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Dextromethorphan is a white powder. Available primarily in tablet, capsule and liquid form.

Synonyms: 3-methoxy-17-methyl-9 a, 13 a, 14 a-morphinan hydrobromide monohydrate; dextromethorphan hydrobromide, DXM, “robbo tripping”; Anaplex-DM®, Diabe-Tuss DM™, Benylin®, Pertussin®, Delsym®, Sucrets®, Bromfed-DM®, Robitussin®, Vicks Formula 44, etc.

Source: Synthetic analog of codeine and d-isomer of 3-methoxy-N-methymorphinan. Available as lozenges, capsules, tablets, and cough syrups, in a variety of prescription medications and over-the-counter cough and cold remedies. Products contain dextromethorphan alone or in combination with guaifenesin, brompheniramine, pseudoephedrine, phenylephrine, promethazine, codeine, acetaminophen, and/or chlorpheniramine. For example, Diabe-Tuss DM™ syrup contains 15 mg dextromethorphan; Benylin® Adult and Pediatric contain 15 mg and 7.5 mg dextromethorphan, respectively; and Anaplex-DM® contains 30 mg dextromethorphan, 4 mg brompheniramine and 60 mg pseudoephedrine.

Drug Class: Non-opioid antitussive, cough suppressant, CNS depressant (in high doses).

Medical and Recreational Uses: Used as an antitussive for temporary relief of coughs caused by minor throat and bronchial irritation. Recreationally used for effects ranging from mild stimulation and intoxication, to dissociation.

Potency, Purity and Dose: As an antitussive, the recommended dosage for adults and children aged 12 years and older is 60-120 mg daily in divided doses; for children aged 6-12 years, 30-60 mg daily in divided doses; and for children aged 2-6 years, 15-30 mg daily in divided doses. Each brand contains different quantities of dextromethorphan, generally 20-30 mg per dose, and the majority contain other drugs as previously mentioned. Approximate recreational doses are: threshold dose 80-90 mg; light 100-200 mg; common 200-400 mg; strong 400-600; and heavy dose 600-1500 mg.

Route of Administration: Oral.

Pharmacodynamics: Dextromethorphan acts centrally to elevate the threshold for coughing, and has no significant analgesic or sedative properties at antitussive doses. It is proposed that dextromethorphan is a glutamate and NMDA antagonist, and blocks the dopamine reuptake site. It may also increase 5HT 1A activity possibly via NMDA antagonism.

Pharmacokinetics: Dextromethorphan is rapidly absorbed from the gastrointestinal tract and peak plasma concentrations are reached in approximately 2.5 hours. Dextromethorphan is widely distributed, and is rapidly and extensively metabolized by the liver. Dextromethorphan is demethylated to dextrorphan, an active metabolite, and to 3-methoxymorphinan and 3-hydroxymorphinan. It is primarily excreted as unchanged parent drug and dextrorphan.

Molecular Interactions / Receptor Chemistry: The cytochrome P450 2D6 isoenzyme is responsible for the conversion of dextromethorphan to dextrorphan; and P450 3A4 and 3A5 isoenzymes are responsible for converting dextromethorphan to

3-methoxymorphinan and 3-hydroxymorphinan . Potential inhibitors of these isoenzymes could decrease the rate of dextromethorphan elimination if administered concurrently, while potential inducers could increase the rate of elimination.

Blood to Plasma Concentration Ratio: Data not available.

Interpretation of Blood Concentrations: A single 20 mg oral dose of dextromethorphan produced peak concentrations of 1.8 ng/mL in serum after 2.5 hours. Chronic oral dosing of 120 mg daily, in divided doses, resulted in peak plasma dextromethorphan concentrations of 0.5-5.9 ng/mL (mean 2.4 ng/mL) in extensive metabolizers, and 182-231 ng/mL (mean 207 ng/mL) in poor metabolizers.

Interpretation of Urine Test Results: In a 24 hour period, less than 2.5% of a dose is excreted unchanged in the urine, while up to 30% of the conjugated dextrorphan is excreted.

Effects: At recommended doses, dextromethorphan produces little or no CNS depression. At recreational doses, positive effects may include acute euphoria, elevated mood, dissociation of mind from body, creative dream-like experiences, and increased perceptual awareness. Other effects include disorientation, confusion, pupillary dilation, and altered time perception, visual and auditory hallucinations, and decreased sexual functioning. Recreational doses of approximately 100-200 mg have a mild, stimulant effect (likened to MDA); doses of 200-500 mg produce a more intoxicating effect (likened to being ‘drunk and stoned’); 500-1000 mg may result in mild hallucinations and a mild dissociate effect (likened to a low dose of ketamine) and an overall disturbance in thinking, senses and memory; while doses over 1000 mg may produce a fully dissociative effect (likened to a high dose of ketamine). Recreationally abused doses are capable of impairing judgment, memory, language, and other mental performances.

Side Effect Profile: Adverse effects with recommended antitussive doses are rare. However, nausea, other gastrointestinal disturbances, slight drowsiness and dizziness can occur. Following acute doses of between 250-1500 mg, the following clinical and overdose symptoms have been reported: excitation, nausea, vomiting, drowsiness, dizziness, blurred vision, nystagmus, dilated pupils, body itching, rash, ataxia, sweating, hot/cold flashes, fever, hypertension, shallow respiration, urinary retention, diarrhea, opisthotonos (spasm where head and heels are bent back, and torso is bent forward), toxic psychosis (hyperactivity, marked visual and auditory hallucinations), coma, and an increase in heart rate, blood pressure and body temperature. Side effects can be serious if very large doses of the combined preparations are ingested; for example, guaifenesin and dextromethorphan can cause severe nausea and vomiting; chlorpheniramine and dextromethorphan can cause seizure, loss of consciousness and bleeding.

Duration of Effects: Dextromethorphan exerts its antitussive effects within 15-30 minutes of oral administration. The duration of action is approximately 3-6 hours with conventional dosage forms.

Tolerance, Dependence and Withdrawal Effects: At recommended antitussive doses, addiction does not occur. Mild psychological dependence and depression may occur with regular use of increased doses. Abrupt discontinuation of higher doses may produce insomnia, dysphoria and depression. Poor metabolizers of dextromethorphan have been shown to tolerate lower doses of the drug compared to extensive metabolizers, and report greater sedation, dysphoria and psychomotor impairment. Preliminary evidence also suggests that extensive metabolizers may report a greater dextromethorphan abuse potential due to the increased rate of metabolism to the active metabolite dextrorphan.

Drug Interactions: Should not be taken with Monoamine Oxide Inhibitors (MAOIs) and Selective Serotonin Reuptake Inhibitors (SSRIs) because of an apparent serotonin syndrome (fever, hypertension, arrhythmias). Should be used with caution in atopic children due to histamine release. Additive CNS depressant effects when co-administered with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.

Performance Effects: Minimal at therapeutic levels, however, with high doses one can expect gross cognitive and psychomotor impairment.

Effects on Driving: Little to no effect at therapeutic levels, however with high doses one could expect significant impairment. The drug manufacturer states that the combined preparation of promethazine and dextromethorphan may cause marked drowsiness or impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle. Patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy. Similar effects could be seen with other combined dextromethorphan preparations.

DEC Category: CNS depressant

DEC Profile: Data not available; however, the profile for a CNS depressant is: horizontal gaze nystagmus present; vertical gaze nystagmus present at high doses; lack of convergence present; pupil size normal to dilated; reaction to light slow; pulse rate down; blood pressure down; body temperature normal. Such effects are more likely to be seen following recreational doses of dextromethorphan.

Panel’s Assessment of Driving Risks: Minimal to no risk at therapeutic levels. Potentially mild to moderate driving risk with higher recreational use.

References and Recommended Reading:

Cranston JW, Yoast R. Abuse of dextromethorphan. Arch Fam Med 1999;8(2):99-100.

de Zeeuw RA, Jonkman JHG. Genetic differences in oxidative drug metabolism. In Proceedings of the International Association of Forensic Toxicologists, Gronigen, Netherlands, 1988,pp 53-64.

Pender ES, Parks BR. Toxicity with dextromethorphan containing preparations: A literature review and report of two additional cases. Pediatr Emerg Care 1991;7(3):163-5.

Physicians’ Desk Reference, Medical Economics Company, Montvale, NJ, 2002.

Silvasti M, Karttunen P, Tukiainen H, Kokkonen P, Hanninen U, Nykanen S. Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J Clin Pharmacol Ther Toxicol 1987;25(9):493-7.

Zawertailo LA, Kapla HL, Busto UE, Tyndale RF, Sellers EM. Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol 1998;18(4):332-7.