Assessing individual differences in ethanol preference using a cumulative dosing procedure

Preference for ethanol versus a placebo was assessed in 12 normal volunteers using a cumulative dosing preference test. The test consisted of four sampling sessions followed by three choice sessions. During the sampling sessions subjects received either five cumulating oral doses of ethanol (0.1g/kg per dose) or equal volumes of placebo, at 15-min intervals. Subjective and observer-rated drug effects, psychomotor performance, drug liking ratings, and breath ethanol levels were measured at regular intervals. During choice sessions, subjects first chose which of the two substances (drug or placebo) they wished to take and ingested one unit dose. Then, at 15-min intervals throughout the session, they could ingest up to ten additional unit doses of the same substance (i.e., up to 1.1 g/kg ethanol). On average, the subjects chose the ethanol-containing beverage on 75% of the choice sessions, and they self-administered a mean total dose of 0.8g/kg per session. Subjects varied in the amount of ethanol ingested on choice sessions, and the amount they chose was related to their subjective responses to the drug during sampling. Subjects who chose the most ethanol reported experiencing stimulant-like effects from the ethanol, whereas the subjects who chose ethanol less frequently and ingested lower doses reported primarily sedative-like effects from the drug. The results demonstrate that the cumulative dosing procedure can be used effectively to evaluate drug preferences and dose preferences in normal volunteers.     

Lack of preference for flurazepam in normal volunteers

The reinforcing efficacy of flurazepam (15 and 30 mg) in humans was assessed using an experimental choice procedure. Twelve healthy volunteers were tested in two 3-week choice experiments, in which each dose of the drug was compared to placebo. Subjective effects of the drug (and placebo) were monitored using the Profile of Mood States and a 49-item version of the Addiction Research Center Inventory. The lower dose of flurazepam was chosen equally as often as placebo and produced no significant subjective effects. The higher dose (30 mg) was chosen significantly less often than chance, and produced typical tranquilizer-like effects (e.g., sedation). These results are consistent with previous results using other benzodiazepines such as diazepam and lorazepam, and suggest that the reinforcing efficacy of these drugs in normal volunteers is low.     

Assessing methylphenidate preference in ADHD patients using a choice procedure

Rationale Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD) and is associated with positive clinical effects across a wide range of domains. Despite the clinical effectiveness of MPH, concern has arisen with respect to its abuse potential.Objectives To assess MPH preference in adults diagnosed with ADHD using a choice procedure and to evaluate the relationship among drug preference, therapeutic efficacy, and abuse potential in a clinical sample.Methods Participants were ten volunteers (ages 18–22 years) with ADHD who were receiving MPH treatment. Preference was assessed using a double-blind choice procedure with four sampling sessions wherein subjects received either placebo or MPH and eight choice sessions when they chose either capsule or no capsules.Results Overall, MPH was chosen significantly more often than placebo ( ²=52.5; P<0.001) and participants were equally separated into groups of those who chose MPH reliably (MPH choosers) and those who did not (MPH non-choosers). MPH decreased ADHD symptoms and resulted in lower ratings of stimulant effects among MPH choosers. MPH choosers also reported higher levels of baseline ADHD symptoms.Conclusions Despite higher preference of MPH than placebo in this clinical sample, other measures of abuse potential were not elevated, and MPH choosers were more symptomatic than non-choosers. As such, MPH preference in ADHD populations likely reflects therapeutic efficacy rather than abuse potential. Future work should examine MPH choice in diagnosed and non-diagnosed populations to further explore the role of clinical efficacy in the preference of this stimulant drug.     

Cognitive effects of lithium treatment in normal volunteers

Patients taking lithium often report difficulties in concentration, memory, learning, and attention and many of these complaints are verified on psychometric testing. Laboratory tests of cognitive functions in healthy volunteers on chronic lithium demonstrate that disruptions in memory-learning processes are apparent at the time of memory retrieval. Subjects, following chronic lithium treatment, produce more errors of commission in remembering previously occurring events while errors of omission appear to be unaffected. These effects are different from those produced by other psychoactive drugs that can also selectively alter and disrupt cognitive processes.     

Effects of physostigmine on memory test performance in normal volunteers

The effects of an intraveneous infusion of physostigmine (0.94 mg infused over 60 min) on performance in memory tests were studied in 12 young subjects. Drug effects were modest and are discussed in relation to results of physostigmine studies in Alzheimer patients.     

Diazepam dose preference in humans

Diazepam dose preference was studied in 10 human subjects in a hospital setting. Subjects were allowed to select between a standard compound (diazepam or pentobarbital) and one of several doses of diazepam (2–40 mg/capsule) on an ad lib basis. When 5 or 10 mg/capsule diazepam was the standard, no clear cut diazepam dose preference was found. When 30 or 50 mg/capsule pentobarbital was the standard, clear cut diazepam dose preference in some subjects was found. The shape of the dose preference function differed among subjects. Within subjects, diazepam dose preference differed within the self-administration day, with some subjects preferring one dose in the morning and a different dose later in the day.     

The discrimination of drug mixtures using a four-choice procedure in pigeons

Abstract Rationale. The purpose of these experiments was to study drug combinations as discriminative stimuli using a new four-choice procedure. Objectives. To determine whether pigeons could discriminate among a mixture of two drugs, each of the component drugs and saline, and to study other drug combinations in these birds. Methods. Pigeons were trained to discriminate among saline, 5 mg/kg morphine, 5 mg/kg pentobarbital, and a mixture of these two doses using a four-choice procedure. Results. When responding stabilized, the birds responded on the correct key more than 90% of the time. Low doses of all drugs given alone produced responding on the saline key. Higher doses of pentobarbital and chlordiazepoxide produced responding on the pentobarbital key, and higher doses of morphine produced responses on the morphine key. Methamphetamine produced responding on the saline key. None of the drugs given alone produced responding on the mixture key. When pentobarbital was combined with morphine, doses both below and above the combined training doses of these drugs usually produced responding on the mixture key. The combination of chlordiazepoxide with morphine produced similar results. Combinations of methamphetamine with pentobarbital or with morphine produced effects similar to those of pentobarbital or morphine given alone. Conclusions. A wide range of combinations of pentobarbital and morphine, or chlordiazepoxide and morphine produce responding on the mixture key, even though the pigeons were not exposed to these dose combinations during training. The four-choice procedure provides the opportunity to study drug mixtures in a detail not possible with more limited response choices. Electronic Publication     

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.     

Drug preference in normal volunteers: Effects of age and time of day

These experiments assessed the influence of two variables, age of subjects and time of drug administration, on the reinforcing properties of amphetamine and of diazepam in normal volunteers. Three groups of subjects were tested: i) a group of 40–55-year-old subjects (AGE group; N=11) who were tested in the morning, ii) a group of 21–35-year-old subjects (CTL group; N=12) who were also tested in the morning, and iii) a group of 21–35-year-olds who were tested in the late afternoon (AFT group; N=13). All subjects participated in three separate experiments comparing one drug (5 mg d,l-amphetamine, 5 mg diazepam or 10 mg diazepam) to placebo. Each experiment consisted of nine sessions: On the first four sessions subjects sampled two color-coded capsules on alternate sessions and on the following five sessions they chose and ingested the capsule they preferred. Subjective effects of the drugs were monitored using the Profile of Mood States (POMS) and a shortened version of the Addiction Research Center Inventory (ARCI). Subjects in all three groups chose 5 mg diazepam as often as placebo but preferred placebo to 10 mg diazepam. In contrast, they chose amphetamine either as often as or more often than placebo. The subjective effects of diazepam (i.e. sedation) were similar across all three groups, but after amphetamine the AGE group showed greater stimulant effects. In addition, the AFT group showed fewer positive mood effects after amphetamine than the CTL group. The AFT and AGE groups also differed from the CTL group on several measures of mood, independently of drug administration. Despite the modest group differences in subjective effects, it was concluded that neither time of day nor age of subjects substantially affected the reinforcing properties of either drug.     

Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers.

Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg-1 in 10 normal, healthy, male volunteers, using a two-period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg-1 was administered every 12 h as a 30-min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg-1) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12 mg kg-1, median pharmacokinetic parameters included: steady-state volume of distribution of 1.4 and 1.2 l kg-1; total clearance of 12.2 and 14.0 ml h-1 kg-1; renal clearance of 11.1 and 10.3 ml h-1 kg-1; and terminal disposition half-life of 159 and 155 h, respectively. No statistically significant dose-related difference was observed. In addition, a cross-study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg-1.     

Modified sensitivity to pentobarbital in a continuous avoidance situation

Summary Rats were trained on a continuous avoidance schedule where the response was running from one end of a box to the other. In this situation hypers sensitivity to 15 mg/kg of sodium pentobarbital was found, when this dose wainjected before a previous dose was completly metabolized but after the behavior had returned to baseline. Acute tolerance was observed after injections of 40 mg/kg of pentobarbital intraperitoneally and 500 g intraventricularly. The latter finding suggested a CNS component tolerance. The nonsignificant difference in the half life indices of the drug suggested the same recovery rate for tolerance and nontolerance animals, which was not consistent with the hypothesis of increased hepatic metabolism as the mechanism of tolerance after single preinjections.This research was supported by USPHS Grant No. MH-06997-03 to Indiana University.     

Drug preference and mood in humans: d-amphetamine

A total of 31 normal human volunteers participated in a nine-session experiment. During the first four sessions, they received alternately 5 mg d-amphetamine or placebo. During the next five sessions, they were given a choice between amphetamine and placebo. Subjective effects were assessed using the Profile of Mood States (POMS) before the drug was taken and 1, 3, and 6 h later. Subjects chose amphetamine a mean of 4.03 times. Compared with placebo, amphetamine produced changes in mood on the POMS including increased Vigor, Elation, Friendliness, Arousal and Positive Mood and decreased Confusion. These differences were greatest 3 h after ingestion. Mood changes produced by d-amphetamine were comparable in all subjects regardless of the actual number of times each chose the drug. These data suggest that that subjective effects do not predict drug choice. The results are discussed in terms of developing methods for predicting the abuse potential of psychotropic drugs.Portions of these data have been previously reported in a chapter entitled Drug Self-Administration in Humans by the same authors which appeared in Self-Administration of Abused Substances: Methods for Study. National Institute on Drug Abuse. Research Monograph Series No. 20, pp. 68–85 (1978)     

Comparison of ethanol,pentobarbital, and phenobarbital using drug vs. drug discrimination training

Rats learned drug vs. drug (D vs. D) or drug vs. no drug (D vs. N) discriminations in a T-maze shock-escape task with various doses of pentobarbital, phenobarbital, or ethanol. Dose-effect curves were obtained for each drug using D vs. N training. After D vs. N training with any one of these drugs, rats made D choices during substitution tests with the other two drugs, suggesting drug interchangeability. D vs. D training also showed that pentobarbital and phenobarbital were virtually indistinguishable from one another. However, ethanol was readily discriminated from pentobarbital, showing that the two drugs differed. The results show the utility of D vs. D training as a method for studying drug differences that may be too small to detect with substitution tests.     

Drug preference and mood in humans: Preference for d-amphetamine and subject characteristics

Forty-five normal, young, adult volunteers participated in a nine-session experiment. During the first four sessions, they received alternately 5 mg d-amphetamine or placebo. During the next five sessions, they chose between amphetamine and placebo. On the basis of the choice results, subjects retrospectively were divided into the following three groups: (1) five of five drug choices (N=16), (2) four of five drug choices (N=12); and (3) 0–3 of five drug choices (N=17). There was an overall average of 3.76 drug choices per subject. These groups were compared by demographic characteristics, drug use history, and several personality measures, but none predicted drug choice. However, subjects who chose drug on every occasion had significantly higher predrug scores on the anxiety, depression, and confusion subscales of the Profile of Mood States (POMS). The functional relationship between initial dysphoria and consistent amphetamine choosing remains an intriguing question.     

Drug preference and mood in humans: Diazepam

A group of ten normal human volunteers participated in choice experiments comparing d-amphetamine or diazepam with placebo and with each other. Although amphetamine was preferred to placebo by most subjects, 2 mg diazepam and placebo were chosen equally. However, placebo was chosen over higher doses (5 and 10 mg) of diazepam and 5 mg d-amphetamine was preferred to 2 mg diazepam. Subjective effects were assessed using the Profile of Mood States (POMS) before drug was taken and 1, 3, and 6 h later. Compared to placebo, amphetamine produced changes in mood on the POMS including increases in Vigor and Arousal. Doses of 5 and 10 mg diazepam produced decreases in Vigor and Arousal and increases in Fatigue and Confusion. The effects of diazepam were most pronounced 1 h after ingestion and appeared dose-dependent. For one subject who consistently chose diazepam, its subjective effects were similar to placebo and he stated that he could not distinguish them. These results are discussed in terms of the abuse liability of diazepam.Portions of these data have been previously reported in a chapter entitled Drug Self-Administration in Humans by the same authors which appeared in Self-Administration of Abused Substances: Methods for Study. National Institute on Drug Abuse. Research Monograph Series, No. 20, pp. 68–85 (1978)     

Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers

RATIONALE: Ketamine is an NMDA receptor antagonist with psychotogenic and cognitive effects in healthy volunteers and schizophrenic patients which has been proposed to be a useful tool to investigate neurobiological basis of schizophrenia. OBJECTIVE: The present study characterized the effects of a subanesthetic dose of ketamine on memory and related subjective states of awareness in healthy volunteers. METHODS: Twenty-six subjects were given either a 60-min ketamine (0.5 mg/kg per hour) or a placebo infusion. To obtain constant plasma ketamine throughout the experiment, ketamine was administered using a computer-controlled infusion system. Subjects carried out episodic memory tasks involving words presented before and during infusion. Memory performance was assessed with recognition and free recall tasks. Subjective states of awareness were assessed using an experiential approach. Levels of psychopathology were evaluated with BPRS. RESULTS: Ketamine impaired performance in free recall and recognition of words presented during, but not before, infusion. There were no differences between groups concerning states of awareness associated with recognition memory. Subjects under ketamine had higher BPRS total scores as well as BPRS negative and positive cluster scores than control subjects. CONCLUSIONS: Ketamine decreases episodic memory performance by impairing encoding, but not retrieval processes. It does not selectively impair subjective states of awareness associated with recognition memory as it has been seen in patients with schizophrenia. Ketamine might mimic the memory impairment associated with acute, but not chronic, forms of schizophrenia.     

Intravenous self-administration of pentobarbital and ethanol in rats

Rats provided with unlimited access to intravenous doses of ethanol (30, 60, 90, 180, and 360 mg/kg/infusion) failed to initiate and maintain lever pressing that resulted in ethanol delivery. When pentobarbital (0.5 mg/kg/infusion) was substituted for ethanol, lever pressing increased. There were three indications of the positive reinforcing effects of pentobarbital: (1) a greater number of lever presses occurred when pentobarbital was response-contingent than when saline was available; (2) a greater number of responses were made on the pentobarbital lever than on a control "activity" lever; and (3) systematic changes in lever pressing were a function of pentobarbital dose (0.125, 0.25, 0.5, 1.0, and 2.0 mg/kg/infusion). Sequential substitution of ethanol (30, 90, 360 mg/kg/infusion) for pentobarbital failed to maintain lever pressing. However, access to combinations of ethanol (1, 3, 10, 30, 60 mg/kg/infusion) and a nonreinforcing dose of pentobarbital (0.125 or 0.25 mg/kg/infusion) did maintain lever pressing. As the dose of ethanol increased, the daily number of infusions first increased then decreased. Following a history of self-administration of ethanol-pentobarbital combinations, a retest of ethanol alone (10 or 30 mg/kg/infusions) followed by pentobarbital alone (0.125 or 0.25 mg/kg/infusion) failed to maintain lever pressing.     

Drug preference and mood in humans: Repeated assessment of d-amphetamine

Ten normal human volunteers participated in 3 identical choice experiments comparing 5 mg d-amphetamine and placebo. Each experiment consisted of 9 sessions. During the first 4 sessions of each experiment, subjects received alternatively drug or placebo. During the next 5 sessions, they were given a choice between amphetamine and placebo. Subjective effects were assessed using the Profile of Mood States (POMS) before drug was taken and 1, 3 and 6 hrs later. Subjects chose amphetamine an average of 4.0, 3.2 and 2.1 times out of 5 during each of the three experiments, in that order. Compared to placebo, amphetamine produced changes in mood as measured by the POMS including increased Vigor, Elation, Arousal and Positive Mood. Mood changes produced by amphetamine were similar across all three experiments despite the decrease in drug preference, suggesting the independence of these two measures. The results are discussed in terms of developing methods for predicting the abuse potential of psychotropic drugs.     

Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing

Summary Twenty-four healthy volunteers participated in a study on the disposition of ergotamine following oral and rectal administration. Plasma samples were collected surrounding each dose of medication and a new mass spectrometry method was used for quantitation of the samples. A mean peak plasma concentration of 454 pg/ml was measured an average of 50 min following a 2 mg rectal dose. In contrast, the 2 mg oral dose produced a mean peak plasma concentration of 21 pg/ml an average of 69 min following the dose. Area under the concentration time curve indicated a relative bioavailability of 5% for the oral dosage form. Conflicting data on ergotamine disposition highlight the factors which may be responsible for determining bioavailability and pharmacologic activities of the compound.Presented in part at the 86th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, Texas USA, March 28, 1985