Chris E. Johanson

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.

Self-administration of psychomotor stimulant drugs: the effects of unlimited access.

Rhesus monkeys surgically prepared with intravenous catheters were given 23 hr daily access to injection of either cocaine, d-amphetamine, 1-amphetamine, d-methamphetamine or diethylpropion on a fixed ratio 1 schedule of reinforcement for a maximum of 30 days. Responding was maintained by all these drugs but showed both day-to-day and hour-to-hour variability. The two animals self-administering 0.2 mg/kg/infusion cocaine died in less than 5 days. All 6 animals given access to 0.05 mg/kg/infusion d-amphetamine or 0.025 mg/kg/infusion d-methamphetamine also died, but tended to survive more days than animals exposed to cocaine. Three of the 5 animals whose responding was maintained by 0.5 mg/kg/infusion diethylpropion and one of the two animals whose responding was maintained by 0.05 mg/kg/infusion 1-amphetamine survived the entire 30 days despite high rates of intake. Food intake was initially decreased, but often returned to predrug levels and was not related to level of drug intake.

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.

Amphetamine induces depletion of dopamine and loss of dopamine uptake sites in caudate

Long-lasting depletion of dopamine and concomitant loss of dopamine uptake sites follow repeated administration of methylamphetamine to rats. We found similar effects after similar treatment with d-amphetamine, but not after treatment with methylphenidate. Methylphenidate also failed to produce long-term depletion of regional catecholamine levels in rhesus monkeys. These long-lasting alterations of the dopaminergic system suggest that amphetamines or their metabolites have toxic interactions with dopaminergic neurons, which do not occur with methylphenidate.

Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys.

The effects of prolonged exposure to high doses of stimulants on stimulant self-administration in rhesus monkeys have not been established. In the present experiment, rates of methamphetamine self-administration as well as the effects of methamphetamine on food-maintained responding were determined before and after a regimen of repeated methamphetamine injections. Increases in self-administration of some doses of methamphetamine as well as tolerance to the rate-decreasing effects of the drug on food-maintained responding were observed following the repeated injection regimen. The results suggest that while tolerance may develop to the rate-decreasing effects of the drug, there may be an increased sensitivity to its reinforcing properties. In addition, since this injection regimen has been shown in previous studies to deplete central monoamines, especially dopamine, the results suggest a role for these monoamines in these behavioral effects of methamphetamine.

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.

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.

Reinforcing and subjective effects of caffeine in normal human volunteers

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults. Subjects (eight females, ten males) were light to moderate users of caffeine, and had no history of drug abuse. A discrete-trial choice procedure was used in which subjects were allowed to choose between the self-administration of color-coded capsules containing either placebo or caffeine. The number of times caffeine was chosen over placebo was used as the primary index of reinforcing efficacy. Subjective effects were measured before and several times after capsule ingestion. The low dose of caffeine was chosen on 42.6% of occasions, not significantly different from chance (50%). The high dose of caffeine was chosen on 38.9% of occasions, significantly less than expected by chance, indicating that this dose served as a punisher. Both doses of caffeine produced stimulant-like subjective effects, with aversive effects such as increased anxiety predominating after the high dose. When subjects were divided into groups of caffeine-sensitive choosers and nonchoosers, a consistent relationship emerged between caffeine choice and subjective effects; nonchoosers reported primarily aversive effects after caffeine (increased anxiety and dysphoria), whereas choosers reported stimulant and “positive” mood effects. When compared with previous findings, these results demonstrate that caffeine is less reinforcing than amphetamine and related psychomotor stimulants.

Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers

The discriminative stimulus (DS) and subjective effects of caffeine (100 and 300 mg, PO) and benzphetamine (12.5 and 50 mg, PO) were studied in 18 normal human volunteers trained to discriminate between d-amphetamine (10 mg) and placebo. d-Amphetamine increased ratings of drug liking and activity level and produced a profile of subjective effects characteristic of amphetamine and related psychomotor stimulants. The DS effects of d-amphetamine generalized only partially to caffeine and benzphetamine; mean percent d-amphetamine-appropriate responding was 42 and 58 after 100 and 300 mg caffeine, respectively, and 17 and 56 after 12.5 and 50 mg benzphetamine, respectively. Neither dose of caffeine affected ratings of drug liking or activity level, but 300 mg caffeine did produce a profile of subjective effects that partially overlapped with that produced by d-amphetamine. Benzphetamine 50 mg, but not 12.5 mg, increased ratings of drug liking and activity level and produced a profile of subjective effects qualitatively similar to, but weaker than, that produced by d-amphetamine. For both caffeine and benzphetamine, a close relationship was observed between their subjective effects and their ability to substitute for the DS effects of d-amphetamine. These results correspond well with findings obtained from similar studies conducted with laboratory animals, providing further support for the reliability and validity of human drug discrimination paradigms.