Drug Effects Questionnaire Research Articles

Impact of Intravenous Naltrexone on Intravenous Morphine-Induced High, Drug Liking, and Euphoric Effects in Experienced, Nondependent Male Opioid Users

Background: Opioid analgesics can be abused by crushing followed by solubilization and intravenous injection to attain rapid absorption. Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, MS-sNT), indicated for management of chronic, moderate to severe pain, contain pellets of morphine sulfate with a sequestered naltrexone core. Should product tampering by crushing occur, the sequestered naltrexone is intended for release to reduce morphine-induced subjective effects.Objective: This study compared self-reports of high, euphoria, and drug-liking effects of intravenous morphine alone versus intravenous morphine combined with naltrexone in a clinical simulation of intravenous abuse of crushed MS-sNT.Methods: This single-center, randomized, double-blind, crossover study characterized subjective effects of naltrexone administered intravenously at the same ratio to morphine present in MS-sNT. Subjects were male and had used prescription opioids five or more times within the previous 12 months to get ‘high’ but were not physically dependent on opioids. The primary outcome was the response to the Drug Effects Questionnaire (DEQ) question #5, “How high are you now?” (100mm Visual Analog Scale [VAS]). The secondary outcome was the response to a Cole/Addiction Research Center Inventory (ARCI) Stimulation-Euphoria modified scale. Additional outcomes included resonse to VAS drug liking, the remaining DEQ questions, and pupillometry.Results: Administration of intravenous naltrexone following intravenous morphine diminished mean high (29.8 vs 85.2 mm), Cole/ARCI Stimulation-Euphoria (13.7 vs 27.8 mm), and drug-liking (38.9 vs 81.4 mm) scores (all p < 0.0001) compared with intravenous morphine alone. No serious adverse events occurred as a result of the tested ratio of naltrexone to morphine.Conclusions: Results in this study population suggest that naltrexone added to morphine in the 4% ratio within MS-sNT mitigates the high, euphoria, and drug liking of morphine alone, potentially reducing the attractiveness for product tampering. Assessment of the true clinical significance of these findings will require further study.

Impact of Intravenous Naltrexone on Intravenous Morphine-Induced High, Drug Liking, and Euphoric Effects in Experienced, Nondependent Male Opioid Users

Background: Opioid analgesics can be abused by crushing followed by solubilization and intravenous injection to attain rapid absorption. Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, MS-sNT), indicated for management of chronic, moderate to severe pain, contain pellets of morphine sulfate with a sequestered naltrexone core. Should product tampering by crushing occur, the sequestered naltrexone is intended for release to reduce morphine-induced subjective effects. Objective: This study compared self-reports of high, euphoria, and drug-liking effects of intravenous morphine alone versus intravenous morphine combined with naltrexone in a clinical simulation of intravenous abuse of crushed MS-sNT. Methods: This single-center, randomized, double-blind, crossover study characterized subjective effects of naltrexone administered intravenously at the same ratio to morphine present in MS-sNT. Subjects were male and had used prescription opioids five or more times within the previous 12 months to get ‘high’ but were not physically dependent on opioids. The primary outcome was the response to the Drug Effects Questionnaire (DEQ) question #5, “How high are you now?” (100mm Visual Analog Scale [VAS]). The secondary outcome was the response to a Cole/Addiction Research Center Inventory (ARCI) Stimulation-Euphoria modified scale. Additional outcomes included resonse to VAS drug liking, the remaining DEQ questions, and pupillometry. Results: Administration of intravenous naltrexone following intravenous morphine diminished mean high (29.8 vs 85.2 mm), Cole/ARCI Stimulation-Euphoria (13.7 vs 27.8 mm), and drug-liking (38.9 vs 81.4 mm) scores (all p < 0.0001) compared with intravenous morphine alone. No serious adverse events occurred as a result of the tested ratio of naltrexone to morphine. Conclusions: Results in this study population suggest that naltrexone added to morphine in the 4% ratio within MS-sNT mitigates the high, euphoria, and drug liking of morphine alone, potentially reducing the attractiveness for product tampering. Assessment of the true clinical significance of these findings will require further study.

Comparison of the Behavioral and Cardiovascular Effects of Intranasal and Orald-Amphetamine in Healthy Human Subjects

Recent reports indicate an increase in intranasal use of prescription oral stimulant medication. However, there do not appear to be any published clinical studies that have characterized the behavioral and cardiovascular effects of intranasally administered d-amphetamine, which is commonly prescribed for Attention Deficit Hyperactivity Disorder. In this study, a range of d-amphetamine doses (0, 16, 24, and 32 mg/70 kg) were administered as an intranasal solution delivered using a mucosal atomization device. Equal oral doses were included for comparison. Assessments were conducted before and at regular intervals for 3 hours following drug administration and included self-reported drug-effect questionnaires, cardiovascular indices, a performance task, and 2 measures of impulsivity. d-Amphetamine produced prototypical stimulant effects (eg, increased subject ratings of Stimulated and Like Drug, elevated heart rate and blood pressure, and improved rate and accuracy on the digit symbol substitution task) irrespective of dose, but the onset of these effects was generally earlier following intranasal administration, with significant effects emerging 15 to 30 minutes after intranasal dosing and 45 to 60 minutes after oral dosing. These results demonstrate that intranasal administration of d-amphetamine results in a more rapid onset compared to oral dosing, which could be associated with the popularity of intranasal prescription stimulant use and an enhanced potential for abuse.

Rewarding, Stimulant, and Sedative Alcohol Responses and Relationship to Future Binge Drinking

Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse. To prospectively assess the relationship of acute alcohol responses to future binge drinking. Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses. Participants recruited from the community. High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n = 104) and light drinker controls (n = 86). We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520). Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Timeline Follow-Back, Drinker Inventory of Consequences-Recent, and DSM-IV alcohol abuse and dependence. Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence. The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems. clinicaltrials.gov Identifier: NCT00961792.

Reinforcing effects of d-amphetamine

Progressive-ratio schedules are useful for studying the reinforcing effects of drugs. Earlier human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We used novel response requirements in a modified progressive-ratio procedure and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d-amphetamine (0, 8, 16, and 24 mg). In subsequent sessions, the participants were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure, and cardiovascular measures were included to more fully characterize the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d-Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. These data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between the number of placebo and d-amphetamine capsules earned.

Influence of Verbal Recall of a Recent Stress Experience on Anxiety and Desire for Cocaine in Non-Treatment Seeking, Cocaine-Addicted Volunteers

It has long been postulated that stress increases the risk of drug abuse and relapse. The principal goal of this project was to evaluate the effects of verbal recall of a recent stress experience (specifically meaningful to each individual) on physiological and subjective measures in cocaine-addicted participants. Subjects described a recent stressful non-drug-related experience and a neutral non-stressful experience, and then completed mood and drug effect questionnaires, while heart rate and blood pressure were recorded. Participants (N = 25) were predominantly African American and male. As a group, participants used cocaine for more than 15 years and approximately 18 of the last 30 days, and a majority reported use of nicotine and/or alcohol. All participants were evaluated during a time in which they tested positive for cocaine metabolite. On a scale of 1-10, participants reported their verbal recall of a recent stress event as highly stressful and their verbal recall of a recent neutral event as non-stressful (p < 0.0001). The self-reported vividness of this recall was high (>8 out of 10) for both the stress and neutral events. Heart rate and systolic and diastolic blood pressure did not differ after verbal recall of either stress or neutral events. Similarly, self-reported subjective effects (including ratings of anxiety and craving for cocaine) did not differ after verbal recall of either stress or neutral events. In summary, despite the fact that participants recounted highly stressful and vivid memories, this experience did not elicit significant changes in cardiovascular or subjective effects. These data suggest that simply recalling a stressful event may not be a sufficient enough stimulus to contribute to craving or relapse in cocaine-addicted individuals.

Effects of Low to Moderate Acute Doses of Pramipexole on Impulsivity and Cognition in Healthy Volunteers

The neurotransmitter dopamine is integrally involved in the rewarding effects of drugs, and it has also been thought to mediate impulsive behaviors in animal models. Most of the studies of drug effects on impulsive behaviors in humans have involved drugs with complex actions on different transmitter systems and different receptor subtypes. The present study was designed to characterize the effect of single doses of pramipexole, a D2/D3 agonist, on measures of cognitive and impulsive behavior, as well as on mood in healthy volunteers. Healthy men and women (N = 10) received placebo and 2 doses of pramipexole, 0.25 and 0.50 mg, in a within-subject, double-blinded study. Outcome measures included changes in cognitive performance, assessed by the Automated Neuropsychological Assessment Metrics, several behavioral measures related to impulsive behavior, including the Balloon Analogue Risk Task, Delay Discounting Task, Go/No-Go Task, Card Perseveration Task, and subjective ratings of mood assessed by Addiction Research Center Inventory, Profile of Mood States, and Drug Effects Questionnaire. Pramipexole decreased positive ratings of mood (euphoria, intellectual efficiency, and energy) and increased both subjectively reported sedation and behavioral sedation indicated by impaired cognitive performance on several measures of the Automated Neuropsychological Assessment Metrics. Single low to medium doses of this drug did not produce a decrease in impulsive responding on behavioral measures included in this study. The sedative-like effects observed in this study may reflect presynaptic actions of the drug. Higher doses with postsynaptic actions may be needed to produce either behavioral or subjective stimulant-like effects.

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.

Personality and the Subjective Effects of Acute Amphetamine in Healthy Volunteers

Individual differences in the positive mood and other subjective effects of d-amphetamine have been linked to personality traits related to sensation seeking. The current study extends these associations to separate personality traits of reward sensitivity, physical fearlessness, and impulsivity. A total of 128 healthy volunteers received oral doses of d-amphetamine (10 and 20 mg) or placebo in counterbalanced order. Their responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Participants completed the Multidimensional Personality Questionnaire Brief Form to assess personality traits related to reward sensitivity (Agentic Positive Emotionality and Social Potency (SP)), physical fear (Harm Avoidance (HA)), and impulsivity (Control (CL)). Participants were rank ordered on each trait, and individuals with scores in the top and bottom thirds of scores on each trait were compared using ANCOVA. High trait physical fearlessness (low HA) was associated with greater positive activational effects of 10 mg d-amphetamine. High trait reward sensitivity (high SP) was marginally associated with greater positive activational effects of 20 mg d-amphetamine. High trait impulsivity (low CL) was unrelated to positive drug effects in response either dose. The two separate personality traits of physical fearlessness and reward sensitivity are associated with d-amphetamine effects on mood in healthy volunteers. Implications for the vulnerability to psychostimulant addiction in healthy nonaddicts are discussed.

Association between the Casein Kinase 1 Epsilon Gene Region and Subjective Response to D-Amphetamine

Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p=0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p=0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans.

Oxazepam does not modulate the behavioral effects of d-amphetamine in humans

Benzodiazepines, which are γ-aminobutyric acid-A (GABA A) receptor positive modulators, can block the behavioral effects of psychomotor stimulants. In the present study, the ability of oxazepam, which may have less abuse potential compared to some other benzodiazepines, to attenuate the discriminative-stimulus, subject-rated and psychomotor performance effects of d-amphetamine in humans was determined. Six healthy participants (2 female, 4 male) learned to discriminate 15 mg oral d-amphetamine. After acquiring the discrimination (i.e., ≥ 80% correct responding on 4 consecutive days), the effects of d-amphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with acutely administered oxazepam (0 and 20 mg) were assessed. d-Amphetamine alone functioned as a discriminative stimulus, produced stimulant-like subject-rated effects (e.g., increased ratings of Stimulated on a Drug–Effect Questionnaire) and enhanced psychomotor performance. Oxazepam alone increased subject ratings of sedation (e.g., increased ratings of Sluggish, Fatigued and Lazy on a Drug–Effect Questionnaire) and impaired psychomotor performance. Oxazepam alone did not occasion d-amphetamine-like discriminative-stimulus effects, and had no effect on the discriminative-stimulus or subject-rated effects of d-amphetamine when given in combination. The results of this experiment are discordant with previous research and suggest that benzodiazepines differ in their ability to modulate the behavioral effects of d-amphetamine.

Behavioral and physiological effects of cocaine in humans following triazolam

Rationale: Cocaine abuse represents a significant public health problem. Gamma-aminobutyric acid (GABA) agonists may attenuate the behavioral effects of cocaine and may be effective pharmacotherapies for cocaine abuse and dependence. Objectives: The aim of this experiment was to determine the combined effects of oral cocaine (0 and 300 mg) and triazolam (0 and 0.5 mg), a GABA A modulator, in 10 individuals with recent histories of cocaine use. Methods: Volunteers received each of the four possible drug combinations in mixed order. Drug effects were assessed using a battery of subject-rated drug-effect questionnaires and physiological indices. Results: Cocaine alone produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of High, Like Drug, and Willing to Take Drug Again). Triazolam alone produced sedative-like effects (e.g., increased scores on the Pentobarbital, Chlorpromazine, Alcohol Group [PCAG] scale of the Addiction Research Center Inventory [ARCI]). Triazolam pretreatment did not significantly attenuate the subject-rated effects of cocaine. Conclusions: While the results of this study do not support the utility of GABA A modulators as pharmacotherapies for cocaine abuse, future research should test other benzodiazepines (e.g., alprazolam) using more sophisticated methods (e.g., dose–response curves for the drugs alone and in combination) and behavioral arrangements (e.g., drug discrimination).

Differential Effects In Humans After Repeated Administrations Of Zolpidem And Triazolam

Zolpidem, a commonly prescribed hypnotic, is an imidazopyridine that purportedly has a unique benzodiazepine-receptor binding profile. Despite its unique binding profile, human laboratory experiments have generally failed to demonstrate meaningful behavioral pharmacological differences between zolpidem and classic benzodiazepine-receptor agonists like triazolam. In this article, two groups of nondrug-abusing volunteers received 15 mg zolpidem (N=11) or 0.375 mg zolpidem (N=15) on four separate occasions and placebo on two other occasions. In both groups, the order of drug administration was quasi-random. Drug effects were assessed with a battery of laboratory performance tasks and subject-rated drug-effect questionnaires. Zolpidem and triazolam produced prototypical sedative-like effects (e.g., impaired performance, increased subject-ratings of sedation). The performance-impairing effects of triazolam, but not zolpidem, were significantly less after the final administration relative to the initial administration. The subject-rated effects of both zolpidem and triazolam were significantly less after the final administration relative to the initial administration. The results of this experiment suggest that zolpidem and triazolam differ in terms of tolerance-producing effects. Future studies should assess the tolerance-producing effects of zolpidem across a range of doses, as well as other novel sedatives such as zaleplon.

Differential subjective effects of d-amphetamine by gender, hormone levels and menstrual cycle phase

Estrogen and progesterone interact with monoamines in ways that suggest the potential modulation of responses to psychoactive drugs by endogenous steroids, both between menstrual phases and between the sexes. The present study assessed the subjective and physiological effects of a single dose of d-amphetamine (AMPH; 15 mg oral) in healthy, normally cycling women ( n=13), who received amphetamine and placebo (PL) during both the follicular and luteal phases of a single menstrual cycle, and in healthy men ( n=7). Females reported greater amphetamine-induced subjective stimulation [Addiction Research Center Inventory (ARCI)-A, ARCI-MBG; Drug Effects Questionnaire (DEQ) Feel Drug, Feel High, Want More] during the follicular phase than the luteal phase. Within the follicular phase, the magnitude of individuals' AMPH-induced stimulation was positively associated with baseline (predrug) salivary estradiol [ r=+.55–.78; Profile of Mood States (POMS) Vigor, Positive Mood, Elation], and negatively associated with salivary progesterone [ r=−.66–.68; POMS Friendliness; Subjective States Questionnaire (SSQ) Pleasant Sedation]. Sex differences also emerged. Males reported feeling greater AMPH-induced stimulation (ARCI-A, ARCI-MBG; DEQ Feel Drug, Want More) than females in the luteal phase. Thus, higher levels of estrogen and lower levels of progesterone are associated with greater subjective stimulation after AMPH in women, and these hormonal influences contribute to sex differences in amphetamine responding.

Mecamylamine Modifies the Pharmacokinetics and Reinforcing Effects of Alcohol

Central nicotinic cholinergic receptors modify alcohol-induced mesolimbic dopamine activation, which seems to be important in the reinforcing properties of alcohol. Consistent with this model, acute administration to rats of the tertiary nicotinic receptor antagonist mecamylamine blocks both alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens. This study was conducted to test the hypothesis that, during the ascending limb of the blood alcohol concentration curve, mecamylamine would reduce the stimulating and pleasurable effects of an intoxicating dose of alcohol in humans. Ten female and 10 male volunteers with no history of alcohol or substance use disorders, including nicotine dependence, completed the study. During two laboratory sessions, subjects consumed three aliquots of an alcohol-containing drink, with a total ethanol content of 0.7 g/kg (in women) or 0.8 g/kg (in men), over a 30-min period. Two hours before the first drink, subjects were pretreated with mecamylamine or placebo, with the order of sessions counterbalanced. Primary outcome measures included the Drug Effect Questionnaire, the central stimulation subscale of the Alcohol Sensation Scale, and the stimulant subscale of the Biphasic Alcohol Effects Scale. Breath alcohol level (BAL) was examined to identify the ascending and descending limbs of the blood alcohol curve and to assess pharmacokinetic interactions between alcohol and mecamylamine. Significant effects of time, study drug, and their interaction were observed. Compared with placebo, mecamylamine reduced BAL. After controlling for BAL at each time point, mecamylamine also reduced the Drug Effect Questionnaire and Alcohol Sensation Scale stimulant subscale scores, with a trend for a similar effect on the Biphasic Alcohol Effects Scale score. Mecamylamine seems to modify both the pharmacokinetic profile of alcohol and the rewarding effects of alcohol in healthy volunteers.

Sensitization to the cardiovascular but not subject-rated effects of oral cocaine in humans

Background: Despite a substantial nonhuman literature in the area, few studies have experimentally evaluated the effects of repeated stimulant administration in human participants. This study examined the effects of repeated cocaine in individuals with histories of abuse and dependence. Methods: Twenty-two individuals with recent histories of cocaine abuse received under double-blind conditions, in pseudorandom order, four administrations of oral cocaine (150 mg [ n = 14] or 200 mg [ n = 8]) and two administrations of placebo. All administrations were given on separate days. Cardiovascular measures were collected and included heart rate, systolic pressure, diastolic pressure, mean arterial pressure, and pressure rate product. Subject-rated effects were assessed using the Addiction Research Center Inventory (ARCI) and a 15-item drug-effect questionnaire. Results: There were significant differences between placebo days and cocaine days in both cardiovascular and subject-rated effects. Moreover, three of five cardiovascular measures analyzed revealed a significant main effect for day of cocaine administration. A planned follow-up contrast revealed a significant increasing linear trend for each of these variables across days. No significant effects were found for day of administration for the subject-rated items. Conclusions: These results indicate that, under controlled laboratory conditions, repeated oral cocaine administration may result in sensitization to the cardiovascular effects, but not subject-rated effects.

Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in non-drug-abusing humans.

The reinforcing effects of methylphenidate (20-40 mg), d-amphetamine (10-20 mg), and placebo were assessed in eight healthy, non-sleep-deprived, non-drug-abusing outpatient volunteers. A modified progressive-ratio schedule was used to assess drug reinforcement in which a sampling session always preceded a self-administration session. During sampling sessions, volunteers received a drug dose to acquaint them with the drug effects. Drug doses were administered in eight identical capsules (i.e., each capsule contained 12.5% of the total dose). During self-administration sessions, which generally were conducted the next day, volunteers were given eight opportunities to work on a computer and could earn all, or some, of the capsules that were administered the previous day. To earn the first capsule, volunteers had to click a computer mouse 50 times. The number of clicks required to earn each additional capsule doubled (i.e., 100, 200, 400, 800, 1,600, 3,200, and 6,400 clicks). The dependent measure on this task was the break point (i.e., the last ratio completed). To characterize more fully the behavioral effects of methylphenidate and d-amphetamine, a battery of subject-rated drug-effect questionnaires, performance tasks, and physiologic measures was also used. Both doses of d-amphetamine increased the break point significantly above placebo levels, whereas only the high dose of methylphenidate did so. Break-point values for the doses of methylphenidate and d-amphetamine that maintained the greatest responding did not differ significantly. Methylphenidate and d-amphetamine produced some stimulantlike subject-rated drug effects (e.g., increased ratings of "drug liking"). These data suggest that methylphenidate, like d-amphetamine, can function as a reinforcer under a modified progressive-ratio schedule and, by inference, has at least some abuse potential in healthy, non-sleep-deprived, non-drug-abusing volunteers.

Zolpidem and triazolam interact differentially with a delay interval on a digit‐enter‐and‐recall task

Zolpidem (AMBIEN®), an imidazopyridine, is now the most commonly prescribed hypnotic in the United States. Zolpidem is neuropharmacologically distinct from benzodiazepine hypnotics in that it binds with low affinity to α5-containing GABAA-receptor subtypes. Despite its unique benzodiazepine-receptor binding profile, the results of most of the published studies conducted with humans suggest that the absolute magnitude of impairment produced by zolpidem is comparable to that observed with benzodiazepine hypnotics like triazolam. The present study compared the acute effects of zolpidem (0, 7.5, 15 and 22.5 mg) and triazolam (0, 0.1875, 0.375 and 0.5625 mg) in 10 non-drug-abusing humans using a Digit-Enter-and-Recall task with varying delay intervals (0, 10 and 20 s). To more fully characterize the behavioral effects of zolpidem and triazolam, several other performance tasks and subject-rated drug-effect questionnaires were included. Zolpidem and triazolam impaired performance on the Digit-Enter-and-Recall task as a function of dose under all delay intervals. However, the dose-related effects of the drugs interacted differentially with the delay interval such that zolpidem produced significantly less impairment than triazolam following the longest delay (i.e., 20 s). Zolpidem and triazolam produced comparable dose-related impairment on the digit symbol substitution test (DSST), circular lights task, and picture recall/recognition task. Zolpidem and triazolam generally produced qualitatively and quantitatively similar subject-rated drug effects, although some between-drug differences were observed. Consistent with the pharmacokinetics of these drugs, the effects of zolpidem peaked sooner and were shorter in duration than those observed with triazolam. The results of this experiment suggest that zolpidem may have less potential than triazolam to impair recall, which may be due to differences between these compounds in terms of their benzodiazepine-receptor binding profile. The results of the present study are also concordant with previous studies that found that drugs that act at the GABAA-receptor complex can be differentiated based on their interaction with the delay interval on a Digit-Enter-and-Recall task. Copyright © 2001 John Wiley & Sons, Ltd.

Zolpidem and triazolam interact differentially with a delay interval on a digit-enter-and-recall task.

Zolpidem (AMBIEN((R))), an imidazopyridine, is now the most commonly prescribed hypnotic in the United States. Zolpidem is neuropharmacologically distinct from benzodiazepine hypnotics in that it binds with low affinity to alpha(5)-containing GABA(A)-receptor subtypes. Despite its unique benzodiazepine-receptor binding profile, the results of most of the published studies conducted with humans suggest that the absolute magnitude of impairment produced by zolpidem is comparable to that observed with benzodiazepine hypnotics like triazolam. The present study compared the acute effects of zolpidem (0, 7.5, 15 and 22.5 mg) and triazolam (0, 0.1875, 0.375 and 0.5625 mg) in 10 non-drug-abusing humans using a Digit-Enter-and-Recall task with varying delay intervals (0, 10 and 20 s). To more fully characterize the behavioral effects of zolpidem and triazolam, several other performance tasks and subject-rated drug-effect questionnaires were included. Zolpidem and triazolam impaired performance on the Digit-Enter-and-Recall task as a function of dose under all delay intervals. However, the dose-related effects of the drugs interacted differentially with the delay interval such that zolpidem produced significantly less impairment than triazolam following the longest delay (i.e., 20 s). Zolpidem and triazolam produced comparable dose-related impairment on the digit symbol substitution test (DSST), circular lights task, and picture recall/recognition task. Zolpidem and triazolam generally produced qualitatively and quantitatively similar subject-rated drug effects, although some between-drug differences were observed. Consistent with the pharmacokinetics of these drugs, the effects of zolpidem peaked sooner and were shorter in duration than those observed with triazolam. The results of this experiment suggest that zolpidem may have less potential than triazolam to impair recall, which may be due to differences between these compounds in terms of their benzodiazepine-receptor binding profile. The results of the present study are also concordant with previous studies that found that drugs that act at the GABA(A)-receptor complex can be differentiated based on their interaction with the delay interval on a Digit-Enter-and-Recall task. Copyright 2001 John Wiley & Sons, Ltd.

The Abuse Potential of Zolpidem Administered Alone and With Alcohol

The abuse potential of zolpidem, alone and in combination with alcohol, was examined in healthy volunteers with a history of social use of alcohol and drugs. Zolpidem, a short-acting imidazopyridine hypnotic with selectivity for a benzodiazepine receptor subtype (BZ 1 or omega 1), was administered double blind at 0, 10, or 15 mg with alcohol (0.75 g ethanol/kg b.wt.) or with placebo beverage in a randomized, six-way crossover design. Outcome measures included the Drug Effect Questionnaire (DEQ), the Addiction Research Center Inventory (ARCI-40), and the Profile of Mood States (POMS). Blood alcohol concentrations (BACs) were not significantly modified by zolpidem. Relative to placebo, zolpidem and alcohol significantly ( p < 0.05) increased drug strength perception, drug-liking, and drug-disliking scores on the DEQ. On the ARCI-40, zolpidem and alcohol significantly increased sedation/intoxication and dysphoria/fear scores, but did not significantly change euphoria/well-being scores. Zolpidem and alcohol were rated more unfavorably than placebo on the POMS. Alcohol did not have additive effects on the subjective ratings for zolpidem. It is concluded that, for this population and at the doses tested, the abuse potential of zolpidem appears to be modest and not increased by alcohol.