Review of: Levin FR et al, Drug Alcohol Depend 2020;206:107700

In 2017, an estimated 2.2 million Americans used cocaine, with about 966,000 of them meeting criteria for cocaine use disorder (CUD) (SAMHSA, 2018). Unfortunately, there are still no FDA-approved treatments for CUD. Amphetamines increase synaptic dopamine transmission and may therefore reduce the reinforcing properties of cocaine. Topiramate, an anticonvulsant that enhances gamma amino butyric acid (GABA) activity, can reduce cocaine-induced dopamine release and may modulate the reinforcing effects of co-administered amphetamines. Previously, a single-site study suggested that a combination of amphetamine and topiramate can reduce cocaine use in individuals with high baseline cocaine consumption (Mariani JJ et al, Biol Psychiatry 2012;72(11):950–956). Now, researchers have conducted a larger trial with the same combination, among people who use cocaine, across two large metropolitan areas.

This trial tested the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate vs placebo in double-blinded, randomized design. The study was conducted over a 12-week period and included 127 adults (96 men, ages 18–60) with CUD. Participants reported using cocaine for at least 9 days in the previous month. MAS-ER was titrated to a maximum dose of 60 mg/day, and topiramate was increased to a maximum dose of 100 mg twice/day. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence, as measured by urine toxicology and self-report. Funding was provided by the National Institute on Drug Abuse.

The proportion of participants achieving 3 weeks of abstinence was significantly larger in the treatment compared to the placebo group (14.1% vs 0.0%, p = 0.03) after controlling for other factors. Secondary analyses showed that the proportion of participants who achieved any 3 consecutive weeks of abstinence (but not necessarily end-of-study abstinence) was higher for those receiving MAS-ER and topiramate (21.9%) compared to placebo (6.3%). Cocaine cravings also were significantly less prevalent among the treatment group (p < 0.001). Dropouts were high in both study arms (34% in the treatment group, 41% in the placebo group). Dry mouth was the only adverse event significantly more common in the treatment group than the placebo arm (16% vs 5%). Among those receiving MAS-ER and topiramate, 20.3% were discontinued from the medications due to increased blood pressure and heart rate.

CATR’s Take
The combination of amphetamine and topiramate can increase abstinence and decrease cravings among those with CUD. However, cardiovascular side effects limit widespread use, and it remains unclear whether the combination of MAS-ER and topiramate outperforms either medication alone.