Psychiatric Pharmacy Essentials: Major Clinical Trials in Substance Use Disorders

Numerous pharmacologic regimens have been trialed for management of substance use disorders, often with concomitant behavioral interventions.

Essential Questions and References

What is the evidence for combination of pharmacotherapy and behavioral interventions for managing symptoms of alcohol use disorder?

• Anton RF, O’Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence. The COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-17. [PubMed]

What treatment options are available for treatment of opioid use disorder?

• Pinto H, Maskrey V, Swift L, et al. The SUMMIT trial: a field comparison of buprenorphine versus methadone maintenance treatment. J Subst Abuse Treat. 2010;39(4)340-52. [PubMed] 
• Lee JD, Nunes Jr EV, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-18. [PubMed] 
• Opheim A, Gaulen Z, Solli KK, et al. Risk of Relapse Among Opioid-Dependent Patients Treated With Extended-Release Naltrexone or Buprenorphine-Naloxone: A Randomized Clinical Trial. Am J Addict. 2021;30(5):453-460. [PubMed]

What treatment options are there for pregnant people with opioid use disorder?

• Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320-31. [PubMed]
• Winhusen TJ, Lofwall MR, Kropp F, et al. Extended-release vs sublingual buprenorphine in pregnancy through 12 months post partum: a randomized clinical trial. JAMA Intern Med. 2026;186(5):533-543. [PubMed]

What is the evidence for use of varenicline in patients with psychiatric disorders?

• Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;10037(387):2507-20. [PubMed]

How do e-cigarettes compare to traditional nicotine replacement therapy for smoking cessation?

• Hajek P, Phillips-Waller A, Przulj D, et al. A randomized trial of e-cigarettes versus nicotine-replacement therapy. N Engl J Med. 2019;380(7):629-37. [PubMed]
• Myers Smith K, Phillips-Waller A, Pesola F, et al. E-cigarettes versus nicotine replacement treatment as harm reduction interventions for smokers who find quitting difficult: randomized controlled trial. Addiction. 2022;117(1):224-233. [PubMed]
• CDC. Electronic Cigarettes. [Weblink]

How does combination treatment for tobacco use disorder and alcohol use disorder impact smoking and alcohol cessation?

• Ray LA, Green R, Enders C, et al. Efficacy of combining varenicline and naltrexone for smoking cessation and drinking reduction: a randomized clinical trial. Am J Psychiatry. 2021;178(9):818-28. [PubMed] 
• King A, Vena A, de Wit H, et al. Effect of combination treatment with varenicline and nicotine patch on smoking cessation among smokers who drink heavily: a randomized clinical trial. JAMA Netw Open. 2022;5(3):e220951. [PubMed] 

What evidence is there for psychedelics for alcohol use disorder?

• Bogenschutz MP, Forcehimes AA, pommy JA et al. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015; 29(3): 289-99. [PubMed]
• Bogenschutz BP, Ross S, Bhatt S et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs. Placebo in the Treatment of Adult Patients With Alcohol Use Disorder. JAMA Psychiatry. 2022;79(10):953-62. [PubMed]    
• Jensen ME, Stenbæk DS, Juul TS, et al. Psilocybin-assisted therapy for reducing alcohol intake in patients with alcohol use disorder: protocol for a randomised, double-blinded, placebo-controlled 12-week clinical trial (The QUANTUM Trip Trial). BMJ Open. 2022;12(10):e066019. [PubMed]

What evidence is there for glucagon-like pedtide-1 agonists (GLP-1a) for alcohol use disorder?

• Klausen MK, Jensen ME, Møller M, et al. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight. 2022;7(19):e159863. [PubMed]
• Hendershot CS, Bremmer MP, Paladino MB, et al. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025;82(4):395-405. [PubMed]
• Klausen MK, Justesen SK, Pedersen JN, et al. Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial. Lancet. 2026;407(10540):1687-1698. [PubMed]

What evidence is there for GLP-1a for tobacco use disorder?

• Lengsfeld S, Burkard T, Meienberg A, et al. Effect of dulaglutide in promoting abstinence during smoking cessation: a single-centre, randomized, double-blind, placebo-controlled, parallel group trial. EClinicalMedicine. 2023;57:101865. [PubMed]
• Yammine L, Green CE, Kosten TR, et al. Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial. Nicotine Tob Res. 2021;23(10):1682-1690. [PubMed]

What treatment options are there for methamphetamine use disorder?

• McKetin R, Shoptaw S, Saunders L, et al. Mirtazapine for Methamphetamine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2026;83(6):581-589. [PubMed]