Dextromethorphan/Bupropion (Auvelity) Patient Guide: Benefits, Dosing, and Side Effects Explained

This guide is adapted from the clinician guide authored by Sebastián Malleza, M.D., M.Sc. at the Psychopharmacology Institute. For the complete clinical resource, visit: Dextromethorphan/Bupropion Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

What is Dextromethorphan/Bupropion?

Dextromethorphan/Bupropion (brand name Auvelity) is the first oral NMDA receptor antagonist approved for treating major depressive disorder (MDD) in adults.[3] It combines two medications: dextromethorphan (commonly found in cough medicines) and bupropion (an antidepressant also known as Wellbutrin).

The primary clinical advantage of this medication is a rapid onset of antidepressant effect, with symptom improvement seen as early as the first week of treatment [3,5].

Compared to other antidepressants, Dextromethorphan/Bupropion may offer these advantages:

• Faster onset of action compared to traditional antidepressants (improvement seen within 1 week)[3,5]
• Lower rates of sexual side effects compared to SSRIs/SNRIs[15]
• May be helpful when depression is accompanied by fatigue or low motivation (anhedonia)
• Option for patients who haven’t responded adequately to SSRIs or SNRIs

Your doctor might recommend alternatives if you:

• Have a history of seizures or eating disorders (anorexia/bulimia) — these are absolute contraindications[3]
• Are undergoing withdrawal from alcohol, benzodiazepines, or sedatives[3]
• Take many other medications (this drug has significant drug interactions)[3]
• Have concerns about cost (brand-name only)[1]
• Are pregnant or breastfeeding[3]
• Have a history of substance abuse (dextromethorphan has potential for misuse)[21,22]

How Does This Medication Work?

Dextromethorphan/Bupropion works through multiple mechanisms:[3,4]

Dextromethorphan component:

• Blocks NMDA receptors in the brain, similar to ketamine and esketamine
• This glutamate system modulation may contribute to faster antidepressant effects[4,5]
• Also activates sigma-1 receptors, which may support neuroplasticity and brain health[6,9,10]

Bupropion component:

• Increases norepinephrine and dopamine in the brain (NDRI mechanism)
• Importantly, bupropion also blocks the enzyme CYP2D6, which normally breaks down dextromethorphan very quickly
• This blockade allows dextromethorphan to stay in your system longer (half-life increases to about 22 hours), making it effective as an antidepressant[3]

The combination of these mechanisms provides a unique approach to treating depression that differs from traditional SSRIs and SNRIs.[4]

How to Take This Medication

Dextromethorphan/Bupropion comes as extended-release tablets containing 45 mg dextromethorphan and 105 mg bupropion[3].

Typical dosing schedule:

• Days 1-3: One tablet once daily in the morning[3]
• Day 4 and beyond: One tablet twice daily, with doses separated by at least 8 hours[3]
• Maximum dose: Two tablets per day (90 mg dextromethorphan/210 mg bupropion)[3]

Important instructions:

• May be taken with or without food[3]
• Swallow tablets whole — do not crush, divide, or chew[3]
• Take doses at least 8 hours apart
• Avoid taking the second dose too late in the day to prevent insomnia
• If you miss a dose, take it as soon as you remember. If it’s almost time for your next dose, skip the missed dose and continue with your regular schedule. Do not take two doses to make up for a missed one.

Dose adjustments may be needed if you:

• Take strong CYP2D6 inhibitors (such as paroxetine or fluoxetine): One tablet once daily only[3]
• Are a CYP2D6 poor metabolizer (determined by genetic testing): One tablet once daily only[3]
• Have moderate kidney impairment: One tablet once daily only[3]

Common Side Effects

Many side effects improve over time as your body adjusts to the medication.

Neurological effects:

• Dizziness (16% incidence)[3,5]
  • Most common side effect
  • Take precautions to reduce fall risk
  • Avoid driving or operating machinery until you know how the medication affects you
• Headache (8% incidence)[3,14]
• Somnolence/drowsiness (7% incidence)[3]
  • Despite containing bupropion, which is typically activating
• Anxiety (4% incidence)[3]
  • Most common reason for stopping the medication in clinical trials
• Insomnia (4% incidence)[3]
  • Ensure doses are at least 8 hours apart
  • Avoid evening doses

Digestive system effects:

• Nausea (13% incidence)[3,5]
  • Can be minimized by taking with food
  • Generally improves within the first week of treatment
• Diarrhea (7% incidence)[14]
  • Usually mild and self-limiting
• Dry mouth (6% incidence)[3]
• Constipation (4% incidence)[3]

Other common side effects:

• Sexual dysfunction (6% incidence)[3]
  • Significantly lower than SSRIs/SNRIs
  • Bupropion component may actually help with sexual function[15]
• Increased sweating (5% incidence)[3]

Important Safety Information

Do Not Take Dextromethorphan/Bupropion If You:

• Have a seizure disorder or history of seizures[3]
• Have an eating disorder (anorexia nervosa or bulimia)[3]
• Are currently taking or have recently taken (within 14 days) MAOIs (monoamine oxidase inhibitors)[3]
• Are undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs[3]
• Are already taking another bupropion-containing product (Wellbutrin, Zyban, Contrave, Forfivo)[3]

Talk to Your Doctor Before Taking This Medication If You:

• Take other medications that affect serotonin (other antidepressants, triptans, tramadol)[3]
• Take medications metabolized by CYP2D6 (your doctor can check this)[3]
• Take medications that lower seizure threshold[3]
• Have a history of bipolar disorder[3]
• Have narrow-angle glaucoma[3,20]
• Have high blood pressure or heart disease[3]
• Have liver or kidney problems[3]
• Have a history of substance abuse[21-26]
• Are pregnant, planning pregnancy, or breastfeeding[3]

Major Drug Interactions:

Medications that increase Dextromethorphan/Bupropion levels:

• Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) — dose reduction required[3]
• CYP2B6 inhibitors (clopidogrel) — monitor for side effects[3]

Medications that decrease Dextromethorphan/Bupropion effectiveness:

• Strong CYP2B6 inducers (carbamazepine, rifampin, phenytoin) — avoid combination[3]

Dextromethorphan/Bupropion increases levels of:

• Many antidepressants (venlafaxine, duloxetine, nortriptyline, paroxetine, fluoxetine, sertraline)[3]
• Some antipsychotics (haloperidol, risperidone, aripiprazole)[3]
• Beta-blockers (metoprolol)[3]
• Certain heart rhythm medications (propafenone, flecainide)[3]

Important note about drug testing: Bupropion can cause false-positive urine tests for amphetamines.[12,13] If you need drug testing, inform the testing facility that you take this medication.

When to Contact Your Doctor Immediately

Contact your healthcare provider right away if you experience:

• Seizures — stop the medication immediately and seek emergency care[3]
• Unusual changes in behavior, thoughts of suicide, or worsening depression[3]
• Signs of serotonin syndrome: agitation, hallucinations, rapid heart rate, fever, excessive sweating, shivering, muscle stiffness or twitching, trouble with coordination, nausea, vomiting, or diarrhea[3]
• Signs of mania: decreased need for sleep, racing thoughts, excessive energy, reckless behavior[3,16]
• Severe increase in blood pressure[3]
• Psychotic symptoms: hallucinations, delusions, paranoia, confusion[3,18,19]
• Eye pain, vision changes, or eye redness/swelling (may indicate angle-closure glaucoma)[3,20]
• Severe allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing

Starting and Stopping the Medication

Starting: Unlike many traditional antidepressants that may take 4-6 weeks to work, Dextromethorphan/Bupropion showed improvement as early as the first week in clinical trials[3,5]. However, continue taking the medication as prescribed even if you don’t feel immediate improvement.

Stopping: Talk to your doctor before stopping this medication. While specific tapering guidelines have not been established, abrupt discontinuation should generally be avoided. Your doctor will advise you on the safest way to stop if needed.

Special Considerations

Pregnancy and Breastfeeding

• Not recommended during pregnancy: Animal studies show potential fetal harm and concerns about effects on brain development[3].
• The manufacturer recommends discontinuing treatment if you become pregnant[3].
• Not recommended during breastfeeding: Breastfeeding should be avoided during treatment and for 5 days after the final dose due to potential effects on the infant’s brain development[3].
• If you are planning to become pregnant, discuss alternative treatments with your doctor.

Older Adults

• Limited data: No patients 65 years or older were enrolled in the main clinical trials[3]
• Effects in elderly patients have not been well studied
• Your doctor may use extra caution and monitoring if prescribing this medication

Kidney Problems

• Mild impairment: No dose adjustment needed[3]
• Moderate impairment: Reduce to one tablet once daily[3]
• Severe impairment or dialysis: Not recommended (not studied)[3]

Liver Problems

• Mild to moderate impairment: No dose adjustment needed[3]
• Severe impairment: Not recommended (not studied)[3]

Genetic Factors (CYP2D6)

• Some people metabolize dextromethorphan slowly due to their genetics (CYP2D6 poor metabolizers)[3]
• These individuals may have about 3 times higher dextromethorphan levels[3]
• Dose adjustment to one tablet once daily is required[3]
• Genetic testing can determine your metabolizer status

Important Note About Abuse Potential

Both components of this medication have potential for misuse:

• Dextromethorphan: At high doses (much higher than in this medication), dextromethorphan can cause dissociative and hallucinogenic effects.[21,22] Fatal overdoses have been reported with dextromethorphan abuse[23]
• Bupropion: Has been misused for its stimulant-like effects[24-26]

This medication should be used with caution in individuals with a history of substance use disorder. Your doctor will monitor for signs of misuse.

References

1. McCarthy, B., et al. (2023). Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder. Clinical Psychopharmacology and Neuroscience, 21(4), 609–616.
2. Read, M. (2020). Axsome Therapeutics Announces Topline Results of the STRIDE-1 Phase 3 Trial in Treatment Resistant Depression. BioSpace.
3. Food & Drug Administration. (2024). AUVELITY® (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets, for oral use prescribing information.
4. Stahl, S. M. (2019). Dextromethorphan/Bupropion: A Novel Oral NMDA Receptor Antagonist with Multimodal Activity. CNS Spectrums, 24(5), 461–466.
5. Iosifescu, D. V., et al. (2022). Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). The Journal of Clinical Psychiatry, 83(4), 21m14345.
6. Zanos, P., et al. (2018). Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacological Reviews, 70(3), 621–660.
7. McIntyre, R. S., et al. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression. American Journal of Psychiatry, 178(5), 383–399.
8. Duman, R. S., et al. (2016). Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nature Medicine, 22(3), 238–249.
9. Hashimoto, K. (2009). Sigma-1 receptors and selective serotonin reuptake inhibitors: Clinical implications of their relationship. Central Nervous System Agents in Medicinal Chemistry, 9(3), 197–204.
10. Fishback, J. A., et al. (2010). Sigma receptors: Potential targets for a new class of antidepressant drug. Pharmacology & Therapeutics, 127(3), 271–282.
11. Costa, R., et al. (2019). Pharmacokinetic and pharmacodynamic of bupropion: Integrative overview of relevant clinical and forensic aspects. Drug Metabolism Reviews, 51(3), 293–313.
12. Casey, E. R., et al. (2011). Frequency of False Positive Amphetamine Screens due to Bupropion Using the Syva Emit II Immunoassay. Journal of Medical Toxicology, 7(2), 105–108.
13. Battini, V., et al. (2023). Psychiatric and non-psychiatric drugs causing false-positive amphetamines urine test in psychiatric patients: A pharmacovigilance analysis using FAERS. Expert Review of Clinical Pharmacology.
14. Tabuteau, H., et al. (2022). Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. The American Journal of Psychiatry, 179(7), 490–499.
15. Clayton, A. H., et al. (2004). A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. The Journal of Clinical Psychiatry, 65(1), 62–67.
16. Bostwick, J. M. (1996). Dextromethorphan-induced manic symptoms in a bipolar patient on lithium. Psychosomatics, 37(6), 571–573.
17. Lee, S.-Y., et al. (2020). Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: A 12-week double-blind randomized clinical trial. International Journal of Bipolar Disorders, 8, 11.
18. Omri, M., et al. (2024). Understanding De Novo Bupropion-Induced Psychosis and Its Management Strategies: A Case Report and Literature Review. Cureus.
19. Price, L. H., & Lebel, J. (2000). Dextromethorphan-Induced Psychosis. American Journal of Psychiatry, 157(2), 304–304.
20. Narayanan, V. (2019). Ocular Adverse Effects of Antidepressants – Need for an Ophthalmic Screening and Follow up Protocol. Ophthalmology Research: An International Journal, 1–6.
21. Gupta, L., et al. (2024). Dextromethorphan: A double-edged drug – Unveiling the pernicious repercussions of Abuse and forensic implications. Emerging Trends in Drugs, Addictions, and Health, 4, 100161.
22. Stanciu, C. N., et al. (2016). Recreational use of dextromethorphan, “Robotripping”-A brief review. The American Journal on Addictions, 25(5), 374–377.
23. Logan, B. K., et al. (2009). Five deaths resulting from abuse of dextromethorphan sold over the internet. Journal of Analytical Toxicology, 33(2), 99–103.
24. Evans, E. A., & Sullivan, M. A. (2014). Abuse and misuse of antidepressants. Substance Abuse and Rehabilitation, 5, 107–120.
25. Stassinos, G. L., & Klein-Schwartz, W. (2016). Bupropion “abuse” reported to US poison centers. Journal of Addiction Medicine, 10(5), 357–362.
26. Kaur, J., et al. (2024). Do not overlook bupropion misuse. Primary Care Companion for CNS Disorders, 26(2), 54349.

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Disclaimer: This information is not a substitute for professional medical advice. Always consult with your healthcare provider regarding your specific medical condition and treatment options.