E. H. Uhlenhuth

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.

INDIVIDUAL DIFFERENCES IN THE REINFORCING AND SUBJECTIVE EFFECTS OF AMPHETAMINE AND DIAZEPAM

This study explored the relation between the reinforcing properties of different drugs and their subjective effects. Preference for a drug (amphetamine or diazepam) over placebo was measured in a choice procedure, and mood changes after drug administration were monitored by self-report questionnaires. Individual differences in behavioral drug preferences were then examined for their relationships to subjective drug responses as well as other subject variables. In Part I, the subjective effects of amphetamine were compared in those subjects who consistently preferred (i.e. chose) amphetamine over placebo, and those who preferred placebo over amphetamine. The two subject groups showed markedly different subjective responses to the stimulant drug: the choosers reported increased positive mood and euphoria, whereas the non-choosers reported only increased anxiety and depression. In Part II, the subjective effects of diazepam in consistent choosers of diazepam were compared to the subjective effects in consistent non-choosers of the drug. The non-choosers showed appreciable subjective effects, which were predominantly sedative in quality. In contrast to the results with amphetamine, the choosers showed negligible subjective drug effects. These results underline the importance of considering more than one response measure when attempting to characterize the reinforcing effects of drugs.

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.

Moclobemide in social phobia: A controlled dose-response trial

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

A cross-national comparison of anti-anxiety/sedative drug use

Findings are reported from a 1981 cross-national survey of the use of anti-anxiety/sedative medications by adults in the general population of the United States and 10 Western European countries. Representative national samples in the 11 countries were asked a standard set of questions about their use of these medications during the preceding 12 months. Data were obtained by personal interview in the course of a household visit. The number of persons interviewed ranged from 1486 to 2018. The data provide comparable estimates of past-year prevalence of use-the proportion of the population who took these medications one or more times, and duration of use-and the proportion of the population who took these medications daily for various lengths of time. Rates for past-year prevalence of use varied from 17.6% in Belgium to 7.4% in the Netherlands. The United States at 12.9% was in the middle of the distribution. There was wide variation among countries in the prevalence of long-term and short-term use, but regular daily use for 3 months or less was the predominant pattern in 10 of the 11 countries surveyed. Past-year prevalence rates were much higher for women than for men in every country surveyed. At the national level, the data show that simple past-year prevalence rates and durational parameters of use are relatively independent.

Drug, doctor's verbal attitude and clinic setting in the symptomatic response to pharmacotherapy

Summary138 psychoneurotic outpatients manifesting anxiety were treated for 6 weeks with medication and brief, supportive interviews every 2 weeks with a psychiatric resident. The patients were divided among 12 different treatment conditions composed of 1. meprobamate 1,600 mg q.i.d. versus an identical placebo in a double-blind arrangement, 2. a doctor expressing an enthusiastic attitude toward the medication versus a doctor expressing a skeptical attitude toward the medication and 3. three different psychiatric outpatient clinics.The patients symptomatic condition was assessed at each visit by means of five ratings made by the patient before each interview and three ratings made by his doctor afterward. These ratings included an overall judgment of change, a checklist of 64 common symptoms, a score based on the patients presenting complaints and adjective checklists for registering anxiety and depression.The results at one clinic showed the expected interaction between medication and doctors expressed attitude: with the enthusiastic doctors, patients taking meprobamate improved more than patients taking placebo; whereas with the skeptical doctors, patients taking placebo tended to improve more than patients taking meprobamate. At the other two clinics, however, this interaction was absent or possibly reversed, with meprobamate tending to be superior to placebo with skeptical doctors.Some striking clinic differences among the characteristics of patients were found, particularly in social class status and the commonly associated styles of complaint and goals and expectations regarding treatment. The clinic showing the anticipated interaction between medication and doctors verbal attitude had patients with the lowest social class standing. The doctors at this clinic also came from backgrounds of lower social class than the doctors at the other two clinics. These differences suggest that the participants at this clinic may have assigned meanings to the enthusiastic and the skeptical attitudes contrasting with the meanings assigned at the other two clinics. The possible relevenace of these differences to the results is discussed.

The discriminative stimulus and subjective effects of phenylpropanolamine, mazindol and d-amphetamine in humans

The discriminative stimulus (DS) and subjective effects of two anorectic drugs, phenylpropanolamine (PPA) and mazindol (MAZ), were studied in a group of normal, healthy adults trained to discriminate between placebo and 10 mg d-amphetamine (AMP). Of 20 subjects who underwent discrimination training, 12 (discriminators) reliably learned the AMP-placebo discrimination. Each discriminator was tested with two doses of PPA (25 and 75 mg) and two doses of MAZ (0.5 and 2.0 mg) to determine whether the DS effects of these drugs would substitute for those of AMP. The high dose of each drug produced primarily (approximately 80%) drug-appropriate responding, whereas the low dose of each drug resulted in primarily placebo-appropriate responding. The subjective effects of PPA were a biphasic function of dose, with 25 mg producing mild sedative-like effects and 75 mg producing stimulant-like effects similar to, but weaker than, those obtained with AMP. MAZ, on the other hand, produced only a few changes in mood (increased anxiety, decreased hunger). Thus, although both PPA and MAZ substituted for AMP in terms of discrimination responding, only PPA produced AMP-like subjective effects. These results provide evidence for a dissociation between the subjective effects (as measured by self-report questionnaires) and the DS effects of drugs in humans.

Personality dimensions in panic disorder and generalized anxiety disorder

To make a dimensional assessment of personality in individuals with pathological anxiety, the Tridimensional Personality Questionnaire (TPQ) was administered to 32 patients with panic disorder (PD) and 49 patients with generalized anxiety disorder (GAD). The most striking findings were a substantially increased score on the harm avoidance dimension in both groups of patients, and a lack of significant differences between the TPQ scores in patients with PD and GAD. The former finding suggests that higher levels of harm avoidance may be common to (although not necessarily specific for) various types of anxiety disorders. The latter finding is in agreement with the findings that PD and GAD do not differ significantly with respect to the associated personality disorder diagnoses, which may further cast a doubt on the validity of the distinction between PD and GAD.

The discriminative stimulus and subjective effects of d-amphetamine in humans

Seventeen normal, healthy adults were trained to discriminate between orally administered d-amphetamine (AMP; 10 mg) and placebo. Standardized subjective effects questionnaires were used to examine the relationship between the subjective and discriminative stimulus effects of AMP. Seven of the subjects were able to learn the discrimination reliably. These seven “discriminators” did not differ from the ten “nondiscriminators” in their subjective ratings of mood in the absence of drug. Discriminators were generally more sensitive than nondiscriminators to the subjective effects of AMP, although this difference in sensitivity reached statistical significance only for ratings of “hungry.” Stimulus substituion was tested in the discriminators with other doses of AMP (2.5 and 5 mg) and with 10 mg diazepam. The discriminative stimulus properties of AMP were dose-dependent, with 5 mg being the threshold dose. In five of the seven subjects the discriminative stimulus properties of diazepam did not substitute for those of AMP. The results demonstrate that the experimental paradigm can be used successfully to study the discriminative stimulus properties of drugs directly in humans.

Smooth-pursuit eye movements, and diazepam, CPZ, and secobarbital

This study examined the effects on smooth-pursuit eye tracking of single doses of CPZ (0.667 and 1.334 mg/kg), diazepam (0.071, 0.142, and 0.284 mg/kg), and secobarbital (100 mg). Only the barbiturate significantly affected the ability to follow a moving target with smooth-pursuit eye movements. In repeated testing of a single subject, 130 mg of secobarbital disrupted smooth-pursuit movements at least until 24 hrs after ingestion.