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Although methamphetamine and alcohol are commonly used together in a binge-like pattern, there is a dearth of empirical data investigating the repeated effects of this drug combination. The current study examined acute and residual mood, performance, and physiological effects of methamphetamine alone, alcohol alone, and the combination. Nine adult male volunteers completed this 20-day within-participant, residential laboratory study. During four 5-day blocks of sessions, participants were administered oral methamphetamine (0, 10 mg) combined with alcohol (0, 0.375, 0.75 g/kg) three times (day 2: AM, day 2: PM, and day 3: PM). Breath alcohol concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and repeatedly thereafter. Subjective and objective sleep measures were also assessed; residual effects were assessed on days 3–5 of each block. Following the first drug administration, the methamphetamine–alcohol combination produced greater elevations of heart rate and ratings of “good drug effect” compared to either drug alone. Methamphetamine attenuated alcohol-related performance decrements and feelings of intoxication, whereas alcohol attenuated methamphetamine-related sleep disruptions. By the third administration, many of these effects were significantly diminished, suggesting that participants developed tolerance. Few residual effects were observed. These data show that methamphetamine combined with alcohol produced a profile of effects that was different from the effects of either drug alone. The largely positive effects of the drug combination (i.e., greater euphoria, and fewer performance and sleep disruptions) might explain why these drugs are often used in combination.

Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals.This study examined the effects of methamphetamine and MDMA using a within-subject design.Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed.Acutely, both drugs increased cardiovascular measures and "positive" subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased "negative" subjective-effect ratings. Few residual drug effects were noted for either drug.It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).

Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence.This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D(2) receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers.In order to achieve steady-state concentrations, participants (n = 8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose-response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a "sample" trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00.Cocaine's reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo.These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence.

Methamphetamine attenuates disruptions that occur after changes in work shifts. The reinforcing effects of the drug during shift work have yet to be characterized. This study examined methamphetamine-related mood, performance, and reinforcing effects during simulated shift work. Ten volunteers (four women and six men) completed this 19-day study. Participants were given an opportunity to self-administer oral methamphetamine (10 mg) or receive a $1 voucher before and after an 8-h work period for four consecutive days under two shift conditions: (1) “day shift” in which they went to bed at 2400 hours and woke up at 0800 hours and (2) “night shift” when they went to bed at 1600 hours and woke up at 2400 hours. Thus, participants completed task batteries either from 0815 to 1715 hours or from 0015 to 0915 hours. Shift conditions alternated three times during the study and were separated by an “off” day. Night-shift work disrupted psychomotor task performance and some ratings of mood, especially on the first night. Consistent with this, participants chose to take methamphetamine significantly more often on the first night-shift night compared with the first day-shift day. Regardless of shift condition, however, participants selected markedly more methamphetamine doses before the work period than after it (73% versus 34%). These data show that methamphetamine self-administration occurred more often before work rather than after work, suggesting that the use of stimulants by shift workers may be one strategy employed to meet behavioral demands especially under conditions engendering poor performance, fatigue, and/or sleep disruptions.

Oral Delta-9-tetrahydrocannabinol (Delta(9)-THC; Marinol) is medically available for the treatment of nausea associated with cancer chemotherapy and for wasting syndromes related to HIV/AIDS. Little is known about its reinforcing effects.This study was conducted to characterize the reinforcing effects of oral Delta(9)-THC in experienced marijuana smokers under controlled laboratory conditions.Ten healthy male marijuana users completed this 17-day residential study. On days 2, 6, 10, and 14, at 0900 h, participants received a "sample" oral dose of Delta(9)-THC (0, 10, 20 mg) and an alternative reinforcer, a 2 US dollars voucher (redeemable for cash at study's end). Over the next 3 days, they had 11 opportunities to self-administer either the sampled dose of Delta(9)-THC or to receive a 2 US dollars voucher.Participants chose active Delta(9)-THC (10 and 20 mg) more often than placebo (two selections vs approximately four selections, respectively). However, they chose active Delta(9)-THC on less than 50% of choice opportunities. Both active Delta(9)-THC doses produced significant increases in "positive" subjective effects, impaired psychomotor performance, and increased heart rate, relative to the placebo conditions.These data indicate that oral Delta(9)-THC may have modest abuse liability in experienced marijuana smokers.

Rationale. Although smoked marijuana contains at least 60 cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral Δ9-THC with repeated doses of smoked marijuana in the same individuals. Objective. To compare the effects of oral Δ9-THC and smoked marijuana in humans under controlled laboratory conditions. Methods. Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% Δ9-THC, q.i.d.) were smoked or Δ9-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. Results. Relative to placebo baseline, oral Δ9-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral Δ9-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. Conclusion. These results indicate that the behavioral profile of effects of smoked marijuana (3.1% Δ9-THC) is similar to the effects of oral Δ9-THC (20 mg), with some subtle differences.

Rationale. The discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. Objective. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Methods. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Results. Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. Conclusion. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

Rationale. Previous studies have shown that buprenorphine differentially suppresses the reinforcing effects of different drugs (cocaine, alfentanil), drug versus nondrug reinforcers (food, drug), and the same reinforcer (food) maintained under different schedules of reinforcement. Objectives. The purpose of the present study was to determine whether buprenorphine (0.03, 0.1, 0.3 mg/kg) differentially affects candy versus sweetened fluid self-administration. The hypotheses were that (1) candy would maintain higher rates of responding and would be chosen on more occasions than sweetened fluid, and (2) buprenorphine would produce smaller disruptions in responding for the more-preferred reinforcer. Methods. During separate sessions, rhesus monkeys self-administered candy alone, sweetened fluid alone, or had the opportunity to choose between candy and sweetened fluid. Monkeys responded under a second order, two-chain schedule of reinforcement. Results. Candy was a more-preferred reinforcer than sweetened fluid. Buprenorphine significantly decreased rates of responding for fluid, but increased rates of responding for candy. Although buprenorphine significantly decreased both candy and fluid intake, it produced a more robust, and longer-lasting suppression of sweetened-fluid intake than candy. Choice to self-administer candy or fluid was not affected by buprenorphine. Conclusions. These results demonstrate that behavior maintained by a less-preferred reinforcer is more easily disrupted by buprenorphine than is behavior maintained by a more-preferred reinforcer.

Rationale: Feeding consists of appetitive or foraging behavior followed by consummatory behavior. Objectives: To determine if pharmacological manipulations can differentially affect appetitive and consummatory aspects of food intake, and to compare these results to those obtained using naturalistic dietary manipulations. Methods: Responding of baboons was studied using a schedule of reinforcement that simulated food "seeking" and food "taking." Responding during the seeking component was reinforced by stimuli paired with food, while responding during the taking component was reinforced with food. The effects of intramuscular amphetamine (AMPH), dexfenfluramine (DFEN), diethylpropion (DEP), phencyclidine (PCP), diazepam (DZP), as well as caloric prefeeding and acute food deprivation were determined. Results: AMPH decreased food taking and increased food seeking, DEP decreased food taking without affecting food seeking, DFEN and PCP decreased both food taking and food seeking, while DZP increased both food taking and food seeking. Caloric prefeeding decreased food taking and increased food seeking, i.e., resembled AMPH, while acute deprivation increased both food taking and food seeking, i.e., resembled DZP. Conclusions: Manipulations that increase dopamine turnover, such as AMPH, increase food seeking, while decreasing food intake. In contrast, manipulations that increase serotonin turnover, such as DFEN, decrease both food seeking and food taking.

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.

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.

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% Δ9-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.

Rationale: Clinical data suggest that stimuli paired with cocaine use acquire emergent stimulus effects, such as the ability to elicit cocaine craving. Objectives: The purpose of this study was to determine the conditioned effects of neutral stimuli paired with cocaine smoking. Methods: Eight experienced adult cocaine smokers participated in 22 experimental sessions while residing on a Clinical Research Center. One set of cues (CS–) was paired with placebo smoked cocaine and one set of cues (CS+) was paired with 25 mg smoked cocaine. Results: After 18 training trials, the effects of cocaine on heart rate and ratings of ”anxious” were greater, and skin temperature and ratings of ”tired” were smaller when compared to the effects of cocaine after the first training trial. When instructed to select a cue to experience after training, seven of eight participants selected the CS+, while only three of the participants selected the CS+ prior to training, i.e., the CS+ functioned as a conditioned reinforcer. Presentation of the CS+ alone without cocaine during extinction trials increased HR, SP, and ratings of ”anxious””tired”, and ”I want cocaine” and decreased skin temperature. These changes elicited by presentation of the CS+ decreased over the course of the extinction sessions. Conclusions: The present results indicate that classical conditioning is one mechanism by which stimuli paired with cocaine acquire emergent stimulus effects.

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.

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.

Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. We investigated the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. In study 1, daily marijuana smokers (n = 10), averaging 9.4 (±3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers (n = 11), averaging 11.9 (±5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. In study 1, during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence.

No studies to date have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol in HIV(+) marijuana smokers.The aim of this study was to compare dronabinol (0, 10, 20, 30 mg p.o.) and marijuana [0.0, 1.8, 2.8, 3.9% Delta(9)-tetrahydrocannabinol (THC)] in two samples of HIV(+) marijuana smokers: those with (n=15) and those without (n=15) a clinically significant loss of muscle mass (90% body cell mass/height), which is one component of AIDS wasting.Mood, physical symptoms, self-selected food intake, cardiovascular data, and cognitive task performance were measured before and repeatedly after dronabinol and marijuana administration in eight 7-h sessions. Marijuana and dronabinol were administered in randomized order using a within-subject, staggered, double-dummy design.As compared to placebo, (1) marijuana (1.8, 2.8, 3.9% THC) and the lower dronabinol doses (10, 20 mg) were well tolerated (e.g., few physical symptoms, significant increases in ratings of "good drug effect") in both groups of participants; the highest dose of dronabinol (30 mg) was poorly tolerated in a subset of participants; (2) marijuana and dronabinol significantly increased caloric intake in the low bioelectrical impedance analysis (BIA) group but not in the normal BIA group; and (3) drug effects on cognitive performance were minor.These data suggest that for experienced marijuana smokers with clinically significant muscle mass loss, both dronabinol (at acute doses at least four to eight times the current recommendation) and marijuana produce substantial and comparable increases in food intake without producing adverse effects.

Increased sleepiness while working and sleep disruptions are common complaints among shift workers. Consequently, shift workers may be more susceptible to diminished performance and work-related accidents.To examine the effects of the central nervous system stimulant methamphetamine on psychomotor task performance, subjective effects, and food intake during shift work under laboratory conditions.Seven participants completed this 23-day, within-participant design, residential laboratory study. They received a single oral methamphetamine dose (0, 5, 10 mg) 1 h after waking for three consecutive days under two shift conditions: (1) during the day shift, participants performed computerized psychomotor tasks from 0830 hours to 1730 hours and went to bed at 2400 hours and (2) during the night shift, participants performed tasks from 0030 hours to 0930 hours and went to bed at 1600 hours. Shifts alternated three times during the study; shift conditions were separated by an "off" day during which participants were not on a schedule and data were not collected.When participants received placebo, psychomotor task performance and subjective effects were disrupted during the night shift, relative to the day shift. Changing shift conditions did not alter food intake significantly. Methamphetamine reversed performance and subjective-effects disruptions, and decreased food intake during the night shift.These data indicate that shift changes produce performance impairments and mood alterations, and that a single low to moderate dose of methamphetamine attenuates many shift change-related disruptions in performance and mood.

Rationale. Studies in non-human animals suggest that opioid antagonists block the reinforcing effects of cannabinoids. Objective. The present studies in humans investigated how naltrexone modulates (1) the subjective and physiological effects of oral THC in comparison to methadone, (2) the reinforcing effects of oral THC, and (3) plasma levels of oral THC. Methods. In study 1, marijuana smokers (n=9) received naltrexone (0, 50 mg) followed 30 min later by THC (0, 15, 30 mg) or methadone (5, 10 mg). Subjective effects, task performance, pupillary diameter, and cardiovascular parameters were measured repeatedly. In study 2a, marijuana smokers (n=23) were randomly assigned to one THC dose condition (0, 15 or 30 mg). One set of color-coded capsules containing THC and active naltrexone (50 mg) was given in one session, while another set of color-coded capsules containing THC and placebo naltrexone was given in another session. In the final three sessions, participants chose which color capsules they would receive. In study 2b, a subset of participants from study 2a (n=7) received naltrexone (0, 50 mg) 30 min prior to oral THC (30 mg) administration, and blood was drawn repeatedly. Results. Pretreatment with naltrexone significantly increased many of the "positive" subjective effects of oral THC (30 mg) e.g. ratings of Good Drug Effect and Capsule Liking. Naltrexone tended to increase the reinforcing effects of oral THC (30 mg), as indicated by performance in a drug choice test. Naltrexone did not alter plasma THC levels. Conclusions. These studies demonstrate that naltrexone increases the subjective effects of oral THC. Thus, oral THC's effects are enhanced rather than antagonized by opioid receptor blockade in heavy marijuana smokers.

Rationale. Symptoms of marijuana withdrawal include increased irritability, depression and anxiety, and decreased sleep quality. Nefazodone, which is an antidepressant with sedative properties, may attenuate symptoms of marijuana withdrawal. Objective. The present within-subject, placebo-controlled study investigated the effects of nefazodone during marijuana withdrawal. Methods. Marijuana smokers [n=7; averaging 6.0 (±1.3) marijuana cigarettes/day, 6.4 (±0.4) days/week], not seeking treatment for marijuana use, were maintained on two doses of nefazodone (0, 450 mg/day) for 26 days each. Each maintenance condition began with an outpatient phase (9 days) and continued with an inpatient phase (17 days) in a residential laboratory. Marijuana was smoked 5 times per inpatient day at 1000, 1300, 1600, 1900 and 2200 hours. On days 1–4 (baseline), the first four marijuana cigarettes were placebo (0.00% THC), while the final marijuana cigarette was active (3.04% THC). On inpatient days 5–8, only active marijuana was smoked, while on days 9–16, only placebo marijuana was smoked. Mood, psychomotor task performance, food intake and sleep were measured daily. The order of maintenance dose was counterbalanced between groups. Results. Nefazodone maintenance did not alter the acute effects of active marijuana as compared to placebo nefazodone maintenance. During marijuana withdrawal, nefazodone decreased ratings of "Anxious", and "Muscle Pain", while having no effect on the marked increase in ratings of "Irritable", "Miserable" or decreased sleep quality. Conclusions. Nefazodone decreased certain marijuana withdrawal symptoms, but participants still reported substantial discomfort. These data provide further evidence of marijuana withdrawal, and highlight the need for more marijuana treatment options.

Rationale: Although common in humans, little is known about the reinforcing efficacy of smoked heroin in laboratory animals. Objectives: To evaluate the reinforcing efficacy of smoked heroin in non-opioid dependent, non-human primates. Methods: Self-administration and location-preference measures were obtained by having monkeys live in two chambers with heroin self-administration (0, 0.3, 0.6 mg/kg; eight dosings available per day) specific to one chamber and no commodity available in the other chamber. Operant responding reinforced by smoked heroin provided a self-administration measure of reinforcement, and the length of time monkeys spent in the heroin-associated chamber provided a location preference estimate of reinforcing efficacy. Results: Four of six monkeys acquired heroin self-administration: these monkeys completed six to eight smoking trials each day when either of the active heroin doses was available. Urine toxicology confirmed that monkeys were absorbing the smoked heroin. The number of completed smoking trials rapidly decreased under extinction conditions, indicating that smoked heroin was an efficacious reinforcer using the self-administration measure. Monkeys developed a location preference for the chamber where heroin was self-administered, indicating that smoked heroin was an efficacious reinforcer using the location-preference measure. Conclusions: Smoked heroin is an efficacious reinforcer in non-opioid dependent rhesus monkeys as measured using a self-administration procedure and estimated using a location-preference procedure.

Rationale: Few studies have systematically determined whether the response to cocaine in human females is related to hormonal fluctuations at different phases of the menstrual cycle. Objectives: To investigate the responses to repeated doses of smoked cocaine in women during two phases of the menstrual cycle using a within-subject design. Methods: Eleven non-treatment seeking female cocaine smokers were administered smoked cocaine during the follicular and mid-luteal phases of the menstrual cycle. The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, there were four cocaine administration sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12, or 25 mg cocaine base, depending on the session) at 14-min intervals. Results: The number of cocaine doses administered did not vary between the follicular and luteal phases. After cocaine administration, heart rate and several ratings – such as "good drug effect", "high", "stimulated", and "drug quality ratings" – were increased more during the follicular phase than the luteal phase, although, for some measures, these effects varied based on the cocaine dose. Further, dysphoric mood during the luteal phase was improved after cocaine administration. Conclusions: These results indicate that the cardiovascular and subjective effects of repeated doses of smoked cocaine are complex and vary as a function of menstrual cycle phase and cocaine dose.

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.

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 $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.

Clinical evidence suggests that pergolide, a D1/D2 dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide's effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of "High," "Stimulated," cocaine "Potency," estimates of street value, and heart rate, 2) increased ratings of "I want cocaine," and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine's subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted.

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse.

The present study investigated the effect of alprazolam on the pattern of food intake in seven male participants living in a residential laboratory for 17 days. A wide selection of meals, snacks and beverages was freely available. Capsule administration occurred at 1300 and 1730 hours. Food intake on days when alprazolam (0.75 mg) was administered (days 2, 11) was compared to days when no capsule (days 1, 9) or placebo (days 3, 10) was administered. Alprazolam increased total caloric intake by approximately 975 kcal from a baseline of 2800 kcal. Alprazolam increased the number of eating occasions occurring in the evening (1700-2330 hour), without altering the size of eating occasions (kcal), or the proportion of total calories derived from carbohydrate, fat and protein. These data demonstrate alprazolam's robust effects on food intake in humans.

The effect of task performance feedback and associated monetary earnings on drug self-administration were evaluated using eight subjects in a residential laboratory setting. The hypothesis was that if subjects believed that d-amphetamine impaired performance and reduced monetary earnings, d-amphetamine self-administration would decrease. Subjects performed computer tasks every day: on certain days that they received capsules, subjects were given bogus feedback regarding their performance ("better" or "worse" than average). On sample days, subjects were required to take d-amphetamine (10 mg BID) or placebo (0 mg BID) capsules. On choice days, subjects could choose between either d-amphetamine or placebo. Subjects received feedback on their task performance on 2 sample days and 2 of 4 choice days. Subjects received no feedback on the remaining two choice days. When subjects received no feedback, they chose d-amphetamine over placebo 78% of the time, and when they were given better feedback messages, they chose d-amphetamine 87.5% of the time. In contrast, d-amphetamine self-administration decreased significantly to 25% when subjects were told that it impaired their performance on work tasks and resulted in reduced earnings. In reality, d-amphetamine had little effect on work task performance. However, compared to placebo, d-amphetamine significantly increased subjective ratings of "Stimulated" and "Good Drug Effect" and significantly decreased ratings of "Tired" and "Sleepy." These results demonstrate that d-amphetamine served as a reinforcer under conditions in which drug self-administration did not influence monetary earnings, but that d-amphetamine self-administration could be modified by feedback/monetary earnings. Thus, contingencies associated with performance have important implications for drug use in the workplace.

The effects of d-amphetamine (0.5-4.0 mg/kg IP) and haloperidol (0.015-1.0 mg/kg IP) alone and in combination on intake of a sweetened milk solution were determined in rats. Experimental sessions consisted of a 15-min access to the milk solution once a day, 7 days a week. d-Amphetamine was administered 15 min prior to the session and haloperidol was administered 60 min prior to the session. The interaction of these compounds was determined by repeated determination of the dose-response function for d-amphetamine in combination with different doses of haloperidol. When given alone, each drug produced a dose-dependent decrease in milk intake. In combination with haloperidol, the decrement caused by d-amphetamine was shifted to lower doses in a dose-dependent manner. Isobolographic analysis of the interaction indicates that the intermediate doses (0.03-0.06 mg/kg) of haloperidol were additive and the highest doses (0.12-0.25 mg/kg) of haloperidol were infraadditive with d-amphetamine. Dose-dependent neuropharmacological actions of these compounds may account for dose-dependent interactions.

Food intake of four adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22 h. Food was available under a two-component operant schedule. Following completion of the first “procurement component” response requirement, access to food, i.e., a meal, became available under the second “consumption component” during which each response produced a 1-g food pellet. After a 10-min interval in which no response occurred, the consumption component was terminated. The effects of diazepam (DZP: 0.12–4.0 mg/kg) were determined by having the baboons drink a dose on Tuesdays and Fridays 45–60 min before the daily session. DZP produced dose-dependent increases in food intake in three of the four baboons. DZP increased the size of the first two meals and total duration of eating, but had no effect on eating rate or the number of meals within a session. The effect of DZP on the topography of feeding of baboons differs from previous reports on the effects of benzodiazepines on the topography of feeding in rodents. This suggests that species or procedural differences influence the effects of DZP on food intake.