|Trade names||Robitussin, Delsym, DM, DexAlone, Duract, others|
|Metabolism||Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5|
|Elimination half-life||2–4 hours (extensive metabolizers); 24 hours (poor metabolizers)|
|CompTox Dashboard (EPA)|
|ECHA InfoCard||100.004.321 |
|Chemical and physical data|
|Molar mass||271.40 g/mol g·mol−1|
|3D model (JSmol)|
|Melting point||111 °C (232 °F)|
DXM is also used recreationally. When exceeding approved dosages, dextromethorphan acts as a dissociative hallucinogen. It has multiple mechanisms of action, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist. DXM and its major metabolite, dextrorphan, also act as an NMDA receptor antagonist at high doses, which produces effects similar to, yet distinct from, the dissociative states created by other dissociative anesthetics such as ketamine, nitrous oxide, and phencyclidine.
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 particle irritants. However, controlled studies have found the symptomatic effectiveness of dextromethorphan similar to placebo.
In 2010, the FDA approved the combination drug dextromethorphan/quinidine for the treatment of pseudobulbar affect (uncontrollable laughing/crying). Dextromethorphan is the actual therapeutic agent in the combination; quinidine merely serves to inhibit the enzymatic degradation of dextromethorphan and thereby increase its circulating concentrations via inhibition of CYP2D6.
In 2013, a randomized clinical trial was conducted at Tabriz University of Medical Sciences in Tabriz, Iran, that indicated dextromethorphan may help reduce the overall discomfort and duration of withdrawal symptoms associated with opioid use disorder. When combined with clonidine, dextromethorphan reduced the overall time needed for withdrawal symptoms to peak by 24 hours while also reducing the severity of the symptoms compared to Clonidine alone.
In 2016, the ASA released a promising study with the combination of dextromethorphan with pregabalin, acetaminophen, and naproxen which showed a decrease in postoperative pain intensity (preemptive analgesia).
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 healthcare professional.
A rare side effect is respiratory depression.
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 50 mg or more every day for as long as a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA receptor antagonists such as PCP, but not with dextromethorphan.
Dependence and withdrawal
In many documented cases, dextromethorphan has produced psychological dependence in people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence. It is considered less addictive than the other common weak opiate cough suppressant, codeine. Since dextromethorphan also acts as a serotonin reuptake inhibitor, users describe that regular recreational use over a long period of time can cause withdrawal symptoms similar to those of antidepressant discontinuation syndrome. Additionally, disturbances have been reported in sleep, senses, movement, mood, and thinking.
Adverse effects of dextromethorphan in overdose at doses 3 to 10 times the recommended therapeutic dose:
- delusions of grandeur
- blurred vision
- double vision
- bloodshot eyes
- dilated pupils
- bruxia (teeth grinding)
- shallow respiration
- urinary retention
- muscle spasms
- slurred speech
- false positives on drug screens
- inability to focus eyes
- skin rash
- severe itchiness
- spontaneous memory recall
- acute psychosis
Episodic acute psychosis can occur with high doses of DXM taken for recreational use, and an abundance of psychiatric symptoms can result, including dissociation and other PCP-like symptoms.
Dextromethorphan should not be taken with monoamine oxidase inhibitors (MAOIs) due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body.
Caution should be exercised when taking dextromethorphan when drinking grapefruit juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan, through the inhibition of the cytochrome p450 system in the liver, and can lead to excessive accumulation and prolonged effects. Grapefruit and grapefruit juices (especially white grapefruit juice, but also including other citrus fruits such as bergamot and lime, as well as a number of noncitrus fruits) generally are recommended to be avoided while using dextromethorphan and numerous other medications.
|5-HT1B/1D||61% at 1 μM||54% at 1 μM||Rat|
|α2||60% at 1 μM||>1,000||Rat|
|β||>1,000||35% at 1 μM||Rat|
|H1||>1,000||95% at 1 μM||Rat|
|mAChRs||>1,000||100% at 1 μM||Rat|
|Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.|
- Uncompetitive antagonist of the NMDA receptor via the MK-801/PCP site
- Sigma σ1 receptor agonist
- μ-Opioid receptor agonist
- SERT and NET blocker (i.e., serotonin–norepinephrine reuptake inhibitor)
- Negative allosteric modulator of nicotinic acetylcholine receptors
- Ligand of the serotonin 5-HT1B/1D, histamine H1, α2-adrenergic, and muscarinic acetylcholine receptors
Rather than acting as a direct NMDA receptor antagonist itself, dextromethorphan acts as a prodrug of its much more potent metabolite dextrorphan, and this is the actual mediator of its dissociative effects. What role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects is not entirely clear.
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 dose necessary for effective antitussive therapy is between 10 and 45 mg, depending on the individual. The International Society for the Study of Cough recommends "an adequate first dose of medication is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."
DXM has an elimination half-life of approximately 4 hours in individuals with an extensive metabolizer phenotype; this is increased to approximately 13 hours when DXM is given in combination with quinidine. The duration of action after oral administration is about three to eight hours for dextromethorphan hydrobromide, and 10 to 12 hours for dextromethorphan polistirex. Around one in 10 of the Caucasian population has little or no CYP2D6 enzyme activity, leading to long-lived high drug levels.
The first pass through the hepatic portal vein results in some of the drug 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), 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.
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 at least 80% of the DXO formed during DXM metabolism. 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. 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. A number of alleles for CYP2D6 are known, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups.
A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRIs and tricyclic antidepressants, some antipsychotics, and the commonly available antihistamine diphenhydramine. Therefore, the potential of interactions exists between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers.
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.
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.
Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As its pure form, dextromethorphan occurs as an odorless, opalescent white powder. It is freely soluble in chloroform and insoluble in water; the hydrobromide salt is water-soluble up to 1.5 g/100 mL at 25 °C. 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).
The racemic parent compound racemorphan was first described in a Swiss and US patent application from Hoffmann-La Roche in 1946 and 1947, respectively; a patent was granted in 1950. A resolution of the two isomers of racemorphan with tartaric acid was published in 1952, and DXM was successfully tested in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine. DXM was approved by the FDA in 1958 as an over-the-counter antitussive. As had been initially hoped, DXM was a solution for some of the problems associated with the use of codeine phosphate as a cough suppressant, such as sedation and opiate dependence, but like the dissociative anesthetics phencyclidine and ketamine, DXM later became associated with nonmedical use.
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 misuse. A few years later, products with an unpleasant taste were introduced (such as Robitussin, Vicks-44, and Dextrotussion), but later the same manufacturers began producing products with a better taste. The advent of widespread internet access in the 1990s allowed users to rapidly disseminate information about DXM, and online discussion groups formed around use and acquisition of the drug. As early as 1996, DXM HBr powder could be purchased in bulk from online retailers, allowing users to avoid consuming DXM in syrup preparations. As of January 1, 2012, dextromethorphan is prohibited for sale to minors in the State of California and in the State of Oregon as of January 1, 2018, except with a doctor's prescription. Several other states have also began regulating sales of dextromethorphan to minors.
In Indonesia, the National Agency of Drug and Food Control (BPOM-RI) prohibited single-component dextromethorphan drug sales with or without prescription. Indonesia is the only country in the world that makes single-component dextromethorphan illegal even by prescription and violators may be prosecuted by law. National Anti-Narcotics Agency (BNN RI) has even threatened to revoke pharmacies' and drug stores' licenses if they still stock dextromethorphan, and will notify the police for criminal prosecution. As a result of this regulation, 130 drugs have been withdrawn from the market, but drugs containing multicomponent dextromethorphan can be sold over the counter. In its official press release, BPOM-RI also stated that dextromethorphan is often used as a substitute for marijuana, amphetamine, and heroin by drug abusers, and its use as an antitussive is less beneficial nowadays.
Society and culture
It may be used in generic labels and store brands, Benylin DM, Mucinex DM, Camydex-20 tablets, Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, Charcoal D, Cinfatós and others. It has been used in counterfeit medications.
Over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug. At doses much higher than medically recommended, DXM and its major metabolite, dextrorphan, acts as an NMDA receptor antagonist, which produces dissociative hallucinogenic states somewhat similar to ketamine and phencyclidine. Along with other drugs such as ketamine or phencyclidine, also known as PCP, there is a street name for dextromethorphan-infused substances which is also known as "Angel". It may produce distortions of the visual field – feelings of dissociation, distorted bodily perception, excitement, and a loss of sense of time. Some users report stimulant-like euphoria, particularly in response to music. Dextromethorphan usually provides its recreational effects in a non-linear fashion, so that they are experienced in significantly varied stages. These stages are commonly referred to as "plateaus". These plateaus are labeled between one and four, one being the lowest and so on. Each plateau is said to come with different related effects and experiences. Teens tend to have a higher likelihood to use dextromethorphan-related drugs as they are easier to access, and an easier way to cope with psychiatric disorders.
Dextromethorphan/quinidine is also under investigation for the treatment of a variety of other neurological and neuropsychiatric conditions besides pseudobulbar affect, such as agitation associated with Alzheimer's disease and major depressive disorder.
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