Approved Medications for Substance Use Disorders: An Umbrella Review of Systematic Reviews and Completed Phase 3...

This umbrella review of systematic reviews, meta-analyses, and completed phase 3 randomized controlled trials (RCTs) over the past 10 years covers approved pharmacological treatments for substance use disorders (SUD) worldwide, providing clinicians and researchers with a detailed analysis of current pharmacotherapies and bridging the gap between evolving pharmacological interventions and clinical practice.

This PROSPERO-registered umbrella review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Peer-reviewed systematic reviews were selected to include systematic reviews of RCTs and meta-analyses that examined approved medications for treatment, withdrawal management, or overdose reversal of SUD in all populations. Reviews published in peer-reviewed journals from 1 January 2016 to 1 January 2026, including medications that received worldwide approvals from World Health Organization (WHO)-listed Authorities plus those in the ten most populous countries were included. Reviews of preclinical studies and those not meeting systematic review standards or missing required data were excluded. We also included completed phase 3 SUD medications, including only RCTs with posted results from 2016 to 2026; preclinical studies and those with missing required data were excluded. We searched PubMed, MEDLINE, and the Cochrane Library databases for systematic reviews using keywords related to SUD. We also searched for phase 3 medications on the WHO International Clinical Trials Registry Platform. Risk of bias and methodological quality were assessed using the Risk if Bias in Systematic Reviews (ROBIS) and A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) tools for systematic reviews and using the Cochrane risk of bias (RoB2) tool for phase 3 RCTs. Two independent reviewers conducted the selection process, resolving discrepancies through discussion, consultation with a third reviewer, and reaching consensus. The results were synthesized narratively and presented by each medication in summaries and tables.

Sixteen systematic reviews were reviewed, containing 371 RCTs (n = 131,965) and 62 observational studies (OS) (n = 229,225) examining 41 approved medications (with 25 distinct molecules) for SUD worldwide as of 1 January 2026: Eighty-six RCTs (n = 18,643) covering seven medications for alcohol use disorder (AUD), showed a reduction of risk of returning to any drinking ranging from 7 to 17% compared with placebo; three for alcohol withdrawal/intoxication. A total of 49 RCTs (n = 7804) and 21 OS (n = 155,111) covering 12 medications for opioid use disorder (OUD), showed that the highest abstinence rates ranged from 41 to 43% compared with 5% in placebo. Forty-one OS (n = 74,114) covering nine medications for opioid overdose reversal, with survival rates ranging from 92 to 98%; one for opioid withdrawal. A total of 223 RCTs (n = 104,524) covering eight medications for tobacco use disorder (TUD), showed 1.3-2.3 times more likelihood to experience abstinence compared with placebo; and 13 RCTs (n = 994) covering one medication in sedative-hypnotic or anxiolytic use disorder (SHAUD) for benzodiazepine overdose reversal. Four completed phase 3 RCTs with posted results were reviewed, which included 1026 participants examining four pipeline medication treatments for SUD worldwide as of 1 January 2026: three RCTs (n = 623) covering three medications for AUD, and one RCT (n = 403) covering one combination medication treatment for stimulant use disorder (StUD).

Recent advancements in medications for SUD have expanded the range of pharmacologic treatments available for clinical practice. Effective medications are available for tobacco, opioid, and alcohol use disorders, and promising medications are emerging beyond the currently approved treatment landscape.

PROSPERO ID: CRD420251036330.