Dextromethorphan
Encyclopedia
Dextromethorphan 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 and 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), as well as the active metabolite 3-methoxymorphinan
which produces local anesthetic effects in rats with a potency above dextrorphan but below dextromethorphan itself.
"; it is implied that the compound was first found to have clinical potential in this study. It was first patented in 1954. The U.S. Food and Drug Administration (FDA) approved dextromethorphan as a prescription antitussive drug on September 24, 1954, and subsequently as an over-the-counter
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.
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, and was replaced by cough syrup in an attempt to cut down on abuse.
and common cold
), as well as those resulting from inhaled irritants.
A 2004 study showed that dextromethorphan was no more effective for children than a placebo. 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.
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
. Dextromethorphan is also being investigated as a possible treatment for neuropathic pain
and pain associated with fibromyalgia
. On October 29, 2010 The FDA approved the combination product (Nuedexta) manufactured by Avanir pharmaceutical corporation for the treatment of pseudobulbar affect (PBA).
hallucinogen. Certain effects that are similar to the dissociative agents 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. Some users report stimulant-like euphoria
. 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."
of levomethorphan
, which is the methyl ether
of levorphanol
, both opioid
analgesic
s. 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).
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 receptor
s and opioid receptor
s, even at high recreational doses. 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. It is not entirely clear what role, if any, (+)-3-methoxymorphinan
, dextromethorphan's other major metabolite, plays in its effects.
, 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 is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."
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.
Because administration of dextromethorphan can trigger a histamine
release (an allergic reaction), its use in atopic children is very limited.
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), 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 100% 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. There are a number of known allele
s 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
antidepressant
s, 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.
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.
At normal doses:
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 50 mg and up every day up to a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA antagonists such as PCP, but not with dextromethorphan. 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.
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.
s (MAOIs) or Serotonin reuptake inhibitors (like SSRIs and SNRIs) 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.
juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
. It is one of the active ingredients in many over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
cold
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
and cough
Cough
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...
medicines, such as Robitussin
Robitussin
Robitussin is a line of cold and cough medicines currently produced by Pfizer. Robitussin is available in various formulations. Robitussin contains an expectorant ; Robitussin DM adds a cough suppressant to the expectorant ; Robitussin CF is a cold formula that adds an expectorant and a nasal...
, NyQuil
NyQuil
NyQuil is a brand of over the counter medication which is intended to relieve various symptoms of the common cold. Because all of the medications within the NyQuil imprint contain sedating antihistamines, hypnotics, and/or alcohol, they are intended to be taken before sleep...
, Dimetapp
Dimetapp
Dimetapp is a combination preparation marketed to relieve symptoms of the common cold, manufactured by Pfizer . It contains brompheniramine and phenylephrine . Dimetapp DM additionally contains dextromethorphan...
, Vicks
Vicks
Vicks is a line of over-the-counter medications owned by the American company Procter & Gamble. Vicks manufactures NyQuil and its sister medication, DayQuil. The Vicks brand also produces Formula 44 cough medicines, cough drops, VapoRub, and a number of inhaled breathing treatments...
, Coricidin
Coricidin
Coricidin, Coricidin 'D , or CoricidinHBP , is the name of a drug marketed by Schering-Plough that contains dextromethorphan and chlorpheniramine maleate...
, Delsym
Delsym
Delsym is an American brand of over-the-counter cough medicine owned by Reckitt Benckiser. It is different from most brands of cough medicine in that the active ingredient is "time released". The time release feature allows the drug to suppress the cough reflex for a longer period of time...
, and others, including generic
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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
Throat lozenge
A throat lozenge, cough drop, troche, or cough sweet is a small, medicated tablet intended to be dissolved slowly in the mouth to temporarily stop coughs and lubricate and soothe irritated tissues of the throat , possibly from the common cold or influenza...
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
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor
Sigma-1 receptor
The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
agonist and the action of its major metabolite dextrorphan
Dextrorphan
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
as an NMDA receptor antagonist
NMDA receptor antagonist
NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...
, producing effects similar to those of the controlled substances ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
and phencyclidine
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(PCP), as well as the active metabolite 3-methoxymorphinan
3-Methoxymorphinan
3-Methoxymorphinan is a dextromethorphan metabolite that has been shown to produce local anesthetic effects. It is metabolized in the liver by the enzyme CYP3A4....
which produces local anesthetic effects in rats with a potency above dextrorphan but below dextromethorphan itself.
History
Dextromethorphan was identified as one of three compounds tested as part of US Navy and CIA-funded research that sought a "nonaddictive substitute for codeineCodeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
"; it is implied that the compound was first found to have clinical potential in this study. It was first patented in 1954. The U.S. Food and Drug Administration (FDA) approved dextromethorphan as a prescription antitussive drug on September 24, 1954, and subsequently as an over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
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
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
phosphate, the most widely used cough medication at the time.
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, and was replaced by cough syrup in an attempt to cut down on abuse.
Uses
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 fluInfluenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
and common cold
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
), as well as those resulting from inhaled irritants.
A 2004 study showed that dextromethorphan was no more effective for children than a placebo. Studies conducted by the American Academy of Pediatrics
American Academy of Pediatrics
The American Academy of Pediatrics is the major professional association of pediatricians in the United States. The AAP was founded in 1930 by 35 pediatricians to address pediatric healthcare standards. It currently has 60,000 members in primary care and sub-specialist areas...
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.
In addition, a combination of dextromethorphan and quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect
Pseudobulbar affect
Pseudobulbar affect , emotional lability, labile affect or emotional incontinence refers to a neurologic disorder characterized by involuntary crying or uncontrollable episodes of crying and/or laughing, or other emotional displays. PBA occurs secondary to neurologic disease or brain injury...
) in patients with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Dextromethorphan is also being investigated as a possible treatment for neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
and pain associated with fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
. On October 29, 2010 The FDA approved the combination product (Nuedexta) manufactured by Avanir pharmaceutical corporation for the treatment of pseudobulbar affect (PBA).
Recreational use
Since their introduction, over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug. At doses higher than medically recommended, dextromethorphan is classified as a dissociativeDissociative drug
Dissociatives are a class of psychoactive drugs which are said to reduce or block signals to the conscious mind from other parts of the brain...
hallucinogen. Certain effects that are similar to the dissociative agents ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
and phencyclidine
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(PCP). It can produce distortions of the visual field - feelings of dissociation
Dissociation
Dissociation is an altered state of consciousness characterized by partial or complete disruption of the normal integration of a person’s normal conscious or psychological functioning. Dissociation is most commonly experienced as a subjective perception of one's consciousness being detached from...
, distortions of bodily perception, excitement, as well as a loss of comprehension of time. Some users report stimulant-like euphoria
Euphoria
Euphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
. 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."
Chemistry
Dextromethorphan is the dextrorotatory enantiomerEnantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
of levomethorphan
Levomethorphan
Levomethorphan is the l-stereoisomer of methorphan. The effects of the two isomers are quite different. Dextromethorphan is an antitussive at low doses and a dissociative at much higher doses, whereas levomethorphan is an opioid analgesic...
, which is the methyl ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
of levorphanol
Levorphanol
Levorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...
, both opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
s. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan
Morphinan
Morphinan is the base chemical structure of a large chemical class of psychoactive drugs, consisting of opioid analgesics, cough suppressants, and dissociative hallucinogens, among others.- Chemical Derivatives :Immediate derivatives of morphinan include:...
. As the pure free base, dextromethorphan occurs as an odorless, white to slightly yellow crystalline powder. It is freely soluble in chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
and insoluble in water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
. 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
Sodium polystyrene sulfonate
Sodium polystyrene sulfonate is a type of polymer and ionomer based on polystyrene. It is the sodium salt of polystyrene sulfonic acid.-Chemical properties:...
. Dextromethorphan's specific rotation
Specific rotation
In stereochemistry, the specific rotation of a chemical compound [α] is defined as the observed angle of optical rotation α when plane-polarized light is passed through a sample with a path length of 1 decimeter and a sample concentration of 1 gram per 1 millilitre. It is the main property used to...
in water is +27.6° (20°C, Sodium D-line).
Pharmacodynamics
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:
- Uncompetitive NMDA receptorNMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
(PCP site) antagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(Ki = 7,253 nM). - σ1Sigma-1 receptorThe sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
and σ2Sigma-2 receptorThe sigma-2 receptor is a sigma receptor which preferentially binds to siramesine and PB28. Unlike sigma-1 receptor, it has not yet been cloned.Activation of the receptor can cause apoptosis...
sigma receptorSigma receptorThe sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
agonist (Ki = 205 nM and 11,060 nM, respectively). In a comparative investigation of dimemorfanDimemorfanDimemorfan is an antitussive or cough suppressant which acts as a sigma receptor agonist. It is an analogue of dextromethorphan and dextrorphan, but lacks significant NMDA receptor antagonistic action and dissociative effects, thereby having reduced abuse potential and adverse effects in comparison....
, dextromethorphan and dextrorphanDextrorphanDextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
in mouse cells, dextromethorpan binds with relatively high affinity to Sigma-1 receptors and with very low affinity to Sigma-2 receptors. - α3β4-, α4β2-, and α7-nACh receptorNicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
(Ki = in the μM range) antagonist. Dextromethorphan binds to nicotinic receptors in frog eggs (XenopusXenopusXenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus...
oocytes), human embryonic kidney cells and mouse tissue. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain. - μ-, δ-, and κ-opioid receptorOpioid receptorOpioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
agonistAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
(Ki = 1,280 nM, 11,500 nM, and 7,000 nM, respectively). - SERTSerotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
and NETNorepinephrine transporterThe norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
blockerReuptake inhibitorA reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
(Ki = 23 nM and 240 nM, respectively). - NADPH oxidaseNADPH oxidaseThe NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...
inhibitor.
Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s and opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
s, even at high recreational doses. Instead of acting as a direct antagonist of the NMDA receptor itself, it is likely that dextromethorphan functions as a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
to its nearly 10-fold more potent metabolite dextrorphan
Dextrorphan
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
, and this is the true mediator of its dissociative effects. It is not entirely clear what role, if any, (+)-3-methoxymorphinan
3-Methoxymorphinan
3-Methoxymorphinan is a dextromethorphan metabolite that has been shown to produce local anesthetic effects. It is metabolized in the liver by the enzyme CYP3A4....
, dextromethorphan's other major metabolite, plays in its effects.
Pharmacokinetics
Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, where it enters the bloodstream and crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
.
At therapeutic doses, dextromethorphan acts centrally
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(meaning that it acts on the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
) as opposed to locally (on the respiratory tract
Respiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
and converted into the active metabolite dextrorphan
Dextrorphan
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
in the liver by the cytochrome P450 enzyme CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. 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 is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."
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
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
enzyme activity leading to long lived high drug levels.
Because administration of dextromethorphan can trigger a histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release (an allergic reaction), its use in atopic children is very limited.
Metabolism
The first-pass through the hepatic portal veinHepatic portal vein
The hepatic portal vein is not a true vein, because it does not conduct blood directly to the heart. It is a vessel in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to capillary beds in the liver...
results in some of the drug's being metabolized by O-demethylation into an active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of dextromethorphan called dextrorphan
Dextrorphan
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
(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
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
.
A major metabolic catalyst involved is the cytochrome P450 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
known as 2D6, or CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. 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. As CYP2D6 is a major metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
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. There are a number of known allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s 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
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. Some types of medications known to inhibit CYP2D6 include certain SSRI and tricyclic
Tricyclic
Tricyclics are chemical compounds that contain three interconnected rings of atoms.Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs...
antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s, some antipsychotics, and the commonly-available antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
– 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
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. 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
CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
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.
Side effects
Side-effects of dextromethorphan use can include:At normal doses:
- Sudden infant death syndromeSudden infant death syndromeSudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...
- body rashRashA rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
/itching (see below) - nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- drowsiness
- dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
- Closed-eye hallucinationClosed-eye hallucinationClosed-eye hallucinations and closed-eye visualizations are a distinct class of hallucination. These types of hallucinations generally only occur when one's eyes are closed or when one is in a darkened room. They are a form of phosphene....
- Difficulty breathing
At dosages 12.5 to 75 times the recommended therapeutic dose:
- hallucinations
- disassociation
- vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- blurred vision
- dilated pupils
- sweatingSweatingPerspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
- feverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
- bruxia
- hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
- shallow respirationRespiratory systemThe respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
- diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- urinary retentionUrinary retentionUrinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
Dextromethorphan can also cause other gastrointestinal disturbances. Dextromethorphan had been thought to cause Olney's Lesions
Olney's lesions
Olney's lesions, also known as NMDA receptor antagonist neurotoxicity , are a potential form of brain damage. They are named after John Olney, who conducted a study investigating neurotoxicity caused by PCP and related drugs in 1989.-History:...
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 and up every day up to a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA antagonists such as PCP, but not with dextromethorphan. In some rare documented cases, dextromethorphan has produced psychological dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
in some people who used it recreationally. However, it does not produce physical addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
, according to the WHO
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
Committee on Drug Dependence.
Contraindications
Because dextromethorphan can trigger a histamineHistamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
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.
Drug interactions
Dextromethorphan should not be taken with Monoamine oxidase inhibitorMonoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (MAOIs) or Serotonin reuptake inhibitors (like SSRIs and SNRIs) due to the potential for serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body.
Food interactions
Caution should be exercised when taking dextromethorphan when drinking grapefruitGrapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan.