What are the neurologic effects of dextromethorphan (DM)?

Neurologic Effects of Dextromethorphan

Dextromethorphan produces dose-dependent neurologic effects ranging from therapeutic antitussive action at standard doses to significant CNS depression, dissociative symptoms, and psychiatric disturbances at supratherapeutic doses, with FDA approval for pseudobulbar affect when combined with quinidine. 1

Therapeutic Neurologic Effects

FDA-Approved Indication:

• The combination of dextromethorphan/quinidine is FDA-approved for pseudobulbar affect, a neurologic condition characterized by pathological laughing and crying 1
• This formulation works through NMDA receptor antagonism in the central nervous system 2

Antitussive Mechanism:

• At therapeutic doses (30-60 mg), dextromethorphan acts centrally to suppress cough without producing the neuronal vacuolation seen with more potent NMDA antagonists like MK-801 3
• Standard over-the-counter doses are typically subterapeutic for optimal cough suppression 4

Adverse Neurologic Effects at Therapeutic Doses

Common Dose-Related Symptoms:

• Neurological disturbances including dizziness, confusion, and sedation occur infrequently but are the predominant adverse effects when they do occur 5
• CNS depressant effects can impair driving ability even at moderately elevated doses (150-1220 ng/mL blood concentrations) 6

Seizure Threshold:

• Dextromethorphan does not possess anticonvulsant properties, unlike other sedatives 1
• However, high doses (20-42 mg/kg/day) have demonstrated ability to suppress epileptiform discharges in refractory epilepsy through NMDA receptor blockade 2

Toxic Neurologic Effects at High Doses

Psychiatric and Behavioral Manifestations:

• At supratherapeutic doses, dextromethorphan produces phencyclidine-like effects on the NMDA receptor system, causing mania, hallucinations, and psychosis 7
• Blood concentrations associated with violent behavior, assault, suicide, and homicide range from 300 to 19,000 μg/L 7
• Dissociative and hallucinogenic effects occur at high doses, making it a drug of abuse 6

CNS Depression:

• Marked behavioral changes indicative of neurologic effects occur at doses ≥120 mg/kg/day in females and ≥150 mg/kg/day in males 3
• Symptoms include gross CNS depressant intoxication with impaired coordination, weaving, and altered consciousness 6
• Mortality can occur at the highest doses 3

Special Populations and Drug Interactions

Geriatric Considerations:

• The dextromethorphan/quinidine combination requires caution in older adults due to increased fall risk and drug interactions 4
• Limited efficacy exists for behavioral symptoms of dementia without pseudobulbar affect 4

Critical Drug Interaction:

• Coadministration with monoamine oxidase inhibitors (MAOIs) represents a particular safety concern and should be avoided 5

Neuropathologic Safety Profile

Absence of Structural Neurotoxicity:

• Unlike more potent NMDA antagonists (e.g., MK-801), oral dextromethorphan does not produce neuronal vacuolation in the retrosplenial/posterior cingulate cortex even with repeated administration up to 400 mg/kg/day 3
• No detectable neuropathologic changes occur following single or repeated oral administration at any tested dose 3

Clinical Monitoring Recommendations

When to Suspect Dextromethorphan Toxicity:

• Consider dextromethorphan as a causative agent in patients presenting with acute mania, psychosis, hallucinations, or unexplained CNS depression 7
• Abusers are at significant risk for violent and self-destructive acts requiring immediate intervention 7

Therapeutic Drug Monitoring:

• Plasma concentrations of 74-1730 ng/mL (dextromethorphan) and 349-3790 ng/mL (dextrorphan metabolite) are sufficient to block NMDA receptors therapeutically 2
• CSF concentrations are lower than plasma levels 2