Marian W. Fischman

Abstinence symptoms following smoked marijuana in humans

Abstract Symptoms of withdrawal after oral Δ9-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans. In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330 hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were smoked at 1000, 1400, 1800, and 2200 hours. Placebo marijuana was administered on days 1–4 . One of the active marijuana doses was administered on days 5–8, followed by 4 days of placebo marijuana (days 9–12). The other concentration of active marijuana cigarettes was administered on days 13–16, followed by 4 days of placebo marijuana (days 17–20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups. Both active doses of marijuana increased ratings of “High,” and “Good Drug Effect,” and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1–4). Abstinence from active marijuana increased ratings such as “Anxious,”“Irritable,” and “Stomach pain,” and significantly decreased food intake compared to baseline. This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms.

Abstinence symptoms following oral THC administration to humans

Abstract Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (nu2005=u20056) and female (nu2005=u20056) marijuana smokers worked on five psychomotor tasks during the day (0915–1700u2005hours), and in the evening engaged in private or social recreational activities (1700–2330u2005hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330u2005hours. Capsules were administered at 1000, 1400, 1800, and 2200u2005hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20u2005mg qid) and on days 12–15 (30u2005mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use.

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% Δ9-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 Δ9-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 Δ9-THC concentration-dependent manner. These data demonstrate that acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users.

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidates side effects may counterbalance its reinforcing effects.

Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans

Abstract. Rationale: Data obtained in laboratory animals and humans suggest that dopamine D1 receptor antagonists decrease cocaine self-administration and block cocaines discriminative stimulus and subjective effects. Objectives: This study investigates the effects of the selective dopamine D1 antagonist, ecopipam (SCHxa039166), on the reinforcing, cardiovascular, and subjective effects of cocaine in humans. Methods: Ten non-treatment-seeking cocaine smokers (two females, eight males), residing on an inpatient research unit, were maintained on placebo and ecopipam (100xa0mg p.o.) in random order using a within-subjects, cross-over design. Cocaine self-administration (0, 12, 25, and 50xa0mg) was tested beginning on the 5thxa0day of each 8-day maintenance condition. A six-trial choice procedure (cocaine vs

Depot naltrexone: long-lasting antagonism of the effects of heroin in humans

5 merchandise vouchers) was utilized, with sessions consisting of one sample trial, when participants smoked the cocaine dose available that day, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one merchandise voucher. Results: In the presence of placebo cocaine, ecopipam significantly decreased cocaine craving while increasing alcohol and tobacco craving. In the presence of active cocaine, ecopipam increased cocaine self-administration (12xa0mg) and increased ratings of good drug effect, high, stimulated, and dose quality (25 and 50xa0mg). Ecopipam produced small but significant increases in blood pressure, regardless of cocaine dose. Conclusions: Maintenance on the long-acting dopamine D1 antagonist, ecopipam, enhanced both cocaine self-administration as well as its subjective effects compared to maintenance on placebo. These data suggest that chronic antagonism of the dopamine D1 receptor may not be a useful approach for the treatment of cocaine abuse.

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans.

Abstract.Rationale: Naltrexone, an opioid antagonist, is currently approved as a treatment for heroin dependence. However, naltrexone is generally not well accepted by patients, and medication non-compliance is a difficult obstacle to treatment. A sustained-release form of naltrexone may improve compliance. Objective: The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex®). Methods: Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, six participants received 192xa0mg naltrexone base and six participants received 384xa0mg naltrexone base. For safety, the low dose of depot naltrexone was tested before the high dose. The effects of heroin (0, 6.25, 12.5, 18.75, 25xa0mg, IV) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Active heroin doses were administered in ascending order during the week, while placebo could be administered on any day. Subjective, performance, and physiological effects were measured both before and after heroin administration. The hypotheses were that depot naltrexone would antagonize the effects of heroin, and that the high dose of depot naltrexone would produce a more effective and longer-lasting antagonism than the low dose. Results: The low and high doses of depot naltrexone antagonized heroin-induced subjective ratings for 3 and 5 weeks, respectively. Plasma levels of naltrexone remained above 1xa0ng/ml for approximately 3 and 4 weeks after administration of 192xa0mg and 384xa0mg naltrexone. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. Conclusions: These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting antagonism of the effects of heroin.

Bupropion SR worsens mood during marijuana withdrawal in humans

Rationale: Data in laboratory animals suggest that D1 receptor agonists may have potential utility for the treatment of cocaine abuse. Objective: The effects of ABT-431, a selective agonist at the dopamine D1 receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. Method: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4u2008mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50u2008mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus

The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans.

5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. Results:u2008ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of “High,”“Stimulated,” dose liking, estimates of dose value, “Quality,” and “Potency.” Furthermore, there was a trend for ABT-431 (4u2008mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. Conclusions: These data suggest that D1 agonists may have potential utility for the treatment of cocaine abuse.

Methamphetamine self-administration by humans

Abstract 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 (300xa0mg/day) or placebo (0xa0mg/day) bupropion for 11xa0days, and were then maintained inpatient on the same bupropion dose for 17xa0days. For the first 4xa0inpatient days, participants smoked active marijuana [2.8% Δ9-tetrahydrocannabinol (THC)] 5xa0times/day. For the remaining inpatient days, participants smoked placebo marijuana (0.0% THC) 5xa0times/day. Participants were then maintained outpatient on the alternate dose of bupropion for 11xa0days, 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.