Dextromethorphan is in Auvelity because it works as an antidepressant through a completely different mechanism than traditional options. Most antidepressants target serotonin or norepinephrine. Dextromethorphan instead blocks a receptor in the brain called NMDA and activates another called sigma-1, both of which play roles in mood regulation. This gives Auvelity a faster onset of action than conventional antidepressants, with measurable symptom improvement appearing within the first week of treatment.
How Dextromethorphan Treats Depression
You probably recognize dextromethorphan as a cough suppressant found in over-the-counter cold medicines. But at certain levels in the bloodstream, it has meaningful effects on brain chemistry that go well beyond suppressing a cough reflex.
Dextromethorphan blocks NMDA receptors, which are involved in a signaling system that uses the brain chemical glutamate. This is the same basic mechanism that makes ketamine effective for depression, though dextromethorphan is a milder version. On top of that, dextromethorphan acts as an agonist at sigma-1 receptors, which are thought to influence how nerve cells adapt and respond to stress. It also interacts with serotonin and norepinephrine transporters, similar to how traditional antidepressants work. This combination of actions across multiple brain systems is why the drug is described as having “multimodal” activity.
The NMDA-blocking action is the key differentiator. Standard SSRIs and SNRIs take four to six weeks to reach full effect because they rely on gradual changes in serotonin signaling. Targeting the glutamate system appears to produce mood improvements much faster.
Why Bupropion Is Paired With It
Here’s the problem with dextromethorphan on its own: your body breaks it down too quickly. An enzyme in the liver called CYP2D6 rapidly converts dextromethorphan into a different compound called dextrorphan. Once that conversion happens, the therapeutic blood levels needed for an antidepressant effect disappear before the drug can do its job.
Bupropion solves this. It competitively inhibits CYP2D6, essentially blocking the enzyme that would otherwise chew through the dextromethorphan. With bupropion on board, plasma concentrations of dextromethorphan rise and stay elevated long enough to produce a sustained antidepressant effect. Bupropion also happens to be an established antidepressant in its own right, so both ingredients contribute to the therapeutic benefit. Each Auvelity tablet contains 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride. The dextromethorphan is formulated for immediate release while the bupropion is extended-release.
This pairing isn’t arbitrary. Without the metabolic protection bupropion provides, you’d need much higher doses of dextromethorphan to maintain effective blood levels, which would increase the risk of side effects. The combination keeps the dose of each ingredient relatively low while maximizing the antidepressant effect of both.
How Quickly It Works
Speed of onset is one of the primary reasons dextromethorphan was developed into a depression treatment. In the GEMINI clinical trial, Auvelity showed statistically significant symptom improvement compared to placebo as early as week one. At that point, twice as many patients on Auvelity had achieved at least a 50% reduction in depression scores compared to placebo (15% versus 7%). On a clinician-rated improvement scale, 22% of Auvelity patients were rated as “much improved” or “very much improved” at week one, compared to 13% on placebo.
By week two, 17% of patients on Auvelity had reached remission (a depression score low enough to be considered no longer clinically depressed), versus 8% on placebo. By week six, the remission rate climbed to 40% for Auvelity compared to 17% for placebo. That six-week remission rate is notable because it’s roughly the same timeframe where many patients on traditional antidepressants are only beginning to feel initial effects.
What Makes This Approach Different
Nearly every major antidepressant approved in the past four decades has worked primarily through serotonin, norepinephrine, or dopamine. Auvelity is significant because it’s the first oral antidepressant to leverage the glutamate system for treating major depressive disorder. The FDA approved it in August 2022.
Ketamine and its derivative esketamine (Spravato) also target NMDA receptors, but those require administration in a clinical setting, either through an IV or a nasal spray with mandatory observation periods. Auvelity is a tablet you take at home, which makes it far more practical for long-term daily use. The tradeoff is that dextromethorphan’s NMDA blockade is less potent than ketamine’s, so the rapid effects, while real, are not as dramatic as what some patients experience with ketamine infusions.
The inclusion of dextromethorphan also means Auvelity carries some precautions that don’t apply to standard antidepressants. It should not be combined with monoamine oxidase inhibitors, and because dextromethorphan affects serotonin transporters, there is a risk of serotonin syndrome when combined with other serotonergic drugs. The most commonly reported side effects in clinical trials were dizziness, headache, diarrhea, somnolence, and dry mouth.