Pilot safety evaluation of varenicline for the treatment of methamphetamine dependence

Todd Zorick, Rajkumar J Sevak, Karen Miotto, Steven Shoptaw, Aimee-Noelle Swanson, Clayton Clement, Richard De La Garza 2nd, Thomas F Newton, Edythe D London, Todd Zorick, Rajkumar J Sevak, Karen Miotto, Steven Shoptaw, Aimee-Noelle Swanson, Clayton Clement, Richard De La Garza 2nd, Thomas F Newton, Edythe D London

Abstract

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: acetylcholine; methamphetamine; nicotinic; safety; treatment; varenicline.

Figures

Figure 1
Figure 1
Time-course of effects of methamphetamine (MA) and saline varenicline or placebo maintenance on systolic pressure (top panel), diastolic pressure (middle panel) and heart rate (bottom panel). Notes: The data collected during infusion sessions in phase I (day 9) and phase II (day 7) are shown. X-axis: Time in min, relative to the first MA infusion. Data are expressed as mean of eight participants. Unidirectional brackets indicate one standard error of mean.
Figure 2
Figure 2
Average BDI scores across study conditions during test compound administration (varenicline and placebo). BDI scores were recorded in the mornings after each dose of both varenicline and placebo study conditions, and were averaged across both study conditions and participants. Notes: Bars represent mean of eight participants and 64 measurements for placebo, 63 for varenicline. Unidirectional brackets indicate one standard deviation. Abbreviation: BDI, Beck’s Depression Inventory.

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Source: PubMed

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