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Dextromethorphan is a common antitussive agent found in many over-the-counter cough and cold preparations. Dextromethorphan is often found in combination products containing antihistamines (See Antihistamines), decongestants (See Pseudoephedrine, Phenylephrine, and Other Decongestants), ethanol (See Ethanol), or acetaminophen (See Acetaminophen). Common combination products containing dextromethorphan include Coricidin HBP Cough & Cold Tablets, Robitussin DM, and NyQuil Nighttime Cold Medicine. Dextromethorphan is well tolerated at therapeutic doses, and serious toxicity rarely occurs, even with moderate to high doses. However, major toxicity and death have been reported, caused either by dextromethorphan as a sole agent or more commonly by co-ingestants, drug-drug interactions, or genetic polymorphism. Intentional abuse, especially among adolescents and young adults, has been a rising problem owing to the hallucinogenic potential at high doses. Common slang terms include “triple C,” “CCC,” “skittles,” “robo,” “DXM,” and “dex.”


  1. Mechanism of toxicity. Although dextromethorphan is structurally related to opioids (its active metabolite is the d-isomer of levorphanol) and it has antitussive activity approximately equal to that of codeine, it has no apparent activity at mu or kappa receptors and does not produce a typical opioid syndrome in overdose.

    1. Dextromethorphan is metabolized in the liver by the cytochrome P-450 isoenzyme CYP2D6 to dextrorphan. Both dextromethorphan and dextrorphan antagonize N-methyl-d-aspartate (NMDA) glutamate receptors, although dextrorphan is more potent and primarily responsible for the psychoactive effects of high-dose dextromethorphan. Genetic polymorphism of CYP2D6 may explain the variable clinical responses reported; extensive metabolizers are more likely to experience the “desirable” psychoactive effects with recreational use.

    2. Dextromethorphan and dextrorphan inhibit reuptake of serotonin and may lead to serotonin syndrome (See Hyperthermia), especially in patients taking agents that increase serotonin levels, such as selective serotonin reuptake inhibitors (See Antidepressants, General (Noncyclic)) and monoamine oxidase inhibitors (See Monoamine Oxidase Inhibitors). Serotoninergic effects, as well as NMDA glutamate receptor inhibition, may explain the acute and chronic abuse potential of dextromethorphan.

    3. Dextromethorphan hydrobromide can cause bromide poisoning (See Bromides).

    4. Many of the combination preparations contain acetaminophen, and overdose or abuse may result in hepatotoxicity (p 69).

    5. Pharmacokinetics. Dextromethorphan is well absorbed orally, and effects are often apparent within 15–30 minutes (peak, 2–2.5 hours). The volume of distribution is approximately 5–6 L/kg. The rate of metabolism is dependent on CYP2D6 polymorphism. Dextromethorphan has a plasma half-life of about 3–4 hours in extensive metabolizers versus a half-life exceeding 24 hours in slow metabolizers (about 10% of the population). In addition, dextromethorphan competitively inhibits CYP2D6-mediated metabolism of other drugs, leading to many potential drug interactions (see also Table II–61).

  2. Toxic dose. Establishing a clear correlation between dose and clinical effects is problematic, given wide patient variability, genetic polymorphism, and the fact that most of the scientific literature is comprised of self-reported poisonings involving combination products lacking laboratory confirmation. Moderate symptoms usually occur when the amount of dextromethorphan exceeds 10 mg/kg. Severe poisoning is associated with ingestions of more than 20–30 mg/kg. The usual recommended adult daily dose ...

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