Cannabis misuse accounts for nearly all of the substance abuse treatment admissions among youth in the United States. Most youth do not experience sustained benefit from existing psychosocial treatments; however, medication development research for treating adolescent cannabis misuse is almost nonexistent. We conducted a double-blind, placebo-controlled, pilot study to test the potential efficacy of topiramate plus motivational enhancement therapy (MET) for treating cannabis use among adolescents. Sixty-six heavy cannabis users, ages 15 to 24 years, were randomized to one of two 6-week treatment conditions: topiramate plus MET or placebo plus MET. Topiramate was titrated over 4 weeks then stabilized at 200 mg/day for 2 weeks. MET was delivered biweekly for a total of three sessions. Only 48 percent of youths randomized to topiramate completed the 6-week trial (n = 19), compared with 77 percent of youths in the placebo condition (n = 20). Adverse medication side effects were the most common reason for withdrawal among participants in the topiramate group. Latent growth models showed that topiramate was superior to placebo for reducing the number of grams smoked per use day, but it did not improve abstinence rates. The same pattern of results was found when values for missing outcomes were imputed. We show that topiramate combined with MET demonstrated efficacy for reducing how much cannabis adolescents smoked when they used but did not affect abstinence rates. The magnitude of this effect was modest, however, and topiramate was poorly tolerated by youths, which calls into question the clinical importance of these findings.