupled CB1 and CB2 receptors, which were initially discovered in brain and spleen tissue, respectively. However, THC also has CB1/2 receptor-independent effects. Because of its immune-inhibitory potential, THC and related cannabinoids are being considered for the treatment of inflammatory skin diseases. Here we investigated the mechanism of the anti-inflammatory activity of THC and the role of CB1 and CB2 receptors. We evaluated the impact of topically applied THC on DNFB-mediated allergic contact dermatitis in wild-type and CB1/2 receptor-deficient mice. We performed immunohistochemical analyses for infiltrating immune cells and studied the influence of THC on the interaction between T cells, keratinocytes and myeloid immune cells in vitro. Topical THC application effectively decreased contact allergic ear swelling and myeloid immune cell infiltration not only in wild-type but also in CB1/2 receptor-deficient mice. We found that THC (1) inhibited the production of IFNγ by T cells, (2) decreased the production of CCL2 and of IFNγ-induced CCL8 and CXL10 by epidermal keratinocytes and (3) thereby limited the recruitment of myeloid immune cells in vitro in a CB1/2 receptor-independent manner. Topically applied THC can effectively attenuate contact allergic inflammation by decreasing keratinocyte-derived pro-inflammatory mediators that orchestrate myeloid immune cell infiltration independent of CB1/2 receptors. This has important implications for the future development of strategies to harness cannabinoids for the treatment of inflammatory skin diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information.

PubMed

Ranganathan, Mohini; Radhakrishnan, Rajiv; Addy, Peter H; Schnakenberg-Martin, Ashley M; Williams, Ashley H; Carbuto, Michelle; Elander, Jacqueline; Pittman, Brian; Andrew Sewell, R; Skosnik, Patrick D; D'Souza, Deepak Cyril

2017-10-03

Cannabis and agonists of the brain cannabinoid receptor (CB 1 R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Δ 9 -Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) (n=38) or while under the influence of THC (experiment #2) (n=57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730. Copyright © 2017. Published by Elsevier Inc.

Persistent effects of chronic Δ9-THC exposure on motor impulsivity in rats.

PubMed

Irimia, Cristina; Polis, Ilham Y; Stouffer, David; Parsons, Loren H

2015-08-01

In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre-existing cognitive deficits from possible consequences of prolonged marijuana exposure. To evaluate the effects of long-term exposure to Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5-Choice Serial Reaction Time Task (5-CSRTT). Ten 14-day cycles of Δ9-THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Δ9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Δ9-THC exposure that persisted for the remaining dosing and testing cycles. Δ9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Δ9-THC abstinence. Δ9-THC-related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Δ9-THC abstinence. These observations demonstrate that long-term intermittent exposure to clinically meaningful Δ9-THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance.

An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

PubMed Central

Kollins, Scott H.; Schoenfelder, Erin N.; English, Joseph S.; Holdaway, Alex; Van Voorhees, Elizabeth; O’Brien, Benjamin R.; Dew, Rachel; Chrisman, Allan K.

2014-01-01

Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew).

PubMed

Parker, Linda A; Kwiatkowska, Magdalena; Burton, Page; Mechoulam, Raphael

2004-01-01

Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance. To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew. Shrews were injected with vehicle or one of two cannabinoids [Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg)] 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716. Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716. These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.

Cannabinoids in oral fluid following passive exposure to marijuana smoke.

PubMed

Moore, Christine; Coulter, Cynthia; Uges, Donald; Tuyay, James; van der Linde, Susanne; van Leeuwen, Arthur; Garnier, Margaux; Orbita, Jonathan

2011-10-10

The concentration of tetrahydrocannabinol (THC) and its main metabolite 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) as well as cannabinol (CBN), and cannabidiol (CBD) were measured in oral fluid following realistic exposure to marijuana in a Dutch coffee-shop. Ten healthy subjects, who were not marijuana smokers, volunteered to spend 3h in two different coffee shops in Groningen, The Netherlands. Subjects gave two oral fluid specimens at each time point: before entering the store, after 20 min, 40 min, 1h, 2h, and 3h of exposure. The specimens were collected outside the shop. Volunteers left the shop completely after 3h and also provided specimens approximately 12-22 h after beginning the exposure. The oral fluid specimens were subjected to immunoassay screening; confirmation for THC, cannabinol and cannabidiol using GC/MS; and THC-COOH using two-dimensional GC-GC/MS. THC was detectable in all oral fluid specimens taken 3h after exposure to smoke from recreationally used marijuana. In 50% of the volunteers, the concentration at the 3h time-point exceeded 4 ng/mL of THC, which is the current recommended cut-off concentration for immunoassay screening; the concentration of THC in 70% of the oral fluid specimens exceeded 2 ng/mL, currently proposed as the confirmatory cut-off concentration. THC-COOH was not detected in any specimens from passively exposed individuals. Therefore it is recommended that in order to avoid false positive oral fluid results assigned to marijuana use, by analyzing for only THC, the metabolite THC-COOH should also be monitored. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Molecularly imprinted solid phase extraction for simultaneous determination of Δ9-tetrahydrocannabinol and its main metabolites by gas chromatography-mass spectrometry in urine samples.

PubMed

Nestić, Marina; Babić, Sandra; Pavlović, Dragana Mutavdžić; Sutlović, Davorka

2013-09-10

In presented paper analytical method based on solid-phase extraction using molecularly imprinted polymer and gas chromatography-mass spectrometry has been developed and validated for the confirmation of THC, THC-OH and THC-COOH in urine samples. Non-covalent molecularly imprinted polymers of THC-OH were prepared using different functional monomers (methacrylic acid, 4-vinylpyridine, and 2-hydroxyethyl methacrylate), ethylene glycol dimethacrylate as a cross-linker and 2,2'-azobis-isobutyronitrile as an initiator of radical polymerization. Analytes were extracted from urine samples using prepared polymer sorbent with highest binding selectivity and capability. Before extraction, urine samples were hydrolyzed with alkaline. Elution was performed with chloroform:ethyl acetate (60:40, v/v). Dry extracts were silylated with BSTFA+1% TMCS. Detection and quantification were performed using gas chromatography-mass spectrometry in single ion recording mode. The developed method was linear over the range from LOQ to 150 ng mL(-1) for all three analytes. For THC, THC-OH and THC-COOH LOD was 2.5, 1 and 1 ng mL(-1), and LOQ was 3, 2 and 2 ng mL(-1), respectively. The precision, accuracy, recovery and matrix effect were investigated at 5, 25 and 50 ng mL(-1). In the investigated concentration range recoveries were 71.9% for THC, 78.6% for THC-OH and 75.2% for THC-COOH. Matrix effect was not significant (<10%) for all analytes in the concentration range from 5 ng mL(-1) to 50 ng mL(-1). Extraction recovery on non-imprinted polymer was relatively high indicating high non-specific binding. Optimized and validated method was applied to 15 post-mortem urine samples. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Tensor hypercontraction. II. Least-squares renormalization

NASA Astrophysics Data System (ADS)

Parrish, Robert M.; Hohenstein, Edward G.; Martínez, Todd J.; Sherrill, C. David

2012-12-01

The least-squares tensor hypercontraction (LS-THC) representation for the electron repulsion integral (ERI) tensor is presented. Recently, we developed the generic tensor hypercontraction (THC) ansatz, which represents the fourth-order ERI tensor as a product of five second-order tensors [E. G. Hohenstein, R. M. Parrish, and T. J. Martínez, J. Chem. Phys. 137, 044103 (2012)], 10.1063/1.4732310. Our initial algorithm for the generation of the THC factors involved a two-sided invocation of overlap-metric density fitting, followed by a PARAFAC decomposition, and is denoted PARAFAC tensor hypercontraction (PF-THC). LS-THC supersedes PF-THC by producing the THC factors through a least-squares renormalization of a spatial quadrature over the otherwise singular 1/r12 operator. Remarkably, an analytical and simple formula for the LS-THC factors exists. Using this formula, the factors may be generated with O(N^5) effort if exact integrals are decomposed, or O(N^4) effort if the decomposition is applied to density-fitted integrals, using any choice of density fitting metric. The accuracy of LS-THC is explored for a range of systems using both conventional and density-fitted integrals in the context of MP2. The grid fitting error is found to be negligible even for extremely sparse spatial quadrature grids. For the case of density-fitted integrals, the additional error incurred by the grid fitting step is generally markedly smaller than the underlying Coulomb-metric density fitting error. The present results, coupled with our previously published factorizations of MP2 and MP3, provide an efficient, robust O(N^4) approach to both methods. Moreover, LS-THC is generally applicable to many other methods in quantum chemistry.

Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent mechanism.

PubMed

Xiong, W; Koo, B-N; Morton, R; Zhang, L

2011-06-16

Δ⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT(3A) receptors (h5-HT(3A)Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC₅₀ values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT(3A)Rs. In these cells, CBD and THC did not stimulate specific [³⁵S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT(3A)Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT(3A)R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT(3A) receptors through a mechanism that is dependent on receptor desensitization. Published by Elsevier Ltd.

Psychotropic and Nonpsychotropic Cannabis Derivatives Inhibit Human 5-HT3A receptors through a Receptor Desensitization-Dependent Mechanism

PubMed Central

Xiong, Wei; Koo, Bon-Nyeo; Morton, Russell; Zhang, Li

2011-01-01

Δ9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and non-psychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT3A receptors (h5-HT3ARs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC50 values for CBD and THC-induced inhibition were 110 nM and 322 nM respectively in HEK 293 cells expressing h5-HT3ARs. In these cells, CBD and THC did not stimulate specific [35S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT3ARs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT3AR cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT3A receptors through a mechanism that is dependent on receptor desensitization. PMID:21477640

Tensor hypercontraction. II. Least-squares renormalization.

PubMed

Parrish, Robert M; Hohenstein, Edward G; Martínez, Todd J; Sherrill, C David

2012-12-14

The least-squares tensor hypercontraction (LS-THC) representation for the electron repulsion integral (ERI) tensor is presented. Recently, we developed the generic tensor hypercontraction (THC) ansatz, which represents the fourth-order ERI tensor as a product of five second-order tensors [E. G. Hohenstein, R. M. Parrish, and T. J. Martínez, J. Chem. Phys. 137, 044103 (2012)]. Our initial algorithm for the generation of the THC factors involved a two-sided invocation of overlap-metric density fitting, followed by a PARAFAC decomposition, and is denoted PARAFAC tensor hypercontraction (PF-THC). LS-THC supersedes PF-THC by producing the THC factors through a least-squares renormalization of a spatial quadrature over the otherwise singular 1∕r(12) operator. Remarkably, an analytical and simple formula for the LS-THC factors exists. Using this formula, the factors may be generated with O(N(5)) effort if exact integrals are decomposed, or O(N(4)) effort if the decomposition is applied to density-fitted integrals, using any choice of density fitting metric. The accuracy of LS-THC is explored for a range of systems using both conventional and density-fitted integrals in the context of MP2. The grid fitting error is found to be negligible even for extremely sparse spatial quadrature grids. For the case of density-fitted integrals, the additional error incurred by the grid fitting step is generally markedly smaller than the underlying Coulomb-metric density fitting error. The present results, coupled with our previously published factorizations of MP2 and MP3, provide an efficient, robust O(N(4)) approach to both methods. Moreover, LS-THC is generally applicable to many other methods in quantum chemistry.

Effect of oral THC pretreatment on marijuana cue-induced responses in cannabis dependent volunteers.

PubMed

Lundahl, Leslie H; Greenwald, Mark K

2015-04-01

The current study tested whether oral Δ(9)-tetrahydrocannabinol (THC: 0-, 10-, and 20-mg) pretreatment would attenuate polysensory cue-induced craving for marijuana. Cannabis dependent participants (7 males and 7 females, who smoked on average 5.4 ± 1.1 blunts daily) completed 3 experimental sessions (oral THC pretreatment dose; counterbalanced order) using a placebo-controlled within-subject crossover design. During each session, participants completed a baseline evaluation and were first exposed to neutral cues then marijuana cues while physiological measures and subjective ratings of mood, craving, and drug effect were recorded. Following placebo oral THC pretreatment, marijuana (vs. neutral) cues significantly increased ratings of marijuana craving (desire and urge to use, Marijuana Craving Questionnaire (MCQ)-Compulsivity scale), anxious mood and feeling hungry. Males also reported feeling more "Down" during marijuana cues relative to females. Pretreatment with oral THC (10-mg and/or 20-mg vs. placebo) significantly attenuated marijuana cue-induced increases in craving and anxiety but not hunger. Oral THC attenuation of the cue-induced increase in MCQ-Compulsivity ratings was observed in females only. Oral THC produced statistically (but not clinically) significant increases in heart rate and decreases in diastolic blood pressure, independent of cues. These marijuana-cue findings replicate earlier results and further demonstrate that oral THC can attenuate selected effects during marijuana multi-cue exposure, and that some of these effects may be sex-related. Results of this study suggest oral THC may be effective for reducing marijuana cue-elicited (conditioned) effects. Further study is needed to determine whether females may selectively benefit from oral THC for this purpose. Copyright © 2015. Published by Elsevier Ireland Ltd.

Substorm-associated large-scale magnetic field changes in the magnetotail: a prerequisite for magnetotail deflation events

NASA Astrophysics Data System (ADS)

Nakai, H.; Kamide, Y.

2003-04-01

An attempt is made to search for a critical condition in the lobe magnetic field to initiate large-scale magnetic field changes associated with substorm expansions. Using data from ISEE-1 for 1978, sudden decreases in the lobe magnetic field accompanied by magnetic field dipolarizations are identified. In this study, such events are designated as the magnetotail deflation. The magnetic field component parallel to the equatorial plane, BE , is normalized to a fixed geocentric distance, BEN , and is corrected for the compression effect of the solar wind dynamic pres-sure, BENC . It is shown that the BENC value just prior to a magnetotail deflation correlates well with the Dst index; BENC = 37.5 - 0.217 Dst0, where Dst0 denotes the Dst value corrected for the solar wind dynamic pressure. This regression function appears to delineate the upper limit of BENC values, when they are sorted by the Dst0 index. On the basis of this finding it is suggested that a prerequisite condition for magnetotail deflations must exist in the magnetosphere.

Shear thickening in concentrated suspensions: phenomenology, mechanisms and relations to jamming

NASA Astrophysics Data System (ADS)

Brown, Eric; Jaeger, Heinrich M.

2014-04-01

Shear thickening is a type of non-Newtonian behavior in which the stress required to shear a fluid increases faster than linearly with shear rate. Many concentrated suspensions of particles exhibit an especially dramatic version, known as Discontinuous Shear Thickening (DST), in which the stress suddenly jumps with increasing shear rate and produces solid-like behavior. The best known example of such counter-intuitive response to applied stresses occurs in mixtures of cornstarch in water. Over the last several years, this shear-induced solid-like behavior together with a variety of other unusual fluid phenomena has generated considerable interest in the physics of densely packed suspensions. In this review, we discuss the common physical properties of systems exhibiting shear thickening, and different mechanisms and models proposed to describe it. We then suggest how these mechanisms may be related and generalized, and propose a general phase diagram for shear thickening systems. We also discuss how recent work has related the physics of shear thickening to that of granular materials and jammed systems. Since DST is described by models that require only simple generic interactions between particles, we outline the broader context of other concentrated many-particle systems such as foams and emulsions, and explain why DST is restricted to the parameter regime of hard-particle suspensions. Finally, we discuss some of the outstanding problems and emerging opportunities.

A thermodynamic study of the gaseous thorium carbides, ThC, ThC2, ThC3, ThC4, ThC5, and ThC6

NASA Astrophysics Data System (ADS)

Gupta, Satish K.; Gingerich, Karl A.

1980-02-01

Six gaseous carbides of thorium, ThCn(n=1-6), have been identified in a Knudsen effusion mass spectrometric investigation of the vapor phase above a thorium-uranium-rhodium-graphite system at high temperatures. The partial pressures of the thorium containing species were measured as a function of temperature in the 2300-2700 °K range. Third law enthalpies for the reactions Th(g)+nC(graphite) =ThCn, n=1 to 6, and of various other homogeneous and heterogeneous reactions were evaluated. By combining the experimental enthalpies with appropriate thermodynamic data taken from literature, the following values for the atomization energies ΔH °at,298, and standard heats of formation ΔH °f,298 of thorium carbides have been derived:

Sex-dimorphic psychomotor activation after perinatal exposure to (-)-delta 9-tetrahydrocannabinol. An ontogenic study in Wistar rats.

PubMed

Navarro, M; Rubio, P; Rodríguez de Fonseca, F

1994-12-01

The ontogeny and the adult expression of motor behaviors were studied in male and female rats born from mothers exposed to delta 9-tetrahydrocannabinol (THC, 5 mg/kg) during gestation and lactation. Perinatal exposure to THC increased both rearing and locomotor activities in males and females at immature preweanling ages (P-15 and P-20). These effects disappeared after ceasing THC exposure (postweaning ages), but they were observed again in adult (P-70) females. The effects appeared as persistently high motor activity in familiar environments, disappearing the characteristic habituation profile in locomotor and exploratory behaviors. In novel environment condition tests, adult (P-70) THC-exposed females, but not males, exhibited lower locomotor activity in the socio-sexual approach test, and an increase in the emergence latency in the dark-light emergence test. Additionally, animals of both sexes exposed to THC showed a increase in the time spent grooming measured in novelty conditions. These findings suggest that perinatal exposure to THC affects both the development and the adult expression of motor behaviors and it resulted in a sex-dimorphic psychomotor activation very similar to that observed after perinatal exposure to other drugs of abuse. A possible role of THC-induced pituitary-adrenal (PA) axis activation was also evaluated by measuring plasma corticosterone levels in adult animals perinatally exposed: THC-exposed females exhibit a clear increase of this adrenal hormone, whereas THC-exposed males displayed lower levels of this hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetrahydrocurcumin is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis.

PubMed

Lai, Ching-Shu; Wu, Jia-Ching; Yu, Shih-Feng; Badmaev, Vladimir; Nagabhushanam, Kalyanam; Ho, Chi-Tang; Pan, Min-Hsiung

2011-12-01

Tetrahydrocurcumin (THC), a major metabolite of curcumin (CUR), has been demonstrated to be anti-cancerogenic and anti-angiogenic and prevents type II diabetes. In this present study, we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of CUR and THC in azoxymethane (AOM)-induced colon carcinogenesis in mice. All mice were sacrificed at 6 and 23 wk, and colonic tissue was collected and examined. We found that dietary administration of both CUR and THC could reduce aberrant crypt foci and polyps formation, while THC showed a better inhibitory effect than CUR. At the molecular level, results from Western blot analysis and immunohistochemistry staining showed that dietary CUR and THC exhibited anti-inflammatory activity by decreasing the levels of inducible NOS and COX-2 through downregulation of ERK1/2 activation. In addition, both dietary CUR and THC significantly decreased AOM-induced Wnt-1 and β-catenin protein expression, as well as the phosphorylation of GSK-3β in colonic tissue. Moreover, dietary feeding with CUR and THC markedly reduced the protein level of connexin-43, an important molecule of gap junctions, indicating that both CUR and THC might interfer with the intercellular communication of crypt cells. Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary THC against AOM-induced colonic tumorigenesis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Direct antigonadal activity of cannabinoids: suppression of rat granulosa cell functions.

PubMed

Adashi, E Y; Jones, P B; Hsueh, A J

1983-02-01

The direct effects of delta 9-tetrahydrocannabinol (THC) and related cannabinoids on ovarian granulosa cells were studied in vitro. Granulosa cells from immature, hypophysectomized, estrogen-treated rats were cultured for 2 days in an androstenedione-supplemented medium in the presence or absence of follicle-stimulating hormone (FSH) (10 ng/ml) with or without cannabinoids. FSH treatment increased progesterone and estrogen biosynthesis, whereas concomitant treatment with THC led to a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen with ED50 values of 3.5 +/- 0.3 X 10(-7) and 1.8 +/- 0.2 X 10(-6) M, respectively. Treatment with related but nonpsychoactive cannabinoids (cannabidiol, cannabinol, cannabigerol, or cannabichromene) was equally effective. The THC-induced inhibition of progesterone production was reversible and was associated with an inhibition of pregnenolone biosynthesis and a decrease of 3 beta-hydroxysteroid dehydrogenase activity. In addition, treatment with THC brought about a dose-dependent inhibition of the FSH-induced increase in luteinizing hormone (LH) receptors. The inhibitory effects of THC were not associated with changes in cell number, protein content, or cell viability. Thus, THC exerts direct inhibitory effects on FSH-dependent functions related to steroidogenesis and the acquisition of LH receptors, all of which are essential to follicular maturation. Because plasma concentrations of THC similar to those used in this study have been reported in human beings, repeated exposure of female users to THC may lead to ovarian dysfunction, due in part, to the direct antigonadal activity to THC.

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

PubMed

Sellers, Edward M; Schoedel, Kerri; Bartlett, Cindy; Romach, Myroslava; Russo, Ethan B; Stott, Colin G; Wright, Stephen; White, Linda; Duncombe, Paul; Chen, Chien-Feng

2013-07-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. © The Author(s) 2013.

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats.

PubMed

Fadda, Paola; Robinson, Lianne; Fratta, Walter; Pertwee, Roger G; Riedel, Gernot

2004-12-01

Cannabinoid receptors in the brain (CB(1)) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Delta(9)-tetrahydrocannabinol (Delta(9)-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Delta(9)-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Delta(9)-THC. Despite considerable amounts of Delta(9)-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Delta(9)-THC-rich extract. CBD-rich extracts also did not alter Delta(9)-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Delta(9)-THC-induced spatial memory deficits is dependent on the ratio between CBD and Delta(9)-THC.

The psychoactive substance of cannabis Δ9-tetrahydrocannabinol (THC) negatively regulates CFTR in airway cells.

PubMed

Chang, Sheng-Wei; Wellmerling, Jack; Zhang, Xiaoli; Rayner, Rachael E; Osman, Wissam; Mertz, Sara; Amer, Amal O; Peeples, Mark E; Boyaka, Prosper N; Cormet-Boyaka, Estelle

2018-06-18

Marijuana consumption is on the rise in the US but the health benefits of cannabis smoking are controversial and the impact of cannabis components on lung homeostasis is not well-understood. Lung function requires a fine regulation of the ion channel CFTR, which is responsible for fluid homeostasis and mucocilliary clearance. The goal of this study was to assess the effect that exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive substance present in marijuana, has on CFTR expression and function. Cultures of human bronchial epithelial cell line 16HBE14o- and primary human airway epithelial cells were exposed to THC. The expression of CFTR protein was determined by immunoblotting and CFTR function was measured using Ussing chambers. We also used specific pharmacological inhibitors of EGFR and ERK to determine the role of this pathway in THC-induced regulation of CFTR. THC decreased CFTR protein expression in primary human bronchial epithelial cells. This decrease was associated with reduced CFTR-mediated short-circuit currents. THC also induced activation of the ERK MAPK pathway via activation of EGFR. Inhibition of EGFR or MEK/ERK prevented THC-induced down regulation of CFTR protein expression. THC negatively regulates CFTR and this is mediated through the EGFR/ERK axis. This study provides the first evidence that THC present in marijuana reduces the expression and function of CFTR in airway epithelial cells. Copyright © 2018. Published by Elsevier B.V.

Marijuana, receptors and immunomodulation.

PubMed

Friedman, H; Klein, T W; Newton, C; Daaka, Y

1995-01-01

THC, the major psychoactive component of marijuana, has been shown both in humans and experimental animals to have immunomodulatory properties. For example, marijuana smokers may show impaired immunological functions, including deficiency of blood leukocyte blastogenesis to mitogens. Detailed studies with mice have shown that animals given THC can show marked immunomodulation, including suppression of antibody formation, deficient cytokine production, etc. However, recent studies have also shown that lymphoid cells evince enhanced production or release or IL1, but suppression of IL2 and interferon production. Such lymphoid cells treated in vitro with THC also show suppressed blastogenesis to antigens and mitogens, suppressed NK activity, etc. In contrast, it has recently been shown that THC can enhance production or release of pro-inflammatory cytokines. This includes release of these cytokines from macrophages, including augmented release of IL1, TNF alpha, and IL6 activity. Susceptibility of mice to infection with opportunistic organisms such as L. pneumophila has been found and this increased susceptibility can be modulated by THC. A toxic shock-like death to Legionella has been induced by THC treatment given one day before and one day after infection. Receptors to THC have been detected in the brain as well as in peripheral tissues, including lymphoid cells. Thus, immunomodulation induced by THC may be related to receptor effects as well as unrelated to such receptors. It is clear that THC and other cannabinoids are excellent tools for studying the mechanisms of immune modulation, especially altered susceptibility to microbial infection.

Finding cannabinoids in hair does not prove cannabis consumption.

PubMed

Moosmann, Bjoern; Roth, Nadine; Auwärter, Volker

2015-10-07

Hair analysis for cannabinoids is extensively applied in workplace drug testing and in child protection cases, although valid data on incorporation of the main analytical targets, ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-THC (THC-COOH), into human hair is widely missing. Furthermore, ∆9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of THC, is found in the hair of persons who solely handled cannabis material. In the light of the serious consequences of positive test results the mechanisms of drug incorporation into hair urgently need scientific evaluation. Here we show that neither THC nor THCA-A are incorporated into human hair in relevant amounts after systemic uptake. THC-COOH, which is considered an incontestable proof of THC uptake according to the current scientific doctrine, was found in hair, but was also present in older hair segments, which already grew before the oral THC intake and in sebum/sweat samples. Our studies show that all three cannabinoids can be present in hair of non-consuming individuals because of transfer through cannabis consumers, via their hands, their sebum/sweat, or cannabis smoke. This is of concern for e.g. child-custody cases as cannabinoid findings in a child's hair may be caused by close contact to cannabis consumers rather than by inhalation of side-stream smoke.

DOUBLE SHELL TANK (DST) HYDROXIDE DEPLETION MODEL FOR CARBON DIOXIDE ABSORPTION

DOE Office of Scientific and Technical Information (OSTI.GOV)

OGDEN DM; KIRCH NW

2007-10-31

This document generates a supernatant hydroxide ion depletion model based on mechanistic principles. The carbon dioxide absorption mechanistic model is developed in this report. The report also benchmarks the model against historical tank supernatant hydroxide data and vapor space carbon dioxide data. A comparison of the newly generated mechanistic model with previously applied empirical hydroxide depletion equations is also performed.

TANK SPACE ALTERNATIVES ANALYSIS REPORT

DOE Office of Scientific and Technical Information (OSTI.GOV)

TURNER DA; KIRCH NW; WASHENFELDER DJ

2010-04-27

This report addresses the projected shortfall of double-shell tank (DST) space starting in 2018. Using a multi-variant methodology, a total of eight new-term options and 17 long-term options for recovering DST space were evaluated. These include 11 options that were previously evaluated in RPP-7702, Tank Space Options Report (Rev. 1). Based on the results of this evaluation, two near-term and three long-term options have been identified as being sufficient to overcome the shortfall of DST space projected to occur between 2018 and 2025.

Development of a Low Strain-Rate Gun Propellant Bed Compression Test and its Use in Evaluating Mechanical Response

DTIC Science & Technology

2016-09-01

heuristics, die and propellant geometries from similar facilities reported in the literature [2,3] and the DST Group design .  bed* (mm) φbed...compliance curves from the experimental data. In UNCLASSIFIED DST- Group -TR-3291 UNCLASSIFIED 18 Figure 13, the red axial compliance traces were...UNCLASSIFIED DST- Group -TR-3291 UNCLASSIFIED 46 At a test temperature of -60˚C, the equivalent strain rates are within the 10 to 500 s-1 given in

Major Geomagnetic Storms (Dst less than or equal to -100 nT) Generated by Corotating Interaction Regions

NASA Technical Reports Server (NTRS)

Richardson, I. G.; Webb, D. F.; Zhang, J.; Berdichevsky, B. D.; Biesecker, D. A.; Kasper, J. C.; Kataoka, R.; Steinberg, J. T.; Thompson, B. J.; Wu, C.-C.;

Dst and a map of average equivalent ring current: 1958-2007

NASA Astrophysics Data System (ADS)

Love, J. J.

2008-12-01

A new Dst index construction is made using the original hourly magnetic-observatory data collected over the years 1958-2007; stations: Hermanus South Africa, Kakioka Japan, Honolulu Hawaii, and San Juan Puerto Rico. The construction method we use is generally consistent with the algorithm defined by Sugiura (1964), and which forms the basis for the standard Kyoto Dst index. This involves corrections for observatory baseline shifts, subtraction of the main-field secular variation, and subtraction of specific harmonics that approximate the solar-quiet (Sq) variation. Fourier analysis of the observatory data reveals the nature of Sq: it consists primarily of periodic variation driven by the Earth's rotation, the Moon's orbit, the Earth's orbit, and, to some extent, the solar cycle. Cross coupling of the harmonics associated with each of the external periodic driving forces results in a seemingly complicated Sq time series that is sometimes considered to be relatively random and unpredictable, but which is, in fact, well described in terms of Fourier series. Working in the frequency domain, Sq can be filtered out, and, upon return to the time domain, the local disturbance time series (Dist) for each observatory can be recovered. After averaging the local disturbance time series from each observatory, the global magnetic disturbance time series Dst is obtained. Analysis of this new Dst index is compared with that produced by Kyoto, and various biases and differences are discussed. The combination of the Dist and Dst time series can be used to explore the local-time/universal-time symmetry of an equivalent ring current. Individual magnetic storms can have a complicated disturbance field that is asymmetrical in longitude, presumably due to partial ring currents. Using 50 years of data we map the average local-time magnetic disturbance, finding that it is very nearly proportional to Dst. To our surprise, the primary asymmetry in mean magnetic disturbance is not between midnight and noon, but rather between dawn and dusk, with greatest mean disturbance occurring at dusk. As a result, proposed corrections to Dst for magnetopause and tail currents might be reasonably reconsidered.

Medical Marijuana in Certain Neurological Disorders

MedlinePlus

... of chemicals in the plant: cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD and THC are taken from the cannabis plant for use ... also can be created (synthesized) in a lab. THC has a stronger intoxicating effect than CBD. Is ...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA.

PubMed

Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W; Marusich, Julie A; Kevin, Richard C; McGregor, Iain S; Wiley, Jenny L; Thomas, Brian F

2018-05-01

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB 1 ) receptor and produce effects similar to those of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB 1 and human CB 2 receptors, 2) function in [ 35 S]GTP γ S and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in [ 35 S]GTP γ S and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB 1 than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB 1 receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Controlled vaporized cannabis, with and without alcohol: subjective effects and oral fluid-blood cannabinoid relationships.

PubMed

Hartman, Rebecca L; Brown, Timothy L; Milavetz, Gary; Spurgin, Andrew; Gorelick, David A; Gaffney, Gary; Huestis, Marilyn A

2016-07-01

Vaporized cannabis and concurrent cannabis and alcohol intake are commonplace. We evaluated the subjective effects of cannabis, with and without alcohol, relative to blood and oral fluid (OF, advantageous for cannabis exposure screening) cannabinoid concentrations and OF/blood and OF/plasma vaporized-cannabinoid relationships. Healthy adult occasional-to-moderate cannabis smokers received a vaporized placebo or active cannabis (2.9% and 6.7% Δ(9) -tetrahydrocannabinol, THC) with or without oral low-dose alcohol (~0.065g/210L peak breath alcohol concentration [BrAC]) in a within-subjects design. Blood and OF were collected up to 8.3 h post-dose and subjective effects measured at matched time points with visual-analogue scales and 5-point Likert scales. Linear mixed models evaluated subjective effects by THC concentration, BrAC, and interactions. Effects by time point were evaluated by dose-wise analysis of variance (ANOVA). OF versus blood or plasma cannabinoid ratios and correlations were evaluated in paired-positive specimens. Nineteen participants (13 men) completed the study. Blood THC concentration or BrAC significantly associated with subjective effects including 'high', while OF contamination prevented significant OF concentration associations <1.4 h post-dose. Subjective effects persisted through 3.3-4.3 h, with alcohol potentiating the duration of the cannabis effects. Effect-versus-THC concentration and effect-versus-alcohol concentration hystereses were counterclockwise and clockwise, respectively. OF/blood and OF/plasma THC significantly correlated (all Spearman r≥0.71), but variability was high. Vaporized cannabis subjective effects were similar to those previously reported after smoking, with duration extended by concurrent alcohol. Cannabis intake was identified by OF testing, but OF concentration variability limited interpretation. Blood THC concentrations were more consistent across subjects and more accurate at predicting cannabis' subjective effects. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Δ9-Tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-Stimulation in Mice

PubMed Central

Grim, Travis W.; Owens, Robert A.; Lazenka, Matthew F.; Sim-Selley, Laura J.; Abdullah, Rehab A.; Niphakis, Micah J.; Vann, Robert E.; Cravatt, Benjamin F.; Wiley, Jenny L.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. PMID:25398241

Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

PubMed

Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

2015-02-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Suppressive effect of delta 9-tetrahydrocannabinol in vitro on phagocytosis by murine macrophages.

PubMed

Friedman, M; Cepero, M L; Klein, T; Friedman, H

1986-06-01

Incubation of normal mouse peritoneal cells consisting of over 90% phagocytizing macrophages with delta 9-tetrahydrocannabinol (THC) resulted in a inhibition of phagocytic function. The THC in a dose-related manner suppressed the percentage of macrophages per culture which ingested yeast and the average number of yeast particles ingested by the phagocytizing macrophages. The vehicle used to suspend the THC in vitro, i.e., DMSO, had no detectable effect on macrophage function. Suppression of phagocytosis with no effects on viability or cell number occurred with doses of 10 micrograms or less THC per milliliter culture medium. Measurable suppression also occurred after 24- to 48-hr treatment of the macrophages with the THC. This compound had little if any detectable effect on phagocytosis when added directly to the cultures shortly before testing for phagocytosis. Further studies concerning the effects of THC on macrophage function appear warranted.

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

PubMed

Henquet, Cécile; Rosa, Araceli; Krabbendam, Lydia; Papiol, Sergi; Fananás, Lourdes; Drukker, Marjan; Ramaekers, Johannes G; van Os, Jim

2006-12-01

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-9-THC on cognition and psychosis are moderated by COMT Val(158)Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

Has the intake of THC by cannabis users changed over the last decade? Evidence of increased exposure by analysis of blood THC concentrations in impaired drivers.

PubMed

Vindenes, Vigdis; Strand, Dag Helge; Kristoffersen, Lena; Boix, Fernando; Mørland, Jørg

2013-03-10

The main psychoactive substance, Δ9-tetrahydrocannabinol (THC) can be present in highly variable amounts in different cannabis preparations. An increase in THC content in cannabis products has been suggested, and reported from several countries. However, it has not yet been investigated if products with high potency lead to increased human exposure, and thus to higher risk of adverse effects. In this study, we examined the mean concentrations of THC in whole blood samples from drivers apprehended in Norway in the period between 2000 and 2010 suspected of driving under the influence of drugs. Cases with only THC (n=1747) have been compared to cases with only ethanol (n=38796) or amphetamines (n=2493). The increase in mean THC concentration measured from 2000 to 2010 was from 4.0 ± 0.3 to 6.6 ± 0.4 ng/ml (58%), compared to 3% for ethanol and 16% for the amphetamines. This increase in THC concentrations was to some extent paralleled by an increase in the percentage of drivers which were judged as lightly impaired by a physician. Monitoring concentrations of drugs of abuse in blood from apprehended drivers indicated an increasing exposure to THC in Norway. If similar trends are observed globally, it should be further explored if this type of information could be used to elucidate the drug consumption patterns in a population and accordingly the consequences with regard to adverse effects of cannabis from a public health perspective. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Collagen gel droplet-embedded culture drug sensitivity test for adjuvant chemotherapy after complete resection of non-small-cell lung cancer.

PubMed

Inoue, Masayoshi; Maeda, Hajime; Takeuchi, Yukiyasu; Fukuhara, Kenjiro; Shintani, Yasushi; Funakoshi, Yasunobu; Funaki, Soichiro; Nojiri, Takashi; Kusu, Takashi; Kusumoto, Hidenori; Kimura, Toru; Okumura, Meinoshin

2018-04-01

We conducted a prospective clinical study to individualize adjuvant chemotherapy after complete resection of non-small-cell lung cancer (NSCLC), based on the drug sensitivity test. Patients with resectable c-stage IB-IIIA NSCLC were registered between 2005 and 2010. We performed the collagen gel droplet-embedded culture drug sensitivity test (CD-DST) on a fresh surgical specimen to assess in vitro chemosensitivity and evaluated the prognostic outcome after adjuvant chemotherapy with carboplatin/paclitaxel based on the CD-DST. Among 92 registered patients, 87 were eligible for inclusion in the analysis. The success rate of CD-DST was 86% and chemosensitivity to carboplatin and/or paclitaxel was evident in 57 (76%) of the 75 patients. Adjuvant chemotherapy was completed in 22 (73%) of 30 patients. The 5-year overall survival rates were 71, 73, and 75% for all, CD-DST success, and chemosensitive patients, respectively. The 5-year disease-free survival and overall survival rates of the chemosensitive patients who completed adjuvant chemotherapy using carboplatin/paclitaxel were 68 and 82%, respectively. The 5-year disease-free survival and overall survival rates of the patients with stage II-IIIA chemosensitive NSCLC were 58 and 75%, respectively. Comparative analyses of the chemosensitive and non-chemosensitive/CD-DST failure groups showed no significant survival difference. CD-DST can be used to evaluate chemosensitivity after lung cancer surgery; however, its clinical efficacy for assessing individualized treatment remains uncertain.

Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders

PubMed Central

Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J.; Rohrback, Brian G.; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel

2015-01-01

Objective To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regards to their relevance to epilepsy and other selected neuropsychiatric disorders. Methods We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology and data from studies with animal models and human subjects. Results Cannabis has been used to treat disease since ancient times. Δ9-THC is the major psychoactive ingredient and cannabidiol (CBD) is the major non-psychoactive ingredient in cannabis. Cannabis and Δ9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. Psychotropic effects of Δ9-THC limit tolerability. CBD is anticonvulsant in many acute animal models but there is limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of melastatin type 8 channel; the 5-HT1a receptor; the α3 and α1 glycine receptors; and the transient receptor potential of ankyrin type 1 channel. CBD has neuroprotective and anti-inflammatory effects. CBD appears to be well tolerated in humans but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ9-THC medical marijuana have claimed efficacy, but studies were not controlled. Significance CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. PMID:24854329