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Previously, we reported that gabapentin, a nonselective gamma-aminobutyric acid agonist, reduced 'positive' subjective effects of cocaine without reducing cocaine self-administration. We speculated that the self-administration procedure used in that study was not sensitive to subtle shifts in the reinforcing effects of cocaine. Thus, this study examined the effects of gabapentin maintenance on cocaine self-administration using a purchase-cocaine choice procedure. During this 48-day inpatient/outpatient study, nontreatment-seeking cocaine abusers (n = 12) were maintained on gabapentin (0, 600, 1200 mg/day); four doses of cocaine (0, 12, 25, 50 mg) were each tested twice under each gabapentin condition. All cocaine testing was conducted while participants were inpatients. Before the start of each session, participants were provided with 25 dollars (five 5 dollar bills, one for each choice opportunity) and smoked the 'sample' cocaine dose once. Subsequently, participants were given five opportunities to purchase the sampled dose of cocaine (at 5 dollars per dose) or to keep 5 dollars for that choice trial. Choice to self-administer cocaine increased significantly with escalating cocaine doses; gabapentin maintenance did not alter choice to self-administer cocaine. These results concur with findings from our previous investigations of gabapentin and with those from a clinical trial examining the effects of larger gabapentin doses on cocaine use by treatment-seeking cocaine-dependent individuals. Together, the data indicate that gabapentin does not show promise as a treatment medication for cocaine dependence.

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.

Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration; yet, this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine whether tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone (0, 5, and 20 mg/70 kg, orally) were compared, using a within-session cumulative dosing procedure, on the first and fifth days of the 'daily' dosing phase to assess for tolerance; active oxycodone was administered on the second and fourth days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the first and the fifth day of a 5-day 'intermittent' dosing phase; placebo medication was administered on the second and fourth days of the intermittent dosing phase. A 9-day 'washout' period occurred between phases during which no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the cold pressor test, pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the first and the fifth days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the fifth compared with the first day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the first and the fifth days of either dosing phase were detected. Although obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug's positive subjective effects related to abuse liability.

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.

Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of cocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective effects of smoked cocaine in humans. To examine whether attenuation of HPA function at the pituitary level reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced order under each pre-treatment condition. Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocorticotrophic hormone and cortisol release. Maximal heart rate following cocaine administration was significantly increased by dexamethasone. However, the subjective effects of cocaine were not affected by dexamethasone pre-treatment. These results extend our earlier findings with humans, indicating that the role of the HPA axis in mediating the effects of cocaine is limited. These data are concordant with findings in non-human primates, but contrast with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans.

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

The availability of alternative reinforcers can reduce drug self-administration. This 21-day residential study investigated the effect of monetary alternatives on marijuana self-administration. Three female and four male participants performed computer tasks (baseline) in the morning before smoking a sample marijuana cigarette (0.0, 1.8, or 3.9% delta 9-tetrahydrocannabinol (THC) and receiving the sample alternative ($5.00 voucher). In the afternoon, participants had five opportunities to choose either the marijuana cigarette sampled earlier or a voucher for $5.00. Participants were required to meet a criterion level of task performance to obtain each choice. The monetary performance criterion varied from day to day (80, 100, or 120% of baseline); the marijuana performance criterion remained constant at 100% of baseline. Choices were delivered in the evening, after task completion. Marijuana choice varied as a function of THC concentration and criterion to earn money. Active marijuana was always chosen more often than placebo, and active and placebo marijuana were chosen over money when the criterion to earn money was high. Task performance improved when criteria were imposed, even after participants had smoked the sample marijuana cigarette. Subjective ratings of drug effects increased with increasing THC concentration, but did not predict choice. The availability of a monetary alternative was effective in shifting choice to self-administer marijuana, and marijuana choice was sensitive to contingency manipulations. The results further indicate that contingency manipulations may override the performance-impairing effects of marijuana observed in other studies.

Seven male research volunteers reporting intravenous cocaine and morphine use participated in 12 cocaine self-administration sessions. A session consisted of sublingual buprenorphine pretreatment (0, 2, 4mg) 50min before seven self-administration trials. The first three trials were sampling trials, in which subjects were given each of the three reinforcers available for that session; the remaining four trials were choice trials in which subjects could choose between two doses of cocaine and tokens exchangeable for special privileges. Each buprenorphine dose was tested for four consecutive days under different cocaine dose/token combinations (e.g. 8mg vs 16mg vs two tokens). Following placebo, under all choice conditions, subjects reliably chose higher doses of cocaine over lower doses, and tokens about as often as high cocaine doses. Buprenorphine (4mg) significantly decreased high-dose cocaine choice and increased token choice, when the available cocaine doses were 16 and 32mg/70kg. Both buprenorphine doses significantly increased ratings of "sedated" and opiate symptoms and decreased ratings of "bad drug effect" following all cocaine doses. Both buprenorphine doses, in combination with cocaine doses greater than 8mg, significantly increased self-reported "high" and occasionally increased "stimulated" scores above values seen following cocaine alone. The results demonstrate that in the presence of non-drug alternative to cocaine (tokens), buprenorphine decreased high-dose cocaine choice. Despite the decrease, subjects were clearly intoxicated from a drug combination that mimicked a cocaine-heroin ("speedball") effect. Although buprenorphine may be useful in reducing cocaine use, the complex relationship between this reduction in use, behavioral alternatives, and the subjective effects of the drug combination remains unclear.

The effect of monetary contingencies on alprazolam self-administration was evaluated in seven male volunteers living in a residential laboratory. Drug administration occurred prior to an afternoon work session (13.00 h), and at the onset of an evening recreation period (17.30 h). On ‘sample’ days, p

The purpose of this study was to examine, in healthy volunteers without histories of extensive sedative use, the acute behavioral effects of doses of alprazolam used in clinical applications. Subjects participated in daily sessions over 12 study days. They consumed a standard breakfast, received an oral drug dose (0, 0.25, 0.5, 1 mg) and completed performance tasks for 3 hours after dosing. Tasks included a digit-symbol substitution task, a repeated-acquisition of response sequences task, a differential reinforcement of low response rate task designed to monitor time estimation, a number recognition task, and a second-order repeated-acquisition of response sequences task. Each active dose was administered prior to two sessions, according to a randomized block design, and placebo sessions separated successive active-dose sessions. With the exception of the second-order repeated acquisition of response sequences task, dose-related changes in performance were observed during all tasks, but effects were significant only following the 1 mg dose. No drug-related changes were observed on visual-analog scale ratings of drug effect. The data indicate that the risk of adverse performance effects following use of alprazolam is related to dose, with risks increasing at doses at or above 0.5 mg.

DN-2327 (pazinaclone) is a new non-benzodiazepine compound which has high affinity for benzodiazepine receptors. The acute behavioral effects and abuse liability of DN-2327 (2, 4 and 8mg) were compared to those of the benzodiazepine anxiolytic alprazolam (0.25, 0.5 and 1mg) in ten normal adult male volunteers using a double-blind, placebo-controlled, outpatient design. For both drugs, the neck effect occurred approximately 1.5h after drug administration. Both drugs also produced comparable dose-related effects on several measures related to sedation, as well as on subject- and observer-rated strength of drug effect. Both alprazolam and DN-2327 produced dose-related impairments on various performance measures; on some tasks, the impairment was greater for DN-2327. In contrast, there were no differences between DN-2327 and alprazolam on observer-rated measures. Although no measures of drug-taking were made in this study, to the extent that self-reported effects predict reinforcing effects, the data suggest little liability for abuse of the two compounds in this subject population. Ratings of 'drug liking' and 'willing to take the drug again' were not increased following alprazolam. Although DN-2327 did not increase ratings of 'willing to take the drug again', DN-2327 did produce small but significant increases on ratings of 'drug liking'. Overall, these results suggest that the non-benzodiazepine DN-2327 has a pharmacological profile that is similar to that of benzodiazepines.

In a study examining the effects of pharmacological manipulations on "demand" for food, responding of six adult male baboons (Papio c. anubis) was maintained under a fixed-ratio schedule of food reinforcement during daily 22h experimental sessions. Increasing the response requirement decreased daily food intake. Administration of anorectic drugs (amphetamine, fenfluramine, diethylpropion, phenmetrazine, phenylpropanolamine and mazindol) produced parallel dose-dependent downward shifts in responding at all response costs. In contrast, administration of the anxiolytic, diazepam, produced parallel dose-dependent upward shifts in responding at all response costs. Oral phencyclidine decreased intake during the first 8h of the session, but compensatory feeding later in the day eliminated this effect. Changes in pellet intake were fitted to a theoretical equation derived by Hursh et al. (1988) to describe changes in demand for a commodity. When responding increases as a result of increasing cost, demand is said to be inelastic, but when responding decreases as a result of increasing cost, demand is said to be elastic. Administration of anorectic drugs, while decreasing maximal intake at minimal cost, had no effect on the elasticity of demand for food. Similarly, diazepam increased maximal intake at minimal cost without affecting the elasticity of demand for food. The effect of anorectic drugs differs from the previously reported effects of caloric substitutes which increase the elasticity of demand for food. Thus, anorectic drugs do not function as caloric substitutes, in an economic sense, for food.

Six subjects, reporting marijuana use between two and 30 times per month, participated in studies of the acute effects of smoked marijuana (0.0%, 2.0% and 3.5% Delta(9)-THC, w/w) on heart rate, ratings of drug effect and task performance. Marijuana was administered using a uniform-puffing procedure with monetary contingencies associated with puff and breathhold duration. In general, heart rate and ratings, of "High" and dose "Potency" were increased by marijuana, and performance on some tasks was altered by drug administration. The relative sensitivity of the measures varied across subjects, and no single measure, such as heart rate or verbal rating of drug effect, could be used to predict the behavioral effects of marijuana. Marijuana puff durations were decreased at the highest dose, but dose-related changes in heart rate and task performance indicated that the change in smoking topography did not result in complete compensation for increased cannabinoid concentrations in marijuana smoke.