Amie S. Ward

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 (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); 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 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg 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.

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration 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, 4 mg IV) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus

Binge cocaine self-administration in humans: intravenous cocaine.

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: ABT-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 (4 mg) 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.

Zolpidem-related effects on performance and mood during simulated night-shift work.

Abstract Cocaine is frequently used in intermittent cycles of repeated dosing, or “binges.” This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of “I want cocaine” decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of “binge” cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use.

Fluoxetine-Maintained Obese Humans: Effect on Food Intake and Body Weight

The effects of zolpidem, a nonbenzodiazepine hypnotic, on psychomotor task performance, subjective effects, and food intake were examined during simulated shift work. Seven participants completed this 23-day, within-participant design, residential laboratory study. They received a single oral zolpidem dose (0, 5, or 10 mg) 1 hr before bedtime for 3 consecutive days under 2 shift conditions: day shift and night shift. When participants received placebo, next-day performance and subjective effects were disrupted, and food intake was decreased during the night shift. Zolpidem improved subjective reports of sleep quality and, to a lesser extent, next-day performance. Next-day mood, however, was worsened by zolpidem. Food intake was unaffected by zolpidem. These data indicate that shift changes produce performance impairments, mood alterations, and decreases in food intake, and that zolpidem attenuates some shift-change-related disruptions.

Cognitive performance by humans during a smoked cocaine binge-abstinence cycle.

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.

Variations in cocaine self-administration by inbred rat strains under a progressive-ratio schedule

Five cocaine-dependent individuals completed a 22-day inpatient study of sleep and cognition. Following 3 days of drug-free baseline, participants underwent 3 days of twice-daily smoked cocaine base self-administration (6 50-mg doses, 14 minutes apart), followed by 15 days of abstinence. Each morning and afternoon, the CDR repeatable, multiple-version, computerized cognitive battery (whose stability following practice has been documented) was administered. During abstinence, performance deteriorated on vigilance tasks (especially reaction time) as well as on immediate and delayed verbal recognition tasks but not on working memory tasks. Declines were most evident in the afternoon. Data suggest that abstinence can unmask cognitive deficits induced by chronic cocaine use and circadian factors may mediate their severity.

The effects of a monetary alternative on marijuana self-administration.

This study investigated the influence of genetics on extent of cocaine taking in rats that were self-administering cocaine under a progressive-ratio schedule. Fischer 344, ACI and Brown Norway rats were subjects because previous genetic studies on dopamine receptor loci have indicated that these are genetically divergent strains. All subjects were assessed for acquisition and stability of cocaine self-administration under a progressive-ratio schedule. Subsequently, a dose-effect curve for cocaine self-administration was determined for each strain. Fischer 344 rats maintained a higher average breaking point than did the ACI or Brown Norway strains. In addition, dopamine receptor antagonists differentially reduced the ability of cocaine to serve as a reinforcer across the three strains. The D1-selective dopamine receptor antagonist, SCH 23390, and the D2/D3-selective dopamine receptor antagonist, eticlopride, were significantly more effective in reducing the self-administration of cocaine in Brown Norway rats than for the other two strains. The results of this study demonstrate that genetic differences may play an important role in determining responding under progressive-ratio schedules for cocaine, possibly due to differences in the reinforcing efficacy of cocaine.

Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans

The availability of alternative reinforcers can reduce drug self-administration. This 21-day residential study investigated the effect of monetary alternatives on marijuana self-administration. Three female and four male participants performed computer tasks (baseline) in the morning before smoking a sample marijuana cigarette (0.0,1.8, or 3.9% Δ9-tetrahydrocannabinol (THC)) and receiving the sample alternative (