Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers

Acetylcholine (ACh) has been implicated in the reinforcing and locomotor-activating effects produced by methamphetamine (Meth). Of interest, recent data suggest that acetylcholinesterase (AChE) inhibitors attenuate Meth-seeking behaviour in rats. We conducted this study in order to determine the safety (adverse events, mood changes, cardiovascular effects) and preliminary efficacy (subjective effects) of the AChE inhibitor rivastigmine (Riv) when tested in combination with Meth. Twenty-three non-treatment-seeking Meth-dependent participants resided in an in-patient unit at UCLA for 2 wk, and completed this double-blind, between-subjects, placebo-controlled study. Prior to randomization to study drug, infusions of saline (day 4, 0 mg i.v.) and Meth (day 5, 30 mg i.v.) were given to all participants at 11:30 hours in single-blinded fashion. On day 7 and continuing to day 11, participants were randomized to receive oral placebo (0 mg, n=7) or Riv, (1.5 mg, n=7; 3 mg, n=9). On day 11, the subjects received saline and Meth infusions again (randomized to either 11:30 or 14:30 hours), under double-blind conditions. The data analyses compared across-study measures of adverse events and mood, and a post-randomization analysis of cardiovascular and subjective effects (on day 11). The data reveal that rivastigmine was not associated with increased adverse events or alterations in mood. As expected, acute Meth exposure (30 mg i.v.) increased heart rate and blood pressure, as well as several positive subjective effects, Addiction Research Center Inventory (ARCI) ratings, and reported monetary value (p < 0.05). The data indicated that Riv, at 3 mg, significantly attenuated Meth-induced increases in diastolic blood pressure, and self-reports of 'anxious' and 'desire' (p < 0.05). Taken together, the findings in the current report Suggest that pharmacological manipulations that enhance brain ACh warrant continued investigation as potential treatments for Meth addiction.