Biomedical subjects

Craig R Rush

Publications and source records attributed to Craig R Rush.

33 records · Page 2Linked to original sources

PubMed2004

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

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

Adult↗

PubMed2003

Baclofen does not alter the reinforcing, subject-rated or cardiovascular effects of intranasal cocaine in humans.

RATIONALE: There is evidence from research in animals and humans that the gamma-aminobutyric acid B receptor subtype (GABA(B)) agonist baclofen may have promise as a pharmacotherapy for cocaine addiction. OBJECTIVES: In the present study, the ability of baclofen to modify the reinforcing, subject-rated and cardiovascular effects of intranasal cocaine in humans was determined. METHODS: Non-treatment-seeking volunteers ( n=7) with recent histories of cocaine use were recruited to participate in this placebo-controlled, double-blind study. Baclofen (0, 10, 20 and 30 mg) was administered orally, followed approximately 1.5 h later by intranasal cocaine (4 mg [placebo] and 45 mg). Subject-rated and cardiovascular measures were taken prior to baclofen administration and then at regular intervals after cocaine was administered. The reinforcing effects of cocaine and cocaine-baclofen combinations were assessed using the Multiple-Choice Procedure. RESULTS: Intranasal cocaine significantly increased the crossover point on the Multiple-Choice Procedure relative to placebo, suggesting that this cocaine dose functioned as a reinforcer. This dose of intranasal cocaine also produced increases in subject-rated effects typical of psychostimulants and elevated cardiovascular measures. The time course for the effects of cocaine was consistent with its pharmacokinetic profile following intranasal administration; increases in subject-rated and cardiovascular effects were observed almost immediately following administration and peaked at approximately 30 min. Pretreatment with baclofen had no significant effect alone, nor in combination with cocaine, on any outcome. CONCLUSIONS: These data demonstrated that acute administration of three clinically relevant baclofen doses did not influence the acute behavioral effects of intranasal cocaine in humans.

Administration, Intranasal↗

PubMed2003

Effects of d-amphetamine on behavioral control in stimulant abusers: the role of prepotent response tendencies.

The present study examined the effects of d-amphetamine on the ability to execute and inhibit behavior in a context where preliminary information signaled the likelihood that a response should be executed or suppressed. Eight adults (5 men and 3 women) with a history of stimulant abuse performed a cued go no-go task that required quick responses to go targets and suppression of responses to no-go targets. Performance was tested under four oral doses of d-amphetamine, 0 (placebo), 5, 10 and 20 mg, administered double-blind and in mixed order. d-Amphetamine produced a dose-dependent increase in inhibitory failures following invalid go cues and had no effect on inhibitory failures following valid no-go cues. d-Amphetamine had little effect on response execution as measured by reaction time. Subjective and physiological effects of d-amphetamine were also observed. The findings demonstrate that stimulant effects on fundamental aspects of behavioral control can be mediated by environmental cues that alter response tendencies. Identification of environmental conditions in which stimulants are likely to disinhibit behavior could provide insight into mechanisms that underlie the association between long-term stimulant use and poor impulse control.

Adult↗

PubMed2003

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

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

Administration, Intranasal↗

PubMed2003

Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans.

Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., > or = 80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D2 dopamine and 5-hydroxytryptamine (5-HT)2 serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of d-amphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drug-discrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D2 dopamine (e.g., haloperidol) or 5-HT2 serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/dependence.

Adolescent↗

PubMed2003

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).

Adult↗

PubMed2003

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.

Adult↗

PubMed2003

Discriminative-stimulus effects of triazolam in light and moderate drinkers.

BACKGROUND: The results of previous laboratory experiments with humans suggest that light and moderate drinkers respond differentially to the effects of benzodiazepines. The aim of this study was to further assess the behavioral effects of a benzodiazepine in light and moderate drinkers. METHODS: To accomplish this aim, 12 volunteers (6 light drinkers and 6 moderate drinkers) learned to discriminate 0.375 mg of triazolam, a triazolobenzodiazepine hypnotic. After they learned this discrimination, a test-of-novel-doses phase was conducted in which a range of doses of triazolam (0, 0.06, 0.125, 0.25, and 0.375 mg) was tested in both groups of volunteers. The subject-rated and performance-impairing effects of triazolam were assessed concurrently. RESULTS: There was not a significant difference between the groups in terms of the number of trials needed to learn the discrimination, nor did the proportion of light and moderate drinkers who learned to accurately discriminate 0.375 mg of triazolam differ significantly. The discriminative-stimulus, subject-rated, and performance-impairing effects of triazolam were an orderly function of dose but did not differ across the light and moderate drinkers. CONCLUSIONS: Future studies should examine the discriminative-stimulus effects of a lower dose of triazolam (e.g., 0.25 mg) in light and moderate drinks or use a fading procedure to determine differences in terms of the lowest discriminable dose.

Adult↗

PubMed2003

Alcohol choice and amphetamine effects in light and moderate drinkers.

BACKGROUND: The results of previously published reports suggest that light and moderate drinkers respond differently to the effects of commonly abused sedatives (e.g., diazepam or ethanol). The purpose of this experiment was to determine whether light and moderate drinkers respond differentially to the effects of ethanol and d-amphetamine. METHODS: In the first phase of this experiment, volunteers (eight light drinkers and eight moderate drinkers) randomly sampled 0.5 g/kg of ethanol and placebo across two separate sessions. In the second phase, volunteers completed three sessions in which they chose either ethanol or placebo. In the third phase, volunteers received 0, 5, 10, and 15 mg of d-amphetamine. Each dose was tested twice. After drug administration in each phase, volunteers completed a battery of subject-rated, performance, and physiologic measures periodically for 5 hr. RESULTS: Ethanol produced prototypical subject-rated effects (e.g., increased ratings on the Alcohol Sensation Scale), but it was chosen over placebo infrequently. Light and moderate drinkers did not differ in terms of the self-reported or reinforcing effects of ethanol. d-Amphetamine produced prototypical subject-rated stimulant-like effects (e.g., dose-dependent increases in ratings of High and Rush). Moderate drinkers reported significantly greater drug effects than light drinkers. Responses to ethanol reliably predicted subsequent responses to d-amphetamine on several measures. CONCLUSIONS: The results of this experiment suggest that even moderate ethanol use may increase an individual's vulnerability to abuse drugs. Future studies should determine whether light and moderate drinkers respond differentially to other commonly abused drugs (e.g., opioids) and whether behavioral responses to ethanol also predict responses to these compounds.

Adult↗

PubMed2003

Clinical neuropharmacology of drugs of abuse: a comparison of drug-discrimination and subject-report measures.

Advances in molecular pharmacology and behavioral science have helped elucidate the structure and function of the central nervous system and its relationship to behavior and has sparked the development of pharmacological agents that have increasingly selective and potent effects with fewer adverse side effects. The sensitivity and predictive validity of the two most commonly used methodologies for assessing the neuropharmacological effects of centrally active drugs, subject report of drug effects and drug discrimination, were examined. The sensitivity of the measures was comparable across stimulant, sedative, and opioid drugs. Results with drug-discrimination methodologies were generally consistent with hypothesized neuropharmacological mechanisms across all drug classes, whereas subject reports conformed under more limited testing conditions. Firm conclusions regarding the relative utility of drug-discrimination and subject-report measures for clinical studies of neuropharmacological mechanisms are limited by the small number of studies in which the two methodologies have been tested using identical pharmacological pretreatment manipulations.

Cues↗

PubMed2002

Discriminative-stimulus effects of modafinil in cocaine-trained humans.

Modafinil is a novel stimulant that is effective in the treatment of narcolepsy and excessive daytime sleepiness. In vitro and in vivo neuropharmacological data suggest that the mechanism of action of modafinil is distinct from that of prototypical abused stimulants like cocaine and d-amphetamine. In the present experiment, six human volunteers with recent histories of cocaine use learned to discriminate 150 mg oral cocaine HCL. After acquiring the discrimination (i.e. > or = 80% correct responding on 4 consecutive days), a range of doses of oral cocaine (50, 100, and 150 mg), modafinil (200, 400, and 600 mg), and placebo were tested to determine if they shared discriminative-stimulus and self-reported effects with 150 mg cocaine. Methylphenidate (60 mg) and triazolam (0.5 mg) were included as positive and negative controls, respectively. Cocaine and methylphenidate, but neither modafinil nor triazolam, produced cocaine-like discriminative-stimulus, subject-rated, and cardiovascular effects. The results of the present experiment suggest that cocaine discrimination in humans is pharmacologically specific within and across drug classes.

Adult↗

PubMed2002

Acute effects of oral cocaine on inhibitory control of behavior in humans.

Studies of humans show that individuals with histories of cocaine abuse display reduced inhibitory control over behavioral impulses. The present study tested the effects of oral cocaine on the ability to inhibit behavior in humans. Eight adult volunteers (seven men and one woman) with a history of cocaine abuse participated as in-patient volunteers. Response inhibition and response execution were measured by a stop-signal paradigm using a choice reaction time task that engaged subjects in responding to go-signals when stop-signals occasionally informed them to inhibit the response. Subjects' performance on the task was tested just before and 1 h after a randomized, double-blind administration of 0 mg (placebo), 50, 100, and 150 mg of oral cocaine HCl. Cocaine reduced subjects' ability to inhibit responses to stop-signals. By contrast, no effect of cocaine was observed on the ability to execute responses in terms of their speed and accuracy. Subjective and physiological effects of cocaine were also observed. Together, the findings indicate that acute administration of cocaine can impair the ability to inhibit behavioral responses at doses that do not affect the ability to respond. These findings are important because they identify a specific disinhibiting effect of cocaine that could help explain the documented association between long-term cocaine use and poor impulse control.

Administration, Oral↗

PubMed2002

Impaired inhibitory control of behavior in chronic cocaine users.

This study examined the ability to inhibit and execute behavioral responses in adult cocaine users and in an aged-matched sample with no history of cocaine use. Subjects (n=22) were identified as cocaine users by testing positive for the presence of cocaine or benzoylecgonine in urine-analysis and by self-reported cocaine use. Control subjects (n=22) tested negative in urine-analysis and reported no past cocaine use. Response inhibition and response execution were measured by a stop-signal paradigm using a choice reaction time task that engaged subjects in responding to go-signals when stop-signals occasionally informed them to inhibit the response. Cocaine users displayed significantly poorer ability to inhibit their behavioral responses than did controls. Specifically, cocaine users required more time to inhibit responses to stop-signals and displayed a lower probability of inhibiting their responses. Cocaine users did not differ from controls in their ability to execute responses as measured by their speed and accuracy of responses to go-signals. These findings are important because they identify a specific deficit involving behavioral inhibition that could contribute to cocaine abuse, and explain its association with other disorders of self-regulation, such as ADHD.

Adolescent↗

PubMed2002

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.

Administration, Oral↗

PubMed2002

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

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

Adult↗