Is DXM (Dextromethorphan) a safe treatment for mood disorders?

DXM is NOT a safe or recommended treatment for mood disorders when used alone

DXM (dextromethorphan) should not be used as monotherapy for mood disorders, as high-dose or chronic use can actually induce depression-like symptoms and suppress neurogenesis. 1 The only evidence-based use of DXM for mood disorders is in the specific FDA-approved combination formulation with bupropion (not as standalone DXM), which has demonstrated efficacy for major depressive disorder through pharmacokinetic and pharmacodynamic synergy. 2, 3, 4

Critical Safety Concerns with DXM Monotherapy

Chronic high-dose DXM abuse causes psychiatric harm, not benefit:

• Repeated high-dose DXM treatment (40 mg/kg/day for 2 weeks) significantly increases depression-like behavior in animal models 1
• DXM suppresses hippocampal neurogenesis, decreasing both proliferative cells and immature neurons, which is associated with mood disorder pathophysiology 1
• Chronic DXM use leads to depressive-related symptoms and emotional distress in humans 5
• High doses of DXM can induce euphoria, dissociative effects, and hallucinations, making it a drug of abuse among adolescents 5

The Only Evidence-Based Use: DXM/Bupropion Combination

DXM has demonstrated antidepressant efficacy ONLY when combined with bupropion in a specific formulation:

• The DXM/bupropion combination shows replicated, relatively rapid onset efficacy in adults with major depressive disorder (MDD) 3, 4
• This combination represents pharmacokinetic and pharmacodynamic synergy that may account for rapid action, with bupropion inhibiting CYP2D6 metabolism of DXM, increasing DXM bioavailability 2, 3
• The combination is well-tolerated and safe when used as prescribed for MDD 3, 4
• Preliminary evidence suggests potential efficacy in bipolar depression, though results are mixed and require further study 3, 4

Why DXM/Bupropion Works (But DXM Alone Does Not)

The mechanism requires both components:

• DXM acts as an NMDA receptor antagonist (similar to ketamine), targeting glutamatergic signaling implicated in depression 3
• Bupropion serves dual roles: (1) provides norepinephrine-dopamine reuptake inhibition with antidepressant effects, and (2) inhibits DXM metabolism to achieve therapeutic DXM levels at lower doses 2, 3
• Without bupropion, achieving therapeutic NMDA antagonism would require dangerously high DXM doses that cause the adverse psychiatric effects described above 1

Comparison to Guideline-Recommended Treatments

Major depressive disorder guidelines do not include DXM monotherapy:

• Second-generation antidepressants (SSRIs, SNRIs) remain first-line for MDD, with no clinically significant differences in efficacy among them 6
• For treatment-resistant depression, ketamine infusion or intranasal esketamine are recommended after failure of at least 2 adequate antidepressant trials 6
• DXM/bupropion combination represents a mechanistically novel option targeting glutamate (like ketamine), but is distinct from DXM alone 2, 3

Common Pitfalls to Avoid

• Never recommend over-the-counter DXM cough preparations for mood disorders - the doses used for cough suppression (15-30 mg) are subtherapeutic for any antidepressant effect, while higher doses cause psychiatric harm 6, 1
• Do not confuse DXM abuse with therapeutic use - the psychiatric symptoms from DXM abuse (depression, anxiety, dissociation) are adverse effects, not therapeutic benefits 5, 1
• Recognize that DXM's cough suppressant use is unrelated to mood treatment - guidelines recommend DXM at 60 mg for cough suppression, but this has no relevance to mood disorders 6

Bottom Line Algorithm

For patients asking about DXM for mood disorders:

1. If asking about DXM alone or over-the-counter DXM: Strongly advise against use, as it can worsen depression and cause neurological harm at high doses 1
2. If asking about prescription DXM/bupropion combination: This is a legitimate FDA-approved option for MDD, but requires proper medical supervision and should only be prescribed by qualified clinicians 2, 3, 4
3. For treatment-resistant depression: Consider ketamine/esketamine (after ≥2 failed antidepressant trials) or DXM/bupropion combination, but never standalone DXM 6, 3