Physical dependence increases the relative reinforcing effects of caffeine versus placebo

Using a within-subject cross-over design, this study examined the role of physical dependence in caffeine reinforcement by experimentally manipulating physical dependence. Each subject was exposed to two chronic drug phases (300 mg/70 kg/day caffeine and placebo) for 9–12 days, with order of phases counterbalanced across subjects. On 2 separate days immediately following each of the chronic drug exposures, subjects received acute doses of either caffeine (300 mg/ 70 kg) or placebo in counterbalanced order. The reinforcing effects of these drugs were then determined by using a multiple-choice procedure in which subjects made a series of discrete choices between receiving varying amounts of money or receiving the drug again, and a choice between the two drugs. To ensure that subjects completed the form carefully, following exposure to both of the acute drug administrations, one of the subject’s previous choices from the multiple-choice form was randomly selected and the consequence of that choice was implemented. When subjects were maintained on chronic caffeine, they were willing to forfeit significantly more money and showed significant increases in typical withdrawal symptoms (e.g. fatigue, mood disturbance) after receiving placebo as compared to the other three conditions. When subjects were maintained on chronic caffeine, they also chose to receive caffeine over placebo twice as often than when they were maintained on chronic placebo. These findings provide the strongest evidence to date indicating that caffeine physical dependence increases the relative reinforcing effects of caffeine versus placebo. Received: 1 June 1997/Final version: 3 February 1998     

Sensitivity of the fear-inhibited light reflex to diazepam

 We have shown previously that pupil diameter increases and the amplitude of the pupillary light reflex is reduced when subjects are under threat of an aversive event (electric shock), and that light reflex amplitude correlates negatively with subjective anxiety. We have suggested that the “fear-inhibited light reflex” paradigm could be used as a laboratory model of human anxiety. In the present study, we examined whether two doses (5 mg and 10 mg) of the anxiolytic drug diazepam would antagonize the effects of threat on the pupillary light reflex. Twelve healthy male volunteers participated in three weekly sessions, each associated with one of three treatments (diazepam 5 mg or 10 mg or placebo) in a double-blind, balanced, cross-over design. The light reflex was recorded during either the anticipation of a shock (“threat” blocks) or periods in which no shocks were anticipated (“safe” blocks). At the end of each “threat” or “safe” block, subjects rated their anxiety using visual analogue scales. Two-factor ANOVA (treatment × condition) showed that diazepam treatment antagonized the effect of threat on light reflex amplitude in a dose-dependent manner but it did not affect the threat-induced increase in pupil diameter. Diazepam had no effect on the pupillary light reflex in the “safe” condition. Diazepam also reduced subjective anxiety and alertness in the threat condition. These results show the sensitivity of the threat-induced reduction of light reflex amplitude to anxiolytic drugs, and provide further evidence for the utility of the fear-inhibited light reflex paradigm as a laboratory model of human anxiety. Received: 20 March 1997/Final version: 7 July 1997     

Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans

Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., “I feel a good drug effect,”“I feel high”), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs. Received: 20 May 1997/Final version: 13 November 1998     

Subjective and cardiovascular effects of intravenous nicotine in smokers and non-smokers

The present study assessed the subjective and cardiovascular effects of intravenous nicotine in smokers and nonsmokers. Nonsmokers (n = 5) and smokers (n = 5) were administered a single dose of nicotine (0.75 or 1.5 mg) or saline on each of 3 days. The nicotine doses were given in ascending order in a double-blind fashion. Although smokers and nonsmokers manifested significant increases in systolic and diastolic blood pressure and heart rate 1 min after administration of all active test doses, the difference between peak heart rate and that measured at later times was greater in nonsmokers than in smokers. Nonsmokers and smokers also differed in subjective self-reports. In response to items on visual analogue scales indicative of positive effects (e.g., “good effects,”“like drug,”“use again,” and “feel energetic”), smokers but not nonsmokers reported high scores (> 40) after nicotine injection. In addition, responses on the MBG and LSD subscales of the Addiction Research Center Inventory indicated that smokers experienced positive subjective effects after the test doses, whereas nonsmokers experienced disorientation. The fact that intravenous nicotine was not associated with positive subjective effects in nonsmokers indicates that repeated exposure is required to establish positive reinforcing effects of nicotine. Received: 11 August 1995 /Final version: 30 May 1996     

Efficacy and safety of spirapril,a new ace-inhibitor,in elderly hypertensive patients

Objective: To compare the safety, efficacy, tolerability and duration of the antihypertensive effect of an ACE-inhibitor spirapril 3 mg or 6 mg in elderly (≥ 60 y) hypertensive patients in a multicentre, observational, double-blind randomised study. Methods: After a four-week placebo period, 39 patients were randomised to six weeks of treatment with spirapril 3 mg and 47 patients with spirapril 6 mg. Results: In the sitting position the mean (SD) decrease in systolic blood pressure (SBP) was 12(15) mmHg (95% confidence interval 7 to 17 mmHg) and in dia- stolic blood pressure (DBP) 10(7) mmHg (8 to 12 mmHg) in the 3-mg group and 10(13) mmHg (6 to 14 mmHg) and 9(7) mmHg (7 to 11 mmHg), respectively, in the 6-mg group (P < 0.001 compared to placebo period in both groups). Spirapril 3mg and 6 mg produced DBP ≤ 90 mmHg or a fall ≥ 10 mmHg in 53% and 51% of the patients, respectively. DBP was ≤ 90 mmHg in 36% and SBP ≤ 160 mmHg in 67% of the patients taking 3 mg and in 26% and 63% of the patients taking 6 mg spirapril. The most commonly reported adverse effects were cough (13–17%), dizziness, headache and insomnia. A trend to a more frequent adverse effects was observed in patients receiving spirapril 6 mg. Spirapril was both cholesterol- and glucose-neutral. Conclusion: According to our study, spirapril 3mg seems to be a suitable starting dose for the treatment of hypertension in the elderly patients. Received: 8 August 1995/Accepted in revised form: 7 November 1995     

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of “negative” subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure. Received: 7 July 1997/Final version: 18 December 1997     

Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms

The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome. Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either centrally and peripherally (mecamylamine 1 mg/kg SC) or peripherally only (chlorisondamine 1 mg/kg SC). Statistical evaluation revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals’ baseline sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg SC) reversed the behavioral nicotine abstinence syndrome. Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors may contribute significantly to the overall withdrawal reaction. Received: 21 March 1996/Final version: 30 September 1996     

Mecamylamine does not precipitate withdrawal in cigarette smokers

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine’s effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers’ subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation. Received: 20 April 1996/Final version: 3 June 1996     

Abstinence symptoms following oral THC administration to humans

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ⁹-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use. Received: 13 April 1998/Final version: 1 July 1998     

Discriminative stimulus effects of S(−)–methcathinone (CAT): a potent stimulant drug of abuse

Methcathinone (“CAT”) is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the present study, S(−)-methcathinone [S(−)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established, the S(−)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60–90 min. In tests of stimulus generalization (substitution), the S(−)-CAT (ED₅₀ = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED₅₀ = 0.17 mg/kg), S(−)-cathinone (ED₅₀ =  0.19 mg/kg), S(+)-amphetamine (ED₅₀ = 0.23 mg/kg), aminorex (ED₅₀ = 0.27 mg/kg), (±)-CAT (ED₅₀ = 0.25 mg/kg), (±)-cathinone (ED₅₀ = 0.41 mg/kg), R(+)-CAT (ED₅₀ = 0.43 mg/kg), cis-4-methylaminorex (ED₅₀ = 0.49 mg/kg), methylphenidate (ED₅₀ = 0.83 mg/kg), and cocaine (ED₅₀ = 1.47 mg/kg). S(−)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol (AD₅₀ = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(−)-CAT stimulus. It is concluded that S(−)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic mechanism. Received: 4 August 1997/Final version: 27 March 1998     

Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Effects of pergolide on intravenous cocaine self-administration in men and women

Clinical evidence suggests that pergolide, a D₁/D₂ dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide’s effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/ week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of “High,”“Stimulated,” cocaine “Potency,” estimates of street value, and heart rate, 2) increased ratings of “I want cocaine,” and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine’s subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted. Received: 29 April 1997/Final version: 14 October 1997     

Conditioned flavour preference negatively reinforced by caffeine in human volunteers

This study examined whether 100 mg caffeine could reinforce preference for the flavour of a novel drink in moderate caffeine users, both after overnight caffeine abstinence and 2 h after receiving 100 mg caffeine, using a two-stage between-groups procedure with 36 volunteers. In the first stage, liking for a test drink (fruit tea) was assessed at breakfast following overnight caffeine abstinence, with half the subjects receiving caffeine. Liking for the tea increased significantly over four trials for subjects receiving caffeine, and decreased significantly in those without caffeine. These effects were greatest in subjects who rated the drink as highly novel. In stage two, subjects evaluated a second drink (fruit-juice) 2 h after receiving the tea, and again half the subjects received caffeine Those subjects who received caffeine in stage two but not stage one showed a significant increase in liking for the fruit-juice over the 4 test days, whereas subjects who did not receive caffeine at either stage showed a progressive decrease in liking for this drink. In contrast, no significant change in liking for the fruit-juice was seen at stage two for subjects who had received caffeine in stage one, regardless of the presence or absence of caffeine at stage two. Caffeine at breakfast increased ratings of energetic and lively, and energetic ratings also increased following caffeine in the fruit-juice in subjects who had not had caffeine at breakfast. Overall, these data are consistent with a negative reinforcement model of caffeine reinforcement, and demonstrate further the utility of the conditioned flavour preference method for evaluating reinforcing effects of drugs in humans. Received: 30 September 1997/Final version: 17 November 1997     

The acetylcholine releaser linopirdine increases parietal regional cerebral blood flow in Alzheimer’s disease

Centrally acting cholinergic drugs have been reported to increase regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) in brain regions affected by Alzheimer’s disease (AD). We studied the effects of the acetylcholine releaser linopirdine (LPD) on SPECT rCBF in patients with probable AD. Twenty-four AD patients (12 M, 12 F; mean age ± SD = 68.9 ±8.2 years) and 13 healthy controls (8 M, 5 F; 68.4 ± 8.0 years) participated. AD patients were scanned with 20 mCi of Tc-99m-ECD at baseline and following 4 weeks of treatment with LPD 40 mg TID (n = 15) or placebo TID (n = 9) in a double-blind trial. Healthy subjects were scanned for comparison with baseline AD scans. Cortical/cerebellar rCBF ratios were derived for nine cortical structures. The combined parietal association cortex showed a 20.6% reduction in patients relative to controls. Patients treated with LPD showed an increase in parietal rCBF of 4.1 ± 5.8%; whereas those treated with placebo showed a decrease of −2.0 ± 7.4% (F = 5.13; df = 1, 22; P = 0.03). These data support the conclusion that rCBF abnormalities in AD are, in part, truly “functional” and can be selectively altered with pharmacological interventions. The parietal activation seen with LPD and other cholinergic AD drug therapies suggests the importance of measuring parietal lobe neuropsychological function in the course of evaluating these drugs. Received: 19 September 1996 /Final version: 17 February 1997     

Modulating effects of a cold water stimulus on opioid effects in volunteers

The purpose of this study was to characterize the effect of a painful stimulus on morphine and butorphanol effects in healthy non-drug abusing volunteers. Thirteen subjects with no history of opiate dependence participated in a randomized, placebo-controlled, double-blind, crossover trial in which each subject received saline, 2 mg/70 kg butorphanol, and 10 mg/70 kg morphine, IV, in each of two conditions, periodic forearm immersions into either ice-cold water (2°C) or into warm water (37°C). Both opioids reduced self-reported ratings of pain intensity, indicative of analgesia. Several of the subjective effects of morphine were attenuated either during or in between cold-water immersions, including visual analog scale ratings of “coasting (spaced out),”“high (drug “high”),”“sleepy (drowsy, tired),” and “lightheaded”. In contrast, some of butorphanol’s subjective effects were increased by the cold-water manipulation. Morphine impaired psychomotor performance during one of the warm-water immersions, but not during the cold-water immersions. Psychomotor impairment induced by butorphanol was not affected by water temperature. This study provides evidence that opioid effects can be modulated by a painful stimulus in humans. Received: 6 March 1996/Final version: 17 October 1996     

Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects

  Objective: Deflazacort, a synthetic oxazoline derivative of prednisolone, has been suggested as having major advantages over other glucocorticoids, as it is claimed to cause fewer adverse effects at equivalent antiinflammatory potency. The assumed equipotency ratio of deflazacort versus other glucocorticoids is critical for this assumption. Methods: In a randomized cross-over study we compared the acute effects of deflazacort and prednisolone on serum cortisol, osteocalcin, insulin and blood cells (eosinophils and lymphocytes) in normal subjects. On seven occasions separated by a wash out period ≥ 1 week all participants received placebo, prednisolone (8 mg, 20 mg, 40 mg) and deflazacort (12 mg, 30 mg, 60 mg). The medication was given orally at 20.00 h as a single dose. Blood was collected at 8.00 h before and after each medication. Log (dose) response relationships were calculated and were used to compare the drugs. Results: The following equipotent dose ratios (mg deflazacort: mg prednisolone) were found: osteocalcin suppression 1.54, cortisol suppression 2.27, suppression of eosinophils 1.14 and lymphocytes 2.77. As parallelism between regression curves was rejected, equipotency could not be calculated for insulin. In 3 subjects even the highest dose of deflazacort failed to suppress serum cortisol. Conclusion: Our study highlights the difficulties of establishing equipotency ratios for glucocorticoids. It casts doubts on the generally assumed equipotency dose ratio of deflazacort vs prednisolone, as both for cortisol and lymphocytes the 95% CI was > 1.2. Thus, reduced adverse effects during deflazacort therapy may be a consequence of lower effective glucocorticoid dosage. Received: 11 December 1995 /Accepted in revised form: 16 March 1996     

Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans

Alternate-day buprenorphine dosing was compared to daily dosing in opioid-dependent outpatients and choice of alternate-day versus daily dosing was assessed. Four dosing schedules were presented in random order under blind and open dosing conditions. Subjects received two exposures to each dosing schedule. During daily dosing, subjects received maintenance doses every 24 h. During blind alternate-day dosing, subjects received double maintenance doses every 48 h; placebo was interposed on intervening days. During open alternate-day dosing, subjects received twice their maintenance dose on Monday, Wednesday and Friday and maintenance doses on Sunday. After completing two exposures to each dosing schedule, subjects chose either daily or alternate-day schedules each week for 1 month. Study participation was contingent on daily attendance and opioid abstinence. Ten subjects were exposed to the four conditions once. Seven subjects repeated these conditions and participated in the choice phase. The effects of daily versus alternate-day dosing were not influenced by blind or open dosing conditions. Subjects’ ratings of withdrawal, “sick” and sedation were lower during daily than during alternate-day dosing, but the difference between treatments was small. Nonetheless, subjects still chose alternate-day dosing on 96% of occasions, suggesting that the subject-rated differences between dosing schedules were not influential. These results extend prior findings to open-dosing conditions, and replicate the safety and acceptability of alternate-day buprenorphine treatment. Choice of alternate-day buprenorphine administration underscores the procedure’s clinical utility and potential use as a positive reinforcer to enhance opioid treatment. Received: 1 August 1996/Final version: 11 September 1997     

Trazodone and triazolam: acute subject-rated and performance-impairing effects in healthy volunteers

The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone”s and triazolam”s effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of “dizzy”, “excited”, “nervous”, “restless”, “stomach turning” and “itchy skin”. Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse. Received: 9 May 1996 / Final version: 15 September 1996     

Binge cocaine self-administration in humans: intravenous cocaine

Cocaine is frequently used in intermittent cycles of repeated dosing, or “binges.” This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of “I want cocaine” decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of “binge” cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use. Received: 14 November 1996/Final version: 8 March 1997     

The effects of a low dose of caffeine on cognitive performance

There is little evidence concerning the effects of caffeine in doses typical of one cup of tea. The present study investigated the effect of 60 mg caffeine, consumed in either tea or hot water, on performance on a subset of the CANTAB test battery. Eight males participated in a practice session and four test sessions. In each test session, the participant consumed a different hot beverage and then, over approximately 90 min, completed nine tests from the CANTAB battery. The four beverages were created by crossing beverage identity (tea or hot water) and caffeine dose (0 or 60 mg). Significant speeding of reaction time by caffeine consumption was found in pattern recognition, delayed match to sample, and match to sample visual search. The effect on reaction time of 60 mg caffeine can be detected, and may be evident within minutes of consumption. Received: 16 March 1998/Final version: 27 July 1998