What are the risks of using amantadine with cocaine?

Amantadine and Cocaine: Significant Risk of CNS Toxicity

The combination of amantadine and cocaine poses serious risks due to additive central nervous system stimulation, potentially leading to severe neuropsychiatric complications including seizures, agitation, psychosis, and cardiovascular toxicity.

Primary Mechanism of Concern

Amantadine has multiple CNS-stimulating properties that create dangerous synergy with cocaine:

• Dopaminergic and noradrenergic activity: Amantadine releases dopamine and norepinephrine from neuronal storage sites, the same neurotransmitters that cocaine blocks reuptake of, creating potentially dangerous additive effects 1, 2
• Direct CNS stimulation: Amantadine causes nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness in 5-10% of patients at therapeutic doses 3
• Monoamine oxidase A blockade: This further potentiates catecholamine effects 1

Documented CNS Toxicity Profile

The CDC and ACIP guidelines explicitly warn about amantadine's CNS effects:

• Serious adverse reactions include marked behavioral changes, delirium, hallucinations, agitation, and seizures 3
• Increased seizure risk: An increased incidence of seizures has been reported in patients with seizure disorders taking amantadine, requiring close observation 3, 4
• Psychosis and confusion: More frequent in elderly patients and those with altered mental states 3

Specific Drug Interaction Warnings

Careful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants 3. Cocaine is one of the most potent CNS stimulants available, making this combination particularly hazardous.

Cocaine Use Disorder Context

Paradoxically, amantadine has been studied as a treatment for cocaine withdrawal, but results are discouraging:

• No efficacy demonstrated: Amantadine (200 mg daily or 400 mg daily) was no more effective than placebo in reducing cocaine use or craving in methadone-maintained patients 5
• Acute administration ineffective: Single doses of amantadine were actually less effective than placebo in reducing cocaine craving 6
• Withdrawal management only: While amantadine may help alleviate withdrawal symptoms, it does not prevent ongoing cocaine use 2

Critical Clinical Pitfalls

Avoid these dangerous scenarios:

• Active cocaine use: Never prescribe amantadine to patients actively using cocaine due to additive CNS stimulation 3
• Dose escalation: Higher doses of amantadine (>100 mg/day) significantly increase CNS toxicity risk, particularly when combined with other stimulants 3
• Renal impairment: Reduced renal function increases amantadine plasma concentrations and toxicity risk, which is particularly dangerous when combined with cocaine 7
• Polypharmacy: Concomitant use of other CNS stimulants or anticholinergic drugs increases adverse CNS reactions 3

Cardiovascular Considerations

While not explicitly detailed in the guidelines, both amantadine and cocaine have cardiovascular effects:

• Cardiac toxicity: Acute amantadine overdosage can cause cardiac arrhythmias 3
• Additive effects: Combined with cocaine's well-known cardiotoxicity, this creates significant risk for arrhythmias and cardiovascular events

Practical Management Algorithm

If a patient on amantadine discloses cocaine use:

1. Immediately discontinue amantadine to prevent additive CNS toxicity
2. Monitor for withdrawal symptoms from both substances
3. Screen for complications: Assess for seizures, psychosis, agitation, and cardiovascular instability
4. Consider alternative treatments: If amantadine was prescribed for influenza prophylaxis, consider rimantadine (though it carries similar warnings) or neuraminidase inhibitors; if for Parkinson's disease, discuss alternatives with neurology 3

If prescribing amantadine to any patient:

• Screen for substance use: Explicitly ask about cocaine and other stimulant use before prescribing 3
• Use lowest effective dose: Particularly in elderly patients or those with risk factors, use ≤100 mg/day 3
• Monitor closely: Watch for CNS side effects, especially in the first week of therapy 3