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.     

Single doses of THC and cocaine decrease proficiency of impulse control in heavy cannabis users

BACKGROUND AND PURPOSE

Cannabis is the most popular drug used in the European Union, closely followed by cocaine. Whereas cannabis impairs neurocognitive function in occasional cannabis users, such impairments appear less prominent in heavy users, possibly as a result of tolerance. The present study was designed to assess whether the impairing effects of Δ⁹-tetrahydrocannabinol (THC) in heavy cannabis users would present in a wide range of neuropsychological functions or selectively affect specific performance domains. We also assessed the acute effects of cocaine on neurocognitive functions of heavy cannabis users.

EXPERIMENTAL APPROACH

Heavy cannabis users, who had a history of cocaine use (n = 61), participated in a double-blind, placebo-controlled, three-way crossover study. Subjects received single doses of cocaine HCl (300 mg), cannabis (THC μg·kg⁻¹) and placebo, and completed a number of tests measuring impulse control and psychomotor function.

KEY RESULTS

Single doses of cannabis impaired psychomotor function and increased response errors during impulsivity tasks. Single doses of cocaine improved psychomotor function and decreased response time in impulsivity tasks, but increased errors.

CONCLUSIONS AND IMPLICATIONS

Heavy cannabis users display impairments in a broad range of neuropsychological domains during THC intoxication. Impairments observed in psychomotor tasks, but not in impulsivity tasks, appeared smaller in magnitude as compared with those previously reported in occasional cannabis users. Heavy cannabis users were sensitive to the stimulating and inhibitory effects of cocaine on psychomotor function and impulsivity respectively. The reduction in proficiency in impulse control may put drug users at increased risk of repeated drug use and addiction.     

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.     

Exercise increases plasma THC concentrations in regular cannabis users

Background

The major psychoactive ingredient of cannabis, Δ⁹-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users.

Methods

Fourteen regular cannabis users completed 35 min of exercise on a stationary bicycle in either a fed or overnight fasted state. Plasma cannabinoid levels were assessed prior to exercise, immediately post-exercise and 2 h post-exercise. Plasma samples were also analyzed for indices of lipolysis (free fatty acids (FFA) and glycerol).

Results

Exercise induced a small, statistically significant increase in plasma THC levels accompanied by increased plasma FFA and glycerol levels. Exercise-induced increases in plasma THC concentrations were positively correlated with body mass index. Fasting induced a significant increase in plasma FFA levels, and a lowering of blood glucose, but did not significantly alter plasma cannabinoid levels.

Conclusions

Here we demonstrate that exercise enhances plasma THC levels in regular cannabis users. The lack of a fasting effect may reflect the modest duration of fasting used which was associated with only a modest increase in fat utilization relative to exercise. Overall, these results suggest that exercise may elevate blood THC levels by releasing dormant THC from fat stores. These data suggest the interpretation of blood THC levels in roadside and workplace tests might be complicated by recent exercise.     

A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid

Rationale

Standardized Field Sobriety Tests (SFST) and oral fluid devices are used to screen for driving impairment and roadside drug detection, respectively. SFST have been validated for alcohol, but their sensitivity to impairment induced by other drugs is relatively unknown. The sensitivity and specificity for Δ⁹-tetrahydrocannabinol (THC) of most oral fluid devices have been low.

Objective

This study assessed the effects of smoking cannabis with and without alcohol on SFST performance. Presence of THC in oral fluid was examined with two devices (Dr?ger Drug Test? 5000 and Securetec Drugwipe? 5).

Methods

Twenty heavy cannabis users (15 males and 5 females; mean age, 24.3?years) participated in a double-blind, placebo-controlled study assessing percentage of impaired individuals on the SFST and the sensitivity of two oral fluid devices. Participants received alcohol doses or alcohol placebo in combination with 400?μg/kg body weight THC. We aimed to reach peak blood alcohol concentration values of 0.5 and 0.7?mg/mL.

Results

Cannabis was significantly related to performance on the one-leg stand (p?=?0.037). Alcohol in combination with cannabis was significantly related to impairment on horizontal gaze nystagmus (p?=?0.029). The Dr?ger Drug Test? 5000 demonstrated a high sensitivity for THC, whereas the sensitivity of the Securetec Drugwipe? 5 was low.

Conclusions

SFST were mildly sensitive to impairment from cannabis in heavy users. Lack of sensitivity might be attributed to tolerance and time of testing. SFST were sensitive to both doses of alcohol. The Dr?ger Drug Test? 5000 appears to be a promising tool for detecting THC in oral fluid as far as correct THC detection is concerned.     

Altered cerebral blood flow and neurocognitive correlates in adolescent cannabis users

Rationale

In drug-dependent individuals, the primary excessive motivation is for drugs. Studies also indicate altered interest for “natural” rewarding activities associated with motivational disorders that may be relevant to drug dependence. However, to date, the impact of drug dependence and withdrawal upon motivation for “natural” rewards remains unclear.

Methods and objectives

In the present study, we use a food-driven operant behavior paradigm to assess the impact of opiate intake and withdrawal upon the motivational properties of highly palatable food (HPF) in mice.

Results

Our findings indicate that early (8-h) opiate withdrawal does not affect either the motivational or the discriminative properties of HPF intake. However, starting 32?h after the last morphine injection, opiate withdrawal increases operant behavior aimed at obtaining HPF. The increased HPF-driven behavior lasts at least 12?days following opiate withdrawal, indicating long-lasting effects upon motivation. Using a paradigm of reward contingency reversal, we also address the impact of opiate withdrawal upon cognitive functions. Our results indicate that opiate withdrawal does not affect the ability to learn a new operant rule to obtain HPF. Indeed, opiate withdrawal ameliorates the acquisition of the new HPF-driven operant task, most probably due to the persistent and long-lasting increased motivation. Finally, analysis of ambulatory activity and body weight (BW) changes reveal that motivational and cognitive effects are totally independent of caloric and/or motor effects of opiate dosing and withdrawal.

Conclusions

These results clearly demonstrate that excessive opiate intake and withdrawal produces dramatic and long-lasting motivational disorders relevant to drug dependence.     

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

Abstract Rationale. Although some aspects of memory functions are known to be acutely impaired by Δ⁹-tetrahydrocannabinol (Δ⁹-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. Objective. The present study aimed to detail the acute and residual cognitive effects of Δ⁹-THC in infrequent cannabis users. Methods. A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg Δ⁹-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. Results. Δ⁹-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 Δ⁹-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by Δ⁹-THC. In several tasks, Δ⁹-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 Δ⁹-THC. No effects of Δ⁹-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral Δ⁹-THC are minimal. Conclusions. These data demonstrate that oral Δ⁹-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory. Electronic Publication     

Characterizing smoking topography of cannabis in heavy users

Rationale  

Little is known about the smoking topography characteristics of heavy cannabis users. Such measures may be able to predict cannabis use-related outcomes and could be used to validate self-reported measures of cannabis use.     

Tolerance and selective cross-tolerance to the motivational effects of opioids

The issue of whether tolerance develops to the motivational effects of opioids was addressed by use of an unbiased place preference conditioning procedure. Administration of the μ-opioid agonists morphine or fentanyl produced dose-related preferences for the drug-associated place in control rats. In contrast, the κ-opioid agonist, U-69593 produced conditioned place aversions. Non-contingent administration of morphine (5.0 mg/kg/12 h) for 4 days prior to conditioning resulted in tolerance to its reinforcing effects, and cross-tolerance to the effects of fentanyl. No cross-tolerance to the motivational effects of the psychostimulantd-amphetamine or the κ-opioid agonist U-69593 was observed. Chronic administration of U-69593 prior to conditioning produced tolerance to its aversive effects. This treatment did not, however, modify the reinforcement produced by morphine. These data demonstrate that tolerance develops to both the reinforcing and aversive properties of opioids and suggest that differential cross-tolerance may provide a useful method for determining the pharmacological basis underlying drug-induced motivational effects.     

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.     

Verbal learning and memory in adolescent cannabis users,alcohol users and non-users

Rationale  

Long-term heavy cannabis use can result in memory impairment. Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis.     

Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats

 The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED₅₀ for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED₅₀ for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED₅₀ for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED₅₀ for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist. Received: 17 September 1996 / Final version: 13 March 1997     

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7.     

Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination

The effect of 9-tetrahydrocannabinol ( 9-THC) and alcohol, singly and in combination, on divided attention performance was investigated in cannabis users and non-users who were matched for alcohol use. Both cannabis and alcohol produced decrements in central and peripheral signal detections. Drug and alcohol effects were greater for signal presentations in the periphery. Cannabis users were less impaired in peripheral signal detection than non-users while intoxicated by cannabis and/or alcohol. These findings suggest the development of tolerance and cross-tolerance in regular cannabis users and/or the ability to compensate for intoxication effects.     

Attentional bias to cannabis cues in cannabis users but not cocaine users

Attentional bias to drug cues has been associated with the problematic use of drugs, including cannabis. The cognitive mechanisms underlying this bias are not fully understood. The purpose of this study was to determine whether cannabis-cue attentional bias is associated with disruptions in attentional processing. To this end, a novel cannabis-cue visual probe task that incorporated eye tracking technology and attention-based metrics derived from signal detection theory was administered to seventeen individuals who reported daily/near-daily cannabis use. Seventeen individuals with cocaine use disorder were also enrolled as a clinical-control group. Cannabis and neutral images were briefly presented side-by-side on a computer screen, followed by the appearance of a “go” or “no-go” target upon offset of both images to permit assessment of attention-based performance. Cannabis users exhibited attentional bias to cannabis cues, as measured by fixation time and response time, but not cue-dependent disruptions on subsequent attentional performance. Cocaine users did not display an attentional bias to cannabis cues but did display poorer attentional performance relative to cannabis users. These results indicate that attentional bias to cannabis cues is selective to cannabis use history and not associated with impaired attentional processing.     

Tolerance to ethanol and cross-tolerance to pentobarbital and barbital

A chronic regimen of ethanol by intubation, which produced clear tolerance to ethanol-induced hypothermia, ataxia and narcosis, produced only a marginal degree of cross-tolerance to these effects of pentobarbital. The lack of appreciable cross-tolerance to pentobarbital-induced hypothermia and ataxia was also observed over a wide range of test doses. However, cross-tolerance to barbital was observed after chronic treatment with ethanol. Increased rate of drug biotransformation did not contribute significantly to the observed tolerance and cross-tolerance. The difference in the extent of cross-tolerance between ethanol and the two barbiturates is consistent with the hypothesis that there is a degree of specificity in the sites of action of ethanol and other sedative-hypnotic drugs.     

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

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.