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

The discriminative stimulus (DS) and subjective effects of two anorectic drugs, phenylpropanolamine (PPA) and mazindol (MAZ), were studied in a group of normal, healthy adults trained to discriminate between placebo and 10 mg d-amphetamine (AMP). Of 20 subjects who underwent discrimination training, 12 (discriminators) reliably learned the AMP-placebo discrimination. Each discriminator was tested with two doses of PPA (25 and 75 mg) and two doses of MAZ (0.5 and 2.0 mg) to determine whether the DS effects of these drugs would substitute for those of AMP. The high dose of each drug produced primarily (approximately 80%) drug-appropriate responding, whereas the low dose of each drug resulted in primarily placebo-appropriate responding. The subjective effects of PPA were a biphasic function of dose, with 25 mg producing mild sedative-like effects and 75 mg producing stimulant-like effects similar to, but weaker than, those obtained with AMP. MAZ, on the other hand, produced only a few changes in mood (increased anxiety, decreased hunger). Thus, although both PPA and MAZ substituted for AMP in terms of discrimination responding, only PPA produced AMP-like subjective effects. These results provide evidence for a dissociation between the subjective effects (as measured by self-report questionnaires) and the DS effects of drugs in humans.     

Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers

The discriminative stimulus (DS) and subjective effects of caffeine (100 and 300 mg, PO) and benzphetamine (12.5 and 50 mg, PO) were studied in 18 normal human volunteers trained to discriminate between d-amphetamine (10 mg) and placebo. d-Amphetamine increased ratings of drug liking and activity level and produced a profile of subjective effects characteristic of amphetamine and related psychomotor stimulants. The DS effects of d-amphetamine generalized only partially to caffeine and benzphetamine; mean percent d-amphetamine-appropriate responding was 42 and 58 after 100 and 300 mg caffeine, respectively, and 17 and 56 after 12.5 and 50 mg benzphetamine, respectively. Neither dose of caffeine affected ratings of drug liking or activity level, but 300 mg caffeine did produce a profile of subjective effects that partially overlapped with that produced by d-amphetamine. Benzphetamine 50 mg, but not 12.5 mg, increased ratings of drug liking and activity level and produced a profile of subjective effects qualitatively similar to, but weaker than, that produced by d-amphetamine. For both caffeine and benzphetamine, a close relationship was observed between their subjective effects and their ability to substitute for the DS effects of d-amphetamine. These results correspond well with findings obtained from similar studies conducted with laboratory animals, providing further support for the reliability and validity of human drug discrimination paradigms.     

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

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

Discriminative stimulus and subjective effects of theobromine and caffeine in humans

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

Interaction of expectancy and the pharmacological effects ofd-amphetamine: subjective effects and self-administration

The study examined the effects of expectation on the subjective effects and oral self-administration of 15 mgd-amphetamine (AMP) and placebo in 40 volunteers who reported no prior use of stimulants other than caffeine. A balanced placebo design was used to create four groups: told Placebo/got Placebo (P/P), told Placebo/got Stimulant (P/S), told Stimulant/got Placebo (S/P), told Stimulant/got Stimulant (S/S). There were three sessions. On one session (INFO), participants received a capsule containing AMP or placebo and were given information about the contents of the capsule according to the balanced placebo design. On another session (NO INFO), participants received no information about the capsule's contents and were given placebo. On the final session, participants were allowed to choose either the INFO or NO INFO capsule. Participants came to the laboratory to ingest their capsules, and then returned to their normal environments where they completed subjective effects questionnaires every 2 h for 8 h. Expectancies influenced the subjective effects reported during the INFO session, regardless of whether subjects actually received AMP or placebo: subjects who expected a stimulant had higher ratings of feel drug and like drug. The pharmacological effects of AMP were also evident on the INFO sessions: AMP produced its prototypic subjective effects regardless of subjects' expectancies. Significant interactions between drug and expectancy were obtained on self-report measures of anxiety and arousal: anxiety was higher for groups who received substances that did not match their expectations (P/S and S/P) and arousal increased most in volunteers who expected placebo but received stimulant. Choice of drug was determined primarily by pharmacology: participants who received AMP on the INFO session usually chose that capsule, regardless of information about its identity (P/S: 8/10; S/S: 9/10). In contrast, participants who received placebo on the INFO session chose this capsule at chance levels, regardless of information about its identity (S/P: 3/10; P/P: 6/10). Thus, expectancy influenced some of the subjective effects of AMP and placebo, but the pharmacological effects of the AMP were instrumental in determining whether volunteers would self-administer the drug.     

Discriminative stimulus effects ofd-amphetamine,methylphenidate, and diazepam in humans

Eight male community volunteers, who reported current psychomotor stimulant use, were trained to discriminate between the presence and absence of orally administered d-amphetamine 30 mg. During daily experimental sessions, in which a single drug dose or placebo was tested, physiological and subjective measures were assessed and subjects indicated their discrimination by responding on an operant color-tracking procedure. During four test of acquisition sessions, discriminative responding indicated that all subjects learned the discrimination, and d-amphetamine produced physiological and subjective effects typical of psychomotor stimulants. Generalization testing then followed in which dose-response curves were determined for the following drugs: d-amphetamine (3.75, 7.5, 15 and 30 mg), diazepam (5, 10, 20 and 40 mg), and methylphenidate (7.5, 15, 30 and 60 mg). d-Amphetamine and methylphenidate produced dose-related increases in d-amphetamine-appropriate responding, whereas no dose of diazepam substituted for d-amphetamine in any subject. d-Amphetamine and methylphenidate produced a similar pattern of subjective changes, including increased ratings of euphoria and drug liking and decreased sedation. In contrast, diazepam increased subjective scales of sedation and dysphoria. These results are consistent with similar studies testing animals and humans and demonstrate the utility of human drug discrimination research as an integral component of drug abuse liability testing.     

Effects of the NMDA antagonist memantine on human methamphetamine discrimination

Abstract Rationale. The discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. Objective. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Methods. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Results. Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. Conclusion. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects. Electronic Publication     

Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers

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

Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats

The discriminative stimulus (DS) properties ofd-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N=8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0–5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.     

Effects of alprazolam, caffeine, and zolpidem in humans trained to discriminate triazolam from placebo

This study compared the discriminative stimulus effects of zolpidem, a nonbenzodiazepine hypnotic, to benzodiazepines. Eight participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. The discriminative stimulus effects, self-reported subjective effects, and performance effects of triazolam (0.05-0.35 mg/70 kg), alprazolam (0.25-1.75 mg/70 kg), zolpidem (2.5-35 mg/70 kg) and caffeine (75-525 mg/70 kg) were assessed under two-response and novel-response drug discrimination procedures. Under the two-response procedure, triazolam, alprazolam and zolpidem fully substituted for triazolam and caffeine did not. Under the novel-response procedure, triazolam and alprazolam substituted for triazolam and zolpidem partially substituted for triazolam. Zolpidem, but not triazolam or alprazolam, also produced some novel responding. Caffeine produced both placebo-appropriate and novel responding. The self-reported effects of triazolam, alprazolam and zolpidem were similar. Overall, zolpidem produced similar, but not identical, effects as the benzodiazepines.     

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents

Rationale: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. Objectives: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3′-, 4′-, 3′,4′′- and 4′,4′′-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. Methods: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. Results: All of the compounds displaced [³H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([³H]nisoxetine) and serotonin ([³H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [³H]pirenzepine binding to muscarinic M₁ receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2–3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate IP saline from 29 μmol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4′-Cl-BZT, the cocaine discriminative-stimulus effects were shifted leftward by co-administration of the present BZT analogs. Conclusions: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers. Electronic Publication     

Transdermal nicotine maintenance attenuates the subjective and reinforcing effects of intravenous nicotine, but not cocaine or caffeine, in cigarette-smoking stimulant abusers.

The effects of transdermal nicotine maintenance on the subjective, reinforcing, and cardiovascular effects of intravenously administered cocaine, caffeine, and nicotine were examined using double-blind procedures in nine volunteers with histories of using tobacco, caffeine, and cocaine. Each participant was exposed to two chronic drug maintenance phases (21 mg/day nicotine transdermal patch and placebo transdermal patch). Within each drug phase, the participant received intravenous injections of placebo, cocaine (15 and 30 mg/70 kg), caffeine (200 and 400 mg/70 kg), and nicotine (1.0 and 2.0 mg/70 kg) in mixed order across days. Subjective and cardiovascular data were collected before and repeatedly after drug or placebo injection. Reinforcing effects were also assessed after each injection with a Drug vs Money Multiple-Choice Form. Intravenous cocaine produced robust dose-related increases in subjective and reinforcing effects; these effects were not altered by nicotine maintenance. Intravenous caffeine produced elevations on several subjective ratings; nicotine maintenance did not affect these ratings. Under the placebo maintenance condition, intravenous nicotine produced robust dose-related subjective effects, with maximal increases similar to the high dose of cocaine; nicotine maintenance significantly decreased the subjective and reinforcing effects of intravenous nicotine. The results of the present study demonstrate that chronic nicotine maintenance produces tolerance to the effects of intravenous nicotine, but does not affect the subjective or reinforcing effects of cocaine or caffeine.     

Individual differences in humans responding under a cocaine discrimination procedure: discriminators versus nondiscriminators

Twenty-six cocaine-abusing volunteers were trained to discriminate cocaine (80 mg/70 kg, p.o.) from placebo. On the basis of a discrimination acquisition criterion (i.e., >80% drug-appropriate responding for 4 consecutive sessions within 8-10 sessions), 18 participants were classified as discriminators (Ds) and 8 as nondiscriminators (NDs). Relative to Ds, NDs reported a greater amount of cocaine use per time. During the training phase, NDs showed significantly lower ratings than Ds on a stimulant ratings scale, regardless of the training drug condition. During the test-of-acquisition phase, cocaine-induced increases in scores on ratings of drug strength, anxious-nervous and cocaine high, as well as on a euphoria ratings scale, were significantly greater in Ds than NDs, relative to placebo. These results suggest that drug use history, general arousal level, and drug sensitivity may be important variables influencing the acquisition of cocaine versus placebo discrimination in cocaine abusers.     

The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man.

1 The effects of two doses of delta 9THC (2.5 and 10 mg), delivered by paced smoking of herbal cigarettes, on CNV magnitude, subjective mood ratings and heart rate were studied in 20 subjects. 2 There were highly significant interactions between drug dosage and Extraversion and Neuroticism scores, so that the direction and degree of response to the different doses of delta 9THC depended on the personality characteristics of the subjects. 3 The effects of 9 mg delta 9THC and placebo, delivered in herbal cigarettes smoked naturally, on smoking behaviour, subjective mood ratings, measures of autonomic activity and auditory and visual cortical evoked responses were compared in 12 subjects. 4 Smoking behaviour, subjective 'high' rating and elevation of heart rates were the most significant discriminators between drug and placebo. The latency of some of the components of the visual evoked responses was also increased by delta 9THC. 5 There was a significant correlation between the effects of delta 9THC on skin conductance reactivity and the basal (pre-drug) level, reactivity increasing after drug in subjects with low basal reactivity and decreasing in those with high basal levels. 6 Both experiments provided clear evidence of dose-dependent biphasic stimulant and depressant actions of delta 9THC on both subjective and objective measures, and these effects were influenced by the personality and the starting state of the subjects.     

Effects of captopril and enalapril on electroencephalogram and cognitive performance in healthy volunteers

Objective: Captopril and enalapril have been reported to influence cognitive functions and quality of life in hypertensive patients. Methods: The effects of captopril (12.5 mg and 25 mg) and enalapril (5 mg and 10 mg) administered during 7-day periods on electroencephalogram (EEG), cognitive functions, and subjective assessments were investigated in healthy males. Results: Neither captopril nor enalapril influenced EEG and cognitive functions compared with placebo. Captopril 12.5 mg decreased subjective activity compared with placebo. Enalapril did not alter subjective ratings. Both systolic and diastolic blood pressure were significantly lower after administration of captopril 25 mg, whereas blood pressure was unaffected by enalapril compared with placebo. Conclusion: Our results suggest that central effects of captopril and enalapril were minor and not constant in young healthy men. Received: 21 September 1998 / Accepted in revised form: 1 February 1999     

A role for corticotropin releasing factor (CRF) in ethanol consumption,sensitivity, and reward as revealed by CRF-deficient mice

Abstract Rationale. The alcohol discriminative stimulus has been extensively studied in animals and demonstrated to be pharmacologically complex. In contrast, however, the alcohol stimulus has been less frequently studied in humans. Objectives. The aim of the experiments reported here was to characterise pharmacologically an alcohol discriminative stimulus in social drinkers. Methods. Volunteers were first trained to discriminate a dose of 0.2 g/kg alcohol from placebo, using an established method. We then investigated the generalisation response and subjective effects following a range of doses of the γ-amino-butyric acid (GABA)_A benzodiazepine-receptor agonist lorazepam (0, 0.5, 1 and 2 mg, PO). Results. Low doses of lorazepam (0.5 and 1 mg) did not cross-generalise with the alcohol stimulus and produced only minimal subjective effects. However, a dose of 2 mg lorazepam substituted (60.8%) for the stimulus (P<0.02) and increased subjective ratings of "lightheaded" (P<0.05). Conclusions. These results are consistent with the pre-clinical literature and indicate the cross-species generality of the GABA_A component of the alcohol discriminative stimulus. Electronic Publication     

Discriminative stimulus properties of (+/-)-3,4-methylenedioxymethamphetamine and (+/-)-3,4-methylenedioxyamphetamine in pigeons

Pigeons trained to discriminate (+)-amphetamine (AMPH) from saline in a two-key food-maintained drug discrimination paradigm, were used to investigate the discriminative stimulus (DS) effects of two structural analogues of amphetamine, namely (+/-)-3,4-methylenedioxymethamphetamine (MDMA) and (+/-)-3,4-methylenedioxyamphetamine (MDA). After discrimination performance was stable (90% injection-appropriate responding), test sessions with various doses of AMPH were conducted and a dose-dependent relationship for AMPH-appropriate responding was obtained. Both MDMA (3.0 mg/kg) and MDA (3.0 or 5.6 mg/kg) substituted for AMPH; however, at these doses MDA produced a greater decrease in response rate compared to AMPH and MDMA. Furthermore, while MDMA and MDA were similar in potency in producing drug-appropriate responding, both were less potent than AMPH. These results indicate that MDMA and MDA have DS effects similar to AMPH in pigeons.     

A low dose alcohol drug discrimination in social drinkers: relationship with subjective effects

RATIONALE: Although well characterised in animals, relatively little is known about alcohol discriminative stimulus effects in humans. OBJECTIVE: The study was carried out to investigate the correspondence of subjective effects and the discriminative response during the acquisition of a low dose alcohol discrimination in humans. METHODS: Healthy volunteers completed an Alcohol Use Questionnaire and were then trained to discriminate a dose of 0.2 g/kg alcohol from placebo using a money reinforced technique. Subjects sampled drinks during training, but also completed rating scales measuring Taste, Like/Dislike and Subjective Effects for each drink. RESULTS: Thirty-two subjects learned the discrimination (discriminators; Ds). In these subjects, differences between placebo scores and alcohol scores for Lightheadedness, Relaxed, Arousal and Fatigue were greater following acquisition of the discrimination, compared with differences at the start of training. Differences in other measures remained consistent. Twenty-six of the volunteers failed to learn the discrimination (non-discriminators; NDs). These subjects reported drinking approximately twice as much alcohol during the preceding 6 months, as the Ds (4.35+/-0.53 g/kg per week versus 2.08+/-0.19 g/kg per week, respectively, P<0.001). There were no alcohol specific differences in ratings for Lightheadedness, Relaxed, Arousal or Fatigue between the Ds and the NDs. However, Dislike scores did differentiate between the Ds and the NDs in that the NDs had reduced ratings for the alcohol drink only compared with the Ds (P<0.02). CONCLUSIONS: These results support the suggestion from animal studies, that the alcohol stimulus is a compound, and characterise the subjective effects which contribute to a low dose cue in humans. In addition, the data suggest that previous drinking experience may selectively alter aversive responses to alcohol and that this, in addition to differences in general arousal levels, may have affected subjects' ability to learn the discrimination.     

Assessment of pharmacokinetics and pharmacodynamic effects related to abuse potential of a unique oral osmotic-controlled extended-release methylphenidate formulation in humans

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.