View source for Dextromethorphan

{{Short description|Cough suppressant, antidepressant, and dissociative drug}}
{{Distinguish|Dextrorphan|Dexamethasone|Dextroamphetamine}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 470624518
| image = Dextromethorphan.svg
| image_class = skin-invert-image
| alt = 
| image2 = Dextromethorphan-from-xtal-3D-balls-A.png
| alt2 = 

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|d|ɛ|k|.|s|t|r|oʊ|.|m|ə|ˈ|θ|ɔː|ɹ|ˌ|f|æ|n|audio=LL-Q1860 (eng)-Naomi Persephone Amethyst (NaomiAmethyst)-dextromethorphan.wav}}<br />{{respell|DEK|stroh|məth|OR|fan}}
| tradename = Robitussin, Delsym, others
| Drugs.com = {{drugs.com|monograph|dextromethorphan}}
| MedlinePlus = a682492
| DailyMedID = Dextromethorphan
| pregnancy_AU = A
| addiction_liability = Low–moderate
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Antitussive]];<ref>{{cite web|url=https://www.drugs.com/monograph/dextromethorphan.html|title=Dextromethorphan Monograph for Professionals|website=Drugs.com}}</ref><ref>{{cite journal | vauthors = Windhab LG, Gastberger S, Hulka LM, Baumgartner MR, Soyka M, Müller TJ, Seifritz E, Mutschler J | title = Dextromethorphan Abuse Among Opioid-Dependent Patients | journal = Clinical Neuropharmacology | volume = 43 | issue = 5 | pages = 127–133 | year = 2020 | pmid = 32947422 | doi = 10.1097/WNF.0000000000000403 | s2cid = 221798401 | url = https://boris.unibe.ch/150461/ }}</ref><br>[[Serotonin–norepinephrine reuptake inhibitor]];<ref>{{Cite journal |last=McCarthy |first=Brian|date=2023-11-30 |title=Dextromethorphan-bupropion (Auvelity) for the Treatment of Major Depressive Disorder |journal=Clinical Psychopharmacology and Neuroscience|volume=21 |issue=4 |pages=609–616 |doi=10.9758/cpn.23.1081 |pmid=37859435|pmc=10591164 }}</ref> [[NMDA receptor antagonist]]; [[Dissociative hallucinogen]]
| ATC_prefix = R05
| ATC_suffix = DA09

<!-- Legal status -->
| legal_AU = S2
| legal_UK = P
| legal_US = OTC
| legal_CA = OTC
| legal_UN = Unscheduled
| legal_status = SE: Förteckning V

<!-- Pharmacokinetic data -->
| bioavailability = 11%<ref name="pmid15500572">{{cite journal | vauthors = Kukanich B, Papich MG | title = Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 27 | issue = 5 | pages = 337–341 | date = October 2004 | pmid = 15500572 | doi = 10.1111/j.1365-2885.2004.00608.x }}</ref>
| metabolism = [[Liver]] enzymes: major [[CYP2D6]], minor [[CYP3A4]], and minor [[CYP3A5]]
| metabolites = * [[Dextrorphan]]
* [[ 3-methoxymorphinan]]
| elimination_half-life = 2–4 hours ([[extensive metabolizer]]s); 24 hours ([[poor metabolizer]]s)<ref name = MSR>{{cite web|title=Balminil DM, Benylin DM (dextromethorphan) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=15 April 2014|url=http://reference.medscape.com/drug/balminil-dm-benylin-dm-dextromethorphan-343401#showall}}</ref>
| duration_of_action = 3–8 hours
| excretion = [[Kidney]]

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 125-71-3
| PubChem = 5360696
| IUPHAR_ligand = 6953
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00514
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 13109865
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7355X3ROTS
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03742
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 4470
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 52440
| synonyms = DXM, 3-methoxy-N-methylmorphinan

<!-- Chemical data -->
| IUPAC_name = (4b''S'',8a''R'',9''S'')-3-Methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5''H''-9,4b-(epiminoethano)phenanthrene
| C = 18
| H = 25
| N = 1
| O = 1
| chirality = [[Dextrorotatory]] [[enantiomer]]
| SMILES = CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc4c3cc(cc4)OC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MKXZASYAUGDDCJ-NJAFHUGGSA-N
| melting_point = 111
}}

'''Dextromethorphan''', sold under the brand name '''Robitussin''' among others, is a [[cough suppressant]] used in many [[cough]] and [[Common cold|cold]] medicines.<ref>{{cite journal |last=Dicpinigaitis |first=P |date=2022-09-12 |title=The Current and Emerging Treatment Landscape for Chronic Cough |url=https://www.ajmc.com/view/the-current-and-emerging-treatment-landscape-for-chronic-cough |journal=The American Journal of Managed Care |series=Uncovering the Economic Burden of Chronic Cough and the Promising Role of Emerging Targeted Therapies |language=en |volume=28 |issue=9 |pages=S159–S165 |doi=10.37765/ajmc.2022.89244 |pmid=36198074 |s2cid=252736111 |quote=By sales, dextromethorphan is the most widely used OTC antitussive drug in the United States, and approximately 85% to 90% of OTC cough medicines contain dextromethorphan}}</ref> In 2022, the US [[Food and Drug Administration]] (FDA) approved the combination [[dextromethorphan/bupropion]] to serve as a rapid-acting [[antidepressant]] in people with [[major depressive disorder]].<ref>{{cite journal | vauthors = Majeed A, Xiong J, Teopiz KM, Ng J, Ho R, Rosenblat JD, Phan L, Cao B, McIntyre RS | title = Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials | journal = Expert Opinion on Emerging Drugs | volume = 26 | issue = 1 | pages = 63–74 | date = March 2021 | pmid = 33682569 | doi = 10.1080/14728214.2021.1898588 | s2cid = 232141396 }}</ref>

It is in the [[morphinan]] class of medications with [[sedative]], [[dissociative]], and [[stimulant]] properties (at lower doses). Dextromethorphan does not have a significant [[Affinity (pharmacology)|affinity]] for the [[Μ-opioid receptor|mu-opioid receptor]] activity typical of morphinan compounds and exerts its therapeutic effects through several other receptors.<ref name="pmid27139517" /> In its pure form, dextromethorphan occurs as a white powder.<ref name="ref tables">{{cite web|url=http://www.pharmacopeia.cn/v29240/usp29nf24s0_alpha-2-13.html|title=Reference Tables: Description and Solubility{{dash}}D|archive-url=https://web.archive.org/web/20170704164745/http://www.pharmacopeia.cn/v29240/usp29nf24s0_alpha-2-13.html|archive-date=2017-07-04|url-status=dead|access-date=2011-05-06 }}</ref>

When exceeding approved dosages, dextromethorphan acts as a [[dissociative|dissociative hallucinogen]]. It has multiple [[mechanism of action|mechanisms of action]], including actions as a nonselective [[serotonin reuptake inhibitor]]<ref name="Schwartz, Pizon, Brooks 2008">{{cite journal | vauthors = Schwartz AR, Pizon AF, Brooks DE | title = Dextromethorphan-induced serotonin syndrome | journal = Clinical Toxicology | volume = 46 | issue = 8 | pages = 771–773 | date = September 2008 | pmid = 19238739 | doi = 10.1080/15563650701668625 | s2cid = 37817922 | doi-access = free | title-link = doi }}</ref> and a [[sigma-1 receptor]] agonist.<ref name="pmid17386960">{{cite journal | vauthors = Shin EJ, Nah SY, Chae JS, Bing G, Shin SW, Yen TP, Baek IH, Kim WK, Maurice T, Nabeshima T, Kim HC | title = Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats | journal = Neurochemistry International | volume = 50 | issue = 6 | pages = 791–799 | date = May 2007 | pmid = 17386960 | doi = 10.1016/j.neuint.2007.01.008 | s2cid = 43230896 }}</ref><ref name="pmid15723099">{{cite journal | vauthors = Shin EJ, Nah SY, Kim WK, Ko KH, Jhoo WK, Lim YK, Cha JY, Chen CF, Kim HC | title = The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan | journal = British Journal of Pharmacology | volume = 144 | issue = 7 | pages = 908–918 | date = April 2005 | pmid = 15723099 | pmc = 1576070 | doi = 10.1038/sj.bjp.0705998 }}</ref> Dextromethorphan and its major [[metabolite]], [[dextrorphan]], also block the [[NMDA receptor]] at high doses, which produces effects similar to other [[dissociative anesthetics]] such as [[ketamine]], [[Nitrous oxide (medication)|nitrous oxide]], and [[phencyclidine]].

<!-- Society and culture -->
It was patented in 1949 and approved for medical use in 1953.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title= Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=527 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA527 }}</ref> In 2022, the combination with [[promethazine]] was the 260th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="Top 300 of 2022">{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Dextromethorphan; Promethazine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/DextromethorphanPromethazine | access-date = 30 August 2024 }}</ref> In 2022, the combination with [[brompheniramine]] and [[pseudoephedrine]] was the 265th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref name="Top 300 of 2022" /><ref>{{cite web | title = Brompheniramine; Dextromethorphan; Pseudoephedrine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/BrompheniramineDextromethorphanPseudoephedrine | access-date = 30 August 2024 }}</ref>
{{TOC limit|3}}

==Medical uses==
[[File:Dextrometorfano.jpg|thumb|upright=1.2|right|Store-brand dextromethorphan cough syrup]]

===Cough suppression===
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 [[influenza|flu]] and [[common cold]]), or from inhaled particle irritants, as well as chronic cough at a higher dosage.<ref name="Young Smith 2011 pp. 224–230">{{cite journal | vauthors = Young EC, Smith JA | title = Pharmacologic therapy for cough | journal = Current Opinion in Pharmacology | volume = 11 | issue = 3 | pages = 224–230 | date = June 2011 | pmid = 21724464 | doi = 10.1016/j.coph.2011.06.003 | publisher = Elsevier BV }}</ref><ref name = AMH>{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | place = Adelaide | editor = Rossi, S }}{{page needed|date=April 2015}}</ref> Dextromethorphan is available alone in the form of [[cough syrup]] and [[pill (pharmacy)|pill]]s as well as in combination with other agents.

===Pseudobulbar affect===
In 2010, the FDA approved the combination drug [[dextromethorphan/quinidine]] under the brand name Nuedexta<ref name="Nuedexta FDA label">{{cite web | title=Nuedexta- dextromethorphan hydrobromide and quinidine sulfate capsule, gelatin coated | website=DailyMed | date=23 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=484e0918-3442-49dc-8ccf-177f1f3ee9f3 | access-date=23 October 2020}}</ref> for the treatment of [[pseudobulbar affect]] (uncontrollable laughing/crying). Dextromethorphan is the active therapeutic agent in the combination; [[quinidine]] merely serves to inhibit the [[enzymatic]] [[catabolism|degradation]] of dextromethorphan and thereby increase its circulating concentrations via inhibition of [[CYP2D6]].<ref name="NguyenThomas2016">{{cite journal | vauthors = Nguyen L, Thomas KL, Lucke-Wold BP, Cavendish JZ, Crowe MS, Matsumoto RR | title = Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders | journal = Pharmacology & Therapeutics | volume = 159 | pages = 1–22 | date = March 2016 | pmid = 26826604 | doi = 10.1016/j.pharmthera.2016.01.016 }}</ref>

===Major depressive disorder ===
The combination medicine [[dextromethorphan/bupropion]] is approved for [[treatment-resistant major depressive disorder|major depressive disorder]] under the brand name Auvelity.<ref name="Auvelity Label">{{cite web | title=Auvelity (dextromethorphan hydrobromide/bupropion hydrochloride) | website=Axsome Therapeutics | url=https://www.axsome.com/auvelity-prescribing-information.pdf | access-date=19 August 2022 | archive-date=21 August 2022 | archive-url=https://web.archive.org/web/20220821043349/https://www.axsome.com/auvelity-prescribing-information.pdf | url-status=live }}</ref><ref name="pmid36301443">{{cite journal |vauthors=Keam SJ |title=Dextromethorphan/Bupropion: First Approval |journal=[[CNS Drugs]] |volume=36 |issue=11 |pages=1229–1238 |date=November 2022 |pmid=36301443 |doi=10.1007/s40263-022-00968-4|s2cid=253158902 |url=https://figshare.com/articles/online_resource/Dextromethorphan_Bupropion_First_Approval/21320970 }}</ref>

==Adverse effects==
Side effects of dextromethorphan at normal therapeutic doses can include:<ref name = MSR/><ref name = AMH/><ref name="nhtsa">{{cite web|url=http://www.nhtsa.dot.gov/PEOPLE/injury/research/job185drugs/dextromethorphan.htm|title=Dextromethorphan|work=National Highway Traffic Safety Administration (NHTSA)|archive-url=https://web.archive.org/web/20080801054711/http://www.nhtsa.dot.gov/PEOPLE/injury/research/job185drugs/dextromethorphan.htm|archive-date=2008-08-01}}</ref>

{{Columns-list|colwidth=20em|
* Body [[rash]]/[[itching]]
* [[Nausea]]
* [[Vomiting]]
* [[Drowsiness]]
* [[Dizziness]]
* [[Constipation]]
* [[Diarrhea]]
* [[Sedation]]
* [[Confusion]]
* [[Anxiety]]
* [[Closed-eye hallucinations]]}}

A rare side effect is [[respiratory depression]].<ref name = AMH/>

===Neurotoxicity===

Dextromethorphan was once 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&nbsp;mg or more every day for as long as a month. Neurotoxic changes, including vacuolation, have been observed in [[posterior cingulate]] and [[retrosplenial cortex|retrosplenial cortices]] of rats administered other [[NMDA receptor antagonist]]s such as PCP, but not with dextromethorphan.<ref>{{cite journal | vauthors = Olney JW, Labruyere J, Price MT | title = Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs | journal = Science | volume = 244 | issue = 4910 | pages = 1360–1362 | date = June 1989 | pmid = 2660263 | doi = 10.1126/science.2660263 | bibcode = 1989Sci...244.1360O }}</ref><ref>{{cite journal | vauthors = Carliss RD, Radovsky A, Chengelis CP, O'Neill TP, Shuey DL | title = Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain | journal = Neurotoxicology | volume = 28 | issue = 4 | pages = 813–818 | date = July 2007 | pmid = 17573115 | doi = 10.1016/j.neuro.2007.03.009 | bibcode = 2007NeuTx..28..813C }}</ref>

===Dependence and withdrawal===
In many documented cases{{Citation needed|date=August 2020}}, dextromethorphan has produced [[substance dependence|psychological dependence]] in people who used it recreationally. It is considered less addictive than other common cough suppressants, such as the opiate [[codeine]].<ref name = MSR/> Since dextromethorphan also acts as a serotonin reuptake inhibitor, users report 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.

==Interactions==
[[Serotonin syndrome]] may result from the combined use of dextromethorphan and [[Serotonin|serotonergic]] antidepressants such as [[selective serotonin reuptake inhibitor]]s (SSRIs) or [[monoamine oxidase inhibitor]]s (MAOIs).<ref>{{cite journal | vauthors = Dy P, Arcega V, Ghali W, Wolfe W | title = Serotonin syndrome caused by drug to drug interaction between escitalopram and dextromethorphan | journal = BMJ Case Reports | volume = 2017 | pages = bcr–2017–221486 | date = August 2017 | pmid = 28784915 | pmc = 5747823 | doi = 10.1136/bcr-2017-221486 }}</ref> Further research is needed to determine whether doses of dextromethorphan beyond those normally used therapeutically are needed to produce this effect.<ref name="Schwartz, Pizon, Brooks 2008"/> In any case, dextromethorphan should not be taken with MAOIs due to the possibility of this complication.<ref name="nhtsa" /> Serotonin syndrome is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of [[serotonin]] in the body.

Combining [[Alcohol (drug)|alcohol]] with dextromethorphan significantly increases the risk of overdose, according to the [[NIAAA]].<ref>{{cite web |title=Harmful Interactions {{!}} National Institute on Alcohol Abuse and Alcoholism (NIAAA) |url=https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/harmful-interactions-mixing-alcohol-with-medicines |website=www.niaaa.nih.gov}}</ref>

[[Grapefruit drug interactions|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 of the drug which both increases and prolongs effects. [[Grapefruit]] and grapefruit juices (especially white grapefruit juice, but also including other citrus fruits such as [[Bergamot orange|bergamot]] and [[Lime (fruit)|lime]], as well as a number of noncitrus fruits<ref name="GANFYD.org">{{cite web|url=http://www.ganfyd.org/index.php?title=Inhibitors_of_CYP3A4|title=Inhibitors of CYP3A4|publisher=ganfyd.org|archive-url=https://web.archive.org/web/20170720174834/http://www.ganfyd.org/index.php?title=Inhibitors_of_CYP3A4|archive-date=2017-07-20|url-status=usurped|access-date=23 August 2013}}</ref>) generally are recommended to be avoided while using dextromethorphan and numerous other medications.

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable sortable floatright" style="font-size:small;"
|+ Dextromethorphan and metabolite<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=dextromethorphan&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref><ref name="NguyenThomas2016"/><ref name="pmid17689532">{{cite journal | vauthors = Werling LL, Keller A, Frank JG, Nuwayhid SJ | title = A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder | journal = Experimental Neurology | volume = 207 | issue = 2 | pages = 248–257 | date = October 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013 | s2cid = 38476281 }}</ref><ref name="pmid27139517">{{cite journal | vauthors = Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR | title = Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta) clinical use | journal = Pharmacology & Therapeutics | volume = 164 | pages = 170–182 | date = August 2016 | pmid = 27139517 | doi = 10.1016/j.pharmthera.2016.04.010 | doi-access = free | title-link = doi }}</ref>
|-
! Site !! {{abbr|DXM|Dextromethorphan}} !! {{abbrlink|DXO|Dextrorphan}} !! Species !! Ref
|-
| [[NMDA receptor|{{abbr|NMDAR|N-Methyl-D-aspartate receptor}}<br />(MK-801)]] || 2120–8945 || 486–906 || Rat || <ref name="NguyenThomas2016"/>
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || 142–652 || 118–481 || Rat || <ref name="NguyenThomas2016"/>
|-
| [[Sigma-2 receptor|σ<sub>2</sub>]] || 11060–22864 || 11325–15582 || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|MOR|μ-Opioid receptor}} || 1280<br />{{abbr|ND|No data}} || 420<br />1000+ || Rat<br />Human || <ref name="NguyenThomas2016"/><br /><ref name="pmid7815359">{{cite journal | vauthors = Raynor K, Kong H, Mestek A, Bye LS, Tian M, Liu J, Yu L, Reisine T | title = Characterization of the cloned human mu opioid receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 272 | issue = 1 | pages = 423–428 | date = January 1995 | doi = 10.1016/S0022-3565(25)24351-8 | pmid = 7815359 }}</ref>
|-
| {{abbrlink|DOR|δ-Opioid receptor}} || 11500 || 34700 || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|KOR|κ-Opioid receptor}} || 7000 || 5950 || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|SERT|Serotonin transporter}} || 23–40 || 401–484 || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 240+ || 340+ || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|DAT|Dopamine transporter}} || 1000+ || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 1000+ || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]]<sub>/</sub>[[5-HT1D receptor|<sub>1D</sub>]] || 61% at 1&nbsp;μM || 54% at 1&nbsp;μM || Rat || <ref name="NguyenThomas2016"/>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 1000+ || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] || 1000+ || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>]] || 60% at 1&nbsp;μM || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[Beta-adrenergic receptor|β]] || 1000+ || 35% at 1&nbsp;μM || Rat || <ref name="NguyenThomas2016"/>
|-
| [[D2 receptor|D<sub>2</sub>]] || 1000+ || 1000+ || Rat || <ref name="NguyenThomas2016"/>
|-
| [[H1 receptor|H<sub>1</sub>]] || 1000+ || 95% at 1&nbsp;μM || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|mAChRs|Muscarinic acetylcholine receptors}} || 1000+ || 100% at 1&nbsp;μM || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|nAChRs|Nicotinic acetylcholine receptors}} || 700–8900<br />([[IC50|IC<sub>50</sub>]]) || 1300–29600<br />(IC<sub>50</sub>) || Rat || <ref name="NguyenThomas2016"/>
|-
| {{abbrlink|VDSCs|Voltage-dependent sodium channels}} || 50000+ (IC<sub>50</sub>) || {{abbr|ND|No data}} || Rat || <ref name="pmid17346698">{{cite journal | vauthors = Lee JH, Shin EJ, Jeong SM, Lee BH, Yoon IS, Lee JH, Choi SH, Kim YH, Pyo MK, Lee SM, Chae JS, Rhim H, Oh JW, Kim HC, Nah SY | title = Effects of dextrorotatory morphinans on brain Na+ channels expressed in Xenopus oocytes | journal = European Journal of Pharmacology | volume = 564 | issue = 1–3 | pages = 7–17 | date = June 2007 | pmid = 17346698 | doi = 10.1016/j.ejphar.2007.01.088 }}</ref><ref name="pmid23139844">{{cite journal | vauthors = Gao XF, Yao JJ, He YL, Hu C, Mei YA | title = Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e49384 | year = 2012 | pmid = 23139844 | pmc = 3489664 | doi = 10.1371/journal.pone.0049384 | doi-access = free | title-link = doi | bibcode = 2012PLoSO...749384G }}</ref>
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are K<sub>i</sub> (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.
|}

Dextromethorphan has been found to possess the following actions (<1&nbsp;μM) using rat tissues:<ref name="NguyenThomas2016"/><ref name="pmid24648790" />

* [[Uncompetitive inhibitor|Uncompetitive antagonist]] of the [[NMDA receptor]] via the [[dizocilpine|MK-801]]/{{abbrlink|PCP|phencyclidine}} site<ref name="pmid24648790">{{cite journal | vauthors = Burns JM, Boyer EW | title = Antitussives and substance abuse | journal = Substance Abuse and Rehabilitation | volume = 4 | pages = 75–82 | year = 2013 | pmid = 24648790 | pmc = 3931656 | doi = 10.2147/SAR.S36761 | doi-access = free | title-link = doi }}</ref>
* {{abbrlink|SERT|Serotonin transporter}} and {{abbrlink|NET|norepinephrine transporter}} [[reuptake inhibitor|blocker]] (cf. [[serotonin–norepinephrine reuptake inhibitor]])
* [[Sigma receptor|Sigma]] [[Sigma-1 receptor|σ<sub>1</sub> receptor]] [[agonist]]
* [[Negative allosteric modulator]] of [[nicotinic acetylcholine receptor]]s
* [[Ligand (biochemistry)|Ligand]] of the [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]]<sub>/</sub>[[5-HT1D receptor|<sub>1D</sub>]], [[histamine]] [[H1 receptor|H<sub>1</sub>]], [[alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic]], and [[muscarinic acetylcholine receptor]]s

Dextromethorphan is a [[prodrug]] of [[dextrorphan]], which is the actual mediator of most of its [[dissociative]] effects through acting as a more potent NMDA receptor antagonist than dextromethorphan itself.<ref name="pmid10064839">{{cite journal | vauthors = Chou YC, Liao JF, Chang WY, Lin MF, Chen CF | title = Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan | journal = Brain Research | volume = 821 | issue = 2 | pages = 516–519 | date = March 1999 | pmid = 10064839 | doi = 10.1016/S0006-8993(99)01125-7 | s2cid = 22762264 }}</ref> What role, if any, (+)-[[3-methoxymorphinan]], dextromethorphan's other major metabolite, plays in its effects is not entirely clear.<ref>{{cite journal | vauthors = Schmider J, Greenblatt DJ, Fogelman SM, von Moltke LL, Shader RI | title = Metabolism of dextromethorphan in vitro: involvement of cytochromes P450 2D6 and 3A3/4, with a possible role of 2E1 | journal = Biopharmaceutics & Drug Disposition | volume = 18 | issue = 3 | pages = 227–240 | date = April 1997 | pmid = 9113345 | doi = 10.1002/(SICI)1099-081X(199704)18:3<227::AID-BDD18>3.0.CO;2-L | s2cid = 5638973 }}</ref>

===Pharmacokinetics===
Following oral administration, dextromethorphan is rapidly absorbed from the [[gastrointestinal tract]], where it enters the [[bloodstream]] and crosses the [[blood–brain barrier]].{{Citation needed|date=March 2011}}

At therapeutic doses, dextromethorphan acts [[central nervous system|centrally]] (meaning that it acts on the [[brain]]) as opposed to locally (on the [[respiratory tract]]). It elevates the threshold for coughing, without inhibiting [[cilia]]ry 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&nbsp;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 [[List of medical abbreviations: Q|qds]] recommended."<ref name="MoriceCough">{{cite web|url=http://www.issc.info/cough.html|title=Cough| vauthors = Morice AH |publisher=International Society for the Study of Cough|archive-url=https://web.archive.org/web/20170509013127/http://www.issc.info/cough.html|archive-date=2017-05-09|url-status=live}}</ref>

Dextromethorphan has an [[elimination half-life]] of approximately 4&nbsp;hours in individuals with an extensive metabolizer phenotype; this is increased to approximately 13&nbsp;hours when dextromethorphan is given in combination with [[quinidine]].<ref name="pmid27139517" /> The [[duration of action]] after oral administration is about three to eight hours for dextromethorphan hydrobromide, and 10 to 12 hours for dextromethorphan polistirex.{{Citation needed|date=June 2023}} Around one in 10 of the Caucasian population has little or no CYP2D6 enzyme activity, leading to long-lived high drug levels.<ref name=MoriceCough/>

====Metabolism====
[[File:DXM metabolism.png|class=skin-invert-image|thumb|440x440px|Main metabolic pathways of dextromethorphan degradation, which are catalyzed by cytochrome P450 monooxygenases ([[CYP3A4]] and [[CYP2D6]]) and UDP-glucuronosyl-transferase (UGT)<ref>{{cite journal | vauthors = Strauch K, Lutz U, Bittner N, Lutz WK | title = Dose-response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles | journal = Food and Chemical Toxicology | volume = 47 | issue = 8 | pages = 1928–1935 | date = August 2009 | pmid = 19445995 | doi = 10.1016/j.fct.2009.05.004 }}</ref>]]

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, 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),<ref name="DXMdualprobe">{{cite journal | vauthors = Yu A, Haining RL | title = Comparative contribution to dextromethorphan metabolism by cytochrome P450 isoforms in vitro: can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A activities? | journal = Drug Metabolism and Disposition | volume = 29 | issue = 11 | pages = 1514–1520 | date = November 2001 | pmid = 11602530 | url = http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11602530 | access-date = 2015-04-26 | archive-date = 2020-03-12 | archive-url = https://web.archive.org/web/20200312134718/http://dmd.aspetjournals.org/content/29/11/1514.long | url-status = dead }}</ref> 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.<ref name="nhtsa" />

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 dextromethorphan to dextrorphan contributes to at least 80% of the dextrorphan formed during dextromethorphan metabolism.<ref name="DXMdualprobe"/> 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.<ref name="pmid8841152">{{cite journal | vauthors = Capon DA, Bochner F, Kerry N, Mikus G, Danz C, Somogyi AA | title = The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans | journal = Clinical Pharmacology and Therapeutics | volume = 60 | issue = 3 | pages = 295–307 | date = September 1996 | pmid = 8841152 | doi = 10.1016/S0009-9236(96)90056-9 | s2cid = 10147669 }}</ref> 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 dextromethorphan.<ref name="DXMpolymorphicmetabolism">{{cite journal | vauthors = Woodworth JR, Dennis SR, Moore L, Rotenberg KS | title = The polymorphic metabolism of dextromethorphan | journal = Journal of Clinical Pharmacology | volume = 27 | issue = 2 | pages = 139–143 | date = February 1987 | pmid = 3680565 | doi = 10.1002/j.1552-4604.1987.tb02174.x | s2cid = 37950361 }}</ref> A number of [[allele]]s for CYP2D6 are known, including several completely inactive variants. The distribution of alleles is uneven amongst [[CYP2D6#Ethnic factors in variability|ethnic groups]].

A large number of medications are potent [[CYP2D6#Ligands|inhibitors of CYP2D6]]. Some types of medications known to inhibit CYP2D6 include certain SSRIs and [[tricyclic]] [[antidepressant]]s, some [[antipsychotics]], and the commonly available [[antihistamine]] [[diphenhydramine]]. Therefore, the potential for interactions exists between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers.

Dextromethorphan 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 dextromethorphan.<ref name="DXMdualprobe" />

A number of other CYP enzymes are implicated as minor pathways of dextromethorphan metabolism. CYP2D6 is more effective than CYP3A4 at N-demethylation of dextromethorphan, but since the average individual has a much lower CYP2D6 content in the liver compared to CYP3A4, most N-demethylation of dextromethorphan is catalyzed by CYP3A4.<ref name="DXMdualprobe" />

==Chemistry==
Dextromethorphan is the [[dextrorotation|dextrorotatory]] [[enantiomer]] 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 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&nbsp;°C.<ref>{{cite web|url=http://www.inchem.org/documents/pims/pharm/pim179.htm|title=Dextromethorphan (PIM 179)|website=www.inchem.org|archive-url=https://web.archive.org/web/20170310190514/http://www.inchem.org/documents/pims/pharm/pim179.htm|archive-date=2017-03-10|url-status=live|access-date=2018-03-24}}</ref> Dextromethorphan is commonly available as the monohydrated hydrobromide salt, and is also available in extended-release formulations (sold as dextromethorphan polistirex) contain dextromethorphan bound to an [[ion-exchange resin]] based on [[Sodium polystyrene sulfonate|polystyrene sulfonic acid]].{{cn|date=January 2024}} Dextromethorphan's [[specific rotation]] in water is +27.6° (20&nbsp;°C, Sodium D-line).{{Citation needed|date=March 2011}}

===Synthesis===
Several routes exist for the synthesis of Dextromethorphan. Even though many of the syntheses have been known since the middle of the 20th century, researchers are still working today to further develop the synthesis of Dextromethorphan and, for example, to make it more [[Green chemistry|environmentally friendly]].

This includes the synthesis by means of ionic liquids.{{cn|date=August 2022}}

====Racemate separation====
Since only one of the stereoisomers has the desired effect, the separation of a racemic mixture of hydroxy N- methyl morphinan using tartaric acid and subsequent methylation of the hydroxyl group is a suitable method. By using (D)-tartrate, the (+)-isomer remains as the product.
[[File:Racemate separation for synthesis of Dextromethorphan.svg|class=skin-invert-image|center|Racemate separation for synthesis of Dextromethorphan|650px]]
This synthetic pathway was patented by [[Roche]] in 1950.

====Traditional synthesis====
The traditional synthetic route uses Raney nickel and has been further improved over time, for example by the use of ibuprofen and AlCl<sub>3</sub>.

[[File:Traditional synthesis of Dextromethorphan.svg|class=skin-invert-image|center|700px]]

Overall, it is a cost-effective method with moderate reaction conditions that is easy to handle and suitable for industrial production.{{cn|date=August 2022}}

====Grewe's cyclization====
[[File:Synthesis of Dextromethorphan via Grewe's cyclization.svg|class=skin-invert-image|center|750px]]

Grewe's cyclization is easier to handle in terms of the chemicals used, produces higher yields and higher purity of the product.<ref>{{cite journal| vauthors = Meuzelaar GJ, Neeleman E, Maat L, Sheldon RA |date=2010-06-17|title=ChemInform Abstract: A Novel Synthesis of Substituted 1-Benzyloctahydroisoquinolines by Acid-Catalyzed Cyclization of N-[2-(Cyclohex-1-enyl)ethyl]-N-styrylformamides. |journal= ChemInform |volume=30 | issue=5 |pages=no |doi=10.1002/chin.199905129 |issn=0931-7597}}</ref>

====Improved Grewe's cyclization====
Formylation of octabase prior to cyclization avoids ether cleavage as a side reaction and yields higher than without N-substitution or N-methylation. In this example, the purification was done by formation of a brucine salt.{{cn|date=August 2022}}

[[File:Synthesis of Dextromethorphan via improved Grewe's cyclization.svg|class=skin-invert-image|center|650px]]

This process has also been patented by Roche.

==History==
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,<ref name="Morris">{{cite journal | vauthors = Morris H, Wallach J | title = From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs | journal = Drug Testing and Analysis | volume = 6 | issue = 7–8 | pages = 614–632 | year = 2014 | pmid = 24678061 | doi = 10.1002/dta.1620 }}</ref> and dextromethorphan was successfully tested in 1954 as part of [[US Navy]] and [[CIA]]-funded research on nonaddictive substitutes for [[codeine]].<ref>{{cite web|url=http://www.esd.whs.mil/Portals/54/Documents/FOID/Reading%20Room/NCB/02-A-0846_RELEASE.pdf|title=Memorandum for the Secretary of Defense|archive-url=https://web.archive.org/web/20170916010918/http://www.esd.whs.mil/Portals/54/Documents/FOID/Reading%20Room/NCB/02-A-0846_RELEASE.pdf|archive-date=2017-09-16|url-status=live|access-date=2013-07-28}}</ref>{{Primary source inline|date=July 2024}} Dextromethorphan was approved by the FDA in 1958 as an [[over-the-counter]] antitussive.<ref name=Morris/> As had been initially hoped, dextromethorphan was a solution for some of the problems associated with the use of [[codeine phosphate]] as a cough suppressant, such as sedation and [[opioid dependence|opiate dependence]], but like the dissociative anesthetics [[phencyclidine]] and [[ketamine]], dextromethorphan later became associated with nonmedical use.<ref name="Morris"/><ref name="cesar">{{cite web|url=http://www.cesar.umd.edu/cesar/drugs/dxm.asp|title=Dextromethorphan (DXM)|publisher=Cesar.umd.edu|archive-url=https://web.archive.org/web/20180106073947/http://www.cesar.umd.edu/cesar/drugs/dxm.asp|archive-date=2018-01-06|access-date=2013-07-28}}</ref>

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.<ref name="cesar"/> The advent of widespread internet access in the 1990s allowed users to rapidly disseminate information about dextromethorphan, and online discussion groups formed around use and acquisition of the drug. As early as 1996, dextromethorphan hydrobromide powder could be purchased in bulk from online retailers, allowing users to avoid consuming dextromethorphan in syrup preparations.<ref name=Morris/>

FDA panels considered moving dextromethorphan to prescription status due to its potential for abuse, but voted against the recommendation in September 2010, citing lack of evidence that making it prescription-only would curb abuse.<ref>Nordqvist C. FDA panel: cough meds should stay over the counter. Sept. 14, 2010. Medical News Today Website. http://www.medicalnewstoday.com/articles/201227.php. Accessed May 18, 2020. </ref> Some states have restricted the sale of dextromethorphan to adults or put other restrictions on its purchase in place, similar to those for [[pseudoephedrine]]. 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.<ref name="urlwww.leginfo.ca.gov">{{cite web|url=http://www.leginfo.ca.gov/pub/11-12/bill/sen/sb_0501-0550/sb_514_bill_20110831_chaptered.pdf|title=Senate Bill No. 514|work=An act to add Sections 11110 and 11111 to the Health and Safety Code, relating to nonprescription drugs.|publisher=State of California, Legislative Counsel|archive-url=https://web.archive.org/web/20180308012049/http://www.leginfo.ca.gov/pub/11-12/bill/sen/sb_0501-0550/sb_514_bill_20110831_chaptered.pdf|archive-date=2018-03-08|url-status=live}}</ref> Several [[Dextromethorphan regulation by state|other states]] have also begun regulating sales of dextromethorphan to minors.

In [[Indonesia]], the [[National Agency of Drug and Food Control of Republic of Indonesia|National Agency of Drug and Food Control]] (BPOM-RI) prohibited single-component dextromethorphan drug sales with or without prescription. Indonesia is the only country that makes single-component dextromethorphan illegal over the counter and by prescription<ref>{{cite web | title = BPOM Tetap Batalkan Izin Edar Obat Dekstrometorfan | trans-title = BPOM Still Cancels Dextromethorphan Drug Distribution Permit | language = Indonesian | date = 22 May 2014 | work = VIVAnews | url = http://nasional.news.viva.co.id/news/read/506418-bpom-tetap-batalkan-izin-edar-obat-dekstrometorfan | archive-url = https://web.archive.org/web/20150528120821/http://nasional.news.viva.co.id/news/read/506418-bpom-tetap-batalkan-izin-edar-obat-dekstrometorfan |archive-date=2015-05-28 }}</ref> and violators may be prosecuted by law. [[National Anti-Narcotics Agency (Indonesia)|National Anti-Narcotics Agency (BNN RI)]] has threatened to revoke pharmacies' and drug stores' licenses if they still stock dextromethorphan, and will notify the police for criminal prosecution.<ref>{{cite web|url=http://daerah.sindonews.com/read/878465/21/bnn-ancam-tutup-apotek-penjual-dextromethorphan-1404129585%5B%5D|title=SINDOnews {{!}} Berita Daerah Dan Provinsi Di Indonesia|website=daerah.sindonews.com|language=id-ID|access-date=2017-12-10}} {{Dead link|date=March 2018}}</ref> As a result of this regulation, 130 medications have been withdrawn from the market, but those containing multicomponent dextromethorphan can still be sold over the counter.<ref>{{cite web|url=http://www.pom.go.id/files/edaran_dektrome_2013.pdf|title=Pimpinan dan Apoteker Penanggung Jawab|archive-url=https://web.archive.org/web/20170810021225/http://www.pom.go.id/files/edaran_dektrome_2013.pdf|archive-date=2017-08-10}}</ref><ref>{{cite web|url=http://www.pom.go.id/new/index.php/view/pers/231/Penjelasan-Terkait-Produk-Obat-Batuk-yang-Beredar--dan--Mengandung-Bahan-Dekstrometorfan-Tunggal-.html|title=Badan Pengawas Obat dan Makanan{{dash}}Republik Indonesia|website=www.pom.go.id|language=en-US|archive-url=https://web.archive.org/web/20170203184008/http://www.pom.go.id/new/index.php/view/pers/231/Penjelasan-Terkait-Produk-Obat-Batuk-yang-Beredar--dan--Mengandung-Bahan-Dekstrometorfan-Tunggal-.html|archive-date=2017-02-03|access-date=2017-12-10}}</ref>

==Society and culture==

===Marketing===
It may be used in [[generic drug|generic]] labels and [[store brand]]s, [[Benylin]] DM, Mucinex DM, Camydex-20 tablets, Robitussin, Komix DT, [[NyQuil]], [[Dimetapp]], [[Vicks]], [[Coricidin]], Delsym, [[TheraFlu]], Charcoal D, Cinfatós and others. It has been used in counterfeit medications.{{citation needed|date=August 2023}}

===Recreational use===
[[File:DXM Doses.jpg|thumb|upright=1.2|Dextromethorphan gel capsules]]
{{Main|Recreational use of dextromethorphan}}

[[Over-the-counter substance|Over-the-counter]] preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug.<ref name="cesar" /> At doses much higher than medically recommended, dextromethorphan and its major metabolite, [[dextrorphan]], acts as an [[NMDA receptor antagonist]], which produces dissociative [[hallucinogenic drug|hallucinogenic]] states somewhat similar to [[ketamine]] and [[phencyclidine]].<ref name=dea1>{{cite web |url=http://www.deadiversion.usdoj.gov/drugs_concern/dextro_m/dextro_m.pdf |archive-url=https://web.archive.org/web/20121016221008/http://www.deadiversion.usdoj.gov/drugs_concern/dextro_m/dextro_m.pdf |url-status=dead |archive-date=2012-10-16 |title=Dextromethorphan |work=Drugs and Chemicals of Concern |publisher=[[Drug Enforcement Administration]] |date=August 2010 }}</ref>

It may produce distortions of the visual field, feelings of [[Dissociation (psychology)|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 numbered from one to four, with the first having the mildest effects to fourth being the most intense. Each plateau is said to come with different related effects and experiences.<ref name="Giannini_1997">{{cite book | vauthors = Giannini AJ | title = Drugs of abuse | date = 1997 | publisher = Practice Management Information Corp. | location = Los Angeles | isbn = 1570660530 | edition = 2nd }}{{Page needed|date=March 2011}}</ref>

The first plateau is said to induce music euphoria and mild stimulation, likened to that of [[MDMA]]. The second plateau is likened to a state of being on moderate amounts of [[alcohol (drug)|alcohol]] and [[cannabis (drug)|cannabis]] at the same time, featuring euphoria, sedation and minor hallucinations. The third plateau induces a significant dissociative state which can often cause anxiety in users. Reaching the fourth plateau is said to cause extreme sedation and a significant hallucinatory state as well as complete dissociation from reality. Teenagers tend to have a higher likelihood to use dextromethorphan-related drugs as they are easier to access; youths and young adults with psychiatric disorders are at risk of abusing the drug.<ref>{{cite journal| vauthors = Akerman SC, Hammel JL, Brunette MF |date=2010-12-20|title=Dextromethorphan Abuse and Dependence in Adolescents|journal=Journal of Dual Diagnosis|volume=6|issue=3–4|pages=266–278|doi=10.1080/15504263.2010.537515|s2cid=70666093}}</ref>

==Research==
The combination drug [[dextromethorphan/quinidine]] (AVP-923),<ref name="pmid20373255">{{cite journal | vauthors = Olney N, Rosen H | title = AVP-923, a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect and neuropathic pain | journal = IDrugs | volume = 13 | issue = 4 | pages = 254–265 | date = April 2010 | pmid = 20373255 | doi = }}</ref><ref name="pmid33615952">{{cite journal | vauthors = Khoury R, Marx C, Mirgati S, Velury D, Chakkamparambil B, Grossberg GT | title = AVP-786 as a promising treatment option for Alzheimer's Disease including agitation | journal = Expert Opinion on Pharmacotherapy | volume = 22 | issue = 7 | pages = 783–795 | date = May 2021 | pmid = 33615952 | doi = 10.1080/14656566.2021.1882995 | s2cid = 231987025 }}</ref> traditionally used to treat [[pseudobulbar affect]], is under investigation for the treatment of a variety of other neurological and neuropsychiatric conditions including [[agitation (dementia)|agitation]] associated with [[Alzheimer's disease]], among others.<ref name="NguyenThomas2016" /><ref>{{cite journal | vauthors = Murrough JW, Wade E, Sayed S, Ahle G, Kiraly DD, Welch A, Collins KA, Soleimani L, Iosifescu DV, Charney DS | title = Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial | journal = Journal of Affective Disorders | volume = 218 | pages = 277–283 | date = August 2017 | pmid = 28478356 | doi = 10.1016/j.jad.2017.04.072 | s2cid = 46777150 }}</ref> In 2013, a randomized clinical trial found that dextromethorphan may 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 reducing severity of symptoms compared to clonidine alone.<ref>{{cite journal | vauthors = Malek A, Amiri S, Habibi Asl B | title = The therapeutic effect of adding dextromethorphan to clonidine for reducing symptoms of opioid withdrawal: a randomized clinical trial | journal = ISRN Psychiatry | volume = 2013 | pages = 546030 | year = 2013 | pmid = 23864983 | pmc = 3706070 | doi = 10.1155/2013/546030 | doi-access = free | title-link = doi }}</ref>

==References==
{{Reflist}}

==External links==
{{Commons category-inline}}
* {{cite web | url=https://www.dea.gov/factsheets/dxm | publisher = Drug Enforcement Administration (DEA) | title = DXM}}

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