Does dextromethorphan (NMDA receptor antagonist) cause drowsiness?

Does Dextromethorphan Cause Drowsiness?

Yes, dextromethorphan can cause drowsiness, though this is typically a mild side effect that occurs primarily at therapeutic doses and becomes more pronounced with higher doses or in the context of drug interactions.

Primary Evidence from FDA Labeling

The FDA-approved labeling for dextromethorphan explicitly states that it is used to "help you get to sleep" by suppressing the cough impulse, indicating sedative properties are recognized at therapeutic doses 1.

Clinical Context and Severity

Therapeutic Doses

• At standard antitussive doses, dextromethorphan may produce mild sedation that facilitates sleep, particularly when cough is interfering with rest 1
• This drowsiness is generally considered a therapeutic benefit rather than a problematic adverse effect in the over-the-counter cough suppressant context 1

Overdose and Toxicity

• Somnolence (light sedation) is classified as a "mild effect" in dextromethorphan poisoning guidelines 2
• Patients exhibiting more than mild somnolence after acute ingestion should be referred to an emergency department 2
• At doses >7.5 mg/kg, emergency evaluation is recommended due to risk of more severe CNS depression 2
• In severe overdose, sedation can progress to coma, potentially requiring naloxone administration for respiratory depression 2

Important Drug Interactions Increasing Drowsiness Risk

CYP2D6 Inhibitors

• Methadone and other CYP2D6 inhibitors can significantly increase dextromethorphan levels, leading to delirium, hypersomnia, confusion, and lethargy 3
• An 83-year-old woman developed severe hypersomnia and delirium from dextromethorphan when taking concurrent methadone, with symptoms resolving after discontinuation 3
• Elderly patients are particularly vulnerable to these interactions 3

Serotonergic Medications

• When combined with monoamine oxidase inhibitors (MAOIs) or selective serotonin reuptake inhibitors (SSRIs), dextromethorphan can cause serotonin syndrome 2
• Patients on these combinations require extended monitoring (every 2 hours for 8 hours) due to risk of severe CNS effects including altered consciousness 2

Comparison to Other NMDA Antagonists

While dextromethorphan is an NMDA receptor antagonist like other agents that cause significant sedation, it appears to have a different side effect profile:

• Unlike more potent NMDA antagonists (such as MK-801), dextromethorphan does not produce neuronal vacuolation or neurodegeneration at therapeutic or even high doses in animal studies 4
• At clinically applicable doses (100 mg orally), dextromethorphan did not produce marked sedation in experimental pain studies, though 200 mg produced significant side effects 5

Clinical Monitoring Recommendations

• Patients taking dextromethorphan with CYP2D6 inhibitors should be closely monitored for excessive sedation, confusion, and delirium 3
• Follow-up every 2 hours for up to 4 hours is recommended for patients who have ingested 5-7.5 mg/kg 2
• Any patient with more than mild somnolence requires emergency department evaluation 2

Key Caveat

The drowsiness caused by dextromethorphan at therapeutic doses is generally mild and may be desirable for nighttime cough suppression 1. However, the risk increases substantially with overdose, drug interactions (particularly CYP2D6 inhibitors and serotonergic agents), or in vulnerable populations such as the elderly 2, 3.