Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy

Abstract

Agonist replacement therapies are effective for managing substance abuse disorders including nicotine and opioid dependence. The results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This experiment determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants. We predicted cocaine would be well tolerated during D-amphetamine maintenance. We also predicted D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg, i.n.) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Additional research in humans is needed to determine whether D-amphetamine attenuates the effects of cocaine under different experimental conditions (e.g., higher cocaine doses) and behavioral arrangements (e.g., drug self-administration or discrimination).

Figure 1

Peak effect dose-response functions for cocaine during maintenance on placebo (squares), 15 mg/day d-amphetamine (circles), and 30 mg/day d-amphetamine (triangles) for heart rate, systolic blood pressure, and body temperature. X-axis: Intranasal cocaine dose. Data points represent means for seven volunteers. Filled symbols indicate the data point differs significantly from the placebo condition (i.e., 4 mg cocaine during maintenance on 0 mg d-amphetamine. An asterisk indicates that the data point is significantly different from the corresponding dose of cocaine during maintenance on 0 mg d-amphetamine). Unidirectional error bars (S.E.M.) are shown for clarity.

Figure 2

Peak effect dose-response functions for cocaine during maintenance on placebo (squares), 15 mg/day d-amphetamine (circles), and 30 mg/day d-amphetamine (triangles) for subject ratings of Any Effect, High, Good Effects, Like Drug, Willing to Pay For, and Willing to Take Again from the Drug-Effect Questionnaire. X-axis: Intranasal cocaine dose. The range of possible scores on these items is 0–4. Data points represent means for seven volunteers. Filled symbols indicate the data point differs significantly from the placebo condition (i.e., 4 mg cocaine during maintenance on 0 mg d-amphetamine). An asterisk indicates that the data point is significantly different from the corresponding dose of cocaine during maintenance on 0 mg d-amphetamine. Unidirectional error bars (S.E.M.) are shown for clarity.

Figure 3

Peak effect dose-response functions for cocaine during maintenance on placebo (squares), 15 mg/day d-amphetamine (circles), and 30 mg/day d-amphetamine (triangles) for subject ratings of Good Effects, Like Drug, and Willing to Pay For from the Visual Analog Scales. X-axis: Intranasal cocaine dose. The range of possible scores on these items is 0–100. Data points represent means for seven volunteers. Filled symbols indicate the data point differs significantly from the placebo condition (i.e., 4 mg cocaine during maintenance on 0 mg d-amphetamine). An asterisk indicates that the data point is significantly different from the corresponding dose of cocaine during maintenance on 0 mg d-amphetamine. Unidirectional error bars (S.E.M.) are shown for clarity.