Is Dextromethorphan a Psychedelic?

The answer depends on the dose

STUDY: Willow E et al, CNS Drugs 2026 

STUDY TYPE: Systematic review

FUNDING: ACTTION public-private partnership with the US FDA, multiple pharmaceutical and device companies, and philanthropy.

Background

Dextromethorphan (DXM) is an old cough syrup that was repurposed as the rapid-acting antidepressant Auvelity in 2022. DXM also has an abuse liability, as people take it to induce hallucinatory states (called Robotripping). This review looks at which dose those psychedelic effects kick in.

DXM acts on glutamatergic NMDA receptors, serotonin receptors, and sigma-1 receptors, and it inhibits serotonin-norepinephrine reuptake. That’s a profile that overlaps with both classic psychedelics like psilocybin and dissociative agents like ketamine (DXM’s transition into depression was inspired by ketamine).

The Study

• Eight published studies representing four unique participant samples (104 participants total).
• Doses ranged from 100 to 960 mg in single-dose, crossover, and ascending-dose designs.
• Primary outcomes: hallucinations, mystical experiences, and cognitive effects. Secondary: tolerability and adverse effects.
• Findings synthesized narratively — too much heterogeneity for a meta-analysis.

Results

Psychedelic effects began at 100 mg and intensified with each dose step. At 300–400 mg, participants reported complex visual imagery, audiovisual synesthesia, and mystical experiences, including transcendence of time and space, a sense of sacredness, and what one scale described as a fusion of self into a larger whole.

The 400-mg dose produced the richest psychedelic effects across the studies. Participants compared the experience to psilocybin and LSD.

Adverse effects rose with dose. For cognition, free recall dropped at 100 mg, word recognition at 200 mg, and working memory and divided attention at 300 mg. Above 200 mg, nausea and vomiting became common; above 300 mg, slurred speech, hot flushes, and motor impairment appeared.

DXM did not enhance positive social effects like emotional closeness and interpersonal connection, a contrast with classic psychedelics like MDMA.

Limitations

• Only 104 participants across four unique samples, and several papers drew from the same participants.
• Study populations were primarily young, healthy, white males, limiting generalizability.

Practice Implications

1. The dose-response picture is useful: psychedelic effects begin around 100 mg but become clinically meaningful at 300–400 mg
2. Auvelity uses 90 mg per day, which seems below the psychedelic threshold, but bupropion (the other ingredient in Auvelity) increases the DXM’s peak levels 40-fold and the total exposure to the drug (area under the curve) 60-fold.
3. Although I’m not seeing psychedelic effects in patients on Auvelity, it is concerning, and a call to use it as intended: As an antidepressant accelerator, not a long-term therapy. Consider tapering off to bupropion monotherapy (raising to 300 mg daily) after 1-2 months.
4. Auvelity failed in treatment-resistant depression, but it has new studies (as DXM 30 mg) in treatment-resistant schizophrenia and OCD.

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

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