Drug and Alcohol Review · 6 authors, 5 centres
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This systematic review and meta-analysis of 9 randomized controlled trials (242 participants) found no medication to be clearly effective for treating methamphetamine withdrawal. Amineptine showed some benefit in reducing discontinuation and improving global state, but it is no longer clinically available due to hepatotoxicity. The overall quality of evidence was low to very low, highlighting the urgent need for larger, higher-quality trials.
**Background:** Cessation of chronic methamphetamine use produces a withdrawal syndrome characterized by dysphoric mood, fatigue, sleep disturbance, increased appetite, and psychomotor changes. Withdrawal symptoms can be severe enough to cause relapse, yet no medication is approved for this indication. The last comprehensive Cochrane review on this topic was published in 2008. This systematic review and meta-analysis aimed to update the evidence for pharmacotherapy in methamphetamine withdrawal.
**Methods:** The review followed PRISMA guidelines and was prospectively registered on PROSPERO (CRD42021224850). Four electronic databases (MEDLINE 1966–2020, CINAHL 1982–2020, PsychINFO 1806–2020, EMBASE 1947–2020) were searched through December 2020. ClinicalTrials.gov and reference lists of included papers were also searched. Two reviewers independently screened titles/abstracts and full texts. Included studies were RCTs investigating any pharmacological intervention for methamphetamine/amphetamine withdrawal in participants diagnosed with methamphetamine or amphetamine use disorder or withdrawal by standardized criteria. Data were independently extracted by two authors. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using GRADE. Random-effects meta-analyses were conducted for dichotomous data (relative risk, Mantel–Haenszel method) and continuous data (standardized mean difference, inverse variance method).
**Key Results:** The search yielded 20 results; 9 RCTs (n = 242 participants) met inclusion criteria. Six trials (n = 186) of four medications (amineptine, mirtazapine, modafinil, amantadine) could be meta-analyzed. Mean sample size was 27 participants; 88% were male. One study was low risk of bias, two had some concerns, and six were high risk of bias. The most common bias was selective reporting (6 of 9 studies).
- **Discontinuation rates:** Overall, no difference between treatment and placebo (RR 0.70, 95% CI 0.40–1.23, p = 0.21). Amineptine significantly reduced discontinuation (RR 0.22, 95% CI 0.07–0.72, p = 0.01; I² = 58%; GRADE: very low). - **Global state:** No overall difference (SMD −0.34, 95% CI −1.06 to 0.25, p = 0.39; I² = 69%). Amineptine showed significant improvement (MD −0.49, 95% CI −0.80 to −0.17; GRADE: low). - **Withdrawal symptoms:** No difference between treatment and placebo (SMD 0.17, 95% CI −0.43 to 0.77, p = 0.58; I² = 49%; GRADE: low). - **Craving:** No difference (SMD 0.34, 95% CI −0.77 to 1.45, p = 0.55; I² = 71%; GRADE: very low). - **Safety:** Only one study (amantadine) systematically reported adverse events (RR 2.47, 95% CI 0.76–8.03, p = 0.13; GRADE: very low). Four studies reported no safety data at all.
Three studies (ibudilast, varenicline, modafinil) could not be meta-analyzed. Ibudilast improved 2 of 12 CPT-II domains (variability p < 0.01, r = 0.83; perseverance p = 0.01, r = 0.75). Varenicline improved visual reaction time (p = 0.025, η² = 0.103) but not other neurocognitive tests.
**Clinical Implications:** There is insufficient evidence to recommend any pharmacotherapy for methamphetamine withdrawal. Amineptine showed some benefit but is no longer available due to hepatotoxicity and abuse potential. The low-to-very-low quality of evidence means no medication can be conclusively ruled out. The review highlights a critical gap: only 5 additional RCTs have been published since the 2008 Cochrane review, compared to 27 RCTs for buprenorphine in opioid withdrawal. Future research should focus on adequately powered, high-quality trials with harmonized outcome measures, rigorous safety reporting, and clear randomization procedures. The strategy of using longer-acting medications with similar pharmacological profiles to methamphetamine (analogous to nicotine replacement or buprenorphine) may be a promising avenue.