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Dextromethorphan

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Dextromethorphan
File:DxmFlat+3d.jpg
Clinical data
Pregnancy
category
  • AU: A
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine)
  • US: OTC
Pharmacokinetic data
Bioavailability11%[1]
MetabolismHepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Elimination half-life1.4–3.9 hours
ExcretionRenal
Identifiers
  • ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan)
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.004.321 Edit this at Wikidata
Chemical and physical data
FormulaC18H25NO
Molar mass271.4 g/mol g·mol−1

Dextromethorphan (DM or DXM) is an antitussive drug that is found in many over-the-counter cold and cough preparations, usually in the form of dextromethorphan hydrobromide. It is also commonly used at high doses as a recreational drug.

Chemistry

Dextromethorphan is structurally related to levorphanol, a narcotic (opioid) analgesic. In addition to having a methoxy group that levorphanol does not have, dextromethorphan also has different stereochemistry than levorphanol.[2] However, when DXM is metabolized via CYP2D6, it becomes dextrorphan (dextrorphanol) which is the dextrorotary enantiomer of levorphanol. The full IUPAC name for dextromethorphan is ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan). DXM occurs as white crystals, is sparingly soluble in water, and freely soluble in alcohol. The drug is dextrorotatory in water (at 20 degrees Celsius, Sodium D-line) with a specific rotation of +27.6 degrees.

Indications

The FDA has approved dextromethorphan for over-the-counter sale as a cough suppressant.

Dextromethorphan is being investigated as a possible treatment for pain associated with fibromyalgia, a chronic rheumatological organic fatigue disorder.[3]

Dextromethorphan is also useful in breaking addictions to narcotics and other habit-forming drugs (including nicotine), since it is an inhibitor of many of the brain receptors involved in narcotic action on the brain. For this purpose, DXM is more effective when combined with an oxidase inhibitor, which suppresses its inactivation and increases its half-life; thus it increases the concentration of DXM in the circulating blood and extends its effective duration.[4]

Pharmacodynamics

At therapeutic doses, the drug acts centrally to elevate the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and metabolizes within 15–60 minutes of ingestion. The duration of action after oral administration is approximately three to eight hours for dextromethorphan-hydrobromide and 10 to 12 hours for dextromethorphan-polistrirex. Because administration of DXM can trigger a histamine release (an allergic reaction), its use in atopic children is very limited.

The average dosage necessary for effective antitussive therapy is between 10 mg and 30 mg. The time to re-dose depends on the specific preparation being used.

Side-effects

Side-effects of dextromethorphan use can include body rash/itching, disassociation, nausea as well as other gastrointestinal disturbances, drowsiness, dizziness, excitation, vomiting, blurred vision, dilated pupils, sweating, fever, hypertension, shallow respiration, urinary retention, and increases in heart rate, blood pressure, and body temperature.[5]

Dextromethorphan can also produce psychological dependence due to its potential for recreational use, but does not produce physical addiction, according to the WHO committee on Drug Dependence.

Dextromethorphan, when combined with guaifenesin, an expectorant used in many preparations, is likely to cause nausea and vomiting when the combination is taken at recreational doses.

Drug interactions

Dextromethorphan should not be taken with any of the following:

Contraindications

  • Atopic children should be administered dextromethorphan only under the strict supervision of a health care professional.[5]

Clinical pharmacology

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier. The first-pass through the hepatic portal vein results in some of the drug being metabolized into an active metabolite of dextromethorphan, dextrorphan, the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan is metabolized by various liver enzymes and subsequently undergoes O-demethylation (producing dextrorphan), N-demethylation, 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.[5]

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. 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.[6]

A large number of medications (including antidepressants) are potent inhibitors of CYP2D6 (see CYP2D6 article). There exists, therefore, the potential of interactions between dextromethorphan and concomitant medications. There have been reports of fatal consequences arising from such interactions.[7]

Dextromethorphan crosses the blood-brain barrier, and the following pharmacological actions have been reported:

History

Dextromethorphan was first patented with U.S. patent 2,676,177.

The 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 abuse, and physically addictive properties of codeine phosphate, the most widely-used cough medication at the time (now prescription-only in the United States).[11] As with most cough suppressants, studies show that dextromethorphan's effectiveness is highly debatable,[3] especially in children.[12] See also: Cough medicine controversy

During the 1960s and 1970s, DXM became available in an over-the-counter tablet form by the brand name Romilar. It was put on the shelves in hopes of cutting down on codeine cough remedies. In 1973, Romilar was taken off the shelves after a burst in sales due to common recreational use. It was then replaced by cough syrup, in an attempt to cut down on recreational usage.[11]

More recently (around 2000) gel capsule forms began reappearing in the form of Robitussin CoughGels as well as several generic forms of that preparation.

Recreational use

Since their introduction, over-the-counter preparations containing the drug dextromethorphan have been used in a manner inconsistent with their labeling, often as a recreational drug, to induce intoxication.[11] Dextromethorphan has little to no psychological effect in the doses used medically, however alteration of consciousness generally occurs following ingestion of approximately 7 to 50 times the therapeutic dose over a relatively short period of time.[11]

Slang terms for DXM often correlate to the brands of cough medicine used, such as "tussin", "robo", "dex", "triple C's", and "skittles". Recreational use of DXM is frequently referred to in verb form as "dexing," "tussing," or "robotripping".

Due to abuse and theft concerns, many retailers have moved it behind the counter, so that one must ask a pharmacist to receive it.

Classification

At high doses, dextromethorphan is classified as a dissociative drug, a subclass of hallucinogenic drugs to which ketamine and phencyclidine (PCP) also belong.[13] It generally does not produce withdrawal symptoms characteristic of physically addictive substances, but psychological addiction has been reported by some users.

Legality

Antitussive preparations containing DXM are legal to purchase from most pharmacies worldwide. Since DXM use as a recreational drug usually involves only the ingestion of large quantities of an over-the-counter medication, no legal distinction currently exists between medical and recreational use, sale, or purchase.

However, it is illegal to sell pure DXM powder "without directions for use or warnings, as required by [the] U.S. Food and Drug Administration," since that is considered a "misbranded drug."[13]

DXM was excluded from the Controlled Substances Act (CSA) of 1970 and was specifically excluded from the Single Convention on Narcotic Drugs. DXM is still excluded from the CSA (as of 2007), however officials have warned that it could still be added if increased use warrants its scheduling.[11]

DXM appears to be available over the counter in most countries other than Hong Kong.[14]

Effects

DXM, when consumed in low recreational doses (usually under 200 mg), is often described as having a buoyant, vaguely psychedelic effect similar to a mixture of alcohol, opiates, and marijuana. With higher doses, intense euphoria and vivid imagination may occur as bizarre feelings of dissociation increase. With very high doses, profound alterations in consciousness have been noted, and users often report out of body experiences or temporary psychosis.[15][16] Most users find such high doses to be extremely uncomfortable and are unwilling to repeat it. Flanging (speeding up or slowing down) of sensory input also occurs, which is another unique feature of high dose DXM trips.

In 1981, a paper by Gosselin estimated the lethal dose to be between 50 and 500 mg/kg. It is generally accepted that the antidote to DXM overdose is naloxone, administered intravenously.[17]

Many negative reports of high-dose recreational experiences have come from individuals who inadvertently overdosed on a multi-symptom cold medication, rather than using a cough suppressant whose sole active ingredient is dextromethorphan. That would almost certainly produce a negative experience, and is also highly unsafe. Multi-symptom cold medicines contain other active ingredients such as chlorphenamine that can cause permanent bodily damage, or even death, if taken on the generally-accepted recreational dosing scale of DXM.[18][19]

Individual reactions to recreational doses of dextromethorphan vary widely. Some find the effects of the drug to be immensely pleasurable, similar to a combination of opiates and hallucinogens, while others find that the drug produces dysphoria, panic, or dread. This has been reported to depend largely upon one's mental and emotional status at the time of taking the medication.

Duration

The effects of recreational dosing generally last as long as medical dosing of the same DXM preparation. In other words, taking a recreational dose of an eight-hour DXM-containing cough suppressant will generally produce recreational effects lasting eight hours. The time until wear-off depends on the tolerance of the individual user, as well as on the type of dextromethorphan taken. Dextromethorphan-polistirex is contained in extended-release cough suppressants (generally lasting up to 12 hours) and therefore will produce a longer-lasting recreational effect than the more common and shorter-acting form, dextromethorphan-hydrobromide. Dosage itself has relatively little impact on the length of time the effects last — meaning that taking more DXM is much more likely to heighten its effects rather than lengthen them.

It is possible that DXM also causes an "afterglow," similar to a hangover from alcohol, for as long as one to 14 hours after the actual dose wears off.

Recreational pharmacokinetics

Biochemically, DXM's psychological effects can be attributed largely to dextrorphan (DX), a chemical by-product (or metabolite) that is produced when DXM metabolizes within the body. Both DX and DXM are NMDA receptor antagonists,[20] just like the dissociative hallucinogenic drugs ketamine and phencyclidine (PCP); however for that purpose, DX is more potent than DXM.[21]

Just like all NMDA receptor antagonists, DX/DXM inhibit neurotransmitters (specifically glutamate) from activating receptors in the brain. This can effectively slow or even shut down certain neural pathways, preventing the brain from "communicating with itself," so to speak, which leaves the user feeling disassociated or "disconnected."[22][23]

DX and DXM also have the indirect effect of raising dopamine levels in the brain, which will have an antidepressant/euphoric effect even at relatively low recreational doses.[5] The dopamine response is likely the cause of most of the low-dose recreational effects, since those effects generally consist of euphoria more than hallucination or dissociation.

Recreational effects are generally temporary, however chronic high-dose usage of DXM can lead to toxic psychosis or other psychological problems.[11] In addition, inadvertent overdose of accompanying active ingredients in multi-symptom cold medications can cause permanent physiological damage.

At least in one instance, a person suffering from Borderline Personality Disorder experienced emotional benefits from taking Dextromethorphan in no higher than the reccomended adult dose (30 mg) in an over-the-counter form. This individual had little or no benefit from a wide range of prescription mood stabilizers and antidepressants in the past. Not an endoresment, but an observation based upon one experience. More to follow.

See also

Footnotes

  1. ^ http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2885.2004.00608.x?cookieSet=1&journalCode=jvp
  2. ^ Shulgin, Alexander (2003). "DXM (Dextromethorphan)". Ask Dr. Shulgin Online. Retrieved 2006-05-31. {{cite web}}: External link in |work= (help)
  3. ^ [1] Cough syrup found by University of Florida to reduce fibromyalgia pain "moderately" but not recommended for personal self treatment.
  4. ^ http://www.freepatentsonline.com/6207674.html
  5. ^ a b c d e f g h http://www.nhtsa.dot.gov/PEOPLE/injury/research/job185drugs/dextromethorphan.htm
  6. ^ http://www.nature.com/clpt/journal/v60/n3/abs/clpt1996482a.html
  7. ^ Jones K, Taranto M (2006). "Illicit Drug Manual: Dextromethorphan ("Robo-tripping")". collegehealth-e. 1 (4): 13–17.
  8. ^ http://www.nature.com/bjp/journal/v144/n7/full/0705998a.html
  9. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list uids=10869398
  10. ^ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list uids=1636059
  11. ^ a b c d e f http://www.cesar.umd.edu/cesar/drugs/dxm.asp
  12. ^ [2] "Kids' cough medicine no better than placebo" San Francisco Chronicle, July 8, 2004
  13. ^ a b http://www.erowid.org/psychoactives/research_chems/research_chems_law3.pdf
  14. ^ http://www.erowid.org/chemicals/dxm/dxm_law.shtml
  15. ^ Bornstein, S; Czermak, M; Postel, J., (1968). "Apropos of a case of voluntary medicinal intoxication with dextromethorphan hydrobromide". Annales Medico-Psychologiques. 1 (3): 447–451.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  16. ^ Dodds A, Revai E (1967). "Toxic psychosis due to dextromethorphan". Med J Aust. 2: 231.
  17. ^ Schneider SM, Michelson EA; et al. (1991). "Dextromethorphan poisoning reversed by naloxone". Am. J. Emerg. Med. 9: 237–238. {{cite journal}}: Explicit use of et al. in: |author= (help)
  18. ^ Kirages T, Sulé H, Mycyk M (2003). "Severe manifestations of coricidin intoxication". Am J Emerg Med. 21 (6): 473–5. PMID 14574654.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Kintz, P. and Mangin, P. (1992). "Toxicological findings in a death involving dextromethorphan and terfenadine". Am J Forensic Med Pathol. 13 (4): 351–352. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ http://cat.inist.fr/?aModele=afficheN&cpsidt=914417
  21. ^ http://jpet.aspetjournals.org/cgi/content/full/309/2/515?ijkey=73c6efcf7713b02798c855b5ce4d50f1aa22d299&keytype2=tf_ipsecsha#ABS
  22. ^ Muir, KW (1995). "Clinical experience with excitatory amino acid antagonist drugs". Stroke. 26 (3): 503–513. Retrieved 2007-01-17. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  23. ^ Kristensen, JD (1992). "The NMDA-receptor antagonist CPP abolishes neurogenic 'wind-up pain' after intrathecal administration in humans". Pain. 51 (2): 249–253. PMID 1484720. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

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