Steps physicians report taking to reduce diversion of buprenorphine.

BACKGROUND AND OBJECTIVES: Physicians are challenged to effectively treat opioid dependent patients while minimizing diversion of potentially abusable medications, such as buprenorphine. The present study was designed to obtain information on steps physicians report taking to reduce diversion of buprenorphine. METHOD: National quarterly surveys from 2008 to 2009 of qualified physicians who have prescribed buprenorphine were analyzed (N = 2,330). One part of the survey queried physicians about what steps they had taken to reduce abuse and diversion of buprenorphine from a pre-specified list of 12 steps. Other parts of the survey included questions on the physicians' training and experience. RESULTS: Physicians reported taking a mean of 4.4 steps. Longer experience prescribing buprenorphine, more buprenorphine-related educational training, and concern about diversion as a limitation on using buprenorphine for maintenance were associated with higher number of steps taken. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Physicians are currently taking multiple steps to reduce diversion. Future research needs to verify if these steps are effective or are instead reducing access to treatment.

Human behavioral pharmacology, past, present, and future: symposium presented at the 50th annual meeting of the Behavioral Pharmacology Society.

A symposium held at the 50th annual meeting of the Behavioral Pharmacology Society in May 2007 reviewed progress in the human behavioral pharmacology of drug abuse. Studies on drug self-administration in humans are reviewed that assessed reinforcing and subjective effects of drugs of abuse. The close parallels observed between studies in humans and laboratory animals using similar behavioral techniques have broadened our understanding of the complex nature of the pharmacological and behavioral factors controlling drug self-administration. The symposium also addressed the role that individual differences, such as sex, personality, and genotype play in determining the extent of self-administration of illicit drugs in human populations. Knowledge of how these factors influence human drug self-administration has helped validate similar differences observed in laboratory animals. In recognition that drug self-administration is but one of many choices available in the lives of humans, the symposium addressed the ways in which choice behavior can be studied in humans. These choice studies in human drug abusers have opened up new and exciting avenues of research in laboratory animals. Finally, the symposium reviewed behavioral pharmacology studies conducted in drug abuse treatment settings and the therapeutic benefits that have emerged from these studies.

Effects of acute 3,4-methylenedioxymethamphetamine on sleep and daytime sleepiness in MDMA users: a preliminary study.

STUDY OBJECTIVE: 3,4-Methylenedioxymethamphetamine (MDMA) affects monoamine neurotransmitters that play a critical role in sleep and daytime alertness. However, the acute effects of MDMA on sleep and daytime sleepiness have not been studied under placebo-controlled conditions. This study was designed to establish the effects of acute MDMA or placebo administration and sleep restriction on sleep and daytime sleepiness. DESIGN: Participants with a history of MDMA use were studied on 3 sessions of 3 nights (baseline, treatment, and recovery) and 2 days (following night 2 and 3) per session. On treatment nights (night 2), participants received placebo or 2 mg/kg of MDMA or underwent a restricted bed schedule with placebo. Sleep restriction was a positive control to compare sleep loss and consequent sleepiness associated with MDMA use. The scheduled sleep period was 8 hours long on nonrestricted nights, and standard sleep recordings and daytime sleepiness tests were conducted. Age-matched controls received 1 night and day of standard sleep and daytime sleepiness testing. SETTING: Sleep laboratory. PARTICIPANTS: Seven recreational MDMA-users and 13 matched control subjects. MEASUREMENTS AND RESULTS: Acute MDMA shortened sleep primarily by increasing sleep latency, and it reduced stage 3/4 sleep and suppressed rapid eye movement (REM) sleep. The MDMA-reduced sleep time was not associated with increased daytime sleepiness the following day, as was seen in the sleep-restriction condition. Compared with control subjects, the MDMA users on the first night in the laboratory had shorter total sleep times and less stage 3/4 sleep. Average daily sleep latency on daytime sleepiness tests the day after nighttime placebo administration was increased in MDMA users compared with the control subjects, and MDMA users had an elevated number of sleep-onset REM periods on these tests, compared with control subjects. CONCLUSIONS: Acute MDMA administration disrupts sleep and REM sleep, specifically, without producing daytime sleepiness such as sleep restriction does. Compared with control subjects, recreational MDMA users showed evidence of hyperarousal and impaired REM function. The mechanism behind these effects is likely due to the deleterious effects of MDMA on catecholamines.

Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices.

BACKGROUND: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of micro opioid receptors (microORs). This study examined the duration of action of BUP at microORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers. METHODS: Availability of microOR (measured with positron emission tomography and [(11)C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere. RESULTS: Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain microOR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of microOR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade. CONCLUSIONS: Together with our previous findings, it appears that microOR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.

The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans.

OBJECTIVE: The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4-methylenedioxymethamphetamine (MDMA) in humans. MATERIALS AND METHODS: The subjective and physiological effects of 1.5 mg/kg MDMA were evaluated after 20 mg fluoxetine in eight recreational MDMA users in a double-blind, placebo-controlled study. During phase 1, participants were maintained on placebo for at least 5 days and tested with MDMA and placebo on separate sessions. In phase 2, the procedure was the same except fluoxetine was administered daily for at least 5 days. During sessions, placebo or fluoxetine was given 1 h before the session drug and effects were measured over the next 7 h. RESULTS: MDMA increased positive-like subjective effects on all the Addiction Research Center Inventory scales; Arousal, Elation, Positive Mood, and Vigor on the Profile of Mood States; Drug Liking, Friendly, Good Drug Effect, High, Stimulated, and Talkative on the Visual Analog Scale; and End-of-Session Liking and Crossover Point on the Multiple Choice Procedure. MDMA also increased measures of anxiety. On the Hallucinogenic Rating Scale, all scales except Volition were increased. MDMA also increased blood pressure and heart rate. Fluoxetine treatment attenuated most of the positive-like subjective effects including the Affect and Soma scales of the Hallucinogen Rating Scale. In addition, heart rate but not blood pressure increases were reduced. CONCLUSIONS: These results suggest that blockade of 5-HT reuptake by fluoxetine can dampen the effects of MDMA and further supports the role of 5-HT in its behavioral effects in humans.

Effects of oral cocaine on intravenous cocaine discrimination in humans.

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear.

Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers.

OBJECTIVE: Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. METHOD: Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. RESULTS: Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. CONCLUSIONS: Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

Discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans trained to discriminate among d-amphetamine, meta-chlorophenylpiperazine and placebo.

In animals, two-choice drug discrimination studies have demonstrated that the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) are mediated by dopaminergic and serotonergic systems. In order to delineate the relative role of these systems, three-choice paradigms have been used in animals, with findings indicating a more prominent role for serotonin. Human studies assessing the subjective and physiological effects of MDMA have also indicated a mixed action. To parallel animal studies, the participants in the present study were trained to discriminate among a prototypic dopaminergic agonist, d-amphetamine, a prototypic serotonergic agonist, meta-chlorophenylpiperazine (mCPP) and placebo and then were tested with two doses of MDMA. In addition, subjective and physiological effects were measured. The results demonstrated that humans could be trained to discriminate among 20 mg d-amphetamine, 0.75 mg/kg mCPP and placebo. When tested with 1.0 and 1.5 mg/kg, half the participants reported MDMA to be like amphetamine and half like mCPP. There were no clear differences between these two groups in other dimensions, although there was an indication that the individuals who discriminated MDMA as d-amphetamine were more sensitive to the effects of all the drugs. The subjective effects of all three drugs overlapped, although the effects of MDMA appeared more amphetamine-like.

Impact of formulation on the abuse liability, safety and regulation of medications: the expert panel report.

A scientific meeting was held in April 2005 to consider how the formulation of medications might impact on their potential for abuse. The background papers prepared for this meeting, as well as abstracts of volunteered presentations, are published in this supplemental issue of Drug and Alcohol Dependence. This paper is the Expert Panel Report summarizing the discussions held following the formal presentations and including the suggested recommendations for additional research that emerged from these discussions. There was overwhelming consensus that formulation does play a role in prescription drug abuse, i.e., a formulation of an abused substance can be developed that will decrease its abuse potential, and several examples were cited. Nevertheless, it is imperative that new formulations have similar efficacy and in no way compromise medication access to doctors and patients. However, there was also consensus that a great deal of research and discussion was needed to fully implement a program of risk management through reformulation of existing products or tailoring the formulation of new products to retain clinical efficacy and safety while minimizing potential for abuse. Those who need to take part in this discussion include scientific groups, pharmaceutical companies, as well as governmental and regulatory agencies. The areas where more research is needed include development of standards for assessing tamper-resistance, improved animal models that can address formulation-related variables (e.g., onset, duration), the redesign of human laboratory studies providing appropriate models for comparing formulations, and improved post-marketing surveillance. Finally, knowledge and experience are needed to translate scientific work into a predictable, transparent and reliable regulatory process.

Cocaine-dependence and cocaine-induced paranoia and mid-latency auditory evoked responses and sensory gating.

Cocaine-dependence has been shown to affect the amplitudes of the P50 mid-latency auditory evoked response (MLAER) as well as P50 sensory gating. The effects on subsequent MLAERs (N100 and P200) have not been examined. The objective of the current study was to further assess the effects of chronic cocaine use on the P50, N100, and P200 components. Thirty-four, at least three weeks abstinent, cocaine-dependent individuals and 34 age and gender matched healthy controls were examined. The amplitudes, latencies and gating measures were calculated and compared between the groups. The N100 and P200 were significantly smaller in patients as compared to control subjects. Sensory gating of the P50, the N100, and the P200 were deficient in cocaine-dependent subjects. Latencies of all measured components were prolonged in subjects who reported developing paranoia while intoxicated. Finally, a positive correlation was found between length of abstinence and evoked response amplitudes. We conclude that the effects of cocaine on sensory gating extend beyond the P50 to the N100 and the P200 components. The data also suggest that prolonged latency of the evoked potentials may be a correlate of cocaine-induced psychosis. Finally, the data suggest that some recovery of amplitude and gating occurs with abstinence.

Intravenous cocaine discrimination in humans.

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies.

Thermoregulatory effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans.

RATIONALE: Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause fatal hyperthermia, few studies of the effects of MDMA on core body temperature in humans have been conducted demonstrating increased body temperature. In rats, MDMA causes hyperthermia at warm ambient temperatures but hypothermia at cold ones. OBJECTIVES: In this study, the physiological and subjective effects of MDMA in humans were determined at cold (18 degrees C) and warm (30 degrees C) ambient temperatures in a temperature and humidity-controlled laboratory. METHODS: Ten healthy volunteers who were recreational users of MDMA were recruited. Four laboratory sessions were conducted in a 2x2 design [i.e., two sessions at 30 degrees C and two at 18 degrees C, two during MDMA (2 mg/kg, p.o.) and two during placebo, in double-blind fashion]. Core body temperature (ingested radiotelemetry pill), skin temperature (four weighted sites), heart rate, blood pressure, metabolic rate (indirect calorimetry), shivering (electromyogram levels), and sweat rate (capacitance hygrometry) were measured as well as subjective effects for several time periods following capsule ingestion. RESULTS: MDMA produced significant elevations in core body temperature and metabolic rate in both warm and cold conditions. MDMA also produced significant elevations in blood pressure and heart rate and significantly increased several ratings of subjective effects similar to those previously reported. There were no differences related to ambient temperature for any of the subjective effects, except that ratings of cold and warm were appropriate to the ambient temperature and were not influenced by MDMA. CONCLUSIONS: Unlike findings in rats, MDMA increased core body temperature regardless of ambient temperature in humans. These increases appeared related to increases in metabolic rate, which were substantial. These findings warrant further investigations on the role of MDMA and other stimulants in altering metabolism and thermogenesis.

Reinforcing effects of diazepam under anxiogenic conditions in individuals with social anxiety.

Diazepam (DZ) reinforcement was tested under anxiogenic (public speaking) and neutral (computer task) conditions. Individuals with social anxiety disorder (n = 11) and healthy controls (n = 11) participated in two 5-session phases. Each phase used a standard choice procedure (2 sample, 3 choice sessions) comparing 10-mg DZ and placebo. During the public speaking condition, DZ preference was greater among the participants with social anxiety compared with controls (81.8% vs. 36.4%; p < .05). Participants with social anxiety also gave DZ significantly higher crossover values on the multiple choice procedure under the speech condition compared with the computer condition. Subjective effects indicated that DZ reduced anxiety when levels were elevated during the speech in socially anxious participants. These results suggest that DZ reinforcement may occur under conditions of heightened anxiety by bestowing therapeutic efficacy.

Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers.

The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medication's ability to decrease mu-opioid receptor (muOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. We empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. We predicted and confirmed that higher BUP doses would decrease in vivo muOR availability (measured with PET and [(11)C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (+/-SEM) whole-brain muOR availability 41+/-8, 80+/-2, and 84+/-2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in muOR availability varied across ROIs (prefrontal cortex, 47% vs amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94-98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5-1, 5-6, and 13-14 ng/ml at 2, 16, and 32 mg, respectively). muOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal muOR occupation, muOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration-effect relationships.

Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans.

RATIONALE: Buprenorphine can decrease opioid self-administration by humans and animals, but its ability to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers using clinically relevant dosing schedules has not been extensively studied. OBJECTIVES: We investigated whether daily versus alternating-day administration of high versus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. METHODS: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200,.12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. RESULTS: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average buprenorphine doses (regardless of daily versus alternate-day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline heroin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high-dose buprenorphine. CONCLUSIONS: High-dose buprenorphine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alternative reinforcement. These beneficial effects were retained when high-dose buprenorphine was administered on alternate days.

Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP.

3,4-methylenedioxymethamphetamine (MDMA) is a widely used drug of abuse chemically related to both the amphetamines and mescaline. Laboratory animal studies have shown that MDMA is a potent re-uptake inhibitor and releaser of dopamine and serotonin. Although the subjective and physiological effects of MDMA have been compared to d-amphetamine in humans, no direct comparison with a serotonin releasing agent has been reported and reinforcing effects have not been evaluated. In this paper we report a direct comparison of the reinforcing, subjective, and physiological effects of MDMA (1 and 2 mg/kg) to d-amphetamine (10 and 20 mg), to metachlorophenylpiperazine (mCPP--a serotonin releasing agent (0.5 and 0.75 mg/kg)), and to placebo using a within-subject design in 12 volunteers with moderate MDMA experience. Both the high dose of d-amphetamine and MDMA showed significant reinforcing effects as indicated by high cross-over values on the multiple choice procedure compared to all other treatments. All three drugs showed dose-dependent changes in subjective effects whereas physiological effects were most pronounced for MDMA with almost no changes seen with mCPP. The subjective effects of MDMA were similar both to those of mCPP and d-amphetamine, suggesting that both dopamine and serotonin systems are involved in mediating these effects. In contrast, only the dopaminergic agents, d-amphetamine and MDMA, had reinforcing effects.

Postmarketing surveillance of abuse liability of sibutramine.

The abuse liability of medications is a growing concern as the number of newly approved psychoactive medications increases. Postmarketing surveillance can assist in determining abuse liability, but strategies are not well-defined for medications believed to be at low abuse risk. Using a newly approved medication (sibutramine--an anorectic drug), a novel approach to postmarketing abuse surveillance was introduced. A one-page anonymous questionnaire covering sibutramine, a scheduled anorectic drug (phentermine), and a fabricated name was added to the intake process of 58 treatment programs. From the 8780 completed questionnaires, 8.8% had heard of sibutramine and phentermine. For continued use to get high (a proxy for abuse), the rate for sibutramine was lower than for phentermine (0.6 vs. 2.2%, McNemar's chi(2) = 110.45, P < 0.001) but was higher than for the fabricated name (0.6 vs. 0.3%, McNemar's chi(2) = 11.86, P < 0.001). These results suggest the risk of abuse associated with sibutramine was lower than that associated with a known abused drug, one that itself is considered low risk despite decades of population exposure. The relatively high rate of hearing of sibutramine may be due to the direct-to-consumer advertisement. This approach is only one indicator in a surveillance framework but appears promising and validates findings from laboratory-based abuse liability studies that also indicate low abuse liability for sibutramine.

Reinforcing and subjective effects of methylphenidate: dose and time in bed.

So that reinforcing and subjective effects of methylphenidate as a function of dose and level of sleepiness could be evaluated, 21 volunteers received methylphenidate (5, 10, or 20 mg) or placebo on 2 sampling days. After 4 and 8 hr time in bed (TIB), they chose their preferred capsule on 5 days. Methylphenidate was chosen more frequently after 4 hr TIB (60%) than it was after 8 hr TIB (33%). The strongest preference (68%) was seen in the 10-mg group. At 10 and 20 mg, stimulant-like subjective effects were reported. The 10-mg group was more adversely affected by the restricted bedtime and showed more pronounced drug effects with methylphenidate. These results indicate that sleepiness modulates the reinforcing and subjective effects of methylphenidate.

Establishment of a diazepam preference in human volunteers following a differential-conditioning history of placebo versus diazepam choice.

This study examined whether preference for a drug (diazepam or placebo) could be switched using conditioning procedures. During the first 4 sessions of Phase 1, 6 participants received 5 mg of diazepam or placebo under double-blind conditions. During the remaining 5 sessions of Phase 1, participants selected the drug they wished to receive. The first 4 sessions of Phase 2 were a replication of Phase 1, except that following ingestion of the drug, participants completed a computer task for which they could earn money. Payment for the computer task was lowest following ingestion of the drug they preferred in Phase I and highest following the drug they had avoided. Preference was reassessed during the last 5 sessions of Phase 2. Five of the participants preferred placebo in Phase 1 but diazepam in Phase 2. Subjective responses to the drugs also changed across the 2 phases.

Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence.

In this 12-week double-blind placebo-controlled trial of methylphenidate (MTP) versus placebo in 48 cocaine-dependent attention-deficit/hyperactivity disorder (ADHD) adults, the authors sought to determine whether MTP would be safe, control ADHD symptoms, and affect cocaine use. Efficacy indexes revealed significantly greater ADHD symptom relief in the MTP group. There were no group differences in self-reported cocaine use, urinalysis results, or cocaine craving. Because of the relatively small sample size, the results are preliminary. However, we found that MTP improved subjective reports of ADHD symptoms and did not worsen cocaine use while participants were in treatment.