William W. Stoops

Aripiprazole Attenuates the Discriminative-Stimulus and Subject-Rated Effects of D -Amphetamine in Humans

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie ⩾80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Reinforcing, subject-rated, performance and physiological effects of methylphenidate and d-amphetamine in stimulant abusing humans

Methylphenidate has potential for abuse because it produces behavioural effects similar to those observed with other abused stimulants, such as d-amphetamine and cocaine. The aim of this study was to further characterize the abuse potential of oral methylphenidate relative to oral d-amphetamine. Ten drug-abusing volunteers were recruited to participate in this study, which consisted of seven dose conditions: methylphenidate (16, 32 and 48 mg), d-amphetamine (8, 16 and 24 mg) and placebo. The reinforcing effects of these drugs were assessed during a self-administration session (preceded by a sampling session for each condition) with a modified progressive-ratio procedure. Subject-rated, performance and physiological effects were assessed concurrently during both the sampling and self-administration sessions. The intermediate dose of methylphenidate and d-amphetamine increased responding significantly above placebo levels. Both methylphenidate and d-amphetamine produced dose-dependent increases in stimulant-like subject ratings (e.g. Active, Alert, or Energetic and High), but the effects of these drugs were not isomorphic. These findings are consistent with epidemiological data and previous findings from laboratory studies that suggest methylphenidate has at least some abuse potential.

An Internet-based abstinence reinforcement smoking cessation intervention in rural smokers

The implementation of cigarette smoking abstinence reinforcement programs may be hindered by the time intensive burden placed on patients and treatment providers. The use of remote monitoring and reinforcement of smoking abstinence may enhance the accessibility and acceptability of this intervention, particularly in rural areas where transportation can be unreliable and treatment providers distant. This study determined the effectiveness of an Internet-based abstinence reinforcement intervention in initiating and maintaining smoking abstinence in rural smokers. Sixty-eight smokers were enrolled to evaluate the efficacy of an Internet-based smoking cessation program. During the 6-week intervention period, all participants were asked to record 2 videos of breath carbon monoxide (CO) samples daily. Participants also typed the value of their CO readings into web-based software that provided feedback and reinforcement based on their smoking status. Participants (n=35) in the Abstinence Contingent (AC) group received monetary incentives contingent on recent smoking abstinence (i.e., CO of 4 parts per million or below). Participants (n=33) in the Yoked Control (YC) group received monetary incentives independent of smoking status. Participants in the AC group were significantly more likely than the YC group to post negative CO samples on the study website (OR=4.56; 95% CI=2.18-9.52). Participants assigned to AC were also significantly more likely to achieve some level of continuous abstinence over the 6-week intervention compared to those assigned to YC. These results demonstrate the feasibility and short-term efficacy of delivering reinforcement for smoking abstinence over the Internet to rural populations.

Individual and network factors associated with non-fatal overdose among rural Appalachian drug users

BACKGROUND Fatal overdoses involving prescription opioids have increased significantly in recent years in the United States--especially in rural areas. However, there are scant data about non-fatal overdose among rural drug users. The purpose of this study is to examine the prevalence and correlates of non-fatal overdose and witnessed overdose among rural Appalachian drug users. METHODS Rural drug users were participants in a longitudinal study of social networks and HIV transmission. An interviewer-administered questionnaire elicited information in the following domains: sociodemographic characteristics, drug use (including lifetime overdose and witnessed overdose), psychiatric disorders, HIV risk behaviors and social networks (support, drug and sex networks). Negative binomial regression was used to model the number of lifetime overdoses and witnessed overdoses. RESULTS Of the 400 participants, 28% had ever experienced a non-fatal overdose, while 58.2% had ever witnessed an overdose (fatal or non-fatal). Factors independently associated with a greater number of overdoses included having ever been in drug treatment, past 30-day injection of prescription opioids, meeting the criteria for post-traumatic stress disorder and/or antisocial personality disorder and having more members in ones support network. CONCLUSIONS Rural drug users with history of overdose were more likely to have injected with prescription opioids--which is different from urban heroin users. However, the remaining correlates of non-fatal overdose among this cohort of rural drug users were similar to those of urban heroin users, which suggests current overdose prevention strategies employed in urban settings may be effective in preventing fatal overdose in this population.

Cocaine Choice in Humans During D-Amphetamine Maintenance

The results of preclinical laboratory experiments and clinical trials indicate that agonist replacements such as d-amphetamine may be a viable option for managing cocaine dependence. This study determined the effects of d-amphetamine maintenance on cocaine choice behavior in human participants. We predicted that d-amphetamine maintenance would reduce cocaine choice. Nine cocaine-dependent participants completed the study. Two d-amphetamine maintenance conditions were completed in a counterbalanced order (0 and 40 mg/d). After 3 to 5 days of placebo or d-amphetamine maintenance, the participants completed 5 experimental sessions. During these sessions, the participants first sampled the placebo (ie, 4 mg of intranasal cocaine) identified as drug A. The participants then sampled a second intranasal drug dose (4, 10, 20, or 30 mg of cocaine) identified as drug B. The participants then made 6 discrete choices between drugs A and B. Drug choices were separated by 45 minutes. The primary outcome measure was the number of cocaine choices. All doses of cocaine were chosen significantly more than placebo during both maintenance conditions (ie, placebo and d-amphetamine). Choice of the 20-mg dose of cocaine was significantly lower during d-amphetamine maintenance relative to when this cocaine dose was tested during placebo-d-amphetamine maintenance. Cocaine produced prototypical subject-rated drug effects (eg, good effects, like drug, willing to take again). These effects were not altered to a significant degree by d-amphetamine maintenance. Cocaine was well tolerated during d-amphetamine maintenance, and no unexpected or serious adverse events occurred. These results are concordant with those of previous preclinical experiments, human laboratory studies, and clinical trials that suggest that agonist replacement therapy may be a viable strategy for managing cocaine dependence.

Reinforcing, subject-rated, and physiological effects of intranasal methylphenidate in humans: a dose-response analysis

The results of previously published reports suggest that oral methylphenidate has potential for abuse. An increase in insufflation of methylphenidate has been reported recently. To our knowledge, however, there are no published reports that examined the effects of intranasal methylphenidate. The purpose of this experiment was to characterize the reinforcing, subject-rated, and physiological effects of intranasal methylphenidate (0, 10, 20, and 30 mg). Eight volunteers (five males and three females) with recent histories of recreational stimulant use were recruited to participate in this experiment. Drug doses were administered in a double-blind fashion under medical supervision, but for safety purposes they were administered in ascending order. Intranasal methylphenidate increased the crossover point on the Multiple-Choice Questionnaire in a linear fashion, which suggests that intranasal methylphenidate functioned as a reinforcer. Intranasal methylphenidate also produced linear dose-dependent prototypical stimulant-like subjective effects (e.g. increases in ratings of Good Effects and High). Intranasal methylphenidate increased heart rate as a function of dose, but the magnitude of this effect was not clinically significant (i.e. average peak heart rate following administration of the highest dose was less than 82 beats per min). The results of this study suggest that across a range of doses, intranasal methylphenidate produces behavioral effects that are characteristic of abused stimulants. Future studies should test higher doses and directly compare the behavioral effects of intranasal methylphenidate to those of a prototypical abused stimulant (e.g. cocaine).

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination (≥80% drug-appropriate responding on four consecutive sessions), a range of oral doses of methamphetamine (2.5-15 mg), d-amphetamine (2.5-15 mg), methylphenidate (5-30 mg), and triazolam (0.0625-0.375 mg) was tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. d-Amphetamine and methylphenidate produced dose-related increases in methamphetamine-appropriate responding, whereas triazolam did not. d-Amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the Digit-Symbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans.

Alprazolam attenuates the behavioral effects of d-amphetamine in humans.

Abstract: The results of preclinical behavioral pharmacology studies suggest that γ-aminobutyric acidA (GABAA) receptor modulators attenuate the behavioral effects of commonly abused stimulants such as amphetamines and cocaine under a variety of behavioral arrangements including drug discrimination and self-administration. In the present experiment, 6 healthy humans learned to discriminate 15-mg oral d-amphetamine. After acquiring the discrimination (ie, ≥80% correct responding on 4 consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and following pretreatment with alprazolam (0 and 0.5 mg), a GABAA receptor modulator, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (eg, increased scores on a Stimulant-Sensitive Adjective-Rating Scale). These effects were generally a function of dose. Alprazolam alone did not occasion d-amphetamine-like discriminative stimulus effects, nor did it increase ratings of sedation or impair performance. Alprazolam pretreatment significantly attenuated the discriminative stimulus effects of d-amphetamine, and some of the self-reported drug effects. Future human laboratory experiments should compare the behavioral effects of d-amphetamine alone and following pretreatment with alprazolam using other behavioral arrangements such as drug self-administration. Future laboratory experiments with humans should also determine if benzodiazepines with lower abuse potential (eg, oxazepam) might also attenuate the behavioral effects of d-amphetamine.

Cocaine Effects During d-Amphetamine Maintenance: A Human Laboratory Analysis of Safety, Tolerability and Efficacy

Agonist replacement therapies are effective for managing substance abuse disorders including nicotine and opioid dependence. The results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This experiment determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants. We predicted cocaine would be well tolerated during D-amphetamine maintenance. We also predicted D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg, i.n.) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Additional research in humans is needed to determine whether D-amphetamine attenuates the effects of cocaine under different experimental conditions (e.g., higher cocaine doses) and behavioral arrangements (e.g., drug self-administration or discrimination).

Agonist replacement for stimulant dependence: a review of clinical research.

Stimulant use disorders are an unrelenting public health concern worldwide. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. The present paper reviewed clinical data from human laboratory self-administration studies and clinical trials to determine whether agonist replacement therapy is a viable strategy for managing cocaine and/or amphetamine use disorders. The extant literature suggests that agonist replacement therapy may be effective for managing stimulant use disorders, however, the clinical selection of an agonist replacement medication likely needs to be based on the pharmacological mechanism of the medication and the stimulant abused by patients. Specifically, dopamine releasers appear most effective for reducing cocaine use whereas dopamine reuptake inhibitors appear most effective for reducing amphetamine use.