Dextromethorphan is a common antitussive agent found in many over-the-counter (OTC) cough and cold preparations. Dextromethorphan is often found in combination products containing antihistamines, decongestants, ethanol, or acetaminophen. 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 coingestants, drug-drug interactions, or genetic polymorphism. Recreational use, especially among adolescents and young adults, has been a continuing problem owing to the hallucinogenic potential at high doses. Common slang terms include “triple C,” “skittles,” “robo,” and “DXM.”

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 P450 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, while individuals who are poor metabolizers experience greater sedation and dysphoria.
2. Dextromethorphan and dextrorphan inhibit reuptake of serotonin and may lead to serotonin syndrome, especially in patients taking agents that increase serotonin levels, such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors. Serotoninergic effects, as well as NMDA glutamate receptor inhibition, may explain the recreational use of dextromethorphan.
3. Dextromethorphan hydrobromide can cause bromide poisoning.
4. Many of the combination preparations contain acetaminophen, and overdose may result in hepatotoxicity.
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.

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.

1. Mild-to-moderate intoxication. Nausea, vomiting, nystagmus, mydriasis or miosis, tachycardia, hypertension, dizziness, lethargy, agitation, ataxia, euphoria, dysphoria, and auditory and visual hallucinations (“CEVs,” or closed-eye visualizations, often described as color changes) have been reported.
2. Severe poisoning. Disorientation, stupor, psychosis, dissociative hallucinations, seizures, coma, hyperthermia, QT prolongation, respiratory depression, pulmonary and cerebral edema, and death can occur.
3. Serotonin syndrome. Severe hyperthermia, muscle rigidity, altered mental status, and hypertension may occur, especially with concomitant use of agents that increase serotonin or catecholamine levels as well as CYP2D6 inhibitors that may increase dextromethorphan levels.
4. Withdrawal syndrome. Abdominal pain, vomiting, diarrhea, tachycardia, hypertension, depression, dysphoria, diaphoresis, insomnia, tremor, myalgias, restlessness, and drug craving have been reported.
5. Chronic poisoning. Psychosis, mania, and cognitive deterioration have been reported following chronic abuse. Chronic ingestion of the hydrobromide salt has resulted in bromism.

Should be considered with ingestion of any over-the-counter cough suppressant, especially when the clinical presentation is consistent and toxicology screening is positive for phencyclidine (PCP; dextromethorphan cross-reacts with many PCP immunoassays). Because dextromethorphan often is combined with other ingredients (eg, antihistamines, phenylpropanolamine, or acetaminophen), suspect mixed ingestion.

1. Specific levels. Assays exist for serum and urinalysis but are not generally available. In five teenage fatalities (ages 17-19 years) secondary to recreational dextromethorphan use, postmortem blood concentrations ranged from 950-3,230 ng/mL (median, 1,890 ng/mL). Despite its structural similarity to opioids, dextromethorphan is not likely to produce a false-positive urine opioid immunoassay screen. However, it may produce a false-positive result on PCP immunoassays. Dextromethorphan is readily detected by comprehensive urine toxicology screening.
2. Other useful laboratory studies include electrolytes, glucose, and blood gases (if respiratory depression is suspected). The hydrobromide salt can cause a falsely increased chloride level. Blood ethanol and acetaminophen levels should be obtained if those drugs are contained in the ingested product.

1. Emergency and supportive measures. Most patients with mild symptoms (ie, restlessness, ataxia, or mild drowsiness) can be observed for 4-6 hours and discharged if their condition is improving.
   1. Maintain an open airway and assist ventilation if needed.
   2. Treat seizures and coma if they occur.
2. Specific drugs and antidotes. Although naloxone has been reported to be effective in doses of 0.06-0.4 mg, other cases have failed to respond to doses up to 2.4 mg.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. The volume of distribution of dextromethorphan is very large, and there is no role for enhanced removal procedures.