Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study

Abstract

Background: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers.

Methods: Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected.

Results: Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects.

Conclusions: Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.

Keywords: human laboratory study; methamphetamine; renin-angiotensin system.

Figure 1.

Timeline of study events, including methamphetamine (METH) and perindopril dosing.

Figure 2.

Participant flow, including the number of participants assessed for eligibility, randomized to a treatment group, and analyzed for the placebo (0mg; n=17) and 4-mg (n=14), 8-mg (n=16) and 16-mg (n=12) perindopril treatment groups.

Figure 3.

Posttreatment mean ratings of anxious across methamphetamine (METH) doses (0, 15, and 30mg). Comparisons across treatment doses revealed a significant (P=.0019) main effect of treatment dose. The asterisk (*) indicates that anxious ratings were significantly (P=.0009) lower in the 8-mg treatment group compared with the placebo treatment group. Data are presented as means ± SEs for the 0-mg (n=17), 4-mg (n=14), 8-mg (n=16), and 16-mg (n=12) perindopril groups.

Figure 4.

Posttreatment mean ratings of stimulated across methamphetamine (METH) doses (0, 15, and 30mg). Comparisons across treatment doses revealed a significant (P<.0001) main effect of treatment dose. The asterisk (*) indicates that stimulated ratings were significantly (P=.0070) lower in the 8-mg treatment group compared with the placebo treatment group. Data are presented as means ± SEs for the 0-mg (n=17), 4-mg (n=14), 8-mg (n=16), and 16-mg (n=12) perindopril groups.