Subject-rated Effects Research Articles

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

Opioid antagonists (eg, naltrexone) and positive modulators of γ-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and "positive" subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone.Eight non-treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected.Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like "positive" subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Safety and tolerability of intranasal cocaine during phendimetrazine maintenance.

Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder. This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment. Ten subjects completed this within-subject, placebo-controlled, inpatient study. Subjects were maintained on ascending oral phendimetrazine doses (0, 70, 140, and 210mg/day). After at least seven maintenance days at each dose, subjects received ascending doses of intranasal cocaine (0, 10, 20, 40, and 80mg), separated by 90min, within one session. Cocaine produced prototypical cardiovascular and subject-rated effects (e.g., increased blood pressure and ratings of like drug). The cardiovascular effects of cocaine alone were not clinically significant for an acute drug response (e.g., average heart rate did not approach tachycardia, 100beats/min). Phendimetrazine enhanced peak heart rate following placebo and low cocaine doses, but these effects were also not clinically significant. Phendimetrazine was otherwise devoid of effects alone and did not alter the subject-rated effects of cocaine or hypothetical demand for cocaine on a purchase task. Cocaine was safe and well tolerated during maintenance on a threefold range of phendimetrazine doses. Given this safety profile, the reduced abuse potential of phendimetrazine and promising preclinical research, future human laboratory studies, and possibly clinical trials should evaluate the efficacy of phendimetrazine for reducing cocaine use.

The relationship between methamphetamine self-administration and subject-rated effects

The relationship between methamphetamine self-administration and subject-rated effects

Influence of buspirone on the cardiovascular and subject-rated effects of methamphetamine

Influence of buspirone on the cardiovascular and subject-rated effects of methamphetamine

Methamphetamine self-administration in humans during D-amphetamine maintenance.

Agonist replacement may be a viable treatment approach for managing stimulant use disorders. This study sought to determine the effects of D-amphetamine maintenance on methamphetamine self-administration in stimulant using human participants. We predicted that D-amphetamine maintenance would reduce methamphetamine self-administration. Eight participants completed the protocol, which tested 2 D-amphetamine maintenance conditions in counterbalanced order (0 and 40 mg/d). Participants completed 4 experimental sessions under each maintenance condition in which they first sampled 1 of 4 doses of intranasal methamphetamine (0, 10, 20, or 30 mg). Participants then had the opportunity to respond on a computerized progressive-ratio task to earn portions of the sampled methamphetamine dose. Subject-rated drug effect and physiological measures were completed at regular intervals prior to and after sampling methamphetamine. Methamphetamine was self-administered as an orderly function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects on 12 items of the drug-effects questionnaires, 8 of which were attenuated by D-amphetamine maintenance (eg, increased ratings were attenuated on items such as Any Effect, Like Drug, and Willing to Take Again on the Drug Effect Questionnaire). Methamphetamine produced significant increases in systolic blood pressure, which were attenuated by D-amphetamine maintenance compared to placebo maintenance. Methamphetamine was well tolerated during D-amphetamine maintenance and no adverse events occurred. Although D-amphetamine attenuated some subject-rated effects of methamphetamine, the self-administration results are concordant with those of clinical trials showing that D-amphetamine did not reduce methamphetamine use. Unique pharmacological approaches may be needed for treating amphetamine use disorders.

Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine

Naltrexone and bupropion, when administered alone in clinical trials, modestly reduce amphetamine use. Whether combining these drugs would result in greater reductions in methamphetamine taking relative to either drug alone is undetermined. This study examined the influence of naltrexone, bupropion and a naltrexone–bupropion combination on methamphetamine self-administration in humans. Seven subjects reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind study in which the reinforcing, subject-rated and physiological effects of intranasal methamphetamine (0, 10 and 30mg) were assessed during maintenance on placebo, naltrexone (50mg), bupropion (300mg/day), and naltrexone combined with bupropion. Methamphetamine maintained responding and produced prototypic subjective and physiological effects (e.g., increased ratings of good effects, elevated systolic blood pressure). Maintenance doses were well tolerated and generally devoid of effects. No maintenance condition reduced methamphetamine self-administration or systematically altered the subject-rated effects of methamphetamine. These outcomes demonstrate the robust behavioral effects of methamphetamine that could make it resistant to pharmacological manipulation. Although these outcomes indicate that this combination may be ineffective for managing methamphetamine use disorder, future work should evaluate longer maintenance dosing, individuals with different levels of amphetamine use, adding this combination to a behavioral platform and other pharmacotherapy combinations for reducing methamphetamine use.

Relations between craving and withdrawal and time to first opioid use among prescription opioid abusers initiating buprenorphine detoxification

whereas tramadol produced positive and negative subject-rated effects. These data suggest that tapentadol has significant abuse potential, at least on the level of hydromorphone. The mixed subject-rated profile of tramadol is consistent with previous findings indicating reduced abuse potential relative to the prototypic opioids. Financial support: Grant R01 DA 025649 (PI: WWS) and Departmental Startup Funds awarded to WWS.

Relationship between intranasal cocaine self-administration and subject-rated effects: predictors of cocaine taking on progressive-ratio schedules.

Subject-rated measures and drug self-administration represent two of the most commonly used methods of assessing abuse potential of drugs, as well as screening intervention efficacy in the human laboratory. Although the results from these methods are often consistent, dissociations between subject-rated and self-administration data have been observed. The purpose of the present retrospective analysis was to examine the relationship between subject-rated effects and intranasal cocaine self-administration to help guide future research design and intervention assessment. Data were combined from two previous studies in which drug and an alternative reinforcer (i.e., money) were available on concurrent progressive-ratio schedules of reinforcement. Pearson correlation coefficients and regression model selection utilizing corrected Akaike information criterion were used to determine which subject-rated measures were associated with and best predicted cocaine self-administration. Eleven subject-rated effects were positively associated with cocaine-maintained breakpoints. A combination of three of these subject ratings (i.e., Like Drug, Performance Improved, and Rush) best predicted cocaine taking. The present findings suggest that, at least under certain conditions with intranasal cocaine, some, but not all, positive subject-rated effects may predict drug self-administration. These findings will be useful in guiding future examinations of putative interventions for cocaine-use disorders.

Influence of aripiprazole pretreatment on the reinforcing effects of methamphetamine in humans

Methamphetamine use disorders remain a significant public health concern. Methamphetamine produces its behavioral effects by facilitating release of monoamines like dopamine (DA) and serotonin (5-HT). Results from animal studies show that acute pretreatment with DA and 5-HT antagonists attenuates the effects of methamphetamine, but this area remains largely unexplored in humans. This study sought to assess whether aripiprazole, a partial agonist at D2/5-HT1A receptors and an antagonist at 5-HT2A receptors, would attenuate the reinforcing and subject-rated effects of oral methamphetamine. Seven subjects with histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 4, 8 or 16 mg) following acute pretreatment with aripiprazole (0 and 15 mg). During each Sampling Session, subjects also completed a battery of subject-rated, cardiovascular, and other performance measures. In subsequent Self-Administration Sessions, subjects were provided the opportunity to earn the previously sampled methamphetamine dose on a progressive-ratio procedure. Methamphetamine functioned as a reinforcer, and produced prototypical stimulant-like subject-rated and cardiovascular effects (e.g., increased ratings of Stimulated; elevated blood pressure). Aripiprazole reduced methamphetamine self-administration and attenuated some of the positive subject-rated effects of methamphetamine (e.g., ratings of Like Drug). These results indicate that acute aripiprazole pretreatment attenuates the abuse-related effects of methamphetamine.

Miotic and subject-rated effects of therapeutic doses of tapentadol, tramadol, and hydromorphone in occasional opioid users

Tapentadol is a novel analgesic that activates mu-opioid receptors and blocks norepinephrine reuptake. There is very little information available regarding the non-analgesic pharmacodynamic effects of tapentadol. This outpatient study evaluated the physiological, subject-rated, and performance effects of therapeutic doses of tapentadol compared to two control drugs in humans. This double-blind, within-subject study examined the effects of oral placebo, tapentadol (25, 50, and 75 mg), tramadol (50, 100, and 150 mg), and hydromorphone (2, 4, and 6 mg). Nine occasional opioid users completed the study. Pharmacodynamic drug effects were measured before and for 6 h after drug administration. All three doses of the tested drugs produced comparable, time-dependent decreases in pupil diameter, but the effects were generally not dose dependent. The high dose of tapentadol, as well as all three doses of tramadol and hydromorphone, increased positive subject-rated effects (e.g., "Good Effects" and "Like the Drug") as a function of time. Only tramadol increased negative subject-rated effects (e.g., "Bad Effects" and "Nauseous"); however, these were of low magnitude. The highest tested dose of tapentadol produced a profile of positive effects comparable to that of hydromorphone, whereas tramadol produced positive and negative subject-rated effects. The mixed findings for tramadol are consistent with previous findings indicating that it has a distinct profile of effects relative to prototypic opioids. Future research should examine the effects of higher tapentadol doses, as well as the factors contributing to the different subject-rated profile of effects observed for tramadol relative to tapentadol and hydromorphone.

Influence of acute bupropion pre‐treatment on the effects of intranasal cocaine

The aim of this experiment was to determine the influence of acute bupropion pre-treatment on subject-rated effects and choice of intranasal cocaine versus money. A randomized, within-subject, placebo-controlled, double-blind experiment. An out-patient research unit. Eight cocaine-using adults. Subjects completed nine experimental sessions in which they were pre-treated with 0, 100 or 200 mg oral immediate release bupropion. Ninety minutes later they sampled an intranasal cocaine dose [4 (placebo), 15 or 45 mg] and made six choices between that dose and an alternative reinforcer (US$0.25), available on independent, concurrent progressive ratio schedules. Subjects also completed a battery of subject-rated, performance and physiological measures following the sample doses of cocaine. After 0 mg bupropion, the high dose of cocaine (45 mg) was chosen five of six times on average compared to 2.25 of six choices for placebo cocaine (4 mg) (P < 0.05). Active bupropion reduced choice of 45 mg cocaine to 3.13 (100 mg) or 4.00 (200 mg) out of six drug choices on average. Bupropion also consistently enhanced positive subject-rated effects of cocaine (e.g. good effects; willing to take again) while having no effects of its own. The atypical antidepressant, bupropion, acutely appears to reduce preference for intranasal cocaine versus a small amount of money but to increase reported positive experiences of the drug.

Discriminative-Stimulus, Subject-Rated, and Physiological Effects of Methamphetamine in Humans Pretreated With Aripiprazole

Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, ≥ 80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine.

Amphetamine Self-Administration in Light and Moderate Drinkers

Light and moderate drinkers respond differently to the effects of abused drugs, including stimulants such as amphetamine. The purpose of this study was to determine whether light and moderate drinkers differ in their sensitivity to the reinforcing and subjective effects of d-amphetamine. We hypothesized that moderate drinkers (i.e., participants that reported consuming at least seven alcohol-containing beverages per week) would be more sensitive to the reinforcing and positive subject-rated effects of d-amphetamine than light drinkers. Data from four studies that employed similar d-amphetamine self-administration procedures and subject-rated drug-effect measures were included in the analysis. Light (n = 17) and moderate (n = 16) drinkers sampled placebo, low (8 to 10 mg), and high (16 to 20 mg) doses of oral d-amphetamine administered in eight capsules. Following sampling sessions, participants worked for a maximum of eight capsules, each containing 12.5% of the previously sampled dose, on a modified progressive-ratio schedule of reinforcement. Both active doses of d-amphetamine functioned as a reinforcer in the moderate drinkers, while only the high dose did so in the light drinkers. The moderate drinkers worked for significantly more capsules that contained the high dose of d-amphetamine than did the light drinkers. d-Amphetamine produced prototypical stimulant-like subjective effects (e.g., dose-dependent increases in ratings of Good Effects; Like Drug and Willing to Take Again). Moderate drinkers reported significantly greater subjective effects than the light drinkers. These results are consistent with those from previous laboratory experiments and suggest that moderate alcohol consumption may increase vulnerability to the abuse-related effects of stimulants.

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.

Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans

Aripiprazole is a dopamine D(2) receptor partial agonist undergoing evaluation as a pharmacotherapy for stimulant-use disorders. Acutely administered aripiprazole attenuates the discriminative stimulus and other behavioral effects of d-amphetamine in humans; however, whether aripiprazole attenuates the effects of more commonly abused stimulants is unknown. The aim of this experiment was to assess the discriminative stimulus, subject-rated and cardiovascular effects of oral cocaine alone and following acute administration of aripiprazole in humans. Eight cocaine-dependent subjects learned to discriminate 150 mg cocaine from placebo. After acquiring the discrimination, the effects of cocaine (0, 25, 50, 100 and 200 mg) administered alone and in combination with aripiprazole (15 mg) were determined. Significant effects of cocaine were observed for the drug discrimination task, stimulant-like subject-rated effects and heart rate. Limited effects of aripiprazole were revealed. However, for most measures, fewer doses of cocaine were significantly greater than placebo when combined with aripiprazole, suggesting a reduction in the discriminative stimulus, self-reported and cardiovascular effects of cocaine. These data are consistent with previous studies that have tested acutely administered aripiprazole in combination with d-amphetamine and suggest that the ability of aripiprazole to modify stimulant effects is a function of the duration of treatment (acute vs. chronic).

Stimulant-induced changes in smoking and caloric intake: Influence of rate of onset

Rate-of-onset modulates the subject-rated effects of stimulants. Results of two studies from our laboratory demonstrate that immediate-release methylphenidate increases smoking and decreases caloric intake. Whether rate-of-onset influences the effects of methylphenidate on smoking and eating is unknown. The present experiment examined the influence of a range of doses of immediate- (7.5–30 mg) and sustained-release (18–72 mg) methylphenidate as well as placebo on smoking and eating. Eight cigarette smokers participated. A double-dummy drug administration procedure was used to maintain the double blind because immediate-release methylphenidate produces peak plasma concentrations 1.5–2 h and the sustained-release formulation produces peak plasma concentrations 6–8 h after oral administration. Smoking and eating were assessed for 4 h across the predicted peak effects of both methylphenidate formulations. Measures of smoking included total cigarettes, puffs, and carbon monoxide levels. Snacks and decaffeinated beverages were available ad libitum and caloric intake was monitored during the four-hour smoking session. Immediate- and sustained-release methylphenidate increased smoking and decreased caloric intake. The effects of methylphenidate generally did not vary as a function of formulation. The results of this study may have important implications for the treatment of disorders that require stimulant medications. Smoking should be monitored in patients that are prescribed stimulant medications, regardless of the formulation type.

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 (> or = 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.

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 30mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60mg, IN) within a single session. Cocaine doses were separated by 90min. 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).

Effects of Potential Agonist-Replacement Therapies for Stimulant Dependence on Inhibitory Control in Cocaine Abusers

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go–no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence.

The Safety, Tolerability, and Subject-Rated Effects of Acute Intranasal Cocaine Administration During Aripiprazole Maintenance II: Increased Aripipirazole Dose and Maintenance Period

Objectives: This experiment determined the safety and tolerability of intranasal cocaine during aripiprazole maintenance. Methods: Six cocaine-dependent human subjects were maintained on aripiprazole (15 mg) and placebo for 10 days in counterbalanced order prior to assessing the physiological and subject-rated effects of intranasal cocaine. Results: Intranasal cocaine produced prototypical stimulant-like effects (e.g., increased blood pressure and heart rate, increased subject ratings of Like Drug and Stimulated), and aripiprazole enhanced these effects on several measures. Conclusions: Aripiprazole (15 mg/day) is safe and tolerable when combined with cocaine; however, the usefulness of aripiprazole as a treatment for cocaine-use disorders remains to be determined.