Varenicline (2 mg daily dose) was well-tolerated in the MA-dependent participants who also were cigarette smokers, and had been pre-screened to exclude individuals with substantial medical or psychiatric co-morbidities. No significant differences were observed between the effects of varenicline and placebo in terms of overall adverse events, depressive symptoms, or cardiovascular parameters. Moreover, there was no association between the varenicline treatment and propensity to discontinue the study. Therefore, the present data are consistent with the previously documented safety and tolerability of varenicline treatment in healthy tobacco-dependent subjects with no pre-existing psychiatric or medical conditions.9,11–13
While randomized controlled trials have shown varenicline to be safe and well-tolerated in healthy participants, many case reports of neuropsychiatric disturbances coincident with varenicline treatment have been published recently, eg,.14
Post-marketing surveillance by the FDA has led to the issuance of a “black box warning” about the potential for “serious neuropsychiatric symptoms” for varenicline in July of 2009.15
These concerns have also been addressed by two recent retrospective studies.16,17
In a cohort study of 2700 patients taking varenicline, two suicide attempts were noted in patients with pre-existing psychiatric illness.16
In a retrospective review of 50 patients followed through 12 weeks of varenicline therapy, each of the four patients who discontinued varenicline use due to mood problems had pre-existing psychiatric conditions.17
Taken together, these early reports provide preliminary evidence that varenicline treatment may be associated with a worsening of psychiatric symptoms in a minority of individuals with a history of psychiatric illness. However, the present results, combined with the findings from randomized controlled trials,9,11–13
suggest that varenicline is not likely to be associated with neuropsychiatric sequelae in individuals without a history of psychiatric disease.
To our knowledge, our study is the first to address the safety or tolerability of varenicline when co-administered with a stimulant in humans. Varenicline is well-absorbed orally irrespective of dose or presence of food, is primarily excreted in the urine unmetabolized, and has no documented drug-drug interactions.18
Therefore, there is no a priori
reason that it should interact clinically with MA, which is primarily hepatically metabolized by the cytochrome p450 system.19
Along with the lack of known metabolic interactions for varenicline, our data should provide reassurance to clinicians who may be concerned that patients taking varenicline may be illicitly abusing stimulants, as there is not likely to be additional risk via a potentially harmful interaction between varenicline and MA.
There are several limitations of this pilot study, including the small sample size although there is not even a trend for untoward interactions between varenicline and MA at the doses given. In addition, the repeated dosing with a low dose (3 mg) of IV MA may not allow generalization of these data to clinical populations of MA-dependent patients, who may take substantially greater doses of MA. Lastly, as varenicline was administered over a relatively short period (slightly longer than one week) the present results may not be representative of findings in clinical populations taking varenicline for longer periods of time.
Given the lack of neuropsychiatric adverse events seen in otherwise healthy, MA-dependent participants while taking varenicline, along with the safety and tolerability of varenicline when co-administered with IV MA, we believe that varenicline should continue to be tested as a possible candidate medication for the treatment of MA dependence. In this vein, other investigators have also proposed that varenicline may have utility for the treatment of addictive disorders beyond nicotine dependence.20
Overall, the present data suggest that varenicline warrants further investigation as a potential treatment for MA dependence.