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Systematic (IUPAC) name
CAS number 125-71-3
ATC code R05DA09
PubChem CID 15978238
DrugBank APRD00655
ChemSpider 13109865
Chemical data
Formula C18H25NO 
Mol. mass 271.4 g/mol
SMILES eMolecules & PubChem
Physical data
Melt. point 111 °C (232 °F)
Pharmacokinetic data
Bioavailability 11%[1]
Metabolism Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Half-life 1.4–3.9 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. A(AU) C(US)
Legal status Pharmacy Only (S2) (AU) OTC (US)
Routes Oral
 YesY(what is this?)  (verify)

Dextromethorphan (DXM or DM) is an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder.

DXM is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen. Its mechanism of action is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor, a sigma-1 receptor agonist, and the action of its major metabolite dextrorphan as an NMDA receptor antagonist, producing effects similar to those of the controlled substances ketamine and phencyclidine (PCP).[2]


Dextromethorphan was identified as one of three compounds tested as part of US Navy and CIA-funded research that sought a "nonaddictive substitute for codeine"; it is implied that the compound was first found to have clinical potential in this study[3]. It was first patented under U.S. Patent 2,676,177. The U.S. Food and Drug Administration (FDA) approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. This filled the need for a cough suppressant lacking the sedative side-effects, stronger potential for misuse, and physically addictive properties of codeine phosphate, the most widely used cough medication at the time.[4] In the United States, codeine phosphate syrup is still available in small quantities without a prescription in some states, but requires a signature and ID to purchase, similar to modern rules for sale of pseudoephedrine.

During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves after a burst in sales because of frequent abuse, and was replaced by cough syrup in an attempt to cut down on abuse.[4]

More recently (the early 1990s), gel capsule forms began reappearing in the form of Drixoral Cough Liquid Caps and later Robitussin CoughGels as well as several generic forms of that preparation.


The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled irritants.

As with most cough suppressants, studies show that dextromethorphan's effectiveness is unproven,[5] especially in children.[6] Studies conducted by the American Academy of Pediatrics show that dextromethorphan is not superior to a placebo in providing nocturnal symptom relief for children with cough and sleep difficulty due to upper respiratory infections.[7]

In addition, a combination of dextromethorphan and quinidine has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis.[8] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.[9]

Recreational use

Dextromethorphan gel capsules

Since their introduction, over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug.[4] At doses higher than medically recommended, dextromethorphan is classified as a dissociative psychedelic drug, with visible effects that are similar to those of ketamine and phencyclidine (PCP). It can produce distortions of the visual field, feelings of dissociation, distortions of bodily perception, excitement, as well as a loss of comprehension of time.[10][11]


Dextromethorphan is the dextrorotatory enantiomer of the methyl ether of levorphanol, an opioid analgesic. It is also a stereoisomer of levomethorphan, an opioid analgesic. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As the pure free base, dextromethorphan occurs as an odorless, white to slightly yellow crystalline powder. It is freely soluble in chloroform and insoluble in water. Dextromethorphan is commonly available as the monohydrated hydrobromide salt, however some newer extended-release formulations contain dextromethorphan bound to an ion exchange resin based on polystyrene sulfonic acid. Dextromethorphan's specific rotation in water is +27.6° (20°C, Sodium D-line).



Dextromethorphan has been shown to possess the following properties, mainly in binding assays to various receptors of animal tissues. Low Ki values mean strong binding or high affinity; high Ki values mean weak binding to the target or low affinity:

Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptors and opioid receptors, even at high recreational doses.[citation needed] Instead of acting as a direct antagonist of the NMDA receptor itself, it is likely that dextromethorphan functions as a prodrug to its nearly 10-fold more potent metabolite dextrorphan, and this is the true mediator of its dissociative effects.[12] It is not entirely clear what role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects.[24]


Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier.

At therapeutic doses, dextromethorphan acts centrally (meaning that it acts on the brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the active metabolite dextrorphan in the liver by the cytochrome P450 enzyme CYP2D6. The average dosage necessary for effective antitussive therapy is between 10 mg and 45 mg, depending on the individual. The International Society for the Study of Cough recommend "an adequate first dose of medication ie 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."[25]

The duration of action after oral administration is approximately three to eight hours for dextromethorphan-hydrobromide, and ten to twelve hours for dextromethorphan-polistirex. Approximately 1 in 10 of the caucasian population has little or no CYP2D6 enzyme activity leading to long lived high drug levels.[26]

Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited.


The first-pass through the hepatic portal vein results in some of the drug's being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan (DXO). DXO is the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM),[27] and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine.[28]

A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. O-demethylation of DXM to DXO contributes to 100% of the DXO formed during DXM metabolism.[27] As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers.[29] In one study on 252 Americans, 84.3% were found to be "fast" (extensive) metabolizers, 6.8% to be "intermediate" metabolizers, and 8.8% were "slow" metabolizers of DXM.[30] There are a number of known alleles for CYP2D6, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups; see also CYP2D6 - Ethnic factors in variability.

A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRI and tricyclic antidepressants, some antipsychotics, and the commonly-available antihistamine diphenhydramine -- also known as Benadryl. There exists, therefore, the potential of interactions between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers. See also CYP2D6 - Ligands.

DXM is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of DXM.[27]

A number of other CYP enzymes are implicated as minor pathways of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 at N-demethylation of DXM, but, since the average individual has a much lower CYP2B6 content in his/her liver relative to CYP3A4, most N-demethylation of DXM is catalyzed by CYP3A4.[27]

Side effects

Side-effects of dextromethorphan use can include:[28]

  • Note: In the article cited, those marked with asterisks are listed not as side effects per se, but, rather as overdose symptoms, occurring at dosages 12.5 to 75 times the recommended therapeutic dose.

Dextromethorphan can also cause other gastrointestinal disturbances. Dextromethorphan had been thought to cause Olney's Lesions when administered intravenously; however, this was later proven inconclusive, due to lack of research on humans. Tests were performed on rats, giving them 50mg and up every day up to a month. Small lesions were believed to be found during the autopsy on the brain. However the only side effect the rats showed was a change in personality.[32][33] In some rare documented cases, dextromethorphan has produced psychological dependence in some people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence.[34]


Because dextromethorphan can trigger a histamine release (allergic reaction), atopic children, who are especially susceptible to allergic reactions, should be administered dextromethorphan only if absolutely necessary, and only under the strict supervision of a health care professional.[28]

Drug interactions

Dextromethorphan should not be taken with any of the following:

See also


  1. ^ "Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration". Journal of Veterinary Pharmacology and Therapeutics. 
  2. ^ DEXTROMETHORPHAN (Street Names: DXM, CCC, Triple C, Skittles, Robo, Poor Man’s PCP)
  3. ^ Memorandum for the Secretary of Defense"
  4. ^ a b c Dextromethorphan (DXM) | CESAR
  5. ^ Cough medicines "have no benefit" BBC News: Health, Tuesday, July 6, 2004. Accessed July 28, 2007.
  6. ^ "Kids' cough medicine no better than placebo" San Francisco Chronicle, July 8, 2004
  7. ^ Paul IM, Yoder KE, Crowell KR (July 2004). "Effect of Dextromethorphan, Diphenhydramine, and Placebo on Nocturnal Cough and Sleep Quality for Coughing Children and Their Parents." Pediatrics 114 (1):85-90
  8. ^ Brooks B, Thisted R, Appel S, Bradley W, Olney R, Berg J, Pope L, Smith R (2004). "Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial". Neurology 63 (8): 1364–70. PMID 15505150. 
  9. ^ "Cough Drug May Help Fibromyalgia Pain". WebMD. 
  10. ^ AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corp, 1997.
  11. ^ [1]
  12. ^ a b c Chou YC, Liao JF, Chang WY, Lin MF, Chen CF (March 1999). "Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan". Brain Research 821 (2): 516–9. doi:10.1016/S0006-8993(99)01125-7. PMID 10064839. 
  13. ^ Wong BY, Coulter DA, Choi DW, Prince DA (February 1988). "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neuroscience Letters 85 (2): 261–6. doi:10.1016/0304-3940(88)90362-X. PMID 2897648. 
  14. ^ Church J, Jones MG, Davies SN, Lodge D (June 1989). "Antitussive agents as N-methylaspartate antagonists: further studies". Canadian Journal of Physiology and Pharmacology 67 (6): 561–7. PMID 2673498. 
  15. ^ Kamel IR, Wendling WW, Chen D, Wendling KS, Harakal C, Carlsson C (October 2008). "N-methyl-D-aspartate (NMDA) antagonists--S(+)-ketamine, dextrorphan, and dextromethorphan--act as calcium antagonists on bovine cerebral arteries". Journal of Neurosurgical Anesthesiology 20 (4): 241–8. doi:10.1097/ANA.0b013e31817f523f. PMID 18812887. 
  16. ^ Damaj MI, Flood P, Ho KK, May EL, Martin BR (February 2005). "Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity". The Journal of Pharmacology and Experimental Therapeutics 312 (2): 780–5. doi:10.1124/jpet.104.075093. PMID 15356218. 
  17. ^ Lee JH, Shin EJ, Jeong SM, et al. (April 2006). "Effects of dextrorotatory morphinans on alpha3beta4 nicotinic acetylcholine receptors expressed in Xenopus oocytes". European Journal of Pharmacology 536 (1-2): 85–92. doi:10.1016/j.ejphar.2006.02.034. PMID 16563374. 
  18. ^ Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ (2000). "Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors". J. Pharmacol. Exp. Ther. 293 (3): 962–7. PMID 10869398. 
  19. ^ a b Codd EE, Shank RP, Schupsky JJ, Raffa RB (September 1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". The Journal of Pharmacology and Experimental Therapeutics 274 (3): 1263–70. PMID 7562497. 
  20. ^ Henderson MG, Fuller RW (October 1992). "Dextromethorphan antagonizes the acute depletion of brain serotonin by p-chloroamphetamine and H75/12 in rats". Brain Research 594 (2): 323–6. doi:10.1016/0006-8993(92)91144-4. PMID 1280529. 
  21. ^ Gillman PK (October 2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia 95 (4): 434–41. doi:10.1093/bja/aei210. PMID 16051647. 
  22. ^ Schwartz AR, Pizon AF, Brooks DE (September 2008). "Dextromethorphan-induced serotonin syndrome". Clinical Toxicology (Philadelphia, Pa.) 46 (8): 771–3. PMID 19238739. 
  23. ^ Zhang W, Wang T, Qin L, Gao HM, Wilson B, Ali SF, Zhang W, Hong JS, Liu B (20 January 2004). "Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase". The FASEB Journal 18 (3): 589–91. doi:10.1096/fj.03-0983fje. PMID 14734632. 
  24. ^ Schmider J, Greenblatt DJ, Fogelman SM, von Moltke LL, Shader RI (April 1997). "Metabolism of dextromethorphan in vitro: involvement of cytochromes P450 2D6 and 3A3/4, with a possible role of 2E1". Biopharmaceutics & Drug Disposition 18 (3): 227–40. doi:10.1002/(SICI)1099-081X(199704)18:3<227::AID-BDD18>3.0.CO;2-L. PMID 9113345. 
  25. ^ Professor Alyn H Morice paper titled 'Cough' par. 'Dextromethorphan'
  26. ^ Professor Alyn H Morice paper titled 'Cough'
  27. ^ a b c d "Comparative Contribution to Dextromethorphan Metabolism by Cytochrome P450 Isoforms in Vitro: Can Dextromethorphan Be Used as a Dual Probe for Both CYP2D6 and CYP3A Activities?". Retrieved 2008-08-10. 
  28. ^ a b c d e "Dextromethorphan". NHTSA. 
  29. ^ "Clinical Pharmacology & Therapeutics — Abstract of article: The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans[ast"]. Retrieved 2007-07-16. 
  30. ^ "The polymorphic metabolism of dextromethorphan (abstract)". Retrieved 2008-08-10. 
  31. ^ "Child deaths lead to FDA hearing on cough, cold meds -". CNN. 2007-10-17. 
  32. ^ Olney J, Labruyere J, Price M (1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263. 
  33. ^ Hargreaves R, Hill R, Iversen L (1994). "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochir Suppl (Wien) 60: 15–9. PMID 7976530. 
  34. ^ WHO Expert Committee on Drug Dependence (1970) (PDF). Seventeenth Report. World Health Organization. Retrieved 2008-12-29. 

External links


The content of this section is licensed under the GNU Free Documentation License (local copy). It uses material from the Wikipedia article "Dextromethorphan" modified November 23, 2010 with previous authors listed in its history.