{{Short description|Psychoactive cough suppressant medication}} {{Distinguish|Dextromethorphan|Dextrallorphan}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | class = Cough suppressant; NMDA receptor antagonist; Serotonin-norepinephrine reuptake inhibitor; Dissociative hallucinogen | verifiedrevid = 408496712 | IUPAC_name = (+)-17-methyl-9a,13a,14a-morphinan-3-ol | image = Dextrorphan.svg | image_class = skin-invert-image
<!--Clinical data-->| tradename = | legal_US = Unscheduled<ref>{{Cite web |last=Bensinger |first=Peter |date=October 1, 1976 |title=Dextrophan and Nalbuphine; Removal from Schedules |url=https://www.govinfo.gov/content/pkg/FR-1976-10-01/pdf/FR-1976-10-01.pdf |access-date=June 26, 2023 |website=NARA}}</ref>
<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 125-73-5 | ATC_prefix = None | PubChem = 5360697 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = 04B7QNO9WS | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1254766 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 10489895 | synonyms = DXO, Dextrorphanol
<!--Chemical data-->| C = 17 | H = 23 | N = 1 | O = 1 | SMILES = CN1CC[C@@]23CCCC[C@@H]2[C@@H]1Cc4c3cc(O)cc4 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C17H23NO/c1-18-9-8-17-7-3-2-4-14(17)16(18)10-12-5-6-13(19)11-15(12)17/h5-6,11,14,16,19H,2-4,7-10H2,1H3/t14-,16+,17+/m1/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = JAQUASYNZVUNQP-PVAVHDDUSA-N }}
'''Dextrorphan''' ('''DXO''') is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and in high doses a dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6. Dextrorphan is an NMDA antagonist and contributes to the psychoactive effects of dextromethorphan.<ref>{{cite journal | vauthors = Zawertailo LA, Kaplan HL, Busto UE, Tyndale RF, Sellers EM | title = Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study | journal = Journal of Clinical Psychopharmacology | volume = 18 | issue = 4 | pages = 332–337 | date = August 1998 | pmid = 9690700 | doi = 10.1097/00004714-199808000-00014 }}</ref>
==Pharmacology==
===Pharmacodynamics=== {| class="wikitable floatleft" style="font-size:small;" |+ Dextrorphan<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=dextrorphan&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref><ref name="pmid26826604">{{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 = Pharmacol. Ther. | volume = 159 | pages = 1–22 | year = 2016 | pmid = 26826604 | doi = 10.1016/j.pharmthera.2016.01.016 | doi-access = free }}</ref><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 = Exp. Neurol. | volume = 207 | issue = 2 | pages = 248–57 | year = 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 = Pharmacol. Ther. | volume = 164 | pages = 170–82 | year = 2016 | pmid = 27139517 | doi = 10.1016/j.pharmthera.2016.04.010 | doi-access = free }}</ref> |- ! Site !! K<sub>i</sub> (nM) !! Species !! Ref |- | {{abbr|NMDAR|N-Methyl-D-aspartate receptor}}<br />(MK-801) || 486–906 || Rat || <ref name="pmid26826604" /> |- | σ<sub>1</sub> || 118–481 || Rat || <ref name="pmid26826604" /> |- | σ<sub>2</sub> || 11,325–15,582 || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|MOR|μ-Opioid receptor}} || 420<br />>1,000 || Rat<br />Human || <ref name="pmid26826604" /><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 = J. Pharmacol. Exp. Ther. | volume = 272 | issue = 1 | pages = 423–8 | year = 1995 | doi = 10.1016/S0022-3565(25)24351-8 | pmid = 7815359 }}</ref> |- | {{abbrlink|DOR|δ-Opioid receptor}} || 34,700 || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|KOR|κ-Opioid receptor}} || 5,950 || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|SERT|Serotonin transporter}} || 401–484 || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|NET|Norepinephrine transporter}} || ≥340 || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|DAT|Dopamine transporter}} || >1,000 || Rat || <ref name="pmid26826604" /> |- | 5-HT<sub>1A</sub> || >1,000 || Rat || <ref name="pmid26826604" /> |- | 5-HT<sub>1B</sub><sub>/</sub><sub>1D</sub> || 54% at 1 μM || Rat || <ref name="pmid26826604" /> |- | 5-HT<sub>2A</sub> || >1,000 || Rat || <ref name="pmid26826604" /> |- | α<sub>1</sub> ||>1,000 || Rat || <ref name="pmid26826604" /> |- | α<sub>2</sub> || >1,000 || Rat || <ref name="pmid26826604" /> |- | β || 35% at 1 μM || Rat || <ref name="pmid26826604" /> |- | D<sub>2</sub> || >1,000 || Rat || <ref name="pmid26826604" /> |- | H<sub>1</sub> || 95% at 1 μM || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|mAChRs|Muscarinic acetylcholine receptors}} || 100% at 1 μM || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|nAChRs|Nicotinic acetylcholine receptors}} || 1,300–29,600<br />(IC<sub>50</sub>) || Rat || <ref name="pmid26826604" /> |- | {{abbrlink|VDSCs|Voltage-dependent sodium channels}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} |- class="sortbottom" | colspan="4" 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. |}
The pharmacology of dextrorphan is similar to that of dextromethorphan (DXM). However, dextrorphan is much more potent as an NMDA receptor antagonist and much less active as a serotonin reuptake inhibitor, but retains DXM's activity as a norepinephrine reuptake inhibitor.<ref>{{cite journal | vauthors = Pechnick RN, Poland RE | title = Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 309 | issue = 2 | pages = 515–522 | date = May 2004 | pmid = 14742749 | doi = 10.1124/jpet.103.060038 | s2cid = 274504 }}</ref> It also has more affinity for the opioid receptors than dextromethorphan, significantly so at high doses.
===Pharmacokinetics=== Dextrorphan has a notably longer elimination half-life than its parent compound, and therefore has a tendency to accumulate in the blood after repeated administration of normally dosed dextromethorphan formulations.{{citation needed|date=November 2016}} It is further converted to 3-HM by CYP3A4 or glucuronidated.<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 = 1514–20 | date = November 2001 | pmid = 11602530 | url = http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11602530 | archive-date = 2020-03-12 | access-date = 2021-04-22 | archive-url = https://web.archive.org/web/20200312134718/http://dmd.aspetjournals.org/content/29/11/1514.long | url-status = dead }}</ref>
==Society and culture==
===Legal status=== Dextrorphan was formerly a Schedule I controlled substance in the United States, but was unscheduled on October 1, 1976.<ref name="urlDextrorphan Legality">{{cite web | url = http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | title = Lists of: Scheduling Actions Controlled Substances Regulated Chemicals | author = DEA | access-date = 2010-09-24 | archive-date = 2016-04-17 | archive-url = https://web.archive.org/web/20160417085648/http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf | url-status = dead }}</ref>
==Research== Dextrorphan was under development for the treatment of stroke, and reached phase II clinical trials for this indication, but development was discontinued.<ref name="AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800009336|title = Dextrorphan - AdisInsight}}</ref>
==Environmental presence== In 2021, dextrorphan was identified in >75% of sludge samples taken from 12 wastewater treatment plants in California. The same study associated dextrorphan with estrogenic activity by using predictive modelling, before observing it in in vitro.<ref name=Black2021>{{cite journal | vauthors = Black GP, He G, Denison MS, Young TM | title = Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge | journal = Environmental Science & Technology | volume = 55 | issue = 10 | pages = 6729–6739 | date = May 2021 | pmid = 33909413 | pmc = 8378343 | doi = 10.1021/acs.est.0c07846 | bibcode = 2021EnST...55.6729B }}</ref>
{{Clear}}
== See also == * Cough syrup * Racemorphan; Levorphanol * Noscapine * Codeine; Pholcodine * Dextromethorphan; Dimemorfan * Butamirate * Pentoxyverine * Tipepidine * Cloperastine
==References== {{Reflist|2}}
{{Antitussives}} {{Navboxes | title = Recreational uses | titlestyle = background:#ccccff | list1 = {{Drug use}} {{Dissociatives}} }} {{Navboxes | title = Pharmacodynamics | titlestyle = background:#ccccff | list1 = {{Ionotropic glutamate receptor modulators}} {{Monoamine reuptake inhibitors}} {{Nicotinic acetylcholine receptor modulators}} {{Opioid receptor modulators}} {{Sigma receptor modulators}} }}
Category:Antitussives Category:Dissociative drugs Category:Enantiopure drugs Category:Euphoriants Category:Morphinans Category:Mu-opioid receptor agonists Category:Nicotinic antagonists Category:NMDA receptor antagonists Category:Hydroxyarenes Category:Serotonin–norepinephrine reuptake inhibitors Category:Sigma agonists Category:Human drug metabolites Category:Recreational drug metabolites