Hostname: page-component-6766d58669-7fx5l Total loading time: 0 Render date: 2026-05-20T09:51:31.630Z Has data issue: false hasContentIssue false
  • English
  • Français

The Association Between Dextromethorphan/Bupropion with Alcohol and Substance Misuse: Reports to the Food and Drug Administration Adverse Event Reporting System (FAERS)

Published online by Cambridge University Press:  23 October 2024

Angela T.H. Kwan Open the ORCID record for Angela T.H. Kwan [Opens in a new window]  and
Roger S. McIntyre Open the ORCID record for Roger S. McIntyre [Opens in a new window]
Angela T.H. Kwan
Affiliation:
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
Roger S. McIntyre*
Affiliation:
Department of Psychiatry, University of Toronto, Toronto, ON, Canada
*
Corresponding author: Roger S. McIntyre; Email: roger.mcintyre@bcdf.org
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

Dextromethorphan/bupropion (DXM/BUP) received Food and Drug Administration (FDA) approval for the treatment of adults with major depressive disorder (MDD) in August 2022. This combination is not known to have abuse liability and is not currently scheduled by the Drug Enforcement Administration (DEA). Notwithstanding, dextromethorphan is a drug of abuse. Herein, we sought to determine whether DXM/BUP has alcohol and/or substance misuse liability.

Methods

We evaluated spontaneous reports of terms such as “alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse” in the FDA Adverse Event Reporting System (FAERS). The FAERS is a spontaneous reporting database of adverse events submitted to the FDA.

Results

We performed a comparative assessment of the alcohol and/or substance misuse liability of DXM/BUP since its market authorization in August 2022, using acetaminophen as the control. Dextromethorphan served as the upper-bound reference point. Our findings showed that, since August 2022, dextromethorphan had a significant reporting odds ratio (ROR) for “drug abuse.” In contrast, DXM/BUP did not have a significant ROR for any of the categories of alcohol and/or substance misuse evaluated. Limitations of our findings derive largely from the limitations of the FAERS and its data capture method.

Conclusion

The absence of alcohol or substance misuse reported to the FAERS with DXM/BUP accords with the lack of evidence of abuse liability prior to FDA approval and its non-scheduling by the DEA.

Keywords

Dextromethorphan/bupropion (DXM/BUP)antidepressantsdepressionabusesubstance abuse disorder (SUD)comorbiditytoxicity

Information

Type
Original Research
Information
CNS Spectrums , Volume 29 , Issue 5 , October 2024 , pp. 407 - 411
Copyright
© The Author(s), 2024. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

Footnotes

This article has been updated since it was originally published. A notice detailing this has been published.

References

Akbar, D, Rhee, TG, Ceban, F, et al. Dextromethorphan-bupropion for the treatment of depression: a systematic review of efficacy and safety in clinical trials. CNS Drugs. 2023;37(10):867–881.CrossRefGoogle ScholarPubMed
Iosifescu, DV, Jones, A, O’Gorman, C, et al. Efficacy and safety of AXS-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry. 2022;83(4). doi:10.4088/JCP.21m14345 CrossRefGoogle ScholarPubMed
ClinicalTrials.Gov. Accessed January 14, 2024. https://clinicaltrials.gov/search?intr=Bupropion%20dextromethorphan Google Scholar
McIntyre, RS, Alsuwaidan, M, Baune, BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023;22(3):394–412.CrossRefGoogle ScholarPubMed
Silva, AR, Dinis-Oliveira, RJ. Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects. Drug Metab Rev. 2020;52(2):258–282.CrossRefGoogle ScholarPubMed
McClure, EW, Daniels, RN. Classics in chemical neuroscience: dextromethorphan (DXM). ACS Chem Neurosci. 2023;14(12):2256–2270.CrossRefGoogle ScholarPubMed
Nguyen, L, Robson, MJ, Healy, JR, Scandinaro, AL, Matsumoto, RR. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One. 2014;9(2):e89985.CrossRefGoogle ScholarPubMed
Ohi, Y, Tsunekawa, S, Haji, A. Dextromethorphan inhibits the glutamatergic synaptic transmission in the nucleus tractus solitarius of guinea pigs. J Pharmacol Sci. 2011;116(1):54–62.CrossRefGoogle ScholarPubMed
Stahl, SM. Dextromethorphan/bupropion: a novel oral NMDA (N-methyl-d-aspartate) receptor antagonist with multimodal activity—Addendum. CNS Spectr. 2020;25(6):803.CrossRefGoogle ScholarPubMed
Huecker, MR, Smiley, A, Saadabadi, A. Bupropion. Treasure Island, Florida: StatPearls Publishing; 2023.Google Scholar
Hole, K, Arnestad, M, Molden, E, Haslemo, T. Dose-dependent inhibition of CYP2D6 by bupropion in patients with depression. J Clin Psychopharmacol. 2021;41(3):281–285.CrossRefGoogle ScholarPubMed
Sager, JE, Tripathy, S, Price, LSL, et al. In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation. Biochem Pharmacol. 2017;123:85–96.CrossRefGoogle ScholarPubMed
Linn, KA, Long, MT, Pagel, PS. “Robo-tripping”: dextromethorphan abuse and its anesthetic implications. Anesth Pain Med. 2014;4(5):e20990.CrossRefGoogle ScholarPubMed
Karami, S, Major, JM, Calderon, S, McAninch, JK. Trends in dextromethorphan cough and cold products: 2000-2015 National Poison Data System intentional abuse exposure calls. Clin Toxicol. 2018;56(7):656–663.CrossRefGoogle ScholarPubMed
Ritter, D, Ouellette, L, Sheets, JD, et al. “Robo-tripping”: dextromethorphan toxicity and abuse. Am J Emerg Med. 2020;38(4):839–841.CrossRefGoogle ScholarPubMed
Olives, TD, Boley, SP, LeRoy, JM, Stellpflug, SJ. Ten years of robotripping: evidence of tolerance to dextromethorphan hydrobromide in a long-term user. J Med Toxicol. 2019;15(3):192–197.CrossRefGoogle Scholar
Vearrier, D, Grundmann, O. Clinical pharmacology, toxicity, and abuse potential of opioids. J Clin Pharmacol. 2021;61(Suppl 2):S70–S88.CrossRefGoogle ScholarPubMed
Blair, G, Wells, C, Ko, A, et al. Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats. Pharmacol Biochem Behav. 2020;193:172919.CrossRefGoogle ScholarPubMed
Center for Drug Evaluation, Research. Drug Approvals and Databases. U.S. Food and Drug Administration. Published December 20, 2023. Accessed January 14, 2024. https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases Google Scholar
McIntyre, RS, Mansur, RB, Rosenblat, JD, Kwan, ATH. The association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicidality: reports to the Food and Drug Administration Adverse Event Reporting System (FAERS). Expert Opin Drug Saf. Published online December 13, 2023. doi:10.1080/14740338.2023.2295397 Google Scholar
Tenny, S, Hoffman, MR. Odds Ratio. Treasure Island, Florida: StatPearls Publishing; 2023.Google ScholarPubMed
Woods, RH. Potential cerebrovascular accident signal for risankizumab: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS). Br J Clin Pharmacol. 2023;89(8):2386–2395.CrossRefGoogle ScholarPubMed
Puddephatt, JA, Irizar, P, Jones, A, Gage, SH, Goodwin, L. Associations of common mental disorder with alcohol use in the adult general population: a systematic review and meta-analysis. Addiction. 2022;117(6):1543–1572.CrossRefGoogle ScholarPubMed
Saha, S, Lim, CC, Degenhardt, L, et al. Comorbidity between mood and substance-related disorders: a systematic review and meta-analysis. Aust N Z J Psychiatry. 2022;56(7):757–770.CrossRefGoogle ScholarPubMed
Onaemo, VN, Fawehinmi, TO, D’Arcy, C. Comorbid cannabis use disorder with major depression and generalized anxiety disorder: a systematic review with meta-analysis of nationally representative epidemiological surveys. J Affect Disord. 2021;281:467–475.CrossRefGoogle ScholarPubMed
Center for Drug Evaluation, Research. FDA Adverse Event Reporting System (FAERS) Public Dashboard. U.S. Food and Drug Administration. Published December 7, 2023. Accessed January 14, 2024. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard Google Scholar
Fedak, KM, Bernal, A, Capshaw, ZA, Gross, S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol. 2015;12:14.CrossRefGoogle Scholar