Pilot safety evaluation of varenicline for the treatment of methamphetamine dependence

Todd Zorick1, Rajkumar J Sevak1, Karen Miotto1, Steven Shoptaw2,4, Aimee-Noelle Swanson2, Clayton Clement1, Richard De La Garza II1*, Thomas F Newton1*, Edythe D London1,3,41Departments of Psychiatry and Biobehavioral Sciences, 2Family Medicine, 3Molecular and Medical Pharmacology, 4The Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA; *Present address: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USAAbstract: Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4b2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over one week to reach 1 mg twice daily, and then was co-administered with 30 mg methamphetamine, delivered in 10 intravenous (iv) infusions of 3 mg each. Varenicline was found to be safe in combination with iv methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence.Keywords: varenicline, methamphetamine, treatment, safety, nicotinic, acetylcholine