Dextromethorphan-Bupropion (Auvelity)
A fixed-dose oral combination of dextromethorphan (NMDA antagonist) and bupropion (which boosts dextromethorphan levels), FDA-approved in 2022 for depression.
What it treats
Dextromethorphan-bupropion is approved by the U.S. Food and Drug Administration to treat major depressive disorder in adults.
Off-label use is limited given how new the drug is. Off-label means a purpose the label doesn't formally list even though evidence and practice support it.
How it works
Dextromethorphan is best known as a cough suppressant, but at antidepressant doses it acts on NMDA glutamate receptors (similar in mechanism to ketamine, though weaker) and on sigma-1 receptors. It also has some effect on serotonin and norepinephrine reuptake.
Bupropion is the second ingredient. Its main role in this combination isn't its antidepressant activity, though that helps. It's included to block CYP2D6, the liver enzyme that would ordinarily clear dextromethorphan quickly. By slowing the clearance, bupropion raises and steadies dextromethorphan blood levels enough to produce a sustained antidepressant effect.
Receptor mechanism (detail)
Dextromethorphan is a non-competitive NMDA receptor antagonist, a sigma-1 receptor agonist, and a SERT/NET inhibitor. Bupropion is a CYP2D6 inhibitor (used here as a pharmacokinetic booster) and, on its own, an NDRI antidepressant. Together, the combination raises brain dextromethorphan levels enough to engage NMDA and sigma-1 pathways relevant to rapid antidepressant effect while providing supportive noradrenergic and dopaminergic activity from bupropion.
Potency and typical dosing pattern
Ranges are typical framework only, not a prescription for any individual.
Fixed dose: one tablet (dextromethorphan 45 mg / bupropion 105 mg) once daily for the first three days, then one tablet twice daily thereafter, with at least 8 hours between doses.
Maximum: two tablets per day (one tablet twice daily). No titration beyond that.
Safety monitoring
- Blood pressure at baseline and periodically. Bupropion can raise it.
- Seizure history. Bupropion lowers seizure threshold; a history of seizures, eating disorders (anorexia, bulimia), or abrupt discontinuation of alcohol or benzodiazepines is a contraindication.
- Suicidality in the first 4 weeks, especially under age 25 (FDA boxed warning).
- Serotonin syndrome, avoid MAOIs.
- Drug interactions. Bupropion is a strong CYP2D6 inhibitor, so many other drugs are affected.
- Dissociative symptoms. Uncommon at fixed dose but possible.
- Reassess at 2, 4, and 6 to 8 weeks.
What to expect
The first weeks tend to follow a familiar shape, with a faster onset than most SSRIs.
The first days to two weeks
Dizziness, nausea, headache, and dry mouth are common early. Some people notice mild mood improvement within the first week or two.
Common side effects
Common side effects include:
- Dizziness.
- Headache.
- Diarrhea.
- Nausea.
- Dry mouth.
- Sexual dysfunction.
- Sweating.
- Mild dissociative feelings in some.
If a side effect is severe, or it isn't improving, that's a conversation to have with the prescriber rather than a reason to stop on your own.
Serious side effects and warnings
Serious problems are uncommon, but a few are worth knowing.
Boxed warning. Like all antidepressants, dextromethorphan-bupropion carries an FDA boxed warning that it can increase suicidal thoughts and behaviors in children, teenagers, and young adults under 25, especially in the first weeks of treatment or after a dose change.
- Seizures. Bupropion lowers seizure threshold. Contraindicated in seizure disorder, current or prior eating disorders (anorexia, bulimia), and abrupt discontinuation of alcohol or benzodiazepines.
- Blood pressure rise. Bupropion can raise blood pressure; check baseline and periodically.
- Serotonin syndrome. Do not combine with MAOIs; caution with SSRIs, SNRIs, tramadol, triptans, linezolid, methylene blue, St. John's wort.
- Mood switch in bipolar disorder is possible, as with other antidepressants.
- Angle-closure glaucoma in susceptible individuals.
Sexual side effects
Sexual side effects with this combination appear to be lower than with SSRIs, though they aren't absent. Bupropion is generally considered one of the more sexually neutral antidepressants, and adding dextromethorphan doesn't seem to change that dramatically. If sexual side effects appear, they're worth raising with the prescriber.
Weight, appetite, and sleep
Bupropion is weight-neutral to weight-losing, and that profile seems to carry through. Insomnia can occur; because the drug is dosed twice daily, keeping the second dose earlier in the day helps.
Starting and dosing basics
This section is general background, not a dosing instruction for any individual. The right dose is a decision for a prescriber.
Dextromethorphan-bupropion comes as a single fixed-strength extended-release tablet. Day 1 to 3 is one tablet once daily. From day 4 on, it's one tablet twice daily with at least 8 hours between doses. The dose isn't titrated further.
Missed doses and interactions
If you miss a dose, take it when you remember, unless it's within 8 hours of the next dose. In that case, skip the missed dose and take the next one at the scheduled time. Don't take two doses to make up for one.
Interactions matter. Do not combine with MAOIs, and observe a 14-day washout when switching (5 weeks after fluoxetine). Other CYP2D6 substrates (many antidepressants, antipsychotics, opioids, beta-blockers) can accumulate because bupropion inhibits CYP2D6. Serotonergic drugs raise serotonin syndrome risk. Alcohol adds seizure risk on top of bupropion. Give every prescriber and pharmacist a full list of your medications and supplements, including over-the-counter ones.
Stopping and tapering
Dextromethorphan-bupropion isn't a controlled substance and isn't habit-forming in the usual sense.
The body does adjust to it, and stopping abruptly can cause discontinuation symptoms: dizziness, flu-like feelings, irritability. A gradual taper planned with a prescriber avoids most of this.
Pregnancy and breastfeeding
This is an area where individual circumstances matter and the decision belongs with a clinician. Data on this specific combination in pregnancy are limited; bupropion has more data. Anyone who is pregnant, planning a pregnancy, or breastfeeding should talk it through with their prescriber so the specific risks and benefits can be weighed for their situation.
Cost and generic availability
Dextromethorphan-bupropion is brand-only (Auvelity). Costs are typically high without insurance, and coverage often requires prior authorization. Manufacturer assistance may be available.
Common questions
Why is bupropion in this combination? Bupropion blocks the CYP2D6 enzyme that would ordinarily clear dextromethorphan too quickly to work as an antidepressant. By slowing the clearance, bupropion boosts and steadies dextromethorphan levels. Bupropion's own antidepressant activity is a supportive contribution.
How is this different from just taking dextromethorphan? Without something to slow its clearance, dextromethorphan wouldn't build to consistent levels needed for antidepressant effect. Auvelity engineers that pharmacokinetic problem out.
How fast does it work? Faster than most SSRIs. Some people notice mood shifts in the first week or two, though the full effect is usually judged at four to six weeks.
Will it interact with my other medications? Very possibly, given bupropion's CYP2D6 inhibition. Many antidepressants, antipsychotics, opioids, and beta-blockers are affected.
Is it addictive? No, at fixed dose. It's not a controlled substance.
Questions to ask your prescriber
- What are we hoping this treats, and how will we know it's working?
- Given the seizure and blood pressure notes, is my history okay for this?
- Do any of my other medications interact with the CYP2D6 effect?
- Which side effects should I call about?
- If we decide to stop it later, how would we do that safely?
Sources
This guide draws on current prescribing information and public health references and current as of June 8, 2026. It is reviewed for clinical accuracy and updated as guidance changes.
- U.S. Food and Drug Administration. Dextromethorphan-bupropion (Auvelity) prescribing information (2022 approval).
- MedlinePlus, U.S. National Library of Medicine. Dextromethorphan-bupropion.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder.
- National Institute of Mental Health. Mental health medications.
Define this drug class in the network glossary Atypical antidepressant on Shrinktionary
THE KNOWLEDGE PATH
Walk this topic outward.
- MEDICATION Dextromethorphan-Bupropion (Auvelity) (current)
- CLASS Atypical antidepressants
- CONDITION Major Depressive Disorder (on Shrinkopedia)
- MAP The Depression Map (on DR)
- CARE Depression care at shrinkMD
The Knowledge Path is a curated walk. Every step is one decision away from the next.
When to call your prescriber or seek urgent help
Antidepressants are usually safe and helpful, but the first weeks of a new medication, or a recent dose change, are the time to watch for warning signs and tell your prescriber promptly. People under 25 carry a recognized higher risk of new suicidal thoughts early in treatment.
- New or worsening thoughts of suicide or self-harm.
- A sudden change in mood, including new agitation, restlessness, or unusual energy or sleeplessness.
- High fever, fast heartbeat, severe muscle stiffness, shivering, or confusion, which can be signs of serotonin syndrome.
Managing a medication needs a prescriber
Any psychiatric medication has to be started and adjusted by a clinician who can follow you over time. If you don't have a prescriber, our guides section explains the options, including in-person care and telepsychiatry, and how to choose between them.