Introduction
Dextromethorphan/bupropion (DXM/BUP) is a combination treatment that received approval from the United States Food and Drug Administration (FDA) in August 2022 for adults with major depressive disorder (MDD).Reference Akbar, Rhee and Ceban 1 , Reference Iosifescu, Jones and O’Gorman 2 This combination is currently under development for other psychiatric and medical disorders (ie, agitation in Alzheimer’s disease, smoking cessation, and treatment resistant depression). 3 , Reference McIntyre, Alsuwaidan and Baune 4 Dextromethorphan, a synthetic analog of codeine, has little to no affinity for mu (μ), kappa (κ), and/or delta (δ) opioid receptors.Reference Silva and Dinis-Oliveira 5 Consequently, dextromethorphan does not exhibit prominent analgesic, euphoric, and/or respiratory suppression effects.Reference Silva and Dinis-Oliveira 5
Dextromethorphan is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist and a σ1 receptor agonist.Reference McClure and Daniels 6 – Reference Ohi, Tsunekawa and Haji 8 Dextromethorphan also exhibits inhibition of serotonin and norephedrine reuptake transporters as well as modulation of nicotinic receptors.Reference Silva and Dinis-Oliveira 5 The rationale behind the combination of DXM/BUP derives from the pharmacokinetic observation of the rapid and extensive clearance of dextromethorphan when prescribed alone.Reference Stahl 9 Bupropion, an aminoketone, is FDA-approved as an antidepressant for adults with MDD, seasonal affective disorders, and smoking cessation.Reference Huecker, Smiley and Saadabadi 10 Furthermore, bupropion is an inhibitor of cytochrome P450 2D6 (CYP2D6), thereby prolonging the half-life and increasing the bioavailability of dextromethorphan.Reference Hole, Arnestad, Molden and Haslemo 11 , Reference Sager, Tripathy and Price 12
Dextromethorphan, one of the most common antitussive agents in over-the-counter (OTC) cough and cold medicine, is accessible in tablet form or through illicit channels.Reference Silva and Dinis-Oliveira 5 , Reference Linn, Long and Pagel 13 , Reference Karami, Major, Calderon and McAninch 14 Abuse liability of dextromethorphan is well documented.Reference Karami, Major, Calderon and McAninch 14 – Reference Olives, Boley, LeRoy and Stellpflug 16 It could be hypothesized that the abuse liability of dextromethorphan is partially derived from its major active metabolite, dextrorphan.Reference Silva and Dinis-Oliveira 5 , Reference McClure and Daniels 6 , Reference Vearrier and Grundmann 17 Although the combination of DXM/BUP is not scheduled and is not known to have abuse liability, there remains a need to surveil whether there is any association with alcohol and/or substance misuse in the general population.Reference Blair, Wells and Ko 18
Herein, we sought to address the aforementioned concern by evaluating reports to the United States FDA of substance- and alcohol-related behaviors associated with DXM/BUP since its FDA approval in August 2022.
Methods
We retrieved information from the United States Food and Drug Administration Adverse Event Reporting System (FAERS), a database that contains post-marketing adverse event reports submitted to the FDA. Our analysis focused on DXM/BUP starting from August 2022 to coincide with the FDA approval date for DXM/BUP. The identification of DXM/BUP involved using their non-proprietary names and included an assessment of alcohol- and substance-related issues, encompassing categories such as “alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, drug use disorder, and drug abuse.” 19
Our methodology is similar to that of a recent publication examining the safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs).Reference McIntyre, Mansur, Rosenblat and Kwan 20 The timeframe for the considered medications spanned from August 2022 to September 30, 2023, capturing both the number of cases (n) and total cases of psychiatric disorders (N) (Table 1). To examine disproportionate reporting between cases and non-cases, we calculated the reporting odds ratio (ROR) using the formula: odds ratio = (odds of the event in the exposed group)/(odds of the event in the non-exposed group).Reference Tenny and Hoffman 21
Figure 1. Forest plots showing the reporting odds ratio (ROR) for alcohol and substance misuse comparing dextromethorphan/bupropion to acetaminophen as the control.
Table 1. Dextromethorphan/Bupropion-Associated Alcohol and Substance Misuse Cases Identified in the Food and Drug Administration Adverse Event Reporting System (FAERS), Using Acetaminophen as the Control
a Search terms for dextromethorphan/bupropion included: “bupropion hydrochloride/dextromethorphan hydrobromide, bupropion/dextromethorphan, auvelity.”
b Search terms for dextromethorphan included: “dextromethorphan, dextromethorphan hydrobromide.”
The FAERS database was searched from 2022 to September 30, 2023 for dextromethorphan/bupropion, dextromethorphan and acetaminophen (control).
In this context, the ROR represents the odds ratio for the occurrence of substance and alcohol misuse, using codes adopted by the FAERS (ie, “alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, drug use disorder and drug abuse”) associated with DXM/BUP (ie, “bupropion hydrochloride/dextromethorphan hydrobromide, bupropion/dextromethorphan and auvelity”) compared to acetaminophen (ie, acetaminophen, tylenol, and panadol) as the control. Dextromethorphan (ie, dextromethorphan and dextromethorphan hydrobromide) served as an upper-bound reference point. We calculated upper and lower 95% confidence intervals (CI) at an alpha risk of 5%, determining statistical significance based on whether the lower 95% CI exceeded 1.0, indicating disproportionate reporting.Reference Woods 22 Forest plots were generated using RStudio version2023.06.1 + 524 “DesertSunflower” Release (b51c81cc303d4b52b010767e5b30438beb904641, 2023-09-25) for Windows.
Results
The statistical analysis was performed using Microsoft Excel 2021 and R version 4.3.1. For DXM/BUP between August 2022 and September 30, 2023, there were 0 reports of alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, and drug use disorder, with only 1 report of drug abuse. The RORs for DXM/BUP were independently compared to acetaminophen, serving as the control (Table 1).
Comparison of dextromethorphan/bupropion to acetaminophen
When comparing DXM/BUP to acetaminophen as the control, the RORs for alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder, substance abuse, drug dependence, and drug use disorder were all 0. However, for drug abuse, the ROR was 0.018 (95% CI 0.0025–0.13, p ≤ 0.0001), indicating a significantly lower risk compared to acetaminophen.
Additionally, dextromethorphan served as an upper-bound reference point and was compared to acetaminophen across the same categories. The RORs for alcohol problem, alcohol abuse, substance dependence, substance use disorder, and drug use disorder were all 0. For alcoholism (ROR 3.05, 95% CI 0.42–22.25; p = 0.27), substance abuse (0.74; 95% CI 0.18–2.98; p = 0.67), drug dependence (ROR 1.01, 95% CI 0.48–2.16; p = 0.97), and drug abuse (ROR 2.66, 95% CI 1.93–3.65; p ≤ 0.0001), specific RORs were computed.
Discussion
Herein, we did not identify a significant increase in the RORs for all FAERS categories of alcohol and/or substance misuse disorder associated with DXM/BUP since its FDA marketing authorization in August 2022. Additionally, we observed a significantly elevated ROR for dextromethorphan in the category of drug abuse compared to acetaminophen.
The combination DXM/BUP is not commercially available as a proprietary formulation in any other country outside of the United States as of February 2024. Individuals living with MDD have higher rates of substance use disorder (SUD) and alcohol use disorder (AUD) relative to the general population.Reference Puddephatt, Irizar, Jones, Gage and Goodwin 23 – Reference Onaemo, Fawehinmi and D’Arcy 25 Consequently, individuals with MDD have greater susceptibility to misusing drugs with abuse liability, underscoring the importance of characterizing the abuse liability of any approved agents likely to be prescribed and/or self-administered by a person living with MDD.
A limitation of the FAERS is its reliance on spontaneous adverse event reporting and cannot be considered a comprehensive capture of all adverse events experienced in the general population. 26 In addition, comprehensive sociodemographic, clinical, as well as family and treatment histories of individuals reported to the FAERS are not available. Moreover, the FAERS database does not provide sufficient data to inform causative models.Reference Fedak, Bernal, Capshaw and Gross 27 Another limitation of our analysis is the relatively short observation interval, justified by the fact that DXM/BUP was only recently FDA-approved. Nonetheless, it could be conjectured that increased clinician awareness of abuse liability with dextromethorphan may enhance vigilance and reporting of cases for abuse liability if present with DXM/BUP. An additional aspect for consideration is that DXM/BUP is a proprietary product available via prescription indicated for persons with MDD. In contrast, DXM is available through different informal and formal routes (eg, internet) and cannot be assumed to be implemented for identical therapeutic considerations as DXM/BUP. Consequently, the likelihood of reporting safety concerns with DXM may be dissimilar from the likelihood of reporting adverse events with DXM/BUP.
Conclusion
In summary, we did not identify a significant increase in the reporting of alcohol and/or substance misuse abuse with DXM/BUP relative to acetaminophen. However, we did observe a significant increase in abuse liability for dextromethorphan. The absence of alcohol or substance misuse reported to the FAERS with DXM/BUP aligns with the lack of evidence of abuse liability prior to FDA approval and its DEA non-scheduling.
Author contribution
All authors (ATH Kwan and RS McIntyre) conceptualized, designed, and drafted the manuscript, as well as provided critical review for important intellectual concept and approved the final version to be published. ATH Kwan analyzed and interpreted the data. All authors agree to be accountable for all aspects of the work.
Disclosure
Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger S. McIntyre is a CEO of Braxia Scientific Corp.
