Gabapentin increases the abuse liability of alcohol alone and in combination with oxycodone in participants with co-occurring opioid and alcohol use disorder.

BACKGROUND: People who have co-occurring Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) carry a higher risk of adverse outcomes, including drug overdose. Early clinical and preclinical studies suggested that gabapentin may be effective in treating both disorders. The present study was designed to assess the effects of gabapentin on the subjective and physiological effects of oxycodone (OXY) and alcohol (ALC), alone and in combination. METHODS: During an 8-week, inpatient, within-subject, randomized, double-blind, placebo-controlled crossover study, non-treatment seeking participants (N = 13; 12 M/1F; 44.1 ± 3 years of age) with OUD and AUD were maintained on oral morphine (120 mg daily). Under gabapentin (1800 mg/day) and placebo (0 mg/day) maintenance, participants completed nine separate test sessions (three sessions per week) during which they received an oral solution containing 0, 15, or 30 mg/70 kg OXY in combination with 0, 0.5, or 0.75 g/kg ALC. During test sessions, subjective effects and physiological responses were assessed repeatedly on 100-mm visual analog scales (VAS). The primary outcome variable was the VAS rating of drug liking after receiving the drug challenge. RESULTS: Alcohol alone (but not oxycodone alone) produced dose-related increases in several positive subjective responses, including drug liking. Gabapentin significantly increased drug liking when given in combination with ALC and OXY + ALC (p < 0.05). Gabapentin did not clinically compromise respiration or other vital functions. CONCLUSIONS: Gabapentin may increase the abuse liability of ALC and OXY + ALC in those with co-occurring OUD and AUD.

Minocycline attenuates oxycodone-induced positive subjective responses in non-dependent, recreational opioid users.

BACKGROUND: Recent data suggest that glial cells may be involved in the analgesic effects and abuse liability of opioids. Preclinical studies have demonstrated that mu-opioid-receptor-selective agonists, such as oxycodone, activate glia and increase the release of cytokines, causing a suppression of opioid-induced analgesic effects. Preclinical studies also show that certain medications, such as the broad-spectrum tetracycline antibiotic minocycline, inhibit opioid-induced glial activation and thereby enhance the analgesic effects of opioids. Importantly, minocycline reduces the rewarding effects of opioids at the same doses that it enhances opioid-induced analgesia. AIMS: The purpose of the present study was to assess the effects of acute administration of minocycline on the subjective, physiological, and analgesic effects of oxycodone in human research volunteers. DESIGN: This study was a within-subject, randomized, double-blind outpatient study. Participants completed five separate sessions in which they received 0, 100, or 200 mg minocycline (MINO) simultaneously with either 0 or 40 mg oxycodone (OXY). The subjective, physiological, and analgesic effects of OXY were measured before and repeatedly after drug administration. SETTINGS AND PARTICIPANTS: Participants were between 21 and 45 years of age, non-treatment seeking, non-dependent recreational opioid users (N = 12). This study was conducted between 2013 and 2014 at the New York State Psychiatric Institute in New York, NY. FINDINGS: MINO 100 and 200 mg were safe and well-tolerated in combination with OXY 40 mg. MINO 200 mg administered with OXY 40 mg attenuated OXY-induced positive subjective effects such as "Good Effect" and "Liking" compared to OXY alone. MINO did not alter the physiological or analgesic effects of OXY. CONCLUSIONS: MINO may attenuate the abuse liability of mu-opioid-receptor-selective agonists.

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse.

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose.

Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

Hepatitis C infection in non-treatment-seeking heroin users: the burden of cocaine injection.

BACKGROUND AND OBJECTIVES: In heroin dependent individuals, the HIV epidemic has been controlled in countries where access to opioid maintenance treatment (OMT) and needle exchange programs (NEP) have been implemented. However, despite similar routes of contamination for both viruses, the prevalence of hepatitis C (HCV) infection remains high in drug users. The objective of this analysis was to identify the prevalence of HCV and the correlates of being HCV-positive in a sample of out-of-treatment heroin-dependent individuals. METHODS: Data were collected from five inpatient studies (n = 120 participants) conducted at the New York State Psychiatric Institute. A logistic regression was used to identify correlates of being HCV-positive at baseline. RESULTS: Among the 120 heroin-dependent volunteers, 42 were HCV-positive. Participants who had heavier alcohol use, a longer duration of heroin use, or who reported using heroin by injection were more likely to be HCV-positive. Interestingly, participants who had injected cocaine during the previous month had a ninefold greater risk of being HCV-positive compared to non-cocaine users and those who used cocaine by a non-injecting route. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings confirm the risk of being HCV-infected through intravenous drug use, especially with cocaine use. These results underscore the importance of rethinking interventions to prevent HCV infection with combined strategies using pharmacological approaches for cocaine dependence and tailored prevention for cocaine users.

Abuse liability of oxycodone as a function of pain and drug use history.

The relationship between pain and prescription opioid abuse is poorly understood. Determining whether a patient is seeking additional opioid medications in order to alleviate pain or to abuse the drugs can be difficult. The present study was designed to evaluate two variables that may influence the abuse liability of opioids: drug use history and the presence or absence of experimentally induced pain. Eighteen healthy participants completed this outpatient study. One group was abusing prescription opioids (N=9) and one group had used prescription opioids medically but did not abuse them (N=9). All participants completed twelve sessions during which the effects of orally delivered oxycodone (0, 15, 30mg/70kg, PO) were examined. One dose was tested per day under double-blind conditions and sessions were separated by at least 48h. During the first "sample" session each week, participants were given $10 and the dose that was available later that week. During the second "choice" session, participants could self-administer either money or the previously sampled dose. Six sessions involved repeated hand immersions in cold water (4 degrees C) and six sessions involved immersions in warm water (37 degrees C). Most of the positive subjective effects of oxycodone were similar between the groups, but oxycodone self-administration significantly differed between groups. Non-abusers self-administered active doses of oxycodone only when they were in pain while abusers self-administered oxycodone regardless of the pain condition. These data suggest that an assessment of the reinforcing effects of opioids may be a sensitive method for differentiating opioid abusers from non-abusers.

The role of human drug self-administration procedures in the development of medications.

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

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.

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.

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.

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.

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.

Effects of methysergide and loratadine on food intake, mood, and performance of humans living in a residential laboratory.

The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate (p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including "Vomiting," "Stomach Pain," and "Miserable." These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).

Effects of an alternative reinforcer on intravenous heroin self-administration by humans.

Five heroin-dependent research volunteers, maintained on divided daily oral morphine doses, participated in an inpatient study designed to evaluate intravenous (i.v.) heroin self-administration when money ($10, $20 or $40) was concurrently available. Each morning participants received a single injection of heroin (placebo, 6.25, 12.5, 25, or 50 mg/70 kg, i.v.) and each afternoon, they had the opportunity to self-administer all or part of the morning dose. Participants responded under a progressive-ratio schedule (50, 100, ..., 2800) during a 10-trial self-administration task. During each trial, participants could respond for 1/10th of the sampled heroin dose or 1/10th of a single money value. The progressive-ratio value increased independently for each option. The total amount of heroin and/or money chosen during the self-administration task was administered at the end of the task. Heroin dose-dependently increased ratings of 'good drug effect' and 'high', impaired task performance and decreased pupil diameter and blood oxygen saturation. Heroin also dose-dependently increased progressive-ratio break point values, which varied as a function of the alternative money amount. Consistent with previous studies, the present results demonstrate that alternative reinforcers, depending on magnitude, are effective in reducing heroin use in opioid-dependent individuals.

Effects of caffeine withdrawal on humans living in a residential laboratory.

Caffeine withdrawal was examined in caffeine-dependent humans living in a residential laboratory. Ten men and 2 women who reported daily caffeine consumption participated in a 17-day study. From 1000-1700, participants worked on computerized tasks assessing memory, vigilance, and psychomotor skills, with a 1-hr break for lunch. From 1700-2330, participants engaged in private or social, recreational activities. Subjective-effects measures were completed 10 times per day. Participants were maintained on caffeine (100 mg 3 times a day at 0945, 1345, and 1745), except on days 5-6 and 12-13, when caffeine was replaced by placebo. Caffeine abstinence selectively influenced subjective effects without altering social behavior or performance on tasks assessing memory, vigilance, and psychomotor skills. Furthermore, the effects of caffeine on food intake were enhanced after 2 days of caffeine abstinence.

Cyproheptadine produced modest increases in total caloric intake by humans.

Four male and three female normal-weight research volunteers, participating in an 18-day residential study, received oral cyproheptadine (4 mg) or placebo at 0930, 1245, and 1730 hours daily. Food intake, performance, and subjective ratings were measured throughout the day. The interaction between cyproheptadine and carbohydrate consumption was examined by providing subjects diets that engendered varied levels of carbohydrate intake. Three diet conditions were tested for 6 days each: a regular diet, a low-carbohydrate (high-fat) diet, and a high-carbohydrate diet. Placebo was given on days 1, 2, 3, and 6, while cyproheptadine was given on days 4 and 5 of each diet condition. When subjects received placebo and had access to a regular diet, they consumed 2500 kcal/day (59% carbohydrate 28% fat, 13% protein). Total caloric intake decreased (p < 0.007) when subjects received placebo and had access to the low-carbohydrate diet (40% carbohydrate, 43% fat, 17% protein) and increased (p < 0.056) when subjects received placebo and had access to a high-carbohydrate diet (70% carbohydrate, 19% fat, 11% protein). Cyproheptadine significantly increased total daily caloric intake by 20%, to 3000 kcal, only under the regular diet condition. The increase in caloric intake was due to an increase in the number of eating occasions without a change in eating occasion size. Although subjects consumed more food under the regular diet and cyproheptadine condition, cyproheptadine had no effect on the relative contribution of macronutrients to total daily caloric intake. There was no evidence for a modulation of the food-intake increasing effects of cyproheptadine by the macronutrient mix of the available diet. Cyproheptadine also significantly altered self-reported mood: compared to placebo, cyproheptadine produced significant increases in ratings of "Tired", "Sleepy", "Headache", "Can't Concentrate", and "Bad Drug Effect" and decreases in "Alert". Furthermore, cyproheptadine produced small decrements in psychomotor task performance.

Alprazolam increases food intake in humans.

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.