Dextromethorphan

Dextromethorphan

Clinical data
Pregnancy category	AU: A
Routes of administration	Oral
ATC code	R05DA09 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy medicine)
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic (CYP2D6, CYP3A4 and CYP3A5-mediated)
Elimination half-life	1.4–3.9 hours
Excretion	Renal
Identifiers
CAS Number	125-71-3
PubChem CID	5360696
DrugBank	APRD00655
CompTox Dashboard (EPA)	DTXSID3022908
ECHA InfoCard	100.004.321
Chemical and physical data
Formula	Template:Carbon18Template:Hydrogen25Template:NitrogenTemplate:Oxygen
Molar mass	271.4 g/mol

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 used as a recreational drug.

Chemistry

Dextromethorphan is structurally related to levorphanol, a narcotic (opioid) analgesic; the only difference is that dextromethorphan has a methoxy group where levorphanol has an alcohol. The optical isomer of Dextromethorphan, levomethorphan, is also considered to be an opioid). the full IUPAC name for dextromethorphan is 3-methoxy-17-methyl-9(alpha), 13(alpha), 14(alpha)-morphinan hydrobromide monohydrate. 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 of the USA approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. This filled the need for a cough suppressant lacking the abuse liability and addictive properties of codeine phosphate, the most widely used cough medication at the time. The advantage of dextromethorphan preparations over those containing codeine (now prescription-only in the United States) was the lack of physical addiction potential and sedative side-effects, although as with most cough suppressants, studies show that its effectiveness is highly debatable.[1] See also: Cough medicine controversy

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 exerts its activity within 15 to 60 minutes of ingestion. The duration of action after oral administration is approximately three to eight hours. Because administration of DXM can be accompanied by histamine release, its use in atopic children is very limited.

The average dosage necessary for effective antitussive therapy is between 10 mg and 30 mg every four to six hours.

According to the WHO committee on Drug Dependence, dextromethorphan, when used recreationally (see non-medical use of dextromethorphan), does not produce physical addiction but can generate slight psychological dependence in some users.

Can cause shakiness in regular, non-recreational usage.

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.

One well known metabolic catalyst involved is a specific 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 the primary metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan are significantly increased in such poor metabolizers. Deaths and hospitalizations have been reported in recreational use by poor CYP2D6 metabolizers.

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

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

• NMDA glutamatergic receptor antagonist
• Dopamine reuptake inhibitor
• σ₁ and σ₂ receptor agonist (Zhou & Musacchio, 1991)
• α3β4 nicotinic receptor antagonist
• Serotonin reuptake inhibitor

History

Dextromethorphan was first patented with U.S. patent 2,676,177, and was approved for over-the-counter purchase as an antitussive in 1958.

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.

Fibromyalgia treatment

Dextromethorphan is currently being investigated as a potential treatment for fibromyalgia symptoms.

Recreational use

Main article: non-medical use of dextromethorphan

Since their introduction, preparations containing the over-the-counter drug dextromethorphan have been used in a manner inconsistent with their labeling, often as a recreational drug or to induce intoxication (sometimes referred to as "robo-tripping"). 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.

People who study the specific effects of psychotropic substances classify DXM as a dissociative drug, a major subclass of hallucinogenic drugs, along with ketamine and phencyclidine. It generally does not produce withdrawal symptoms characteristic of physically addictive substances, but psychological addiction has been reported by some users.

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. Most users find such high doses to be extremely uncomfortable and most 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 between 50 and 500 mg/kg. Some 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 that can cause permanent bodily damage, or even death, if taken on the generally-accepted recreational dosing scale of DXM.

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.

Physical side effects that can occur after ingestion of recreational doses of DXM include a blotchy skin rash, itching (sometimes referred to as "robo itch," short for "Robitussin itch"), and sweating. Many users become nauseous after ingesting DXM, and some users even report vomiting from pure DXM. However, guaifenesin, an expectorant used in many DXM preparations, is also known to cause nausea, and many users find the taste of preparations sickening. When taken in higher doses, physical side effects can include dilated pupils, difficulty urinating, increased urination frequency, explosive diarrhea, fever, tachycardia, high blood pressure, loss of appetite, shakiness, seizures, insomnia, and possible coma and death (however, in pure DXM, this has only been reported when doses exceed 2,000 mg).

Note: Can last from 2 hours to 12, depending on how high the dosage is, and the tolerance of the user.

Biochemically, DXM's psychological effects have been attributed largely to dextrorphan (DX), a chemical by-product that is produced when DXM metabolizes within the body. Both DX and DXM are what's known as NMDA receptor antagonists, just like the dissociative hallucinogenic drugs ketamine and phencyclidine (PCP); however for that purpose, DX is more potent than DXM. 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.

Hallucinations and disassociation occur at higher doses; Just like all NMDA receptor antagonists, DX/DXM inhibits 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". These effects are generally temporary in all but the most extreme DXM overdose cases, or in cases of inadvertent overdose of accompanying active ingredients in a multi-symptom medication.

Drug Interactions

Dextromethorphan should not be taken with Monoamine Oxidase Inhibitors (MAOIs) and Selective Serotonin Reuptake Inhibitors (SSRIs) because of an apparent serotonin syndrome (fever, hypertension, shaking, loss of coordination, trouble speaking, arrhythmias). Extra care should be given when administering dextromethorphan to atopic children due to histamine release. Additive CNS depressant effects when co-administered with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.

See also

• Dissociatives
  • PCP
  • Ketamine
  • Nitrous oxide
  • Salvia divinorum
• Psychoactive drug

External links

• Dextroverse
• Dextromethorphan FAQ at third-plateau.org
• Erowid