Non-specific effect of naltrexone on ethanol consumption in social drinkers

Rationale: Clinical studies have shown that the opioid antagonist naltrexone is effective in the treatment of alcoholism. However, the mechanism by which it produces this effect is not understood. Objective: This study was designed to investigate the effect of acute naltrexone on consumption of ethanol in healthy, non-problem social drinkers. Methods: Subjects (n=24) participated in an eight-session, within-subject, placebo-controlled choice procedure which measured ethanol preference and consumption. The procedure consisted of two blocks of four sessions in which subjects received either naltrexone (50 mg oral) or placebo 1 h before consuming an ethanol or placebo beverage. On the first two sessions of each block, subjects received a color-coded beverage containing ethanol (0.75 g/kg) or placebo, in five equal portions at 15-min intervals. On the next two sessions of each block, subjects chose which beverage they preferred (i.e., placebo or ethanol) and how much they wished to take, in unit doses (placebo or ethanol 0.15 g/kg/dose). The primary behavioral measures were (1) the number of times subjects chose ethanol over placebo, and (2) the number of doses they consumed. Subjects rated their mood states and subjective drug effects at regular intervals during each session. Results: Naltrexone did not alter the frequency of ethanol (versus placebo) choice. Although naltrexone did decrease the total number of ethanol doses subjects took (mean 2.7 doses after naltrexone; 3.4 doses after placebo), it also decreased the number of placebo ”doses” subjects took on sessions when they chose the placebo beverage (mean 1.6 placebo doses after naltrexone; 2.8 doses after placebo). Ethanol produced its prototypic subjective effects (e.g., increased ratings of ”feel drug”, ”like drug” and ”high”), and these effects were not altered by naltrexone. Naltrexone produced mild sedative-like effects, and several subjects reported adverse effects such as nausea. Conclusions: These findings show that naltrexone reduces ethanol consumption in healthy volunteers, as it does in alcoholics. However, this reduction was not specific to alcohol; subjects also consumed less of a non-alcoholic, placebo beverage. These findings suggest that naltrexone may reduce alcohol consumption by a non-specific mechanism. Received: 17 September 1998 / Final version: 14 April 1999     

Factors influencing the reinforcing and subjective effects of ephedrine in humans

There has been little study of the abuse liability of ephedrine, a naturally occurring drug used in medicine for thousands of years and currently sold as a legal stimulant. The present study measured the reinforcing and subjective effects of ephedrine in a group of 27 adults (18 females and 9 males) with no history of drug dependence. A discrete-trial choice procedure was used to assess the reinforcing effects of a single oral dose of ephedrine selected to produce a moderate subjective response in each subject (range: 37.5-75 mg). A number of variables (gender, current and past drug use, personality, and baseline mood and arousal) were examined in an attempt to identify sources of variability in response to ephedrine. Of the 27 subjects, 5 chose ephedrine on either 2 or 3 out of a possible 3 occasions; overall, ephedrine was chosen on 17% of occasions. In the group as a whole, ephedrine had no effect on ratings of drug liking, but did increase ratings of high and scores on the MBG (euphoria) scale of the Addiction Research Center Inventory. Ephedrine also increased scores on a number of mood scales reflecting CNS stimulation and anxiety. Ephedrine choice was positively associated with current use of marijuana and lower levels of baseline anxiety and hunger, as well as with lower scores on two scales measuring dimensions of the personality trait of harm avoidance. Males and females differed in their response to ephedrine — males chose ephedrine more frequently than females and showed a more positive mood response to the drug. When compared to the results of a prior study of the same design withd-amphetamine, these results demonstrate that ephedrine produces a different profile of subjective effects and is a less efficacious reinforcer than amphetamine, suggesting that ephedrine has a lower liability for abuse.     

Acute tolerance to alcohol: changes in subjective effects among social drinkers

The development of acute of acute tolerance to the subjective effects of alcohol was examined in 32 social drinkers. Measures were made of self-reported level of intoxication and responses to questions from the alcohol scale of the Addiction Research Centre Inventory. The time to peak self-reported intoxication level was found to be 20 min earlier than the time to peak blood alcohol concentration. Changes from the ascending to the descending limb of the blood alcohol curve were found with five of the ARCI questions. In all cases the proportion of alcohol-typical responses was lower on the descending portion of the curve. even though blood alcohol levels were equivalent. Further analyses examined the effects of prior drinking history on the development of acute tolerance. Peak self-reported intoxication levels were significantly lower and occurred earlier for heavier drinkers. Furthermore, for four of the five ARCI questions heavier drinkers were less likely to give analcohol-typical response than lighter drinkers on the ascending portion of the curve.     

Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers

The reinforcing and subjective effects of phenylpropanolamine (PPA, 25 and 75 mg, PO) were compared with those of d-amphetamine (AMP, 5 mg) in a group of normal, healthy adults (eight males, nine females) with no history of drug abuse. A discrete-trial choice procedure was used in which subjects first sampled placebo and a dose of one of the drugs. Subjects were then allowed to choose between self-administration of drug or placebo on three separate occasions. The relative frequency with which active drug was chosen over placebo was used as the primary index of the drug's reinforcing efficacy. Subjective effects were measured with the Profile of Mood States, a short version of the Addiction Research Center Inventory and a series of visual analog scales. Ratings of drug liking, drug labelling, general activity level and strength of drug preference were also obtained. As expected, AMP was chosen significantly more often than expected by chance (69% of occasions). AMP also increased ratings of drug liking, preference strength, and activity level, and produced a profile of subjective effects consistent with its well-established stimulant and euphorigenic properties. The low dose of PPA was without effect on most measures. PPA 75 mg was chosen significantly less often than expected by chance (39% of occasions). This dose of PPA was most frequently labelled as a stimulant, and produced significant increases on ratings of Anxiety and stimulated, and decreases on ratings of sedated and hungry. Unlike AMP, PPA did not affect ratings of drug liking or mood scales reflecting euphoria. In sum, these results indicate that PPA does not possess AMP-like dependence potential.     

Physiological, subjective and reinforcing effects of oral and intravenous cocaine in humans

RATIONALE: There is little comparative information on the qualitative similarity, relative potency and reinforcing effects of oral cocaine versus cocaine administered via other routes. METHODS: The present study used a within-subject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125, 250 mg/70 kg) and intravenous (IV) (12.5, 25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. RESULTS: Cocaine produced dose-dependent increases on heart rate and blood pressure, with effects lasting longer after oral than IV cocaine. Subjective ratings (e.g., "rush," "drug effect," "liking") were qualitatively similar and dose-dependently increased after oral and IV administration, and the duration of effects was similar under both routes. On a money versus drug choice measure of reinforcement, the monetary amounts at which participants chose drug over money increased as a function of cocaine dose under both routes of administration. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as IV cocaine. Across measures, the data suggested that IV cocaine was approximately 10 times more potent than oral cocaine. CONCLUSIONS: Overall, the results of this study support qualitatively similar effects of oral and IV cocaine and suggest that oral cocaine may be an effective tool for studying cocaine's effects in human laboratory studies.     

The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans

Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4-methylenedioxymethamphetamine (MDMA) in humans.Materials and methods The subjective and physiological effects of 1.5 mg/kg MDMA were evaluated after 20 mg fluoxetine in eight recreational MDMA users in a double-blind, placebo-controlled study. During phase 1, participants were maintained on placebo for at least 5 days and tested with MDMA and placebo on separate sessions. In phase 2, the procedure was the same except fluoxetine was administered daily for at least 5 days. During sessions, placebo or fluoxetine was given 1 h before the session drug and effects were measured over the next 7 h.Results MDMA increased positive-like subjective effects on all the Addiction Research Center Inventory scales; Arousal, Elation, Positive Mood, and Vigor on the Profile of Mood States; Drug Liking, Friendly, Good Drug Effect, High, Stimulated, and Talkative on the Visual Analog Scale; and End-of-Session Liking and Crossover Point on the Multiple Choice Procedure. MDMA also increased measures of anxiety. On the Hallucinogenic Rating Scale, all scales except Volition were increased. MDMA also increased blood pressure and heart rate. Fluoxetine treatment attenuated most of the positive-like subjective effects including the Affect and Soma scales of the Hallucinogen Rating Scale. In addition, heart rate but not blood pressure increases were reduced.Conclusions These results suggest that blockade of 5-HT reuptake by fluoxetine can dampen the effects of MDMA and further supports the role of 5-HT in its behavioral effects in humans.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Reinforcing and subjective effects of caffeine in normal human volunteers

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults. Subjects (eight females, ten males) were light to moderate users of caffeine, and had no history of drug abuse. A discrete-trial choice procedure was used in which subjects were allowed to choose between the self-administration of color-coded capsules containing either placebo or caffeine. The number of times caffeine was chosen over placebo was used as the primary index of reinforcing efficacy. Subjective effects were measured before and several times after capsule ingestion. The low dose of caffeine was chosen on 42.6% of occasions, not significantly different from chance (50%). The high dose of caffeine was chosen on 38.9% of occasions, significantly less than expected by chance, indicating that this dose served as a punisher. Both doses of caffeine produced stimulant-like subjective effects, with aversive effects such as increased anxiety predominating after the high dose. When subjects were divided into groups of caffeine-sensitive choosers and nonchoosers, a consistent relationship emerged between caffeine choice and subjective effects; nonchoosers reported primarily aversive effects after caffeine (increased anxiety and dysphoria), whereas choosers reported stimulant and positive mood effects. When compared with previous findings, these results demonstrate that caffeine is less reinforcing than amphetamine and related psychomotor stimulants.     

Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin

Rationale

Naltrexone is an opioid antagonist that is currently approved as a treatment for opioid and alcohol dependence. Although it is highly effective in completely antagonizing the effects of opioids, medication noncompliance is a difficult obstacle to treatment. Therefore, a sustained-release form of naltrexone may improve treatment outcome.

Objective

The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex^®).

Materials and methods

Five heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, the effects of a range of heroin doses (0, 6.25, 12.5, and 25 mg, i.v.) were examined. Participants then received 384 mg naltrexone base. The effects of heroin were again evaluated for the next 6 weeks. One dose of heroin was tested per day and the entire dose range was tested each week. Doses were administered in non-systematic order. During a morning sample session, participants received a dose of heroin and $20 and subjective, performance, and physiological effects were measured both before and after drug administration. During an afternoon choice session, participants were given the opportunity to choose the sampled heroin dose and/or amount of money using a modified progressive ratio procedure.

Results

Depot naltrexone antagonized both the reinforcing and subjective effects of heroin for 4–5 weeks. Subjective ratings of withdrawal were reduced after week 2 and throughout the remainder of the study. The effects of heroin on mean trough pupil diameter began to emerge by week 5. There were no clinically significant effects on respiratory or cardiovascular function.

Conclusions

The present results extend our previous findings by showing that the reinforcing effects of heroin were reduced for 4–5 weeks after administration of 384 mg depot naltrexone.     

Physiological and subjective effects of acute intranasal methamphetamine during atomoxetine maintenance

Rationale

Methamphetamine abuse and dependence are significant public-health concerns. Behavioral therapies are effective for reducing methamphetamine use. However, many patients enrolled in behavioral therapies are unable to achieve significant periods of abstinence suggesting other strategies like pharmacotherapy are needed.

Objectives

This experiment determined the physiological and subjective effects of acutely administered intranasal methamphetamine during atomoxetine maintenance in seven non-treatment seeking stimulant-dependent participants. Atomoxetine was chosen for study because it blocks reuptake at the norepinephrine transporter and increases extracellular dopamine levels in the prefrontal cortex. In this way, atomoxetine might function as an agonist replacement therapy for stimulant-dependent patients.

Methods

After at least 7 days of maintenance on atomoxetine (0 and 80 mg/day), participants were administered ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) across two experimental sessions. Intranasal methamphetamine doses were separated by 90 min.

Results

Intranasal methamphetamine produced prototypical physiological and subjective effects (e.g., increased heart rate, blood pressure, temperature and subjective ratings of Good Effects). Atomoxetine maintenance augmented the heart rate-increasing effects of methamphetamine, but attenuated the pressor effects. The subjective effects of intranasal methamphetamine were similar during atomoxetine and placebo maintenance.

Conclusions

These results suggest that methamphetamine can be safely administered to participants maintained on atomoxetine, but whether it might be an effective pharmacotherapy for methamphetamine dependence remains to be determined.     

Conditioned reinforcing effects of capsules associated with high versus low monetary payoff

The ability of a placebo drug capsule to serve as a conditioned reinforcer as a function of being paired with money reinforcement was evaluated. Volunteers were administered two differently colored capsules that presumably contained two different drugs. Although the volunteers were told they might contain a stimulant, sedative, or placebo, both capsules contained only a placebo. During sessions, volunteers participated in performance tasks. The tasks were programmed so that following one capsule, the amount of money obtained contingent upon responding was greater (high frequency of reinforcement) than following the other capsule (low frequency of reinforcement). During experiment 1, participants were exposed twice each to the two reinforcement conditions (sampling). During sessions 6–8, no tasks were done but participants were allowed to choose which capsule they preferred. During these choice sessions, 9 of 12 participants chose the capsule associated with the high frequency of reinforcement 2 or 3 times. Experiment 2 was designed to explore further whether the differential mood effects observed during sampling sessions could be conditioned. Although this could not be demonstrated, the self-administration results demonstrating the control of choice behavior even in the absence of pharmacological effects suggest that drugs may function as conditioned reinforcers. This finding has implications for broadening our understanding of the determinants of initiation and continued drug use.The opinions expressed by the authors do not necessary reflect those of the United States Government. The authors would like to thank Ed Bunker, Brenda Campbell, Anne Gupman, and William Rea for their technical and statistical assistance. Portions of these data were presented as a poster at the 56th annual meeting of the College on Problems of Drug Dependence in June 1994     

The influences of ethanol and other factors on the excretion of urinary salsolinol in social drinkers

Salsolinol, a substance that may participate in the development of alcoholism, has been identified in urine and other biological samples from alcoholics. Differentials have been observed between alcoholics and controls. Salsolinol forms when dopamine reacts with acetaldehyde, which may exist in higher concentrations in the blood of alcoholics after alcohol ingestion. Hence, it was postulated that there is a relationship between level of social drinking and the elaboration of salsolinol. Salsolinol is also found in certain food and beverage products. Eighty volunteers, balanced for gender, social drinking level, ethanol dose administered and experimental diet provided urine samples 90 minutes and three hours after ethanol was consumed. Salsolinol levels were analysed in urine using high performance liquid chromatography. A 24 hour carryover effect was observed. Diet, ethanol dose and social drinking level had main and interactive effects on excreted quantities of salsolinol. Gender, situational stress and cigarette smoking had minor if any influence on salsolinol excretion. While there was no evident difference in amounts of salsolinol excreted by light and heavy drinkers in the absence of external sources of salsolinol, heavy social drinkers excreted less salsolinol than did light drinkers after consuming a "salsolinol-enriched" diet, suggesting that they differ in some aspect of absorption, distribution, or metabolism of salsolinol after drinking ethanol. Accordingly, studies that attempt to determine whether salsolinol has any relationship to drinking behaviour in humans should be particularly concerned with salsolinol that occurs in exogenous sources.     

Reinforcing and subjective effects of oral Δ9-THC and smoked marijuana in humans

The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.     

Discriminative stimulus and subjective effects of smoked marijuana in humans

The discriminative stimulus (DS) effects of smoked marijuana were studied by training marijuana smokers to discriminate between the effects of marijuana containing 2.7% ⁹-THC (M) and marijuana containing 0.0% ⁹-THC (P). In addition to measures of discrimination responding, subjective effects were assessed with standardized mood questionnaires. The post-smoking increase in expired air carbon monoxide (CO) level was used as an index of smoke inhalation. Relative to P cigarettes, M cigarettes increased heart rate and produced changes on eight mood scales. M cigarettes were rated as harsher and more potent than P cigarettes, and produced lower levels of CO than P cigarettes. The P-M discrimination was readily acquired by most subjects. The DS effects of marijuana showed a rapid onset, appearing within 90 s from the beginning of smoking. The DS effects were dose dependent, with 0.9% ⁹-THC marijuana producing primarily placebo-appropriate discrimination responding, and 1.4% ⁹-THC marijuana producing 100% drug-appropriate responding. This experimental paradigm could be used to determine whether the DS effects of smoked marijuana would generalize to those of other psychoactive drugs. Offprint requests to: L.D. Chait     

Effects of naltrexone pretreatment on the subjective and performance effects of ethanol in social drinkers

Clinical trials suggest that opioid antagonists may be effective in the treatment of alcoholism. For example, two recent clinical trials reported that alcoholics treated with the opioid antagonist naltrexone exhibited higher abstinence rates, decreased craving and a decrease in the amount of alcohol consumed if drinking occurred. The present study examined the hypothesis that naltrexone pretreatment would attenuate the behavioral responses to an acute dose of ethanol in normal, healthy social drinkers. Thirteen healthy male and female social drinkers participated in a six-session, double-blind, placebo-controlled, crossover design study. On each session, subjects ingested a capsule containing naltrexone (25 or 50mg) or placebo and one hour later consumed a beverage containing ethanol (0.5g/kg) or placebo. For three hours after the beverage was consumed, breath alcohol levels were measured and subjects completed standardized subjective effects questionnaires and performance tasks at regular intervals. Ethanol alone produced its prototypic effects, including positive subjective responses such as euphoria and increased ratings of overall liking, as well as increased ratings of confusion. Ethanol also impaired performance on a verbal recall task. Naltrexone alone produced few subjective effects and did not impair psychomotor or verbal recall performance. Contrary to our hypothesis, pretreatment with naltrexone did not alter the positive subjective effects, or any other effects, of ethanol. Further research is needed to determine the influence of factors such as baseline level of ethanol consumption or duration of naltrexone treatment on the interaction between ethanol and the endogenous opioid system.     

Effect of ethanol self-administration on choice behavior: money vs. socializing.

Volunteer chronic alcoholic subjects were exposed to a discrete-trail choice procedure within a residential research setting. Twelve daily trials occurred at 20 min intervals. In each trial a subject chose between 2 mutually exclusive options involving either receipt of money or the opportunity for socializing. The effect of ethanol self-administration was evaluated by requiring randomly over days that a subject consume either 8 drinks of orange juice or 8 drinks of ethanol (89.12 g ethanol total). For all 4 subjects, the mean rate of choosing socialization over money was significantly greater on sessions involving ethanol self-administration than on sessions involving orange juice self-administration.     

Assessment of effects of ethanol self-administration on social interactions in alcoholics

Five volunteer chronic alcoholics participated in an experiment in which the availability or non-availability of a daily ration of 12 ounces (360 ml) of 95-proof ethanol (133.68 g ethanol) was randomly determined. For all subjects, rates of social interaction were significantly higher on ethanol days than non-ethanol days. The study demonstrates the feasibility of using complex molar units of human behavior as dependent variables in behavioral pharmacology research.Supported by USPHS research grant AA-00179 from NIAAA.     

The discriminative stimulus and subjective effects of d-amphetamine in humans

Seventeen normal, healthy adults were trained to discriminate between orally administered d-amphetamine (AMP; 10 mg) and placebo. Standardized subjective effects questionnaires were used to examine the relationship between the subjective and discriminative stimulus effects of AMP. Seven of the subjects were able to learn the discrimination reliably. These seven discriminators did not differ from the ten nondiscriminators in their subjective ratings of mood in the absence of drug. Discriminators were generally more sensitive than nondiscriminators to the subjective effects of AMP, although this difference in sensitivity reached statistical significance only for ratings of hungry. Stimulus substituion was tested in the discriminators with other doses of AMP (2.5 and 5 mg) and with 10 mg diazepam. The discriminative stimulus properties of AMP were dose-dependent, with 5 mg being the threshold dose. In five of the seven subjects the discriminative stimulus properties of diazepam did not substitute for those of AMP. The results demonstrate that the experimental paradigm can be used successfully to study the discriminative stimulus properties of drugs directly in humans.     

Discriminative stimulus and subjective effects of theobromine and caffeine in humans

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.