Lack of Efficacy of a 3-Medication Treatment Protocol for Methamphetamine Dependence

The PROMETA™ protocol, which includes the benzodiazepine antagonist flumazenil, the GABA-agonist gabapentin, and the H₁-histamine antagonist hydroxyzine, is unproven for the treatment of methamphetamine dependence. In this double-blind trial, researchers randomized 120 patients with methamphetamine abuse or dependence to the PROMETA protocol (intravenous flumazenil 2 mg on days 1, 2, 3, 22, and 23; oral gabapentin titrated to 1200 mg per day by day 4 and continued to day 40; and oral hydroxyzine 50 mg prior to flumazenil infusion and as take-home medication through day 10) or to placebo (active hydroxyzine only). Each group received 14 weekly sessions of cognitive behavioral therapy. Outcomes were methamphetamine and other drug use documented by urine testing, self-reported methamphetamine craving, treatment retention, and adverse events.

• Fifty percent of the experimental group and 70% of the placebo group remained in the study through the medication phase (day 40). Only 30% of the experimental group and 43% of the placebo group remained until the end of the study (day 108).

• During follow-up at days 23, 40, and 108, the experimental and placebo groups did not differ significantly with regard to:
  • proportion of methamphetaminenegative urine tests (50%, 40%, and 30% versus 50%, 50%, and 40%, respectively);
  • mean methamphetamine craving score (2.8, 3.1, and 2.2 versus 2.9, 2.9, and 2.4, respectively); or
  • percentage with 3 consecutive negative urine tests (36% and 39% versus 46% and 51% at days 40 and 108, respectively).
• Mild, moderate, and severe adverse events were reported by 73%, 23%, and 4% of the experimental group and 59%, 40%, and 1% of the placebo group, respectively.

Comments:

The PROMETA protocol has been promoted and used as a treatment for methamphetamine dependence despite lack of a strong scientific rationale and proven efficacy. This randomized placebo-controlled trial found no benefit of the PROMETA protocol over placebo for treatment of methamphetamine abuse or dependence. It raises serious questions about the use of the PROMETA protocol for methamphetamine dependence.

Kevin L. Kraemer, MD, MSc

Reference:

Ling W, Shoptaw S, Hillhouse M, et al. Double-blind placebo-controlled evaluation of the PROMETA™ protocol for methamphetamine dependence. Addiction. 2012;107(2):361–369.

Sofuoglu M. Commentary on Ling et al.: The PROMETA™ treatment does not reduce methamphetamine use. Addiction. 2012;107(2):370–371.