Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers

Abstract

Methamphetamine is a highly addictive stimulant and long-term exposure leads to reductions in dopamine. One therapeutic strategy is to develop and test compounds that normalize dopamine. The primary aim of this study was to determine the safety of modafinil treatment during methamphetamine exposure in a controlled clinical setting. Methamphetamine-dependent volunteers (N=13), who were not seeking treatment, were randomized to receive either modafinil (200mg, PO) or matching placebo over three days (Days 1-3 or Days 8-10). On Day 1, subjects were randomized to modafinil or placebo in the morning, and then 3 and 6h later received infusions of methamphetamine (0 and 30 mg, i.v.), after which cardiovascular and subjective effects were assessed. On Day 3, participants completed i.v. self-administration sessions during which they made 10 choices for low doses of methamphetamine (3mg, i.v.) or saline. Days 4-7 were used as a washout period. On Day 8 participants were assigned to the alternate study medication (placebo or modafinil), and the same testing procedures were repeated through Day 10. The data reveal that modafinil treatment was well-tolerated and not associated with increased incidence of adverse events. In general, modafinil reduced by approximately 25% ratings of methamphetamine-induced "Any Drug Effect", "High", and "Want Methamphetamine", and reduced total number of choices for methamphetamine and monetary value of methamphetamine, though none of these measures reached statistical significance. Given these encouraging, though non-significant trends, the primary conclusion is that it appears safe to proceed with modafinil in further clinical evaluations of therapeutic efficacy.

Figure 1

Change in heart rate (upper panel) and systolic blood pressure (lower panel) following infusions of methamphetamine (0 and 30 mg, i.v.) as a function of drug (modafinil; N=13 or placebo; N=13) and time (in min). Values represent change from baseline (given time-point minus t=−15 min). Data represent the mean ± S.E.M. from methamphetamine-dependent participants on Days 1 and 8 of the protocol.

Figure 2

Change in “High” (upper panel) and “Want Methamphetamine” (middle panel) following infusions of methamphetamine (0 and 30 mg, i.v.) as a function of drug (modafinil; N=13 or placebo; N=13) and time (in min). Values represent change from baseline (given time-point minus t=−15 min). The lower panel represents monetary value following infusions of methamphetamine (0 and 30 mg, i.v.) as a function of drug (modafinil; N=13 or placebo; N=13). All data represent the mean ± S.E.M. from methamphetamine-dependent participants on Days 1 and 8 of the protocol.

Figure 3

Self-administration of methamphetamine (0 and 3 mg, i.v.) as a function of drug (modafinil; N=13 or placebo; N=12). Data represent the mean ± S.E.M. from methamphetamine-dependent participants on Days 3 and 10 of the protocol.