Behavioral and subjective effects of marijuana following partial sleep deprivation

This study tested whether performance would be more impaired when marijuana use followed partial sleep deprivation (PSD) than when marijuana use followed a typical night of sleep. Seven recreational marijuana users (mean 15 of last 30 days) completed six test sessions in a double-blind randomized within-subject design. Each session began with an overnight stay in a sleep laboratory. Bed and wake times were calculated from mean data on individual sleep diaries. Time-in-bed was either regular (mean=8.2 h) or shortened (first 65% of regular time-in-bed deprived). At 3 and 5 h after waking, daytime sleepiness was measured with self-report questionnaires and a sleep latency test. Approximately 6.5 h after waking, subjects smoked a marijuana cigarette (0.003, 2, or 3.5% delta-9 tetrahydrocannabinol [THC]). Test batteries were completed 2, 62, and 122 min after smoking ended. Sleepiness was significantly greater following PSD than after regular sleep. Following regular sleep, heart rate increases with active THC doses were comparable, but heart rate with 2% THC was significantly less elevated following PSD. Ratings of ‘impaired’ and ‘stoned’ increased with both THC doses after regular sleep and were further increased with 3.5% THC after PSD. High-potency marijuana increased body sway similarly across sleep conditions. There were no significant effects of marijuana or PSD, alone or in combination, on brake latency. Thus, while PSD increased the dose-dependence of THC effects on heart rate and subjective impairment, it did not enhance the effects of marijuana on standing balance and brake latency.     

Plasma concentrations of delta-9-tetrahydrocannabinol and impaired motor function

Fifty-nine volunteer subjects were allowed to smoke marijuana cigarettes until a satisfactory level of 'high' was obtained. They then had blood samples taken 5, 30, 90 and 150 min following smoking after which they were tested with the roadside sobriety test. Attempts to correlate passing or failing on three coordination tests with plasma concentrations of delta-9-tetrahydrocannabinol (THC) showed that if concentrations measured at 5 min were ignored, failures were almost inevitably associated with plasma concentrations of THC above 25-30 ng/ml. Overall, 94% of subjects failed to pass the test 90 min after smoking and 60% after 150 min, despite the fact that by then plasma concentrations were rather low. It would seem that establishing a clear relation between THC plasma concentrations and clinical impairment will be much more difficult than it has been for alcohol.     

Caffeine antagonism of alcohol-induced driving impairment

The extent to which caffeine antagonizes alcohol-induced impairment of simulated automobile driving at the current lowest legal American limit (0.08% BrAC) was the focus of this study. Fifteen adults swallowed a capsule (0, 200, or 400 mg caffeine) then drank a beverage (0.0 or 0.6 g/kg ethanol) in a within-subject, double-blind, randomized procedure. Forty-five minutes later, participants completed a test battery of subjective effects scales, dynamic posturography, critical flicker fusion (CFF), choice reaction time (CRT), divided attention (Stroop test), and simulated driving. Alcohol alone increased ratings of 'dizzy', 'drug effect', and 'high', slowed CRT and brake latency, and increased body sway. Caffeine alone increased ratings of 'alert' and 'jittery', but did not significantly affect body sway or psychomotor performance. Both caffeine doses comparably counteracted alcohol impairment of brake latency but not CRT or body sway. Brake latency with either alcohol-caffeine combination remained significantly longer than that with placebo. Stroop and CFF performance were unaffected by any drug condition. The results suggest that caffeine may increase alertness and improve reaction time after alcohol use but will not completely counteract alcohol impairment in a driver.     

Marijuana,alcohol, and combined drug effects on the time course of glare recovery

The time course of light adaptation after intense light exposure is significantly delayed by alcohol, marijuana, and a combined dose of alcohol and marijuana. These effects were found in a double blind experiment, using 10 subjects. The experimental treatements were placebo, 0.75 ml/kg of 95% ethanol, 8 and 15 mg of ⁹ tetrahydrocannabinol (THC), and 0.75 ml/kg of 95% ethanol together with 15 mg of THC. The marijuana-induced delay in recovery is doserelated. Both drugs produce delayed recovery for at least 2 h after drug ingestion. The combined alcohol and marijuana treatment produces little more than the effect produced by either drug alone, suggesting some antagonism between the drugs — a suggestion supported by a significantly lower blood alcohol level for the alcohol dose when combined with marijuana than when taken alone.     

Motives for and impairment associated with alcohol and marijuana use among college students

IntroductionAlcohol and marijuana use are prevalent on college campuses. As recreational marijuana use is legalized, more undergraduate students may use marijuana in combination with alcohol. The motives for, frequency of, and impairment associated with dual use (alcohol and marijuana) compared to alcohol-only use may differ. We examined motives for, frequency of, and impairment associated with alcohol use and dual use at a university in a state where recreational marijuana has been legalized.MethodUndergraduate college students completed an anonymous online survey (N = 430) concerning alcohol and marijuana frequency, motives, and impairment. Students were classified as either alcohol-only users (n = 279) or dual users (n = 151).ResultsAnalyses indicated that among alcohol-only users, social motives predicted more alcohol use, while among dual users, enhancement motives predicted more alcohol and marijuana use and impairment. Coping motives predicted more marijuana use among dual users, but not more alcohol use. Frequency of alcohol and marijuana use predicted more impairment across both the alcohol-only and dual users.ConclusionsFuture research should examine the influence of marijuana use over time to understand how motives may change for previous alcohol-only users.     

Interaction between naltrexone and oral THC in heavy marijuana smokers

Abstract Rationale. Studies in non-human animals suggest that opioid antagonists block the reinforcing effects of cannabinoids. Objective. The present studies in humans investigated how naltrexone modulates (1) the subjective and physiological effects of oral THC in comparison to methadone, (2) the reinforcing effects of oral THC, and (3) plasma levels of oral THC. Methods. In study 1, marijuana smokers (n=9) received naltrexone (0, 50 mg) followed 30 min later by THC (0, 15, 30 mg) or methadone (5, 10 mg). Subjective effects, task performance, pupillary diameter, and cardiovascular parameters were measured repeatedly. In study 2a, marijuana smokers (n=23) were randomly assigned to one THC dose condition (0, 15 or 30 mg). One set of color-coded capsules containing THC and active naltrexone (50 mg) was given in one session, while another set of color-coded capsules containing THC and placebo naltrexone was given in another session. In the final three sessions, participants chose which color capsules they would receive. In study 2b, a subset of participants from study 2a (n=7) received naltrexone (0, 50 mg) 30 min prior to oral THC (30 mg) administration, and blood was drawn repeatedly. Results. Pretreatment with naltrexone significantly increased many of the "positive" subjective effects of oral THC (30 mg) e.g. ratings of Good Drug Effect and Capsule Liking. Naltrexone tended to increase the reinforcing effects of oral THC (30 mg), as indicated by performance in a drug choice test. Naltrexone did not alter plasma THC levels. Conclusions. These studies demonstrate that naltrexone increases the subjective effects of oral THC. Thus, oral THC's effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers. Electronic Publication     

Interactions between THC and cannabidiol in mouse models of cannabinoid activity

Rationale Interest persists in characterizing potential interactions between Δ⁹-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 CB₁ agonists.Objectives 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.Results 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 (ED₅₀=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.Conclusions 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 CB₁-receptor-mediated pharmacological effects of marijuana smoke.     

Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2×2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24–0.57) after alcohol alone and 0.37 g/l (range: 0.27–0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol + diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.     

Cannabis effects on driving longitudinal control with and without alcohol

Although evidence suggests cannabis impairs driving, its driving‐performance effects are not fully characterized. We aimed to establish cannabis’ effects on driving longitudinal control (with and without alcohol, drivers’ most common drug combination) relative to psychoactive ?⁹‐tetrahydrocannabinol (THC) blood concentrations. Current occasional (≥1×/last 3 months, ≤3 days per week) cannabis smokers drank placebo or low‐dose alcohol, and inhaled 500 mg placebo, low (2.9%), or high (6.7%) THC vaporized cannabis over 10 min ad libitum in separate sessions (within‐subject, six conditions). Participants drove (National Advanced Driving Simulator, University of Iowa) simulated drives 0.5–1.3 h post‐inhalation. Blood and breath alcohol samples were collected before (0.17 and 0.42 h) and after (1.4 and 2.3 h) driving. We evaluated the mean speed (relative to limit), standard deviation (SD) of speed, percent time spent >10% above/below the speed limit (percent speed high/percent speed low), longitudinal acceleration, and ability to maintain headway relative to a lead vehicle (headway maintenance) against blood THC and breath alcohol concentrations (BrAC). In N=18 completing drivers, THC was associated with a decreased mean speed, increased percent speed low and increased mean following distance during headway maintenance. BrAC was associated with increased SD speed and increased percent speed high, whereas THC was not. Neither was associated with altered longitudinal acceleration. A less‐than‐additive THC*BrAC interaction was detected in percent speed high (considering only non‐zero data and excluding an outlying drive event), suggesting cannabis mitigated drivers’ tendency to drive faster with alcohol. Cannabis was associated with slower driving and greater headway, suggesting a possible awareness of impairment and attempt to compensate. Copyright © 2016 John Wiley & Sons, Ltd.     

Nefazodone decreases anxiety during marijuana withdrawal in humans

Abstract Rationale. Symptoms of marijuana withdrawal include increased irritability, depression and anxiety, and decreased sleep quality. Nefazodone, which is an antidepressant with sedative properties, may attenuate symptoms of marijuana withdrawal. Objective. The present within-subject, placebo-controlled study investigated the effects of nefazodone during marijuana withdrawal. Methods. Marijuana smokers [n=7; averaging 6.0 (±1.3) marijuana cigarettes/day, 6.4 (±0.4) days/week], not seeking treatment for marijuana use, were maintained on two doses of nefazodone (0, 450 mg/day) for 26 days each. Each maintenance condition began with an outpatient phase (9 days) and continued with an inpatient phase (17 days) in a residential laboratory. Marijuana was smoked 5 times per inpatient day at 1000, 1300, 1600, 1900 and 2200 hours. On days 1–4 (baseline), the first four marijuana cigarettes were placebo (0.00% THC), while the final marijuana cigarette was active (3.04% THC). On inpatient days 5–8, only active marijuana was smoked, while on days 9–16, only placebo marijuana was smoked. Mood, psychomotor task performance, food intake and sleep were measured daily. The order of maintenance dose was counterbalanced between groups. Results. Nefazodone maintenance did not alter the acute effects of active marijuana as compared to placebo nefazodone maintenance. During marijuana withdrawal, nefazodone decreased ratings of "Anxious", and "Muscle Pain", while having no effect on the marked increase in ratings of "Irritable", "Miserable" or decreased sleep quality. Conclusions. Nefazodone decreased certain marijuana withdrawal symptoms, but participants still reported substantial discomfort. These data provide further evidence of marijuana withdrawal, and highlight the need for more marijuana treatment options. Electronic Publication     

Marijuana,alcohol and actual driving performance

The objective of the current study was to assess the separate and combined effects of marijuana and alcohol on actual driving performance. Eighteen subjects were treated with drugs and placebo according to a balanced, 6-way, crossover design. On separate evenings they were given weight calibrated Delta(9)-tetrahydrocannabinol (THC) doses of 0, 100 and 200 &mgr;g/kg with and without an alcohol dose sufficient for achieving blood alcohol concentrations (BAC) of 0.04 g/dl while performing a Road Tracking and Car Following Test in normal traffic. Main outcome measures were standard deviation of lateral position (SDLP), time driven out of lane (TOL), reaction time (RT) and standard deviation of headway (SDH). Both THC doses alone, and alcohol alone, significantly impaired the subjects performances in both driving tests. Performance deficits were minor after alcohol and moderate after both THC doses. Combining THC with alcohol dramatically impaired driving performance. Alcohol combined with THC 100 and 200 &mgr;g/kg produced a rise in SDLP the equivalent of that associated with BAC=0.09 and 0.14 g/dl, respectively. Mean TOL rose exponentially with SDLP. Relative to placebo mean RT lengthened by 1.6 s under the combined influence of alcohol and THC 200 &mgr;g/kg. Changes in SDH ranged between 0.9 and 3.8 m. Low doses of THC moderately impair driving performance when given alone but severely impair driving performance in combination with a low dose of alcohol. Copyright 2000 John Wiley & Sons, Ltd.     

Detecting impairment associated with cannabis with and without alcohol on the Standardized Field Sobriety Tests

Rationale

Cannabis and alcohol are the most popular drugs amongst recreational users and most prevalent in injured and deceased drivers. The Standardized Field Sobriety Tests (SFST) are commonly used to establish impairment due to drugs and alcohol, but limited empirical evidence exists concerning the combined effects of these drugs on SFST performance.

Methods

The sample comprised 80 individuals (31 females; 49 males). Age ranged between 21 and 35?years (M?=?26.5, SD?=?5). Forty participants (15 females; 25 males) took part in the low alcohol condition (BAC, <0.05?%), and 40 participants (16 females; 24 males), took part in the high alcohol condition (BAC, >0.05?%). For each part of the study, two levels of ?9-tetrahydrocannabinol (THC) were administered (1.8 and 3?% THC) or a matching placebo cigarette (0?% THC) in combination with alcohol. Performance on the SFST was assessed 30?min post-dosing.

Results

A number of significant differences in SFST performance were identified with 28?% of the sample failing the test (when the head movement and jerks sign was included) when low alcohol and low THC were administered together. When a higher dose of alcohol was administered with a low dose of THC, 38?% of the sample failed the test, and 35?% also failed when the high dose of alcohol was combined with a higher dose of THC.

Conclusions

The current results highlight the limited ability of the SFST to identify drug consumption in the absence of any evidence of driving impairment or physiological indicators.     

Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18–55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated “high.” Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03655717","term_id":"NCT03655717"}}NCT03655717Subject terms: Neuroscience, Predictive markers     

Evaluation of divided attention psychophysical task performance and effects on pupil sizes following smoked,vaporized and oral cannabis administration

Establishing science‐based driving per se blood Δ⁹‐tetrahydrocannabinol (THC) limits is challenging, in part because of prolonged THC detection in chronic, frequent users. Therefore, documenting observable signs of impairment is important for driving under the influence of drugs. We evaluated frequent and occasional cannabis smokers' performance on the modified Romberg balance, one leg stand (OLS), and walk and turn (WAT) tasks, and pupil size effects following controlled placebo (0.001% THC), smoked, vaporized and oral (6.9% [~50.4 mg] THC) cannabis administration. Significant effects following inhaled doses were not observed due to delayed tasks administration 1.5 and 3.5 h post‐dose, but significant impairment was observed after oral dosing (blood THC concentrations peaked 1.5–3.5 h post‐dose). Occasional smokers' odds of exhibiting ≥2 clues on the OLS or WAT following oral dosing were 6.4 (95% CI 2.3–18.4) times higher than after placebo, with THC and 11‐hydroxy‐THC blood concentrations individually producing odds ratios of 1.3 (1.1–1.5) and 1.5 (1.3–1.8) for impairment in these tasks, respectively. Pupil sizes after oral dosing under the direct lighting condition were significantly larger than after placebo by mean (SE, 95% CI) 0.4 (0.1, 0.2–0.6) mm at 1.5 h and 0.5 (0.2, 0.2–0.8) mm at 3.5 h among all participants. Oral cannabis administration impaired occasional cannabis users' performance on the OLS and WAT tasks compared to placebo, supporting other reports showing these tasks are sensitive to cannabis‐related impairment. Occasional smokers' impairment was related to blood THC and 11‐hydroxy‐THC concentrations. These are important public health policy findings as consumption of edible cannabis products increases. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.     

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

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.     

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

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.     

Sensory,perceptual, motor and cognitive functioning and subjective reports following oral administration ofΔ 9-Tetrahydrocannabinol

Three dose levels, 0.2, 0.4 and 0.6 mg/kg, of ⁹-tetrahydrocannabinol (THC) and a placebo were orally administered to 10 frequent and 10 occasional marijuana users. Following ingestion of each dose and the placebo, objective tests selected from a battery of sensory and perceptual motor tests routinely used to evaluate cerebral dysfunction in hospitalized patients were administered. The influence of ⁹-THC on proficiency and variability of performance was minimal. However, when individual test scores and variabilities were combined and converted to standard scores, allowing for analysis of overall performance, THC had a small but consistent detrimental effect on both proficiency and variability of performance. In contrast, THC exerted profound effects on the subjective experiences of the volunteers as assessed by the Subjective Drug Effects Questionnaire. Subjective changes in mood, feeling, perception and somatic sensations were reported by all subjects but were more pronounced in the occasional user group. It was proposed that the small impairment noted in objective test performance after ingestion of ⁹-THC as contrasted to the large effects on subjective responses suggests that the principal effects of marijuana are on the autonomic nervous system rather than on higher cortical functions.Veterans Administration approved Research Project 0864-03. Also supported by U.S. Public Health Service Research Grant No. DA000.56 from the National Institute of Mental Health.     

Visual search and urban driving under the influence of marijuana and alcohol

The purpose of the present study was to assess the effects of low doses of marijuana and alcohol, and their combination, on visual search at intersections and on general driving proficiency in the City Driving Test. Sixteen recreational users of alcohol and marijuana (eight males and eight females) were treated with these substances or placebo according to a balanced, 4-way, cross-over, observer- and subject-blind design. On separate evenings, subjects received weight-calibrated doses of THC, alcohol or placebo in each of the following treatment conditions: alcohol placebo + THC placebo, alcohol + THC placebo, THC 100 &mgr;g/kg + alcohol placebo, THC 100 &mgr;g/kg + alcohol. Alcohol doses administered were sufficient for achieving a blood alcohol concentration (BAC) of about 0.05 g/dl. Initial drinking preceded smoking by one hour. The City Driving Test commenced 15 minutes after smoking and lasted 45 minutes. The test was conducted over a fixed route within the city limits of Maastricht. An eye movement recording system was mounted on each subject's head for providing relative frequency measures of appropriate visual search at intersections. General driving quality was rated by a licensed driving instructor on a shortened version of the Royal Dutch Tourist Association's Driving Proficiency Test. After placebo treatment subjects searched for traffic approaching from side streets on the right in 84% of all cases. Visual search frequency in these subjects did not change when they were treated with alcohol or marijuana alone. However, when treated with the combination of alcohol and marijuana, the frequency of visual search dropped by 3%. Performance as rated on the Driving Proficiency Scale did not differ between treatments. It was concluded that the effects of low doses of THC (100 &mgr;g/kg) and alcohol (BAC < 0.05 g/dl) on higher-level driving skills as measured in the present study are minimal. Copyright 2001 John Wiley & Sons, Ltd.     

High-potency marijuana impairs executive function and inhibitory motor control.

Human performance studies have usually relied on low-potency marijuana (4% THC) for determining THC-induced impairment. The present study was designed to assess the effects of high-potency marijuana (13% THC) on human performance. In all, 20 recreational users of marijuana participated in a double-blind, placebo controlled, three way cross-over study. The treatments consisted of single doses of 0, 250, and 500 microg/kg THC. Performance tests were conducted at regular intervals between 15 min and 6 h postsmoking and included measures of motor control (Critical tracking task), executive function (Tower of London) motor impulsivity (Stop signal task), and risk taking (Iowa gambling task). THC significantly impaired performance in the Critical tracking task and decreased the number of correct decisions in the Tower of London task. In addition, THC significantly increased stop reaction time and the proportions of commission and omission errors in the Stop signal task. THC-induced impairments lasted up to 6 h postsmoking as indicated by the absence of a THC x Time after smoking interaction. Effect sizes for performance impairments produced by THC 250 microg/kg were relatively low but generally increased by a factor of two in case of THC 500 microg/kg. These data suggest that high potency marijuana consistently impairs executive function and motor control. Use of higher doses of THC in controlled studies may offer a reliable indication of THC induced impairment as compared to lower doses of THC that have traditionally been used in performance studies.     

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Introduction Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. Objectives The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an α₂-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. Materials and methods Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. Results THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. Conclusions These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.