Rivastigmine as a Treatment for Methamphetamine Dependence

We recently completed a double-blind placebo-controlled human laboratory study demonstrating
that treatment with a low dose of the acetylcholinesterase (AChE) inhibitor rivastigmine
reduced methamphetamine (METH)-induced craving (see Preliminary Studies, Fig. 2). This
finding is consistent with the preclinical report indicating that the AChE inhibitor
donepezil reduced METH-seeking behavior in rats following exposure to a non-contingent dose
of METH (Hiranita et al. 2006). To extend our clinical findings, we propose a 3-year human
laboratory study to evaluate effects of higher doses of rivastigmine on METH-induced craving
and on self-administration of METH. Our recently completed work indicates that 3mg
rivastigmine attenuated METH-induced craving in the laboratory. Given that higher dosages of
this produce greater inhibition of nicotinic acetylcholine (ACh) receptors (in the treatment
of Alzheimer's disease), it is reasonable to predict that 6mg and 12mg will have more
pronounced effects on craving and other measures of reinforcement. This human laboratory
study is a critical next step in the evaluation of rivastigmine as a potential treatment for
METH dependence. We propose to include only participants exhibiting METH-induced craving by
screening potential participants prior to admission (criterion based upon Preliminary
Studies, Fig. 5). Selection of participants demonstrating METH-induced craving will
facilitate assessment of effects of rivastigmine on craving. The project has the following
objectives:

Primary Objective: To characterize the effects of treatment with rivastigmine (0, 3, and 6
mg) on craving produced by experimental administration of METH (0, 15 and 30mg, IV).

Secondary Objective: To characterize the effects of treatment with rivastigmine (0, 3, and 6
mg) on choices for METH exhibited in a self-administration paradigm (0 and 5mg, IV).