Impulsivity and Treatment Outcomes in Individuals with Cocaine Use Disorder: Examining the Gap between Interest and Adherence.

Background: Impulsivity is implicated in the development and maintenance of Cocaine Use Disorder (CUD). Less work has examined impulsivity's role on interest in initiating treatment, treatment adherence, or treatment response. No pharmacotherapies are approved for CUD, so efforts to understand and bolster the effects of psychotherapy are important in guiding and refining treatment. The present study examined the impact of impulsivity on interest in treatment, treatment initiation, treatment adherence, and treatment outcomes in individuals with CUD. Methods: Following the completion of a larger study on impulsivity and CUD participants were offered 14 sessions of (12 weeks) Cognitive Behavioral Relapse Prevention (CBT-RP). Before starting treatment, participants completed seven self-report and four behavioral measures of impulsivity. Sixty-eight healthy adults (36% female) with CUD (aged 49.4 ± 7.9) expressed an interest in treatment. Results: Greater scores on several self-report measures of impulsivity, and fewer difficulties with delayed gratification were associated with increased interest in treatment in both males and females. 55 participants attended at least 1 treatment session, while 13 participants did attend a single session. Individuals who attended at least one treatment session scored lower on measures of lack of perseverance and procrastination. Still, measures of impulsivity did not reliably predict session attendance nor the frequency of cocaine-positive urine samples throughout treatment. Males attended nearly twice as many treatment sessions as females despite nonsignificant associations between impulsivity in males and the number of sessions attended. Conclusions: Greater impulsivity in individuals with CUD was associated with expressing an interest in treatment, but not treatment adherence or response.

Gabapentin increases the abuse liability of alcohol alone and in combination with oxycodone in participants with co-occurring opioid and alcohol use disorder.

BACKGROUND: People who have co-occurring Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) carry a higher risk of adverse outcomes, including drug overdose. Early clinical and preclinical studies suggested that gabapentin may be effective in treating both disorders. The present study was designed to assess the effects of gabapentin on the subjective and physiological effects of oxycodone (OXY) and alcohol (ALC), alone and in combination. METHODS: During an 8-week, inpatient, within-subject, randomized, double-blind, placebo-controlled crossover study, non-treatment seeking participants (N = 13; 12 M/1F; 44.1 ± 3 years of age) with OUD and AUD were maintained on oral morphine (120 mg daily). Under gabapentin (1800 mg/day) and placebo (0 mg/day) maintenance, participants completed nine separate test sessions (three sessions per week) during which they received an oral solution containing 0, 15, or 30 mg/70 kg OXY in combination with 0, 0.5, or 0.75 g/kg ALC. During test sessions, subjective effects and physiological responses were assessed repeatedly on 100-mm visual analog scales (VAS). The primary outcome variable was the VAS rating of drug liking after receiving the drug challenge. RESULTS: Alcohol alone (but not oxycodone alone) produced dose-related increases in several positive subjective responses, including drug liking. Gabapentin significantly increased drug liking when given in combination with ALC and OXY + ALC (p < 0.05). Gabapentin did not clinically compromise respiration or other vital functions. CONCLUSIONS: Gabapentin may increase the abuse liability of ALC and OXY + ALC in those with co-occurring OUD and AUD.

A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study.

Efforts to translate sub-anesthetic ketamine infusions into widespread clinical use have centered around developing medications with comparable neurobiological activity, but with attenuated psychoactive effects so as to minimize the risk of behavioral toxicity and abuse liability. Converging lines of research, however, suggest that some of the psychoactive effects of sub-anesthetic ketamine may have therapeutic potential. Here, we assess whether a subset of these effects - the so-called mystical-type experience - mediates the effect of ketamine on craving and cocaine use in cocaine dependent research volunteers. We found that ketamine leads to significantly greater acute mystical-type effects (by Hood Mysticism Scale: HMS), dissociation (by Clinician Administered Dissociative States Scale: CADSS), and near-death experience phenomena (by the Near-Death Experience Scale: NDES), relative to the active control midazolam. HMS score, but not the CADSS or NDES score, was found to mediate the effect of ketamine on global improvement (decreased cocaine use and craving) over the post-infusion period. This is the first controlled study to show that mystical-type phenomena, long considered to have therapeutic potential, may work to impact decision-making and behavior in a sustained manner. These data suggest that an important direction for medication development is the identification of ketamine-like pharmacotherapy that is selectively psychoactive (as opposed to free of experiential effects entirely), so that mystical-type perspectival shifts are more reliably produced and factors lending to abuse or behavioral impairment are minimized. Future research can further clarify the relationship between medication-occasioned mystical-type effects and clinical benefit for different disorders. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial.

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

The role of human drug self-administration procedures in the development of medications.

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

Effects of amphetamine, dexfenfluramine, diazepam, and other pharmacological and dietary manipulations on food "seeking" and "taking" behavior in non-human primates.

RATIONALE: Feeding consists of appetitive or foraging behavior followed by consummatory behavior. OBJECTIVES: To determine if pharmacological manipulations can differentially affect appetitive and consummatory aspects of food intake, and to compare these results to those obtained using naturalistic dietary manipulations. METHODS: Responding of baboons was studied using a schedule of reinforcement that simulated food "seeking" and food "taking." Responding during the seeking component was reinforced by stimuli paired with food, while responding during the taking component was reinforced with food. The effects of intramuscular amphetamine (AMPH), dexfenfluramine (DFEN), diethylpropion (DEP), phencyclidine (PCP), diazepam (DZP), as well as caloric prefeeding and acute food deprivation were determined. RESULTS: AMPH decreased food taking and increased food seeking, DEP decreased food taking without affecting food seeking, DFEN and PCP decreased both food taking and food seeking, while DZP increased both food taking and food seeking. Caloric prefeeding decreased food taking and increased food seeking, i.e., resembled AMPH, while acute deprivation increased both food taking and food seeking, i.e., resembled DZP. CONCLUSIONS: Manipulations that increase dopamine turnover, such as AMPH, increase food seeking, while decreasing food intake. In contrast, manipulations that increase serotonin turnover, such as DFEN, decrease both food seeking and food taking.

Effects of acute smoked marijuana on complex cognitive performance.

Although the ability to perform complex cognitive operations is assumed to be impaired following acute marijuana smoking, complex cognitive performance after acute marijuana use has not been adequately assessed under experimental conditions. In the present study, we used a within-participant double-blind design to evaluate the effects acute marijuana smoking on complex cognitive performance in experienced marijuana smokers. Eighteen healthy research volunteers (8 females, 10 males), averaging 24 marijuana cigarettes per week, completed this three-session outpatient study; sessions were separated by at least 72-hrs. During sessions, participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% Delta(9)-THC w/w), and completed additional cognitive tasks. Blood pressure, heart rate, and subjective effects were also assessed throughout sessions. Marijuana cigarettes were administered in a double-blind fashion and the sequence of Delta(9)-THC concentration order was balanced across participants. Although marijuana significantly increased the number of premature responses and the time participants required to complete several tasks, it had no effect on accuracy on measures of cognitive flexibility, mental calculation, and reasoning. Additionally, heart rate and several subjective-effect ratings (e.g., "Good Drug Effect," "High," "Mellow") were significantly increased in a Delta(9)-THC concentration-dependent manner. These data demonstrate that acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users.

Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans.

The effects of oral flupenthixol and intramuscular (i.m.) flupenthixol decanoate in combination with intravenous (i.v.) cocaine were evaluated in male cocaine abusers. Participants resided at an inpatient research unit for 27 days followed by an 11-day outpatient period. Oral flupenthixol (2.5 or 5.0 mg; p.o.) followed by flupenthixol decanoate (10 or 20 mg; i.m.) and placebo were investigated in individuals who were randomly assigned to one of three groups under double-blind conditions (placebo, low or high dose flupenthixol). During the inpatient period, participants had four fixed cocaine dosing sessions; each session they were administered four doses of i.v. cocaine (approx. 48 mg/70 kg), spaced 14 min apart. These sessions occurred once before medication (baseline phase), once following oral medication (oral phase), and twice following intramuscular medication (IM phase). Out of 23 participants, 18 completed the study; 4 of the 5 non-completers were in the high dose flupenthixol group. Overall, there were few subjective, cardiovascular, or cocaine pharmacokinetic differences between the placebo group and the low dose flupenthixol group, indicating that the low dose of flupenthixol was well tolerated, but ineffective. In the high dose flupenthixol group, two out of seven individuals (29%) experienced a dystonic reaction following oral flupenthixol and were medically discharged. Taken together, these findings indicate that flupenthixol is not a good candidate for treating cocaine abusers.

Methamphetamine self-administration by humans.

RATIONALE: Methamphetamine abuse has become increasingly problematic. Yet, the reinforcing effects of methamphetamine in humans have not been systematically evaluated. OBJECTIVE: To characterize methamphetamine's reinforcing effects in human research participants under controlled laboratory conditions. METHODS: Eight healthy research volunteers (one female, seven males) completed this 20-day residential study. On days 1, 5, 9, 13 and 17, at 1000 hours, participants received the "sample" oral dose of methamphetamine (0, 5, 10 mg) that was available for the next 3 days and they also received an alternative reinforcer, a $1 voucher (redeemable for cash at study's end). Over a 3-day period, volunteers participated in an eight-trial choice procedure, during which they had the opportunity to self-administer the dose of methamphetamine they most recently sampled or to receive the $1 voucher. RESULTS: Participants' choice to self-administer methamphetamine significantly increased when active methamphetamine (5 mg and 10 mg) was available compared to placebo. No difference of choice was noted between low-dose and high-dose methamphetamine. However, the sampled 10 mg methamphetamine dose significantly increased several "positive" subjective ratings including "High," "Good Drug Effect," and "Stimulated," whereas the sampled 5 mg methamphetamine dose did not. Both active methamphetamine doses caused significant reductions in daily total caloric intake, relative to the respective placebo conditions. CONCLUSION: These data demonstrate that oral methamphetamine is a positive reinforcer in humans.

Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans.

RATIONALE: Data obtained in laboratory animals and humans suggest that dopamine D1 receptor antagonists decrease cocaine self-administration and block cocaine's discriminative stimulus and subjective effects. OBJECTIVES: This study investigates the effects of the selective dopamine D1 antagonist, ecopipam (SCH 39166), on the reinforcing, cardiovascular, and subjective effects of cocaine in humans. METHODS: Ten non-treatment-seeking cocaine smokers (two females, eight males), residing on an inpatient research unit, were maintained on placebo and ecopipam (100 mg p.o.) in random order using a within-subjects, cross-over design. Cocaine self-administration (0, 12, 25, and 50 mg) was tested beginning on the 5th day of each 8-day maintenance condition. A six-trial choice procedure (cocaine vs $5 merchandise vouchers) was utilized, with sessions consisting of one sample trial, when participants smoked the cocaine dose available that day, and five choice trials, when participants chose between smoking the available cocaine dose or receiving one merchandise voucher. RESULTS: In the presence of placebo cocaine, ecopipam significantly decreased cocaine craving while increasing alcohol and tobacco craving. In the presence of active cocaine, ecopipam increased cocaine self-administration (12 mg) and increased ratings of "good drug effect," "high," "stimulated," and dose quality (25 and 50 mg). Ecopipam produced small but significant increases in blood pressure, regardless of cocaine dose. CONCLUSIONS: Maintenance on the long-acting dopamine D1 antagonist, ecopipam, enhanced both cocaine self-administration as well as its subjective effects compared to maintenance on placebo. These data suggest that chronic antagonism of the dopamine D1 receptor may not be a useful approach for the treatment of cocaine abuse.

Effects of repeated oral methamphetamine administration in humans.

RATIONALE: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. OBJECTIVES: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. METHODS: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4-6 and 10-12; placebo was administered on all other study days. RESULTS: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. CONCLUSIONS: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

Location preference related to smoked heroin self-administration by rhesus monkeys.

RATIONALE: Although common in humans, little is known about the reinforcing efficacy of smoked heroin in laboratory animals. OBJECTIVES: To evaluate the reinforcing efficacy of smoked heroin in non-opioid dependent, non-human primates. METHODS: Self-administration and location-preference measures were obtained by having monkeys live in two chambers with heroin self-administration (0, 0.3, 0.6 mg/kg; eight dosings available per day) specific to one chamber and no commodity available in the other chamber. Operant responding reinforced by smoked heroin provided a self-administration measure of reinforcement, and the length of time monkeys spent in the heroin-associated chamber provided a location preference estimate of reinforcing efficacy. RESULTS: Four of six monkeys acquired heroin self-administration: these monkeys completed six to eight smoking trials each day when either of the active heroin doses was available. Urine toxicology confirmed that monkeys were absorbing the smoked heroin. The number of completed smoking trials rapidly decreased under extinction conditions, indicating that smoked heroin was an efficacious reinforcer using the self-administration measure. Monkeys developed a location preference for the chamber where heroin was self-administered, indicating that smoked heroin was an efficacious reinforcer using the location-preference measure. CONCLUSIONS: Smoked heroin is an efficacious reinforcer in non-opioid dependent rhesus monkeys as measured using a self-administration procedure and estimated using a location-preference procedure.

Neuroendocrine effects of d-fenfluramine and bromocriptine following repeated smoked cocaine in humans.

To study the consequences of repeated smoked cocaine use on central serotonergic and dopaminergic function, the effects of d-fenfluramine (d-FEN) and bromocriptine on plasma hormones were determined at three time-points following repeated cocaine self-administration under carefully controlled conditions. In a 20-day inpatient study, male cocaine abusers (d-FEN: n=10; bromocriptine: n=8) self-administered smoked cocaine (12-50 mg) for 3 days followed by 2 weeks of abstinence. The acute effects of d-FEN (0 or 30 mg po) or bromocriptine (0 or 1.25 mg po) on plasma neuroendocrine levels were determined 1-2, 7-8, and 13-14 days after the last cocaine dose. Blood was drawn before and then every 30-60 min for 4 h after capsule administration. The effects of d-FEN and bromocriptine were also determined in healthy, outpatient controls; d-FEN was removed from medical use in the US midway through the study due to complications associated with chronic administration, so all of the control participants were tested in Italy. Cocaine users had a blunted prolactin and cortisol response to d-FEN that lasted for at least 2 weeks of cocaine abstinence, but had a normal response to bromocriptine, which suppressed prolactin by 50% of baseline. The long-lasting and selective disruptions in serotonin pathways following chronic cocaine use may provide a neurochemical basis for changes in mood commonly reported during cocaine withdrawal.

The effects of D-amphetamine on responding for candy and fruit drink using a fixed ratio and a progressive ratio schedule of reinforcer delivery.

The first purpose of this study was to compare the effects of D-amphetamine (AMPH) on operant responding reinforced under fixed ratio (FR) or progressive ratio (PR) schedules of reinforcement, testing the hypothesis that responding reinforced under a PR operant schedule would be disrupted by lower doses of AMPH than responding reinforced under a FR operant schedule. The second purpose of this study was to test the generalizability of the first hypothesis by comparing the effects of AMPH on responding reinforced by two different reinforcers under both FR and PR operant schedules. Rhesus monkeys had five to six candy and five to six fruit drink sessions per day, and could receive two reinforcers per session. Responding was initially reinforced under a PR procedure, such that the ratio size increased with each subsequent session. The parameters of the PR schedule were individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day. The effects of oral AMPH (0.5, 0.75, 1.0 mg/kg) on responding were assessed. Responding was then stabilized using a FR schedule with parameters individually selected so that monkeys consumed a similar number of candy and fruit-drink reinforcers each day, and the effects of oral AMPH were again assessed. The PR breakpoint was significantly greater for candy than fruit-drink. AMPH produced dose-related decreases in both candy and fruit-drink intake, but each AMPH dose decreased the number of fruit-drink deliveries to a greater extent than the number of candy deliveries. The results failed to support the hypothesis that responding under PR schedules of reinforcement would be disrupted by lower doses of AMPH.

Bupropion SR worsens mood during marijuana withdrawal in humans.

RATIONALE: Symptoms of withdrawal after daily marijuana smoking include increased ratings of irritability and depression. Similar mood symptoms are reported by cigarette smokers during nicotine abstinence. OBJECTIVE: Given the successful use of sustained-release bupropion in treating nicotine dependence, this study investigated how maintenance on bupropion influenced symptoms of marijuana withdrawal compared to maintenance on placebo. METHODS: Marijuana smokers (n=10) were maintained outpatient on active (300 mg/day) or placebo (0 mg/day) bupropion for 11 days, and were then maintained inpatient on the same bupropion dose for 17 days. For the first 4 inpatient days, participants smoked active marijuana [2.8% delta9-tetrahydrocannabinol (THC)] 5 times/day. For the remaining inpatient days, participants smoked placebo marijuana (0.0% THC) 5 times/day. Participants were then maintained outpatient on the alternate dose of bupropion for 11 days, followed by a second inpatient residential stay, paralleling the first. Medication administration was double-blind. Mood, psychomotor task performance, food intake, and sleep were measured daily during each inpatient phase. The order of active and placebo bupropion maintenance was counterbalanced between groups. RESULTS: Bupropion had few behavioral effects when participants smoked active marijuana. During placebo marijuana smoking, i.e., active marijuana withdrawal, ratings of irritability, restlessness, depression, and trouble sleeping were increased by bupropion compared to placebo maintenance. CONCLUSIONS: These data suggest that bupropion does not show promise as a potential treatment medication for marijuana dependence.

Alternative reinforcers differentially modify cocaine self-administration by humans.

Six experienced cocaine smokers (two men, four women) participated in an inpatient study to compare self-administration of smoked cocaine when either a $5 money or merchandise voucher was available as an alternative reinforcer. A six-trial choice procedure was used, with sessions consisting of (1) one sample trial, where participants received the cocaine dose and the alternative reinforcer available that day, and (2) five choice trials, where participants chose between the available cocaine dose and the alternative reinforcer. There were eight sessions: in separate sessions, each dose of cocaine (0, 12, 25, 50 mg) was paired with a money voucher and with a merchandise voucher. The choice to self-administer cocaine significantly increased with escalating cocaine doses, and significantly less cocaine was self-administered when money vouchers were available as compared to merchandise vouchers. These data demonstrate that money vouchers are a more effective alternative reinforcer than merchandise vouchers in cocaine abusers.

Conditioned effects of environmental stimuli paired with smoked cocaine in humans.

RATIONALE: Clinical data suggest that stimuli paired with cocaine use acquire emergent stimulus effects, such as the ability to elicit cocaine craving. OBJECTIVES: The purpose of this study was to determine the conditioned effects of neutral stimuli paired with cocaine smoking. METHODS: Eight experienced adult cocaine smokers participated in 22 experimental sessions while residing on a Clinical Research Center. One set of cues (CS-) was paired with placebo smoked cocaine and one set of cues (CS+) was paired with 25 mg smoked cocaine. RESULTS: After 18 training trials, the effects of cocaine on heart rate and ratings of "anxious" were greater, and skin temperature and ratings of "tired" were smaller when compared to the effects of cocaine after the first training trial. When instructed to select a cue to experience after training, seven of eight participants selected the CS+, while only three of the participants selected the CS+ prior to training, i.e., the CS+ functioned as a conditioned reinforcer. Presentation of the CS+ alone without cocaine during extinction trials increased HR, SP, and ratings of "anxious" "tired", and "I want cocaine" and decreased skin temperature. These changes elicited by presentation of the CS+ decreased over the course of the extinction sessions. CONCLUSIONS: The present results indicate that classical conditioning is one mechanism by which stimuli paired with cocaine acquire emergent stimulus effects.

Effects of amphetamine on food and fruit drink self-administration.

The effects of oral d-amphetamine (0.12-1.0 mg/kg) on the responding of adult baboons were examined during choice sessions. In Experiment 1, responding on 1 lever was reinforced with 1 food pellet, and responding on a 2nd lever was reinforced with 4 food pellets. The response requirement (fixed ratio [FR]) on the latter lever was 4 times the FR value; that is, the unit price (responses/g) was the same. Amphetamine decreased responding on both levers similarly under all conditions. In Experiment 2, responding on 1 lever was reinforced with 1 pellet, and responding on a 2nd lever was reinforced with a sweet fruit drink. Amphetamine decreased responding reinforced by food to the greatest extent when the FR value was large and fruit drink was available. Findings indicate that choice procedures can provide baselines that allow the evaluation of the specificity of a manipulation on intake of a commodity.

Food and cocaine self-administration by baboons: effects of alternatives.

The effects of the availability of an alternative reinforcer on responding maintained by food pellets or drug solutions were examined in 8 adult male baboons (Papio hamadrayas anubis). During daily 23-hr experimental sessions, baboons had access to both food pellets and fluid under a two-choice procedure, in which the response requirement, under a fixed-ratio schedule, differed for the two commodities. There were no restrictions on access to water, which was continuously available from a spout at the rear of each cage. In Experiment 1, the fixed-ratio requirement, or cost, for fluid delivery remained constant while the fixed-ratio requirement for pellets was changed every 2 or 3 days when (a) no fluid, (b) a dilute dextrose vehicle, (c) 0.008 mg/kg per delivery cocaine, (d) 0.016 mg/kg per delivery cocaine, or (e) 0.032 mg/kg per delivery cocaine was available concurrently. In Experiment 1, progressively increasing the response requirement for pellets decreased pellet intake, but for 4 baboons pellet intake at maximum pellet cost was lower when cocaine, compared to the vehicle, was available. Increasing the response requirement for pellets had variable effects on vehicle intake. However, increasing the response requirement for pellets increased intake of at least one dose of cocaine to a greater extent than vehicle in all 8 baboons. Thus, cocaine could be considered a more effective economic substitute than vehicle for pellets. Experiment 2 systematically varied the order in which the response requirements for a pellet delivery were presented and added a control condition in which cocaine doses, yoked to the amount self-administered, were given three times during the session by the experimenter. Again, pellet intake at maximal pellet cost was lower when cocaine, compared to the vehicle, was available. In contrast, experimenter-given cocaine doses did not alter responding maintained by pellets. Thus, the effects of self-administered cocaine on responding maintained by food pellets differed from the effects of experimenter-given cocaine on responding maintained by food pellets.

Limited sex differences in response to "binge" smoked cocaine use in humans.

The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively). The most striking sex difference was that women had higher cocaine plasma concentrations than men (632.7 ng/ml vs. 376.7 mg/ml) after the sixth cocaine dose of the first session. After the first cocaine dose, women reported that they would spend significantly less for the dose than men ($1.58 vs. $3.15). Although cocaine produced similar effects in men and women 4 min after each dose, 15 min after the last dose of the session, heart rate and blood pressure remained elevated in women, but ratings of "I want cocaine" were lower in women as compared to men. Thus, smoking cocaine produced similar acute subjective effects in men and women, but prolonged cardiovascular effects and higher cocaine plasma concentrations in women.