The antidepressant-accelerator finds a new use
STUDY: Zolghadriha A et al, Health Science Reports 2026;9:e72055
STUDY TYPE: Randomized, double-blind, placebo-controlled trial
FUNDING: Zanjan University of Medical Sciences
Background
Glutamate dysregulation plays a role in OCD, and small trials have found promise with glutamatergic meds like amantadine, memantine, lamotrigine, and n-acetylcysteine. This trial tested dextromethorphan (DXM), originally developed as a cough syrup but more recently found to speed up antidepressants in the bupropion-combo Auvelity (also FDA-approved this month for agitation in dementia).
Mechanism: DXM blocks NMDA glutamate receptors and also modulates serotonin, norepinephrine, and sigma-1 receptors.
The Study
- 40 adults with moderate-to-severe OCD (OCD scale [Y-BOCS] score above 16) who hadn’t responded to at least 12 weeks of adequate SSRI doses
- Randomized to DXM 15 mg twice daily added to their existing SSRI, or placebo plus SSRI, for 12 weeks
- Double-blind; all participants remained on their current SSRI throughout
OCD scores (Y-BOCS) dropped from 26.6 to 16.3 in the DXM group (39% reduction) while the placebo group held steady around 25. The difference was significant by week 4 and widened through week 12 (p < 0.001, partial η² = 0.662, a large effect).
Side Effects
No side effects were reported in either group.
Limitations
Very small sample (20 per group), single-center, conducted in Iran, no secondary outcomes measured, and the dose (30 mg/day) may not be optimal. Fluoxetine and paroxetine inhibit DXM metabolism and likely raised DXM levels in some participants, a pharmacokinetic variable that wasn’t tracked.
Practice Implications
These are preliminary results, but supported by the basic science, making DXM a reasonable option when other therapies fail.
Learn more about DXM’s role in clozapine-resistant schizophrenia.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
