Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance

This study investigated the smoking topography of marijuana and its effect on heart rate, subjective reports, and cognitive/psychomotor task performance. Male subjects (N = 12) with histories of moderate marijuana use smoked ad lib one cigarette containing 0, 1.3, or 2.7% delta 9-THC on separate days. Smoking topography measures revealed smaller puff and inhalation volumes and shorter puff duration for the high marijuana dose compared to the low dose. No other smoking behavior differed between the active doses. Heart rate was increased dose dependently over placebo levels. Active marijuana also increased subjective reports of drug effect over placebo, but not dose dependently. Significant memory impairment was observed on a forward and reverse digit span task, and performance was impaired on the digit symbol substitution task by the high, but not low, dose of marijuana. Performance on a divided attention task was not affected by marijuana. Thus, although subjects adjusted their smoking of cigarettes varying in THC content, dose-related effects of marijuana were obtained on several measures. The observed differences and individual variation in smoking topography measures suggest that precise control of smoking behavior would improve the accuracy of marijuana dose delivery.     

Effects of marijuana smoking on subjective ratings and tobacco smoking

Multiple measures of tobacco cigarette smoking and subjective and physiological effect were collected during 90 minute test sessions in volunteer cigarette smokers who also had histories of recreational marijuana use. Before sessions, subjects smoked one marijuana cigarette (placebo or 1.29%, 2.84%, 4.00%) using a standardized puffing procedure. Each dose and placebo was given four times to each subject in a randomized block sequence. Marijuana smoking produced dose-related increases in heart rate, ratings of dose strength and drug liking. However, marijuana produced no significant alterations in tobacco cigarette smoking. Puff duration within each marijuana cigarette varied in a fashion similar to that observed in previous studies of tobacco cigarette smoking: puff duration progressively decreased as the cigarette was smoked. This effect is probably due to progressive decreases in resistance to draw as the cigarette is smoked. Expired air carbon monoxide (CO) levels following marijuana smoking were inversely related to marijuana dose, suggesting the occurrence of some compensatory changes in marijuana smoking in response to dose manipulations. It is concluded that, although marijuana produces dose-related effects on physiological and subjective effects and on marijuana smoking behavior, marijuana differs from a variety of other psychoactive drugs previously studied in this paradigm in that no reliable changes in tobacco smoking were produced.     

Breathhold duration and response to marijuana smoke

Marijuana smokers are frequently observed to hold the smoke in their lungs for prolonged periods (10-15 sec) apparently in the belief that prolonged breathholding intensifies the effects of the drug. The actual influence of breathhold duration on response to marijuana smoke has not been studied. The present study examined the effects of systematic manipulation of breathhold duration on the physiological, cognitive and subjective response to marijuana smoke in a group of eight regular marijuana smokers. Subjects were exposed to each of three breathhold duration conditions (0, 10 and 20 sec) on three occasions, scheduled according to a randomized block design. A controlled smoking procedure was used in which the number of puffs, puff volume and postpuff inhalation volume were held constant. Expired air carbon monoxide levels were measured before and after smoking to monitor smoke intake. Typical marijuana effects (increased heart rate, increased ratings of "high" and impaired memory performance) were observed under each of the breathhold conditions, but there was little evidence that response to marijuana was a function of breathhold duration.     

Effects of acute smoked marijuana on complex cognitive performance.

Although the ability to perform complex cognitive operations is assumed to be impaired following acute marijuana smoking, complex cognitive performance after acute marijuana use has not been adequately assessed under experimental conditions. In the present study, we used a within-participant double-blind design to evaluate the effects acute marijuana smoking on complex cognitive performance in experienced marijuana smokers. Eighteen healthy research volunteers (8 females, 10 males), averaging 24 marijuana cigarettes per week, completed this three-session outpatient study; sessions were separated by at least 72-hrs. During sessions, participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% Delta(9)-THC w/w), and completed additional cognitive tasks. Blood pressure, heart rate, and subjective effects were also assessed throughout sessions. Marijuana cigarettes were administered in a double-blind fashion and the sequence of Delta(9)-THC concentration order was balanced across participants. Although marijuana significantly increased the number of premature responses and the time participants required to complete several tasks, it had no effect on accuracy on measures of cognitive flexibility, mental calculation, and reasoning. Additionally, heart rate and several subjective-effect ratings (e.g., "Good Drug Effect," "High," "Mellow") were significantly increased in a Delta(9)-THC concentration-dependent manner. These data demonstrate that acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users.     

Effects of marijuana on the task-elicited physiological response

Ten healthy male marijuana users smoked either a placebo or active (1.8% delta 9-THC) marijuana cigarette during five daily testing sessions. Ten minutes after drug administration, six subjects (Group I) performed a 10-min serial acquisition task and four subjects (Group II) rested quietly. Blood pressure was sampled at 2-min intervals and heart rate (HR) was recorded continuously. Marijuana alone increased HR by 18 beats/min and mean arterial pressure (MAP) by 3 mmHg, while task performance alone increased HR by 4 beats/min and MAP by 5 mmHg. The combination of drug and task performance had greater cardiovascular effects than either task performance or marijuana alone, with HR increased by 29 beats/min and MAP increased by 15 mmHg. These results suggest that marijuana smoking may increase cardiovascular responsivity.     

Effects of food deprivation on responses to marijuana in humans

The effects of 24h of food deprivation on subjective, physiological and cognitive responses to marijuana were studied in 8 male marijuana smokers. A within-subjects design was used in which subjects smoked active (1.3% THC) and placebo (0.0% THC) marijuana in both a fed and a fasting state. Each of the four experimental conditions - Fed/Active, Fed/Placebo, Fast/Active, Fast/Placebo - was enacted twice according to a randomized block design. A controlled smoking regimen was employed which held inhaled volume of marijuana smoke constant across feeding conditions. Smoke inhalation was monitored by measuring expired-air carbon monoxide (CO) levels before and after smoking. Heart rate and subjective effects of marijuana were assessed before, during and after smoking. A measure of memory performance, free recall, was also assessed after smoking. CO absorption from both placebo and active marijuana did not differ across feeding conditions, indicating that smoke dose was similar across feeding conditions. Typical effects of marijuana, such as elevated heart rate, impaired memory and increased "high" ratings were obtained after smoking active marijuana, but fasting had no effect on the drug response. Lack of a food deprivation effect on marijuana subjective effects and memory performance was noted not only in all subjects, but also in a subset of subjects (n=6) whose physiological states provided verification of their fasting state in Fast sessions.     

Neurophysiological and cognitive effects of smoked marijuana in frequent users

Rationale

Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects.

Objectives

In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana.

Methods

Research volunteers (N = 24), who reported smoking ∼ 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% ?⁹-THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions.

Results

Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling “new” words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and “positive” subjective-effect ratings were increased in a ?⁹-THC concentration-dependent manner.

Conclusions

Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.     

Alcohol and marijuana: comparative dose effect profiles in humans

This study compared subjective and performance dose effect profiles of oral alcohol and smoked marijuana. Male subjects (N = 6) with histories of moderate alcohol and marijuana use received three doses of alcohol (0, 0.6, 1.2 g/kg) and three doses of marijuana (0, 1.3, 2.7% delta 9-THC) in a double-blind, randomized crossover design. Physiological indices indicated that active drug was delivered to subjects dose dependently. Alcohol produced dose-related elevations on several subjective measures of drug effect. The high dose of alcohol impaired performance on circular lights, tracking and digit-symbol substitution (DSST) tasks, whereas the low alcohol dose impaired only circular lights performance. Marijuana produced elevations on subjective report measures, but effects were similar for the two active doses. Minimal performance impairment was seen with marijuana on only one measure (DSST speed). The subjective and performance effect profiles produced by smoked marijuana were similar to that of the low (0.6 g/kg) dose of alcohol. These data are useful for understanding the relative performance impairment produced by alcohol and marijuana and the relationship between their subjective and behavioral effects.     

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     

Effects of marijuana on neurophysiological signals of working and episodic memory

Rationale The primary psychoactive constituent of marijuana, ₉-THC, activates cannabinoid receptors, which are especially abundant in the frontal cortex and hippocampus. Acute marijuana smoking can disrupt working memory (WM) and episodic memory (EM) functions that are known to rely on these regions. However, the effects of marijuana on the brain activity accompanying such cognitive processes remain largely unexplored.Objectives To examine such effects on performance and neurophysiological signals of these functions, EEG recordings were obtained from ten subjects (5M, 5F) performing cognitive tasks before and after smoking marijuana (3.45% ₉-THC) or a placebo. WM was assessed with a spatial N-back task, and EM was evaluated with a test requiring recognition of words after a 5–10 min delay between study and test.Results Marijuana increased heart rate and decreased global theta band EEG power, consistent with increased autonomic arousal. Responses in the WM task were slower and less accurate after smoking marijuana, accompanied by reduced alpha band EEG reactivity in response to increased task difficulty. In the EM task, marijuana was associated with an increased tendency to erroneously identify distracter words as having been previously studied. In both tasks, marijuana attenuated stimulus-locked event-related potentials (ERPs).Conclusions The results suggest that marijuana disrupted both sustained and transient attention processes resulting in impaired memory task performance. In subjects most affected by marijuana a pronounced ERP difference between previously studied words and new distracter words was also reduced, suggesting disruption of neural mechanisms underlying memory for recent study episodes.     

Acute and residual effects of marijuana: profiles of plasma THC levels, physiological, subjective, and performance measures

Three experienced marijuana smokers participated in four 2-day experimental sessions in which they smoked either 0, 1, or 2 marijuana cigarettes containing 2.57% delta 9-tetrahydrocannabinol (THC) at two different times on the first day. A battery of physiological, subjective, and performance measures was repeated throughout day 1 to assess acute effects and on day 2 to measure any residual effects of marijuana. Blood samples were also repeatedly collected to examine the relationship between plasma levels and pharmacological effects of THC. Acutely, marijuana increased heart rate and subjective ratings of drug effects and slightly impaired performance on a circular lights task in all subjects. Performance was also impaired (decreased accuracy and increased response time) on serial addition/subtraction and digit recall tasks on day 1 in two subjects. On day 2, tachycardia and subjective effects of marijuana were not observed. Performance remained impaired on the arithmetic and recall tasks on day 2, although the decrements were not as large as those observed on day 1. In general, plasma THC levels covaried with the other measures. These preliminary results suggest that marijuana can adversely affect complex human performance up to 24 hours after smoking.     

The effects of combinations of intranasal cocaine, smoked marijuana, and task performance on heart rate and blood pressure

Eight adult male research volunteers received cocaine and marijuana, alone and in combination during experimental sessions. Following the determination of baseline cardiovascular indexes, a one-gram marijuana cigarette (0-2.9% delta 9-THC w/w) was smoked, and cocaine hydrochloride (4-96 mg) was inhaled five minutes after completion of marijuana smoking. Subjects performed a learning task 25 and 70 minutes after initiating marijuana smoking. Cocaine increased heart rate, which averaged 68 bpm under resting baseline conditions, by up to 15 bpm, marijuana increased heart rate by up to 27 bpm, and task performance increased heart rate by 5 bpm. The combination of cocaine and marijuana produced increases in heart rate that were similar to those seen with marijuana alone. During task performance in combination with cocaine and marijuana administration, however, heart rate was elevated by 37 bpm. Although more variable, the largest increases in blood pressure were observed following combinations of cocaine, marijuana, and task performance. These findings suggest that the self-administration of cocaine and marijuana under nonresting conditions has greater cardiovascular effects than the self-administration of these drugs under resting conditions.     

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.     

Marijuana: Dose effects on pulse rate,subjective estimates of intoxication,free recall and recognition memory

The effect of marijuana on memory as measured by free recall and recognition, pulse rate and self ratings of intoxication was evaluated in 16 male volunteers. Marijuana containing 0, 5, 10 or 15 mg Δ⁹-THC was evaluated to all subjects by smoking in 4 sessions separated by a 1 week interval. Free recall was reduced in a dose related manner by the drug, but recognition memory was unaffected. A 2 sec word presentation rate produced inferior recall in comparison to a 4 sec rate, but this variable did not interact with drug condition. Intrusion errors increased following intoxication but this effect was not systematically related to dosage of Δ⁹-THC. Both pulse ratings of intoxication increased with dosage.     

Clonidine partially blocks the physiologic effects but not the subjective effects produced by smoking marijuana in male human subjects

Clonidine, an alpha 2-agonist, was studied in three male human subjects in a multi-dose pilot study in combination with smoking marijuana cigarettes. Marijuana alone caused increases in responses on subjective effect questionnaires and increased heart rate. Pretreatment with single oral doses of clonidine three hours prior to marijuana induced no changes in subjective effects prior to smoking marijuana and did not diminish the subjective effects produced by marijuana. Clonidine did substantially reduce but did not abolish the marijuana-induced rise in heart rate. Based on these preliminary data from three subjects, it is concluded that clonidine does not have therapeutic value in the clinical management of active marijuana abuse.     

Acute and Residual Effects of Marijuana in Humans

Marijuana continues to be the most commonly abused illicit drug in the United States. Because many people abuse marijuana during the evening and on weekends and then go to work or school the next day, more research is needed on the residual effects of marijuana. The current study sought to examine both acute and residual subjective, physiologic, and performance effects of smoking a single marijuana cigarette. Ten healthy male volunteers who reported recent use of marijuana resided on a residential research ward. On three separate days, subjects smoked one NIDA marijuana cigarette containing either 0%, 1.8%, or 3.6% Δ⁹-tetrahydrocannabinol (THC) according to a paced puffing procedure. Subjective, physiologic, and performance measures were collected prior to smoking, five times following smoking on that day, and three times on the following morning. Subjects reported robust subjective effects following both active doses of marijuana, which returned to baseline levels within 3.5 h. Heart rate increased and the pupillary light reflex decreased following active dose administration with return to baseline on that day. A new finding was that marijuana smoking acutely produced decrements in smooth pursuit eye tracking. Although robust acute effects of marijuana were found on subjective and physiological measures, and on smooth pursuit eye tracking performance, no effects were evident the day following administration, indicating that the residual effects of smoking a single marijuana cigarette are minimal.     

Bupropion SR worsens mood during marijuana withdrawal in humans

RATIONALE: Symptoms of withdrawal after daily marijuana smoking include increased ratings of irritability and depression. Similar mood symptoms are reported by cigarette smokers during nicotine abstinence. OBJECTIVE: Given the successful use of sustained-release bupropion in treating nicotine dependence, this study investigated how maintenance on bupropion influenced symptoms of marijuana withdrawal compared to maintenance on placebo. METHODS: Marijuana smokers (n=10) were maintained outpatient on active (300 mg/day) or placebo (0 mg/day) bupropion for 11 days, and were then maintained inpatient on the same bupropion dose for 17 days. For the first 4 inpatient days, participants smoked active marijuana [2.8% delta9-tetrahydrocannabinol (THC)] 5 times/day. For the remaining inpatient days, participants smoked placebo marijuana (0.0% THC) 5 times/day. Participants were then maintained outpatient on the alternate dose of bupropion for 11 days, followed by a second inpatient residential stay, paralleling the first. Medication administration was double-blind. Mood, psychomotor task performance, food intake, and sleep were measured daily during each inpatient phase. The order of active and placebo bupropion maintenance was counterbalanced between groups. RESULTS: Bupropion had few behavioral effects when participants smoked active marijuana. During placebo marijuana smoking, i.e., active marijuana withdrawal, ratings of irritability, restlessness, depression, and trouble sleeping were increased by bupropion compared to placebo maintenance. CONCLUSIONS: These data suggest that bupropion does not show promise as a potential treatment medication for marijuana dependence.     

The pharmacologic effects of daily marijuana smoking in humans.

Six healthy male, paid volunteers smoked one NIDA cigarette containing 1.0% THC each day for 13 consecutive days. They were tested before and after the period of drug administration by the following procedure: the subjects smoked one NIDA marijuana cigarette containing 1.0% THC followed 15 minutes later by the intravenous infusion of 52 micrograms/min of deuterated THC for 50 minutes. The THC plasma concentrations, ratings of "high" and heart rate effects produced by the combined drug administration were measured, and absolute bioavailability of smoked THC was calculated on Days 1 and 22. Statistical analyses indicate that the only significant changes induced by daily marijuana exposure were in cardioacceleration.     

Dronabinol and marijuana in HIV+ marijuana smokers: acute effects on caloric intake and mood

Rationale No studies to date have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol in HIV+ marijuana smokers. Objectives The aim of this study was to compare dronabinol (0, 10, 20, 30 mg p.o.) and marijuana [0.0, 1.8, 2.8, 3.9% Δ⁹-tetrahydrocannabinol (THC)] in two samples of HIV+ marijuana smokers: those with (n=15) and those without (n=15) a clinically significant loss of muscle mass (<90% body cell mass/height), which is one component of AIDS wasting. Methods Mood, physical symptoms, self-selected food intake, cardiovascular data, and cognitive task performance were measured before and repeatedly after dronabinol and marijuana administration in eight 7-h sessions. Marijuana and dronabinol were administered in randomized order using a within-subject, staggered, double-dummy design. Results As compared to placebo, (1) marijuana (1.8, 2.8, 3.9% THC) and the lower dronabinol doses (10, 20 mg) were well tolerated (e.g., few physical symptoms, significant increases in ratings of “good drug effect”) in both groups of participants; the highest dose of dronabinol (30 mg) was poorly tolerated in a subset of participants; (2) marijuana and dronabinol significantly increased caloric intake in the low bioelectrical impedance analysis (BIA) group but not in the normal BIA group; and (3) drug effects on cognitive performance were minor. Conclusions These data suggest that for experienced marijuana smokers with clinically significant muscle mass loss, both dronabinol (at acute doses at least four to eight times the current recommendation) and marijuana produce substantial and comparable increases in food intake without producing adverse effects. All authors are associated with the Department of Psychiatry at the College of Physicians and Surgeons of Columbia University.     

Comparison of smoked marijuana and oral Δ<Superscript>9</Superscript>-tetrahydrocannabinol in humans

Abstract Rationale. Although smoked marijuana contains at least 60 cannabinoids, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral Δ⁹-THC with repeated doses of smoked marijuana in the same individuals. Objective. To compare the effects of oral Δ⁹-THC and smoked marijuana in humans under controlled laboratory conditions. Methods. Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% Δ⁹-THC, q.i.d.) were smoked or Δ⁹-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. Results. Relative to placebo baseline, oral Δ⁹-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral Δ⁹-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. Conclusion. These results indicate that the behavioral profile of effects of smoked marijuana (3.1% Δ⁹-THC) is similar to the effects of oral Δ⁹-THC (20 mg), with some subtle differences. Electronic Publication