Preference for high- versus low-potency marijuana.

With many drugs of abuse, humans and other species display a preference for higher doses (or more potent dosage forms) over lower doses (or less potent dosage forms). The present study was designed to determine whether this generalization would hold for marijuana smoking by humans. Twelve regular marijuana smokers participated in two independent and identical choice trials in which, on separate sessions, they first sampled marijuana of two different potencies (0.63% and 1.95% delta-9-tetrahydrocannabinol; THC) and then, on the next session, chose which of the two, as well as how much, to smoke. During sampling sessions, the high-potency marijuana produced a greater heart rate increase and greater subjective effects than the low-potency marijuana. Subjects chose the high-potency marijuana significantly more often than the low-potency marijuana (21 out of 24 choice occasions). These results support the hypothesis that the reinforcing effects of marijuana, and possibly its abuse liability, are positively related to THC content.

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.

Reinforcing and subjective effects of methylphenidate in humans.

This study assessed the reinforcing and subjective effects of methylphenidate in a group of 35 adults (15 females and 20 males) with no history of drug dependence. A discrete-trial choice procedure was used to assess the reinforcing effects of a single oral dose of methylphenidate selected to produce a moderate subjective response in each subject (range 20-40mg). A number of variables (gender, current and past drug use, personality, and baseline mood and arousal) were examined in an attempt to identify sources of variability in drug response. Methylphenidate was chosen on 28% of occasions. In the group as a whole, methylphenidate had no effect on ratings of drug liking, but did increase ratings indicative of "positive" mood, CNS stimulation and anxiety. Within-subject variability in methylphenidate choice was related to variability in subjective response to the drug across choice trials. Methylphenidate choice was also associated with between-subject differences in prior opioid use and several personality dimensions. When compared with the results of a prior study of the same design with d-amphetamine, these results suggest that methylphenidate produces a somewhat different profile of subjective effects, and may be a less efficacious reinforcer than d-amphetamine.

Effects of alcohol pretreatment on human marijuana self-administration.

Alcohol and marijuana are frequently used together, yet there has been little study of how the presence of one drug might affect consumption of the other. The present study examined the effects of alcohol pretreatments on marijuana self-administration in a group of 15 males and 5 females who were users of both drugs. During evening sessions in a recreational setting, pairs of subjects consumed drinks containing 0.0, 0.3 or 0.6 g/kg alcohol 30 min before a 60-min period of ad libitum marijuana smoking. Marijuana self-administration was assessed in several ways: by measuring the number of cigarettes smoked, the increase in expired air carbon monoxide resulting from marijuana smoke inhalation, and the increase in heart rate due to THC absorption. None of these variables was significantly affected by the alcohol pretreatments, although substantial individual differences were observed. These results indicate that low to moderate doses of alcohol do not systematically influence marijuana self-administration.

Factors influencing the reinforcing and subjective effects of ephedrine in humans.

There has been little study of the abuse liability of ephedrine, a naturally occurring drug used in medicine for thousands of years and currently sold as a "legal" stimulant. The present study measured the reinforcing and subjective effects of ephedrine in a group of 27 adults (18 females and 9 males) with no history of drug dependence. A discrete-trial choice procedure was used to assess the reinforcing effects of a single oral dose of ephedrine selected to produce a moderate subjective response in each subject (range: 37.5-75 mg). A number of variables (gender, current and past drug use, personality, and baseline mood and arousal) were examined in an attempt to identify sources of variability in response to ephedrine. Of the 27 subjects, 5 chose ephedrine on either 2 or 3 out of a possible 3 occasions; overall, ephedrine was chosen on 17% of occasions. In the group as a whole, ephedrine had no effect on ratings of drug liking, but did increase ratings of "high" and scores on the MBG ("euphoria") scale of the Addiction Research Center Inventory. Ephedrine also increased scores on a number of mood scales reflecting CNS stimulation and anxiety. Ephedrine choice was positively associated with current use of marijuana and lower levels of baseline anxiety and hunger, as well as with lower scores on two scales measuring dimensions of the personality trait of harm avoidance. Males and females differed in their response to ephedrine--males chose ephedrine more frequently than females and showed a more positive mood response to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors influencing the reinforcing and subjective effects of d-amphetamine in humans.

The reinforcing and subjective effects of oral d-amphetamine (AMP) were studied in a group of non-drug abusing adults (16 males, 13 females). A discrete-trial choice procedure was used to assess the reinforcing effects of a single dose of AMP (range 7.5-20mg across subjects). A number of factors (gender, current and past drug use, personality, motor activity, and baseline mood state and psychophysiological and sensory indices of arousal) were examined in an attempt to explain both within- and between-subject variability in response to AMP. Of the 29 subjects, 11 chose AMP on either two or three out of a possible three occasions. Cigarette smokers reported stronger aversive responses to AMP and chose the drug significantly less often than non-smokers. Subjects with a history of non-medical stimulant use reported less subjective response to AMP than subjects without such history. Within-subject variability in AMP choice was related to variability in subjective response to the drug across choice trials, as well as to variability in baseline mood: AMP was more likely to be chosen when subjects were more aroused and in a more positive mood at the time of the choice. These results provide new information regarding factors that may be relevant in determining individual differences in vulnerability to abuse of psychomotor stimulants.

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.

Factors influencing the subjective response to caffeine.

The subjective effects of caffeine, the most widely used psychoactive drug, vary widely from person to person. The factors responsible for these individual differences remain largely unknown. Data from 36 healthy adults who were light to moderate users of caffeine were examined with the goals of characterizing the subjective effects of caffeine and identifying factors which might correlate with or predict these effects. Subjective effects of 100 and 300mg caffeine were measured with standardized questionnaires. The low dose of caffeine was found to produce negligible subjective effects in the group as a whole, while the high dose produced mild stimulant and anxiogenic effects. As expected, there was considerable intersubject variability in the subjective effects of caffeine. There was no correlation between stimulant and anxiogenic effects after the high dose. Light caffeine users were more accurate than heavy caffeine users in identifying the high dose of caffeine as an active drug, but there was no evidence that light users were generally more sensitive to the subjective effects of caffeine. Current alcohol use, prior recreational use of stimulants, and baseline level of self-reported arousal appeared to influence subjective response to caffeine. Other variables (personality, gender, baseline anxiety, and prior use of other drugs) showed no relationship with mood response to caffeine.

Reinforcing and subjective effects of oral delta 9-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.

Response to marijuana as a function of potency and breathhold duration.

The present study examined the effects of systematic manipulation of breathhold duration (0 and 20 s) on the physiological and subjective response to active (M; 2.3% delta-9-THC) and placebo (P; 0.0% delta-9-THC) marijuana in a group of ten regular marijuana smokers. During the eight-session experiment, subjects were exposed twice to each of four experimental conditions (P0, P20, M0, M20), scheduled according to a randomized block design. A controlled smoking procedure was used in which the number of puffs and puff volume were held constant. Expired-air carbon monoxide (CO) levels were used to monitor smoke intake. Breathhold duration affected CO absorption; significantly more CO was absorbed from both P and M smoke after 20 s of breathholding (mean CO boost = 6.9 ppm) than after no breathholding (mean = 4.4 ppm). Heart rate was minimally affected by the breathhold manipulation. Effects of marijuana on mood were not consistently affected by breathhold duration. The results confirm previous findings that prolonged breathholding does not substantially enhance the effects of inhaled marijuana smoke.

Subjective and behavioral effects of marijuana the morning after smoking.

Twelve regular marijuana smokers participated in a study designed to detect possible after-effects associated with marijuana smoking. Each subject was evaluated for two weekends-during one weekend they received only placebo marijuana (0.0% THC); the other weekend they received active marijuana (2.1% THC). Each weekend subjects received a total of 40 standardized puffs of marijuana smoke, administered during five separate smoking periods in the late afternoons and evenings. Each morning after smoking, subjects completed a series of questionnaires evaluating their sleep and mood, and then performed a battery of tasks to assess their psychomotor and cognitive function. Ratings of "high" and heart rate indicated that effective doses of THC were delivered to the subjects, and expired air carbon monoxide levels demonstrated effective smoke administration over the course of the weekends. No evidence of residual subjective intoxication was found, and most of the behavioral tasks and mood scales were unaffected the morning after. Statistically significant after-effects were obtained on a few measures, but with one exception, these were of negligible magnitude, inconsistent with previous findings, or likely artifacts of the experimental situation. In short, marijuana smoking was not associated with a "hangover" syndrome similar to those reported after use of alcohol or long-acting sedative-hypnotics.

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.

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.

Reinforcing and subjective effects of caffeine in normal human volunteers.

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults. Subjects (eight females, ten males) were light to moderate users of caffeine, and had no history of drug abuse. A discrete-trial choice procedure was used in which subjects were allowed to choose between the self-administration of color-coded capsules containing either placebo or caffeine. The number of times caffeine was chosen over placebo was used as the primary index of reinforcing efficacy. Subjective effects were measured before and several times after capsule ingestion. The low dose of caffeine was chosen on 42.6% of occasions, not significantly different from chance (50%). The high dose of caffeine was chosen on 38.9% of occasions, significantly less than expected by chance, indicating that this dose served as a punisher. Both doses of caffeine produced stimulant-like subjective effects, with aversive effects such as increased anxiety predominating after the high dose. When subjects were divided into groups of caffeine-sensitive choosers and nonchoosers, a consistent relationship emerged between caffeine choice and subjective effects; nonchoosers reported primarily aversive effects after caffeine (increased anxiety and dysphoria), whereas choosers reported stimulant and "positive" mood effects. When compared with previous findings, these results demonstrate that caffeine is less reinforcing than amphetamine and related psychomotor stimulants.

Some physical characteristics of NIDA marijuana cigarettes.

Marijuana cigarettes of three different potencies (0.0%, 1.4% and 2.7% delta-9-tetrahydrocannabinol (THC) content) provided by the National Institute on Drug Abuse (NIDA) were compared on a variety of characteristics, including physical appearance, weight, burn rate, and deliveries of total particulate matter and carbon monoxide. Significant differences between the different potency cigarettes were obtained on most measures. These differences could be relevant to the design and interpretation of pharmacologic/toxicologic and behavioral studies conducted with these cigarettes. The possible basis for these observed differences, methods for minimizing some of them, and other potential problems related to the use of NIDA marijuana cigarettes are discussed.

Reinforcing and subjective effects of oral tripelennamine in normal human volunteers.

Tripelennamine is a prescription antihistamine with a history of abuse when combined parenterally with opioids. The present study examined the reinforcing and subjective effects of oral tripelennamine in a group of 18 normal, healthy adults. Self-administration behavior was measured with a discrete-trial choice procedure. Subjects first sampled color-coded capsules containing either placebo or tripelennamine (25 or 50mg). On three subsequent occasions, subjects were allowed to choose which color-coded capsule to self-administer. The number of times subjects chose tripelennamine over placebo was used as the primary index of reinforcing efficacy. Subjective effects questionnaires were used to measure mood before and several times after capsule ingestion. The low dose of tripelennamine produced no significant mood changes relative to placebo, and was chosen on 39% of occasions, not significantly different from chance. The high dose produced mild sedative-like effects, and was chosen on 33% of occasions, significantly less than expected by chance, indicating that this dose was aversive. The results demonstrate that oral therapeutic doses of tripelennamine are not reinforcing and do not produce positive mood changes in subjects without a history of drug abuse.

A cumulative dosing procedure for administering marijuana smoke to humans.

Subjective, behavioral and physiological effects of smoked marijuana were measured with a cumulative dosing procedure which allowed dose-related effects to be determined within a single experimental session. Five male and three female occasional marijuana smokers participated. Unit doses of marijuana smoke were administered in a standardized manner on four occasions during each session, each occasion spaced 20 minutes apart. This procedure resulted in a cumulative dose of active (1.4%-THC) marijuana of 0, 2, 4 and 8 puffs after the four successive smoking occasions, respectively. Dependent variables were measured after each smoking occasion. Smoke absorption was monitored by measuring expired air carbon monoxide levels. Subjects participated in three identical sessions spaced a week apart in order to assess the reliability of the procedure. During a fourth session, only placebo (0.0%-THC) marijuana was administered throughout the session as a control. Significant linear dose-effect functions were obtained on several measures, with good session-to-session replicability of most effects. The results demonstrate the feasibility of using a cumulative dosing procedure to evaluate dose-related effects of smoked marijuana in humans. The procedure would be especially useful for the assessment of shifts in dose-effect curves as a result of various experimental manipulations.

Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers.

The reinforcing and subjective effects of phenylpropanolamine (PPA, 25 and 75 mg, PO) were compared with those of d-amphetamine (AMP, 5 mg) in a group of normal, healthy adults (eight males, nine females) with no history of drug abuse. A discrete-trial choice procedure was used in which subjects first sampled placebo and a dose of one of the drugs. Subjects were then allowed to choose between self-administration of drug or placebo on three separate occasions. The relative frequency with which active drug was chosen over placebo was used as the primary index of the drug's reinforcing efficacy. Subjective effects were measured with the Profile of Mood States, a short version of the Addiction Research Center Inventory and a series of visual analog scales. Ratings of drug liking, drug labelling, general activity level and strength of drug preference were also obtained. As expected, AMP was chosen significantly more often than expected by chance (69% of occasions). AMP also increased ratings of drug liking, preference strength, and activity level, and produced a profile of subjective effects consistent with its well-established stimulant and euphorigenic properties. The low dose of PPA was without effect on most measures. PPA 75 mg was chosen significantly less often than expected by chance (39% of occasions). This dose of PPA was most frequently labelled as a stimulant, and produced significant increases on ratings of Anxiety and "stimulated," and decreases on ratings of "sedated" and "hungry." Unlike AMP, PPA did not affect ratings of drug liking or mood scales reflecting euphoria. In sum, these results indicate that PPA does not possess AMP-like dependence potential.

Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers.

The discriminative stimulus (DS) and subjective effects of caffeine (100 and 300 mg, PO) and benzphetamine (12.5 and 50 mg, PO) were studied in 18 normal human volunteers trained to discriminate between d-amphetamine (10 mg) and placebo. d-Amphetamine increased ratings of drug liking and activity level and produced a profile of subjective effects characteristic of amphetamine and related psychomotor stimulants. The DS effects of d-amphetamine generalized only partially to caffeine and benzphetamine; mean percent d-amphetamine-appropriate responding was 42 and 58 after 100 and 300 mg caffeine, respectively, and 17 and 56 after 12.5 and 50 mg benzphetamine, respectively. Neither dose of caffeine affected ratings of drug liking or activity level, but 300 mg caffeine did produce a profile of subjective effects that partially overlapped with that produced by d-amphetamine. Benzphetamine 50 mg, but not 12.5 mg, increased ratings of drug liking and activity level and produced a profile of subjective effects qualitatively similar to, but weaker than, that produced by d-amphetamine. For both caffeine and benzphetamine, a close relationship was observed between their subjective effects and their ability to substitute for the DS effects of d-amphetamine. These results correspond well with findings obtained from similar studies conducted with laboratory animals, providing further support for the reliability and validity of human drug discrimination paradigms.