Topiramate was not different from placebo in achieving the primary efficacy goal of abstinence from methamphetamine use in those who remained in the study during weeks 6–12. Positive findings on secondary variables showed that topiramate versus placebo reduced methamphetamine use over time.
Topiramate showed efficacy at reducing methamphetamine use in those who were abstinent at the trial’s outset. In this secondary analysis, 26 subjects (evenly divided between the placebo and topiramate groups) were abstinent at the trial’s outset. With the caveat that these findings were observed in a subset of the total cohort, it is reasonable to propose that topiramate should be considered for relapse prevention rather than simply being targeted to decrease methamphetamine use in current users. In clinical practice, this has the strong rationale of asking patients to be abstinent briefly before commencing medication treatment. Another advantage is that subjects who can manage this short period of abstinence before starting treatment might also be more likely to comply with the medication regimen and maintain higher doses.
Topiramate recipients also were significantly more likely to achieve a 50% or 25% reduction in baseline level of methamphetamine use, suggesting that even when topiramate treatment did not lead to abstinence, it was associated with a significant decrease in risk of harm from methamphetamine use. This was underscored by the observer-rated clinical impression of a global reduction in the severity of methamphetamine dependence in topiramate recipients.
Our study had four important limitations. First, similar to previous pharmacotherapy studies with methamphetamine, attrition after the first 6 weeks of treatment was relatively high, thereby limiting our potential to identify differences between active treatment and placebo. We view this as characteristic of the target population, who are often migratory or whose disease state perhaps is associated with greater dissociation from society than those who abuse other psychostimulants or alcohol. Nevertheless, the compliance enhancement treatment ensured that attrition was no different for topiramate versus placebo despite the higher level of adverse events with topiramate.
Second, unexpectedly, few subjects achieved the maximum target dose of 200 mg/day. Indeed, the majority of subjects took ≤150 mg daily, which might have reduced our ability to demonstrate stronger therapeutic effects. Probably, this occurred because the study protocol allowed liberal downward dose titration of topiramate, thereby inadvertently encouraging the use of the lower topiramate doses. Since alcoholics have tolerated and responded to topiramate at 300 mg/day, the question arises as to whether the final dose that we chose was sufficient. The target dose of 200 mg/day was the same dose that Kampman et al. used in their pilot study of cocaine abstinence [3
]; Johnson et al. later studied it as the maximum dose for safety with methamphetamine [16
]. An additional consideration is the unintended heterogeneity of doses that the subjects—received a common problem in medication studies. Although the medication compliance rate of 70% is higher than that achieved in previous pharmacotherapy studies with methamphetamine [17
], the use of pill count to monitor compliance is fraught with inaccuracy. Medication studies must incorporate specific markers of medication compliance, including blood level monitoring and riboflavin (for both active and placebo medication), to avoid inconclusive results.
The third limitation concerns the effect of topiramate, a mild carbonic anhydrase inhibitor, on the metabolism and excretion of methamphetamine. Urinary filtration of methamphetamine is enhanced by acidification of urine and impeded by alkalinization. This pharmacokinetic mechanism has been demonstrated experimentally by intravenous administration of either an alkalinizing or acidifying agent [20
]. However, carbonic anhydrase inhibition simultaneously acidifies blood and alkalinizes urine. A rise of urine pH should reduce methamphetamine elimination, causing higher blood levels of methamphetamine to be sustained, but the downward pH shift in the plasma should also accelerate methamphetamine’s metabolism. Johnson et al.’s interaction study [16
] suggests that methamphetamine plasma concentrations increase slightly in topiramate’s presence, possibly a net effect of reduced urinary excretion. Due to topiramate’s mild effect on carbonic anhydrase, its net effect on methamphetamine’s metabolism and elimination kinetics may not be significant; on the other hand, the net effect of a pH shift on methamphetamine’s concentration gradient across the blood–brain barrier is unknown. Whether topiramate exerts an unusual pharmacokinetic effect on methamphetamine has an important implication for chronic therapy because although users are consuming less methamphetamine, urine sampling might underestimate the extent of this reduction.
Fourth, from the small therapeutic effect evidenced by this study, a double-blind controlled trial of ampler sample size, testing higher doses, is needed for more definitive conclusions.
In conclusion, topiramate at doses up to 200 mg/day was safely tolerated by currently using methamphetamine-dependent individuals in this study, but its efficacy in helping them achieve abstinence was not supported. Nonetheless, some use reduction variables were indicative of an effect by topiramate. As seen in some other medication studies, a subgroup of “light” users are more responsive to topiramate, possibly because they are more likely to adhere to study requirements, or perhaps because we administered a barely therapeutic dose. Topiramate’s utility in preventing relapse in those who have ceased methamphetamine use should be explored further.