Dextromethorphan | Drug Information, Uses, Side Effects, Chemistry | PharmaCompass.com (2023)

Dextromethorphan | Drug Information, Uses, Side Effects, Chemistry | PharmaCompass.com (1)

Also known as:D-methorphan, Delta-methorphan, Dextromorphan, Delsym, Levomethorphan, Destrometerfano [dcit]

Molecular Formula

C18H25NO

Molecular Weight

271.3972 g/mol

InChI Key

MKXZASYAUGDDCJ-NJAFHUGGSA-N

FDA UNII

7355X3ROTS

Methyl analog of DEXTRORPHAN that shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist (RECEPTORS, N-METHYL-D-ASPARTATE) and acts as a non-competitive channel blocker. It is one of the widely used ANTITUSSIVES, and is also used to study the involvement of glutamate receptors in neurotoxicity.

Dextromethorphan is an Uncompetitive N-methyl-D-aspartate Receptor Antagonist and Sigma-1 Agonist. The mechanism of action of dextromethorphan is as an Uncompetitive NMDA Receptor Antagonist and Sigma-1 Receptor Agonist.

1 2D Structure

Dextromethorphan | Drug Information, Uses, Side Effects, Chemistry | PharmaCompass.com (2)

2 Identification

2.1 Computed Descriptors

2.1.1 InChI

InChI=1S/C18H25NO/c1-19-10-9-18-8-4-3-5-15(18)17(19)11-13-6-7-14(20-2)12-16(13)18/h6-7,12,15,17H,3-5,8-11H2,1-2H3/t15-,17+,18+/m1/s1

2.1.2 InChI Key

MKXZASYAUGDDCJ-NJAFHUGGSA-N

2.1.3 Canonical SMILES

CN1CCC23CCCCC2C1CC4=C3C=C(C=C4)OC

2.1.4 Isomeric SMILES

CN1CC[C@@]23CCCC[C@@H]2[C@@H]1CC4=C3C=C(C=C4)OC

2.2 Other Identifiers

2.2.1 UNII

7355X3ROTS

2.3 Synonyms

2.3.1 MeSH Synonyms

1.D-methorphan

2.Delsym

3.Dextromethorphan Hydrobromide

4.Dextromethorphan Hydrobromide, (+-)-isomer

5.Dextromethorphan Hydrobromide, Monohydrate

6.Dextromethorphan Hydrochloride

7.Dextromethorphan, (+-)-isomer

8.Hydrobromide, Dextromethorphan

9.Hydrochloride, Dextromethorphan

10.L-methorphan

11.Levomethorphan

12.Racemethorphan

2.3.2 Depositor-Supplied Synonyms

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1.D-methorphan

2.Delta-methorphan

3.Dextromorphan

4.Delsym

5.Levomethorphan

6.Destrometerfano [dcit]

7.Dextromethorfan [czech]

8.Dextrometorfano [inn-spanish]

9.L-methorphan

10.Albutussin

21.Dextromethorphane

22.Hsdb 3056

23.Novahistine Dm

24.Creo-terpin

25.Novahistex Dm

26.( )-3-methoxy-n-methylmorphinon

27.Balminil Dm

28.Dextromethorphanum

29.Koffex Dm

30.Hihustan M.

31.125-71-3

32.Unii-7355x3rots

33.Calmylin #1

34.Hold Dm

35.Robitussin Pediatric

36.Ba 2666

37.Delsym Cough Formula

38.Balminil Dm Children

39.Demorphan Hydrobromide

40.Dextromethorphane [inn-french]

41.Dextromethorphanum [inn-latin]

42.Diabe-tuss Dm Syrup

43.Benylin Dm

44.Benylin Dm 12 Hour

45.Dextromethorphan [usp:inn:ban]

46.Cough-x

47.Dextromethorphan (usp)

48.Vicks 44 Cough Relief

49.Benylin Dm For Children

50.Prestwick0_000359

51.Prestwick1_000359

52.Prestwick2_000359

53.Prestwick3_000359

54.Einecs 204-752-2

55.Lopac-d-2531

56.Racemethorphan

57.Dextromethorphan Bromhydrate

58.Morphinan, 3-methoxy-17-methyl-, (9alpha,13alpha,14alpha)-

59.Brn 0088549

60.Pertussin Dm Extra Strength

61.Bspbio_000457

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62.Chembl52440

63.Spbio_002378

64.125-69-9 (hydrobromide)

65.Bpbio1_000503

66.Levomethorphan [ban:dcf:inn]

67.Pertussin Cs Children's Strength

68.Sucrets 4 Hour Cough Suppressant

69.Benylin Dm For Children 12 Hour

70.18609-21-7 (hydrochloride)

71.Hms2090c08

72.Benylin Pediatric Cough Suppressant

73.(+)-3-methoxy-17-methylmorphinan

74.Romilar

75.( )-cis-1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2h-10,4alpha-iminoethanophenanthren

76.Robitussin Pediatric Cough Suppressant

77.3-methoxy-17-methyl-9alpha,13alpha,14alpha-morphinan

78.Benylin Adult Formula Cough Suppressant

79.Triaminic Dm Long Lasting For Children

80.9alpha,13alpha,14alpha-morphinan, 3-methoxy-17-methyl-

81.Ncgc00015333-01

82.Ncgc00015333-02

83.9-alpha,13-alpha,14-alpha-morphinan, 3-methoxy-17-methyl-

84.Ls-91838

85.6700-34-1 (hydrobromide, Mono-hydrate)

86.Robitussin Maximum Strength Cough Suppressant

87.C06947

88.D03742

89.Levomethorphane

90.Levometorfano

91.Levometorfano [inn-spanish]

92.4-21-00-01367 (beilstein Handbook Reference)

93.Levomethorphane [inn-french]

94.Levomethorphanum [inn-latin]

95.Levomethorphanum

96.Brd-k33211335-337-03-7

97.(9alpha,13alpha,14alpha)-17-methyl-3-(methyloxy)morphinan

98.9alpha,13alpha,14alpha-morphinan, 3-methoxy-17-methyl- (8ci)

99.Morphinan, 3-methoxy-17-methyl-, (9-alpha,13-alpha,14-alpha)-

100.Mls000758303

101.Morphinan, 3-methoxy-17-methyl-, (9-alpha,13-alpha,14-alpha)- (9ci)

102.18046-32-7

103.32062-10-5

104.Ac1l1eyt

105.Lopac0_000337

106.Levomethorphan [inn:ban:dcf]

107.Db00514

108.Ncgc00015333-04

109.Ncgc00162126-01

110.Ac-13098

111.Ls-91837

112.Dxm [antitussive]

113.Cid5360696

114.Surecn29949

115.7355x3rots

116.Gtpl6953

117.Ctk8f9098

118.Cid3008

119.Chebi:128891

120.Chebi:580686

121.Molport-003-940-943

122.Molport-004-285-957

123.125-70-2

124.Dap000277

125.Ag-d-54215

126.Cid5362449

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127.3b2-1343

128.Unii-8yb8f78wm1 Component Mkxzasyaugddcj-njafhuggsa-n

129.(1s,9s,10s)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.0?,??.0?,?]heptadeca-2(7),3,5-triene

130.9a'a

131.Afa,13a'a

132.Afa,14a'a

133.Afa-morphinan, 3-methoxy-17-methyl- (8ci);(+)-3-methoxy-17-methylmorphinan;ba 2666;nodex;d-methorphan;

2.3.3 Other Synonyms

1.Unii-427476lzft

2.Deudextromethorphan

3.Dextromethorphan Tannate

2.4 Create Date

2005-06-08

3 Chemical and Physical Properties

Molecular Weight271.3972g/mol
Molecular FormulaC18H25NO
XLogP33.4
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count2
Rotatable Bond Count1
Exact Mass271.193614 g/mol
Monoisotopic Mass271.193614 g/mol
Topological Polar Surface Area12.5 A^2
Heavy Atom Count20
Formal Charge0
Complexity370
Isotope Atom Count0
Defined Atom Stereocenter Count3
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1

4 Drug and Medication Information

4.1 Drug Information

1 of 2
Drug NameDelsym
Active IngredientDextromethorphan polistirex
Dosage FormSuspension, extended release
RouteOral
Strengtheq 30mg hbr/5ml
Market StatusOver the Counter
CompanyReckitt Benckiser

2 of 2
Drug NameDelsym
Active IngredientDextromethorphan polistirex
Dosage FormSuspension, extended release
RouteOral
Strengtheq 30mg hbr/5ml
Market StatusOver the Counter
CompanyReckitt Benckiser

4.2 Therapeutic Uses

Antitussive Agents; Excitatory Amino Acid Antagonists

National Library of Medicine's Medical Subject Headings. Dextromethorphan. Online file (MeSH, 2014). Available from, as of January 30, 2014: http://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html

Dextromethorphan is used for the temporary relief of coughs caused by minor throat and bronchial irritation such as may occur with common colds or with inhaled irritants. Dextromethorphan is most effective in the treatment of chronic, nonproductive cough. The drug is a common ingredient in commercial cough mixtures available without prescription.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2816

Nuedexta is a combination product containing dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor) indicated for the treatment of pseudobulbar affect (PBA). Studies to support the effectiveness of Nuedexta were performed in patients with underlying amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer's disease and other dementias. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) capsule, gelatin coated (December 2013). Available from, as of February 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=484e0918-3442-49dc-8ccf-177f1f3ee9f3

4.3 Drug Warning

Because cases of apparent serotonin syndrome, including 2 fatalities, have been reported in patients receiving dextromethorphan and monoamine oxidase (MAO) inhibitors concomitantly, dextromethorphan preparations should not be used in patients receiving these drugs or for 2 weeks after discontinuing them.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2817

Administration of dextromethorphan may be associated with histamine release, and the drug should be used with caution in atopic children. Dextromethorphan also should be used with caution in sedated or debilitated patients and in patients confined to the supine position. Dextromethorphan should not be taken for persistent or chronic cough (e.g., with smoking, emphysema, asthma) or when coughing is accompanied by excessive secretions, unless directed by a clinician. If cough persists for longer than 1 week, tends to recur, or is accompanied by high fever, rash, or persistent headache, a clinician should be consulted.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2817

Individuals with phenylketonuria (i.e., homozygous deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that some commercially available preparations of dextromethorphan contain aspartame which is metabolized in the GI tract to phenylalanine following oral administration.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2817

Adverse effects with dextromethorphan are rare, but nausea and/or other GI disturbances, slight drowsiness, and dizziness sometimes occur. The drug produces no analgesia or addiction and little or no CNS depression.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2817

Although cough and cold preparations that contain cough suppressants (including dextromethorphan), nasal decongestants, antihistamines, and/or expectorants commonly are used in pediatric patients younger than 2 years of age, systematic reviews of controlled trials have concluded that nonprescription (over-the-counter, OTC) cough and cold preparations are not more effective than placebo in reducing acute cough and other symptoms of upper respiratory tract infection in these patients. Furthermore, adverse events, including deaths, have been (and continue to be) reported in pediatric patients younger than 2 years of age receiving these preparations.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2816

Abuse and recreational use of dextromethorphan have been reported with nonprescription (over-the-counter (OTC)) dextromethorphan-containing preparations and with dextromethorphan powder sold illicitly. Dextromethorphan is a safe and effective cough suppressant with minimal adverse effects when used at recommended dosages; however, the drug can have euphoric, stimulant, and dissociative effects at higher dosages. Abuse of the drug for its euphoric and dissociative effects occurs mainly in adolescents.

American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2816

4.4 Drug Indication

For treatment and relief of dry cough.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Dextromethorphan suppresses the cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan shows high affinity binding to several regions of the brain, including the medullary cough center. This compound is an NMDA receptor antagonist and acts as a non-competitive channel blocker. It is one of the widely used antitussives, and is also used to study the involvement of glutamate receptors in neurotoxicity.

5.2 MeSH Pharmacological Classification

Antitussive Agents

Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally.

Excitatory Amino Acid Antagonists

Drugs that bind to but do not activate excitatory amino acid receptors, thereby blocking the actions of agonists.

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

Dextromethorphan

5.3.2 FDA UNII

7355X3ROTS

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5.3.3 Pharmacological Classes

Established Pharmacologic Class [EPC]

Uncompetitive N-methyl-D-aspartate Receptor Antagonist

Established Pharmacologic Class [EPC]

Sigma-1 Agonist

Mechanisms of Action [MoA]

Uncompetitive NMDA Receptor Antagonists

Mechanisms of Action [MoA]

Sigma-1 Receptor Agonists

5.4 ATC Code

R05DA09 - Dextromethorphan < R05DA - Opium alkaloids and derivatives < R05D - Cough suppressants, excl. combinations with expectorants < R05 - Cough and cold preparations < R - Respiratory system

5.5 Absorption, Distribution and Excretion

ONLY 3% OF DOSE OF DEXTROMETHORPHAN WAS EXCRETED UNCHANGED IN URINE, & NONE IN BILE OF TREATED RATS.

The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970., p. 233

Dextromethorphan and its metabolites are excreted via the kidney. Depending on the metabolism phenotype up to 11% may be excreted unchanged or up to 100% as demethylated conjugated morphinan compounds. In the first 24 hours after dosing, less than 0.1% is eliminated in the feces.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

SIMILARITY OF EXCRETION PATTERN /OF [(3)H]-DEXTROMETHORPHAN/ AFTER ENTERAL & PARENTERAL ROUTES INDICATED THAT FECAL [(3)H] ORIGINATED FROM BILIARY EXCRETION, & RATS WITH CANNULATED BILE DUCTS EXCRETED 77% OF DOSE IN 24-HR BILE, NONE OF WHICH WAS UNCHANGED.

The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970., p. 68

RETENTION OF [(3)H] /DEXTROMETHORPHAN/ IN ANIMALS WAS PROBABLY CAUSED BY PROLONGED ENTERO-HEPATIC CIRCULATION, THEREBY DELAYING EXCRETION. THUS, INTESTINAL TRACT & LIVER WOULD CONTAIN MOST OF RETAINED [(3)H] /DEXTROMETHORPHAN/.

The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970., p. 68

Dextromethorphan is well absorbed from the gastrointestinal tract with maximum serum level occurring at 2.5 hours. Peak concentration of the major metabolite dextrorphan) was 1.6 to 1.7 hours.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

The effect of CYP2D6 polymorphism on the pharmacokinetics and antitussive effect of dextromethorphan hydrobromide and the effect of quinidine sulfate on its pharmacokinetics were investigated in 12 healthy subjects, 6 poor metabolizers and 6 extensive metabolizers, ages 20-26 yr, who were randomized to receive single doses of oral capsules of 30 mg of dextromethorphan, 50 mg of quinidine, and/or placebo on different occasions. The poor metabolizer subjects received dextromethorphan or placebo on 2 separate occasions. The extensive metabolizer subjects received dextromethorphan, with or without pretreatment with a single dose of quinidine, on 2 separate occasions and, on 2 other occasions, received placebo or quinidine separated by 1 wk. The plasma Cmax, area under the plasma concentration vs time curve (AUC), and half-life values for dextromethorphan were 16 fold, 150 fold, and 8 fold greater, respectively, in poor metabolizers than in extensive metabolizers. Quinidine increased the plasma Cmax and AUC in extensive metabolizers 18 fold and 43 fold, respectively. ...

Capon DA et al; Clin Pharmacol Ther 60 (9): 295-307 (1996)

Absorption

Rapidly absorbed from the gastrointestinal tract.

5.6 Metabolism/Metabolites

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

Genetic polymorphism has profound effects on its metabolism. Dextromethorphan undergoes polymorphic metabolism depending on variation in cytochrome P-450 enzyme phenotype. The specific cytochrome P-450 enzyme is P450 2D6(CYP2D6). Fast metabolizers constitute about 84% of the population. After a 30 mg dose plasma levels are less than 5 ng/mL four hours postingestion. Intermediate metabolizers constitute about 6.8% of the population. After an oral dose of 30 mg plasma levels are 10 to 20 ng/mL at 4 hours and less than 5 ng/mL at 24 hours postingestion. Poor metabolizers constitute 5% to 10% of the Caucasian population. The ratio of metabolite to parent drug in 8 hour urine sample is less than 10 to 1 after a 15 mg dose. After an oral dose of 30 mg plasma levels are greater than 10 ng/mL at 4 hours and greater than 5 ng/mL at 24 hours.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

There is a clear first pass metabolism and it is generally assumed that the therapeutic activity is primarily due to its active metabolite, dextrophan.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

It is metabolized in the liver by extensive metabolizers to dextrorphan. Dextrorphan is itself an active antitussive compound. Only small amounts are formed in poor metabolizers. Less than 15% of the dose form minor metabolites including D-methoxymorphinane.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

Hepatic. Rapidly and extensively metabolized to dextrorphan (active metabolite). One well known metabolic catalyst involved is a specific cytochrome P450 enzyme known as 2D6, or CYP2D6.

5.7 Biological Half-Life

The half life of /dextromethorphan/ is approximately 2 to 4 hours in people with normal metabolism.

International Programme on Chemical Safety; Poisons Information Monograph: Dextromethorphan (PIM 179) (1997) Available from, as of February 5, 2014: http://www.inchem.org/pages/pims.html

3-6 hours

Department of Justice; Drug Enforcement Administration (DEA), Dextromethorphan (July 2012). Available from, as of February 7, 2014: http://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf

5.8 Mechanism of Action

Dextromethorphan (DXM) is the dextro isomer of levomethorphan, a semisynthetic morphine derivative. Although structurally similar to other narcotics, DXM does not act as a mu receptor opioid (eg, morphine, heroin). DXM and its metabolite, dextrorphan, act as potent blockers of the N-methyl-d-aspartate (NMDA) receptor.

Department of Justice; Drug Enforcement Administration (DEA), Dextromethorphan (July 2012). Available from, as of February 7, 2014: http://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia (LID) in patients with Parkinson's disease (PD) and abnormal involuntary movements (AIMs) in the unilateral 6-hydroxydopamine (6-OHDA) rat model. These effects have been attributed to N-methyl-d-aspartate (NMDA) antagonism. However, amantadine and dextromethorphan are also thought to block serotonin (5-HT) uptake and cause 5-HT overflow, leading to stimulation of 5-HT(1A) receptors, which has been shown to reduce LID. We undertook a study in 6-OHDA rats to determine whether the anti-dyskinetic effects of these two compounds are mediated by NMDA antagonism and/or 5-HT(1A) agonism. In addition, we assessed the sensorimotor effects of these drugs using the Vibrissae-Stimulated Forelimb Placement and Cylinder tests. Our data show that the AIM-suppressing effect of amantadine was not affected by the 5-HT(1A) antagonist WAY-100635, but was partially reversed by the NMDA agonist d-cycloserine. Conversely, the AIM-suppressing effect of dextromethorphan was prevented by WAY-100635 but not by d-cycloserine. Neither amantadine nor dextromethorphan affected the therapeutic effects of L-DOPA in sensorimotor tests. We conclude that the anti-dyskinetic effect of amantadine is partially dependent on NMDA antagonism, while dextromethorphan suppresses AIMs via indirect 5-HT(1A) agonism. Combined with previous work from our group, our results support the investigation of 5-HT(1A) agonists as pharmacotherapies for LID in PD patients.[Paquette MA et al; Eur J Neurosci 36 (9): 3224-34 (2012)] Full text: <a href='https://www.ncbi.nlm.nih.gov/pmc/?term=PMC3573705' target=new>PMC3573705</a>

Department of Justice; Drug Enforcement Administration (DEA), Dextromethorphan (July 2012). Available from, as of February 7, 2014: http://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf

Dendritic cells (DCs) play an important role in connecting innate and adaptive immunity. Thus, DCs have been regarded as a major target for the development of immunomodulators. In this study, we examined the effect of dextromethorphan (DXM), a common cough suppressant with a high safety profile, on the activation and function of DCs. In the presence of DXM, the LPS-induced expression of the costimulatory molecules in murine bone marrow-derived dendritic cells (BMDCs) was significantly suppressed. In addition, DXM treatment reduced the production of reactive oxygen species (ROS), proinflammatory cytokines, and chemokines in maturing BMDCs that were activated by LPS. Therefore, DXM abrogated the ability of LPS-stimulated DCs to induce Ag-specific T-cell activation, as determined by their decreased proliferation and IFN-gamma secretion in mixed leukocyte cultures. Moreover, the inhibition of LPS-induced MAPK activation and NF-k B translocation may contribute to the suppressive effect of DXM on BMDCs. Remarkably, DXM decreased the LPS-induced surface expression of CD80, CD83, and HLA-DR and the secretion of IL-6 and IL-12 in human monocyte-derived dendritic cells (MDDCs). These findings provide a new insight into the impact of DXM treatment on DCs and suggest that DXM has the potential to be used in treating DC-related acute and chronic diseases.[Chen DY et al; Clin Dev Immunol. 2013;2013:125643. doi: 10.1155/2013/125643. Epub 2013] Full text: <a href='https://www.ncbi.nlm.nih.gov/pmc/?term=PMC3679715' target=new>PMC3679715</a>

Department of Justice; Drug Enforcement Administration (DEA), Dextromethorphan (July 2012). Available from, as of February 7, 2014: http://www.deadiversion.usdoj.gov/drug_chem_info/dextro_m.pdf

Dextromethorphan (DM) is a dextrorotatory morphinan and an over-the-counter non-opioid cough suppressant. We have previously shown that DM protects against LPS-induced dopaminergic neurodegeneration through inhibition of microglia activation. Here, we investigated protective effects of DM against endotoxin shock induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice and the mechanism underlying its protective effect. Mice were given multiple injections of DM (12.5 mg/kg, s.c.) 30 min before and 2, 4 hr after an injection of LPS/GalN (20 ug/700 mg/kg). DM administration decreased LPS/GalN-induced mortality and hepatotoxicity, as evidenced by increased survival rate, decreased serum alanine aminotransferase activity and improved pathology. Furthermore, DM was also effective when it was given 30 min after LPS/GalN injection. The protection was likely associated with reduced serum and liver tumor necrosis factor alpha (TNF-alpha) levels. DM also attenuated production of superoxide and intracellular reactive oxygen species in Kupffer cells and neutrophils. Real-time RT-PCR analysis revealed that DM administration suppressed the expression of a variety of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intercellular adhesion molecular-1 and interleukin-6. DM also decreased the expression of genes related to cell-death pathways, such as the DNA damage protein genes GADD45 and GADD153. In summary, DM is effective in protecting mice against LPS/GalN-induced hepatotoxicity, and the mechanism is likely through a faster TNF-alpha clearance, and decrease of superoxide production and inflammation and cell-death related components. This study not only extends neuroprotective effect of DM, but also suggests that DM may be a novel compound for the therapeutic intervention for sepsis.

Li G et al; Biochem Pharmacol 69 (2): 233-40 (2005)

/The investigators/ showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Shin EJ et al; Neurochem Int 50 (6): 791-9 (2007)

Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor-mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. Excitatory postsynaptic currents (evoked EPSCs: eEPSCs) were evoked in the second-order neurons by electrical stimulation of the tractus solitarius. DEX reversibly decreased the eEPSC amplitude in a concentration-dependent manner. The DEX-induced inhibition of eEPSC was accompanied by an increased paired-pulse ratio. Miniature EPSCs (mEPSCs) were also recorded in the presence of Cd(2+) or tetrodotoxin. DEX decreased the frequency of mEPSCs without affecting their amplitude. Topically applied AMPA provoked an inward current in the neurons, which was unchanged during the perfusion of DEX. BD1047, a s-1-receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a s-1 agonist. Haloperidol, a s-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of s receptors.

Ohi Y et al; J Pharmacol Sci 116 (1): 54-62 (2011)

Dextromethorphan, an antitussive drug, has a neuroprotective property as evidenced by its inhibition of microglial production of pro-inflammatory cytokines and reactive oxygen species. The microglial activation requires NADPH oxidase activity, which is sustained by voltage-gated proton channels in microglia as they dissipate an intracellular acid buildup. In the present study, we examined the effect of dextromethorphan on proton currents in microglial BV2 cells. Dextromethorphan reversibly inhibited proton currents with an IC(50) value of 51.7 uM at an intracellular/extracellular pH gradient of 5.5/7.3. Dextromethorphan did not change the reversal potential or the voltage dependence of the gating. Dextrorphan and 3-hydroxymorphinan, major metabolites of dextromethorphan, and dextromethorphan methiodide were ineffective in inhibiting proton currents. The results indicate that dextromethorphan inhibition of proton currents would suppress NADPH oxidase activity and, eventually, microglial activation.

Song JH, Yeh JZ; Neurosci Lett 516 (1): 94-8 (2012)

Dextromethorphan exhibits neuroprotective effects against inflammation-mediated neurodegeneration. However, relatively little is known regarding the molecular mechanism for this inflammation-mediated neuroprotection. Human K(v)1.3 channels, one of the voltage-gated potassium channels, are widely expressed in the immune and nervous systems. Activation of human K(v)1.3 channels causes neuroglia-mediated neurodegeneration. Agents that inhibit human K(v)1.3 channel activity have been developed as novel drugs for immunosuppression. In the present study, we investigated the effects of dextromethorphan on human K(v)1.3 or K(v)1.2 channel activity heterologously expressed in Xenopus laevis oocytes. The channel currents were measured with the two-electrode voltage clamp technique. Activation of both channels induced outward peak and steady-state currents. Dextromethorphan treatment induced a slight inhibition of peak currents in human K(v)1.2 and K(v)1.3 channels, whereas dextromethorphan profoundly inhibited the steady-state currents of human K(v)1.3 channels compared to K(v)1.2 channel currents. Dextromethorphan's action on steady-state currents of human K(v)1.3 channels was in a concentration-dependent manner. The half-maximal inhibitory concentration (IC(50)) on steady-state currents of human K(v)1.3 channels was 12.8 + or - 1.6 uM. Dextromethorphan also accelerated the C-type inactivation rate, increased the current decay rate, and inhibited currents in a use-dependent manner. These results indicate that dextromethorphan accelerates C-type inactivation of human K(v)1.3 channels and acts as an open-channel blocker. These results further suggest the possibility that dextromethorphan-mediated acceleration of C-type inactivation of human K(v)1.3 channels might be one of the cellular bases of dextromethorphan-mediated protection against inflammation-mediated neurodegeneration.

Lee JH et al; Eur J Pharmacol 651 (1-3): 122-7 (2011)

Dextromethorphan is an opioid-like drug that binds to and acts as antagonist to the NMDA glutamatergic receptor, it is an agonist to the opioid sigma 1 and sigma 2 receptors, it is also an alpha3/beta4 nicotinic receptor antagonist and targets the serotonin reuptake pump. 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.

Bub O, Friedrich L; Cough remedies. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2014). New York, NY: John Wiley & Sons. Online Posting Date: June 15, 2000

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