Craig R. Rush

Behavioral Pharmacology of Zolpidem Relative to Benzodiazepines: A Review

Zolpidem, an imidazopyridine that purportedly binds selectively to certain GABA(A) receptor subtypes, is the most commonly prescribed hypnotic. The present article critically reviewed the extant experimental literature to determine whether the behavioral pharmacologic profile of zolpidem also differs from that of benzodiazepines. Specific topics that are reviewed include: 1) reinforcing effects and abuse potential, 2) discriminative-stimulus effects, 3) subject-rated drug effects, 4) performance-impairing effects, 5) tolerance-producing effects, and 6) physiological dependence-producing effects. Studies that employed both nonhumans and humans are reviewed. Based on the available literature, the most parsimonious conclusion is that despite its unique neuropharmacological profile, the behavioral effects of zolpidem are generally similar to those of benzodiazepines. However, it is important to note the dearth of perspective, experimental studies that directly compared zolpidem and a benzodiazepine. Because of the clinical relevance and paucity of published studies, future research should focus explicitly on assessing the reinforcing effects, abuse potential, performance-impairing effects, tolerance-producing effects, and dependence-producing effects of zolpidem relative to a benzodiazepine. Important issues such as the selection of an appropriate comparison drug and subject population, and the doses tested needed to be considered in these future studies.

Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans

Abstract The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam.

Acute physiological and behavioral effects of oral cocaine in humans: a dose-response analysis

The present study was designed to assess the acute physiological and behavioral effects of a wide range of doses of oral cocaine HCL (placebo, 50, 100, 200, and 300 mg). Nine volunteers (eight males and one female) with recent histories of cocaine use resided on a general inpatient psychiatry unit while they participated. Drug doses were administered in a double-blind fashion under medical supervision, but for safety purposes, they were administered in ascending order. The physiological, subject-rated, and performance effects of oral cocaine HCL were assessed before drug administration and periodically afterwards for 5 h. Oral cocaine HCL increased heart rate and blood pressure as a graded function of dose, but the magnitude of these effects were not clinically significant. Oral cocaine HCL produced positive subject-rated drug effects (e.g. increased ratings of good effects, like drug, and willing to take again), but did not affect performance. Consistent with the pharmacokinetics of oral cocaine HCL, drug effects were generally discernible from placebo 0.5-1 h after administration, peaked approximately 1 h after administration, and progressively abated during the remainder of the experimental session. The results of this experiment demonstrate that across a six-fold range of doses oral cocaine HCL is well tolerated by individuals with recent histories of cocaine use and can be safely administered under controlled laboratory and medical conditions.

Trazodone and triazolam: acute subject-rated and performance-impairing effects in healthy volunteers

Abstract The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone”s and triazolam”s effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of “dizzy”, “excited”, “nervous”, “restless”, “stomach turning” and “itchy skin”. Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse.

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5-15.0 mg), triazolam (0.0625-0.3750 mg), pentobarbital (25-150 mg), caffeine (100-600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines.

Effects of training dose on the relationship between discriminative-stimulus and self-reported drug effects of d-amphetamine in humans.

The aim of the present experiment was to examine the relationship between the discriminative-stimulus and self-reported effects of drugs in humans. To accomplish this aim, nine healthy adult volunteers (four females, five males) were trained to discriminate between placebo and 10 mg d-amphetamine (low-dose group) or 20 mg d-amphetamine (high-dose group). After acquiring the placebo-amphetamine discrimination, a range of doses of d-amphetamine (1.25-20 mg) was tested to determine if they shared discriminative stimulus effects with the training dose. Participants in the low-dose group exhibited a significant leftward shift in the dose-response function for discrimination performance, which is concordant with previous preclinical and human drug discrimination studies that assessed the effects of training dose. Consistent with the drug discrimination findings, participants in the low-dose group exhibited a significant leftward shift in the dose-response function for several self-reported drug effects (e.g., Like the Drug and Stimulated). However, several other self-reported drug effect items were not significantly influenced by training condition (e.g., Anxious/Nervous and Bad Effects). These results suggest that the discriminative-stimulus and self-reported drug effects of d-amphetamine overlap, but are not isomorphic. Furthermore, these results illustrate that behavioral history significantly influences subsequent drug effects in humans.

Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans

The acute behavioural effects of triazolam (0.125 and 0.25 mg), temazepam (15 and 30 mg), and placebo, alone and in combination with ethanol (0 and 0.5 g/kg), were assessed in 10 volunteers. Ethanol alone did not impair performance and produced only a few subject-rated drug effects. Triazolam and temazepam alone produced some performance impairment and a few subject-rated drug effects. These effects tended to be dose-dependent and were comparable for the two drugs across the range of doses tested. The triazolam–ethanol and temazepam–ethanol combinations produced robust performance impairment and sedative-like subject-rated drug effects that were similar in magnitude. The findings of the present study suggest that even a moderate amount of ethanol in combination with a clinical dose of triazolam or temazepam can cause performance impairment that might diminish an individuals ability to respond adequately to unexpected demands (e.g. smoke alarms or middle-of-the-night child care).

Naltrexone does not attenuate the acute behavioral effects of ethanol or pentobarbital in humans.

The aim of the present study was to determine whether naltrexone, an opioid antagonist, attenuates the acute subject-rated, performance-impairing and physiological effects of ethanol or pentobarbital. To accomplish this aim, two separate experiments were conducted. In Experiment 1, eight volunteers (one female, seven males) received ethanol (0, 0.5 and 1.0 g/kg) alone and in combination with naltrexone (0, 50 and 100 mg). In Experiment 2, eight different volunteers (five females, three males) received pentobarbital (0, 150 and 300 mg), alone and in combination with naltrexone (0, 50 and 100 mg). Subjects received one of the nine possible drug-naltrexone combinations under double-blind conditions during each of nine experimental sessions. Order of drug administration was mixed, and at least 48 h separated all sessions. In Experiment 1, subjects orally ingested ethanol 1 h after naltrexone. In Experiment 2, subjects ingested naltrexone 1 h after pentobarbital. The timing of drug administration was arranged so that the peak behavioral effects of ethanol or pentobarbital occurred so that across peak plasma levels of naltrexone. Drug effects were assessed before drug administration and periodically afterwards for 5 h using a battery of subject-rated drug-effect questionnaires and performance measures previously shown to be sensitive to the acute effects of ethanol. Ethanol and pentobarbital produced prototypical subject-rated drug effects (e.g. increased subject ratings of Drunk, Drug Liking, Elated and Good Effects) and impaired performance. Naltrexone did not produce significant effects on these measures. In other words, naltrexone did not attenuate the acute subject-rated and performance-impairing effects of ethanol or pentobarbital. The mechanism by which naltrexone exerts its clinical effect in the treatment of alcohol abuse/dependence remains unclear.

Controlled Laboratory Studies on the Effects of Cocaine in Combination with Other Commonly Abused Drugs in Humans

Publisher Summary Multiple drug use and abuse is well documented among drug abusers in general and cocaine abusers in particular. Multiple drug use among cocaine abusers is a significant public health concern because it is associated with increased morbidity. Data from clinical samples also document high levels of multiple drug use and abuse among cocaine abusers. The study by Higgins and colleagues illustrates the performance effects of cocaine and alcohol, alone and in combination. Controlled laboratory studies that examined the cardio-vascular effects of cocaine alcohol combinations in humans generally support the position that the effects of the drug combination are of larger magnitude than those observed with cocaine alone. This chapter highlights the fact that regular cigarette smoking is more common among cocaine abusers than the general population. Studies suggest that cocaine may increase the reinforcing effects of nicotine, although this effect could be the result of a nonspecific increase in overall activity levels. Experimental results of cocaine-nicotine interactions in humans are sparse, but this chapter elucidates three tentative conclusions. The prevalence of multiple drug abuse among cocaine abusers is striking.

Behavioral Pharmacology of Sedatives, Hypnotics, and Anxiolytics

The purpose of this chapter is to review the behavioral pharmacology and abuse liability of commonly prescribed anxiolytics and hypnotics. More specifically, this chapter reviews the behavioral pharmacology and abuse liability of commonly prescribed benzodiazepines (e.g., alprazolam, diazepam, estazolam, lorazepam, temazepam, and triazolam) and nonbenzodiazepine anxiolytics-hypnotics (e.g., buspirone and zolpidem). The behavioral pharmacology and abuse liability of the benzodiazepines is not exhaustively reviewed since such a review is beyond the scope of this chapter, and comprehensive reviews have previously been published (Woods, Katz, & Winger, 1987, 1992). Instead, this chapter focuses on studies that attempted to determine putative differences between benzodiazepines. This chapter then reviews the behavioral pharmacology and abuse liability of two nonbenzodiazepine compounds marketed for the treatment of anxiety and sleep disorders: buspirone and zolpidem, respectively. Buspirone was the first pyrimidinylpiperazine derivative marketed for the treatment of anxiety disorders, while zolpidem was the first imidazopyridine derivative marketed for the treatment of sleep disorders. Only studies that directly compared these drugs with a benzodiazepine are reviewed in an attempt to determine if these nonbenzodiazepine compounds have an improved abuse liability profile. Both nonhuman and human studies are reviewed.