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.     

Suppression of the cardiac conditioned response by Δ-9-tetrahydrocannabinol: A comparison with other drugs

The effect of smoked marijuana on performance of complex reaction time (RT) tasks was studied in two groups receiving different amounts of practice. Group M-P had no undrugged practice on the task before performing during marijuana intoxication for four consecutive daily sessions. On the fifth test day they performed while non-intoxicated. Group P-M performed the task on four consecutive test days while non-intoxicated, then smoked marijuana on session 5. Significant RT slowing was found on session 1 for group M-P (performing during marijuana intoxication without prior practice). Performance of this group improved rapidly and by the end of session 2 was not different from undrugged performance. Group P-M (receiving four sessions of undrugged practice before marijuana intoxication) showed no RT slowing while intoxicated. Reaction time performance may involve two phases: an early, attention-demanding phase which is sensitive to drug effects and a later, automatic, phase which results from practice and is more resistant to drug effects.Pulse rate, salivary flow and subjective responses were recorded before and after smoking. These physiological and subjective measures showed only slight reduction in the acute effects of the drug over the four days of repeated usage.     

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.     

Reinforcing and subjective effects of oral Δ9-THC and smoked marijuana in humans

The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.     

Factors influencing self-administration of, and subjective response to, placebo marijuana

Self-administration of, and subjective response to, placebo marijuana were studied in two groups of regular marijuana smokers. One group received the drug under a set of instructions that informed them that the marijuana was active (deceptive administration); the other group was informed that the marijuana might be inactive (double-blind administration). Subjects were allowed to smoke placebo marijuana freely for 60min during four identical weekly sessions. Subjects smoked an average of 6.0 half-length cigarettes per session, resulting in a mean increase in expired air carbon monoxide of 14.6 ppm. Placebo self-administration did not change significantly across the four sessions. Smoking was associated with marijuana-like subjective effects. Subjects in the deceptive administration group smoked more placebo marijuana and reported a greater subjective response than the other group during the first session only. Several anamnestic factors (drug use history, current pattern of marijuana use, dimensions of personality) correlated with the amount of placebo self-administered, and subjects with less marijuana experience tended to report stronger subjective responses to the placebo. These results demonstrate the importance of including a placebo control when studying the reinforcing effects of marijuana and identify some factors that might predict placebo responses to marijuana or other drugs.     

Effects of acute marijuana smoking on pulse rate and mood states in women

The effects of marijuana cigarette (1.8% THC) smoking on pulse rate and mood were studied under double-blind placebo-controlled conditions in 28 adult female volunteers during the follicular, luteal, and ovulatory phases of the menstrual cycle. Statistically significant increases in pulse rate, subjective levels of intoxication, and the POMS confusion factor occurred after marijuana smoking. However, no statistically significant differences for any measure were observed following marijuana smoking as a function of menstrual cycle phase. Subjects with a past history of intermittent marijuana use (five or less times weekly) had significantly higher pulse rates, subjective levels of intoxication, and POMS confusion factor scores than did subjects with a past history of regular (six or more times weekly) marijuana use. Persistence of marijuana-induced changes in pulse rate, intoxication, and confusion were also of longer duration for subjects with a past history of intermittent marijuana smoking. The influence of past history of marijuana use on marijuana-induced alterations in pulse rate, intoxication, and mood for females appears to be similar to males. These similarities are not attenuated as a function of the menstrualcycle phase of females.     

Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids

This study investigated the contribution of different cannabinoids to the subjective, behavioral and neurophysiological effects of smoked marijuana. Healthy marijuana users (12 men, 11 women) participated in four sessions. They were randomly assigned to a low or a high delta9-tetrahydrocannabinol group (THC; 1.8% versus 3.6%). In the four sessions under blinded conditions subjects smoked marijuana cigarettes containing placebo (no active cannabinoids), or cigarettes containing THC with low or high levels of cannabichromene (CBC; 0.1% versus 0.5%) and low or high levels of cannabidiol (CBD; 0.2% versus 1.0%). Dependent measures included subjective reports, measures of cognitive task performance and neurophysiological measures [electroencephalographic (EEG) and event-related potential (ERP)]. Compared to placebo, active THC cigarettes produced expected effects on mood, behavior and brain activity. A decrease in performance, reduction in EEG power and attenuation of ERP components reflecting attentional processes were observed during tests of working memory and episodic memory. Most of these effects were not dose-dependent. Varying the concentrations of CBC and CBD did not change subjects' responses on any of the outcome measures. These findings are consistent with previous studies indicating that THC and its metabolites are the primary active constituents of marijuana. They also suggest that neurophysiological EEG and ERP measures are useful biomarkers of the effects of THC.     

Comparison of the subjective effects of Δ<Superscript>9</Superscript>-tetrahydrocannabinol and marijuana in humans

RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.METHODS: In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.CONCLUSION: These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.     

Delta-9-tetrahydrocannabinol content and human marijuana self-administration

The role of marijuana delta-9-tetrahydrocannabinol (THC) content in controlling marijuana smoking behavior was examined in ten regular marijuana smokers. Each subject was allowed to self-administer marijuana of low, medium or high THC content freely over a 30-min period. Each potency of marijuana was color coded, and subjects smoked each potency on five separate occasions to provide the opportunity for them to learn from prior exposures the relative potencies of each marijuana type. Total intake of marijuana smoke during each session was estimated by measuring the post-smoking increase in expired air carbon monoxide (CO) level. Measures of marijuana effect included heart rate and standardized subjective effects scales. There were no differences among the three potencies of marijuana in post-smoking CO boost, and all measures that were sensitive to marijuana showed a clear dose response. Tolerance was observed over the course of the study to the heart-rate increasing effect of marijuana. These results indicate that subjects failed to regulate their intake of marijuana smoke in response to substantial (4-fold) changes in marijuana THC content.     

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.     

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.     

Acute and residual effects of alcohol and marijuana,alone and in combination,on mood and performance

The duration of behavioral impairment after marijuana smoking remains a matter of some debate. Alcohol and marijuana are frequently used together, but there has been little study of the effects of this drug combination on mood and behavior the day after use. The present study was designed to address these issues. Fourteen male and female subjects were each studied under four conditions: alcohol alone, marijuana alone, alcohol and marijuana in combination, and no active treatment. Mood and performance assessments were made during acute intoxication and twice the following day (morning and mid-afternoon). Acutely, each drug alone produced moderate levels of subjective intoxication and some degree of behavioral impairment. The drug combination produced the greatest level of impairment on most tasks and strong overall subjective ratings. There were few significant interactions between the two drugs, indicating that their effects tended to be additive. Only weak evidence was obtained for subjective or behavioral effects the day after active drug treatments, although consistent time-of-day effects (morning versus afternoon) were observed on several subjective and behavioral measures. In sum, this study provided little evidence that moderate doses of alcohol and marijuana, consumed either alone or in combination, produce behavioral or subjective impairment the following day.     

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.     

Effects of smoked marijuana on heart rate, drug ratings and task performance by humans

Six subjects, reporting marijuana use between two and 30 times per month, participated in studies of the acute effects of smoked marijuana (0.0%, 2.0% and 3.5% Delta(9)-THC, w/w) on heart rate, ratings of drug effect and task performance. Marijuana was administered using a uniform-puffing procedure with monetary contingencies associated with puff and breathhold duration. In general, heart rate and ratings, of "High" and dose "Potency" were increased by marijuana, and performance on some tasks was altered by drug administration. The relative sensitivity of the measures varied across subjects, and no single measure, such as heart rate or verbal rating of drug effect, could be used to predict the behavioral effects of marijuana. Marijuana puff durations were decreased at the highest dose, but dose-related changes in heart rate and task performance indicated that the change in smoking topography did not result in complete compensation for increased cannabinoid concentrations in marijuana smoke.     

Effect of d-amphetamine,secobarbital, and marijuana on choice behavior: social versus nonsocial options

The effects of oral d-amphetamine and secobarbital and smoked marijuana on human social conversation and preference for socializing were studied in three separate experiments. During experimental sessions, active drug or placebo was administered using an acute or divided dosing procedure. Subjects who received drug then engaged in a discrete-trial choice procedure in which they made a series of mutually exclusive choices between a social (talking with their nondrugged partner) and nonsocial (sitting quietly alone) option. Lapel microphones and voice operated relays measured seconds of speech. Subjects engaged in greater amounts of conversation and chose the social option more frequently following acute dosing of d-amphetamine and secobarbital compared with placebo. Acute administration of marijuana did not significantly affect social speech or choice behavior, producing slight decreases in both measures. Acute dosing of all drugs significantly increased subjective drug effect or drug high; however, only secobarbital affected the circular lights task, producing significant performance decrements. The shifts in preference toward the social option observed with d-amphetamine and secobarbital suggest that these drugs increased the reinforcing effects of socializing relative to sitting alone. This may be one mechanism by which psychoactive drugs facilitate social conversation.     

Comparison of subjective,pharmacokinetic, and physiological effects of marijuana smoked as joints and blunts

Recent increases in marijuana smoking among the young adult population have been accompanied by the popularization of smoking marijuana as blunts instead of as joints. Blunts consist of marijuana wrapped in tobacco leaves, whereas joints consist of marijuana wrapped in cigarette paper. To date, the effects of marijuana smoked as joints and blunts have not been systematically compared. The current within-subject, randomized, double-blind, placebo-controlled study sought to directly compare the subjective, physiological, and pharmacokinetic effects of marijuana smoked by these two methods. Marijuana blunt smokers (12 women and 12 men) were recruited and participated in a 6-session outpatient study. Participants were blindfolded and smoked three puffs from either a blunt or a joint containing marijuana with varying Δ⁹-tetrahydrocannabinol (THC) concentrations (0.0, 1.8, and 3.6%). Subjective, physiological (heart rate, blood pressure, and carbon monoxide levels) and pharmacokinetic effects (plasma THC concentration) were monitored before and at specified time points for 3 h after smoking. Joints produced greater increases in plasma THC and subjective ratings of marijuana intoxication, strength, and quality compared to blunts, and these effects were more pronounced in women compared to men. However, blunts produced equivalent increases in heart rate and higher carbon monoxide levels than joints, despite producing lower levels of plasma THC. These findings demonstrate that smoking marijuana in a tobacco leaf may increase the risks of marijuana use by enhancing carbon monoxide exposure and increasing heart rate compared to joints.     

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.     

Correlation between pharmacological effects and plasma cocaine concentrations after smoked administration

The relationship between blood cocaine concentrations and pharmacological effects is of both theoretical and practical interest. This study utilized a computer-assisted smoking device for the delivery of three active doses (10, 20, and 40 mg) of cocaine base to seven human volunteers. Doses were administered in an ascending dose design with random placement of placebo. Physiological, subjective, and performance measures were collected concurrently with blood samples. Mean peak plasma cocaine concentrations were achieved at 2 min after the 20-mg and 40-mg doses and at 5 min after the 10-mg dose. Maximal responses in systolic and diastolic blood pressure, "feel", "good" drug, and drug "liking" subjective effects were also achieved immediately after drug administration. Pupil diameter and heart rate increases demonstrated a modest counter-clockwise hysteresis in relation to plasma cocaine concentrations shortly after dosing. Systolic and diastolic blood pressure, heart rate, and some subjective and performance measures of drug effect demonstrated a biphasic response after smoked cocaine. Initial increases above baseline levels were followed by an apparent compensatory decrease below baseline levels at a later time after smoked cocaine. Despite evidence of hysteresis and biphasic responses for some measures, linear correlation was obtained between mean plasma cocaine concentrations and several pharmacological effects over a period of 4 h after dosing. Several subjective and cardiovascular measures returned to baseline levels in the presence of detectable concentrations of cocaine.     

Marijuana: Effects on free recall and subjective organization of pictures and words

The free recall of pictures and words was compared following the administration of marijuana or placebo in a multitrial free recall task. Since pictures are thought to be registered in both visual and verbal memory stores with this encoding being mediated by some form of mental imagery, it was predicted that marijuana would produce a greater deficit in word recall in comparison to picture recall because the drug has been reported to facilitate imagery. A trend in the opposite direction followed intoxication; picture recall was inferior to word recall in the later stages of acquisition. Although overall recall was inferior under marijuana, no differences were found between the treatment conditions in subjective organization as determined by a variety of clustering measures. Recall performance following marijuana intoxication was positively related to level of recall performance in the placebo condition.