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Papers by Chris-Ellyn Johanson

Psychopharmacology, 2002

A Human Laboratory Model of Risk-Taking Behaviour

Behavioural Pharmacology

Lack of effect of social context on the reinforcing effects of diazepam in humans

The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers ... more The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers using a cumulative dose procedure. Under the social (SOC) condition, groups of two to four subjects participated concurrently whereas in the solitary (SOL) condition subjects participated individually. During the first four sessions of each condition, subjects received 20 mg DZP in five divided doses (4 mg) in two of the sessions and placebo (PL) in the other two sessions. Each drug (DZP or PL) was administered in a distinctively colored capsule and labeled by letter code. During the last three choice sessions, subjects chose which capsule they wished to self-administer and were allowed to choose up to a maximum of seven capsules (28 mg DZP) during each session. Subjects also filled out questionnaires that assessed momentary mood. Overall, DZP was chosen on 33% of choice sessions and there were no differences across conditions. There was a tendency for choice to be correlated with levels of weekly alcohol consumption and liking scores, and as well the latter two measures were correlated. DZP produced sedative-like subjective effects that did not appear to be related to setting, choice of drug in the study, or alcohol drinking history. These results partially confirm previous reports of a relationship between DZP preference and alcohol consumption, but differ from previously reported studies in the overall lower level of DZP choice.

Psychopharmacology, 2006

Objective: Preclinical investigations have established that methamphetamine (MA) produces longter... more Objective: Preclinical investigations have established that methamphetamine (MA) produces longterm 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 [ 11 C] methylphenidate and [ 11 C]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.

Psychopharmacology, 2006

Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effect... more Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4methylenedioxymethamphetamine (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 doubleblind, 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.

Psychopharmacology, 2005

Rationale: Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause ... more 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°C) and warm (30°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 2×2 design [i.e., two sessions at 30°C and two at 18°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.

Psychopharmacology, 2002

Rationale: Buprenorphine can decrease opioid self-administration by humans and animals, but its a... more 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 alternateday 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 highdose 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.

Pharmacology Biochemistry and Behavior, 1987

self-administration and resistance to extinction. PHARMACOL BIOCHEM BEHAV 28(1) [81][82][83][84][... more self-administration and resistance to extinction. PHARMACOL BIOCHEM BEHAV 28(1) [81][82][83][84][85][86] 1987.--Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.

Pharmacology Biochemistry and Behavior, 1988

The nature of the scheduled reinjbrcer and adjunctive drinking in nondeprived rhesus monkeys. PHA... more The nature of the scheduled reinjbrcer and adjunctive drinking in nondeprived rhesus monkeys. PHARMACOL BIOCHEM BEHAV 29(2) [295][296][297][298][299][300][301] 1988.--Adjunctive drinking was generated in three free-feeding rhesus monkeys by the contingent and intermittent delivery of flavored pellets. The amount of drinking generated was greater when pellet availability was restricted under fixed-interval schedules compared to a massedreinforcer control condition. The volume of water consumed depended upon the fixed-interval of pellet delivery (FI 180 sec to FI 1800 sec). Peak amounts of water consumed ranged from 532 ml to 650 ml during the 2 hr sessions and the schedule which generated the most drinking was either FI 420 or FI 600 sec, across monkeys. Variables which did not appear to influence the amount of drinking generated within the session were the amount of water consumed outside the session, the rates of responding maintained by pellet delivery and the pattern of responding for pellet delivery. However, when either cocaine or diazepam was the scheduled reinforcer, these same free-feeding monkeys did not engage in adjunctive drinking. The ability of cocaine and diazepam to generate adjunctive drinking was determined first by gradually decreasing the frequency of pellet delivery while keeping drug delivery constant using a second-order schedule of pellet delivery [FR n (FI 300 sec: drug delivery) with n ranging from 1 to 6]. Second, a range of drug doses was tested under a FI 300 sec schedule (cocaine: 0.01-0.3 mg/kg/injection; diazepam: 0.01-0.56 mg/kg/injection). These results suggest that there may be some restriction on the generation of adjunctive drinking depending upon the nature of the scheduled reinforcer.

Reducing cocaine choice in monkeys

Pharmacology Biochemistry and Behavior, 1989

Lack of effect of social context on the reinforcing effects of diazepam in humans

Pharmacology Biochemistry and Behavior, 1992

The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers ... more The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers using a cumulative dose procedure. Under the social (SOC) condition, groups of two to four subjects participated concurrently whereas in the solitary (SOL) condition subjects participated individually. During the first four sessions of each condition, subjects received 20 mg DZP in five divided doses (4 mg) in two of the sessions and placebo (PL) in the other two sessions. Each drug (DZP or PL) was administered in a distinctively colored capsule and labeled by letter code. During the last three choice sessions, subjects chose which capsule they wished to self-administer and were allowed to choose up to a maximum of seven capsules (28 mg DZP) during each session. Subjects also filled out questionnaires that assessed momentary mood. Overall, DZP was chosen on 33% of choice sessions and there were no differences across conditions. There was a tendency for choice to be correlated with levels of weekly alcohol consumption and liking scores, and as well the latter two measures were correlated. DZP produced sedative-like subjective effects that did not appear to be related to setting, choice of drug in the study, or alcohol drinking history. These results partially confirm previous reports of a relationship between DZP preference and alcohol consumption, but differ from previously reported studies in the overall lower level of DZP choice.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations

PAIN, 2012

A critical component in development of opioid analgesics is assessment of their abuse liability (... more A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers A Preliminary Study

Neuropsychopharmacology, 2000

A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally mo... more A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally more opioid receptors that mediate heroin effects. In this preliminary study we examined in vivo mu opioid receptor (muOR) binding in three healthy opioid-dependent volunteers during maintenance on 2 and 16 mg sublingual buprenorphine (BUP) liquid, and after detoxification (0 mg) under double-blind, placebo-controlled conditions, and once in matched controls. Binding measures were obtained with the muOR-selective radioligand [11C]carfentanil (CFN) and PET 4 hrs after BUP administration. BUP induced dose-dependent reductions in muOR availability, 36-50% at 2 mg and 79-95% at 16 mg relative to placebo. Heroin abusers also had greater muOR binding potential in the inferofrontal cortex and anterior cingulate regions during placebo, compared to matched controls. Further studies are warranted to examine the relationship of muOR availability with BUP therapeutic actions, and the clinical implications of increased muOR binding during withdrawal.

Neuropsychopharmacology, 1996

Neuropsychopharmacology, 1994

Expanding treatment capacity for opioid dependence with office-based treatment with buprenorphine: National surveys of physicians

Journal of Substance Abuse Treatment, 2010

Office-based treatment of opioid dependence with buprenorphine has the potential to expand treatm... more Office-based treatment of opioid dependence with buprenorphine has the potential to expand treatment capacity in the United States. However, nationally, little is known about the number, characteristics, and experiences of physicians certified to prescribe buprenorphine. Moreover, little is known about the impact of easing federal regulations on the number of patients a physician is allowed to treat concurrently. To address these questions, surveys of national samples of physicians certified to prescribe buprenorphine (2004-2008) were analyzed (N = 6,892). There has been a continual increase in the number of physicians certified to prescribe buprenorphine, increase in the mean number of patients treated by physicians, and decrease in patients turned away, coinciding temporally with easing of federal regulations. In addition, most physicians prescribed buprenorphine outside of traditional treatment settings. The U.S. experiment in expanding Schedule III-V medications for opioid dependence to physicians outside of formal substance abuse treatment facilities appears to have resulted in expanded capacity.

Personality and the acute subjective effects of d-amphetamine in humans

Journal of Psychopharmacology, 2013

There is evidence that subjective responses to psychoactive drugs are related to personality trai... more There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5, 10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher-order factors ('Euphoria', 'Arousal', 'Dysphoria'). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems.

Intravenous cocaine discrimination in humans

Experimental and Clinical Psychopharmacology, 2006

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20... more 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.

Discriminative stimulus effects of buspirone in humans

Experimental and Clinical Psychopharmacology, 1993

Human Ss (N = 22) were trained to discriminate 15 mg buspirone (BS) from placebo. On the first 4 ... more Human Ss (N = 22) were trained to discriminate 15 mg buspirone (BS) from placebo. On the first 4 sessions, drugs were identified by letter code. During the next 7 sessions, capsules were not identified. Six hours later, Ss reported their identification. If Ss were correct on at least 5 sessions, a third phase began with 8 additional training sessions.

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

Experimental and Clinical Psychopharmacology, 2005

Diazepam (DZ) reinforcement was tested under anxiogenic (public speaking) and neutral (computer t... more 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.

Psychopharmacology, 2002

A Human Laboratory Model of Risk-Taking Behaviour

Behavioural Pharmacology

Lack of effect of social context on the reinforcing effects of diazepam in humans

The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers ... more The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers using a cumulative dose procedure. Under the social (SOC) condition, groups of two to four subjects participated concurrently whereas in the solitary (SOL) condition subjects participated individually. During the first four sessions of each condition, subjects received 20 mg DZP in five divided doses (4 mg) in two of the sessions and placebo (PL) in the other two sessions. Each drug (DZP or PL) was administered in a distinctively colored capsule and labeled by letter code. During the last three choice sessions, subjects chose which capsule they wished to self-administer and were allowed to choose up to a maximum of seven capsules (28 mg DZP) during each session. Subjects also filled out questionnaires that assessed momentary mood. Overall, DZP was chosen on 33% of choice sessions and there were no differences across conditions. There was a tendency for choice to be correlated with levels of weekly alcohol consumption and liking scores, and as well the latter two measures were correlated. DZP produced sedative-like subjective effects that did not appear to be related to setting, choice of drug in the study, or alcohol drinking history. These results partially confirm previous reports of a relationship between DZP preference and alcohol consumption, but differ from previously reported studies in the overall lower level of DZP choice.

Psychopharmacology, 2006

Objective: Preclinical investigations have established that methamphetamine (MA) produces longter... more Objective: Preclinical investigations have established that methamphetamine (MA) produces longterm 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 [ 11 C] methylphenidate and [ 11 C]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.

Psychopharmacology, 2006

Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effect... more Objective The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4methylenedioxymethamphetamine (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 doubleblind, 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.

Psychopharmacology, 2005

Rationale: Although 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) has been reported to cause ... more 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°C) and warm (30°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 2×2 design [i.e., two sessions at 30°C and two at 18°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.

Psychopharmacology, 2002

Rationale: Buprenorphine can decrease opioid self-administration by humans and animals, but its a... more 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 alternateday 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 highdose 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.

Pharmacology Biochemistry and Behavior, 1987

self-administration and resistance to extinction. PHARMACOL BIOCHEM BEHAV 28(1) [81][82][83][84][... more self-administration and resistance to extinction. PHARMACOL BIOCHEM BEHAV 28(1) [81][82][83][84][85][86] 1987.--Self-administration behavior was maintained by a unit dose of 0.03 mg/kg diazepam in 4 of 5 monkeys trained to respond on a lever by successive approximation using diazepam or saline. A dose-response function was determined using diazepam doses ranging between 0.01 and 0.3 mg/kg/infusion. Peak rates of responding occurred at doses of 0.01 or 0.03 mg/kg/infusion and drug intake was directly related to dose. When saline was substituted for diazepam either before or again after the dose-response function was determined, levels of responding remained unexpectedly high, even after as many as 16 consecutive sessions. The rates of responding maintained under extinction conditions appeared to be directly related to the amount of diazepam previously self-administered. For instance, monkeys which did not initially have high rates of responding for saline showed increases in responding after additional exposure to diazepam. Furthermore, the one monkey with low diazepam self-administration rates also had low rates of responding for saline. However, following a period of cocaine self-administration, responding declined in all monkeys when saline was substituted for cocaine. The data suggest that diazepam self-administration affects responding under extinction conditions, an effect which makes the interpretation of diazepam's reinforcing properties difficult.

Pharmacology Biochemistry and Behavior, 1988

The nature of the scheduled reinjbrcer and adjunctive drinking in nondeprived rhesus monkeys. PHA... more The nature of the scheduled reinjbrcer and adjunctive drinking in nondeprived rhesus monkeys. PHARMACOL BIOCHEM BEHAV 29(2) [295][296][297][298][299][300][301] 1988.--Adjunctive drinking was generated in three free-feeding rhesus monkeys by the contingent and intermittent delivery of flavored pellets. The amount of drinking generated was greater when pellet availability was restricted under fixed-interval schedules compared to a massedreinforcer control condition. The volume of water consumed depended upon the fixed-interval of pellet delivery (FI 180 sec to FI 1800 sec). Peak amounts of water consumed ranged from 532 ml to 650 ml during the 2 hr sessions and the schedule which generated the most drinking was either FI 420 or FI 600 sec, across monkeys. Variables which did not appear to influence the amount of drinking generated within the session were the amount of water consumed outside the session, the rates of responding maintained by pellet delivery and the pattern of responding for pellet delivery. However, when either cocaine or diazepam was the scheduled reinforcer, these same free-feeding monkeys did not engage in adjunctive drinking. The ability of cocaine and diazepam to generate adjunctive drinking was determined first by gradually decreasing the frequency of pellet delivery while keeping drug delivery constant using a second-order schedule of pellet delivery [FR n (FI 300 sec: drug delivery) with n ranging from 1 to 6]. Second, a range of drug doses was tested under a FI 300 sec schedule (cocaine: 0.01-0.3 mg/kg/injection; diazepam: 0.01-0.56 mg/kg/injection). These results suggest that there may be some restriction on the generation of adjunctive drinking depending upon the nature of the scheduled reinforcer.

Reducing cocaine choice in monkeys

Pharmacology Biochemistry and Behavior, 1989

Lack of effect of social context on the reinforcing effects of diazepam in humans

Pharmacology Biochemistry and Behavior, 1992

The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers ... more The reinforcing effects of diazepam (DZP) were compared under two conditions in human volunteers using a cumulative dose procedure. Under the social (SOC) condition, groups of two to four subjects participated concurrently whereas in the solitary (SOL) condition subjects participated individually. During the first four sessions of each condition, subjects received 20 mg DZP in five divided doses (4 mg) in two of the sessions and placebo (PL) in the other two sessions. Each drug (DZP or PL) was administered in a distinctively colored capsule and labeled by letter code. During the last three choice sessions, subjects chose which capsule they wished to self-administer and were allowed to choose up to a maximum of seven capsules (28 mg DZP) during each session. Subjects also filled out questionnaires that assessed momentary mood. Overall, DZP was chosen on 33% of choice sessions and there were no differences across conditions. There was a tendency for choice to be correlated with levels of weekly alcohol consumption and liking scores, and as well the latter two measures were correlated. DZP produced sedative-like subjective effects that did not appear to be related to setting, choice of drug in the study, or alcohol drinking history. These results partially confirm previous reports of a relationship between DZP preference and alcohol consumption, but differ from previously reported studies in the overall lower level of DZP choice.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations

PAIN, 2012

A critical component in development of opioid analgesics is assessment of their abuse liability (... more A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers A Preliminary Study

Neuropsychopharmacology, 2000

A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally mo... more A principle of opioid pharmacotherapy is that high medication doses should occupy fractionally more opioid receptors that mediate heroin effects. In this preliminary study we examined in vivo mu opioid receptor (muOR) binding in three healthy opioid-dependent volunteers during maintenance on 2 and 16 mg sublingual buprenorphine (BUP) liquid, and after detoxification (0 mg) under double-blind, placebo-controlled conditions, and once in matched controls. Binding measures were obtained with the muOR-selective radioligand [11C]carfentanil (CFN) and PET 4 hrs after BUP administration. BUP induced dose-dependent reductions in muOR availability, 36-50% at 2 mg and 79-95% at 16 mg relative to placebo. Heroin abusers also had greater muOR binding potential in the inferofrontal cortex and anterior cingulate regions during placebo, compared to matched controls. Further studies are warranted to examine the relationship of muOR availability with BUP therapeutic actions, and the clinical implications of increased muOR binding during withdrawal.

Neuropsychopharmacology, 1996

Neuropsychopharmacology, 1994

Expanding treatment capacity for opioid dependence with office-based treatment with buprenorphine: National surveys of physicians

Journal of Substance Abuse Treatment, 2010

Office-based treatment of opioid dependence with buprenorphine has the potential to expand treatm... more Office-based treatment of opioid dependence with buprenorphine has the potential to expand treatment capacity in the United States. However, nationally, little is known about the number, characteristics, and experiences of physicians certified to prescribe buprenorphine. Moreover, little is known about the impact of easing federal regulations on the number of patients a physician is allowed to treat concurrently. To address these questions, surveys of national samples of physicians certified to prescribe buprenorphine (2004-2008) were analyzed (N = 6,892). There has been a continual increase in the number of physicians certified to prescribe buprenorphine, increase in the mean number of patients treated by physicians, and decrease in patients turned away, coinciding temporally with easing of federal regulations. In addition, most physicians prescribed buprenorphine outside of traditional treatment settings. The U.S. experiment in expanding Schedule III-V medications for opioid dependence to physicians outside of formal substance abuse treatment facilities appears to have resulted in expanded capacity.

Personality and the acute subjective effects of d-amphetamine in humans

Journal of Psychopharmacology, 2013

There is evidence that subjective responses to psychoactive drugs are related to personality trai... more There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5, 10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher-order factors ('Euphoria', 'Arousal', 'Dysphoria'). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems.

Intravenous cocaine discrimination in humans

Experimental and Clinical Psychopharmacology, 2006

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20... more 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.

Discriminative stimulus effects of buspirone in humans

Experimental and Clinical Psychopharmacology, 1993

Human Ss (N = 22) were trained to discriminate 15 mg buspirone (BS) from placebo. On the first 4 ... more Human Ss (N = 22) were trained to discriminate 15 mg buspirone (BS) from placebo. On the first 4 sessions, drugs were identified by letter code. During the next 7 sessions, capsules were not identified. Six hours later, Ss reported their identification. If Ss were correct on at least 5 sessions, a third phase began with 8 additional training sessions.

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

Experimental and Clinical Psychopharmacology, 2005

Diazepam (DZ) reinforcement was tested under anxiogenic (public speaking) and neutral (computer t... more 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.