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.

Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans.

The effects of oral flupenthixol and intramuscular (i.m.) flupenthixol decanoate in combination with intravenous (i.v.) cocaine were evaluated in male cocaine abusers. Participants resided at an inpatient research unit for 27 days followed by an 11-day outpatient period. Oral flupenthixol (2.5 or 5.0 mg; p.o.) followed by flupenthixol decanoate (10 or 20 mg; i.m.) and placebo were investigated in individuals who were randomly assigned to one of three groups under double-blind conditions (placebo, low or high dose flupenthixol). During the inpatient period, participants had four fixed cocaine dosing sessions; each session they were administered four doses of i.v. cocaine (approx. 48 mg/70 kg), spaced 14 min apart. These sessions occurred once before medication (baseline phase), once following oral medication (oral phase), and twice following intramuscular medication (IM phase). Out of 23 participants, 18 completed the study; 4 of the 5 non-completers were in the high dose flupenthixol group. Overall, there were few subjective, cardiovascular, or cocaine pharmacokinetic differences between the placebo group and the low dose flupenthixol group, indicating that the low dose of flupenthixol was well tolerated, but ineffective. In the high dose flupenthixol group, two out of seven individuals (29%) experienced a dystonic reaction following oral flupenthixol and were medically discharged. Taken together, these findings indicate that flupenthixol is not a good candidate for treating cocaine abusers.

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

RATIONALE: Preclinical observations suggest that NMDA receptor-mediated glutamatergic neurotransmission is involved in the expression and maintenance of opioid dependence. OBJECTIVE: The present study evaluated whether memantine, the clinically available non-competitive NMDA receptor antagonist, decreases naloxone-precipitated withdrawal in morphine-dependent humans. METHODS: Eight heroin-dependent, non-treatment seeking, inpatient participants were stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, they received a series of challenges with naloxone (0.4 mg, IM) and the severity of opioid withdrawal was monitored. Either placebo or memantine (60 mg PO) was given 6 h before each naloxone challenge. A modified multiple baseline, across-participants design was used to evaluate the effects of memantine on the severity of naloxone-precipitated opioid withdrawal. RESULTS: Naloxone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as assessed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withdrawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine. Medication effects, assessed 5 h after memantine administration and before naloxone administration, included significant increases in ratings of "strong" and "good" drug effect, and "I feel sedated", "mellow", and "high". CONCLUSIONS: Memantine attenuated the expression of opioid physical dependence in humans, indicating that glutamatergic neurotransmission at the NMDA receptor site contributes to the maintenance of opioid dependence. This finding suggests that memantine may be a useful adjunct in the treatment of opioid dependence.

Methamphetamine self-administration by humans.

RATIONALE: Methamphetamine abuse has become increasingly problematic. Yet, the reinforcing effects of methamphetamine in humans have not been systematically evaluated. OBJECTIVE: To characterize methamphetamine's reinforcing effects in human research participants under controlled laboratory conditions. METHODS: Eight healthy research volunteers (one female, seven males) completed this 20-day residential study. On days 1, 5, 9, 13 and 17, at 1000 hours, participants received the "sample" oral dose of methamphetamine (0, 5, 10 mg) that was available for the next 3 days and they also received an alternative reinforcer, a $1 voucher (redeemable for cash at study's end). Over a 3-day period, volunteers participated in an eight-trial choice procedure, during which they had the opportunity to self-administer the dose of methamphetamine they most recently sampled or to receive the $1 voucher. RESULTS: Participants' choice to self-administer methamphetamine significantly increased when active methamphetamine (5 mg and 10 mg) was available compared to placebo. No difference of choice was noted between low-dose and high-dose methamphetamine. However, the sampled 10 mg methamphetamine dose significantly increased several "positive" subjective ratings including "High," "Good Drug Effect," and "Stimulated," whereas the sampled 5 mg methamphetamine dose did not. Both active methamphetamine doses caused significant reductions in daily total caloric intake, relative to the respective placebo conditions. CONCLUSION: These data demonstrate that oral methamphetamine is a positive reinforcer in humans.

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

RATIONALE: Data obtained in laboratory animals and humans suggest that dopamine D1 receptor antagonists decrease cocaine self-administration and block cocaine's discriminative stimulus and subjective effects. OBJECTIVES: This study investigates the effects of the selective dopamine D1 antagonist, ecopipam (SCH 39166), 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 (100 mg p.o.) in random order using a within-subjects, cross-over design. Cocaine self-administration (0, 12, 25, and 50 mg) was tested beginning on the 5th day of each 8-day maintenance condition. A six-trial choice procedure (cocaine vs $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 (12 mg) and increased ratings of "good drug effect," "high," "stimulated," and dose quality (25 and 50 mg). 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.

Effects of repeated oral methamphetamine administration in humans.

RATIONALE: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. OBJECTIVES: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. METHODS: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4-6 and 10-12; placebo was administered on all other study days. RESULTS: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. CONCLUSIONS: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

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.

Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans.

RATIONALE: Studies have shown that buprenorphine, a partial mu opioid agonist, effectively reduces heroin taking. While previous research with buprenorphine utilized a liquid formulation, a tablet formulation is proposed for clinical use. However, because recent research suggests that the liquid and tablet differ in bio-availability, it is unclear what dose of the buprenorphine tablet effectively antagonizes the reinforcing effects of heroin. OBJECTIVE: The present study was designed to compare the effects of two sublingual doses of buprenorphine maintenance on heroin self-administration. METHODS: Eight heroin-dependent men participated in a 6-week, double-blind, placebo-controlled inpatient study to evaluate the reinforcing effects of intravenous heroin (0, 6.25, 12.5, 25 mg) during maintenance on 8 or 16 mg sublingual buprenorphine. Participants first sampled the available dose of heroin, and then were allowed to respond under a progressive ratio schedule for either heroin or $20. For each heroin dose, one sample session and three choice sessions occurred. Two sessions per day were conducted. A sample session was followed by the first choice session on one day, and the second and third choice sessions occurred on the following day. These sessions were conducted while participants were maintained on daily doses of 8 or 16 mg buprenorphine (3 weeks each). RESULTS: Relative to placebo, 12.5 and 25 mg heroin produced significant increases in break point values under both maintenance dose conditions. The mean break point value for 12.5 mg heroin was significantly lower under 16 mg buprenorphine, compared to 8 mg. CONCLUSIONS: These results demonstrate that the reinforcing effects of heroin were not fully antagonized by these doses of the tablet formulation of buprenorphine, and that 16 mg buprenorphine reduced heroin self-administration relative to 8 mg.

Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain.

The route of administration influences the reinforcing effects of cocaine. Here we assessed whether there were differences in the efficacy of cocaine to block the dopamine transporters (major target for cocaine's reinforcing effects), as a function of route of administration. Positron emission tomography and [11C]cocaine, a dopamine transporter radioligand, were used to compare the levels of dopamine transporter blockade induced by intravenous, smoked and intranasal cocaine in 32 current cocaine abusers. In parallel, the temporal course for the self-reports of "high" were obtained. Cocaine significantly blocked dopamine transporters. The levels of blockade were comparable across all routes of administration and a dose effect was observed for intravenous and intranasal cocaine but not for smoked cocaine. For equivalent levels of cocaine in plasma and DAT blockade, smoked cocaine induced significantly greater self reports of "high" than intranasal cocaine and showed a trend for a greater effect than intravenous cocaine. The time to reach peak subjective was significantly faster for smoked (1.4+/-0.5 min) than for intravenous cocaine (3.1+/-0.9 min), which was faster than intranasal cocaine (14.6+/-8 min). Differences in the reinforcing effects of cocaine as a function of the route of administration are not due to differences in the efficacy of cocaine to block the dopamine transporters. The faster time course for the subjective effects for smoked than intravenous and for intravenous than for intranasal cocaine highlights the importance of the speed of cocaine's delivery into the brain on its reinforcing effects.

Increased sensitivity to alprazolam in females with a paternal history of alcoholism.

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.

Alternative reinforcers differentially modify cocaine self-administration by humans.

Six experienced cocaine smokers (two men, four women) participated in an inpatient study to compare self-administration of smoked cocaine when either a $5 money or merchandise voucher was available as an alternative reinforcer. A six-trial choice procedure was used, with sessions consisting of (1) one sample trial, where participants received the cocaine dose and the alternative reinforcer available that day, and (2) five choice trials, where participants chose between the available cocaine dose and the alternative reinforcer. There were eight sessions: in separate sessions, each dose of cocaine (0, 12, 25, 50 mg) was paired with a money voucher and with a merchandise voucher. The choice to self-administer cocaine significantly increased with escalating cocaine doses, and significantly less cocaine was self-administered when money vouchers were available as compared to merchandise vouchers. These data demonstrate that money vouchers are a more effective alternative reinforcer than merchandise vouchers in cocaine abusers.

Limited sex differences in response to "binge" smoked cocaine use in humans.

The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively). The most striking sex difference was that women had higher cocaine plasma concentrations than men (632.7 ng/ml vs. 376.7 mg/ml) after the sixth cocaine dose of the first session. After the first cocaine dose, women reported that they would spend significantly less for the dose than men ($1.58 vs. $3.15). Although cocaine produced similar effects in men and women 4 min after each dose, 15 min after the last dose of the session, heart rate and blood pressure remained elevated in women, but ratings of "I want cocaine" were lower in women as compared to men. Thus, smoking cocaine produced similar acute subjective effects in men and women, but prolonged cardiovascular effects and higher cocaine plasma concentrations in women.

Positron emission tomography studies of dopamine-enhancing drugs.

Although PET is technologically complex because the restricted time scale requires that radioisotope production, radiotracer synthesis, and PET imaging be carried out in the same place, the payoff is that compounds labeled with these isotopes can be used to track the distribution and movement of drugs in the brain and also measure drug effects on specific molecular targets in the human brain. Provided that appropriate radiotracers are available, one can determine the amount of a drug that gets into the brain, the minimum effective dose, the duration of action, or the binding site occupancy required to elicit a particular therapeutic or behavioral effect with a relatively small number of PET studies. Because studies are carried out directly in humans, the relationship of these parameters to behavior and to therapeutic efficacy can be evaluated. The possibilities are enormous and are largely driven by advances in PET technology (including radiotracer chemistry and instrumentation) that synergize with advances in neuropharmacology.

Fluoxetine-maintained obese humans: effect on food intake and body weight.

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.

Sensitive and selective liquid chromatographic assay of memantine in plasma with fluorescence detection after pre-column derivatization.

A procedure was developed for the determination of memantine in plasma using liquid chromatography with fluorescence detection. Following a liquid-liquid extraction from 1 ml of plasma containing the internal standard amantadine, the extract was derivatized at room temperature with dansyl chloride, and the highly fluorescent derivatives were chromatographed with a reversed-phase C18 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated memantine and amantadine were eluted in less than 13 min with no interference from endogenous material. The calibration curve was linear over the concentration range of 3-400 ng/ml with inter- and intra-assay imprecision (C.V.) of less than 10%. The limit of quantitation was 3 ng/ml, and no major antidepressant, neuroleptic or their respective metabolites interfered with the quantitation of memantine. This method could also be applied to the quantitation of amantadine.

Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans.

Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., "I feel a good drug effect," "I feel high"), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs.

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 i.v.) 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 $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.

Food "cravings" and the acute effects of alprazolam on food intake in women with premenstrual dysphoric disorder.

Women with premenstrual dysphoric disorder (PMS) report negative mood premenstrually, and increased food cravings and food intake. Although the benzodiazepine alprazolam has been used to treat PMS, alprazolam has been shown to increase food intake. The present study investigated the acute effects of alprazolam (0, 0.25, 0.50, 0.75 mg) on food intake in 19 women with PMS. Each dose was tested once during the premenstrual phase and again during the postmenstrual phase. Each session, before drug administration, participants completed a Food Desirability Questionnaire and selected lunch, which was consumed 3.5 h after drug administration. Desire for foods containing fat were significantly increased premenstrually compared to postmenstrually, while desires for carbohydrate (CHO) alone and beverages did not change as a function of menstrual cycle phase. Cognitive Restraint scores predicted the amount of food consumed, i. e. restrained eaters consumed less food at lunch. Alprazolam significantly increased food intake, specifically fat, premenstrually compared to postmenstrually. Restrained eaters consumed 26% more calories premenstrually following 0.75 mg alprazolam relative to placebo, whereas unrestrained eaters consumed 9% more calories. Thus, women with PMS, particularly restrained eaters, are more sensitive to the food-intake increasing effects of alprazolam premenstrually.

Abstinence symptoms following oral THC administration to humans.

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral delta9-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.

Abstinence symptoms following smoked marijuana in humans.

Symptoms of withdrawal after oral delta9-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.