Neurophysiological functioning of occasional and heavy cannabis users during THC intoxication

Rationale  

Experienced cannabis users demonstrate tolerance to some of the impairing acute effects of cannabis.     

Neurocognitive performance during acute THC intoxication in heavy and occasional cannabis users

Performance impairment during Delta(9)-tetrahydrocannabinol (THC) intoxication has been well described in occasional cannabis users. It is less clear whether tolerance develops to the impairing effects of THC in heavy users of cannabis. The aim of the present study was to assess neurocognitive performance during acute THC intoxication in occasional and heavy users. Twenty-four subjects (12 occasional cannabis users and 12 heavy cannabis users) participated in a double-blind, placebo-controlled, two-way mixed model design. Both groups received single doses of THC placebo and 500 microg/kg THC by smoking. Performance tests were conducted at regular intervals between 0 and 8 h after smoking, and included measures of perceptual motor control (critical tracking task), dual task processing (divided attention task), motor inhibition (stop signal task) and cognition (Tower of London). THC significantly impaired performance of occasional cannabis users on critical tracking, divided attention and the stop signal task. THC did not affect the performance of heavy cannabis users except in the stop signal task, i.e. stop reaction time increased, particularly at high THC concentrations. Group comparisons of overall performance in occasional and heavy users did not reveal any persistent performance differences due to residual THC in heavy users. These data indicate that cannabis use history strongly determines the behavioural response to single doses of THC.     

Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users

Introduction

Previous research has shown that heavy cannabis users develop tolerance to the impairing effects of ??9-tetrahydrocannabinol (THC) on neurocognitive functions. Animal studies suggest that chronic cannabis consumption may also produce cross-tolerance for the impairing effects of alcohol, but supportive data in humans is scarce.

Purpose

The present study was designed to assess tolerance and cross-tolerance to the neurocognitive effects of THC and alcohol in heavy cannabis users.

Methods

Twenty-one heavy cannabis users participated in a double-blind, placebo-controlled, three-way study. Subjects underwent three alcohol-dosing conditions that were designed to achieve a steady blood alcohol concentration of about 0, 0.5, and 0.7?mg/ml during a 5-h time window. In addition, subjects smoked a THC cigarette (400???g/kg) at 3?h post-onset of alcohol dosing during every alcohol condition. Performance tests were conducted repeatedly between 0 and 7?h after onset of drinking and included measures of perceptual motor control (critical tracking task), dual task processing (divided-attention task), motor inhibition (stop-signal task), and cognition (Tower of London).

Results

Alcohol significantly impaired critical tracking, divided attention, and stop-signal performance. THC generally did not affect task performance. However, combined effects of THC and alcohol on divided attention were bigger than those by alcohol alone.

Conclusion

In conclusion, the present study generally confirms that heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive task performance. Yet, heavy cannabis users did not develop cross-tolerance to the impairing effects of alcohol, and the presence of the latter even selectively potentiated THC effects on measures of divided attention.     

Executive control among adolescent inhalant and cannabis users

Introduction and Aims. Inhalants are frequently among the first drugs abused by adolescents; however, little is known about how chronic inhalant abuse affects cognition (e.g. executive functioning). Several studies have examined cognitive deficits among inhalant users; however, no study has thoroughly addressed the confounding issues frequently associated with inhalant users (e.g. polysubstance use). The aim of the current study was to examine possible deficits in cognitive control among young, regular inhalant users and explore the relationship between inhalant use and executive functioning. Design and Methods. Three groups (n = 19) of young people (aged 14–24) were recruited: an inhalant‐using group, a drug‐using control group and a community control group. The inhalant and drug‐using controls were matched on demographic, clinical and substance use measures. All three groups were matched on age, sex and education. Cognitive control was assessed using Stroop and Go/No‐Go tasks. Results. There were no significant differences in performance between the groups on any measure. However, three measures (incongruent reaction times and congruent errors for the Stroop and omission errors for the Go/No‐Go) were significantly correlated with inhalant use measures, suggesting inhalant use was associated with poorer performance. Discussion and Conclusions. The lack of significant differences between the groups is surprising; however, it raises important questions regarding cognitive deficits among chronic inhalant users. Further longitudinal studies using well‐matched control participants are required to delineate the nature and timing of cognitive and neurobiological pathology among adolescent inhalant users.[Takagi M, Lubman DI, Cotton S, Fornito A, Baliz Y, Tucker A, Yücel M. Executive control among adolescent inhalant and cannabis users. Drug Alcohol Rev 2010;30:629–637]     

Biomarkers for the effects of cannabis and THC in healthy volunteers

An increasing number of novel therapeutic agents are targeted at cannabinoid receptors. Drug development programmes of new cannabinoid drugs may be facilitated by the identification of useful biomarkers. This systemic literature review aims to assess the usefulness of direct biomarkers for the effects of cannabis and tetrahydrocannabinol (THC) in healthy volunteers. One hundred and sixty-five useful articles were found that investigated the acute effects of cannabis or THC on the central nervous system (CNS) and heart rate in healthy volunteers. Three hundred and eighteen tests (or test variants) were grouped in test clusters and functional domains, to allow their evaluation as a useful biomarker and to study their dose–response effects. Cannabis/THC affected a wide range of CNS domains. In addition to heart rate, subjective effects were the most reliable biomarkers, showing significant responses to cannabis in almost all studies. Some CNS domains showed indications of depression at lower and stimulation at higher doses. Subjective effects and heart rate are currently the most reliable biomarkers to study the effect of cannabis. Cannabis affects most CNS domains, but too many different CNS tests are used to quantify the drug–response relationships reliably. Test standardization, particularly in motor and memory domains, may reveal additional biomarkers.     

Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users

Rationale A single 90-mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans. Objectives The objective of this study is to evaluate whether repeated daily 40-mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher (90 mg) dose. Materials and methods Forty-two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: (1) 40 mg rimonabant daily for 15 days, (2) placebo for 14 days, then 90 mg rimonabant on day 15, or (3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana-scale of the Addiction Research Center Inventory. Results Cannabis-induced tachycardia was significantly lower for the 40-mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40-mg dose significantly decreased peak subjective effects on day 8. Neither the 90-mg nor 40-mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Δ⁹-tetrahydrocannabinnol pharmacokinetics. Conclusions Repeated lower daily rimonabant doses (40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90-mg dose; repeated 40-mg doses attenuated subjective effects after 8 but not 15 days.     

Methodological investigations for a multisite trial of auricular acupuncture for cocaine addiction: A study of active and control auricular zones

We evaluated objective criteria for defining points for needle insertion prior to conducting a multisite clinical trial of auricular acupuncture for cocaine addiction. Thirty-four cocaine-abusing subjects participated in a study in which the trial's active zones (Shenmen, Liver, Lung, and Sympathetic) and control zones (located on the ear helix) were divided into quadrants and assessed along four dimensions: electrical resistance, skin discoloration, skin topography, and tenderness. Acute effects of needles inserted into points of low electrical resistance in one ear and high electrical resistance in the other were also assessed. Results showed that the active zones had lower overall electrical resistance and more subcutaneous ridges than control zones. Zones did not possess significant variability along any single dimension. Acute effects of needling high and low resistance points were similar, differing only for “fullness.” Based on these findings, and in view of the difficulty of accurately measuring electrical resistance at ear points, we do not recommend the use of electrical devices for point determination in the multisite study. At present, there seems to be little scientific basis for the preselection of specific points for needle insertion within auricular zones. Needle placement should be based upon clinical judgement.     

Norcocaine and cocaethylene distribution patterns in hair samples from light,moderate, and heavy cocaine users

Even though hair analysis often seems to be the best choice for retrospective monitoring of cocaine intake, differentiating between incorporated cocaine and external contamination is widely debated. In this study we report results obtained in 90 hair samples from addicts. All samples were analyzed for cocaine, benzoylecgonine, norcocaine, cocaethylene, and tropococaine by gas chromatography‐mass spectrometry (GC‐MS) techniques coupled with direct immersion solid‐phase micro‐extraction. Cocaine concentrations were stratified into three classes of usage: light (0.5–3 ng/mg), moderate (3.1–10 ng/mg) and heavy (10.1–40 ng/mg). The Substance Abuse and Mental Health Services Administration cut‐off criteria for establishing active cocaine use were applied to the results. For all samples criteria were cocaine levels above 0.5 ng/mg (ranging from 1.63 to 39.29 ng/mg, mean 9.49 ng/mg), benzoylecgonine concentrations ≥ 0.05 ng/mg (ranging from 0.19 to 5.77 ng/mg, mean 1.40), and benzoylecgonine to cocaine % ratio ≥5% (from 6.43 to 26.09%). Norcocaine was present in 58.9% of samples (concentration range: 0.22–3.14 ng/mg) and was strongly predictive only of heavy cocaine use (sensitivity 100% for cocaine concentrations above 9.58 ng/mg). Twenty hair samples from moderate and heavy users tested positive for cocaethylene (concentration range: 0.22–1.98 ng/mg, mean 0.73 ng/mg). This study on hair samples with no chance of false positive cases highlights the very limited applications of testing minor cocaine metabolites for definitive proof of active cocaine consumption. © 2015 The Authors. Drug Testing and Analysis Published by John Wiley & Sons, Ltd.     

Acute effects of THC on time perception in frequent and infrequent cannabis users

Rationale

Cannabinoids have been shown to alter time perception, but existing literature has several limitations. Few studies have included both time estimation and production tasks, few control for subvocal counting, most had small sample sizes, some did not record subjects’ cannabis use, many tested only one dose, and used either oral or inhaled administration of Δ⁹-tetrahydrocannabinol (THC), leading to variable pharmacokinetics, and some used whole-plant cannabis containing cannabinoids other than THC. Our study attempted to address these limitations.

Objectives

This study aims to characterize the acute effects of THC and frequent cannabis use on seconds-range time perception. THC was hypothesized to produce transient, dose-related time overestimation and underproduction. Frequent cannabis smokers were hypothesized to show blunted responses to these alterations.

Methods

IV THC was administered at doses from 0.015 to 0.05 mg/kg to 44 subjects who participated in several double-blind, randomized, counterbalanced, crossover, placebo-controlled studies. Visual time estimation and production tasks in the seconds range were presented to subjects three times on each test day.

Results

All doses induced time overestimation and underproduction. Chronic cannabis use had no effect on baseline time perception. While infrequent/nonsmokers showed temporal overestimation at medium and high doses and temporal underproduction at all doses, frequent cannabis users showed no differences. THC effects on time perception were not dose related.

Conclusions

A psychoactive dose of THC increases internal clock speed as indicated by time overestimation and underproduction. This effect is not dose related and is blunted in chronic cannabis smokers who did not otherwise have altered baseline time perception.     

Pattern of cannabis use in ecstasy polydrug users: moderate cannabis use may compensate for self-rated aggression and somatic symptoms

Cannabis is one of the most common 'co-drugs' for ecstasy users. The aim of the present study was to explore self-reported psychobiological problems in ecstasy polydrug users in relation to their pattern of cannabis use. Two hundred and eighty ecstasy polydrug users were allocated into five cannabis groups according to the frequency of their cannabis use. The control group comprised 121 alcohol-tobacco users. There were no significant group differences with regard to age, diagnosed family psychiatric history and level of self-rated stress experienced during 6 months prior to the study. The present study produced three main findings: (a) Ecstasy users with no concomitant use of cannabis displayed more self-rated aggression and somatic symptoms compared with ecstasy users who were smoking cannabis on a monthly or weekly basis. (b) Ecstasy users who reported heavy cannabis use in the past displayed higher paranoid symptoms compared with ecstasy weekly and daily cannabis users. (c) Former heavy cannabis users were the most likely to complain of a variety of ecstasy related long-term problems. In conclusion, moderate cannabis use may help to ameliorate or mask MDMA-induced aggressivity and somatic symptoms. However, this study confirms that heavy cannabis and ecstasy use is associated with several psychobiological problems, which may emerge after a period of abstinence from both drugs.     

Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation

Recent attention has been focused on the long-term impact of cannabis exposure, for which experimental animal studies have validated causal relationships between neurobiological and behavioral alterations during the individual''s lifetime. Here, we show that adolescent exposure to Δ⁹-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, results in behavioral and neurobiological abnormalities in the subsequent generation of rats as a consequence of parental germline exposure to the drug. Adult F1 offspring that were themselves unexposed to THC displayed increased work effort to self-administer heroin, with enhanced stereotyped behaviors during the period of acute heroin withdrawal. On the molecular level, parental THC exposure was associated with changes in the mRNA expression of cannabinoid, dopamine, and glutamatergic receptor genes in the striatum, a key component of the neuronal circuitry mediating compulsive behaviors and reward sensitivity. Specifically, decreased mRNA and protein levels, as well as NMDA receptor binding were observed in the dorsal striatum of adult offspring as a consequence of germline THC exposure. Electrophysiologically, plasticity was altered at excitatory synapses of the striatal circuitry that is known to mediate compulsive and goal-directed behaviors. These findings demonstrate that parental history of germline THC exposure affects the molecular characteristics of the striatum, can impact offspring phenotype, and could possibly confer enhanced risk for psychiatric disorders in the subsequent generation.     

Effects of carbamazepine on acute responses to smoked cocaine-base in human cocaine users

A double-blind, placebo-controlled cross-over study was conducted to determine the effects of carbamazepine on the acute physiological and subjective responses to a single dose of smoked cocaine-base. Male cocaine users (N=6) were given 400 mg carbamazepine or placebo, each for a period of 5 days. At the end of the 5-day period, a 40 mg dose of smoked cocaine was administered. The results showed a significantly higher heart rate, diastolic blood pressure elevation, and blood pressure-heart rate product under the carbamazepine compared to the placebo condition. There were no effects of carbamazepine on the subjective responses from cocaine. The increase in cardiovascular functions indicates a need to be cautious in the use of carbamazepine in the treatment of cocaine abusers.Supported by National Institute on Drug Abuse Research Grant No. DA05844     

Pulmonary function in cannabis users: Support for a clinical trial of the vaporizer

BackgroundDebates about cannabis policy often mention respiratory symptoms as a negative consequence of use. The cannabis vaporizer, a machine that heats the plant to release cannabinoids in a mist without smoke and other respiratory irritants, appears to have the potential to minimize respiratory complaints.MethodsTwenty frequent cannabis users (uninterested in treatment) reporting at least two respiratory symptoms completed subjective ratings of respiratory symptoms and spirometry measures prior to and following 1 month's use of a cannabis vaporizer in a pre/post-design. Outcome measures included self-reported severity of nine respiratory symptoms as well as spirometry measures, including the maximum amount of air exhaled in 1 s (forced expiratory volume; FEV1) and maximum total lung volume (forced vital capacity; FVC).ResultsThe 12 participants who did not develop a respiratory illness during the trial significantly improved respiratory symptoms (t(11) = 6.22, p = 0.000065, d = 3.75) and FVC, t(11) = 2.90, p = 0.007, d = 1.75. FEV1 improved but not significantly t(11) = 1.77, p = 0.053, d = 1.07.ConclusionsThese preliminary data reveal meaningful improvements in respiratory function, suggesting that a randomized clinical trial of the cannabis vaporizer is warranted. The vaporizer has potential for the administration of medical cannabis and as a harm reduction technique.     

Patterns of simultaneous polysubstance use in drug using university students

Simultaneous polysubstance use (SPU) is a common phenomenon, yet little is known about how various substances are used with one another. In the present study 149 drug-using university students completed structured interviews about their use of various substances. For each substance ever used, participants provided details about the type, order and amount of all substances co-administered during its most recent administration. Alcohol, tobacco and cannabis were frequently co-administered with each other and with all other substances. Chi-squared tests revealed that when alcohol was used in combination with any of cannabis, psilocybin, MDMA, cocaine, amphetamine, methylphenidate (ps < 0.01) or LSD (p < 0.05) its initial use preceded the administration of the other substance. Paired samples t-tests revealed that when alcohol was used with cocaine (p < 0.01) or methylphenidate (p < 0.05) it was ingested in greater quantities than when used in their absence. Patterns of cannabis use were not systematically related to other substances administered. Finally, using one-sample t-tests, tobacco use was demonstrated to be increased relative to 'sober' smoking rates when used with alcohol, cannabis, psilocybin, MDMA, cocaine, amphetamine (ps < 0.001), LSD (p < 0.01) or methylphenidate (p < 0.05). Results suggest that many substances are routinely used in a SPU context and that the pattern in which a substance is used may be related to other substances co-administered.     

Comparable efficacy of behavioral and pharmacological treatments among African American and White cocaine users

ABSTRACT

Multiple randomized clinical trials (RCTs) have evaluated a range of treatments for cocaine dependence, but few of these have focused specifically on the racial diversity observed among cocaine-dependent patients. The present analyses evaluated racial variation in cocaine use and addiction-related psychosocial outcomes at baseline and follow-up among 388 African American and White adults participating in 1 of 5 RCTs evaluating a range of pharmacological and behavioral treatments for cocaine use disorders. General linear modeling (GLM) indicated significant racial variation in cocaine and psychosocial indicators at baseline. At baseline, there were significant racial differences in the number of days paid for work in the 30 days prior to the study, age, days of cocaine use in the past month, age of first cocaine use, psychosocial problems (i.e., employment, cocaine, legal, and family), public assistance status, and prevalence of lifetime anxiety disorders. There were no significant main or interaction effects of race and study on treatment outcomes at posttreatment. These findings suggest that despite significant racial differences at baseline, the pharmacological and behavioral treatments resulted in fairly comparable outcomes across racial groups in these 5 RCTs.