Subjective and physiological effects of acute intranasal methamphetamine during d-amphetamine maintenance

Abstract

Rationale Methamphetamine abuse and dependence are significant public-health concerns. Behavioral therapies are effective for reducing methamphetamine use. However, many patients enrolled in behavioral therapies are unable to achieve significant periods of abstinence, suggesting other strategies like pharmacotherapy are needed. Objectives This experiment determined the subjective and physiological effects of intranasal methamphetamine during D-amphetamine maintenance in eight non-treatment-seeking stimulant-dependent participants. We predicted D-amphetamine maintenance would attenuate the acute subjective effects of intranasal methamphetamine. We also predicted intranasal methamphetamine would be well tolerated during D-amphetamine maintenance. Methods After at least 7 days of maintenance on sustainedrelease D-amphetamine (0 and 45 mg/day), participants were administered ascending doses of intranasal methamphetamine (0, 2.5, 5, 10, and 20 mg) across two experimental sessions. Intranasal methamphetamine doses were separated by 90 min. Results Intranasal methamphetamine produced prototypical subjective and physiological effects (e.g., increased ratings of Like Drug; increased heart rate, blood pressure, and body temperature). The acute effects of intranasal methamphetamine were significantly diminished during D-amphetamine maintenance relative to placebo maintenance. Conclusions These results are concordant with those of clinical trials and provide further support for the use of agonist replacement therapy to manage methamphetamine dependence. Additional research in humans is needed to determine the effectiveness of D-amphetamine under different experimental conditions that more closely reflect use in the natural environment (e.g., higher methamphetamine doses) and behavioral arrangements that are predictive of pharmacotherapy effectiveness (e.g., drug self-administration).

Methamphetamine Self-Administration in Humans During d-Amphetamine Maintenance

“…d -Amphetamine maintenance attenuated some of the positive subject-rated drug-effects, which is consistent with a previous study that showed 45 mg/day d -amphetamine reduced the subject-rated drug-effects of methamphetamine (8). The attenuation of subject-rated drug-effects indicates that subject-rated drug-effects may have less predictive validity to model results observed in the clinic, leading to false positives.…”

“…Few studies have tested agonist replacement for methamphetamine. The results of a recent safety and tolerability study showed that 45 mg/day d -amphetamine significantly reduced subject-rated drug-effects of methamphetamine (0, 2.5, 5, 10, 20 mg) in stimulant-dependent individuals compared to placebo, however this study did not assess self-administration of methamphetamine (8). Previous research has shown that self-administration may have better predictive validity for outcomes observed in clinical trials (reviewed in: 9, 10).…”

Offending: Drug-related expertise and decision making

“…No methamphetamine-induced disruptions were observed in any cognitive domain. The findings are consistent with outcomes from similar intranasal studies: Kirkpatrick, Metcalfe, Greene, and Hart (2008) showed enhanced metacognition with methamphetamine (12 mg) while Rush et al (2011) reported improved visuospatial perception (10, 20 mg). Similar results have been found with the intravenous administration of methamphetamine abusers (Johnson et al, 2005(Johnson et al, , 2007.…”

Methamphetamine self-administration in humans during d-amphetamine maintenance

“…Finally, methamphetamine dose dependently increased systolic blood pressure and d-amphetamine maintenance attenuated these increases, compared to placebo maintenance. These findings are consistent with the results of prior studies that showed intranasal methamphetamine is safe and well-tolerated in a controlled laboratory setting (8,16,17,(22)(23)(24) and that d-amphetamine maintenance reduces some of the cardiovascular effects of methamphetamine (8). The attenuation of cardiovascular effects of methamphetamine during d-amphetamine maintenance may be attributable to participants developing cross-tolerance to the cardiovascular effects of stimulants.…”

“…Few studies have tested agonist replacement for methamphetamine. The results of a recent safety and tolerability study showed that 45 mg/day d-amphetamine significantly reduced subject-rated drug-effects of methamphetamine (0, 2.5, 5, 10, 20 mg) in stimulant-dependent individuals compared to placebo, however this study did not assess self-administration of methamphetamine (8). Previous research has shown that self-administration may have better predictive validity for outcomes observed in clinical trials (reviewed in: 9, 10).…”