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EVIDENCE FROM RANDOMIZED CONTROLLED TRIALS IN SUBSTANCE USE DISORDERS WITH MEMANTINE, GALANTAMINE, N-ACETYLCYSTEINE, AND DOXAZOSIN/PRAZOSIN

Kristine Hawkins — Elizabeth G. Varghese2, Sajoy P. Varghese, MD3, Maju Mathew Koola, MD4 1Cooper Medical School of Rowan University, 2Niles West High School, 3VISN 23, Clinical Resource Hub, Minneapolis VA Medical Center, and University of California, Davis, 4George Washington University School of Medicine and Health Sciences

2026 ASCP Annual Meeting

Background

Substance use disorders (SUDs) remain a major public health challenge, with high relapse rates and limited pharmacologic options across most substances. There have been no novel treatments developed for SUDs since 2006. While existing treatments target isolated components of neurobiological pathways, addiction is increasingly recognized as a disorder involving dysregulation across multiple neurotransmitter systems, including NMDA, nicotinic, and noradrenergic signaling. This complexity suggests monotherapy approaches are likely to be insufficient. Repurposing FDA-approved medications with complementary mechanisms represents a promising strategy to expand treatment options.

Methods

We conducted a review of randomized controlled trials (RCTs) and meta-analyses which evaluated five repurposed pharmacologic agents (galantamine, memantine, Nacetylcysteine, prazosin, and doxazosin) for the treatment of SUDs. A literature search was conducted using PubMed, Google Scholar, ClinicalTrials.gov, SCOPUS, and the Cochrane Library. Eligible studies included RCTs and meta-analyses assessing outcomes such as substance use, abstinence, craving, relapse, or treatment retention across alcohol, tobacco, opioid, cannabis, cocaine, and methamphetamine use disorders. Study characteristics and outcomes were extracted and synthesized into charts with quantitative and qualitative data for analysis.

Results

Across trials, efficacy varied by medication, substance, and patient subgroup. Galantamine (8 RCTs, N=700) demonstrated benefits in tobacco (TUD), alcohol (AUD), cocaine (CocUD) and cannabis (CUD) use disorder, with reductions in cigarette consumption, biochemical markers, and cocaine-positive urine samples. Memantine (17 RCTs, N=1,210) showed limited efficacy as monotherapy but improved outcomes when combined with established treatments such as naltrexone or buprenorphine, particularly for AUD and opioid use disorder (OUD) and had some efficacy signal in TUD and CocUD. NAC (17 RCTs, N=1,715) demonstrated efficacy signals in AUD, OUD, CocUD, CUD and was the only medication to show clinical benefit in methamphetamine use disorder. It’s strongest effects in specific subgroups, including individuals with prior abstinence, moderate to severe AUD, adolescents and young adults, and stimulant use disorders, suggesting a role in relapse prevention. Prazosin (10 RCTs, N=1,521) consistently reduced stress induced craving and drinking outcomes in AUD, particularly among individuals with heightened withdrawal severity or comorbid posttraumatic stress disorder. Doxazosin (7 RCTs, N=377) demonstrated robust effects in CocUD, especially with rapid titration and in genetically defined subgroups, in addition to efficacy signal in TUD and AUD.

Conclusion

Collectively, these findings highlight the limitations of single mechanism treatment approaches for SUDs and support a multidimensional treatment framework. The complementary mechanisms and favorable safety profiles of these agents highlight their potential utility in combination pharmacotherapy strategies. Future research should prioritize study designs to evaluate synergistic effects, optimize patient selection, and advance treatment approaches for SUDs.