1,185
Views
23
CrossRef citations to date
0
Altmetric
Review Articles

Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects

&
Pages 258-282 | Received 27 Dec 2019, Accepted 07 Apr 2020, Published online: 12 May 2020

References

  • Aarnoutse RE, Kleinnijenhuis J, Koopmans PP, Touw DJ, Wieling J, Hekster YA, Burger DM. 2005. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers. Clin Pharmacol Ther. 78(6):664–674.
  • Abanades S, Peiro AM, Farre M. 2004. Club drugs: old medicines as new party drugs. Med Clin (Barc). 123(8):305–311.
  • Abduljalil K, Frank D, Gaedigk A, Klaassen T, Tomalik-Scharte D, Jetter A, Jaehde U, Kirchheiner J, Fuhr U. 2010. Assessment of activity levels for CYP2D6* 1, CYP2D6* 2, and CYP2D6* 41 genes by population pharmacokinetics of dextromethorphan. Clin Pharmacol Ther. 88(5):643–651.
  • Agnich LE, Stogner JM, Miller BL, Marcum CD. 2013. Purple drank prevalence and characteristics of misusers of codeine cough syrup mixtures. Addict Behav. 38(9):2445–2449.
  • Ahmed M, Malik M, Teselink J, Lanctôt KL, Herrmann N. 2019. Current agents in development for treating behavioral and psychological symptoms associated with dementia. Drugs Aging. 36(7):589–605.
  • Aiyer R, Mehta N, Gungor S, Gulati A. 2018. A systematic review of NMDA receptor antagonists for treatment of neuropathic pain in clinical practice. Clin J Pain. 34(5):450–467.
  • Al-Jenoobi FI, Al-Thukair AA, Alam MA, Abbas FA, Al-Mohizea AM, Alkharfy KM, Al-Suwayeh SA. 2015. Effect of Curcuma longa on CYP2D6-and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects. Eur J Drug Metab Pharmacokinet. 40(1):61–66.
  • Aumatell A, Wells RJ. 1993. Chiral differentiation of the optical isomers of racemethorphan and racemorphan in urine by capillary zone electrophoresis. J Chromatogr Sci. 31(12):502–508.
  • Aytha SK, Dannaram S, Moorthy S, Sharma A. 2013. A case of acute psychosis secondary to coricidin overdose. Prim Care Companion CNS Disord. 15(6): PCC.13l01549. DOI:10.4088/PCC.13l01549
  • Bailey B, Daneman R, Daneman N, Mayer JM, Koren G. 2000. Discrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level. Forensic Sci Int. 110(1):61–70.
  • Baldo BA. 2018. Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Arch Toxicol. 92(8):2457–2473.
  • Banerji S, Anderson IB. 2001. Abuse of Coricidin HBP cough & cold tablets: episodes recorded by a poison center. Am J Health Syst Pharm. 58(19):1811–1814.
  • Banken JA, Foster H. 2008. Dextromethorphan: an emerging drug of abuse. Ann N Y Acad Sci. 1139(1):402–411.
  • Barnhart JW, Massad EN. 1979. Determination of dextromethorphan in serum by gas chromatography. J Chromatogr. 163(4):390–395.
  • Battin DG, Varkey TA. 1982. Neuropsychiatric manifestations of bromide ingestion. Postgrad Med J. 58(682):523–524.
  • Bem JL, Peck R. 1992. Dextromethorphan. An overview of safety issues. Drug Saf. 7(3):190–199.
  • Bi S, Zhou H, Wu J, Wang Y. 2018. Interaction of dextromethorphan hydrobromide with DNA: multispectral, voltammetric, and molecular docking technology. J Biomol Struct Dyn. 36(5):1154–1160.
  • Bisaga A, Popik P. 2000. In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-d-aspartate (NMDA) antagonists. Drug Alcohol Depend. 59(1):1–15.
  • Bjoraker KJ, Swanson MA, Coughlin CR, Christodoulou J, Tan ES, Fergeson M, Dyack S, Ahmad A, Friederich MW, Spector EB, et al. 2016. Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycinemia. J Pediatr. 170:234–239.
  • Boland DM, Rein J, Lew EO, Hearn WL. 2003. Fatal cold medication intoxication in an infant. J Anal Toxicol. 27(7):523–526.
  • Bolser DC. 2006. Current and future centrally acting antitussives. Respir Physiol Neurobiol. 152(3):349–355.
  • Bortolotti F, Bertaso A, Gottardo R, Musile G, Tagliaro F. 2013. Dextromethorphan/levomethorphan issues in a case of opiate overdose. Drug Test Anal. 5(9–10):781–784.
  • Braga PC, Fossati A, Vimercati MG, Caputo R, Guffanti EE. 1994. Dextrorphan and dextromethorphan: comparative antitussive effects on guinea pigs. Drugs Exp Clin Res. 20(5):199–203.
  • Brown C, Fezoui M, Selig WM, Schwartz CE, Ellis JL. 2004. Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 141(2):233–240.
  • Brown GR, McLaughlin K, Vaughn K. 2018. Identifying and treating patients with synthetic psychoactive drug intoxication. J Am Acad PAs. 31:1–5.
  • Bryner JK, Wang UK, Hui JW, Bedodo M, MacDougall C, Anderson IB. 2006. Dextromethorphan abuse in adolescence: an increasing trend: 1999–2004. Arch Pediatr Adolesc Med. 160(12):1217–1222.
  • Burton M, Shaw L, Schentag J, Evans W. 2006. Applied pharmacokinetics and pharmacodynamics: principles of therapeutic drug monitoring. Philadelphia: Lippincott Williams & Wilkins.
  • Capon DA, Bochner F, Kerry N, Mikus G, Danz C, Somogyi AA. 1996. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther. 60(3):295–307.
  • Cazet L, Bulteau S, Evin A, Spiers A, Caillet P, Kuhn E, Pivette J, Chaslerie A, Jolliet P, Victorri-Vigneau C. 2018. Interaction between CYP2D6 inhibitor antidepressants and codeine: is this relevant? Expert Opin Drug Metab Toxicol. 14(8):879–886.
  • Chen S-L, Huang E-K, Chow L-H, Tao P-L. 2005. Dextromethorphan differentially affects opioid antinociception in rats. Br J Pharmacol. 144(3):400–404.
  • Chez M, Kile S, Lepage C, Parise C, Benabides B, Hankins A. 2018. A randomized, placebo-controlled, blinded, crossover, pilot study of the effects of dextromethorphan/quinidine for the treatment of neurobehavioral symptoms in adults with autism. J Autism Dev Disord. DOI:10.1007/s10803-018-3703-x.
  • Chou Y-C, Liao J-F, Chang W-Y, Lin M-F, Chen C-F. 1999. Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Res. 821(2):516–519.
  • Chung HS, Choi HK, Kim EM, Park MJ, Chung KH, Yoo YC. 1998. Demographic characteristics of zipeprol-associated deaths in Korea. Arch Pharm Res. 21(3):286–290.
  • Church J, Jones MG, Davies SN, Lodge D. 1989. Antitussive agents as N-methylaspartate antagonists: further studies. Can J Physiol Pharmacol. 67(6):561–567.
  • Church J, Lodge D, Berry SC. 1985. Differential effects of dextrorphan and levorphanol on the excitation of rat spinal neurons by amino acids. Eur J Pharmacol. 111(2):185–190.
  • Chyka PA, Erdman AR, Manoguerra AS, Christianson G, Booze LL, Nelson LS, Woolf AD, Cobaugh DJ, Caravati EM, Scharman EJ, et al. 2007. Dextromethorphan poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 45(6):662–677.
  • Cochems A, Harding P, Liddicoat L. 2007. Dextromethorphan in Wisconsin drivers. J Anal Toxicol. 31(4):227–232.
  • Collins SR. 2018. Mosby’s drug reference for health professions. St. Louis: Elsevier, Inc.
  • Cornish JW, Herman BH, Ehrman RN, Robbins SJ, Childress AR, Bead V, Esmonde CA, Martz K, Poole S, Caruso FS, et al. 2002. A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug Alcohol Depend. 67(2):177–183.
  • Coutts RT, Su P, Baker GB. 1994. Involvement of CYP2D6, CYP3A4, and other cytochrome P-450 isozymes in N-dealkylation reactions. J Pharmacol Toxicol Methods. 31(4):177–186.
  • de la Torre R, Farre M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Cami J. 2004. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit. 26(2):137–144.
  • Dematteis M, Lallement G, Mallaret M. 1998. Dextromethorphan and dextrorphan in rats: common antitussives — different behavioural profiles. Fundam Clin Pharmacol. 12(5):526–537.
  • Desai S, Aldea D, Daneels E, Soliman M, Braksmajer AS, Kopes-Kerr CP. 2006. Chronic addiction to dextromethorphan cough syrup: a case report. J Am Board Fam Med. 19(3):320–323.
  • Desmeules JA, Oestreicher MK, Piguet V, Allaz AF, Dayer P. 1999. Contribution of cytochrome P-4502D6 phenotype to the neuromodulatory effects of dextromethorphan. J Pharmacol Exp Ther. 288(2):607–612.
  • Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. 2002. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci. 71(10):1149–1160.
  • Dickerson DL, Schaepper MA, Peterson MD, Ashworth MD. 2008. Coricidin HBP abuse: patient characteristics and psychiatric manifestations as recorded in an inpatient psychiatric unit. J Addict Dis. 27(1):25–32.
  • Dilich A, Girgis C. 2017. Robo-tripping: a case of robitussin abuse in a methadone maintenance patient. Psychosomatics. 58(5):544–550.
  • Dinis-Oliveira RJ. 2016. Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response. Drug Metabol Rev. 48(4):568–576.
  • Dinis-Oliveira RJ. 2017. Metabolism and metabolomics of ketamine: a toxicological approach. Forensic Sci Res. 2(1):2–10.
  • Dinis-Oliveira RJ. 2019. Metabolism and metabolomics of opiates: a long way of forensic implications to unravel. J Forensic Legal Med. 61:128–140.
  • Dinis-Oliveira RJ, Carvalho F, Duarte JA, Dias R, Magalhães T, Santos A. 2010. Suicide by hanging under the influence of ketamine and ethanol. Forensic Sci Int. 202(1–3):e23–e27.
  • DuBois BN, Mehvar R. 2018. UPLC–MS/MS analysis of dextromethorphan-O-demethylation kinetics in rat brain microsomes. J Chromatogr B. 1096:66–72.
  • Duedahl TH, Dirks J, Petersen KB, Romsing J, Larsen N-E, Dahl JB. 2005. Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect. Pain. 113:360–368.
  • Dy P, Arcega V, Ghali W, Wolfe W. 2017. Serotonin syndrome caused by drug to drug interaction between escitalopram and dextromethorphan. BMJ Case Rep. 2017:bcr2017221486.
  • El-Naby EH, Kamel AH. 2015. Potential transducers based man-tailored biomimetic sensors for selective recognition of dextromethorphan as an antitussive drug. Mater Sci Eng C. 54:217–224.
  • Emancipator K, Kroll MH. 1990. Bromide interference: is less really better? Clin Chem. 36(8):1470–1473.
  • Farmer AD, Holt CB, Downes TJ, Ruggeri E, Del Vecchio S, De Giorgio R. 2018. Pathophysiology, diagnosis, and management of opioid-induced constipation. Lancet Gastroenterol Hepatol. 3(3):203–212.
  • Fluyau D, Revadigar N, Pierre CG. 2020. Clinical benefits and risks of N-methyl-d-aspartate receptor antagonists to treat severe opioid use disorder: a systematic review. Drug Alcohol Depend. 208:107845.
  • Forget P, de Waroux BP, Wallemacq P, Gala J-L. 2008. Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer: a single case re-exposure study. J Pain Symptom Manage. 36(1):92–96.
  • Fralick M, Sacks CA, Kesselheim AS. 2019. Assessment of use of combined dextromethorphan and quinidine in patients with dementia or Parkinson disease after US Food and Drug Administration approval for pseudobulbar affect. JAMA Intern Med. 179(2):224–230.
  • Frances C, Hoizey G, Lamiable D, Millart H, Trenque T. 2003. Bromism from daily over intake of bromide salt. J Toxicol Clin Toxicol. 41(2):181–183.
  • Franklin PH, Murray TF. 1992. High affinity [3H]dextrorphan binding in rat brain is localized to a noncompetitive antagonist site of the activated N-methyl-d-aspartate receptor-cation channel. Mol Pharmacol. 41(1):134–146.
  • Gaedigk A. 2013. Complexities of CYP2D6 gene analysis and interpretation. Int Rev Psychiatry. 25(5):534–553.
  • Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE, the PharmVar Steering Committee. 2018. The Pharmacogene Variation (PharmVar) Consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther. 103(3):399–401.
  • Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. 2017. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 19(1):69–76.
  • Gaikwad R, Gaonkar R, Jadhav S, Thorat V, Jadhav J, Balsara J. 2005. Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats. Indian J Exp Biol. 43(7):620–625.
  • Gao Z, Yu L, Clark S, Trehy M, Moore T, Westenberger B, Buhse L, Kauffman J, Bishop B, Velazquez L, et al. 2015. Dissolution testing for bioavailability of over-the-counter (OTC) drugs—a technical note. AAPS PharmSciTech. 16(5):1227–1233.
  • Garnock-Jones KP. 2011. Dextromethorphan/quinidine: in pseudobulbar affect. CNS Drugs. 25(5):435–445.
  • Gazzaz M, Kinzig M, Schaeffeler E, Jubner M, Hsin CH, Li X, Taubert M, Trueck C, Iltgen-Breburda J, Kraus D, et al. 2018. Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2, and P-glycoprotein activities but somewhat inhibits CYP1A2, CYP2D6, and intestinal CYP3A: so what? Clin Pharmacol Ther. 104(6):1249–1259.
  • Glass SM, Leddy SM, Orwin MC, Miller GP, Furge KA, Furge LL. 2019. Rolapitant is a reversible inhibitor of CYP2D6. Drug Metab Dispos. 47(6):567–573.
  • Glick SD, Maisonneuve IM, Dickinson HA, Kitchen BA. 2001. Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine, and nicotine self-administration in rats. Eur J Pharmacol. 422(1–3):87–90.
  • Grattan T, Marshall A, Higgins K, Morice A. 1995. The effect of inhaled and oral dextromethorphan on citric acid induced cough in man. Br J Clin Pharmacol. 39(3):261–263.
  • Gudin J, Fudin J, Nalamachu S. 2016. Levorphanol use: past, present and future. Postgrad Med. 128(1):46–53.
  • Gunn VL, Taha SH, Liebelt EL, Serwint JR. 2001. Toxicity of over-the-counter cough and cold medications. Pediatrics. 108(3):e52.
  • Gutierrez Rico EM, Kikuchi A, Saito T, Kumondai M, Hishinuma E, Kaneko A, Chan CW, Gitaka J, Nakayoshi T, Oda A, et al. 2020. CYP2D6 genotyping analysis and functional characterization of novel allelic variants in a Ni-Vanuatu and Kenyan population by assessing dextromethorphan O-demethylation activity. Drug Metab Pharmacokinet. 35(1):89–101.
  • Hart M, Agnich LE, Stogner J, Miller BL. 2014. ‘Me and My Drank:’ exploring the relationship between musical preferences and purple drank experimentation. Am J Crim Just. 39(1):172–186.
  • Hendrickson RG, Cloutier RL. 2007. “Crystal dex:” free-base dextromethorphan. J Emerg Med. 32(4):393–396.
  • Hou ZY, Pickle LW, Meyer PS, Woosley RL. 1991. Salivary analysis for determination of dextromethorphan metabolic phenotype. Clin Pharmacol Ther. 49(4):410–419.
  • Hou C-H, Tzeng J-I, Chen Y-W, Lin C-N, Lin M-T, Tu C-H, Wang J-J. 2006. Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats. Eur J Pharmacol. 544(1–3):10–16.
  • Howden CW, Birnie GG, Brodie MJ. 1989. Drug metabolism in liver disease. Pharmacol Ther. 40(3):439–474.
  • Hsieh PF, Tsan YT, Hung DZ, Hsu CL, Lee YC, Chang MH. 2007. Bromism caused by mix-formulated analgesic injectables. Hum Exp Toxicol. 26(12):971–973.
  • Hung Y-M. 2003. Bromide intoxication by the combination of bromide-containing over-the-counter drug and dextromethorphan hydrobromide. Hum Exp Toxicol. 22(8):459–461.
  • Ishmael JE, Franklin PH, Murray TF. 1998. Dextrorotatory opioids induce stereotyped behavior in Sprague-Dawley and Dark Agouti rats. Psychopharmacology. 140(2):206–216.
  • Jacqz-Aigrain E, Funck-Brentano C, Cresteil T. 1993. CYP2D6-and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics. 3:197–204.
  • James LP, Farrar HC, Griebel ML, Bates SR. 1997. Bromism: intoxication from a rare anticonvulsant therapy. Pediatr Emerg Care. 13(4):268–270.
  • Jasinski DR. 2000. Abuse potential of morphine/dextromethorphan combinations. J Pain Symptom Manage. 19(1):S26–S30.
  • Jayachandra S, Sethi MK, Mahajan S, Singh KS, Mara B, Chakraborty P. 2018. Preparation of morphine derivatives using ionic liquids. Arc Org Inorg Chem Sci. 3(2):ID: 000156. DOI:10.32474/AOICS.2018.03.000156
  • Jetter A, Fatkenheuer G, Frank D, Klaassen T, Seeringer A, Doroshyenko O, Kirchheiner J, Hein W, Schomig E, Fuhr U, et al. 2010. Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients? Antivir Ther. 15(7):975–983.
  • Kamei J. 1996. Role of opioidergic and serotonergic mechanisms in cough and antitussives. Pulm Pharmacol. 9(5–6):349–356.
  • Kanaan M, Daali Y, Dayer P, Desmeules J. 2008. Lack of interaction of the NMDA receptor antagonists dextromethorphan and dextrorphan with P-glycoprotein. Curr Drug Metab. 9(2):144–151.
  • Kaplan B, Buchanan J, Krantz MJ. 2011. QTc prolongation due to dextromethorphan. Int J Cardiol. 148(3):363–364.
  • Karami S, Major JM, Calderon S, McAninch JK. 2018. Trends in dextromethorphan cough and cold products: 2000–2015 National Poison Data System intentional abuse exposure calls. Clin Toxicol. 56(7):656–663.
  • Karch SB. 2008. Pharmacokinetics and pharmacodynamics of abused drugs. Boca Raton (FL): CRC Press.
  • Karch SB, Drummer OH. 2016. Karch’s pathology of drug abuse. Boca Raton: CRC Press, Taylor & Francis Group.
  • Kazis A, Kimiskidis V, Niopas I. 2009. Pharmacokinetics of dextromethorphan and dextrorphan in epileptic patients. Acta Neurol Scand. 93(2–3):94–98.
  • Kerry N, Somogyi A, Bochner F, Mikus G. 1994. The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes. Br J Clin Pharmacol. 38(3):243–248.
  • Kinoshita H, Ohkubo T, Yasuda M, Yakushiji F. 2011. Serotonin syndrome induced by dextromethorphan (Medicon) administrated at the conventional dose. Geriatr Gerontol Int. 11(1):121–122.
  • Kintz P, Mangin P. 1992. Toxicological findings in a death involving dextromethorphan and terfenadine. Am J Forensic Med Pathol. 13:351–352.
  • Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA. 1997. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos. 25:853–862.
  • Kongpakwattana K, Sawangjit R, Tawankanjanachot I, Bell JS, Hilmer SN, Chaiyakunapruk N. 2018. Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis. Br J Clin Pharmacol. 84(7):1445–1456.
  • Kunze U. 1976. Chronic bromide intoxication with a severe neurological deficit. J Neurol. 213(2):149–152.
  • Küpfer A, Preisig R. 1983. Inherited defects of hepatic drug metabolism. Semin Liver Dis. 3(4):341–354.
  • Larrey D, Amouyal G, Tinel M, Letteron P, Berson A, Labbe G, Pessayre D. 1987. Polymorphism of dextromethorphan oxidation in a French population. Br J Clin Pharmacol. 24(5):676–679.
  • Larrey D, Babany G, Tinel M, Freneaux E, Amouyal G, Habersetzer F, Letteron P, Pessayre D. 1989. Effect of liver disease on dextromethorphan oxidation capacity and phenotype: a study in 107 patients. Br J Clin Pharmacol. 28(3):297–304.
  • Le Rouzic V, Narayan A, Hunkle A, Marrone GF, Lu Z, Majumdar S, Xu J, Pan Y-X, Pasternak GW. 2019. Pharmacological characterization of levorphanol, a G-protein biased opioid analgesic. Anesth Analg. 128(2):365–373.
  • Lee S-Y, Chen S-L, Chang Y-H, Chu C-H, Chen S-H, Chen PS, Huang S-Y, Tzeng N-S, Wang L-J, Lee IH, et al. 2015. A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment. Int J Neuropsychopharmacol. 18(7):pyv008.
  • Logan BK. 2009. Combined dextromethorphan and chlorpheniramine intoxication in impaired drivers. J Forensic Sci. 54(5):1176–1180.
  • Logan BK, Goldfogel G, Hamilton R, Kuhlman J. 2009. Five deaths resulting from abuse of dextromethorphan sold over the internet. J Anal Toxicol. 33(2):99–103.
  • Logan BK, Yeakel JK, Goldfogel G, Frost MP, Sandstrom G, Wickham DJ. 2012. Dextromethorphan abuse leading to assault, suicide, or homicide. J Forensic Sci. 57(5):1388–1394.
  • Lotrich FE, Rosen J, Pollock BG. 2005. Dextromethorphan-induced delirium and possible methadone interaction. Am J Geriatr Pharmacother. 3(1):17–20.
  • Loyd V, Allen J, Ansel HC. 2014. Ansel’s pharmaceutical dosage forms and drug delivery systems. Philadelphia: Lippincott Williams & Wilkins.
  • Lutz JD, Isoherranen N. 2012. Prediction of relative in vivo metabolite exposure from in vitro data using two model drugs: dextromethorphan and omeprazole. Drug Metab Dispos. 40(1):159–168.
  • Maffeis L, Musolino MC, Cambiaghi S. 2008. Single-plaque vegetating bromoderma. J Am Acad Dermatol. 58(4):682–684.
  • Marier J-F, Deschênes J-L, Hage A, Seliniotakis E, Gritsas A, Flarakos T, Beaudry F, Vachon P. 2005. Enhancing the uptake of dextromethorphan in the CNS of rats by concomitant administration of the P-gp inhibitor verapamil. Life Sci. 77(23):2911–2926.
  • Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J. 2005. Over-the-counter cold medications—postmortem findings in infants and the relationship to cause of death. J Anal Toxicol. 29(7):738–743.
  • Martinak B, Bolis RA, Black JR, Re F, Birur B. 2017. Dextromethorphan in cough syrup: the poor man’s psychosis. Psychopharmacol Bull. 47:59–63.
  • McQueen C. 2017. Comprehensive toxicology. 3rd ed. Amsterdam: Elsevier Science.
  • Meoni P, Tortella F, Bowery N. 1997. An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine. Br J Pharmacol. 120(7):1255–1262.
  • Meyer UA, Skoda RC, Zanger UM. 1990. The genetic polymorphism of debrisoquine/sparteine metabolism—molecular mechanisms. Pharmacol Ther. 46(2):297–308.
  • Miller S. 2005. Dextromethorphan psychosis, dependence and physical withdrawal. Addict Biol. 10(4):325–327.
  • Morrison LM, Unger KA, Watterson JH. 2017. Analysis of dextromethorphan and dextrorphan in skeletal remains following differential microclimate exposure: comparison of acute vs. repeated drug exposure. J Anal Toxicol. 41(6):566–572.
  • Mortimer O, Lindstrom B, Laurell H, Bergman U, Rane A. 1989. Dextromethorphan: polymorphic serum pattern of the O-demethylated and didemethylated metabolites in man. Br J Clin Pharmacol. 27(2):223–227.
  • Moss MJ, Hendrickson RG, Toxicology Investigators C. 2019. Serotonin toxicity: associated agents and clinical characteristics. J Clin Psychopharmacol. 39(6):628–633.
  • Nagai N, Kawakubo T, Kaneko F, Ishii M, Shinohara R, Saito Y, Shimamura H, Ohnishi A, Ogata H. 1996. Pharmacokinetics and polymorphic oxidation of dextromethorphan in a Japanese population. Biopharm Drug Dispos. 17(5):421–433.
  • Netzer R, Pflimlin P, Trube G. 1993. Dextromethorphan blocks N-methyl-d-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. Eur J Pharmacol. 238(2–3):209–216.
  • Ng YY, Lin WL, Chen TW, Lin BC, Tsai SH, Chang CC, Huang TP. 1992. Spurious hyperchloremia and decreased anion gap in a patient with dextromethorphan bromide. Am J Nephrol. 12(4):268–270.
  • Nguyen L, Robson MJ, Healy JR, Scandinaro AL, Matsumoto RR. 2014. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One. 9(2):e89985.
  • Nicholson KL, Hayes BA, Balster RL. 1999. Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. Psychopharmacology (Berl). 146(1):49–59.
  • O’Mathuna B, Farre M, Rostami-Hodjegan A, Yang J, Cuyas E, Torrens M, Pardo R, Abanades S, Maluf S, Tucker GT, et al. 2008. The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans. J Clin Psychopharmacol. 28:523–529.
  • Oda F, Tohyama M, Murakami A, Kanno K, Sonobe N, Sayama K. 2016. Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives. J Dermatol. 43(5):564–566.
  • Olives TD, Boley SP, LeRoy JM, Stellpflug SJ. 2019. Ten years of robotripping: evidence of tolerance to dextromethorphan hydrobromide in a long-term user. J Med Toxicol. 15(3):192–197.
  • Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM. 1996. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol. 41(2):149–156.
  • Parks KA, Kennedy CL. 2004. Club drugs: reasons for and consequences of use. J Psychoact Drugs. 36(3):295–302.
  • Pechnick RN, Poland RE. 2004. Comparison of the effects of dextromethorphan, dextrorphan, and levorphanol on the hypothalamo-pituitary-adrenal axis. J Pharmacol Exp Ther. 309(2):515–522.
  • Pfaff G, Briegel P, Lamprecht I. 1983. Inter-individual variation in the metabolism of dextromethorphan. Int J Pharm. 14(2–3):173–189.
  • Pickering G, Pereira B, Morel V, Tiberghien F, Martin E, Marcaillou F, Picard P, Delage N, de Montgazon G, Sorel M, et al. 2014. Rationale and design of a multicenter randomized clinical trial with memantine and dextromethorphan in ketamine-responder patients. Contemp Clin Trials. 38(2):314–320.
  • Poklis JL, Mulder HA, Peace MR. 2019. The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids. Forensic Sci Int. 294:e25–e27.
  • Pope LE, Khalil MH, Berg JE, Stiles M, Yakatan GJ, Sellers EM. 2004. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol. 44(10):1132–1142.
  • Ramachander G, Williams FD, Emele JF. 1977. Determination of dextrorphan in plasma and evaluation of bioavailability of dextromethorphan hydrobromide in humans. J Pharm Sci. 66(7):1047–1048.
  • Rammer L, Holmgren P, Sandler H. 1988. Fatal intoxication by dextromethorphan: a report on two cases. Forensic Sci Int. 37(4):233–236.
  • Ramsay J, Wright C, Thompson R, Hull D, Morice AH. 2008. Assessment of antitussive efficacy of dextromethorphan in smoking related cough: objective vs. subjective measures. Br J Clin Pharmacol. 65(5):737–741.
  • Repetto MR, Repetto M. 1998. Therapeutic, toxic, and lethal concentrations of 73 drugs affecting respiratory system in human fluids. J Toxicol Clin Toxicol. 36(4):287–293.
  • Repetto MR, Repetto M. 1999. Concentrations in human fluids: 101 drugs affecting the digestive system and metabolism. J Toxicol Clin Toxicol. 37(1):1–9.
  • Ritter D, Ouellette L, Sheets JD, Riley B, Judge B, Cook A, Houseman J, Jones JS. 2019. “Robo-tripping”: dextromethorphan toxicity and abuse. Am J Emerg Med. DOI:10.1016/j.ajem.2019.10.001
  • Rodrigues WC, Wang G, Moore C, Agrawal A, Vincent MJ, Soares JR. 2008. Development and validation of ELISA and GC–MS procedures for the quantification of dextromethorphan and its main metabolite dextrorphan in urine and oral fluid. J Anal Toxicol. 32(3):220–226.
  • Romanelli F, Smith KM. 2009. Dextromethorphan abuse: clinical effects and management. J Am Pharm Assoc. 49(2):e20–e25.
  • Roos FJ, Zysset T, Reichen J. 1991. Differential effect of biliary and micronodular cirrhosis on oxidative drug metabolism: in vivo–in vitro correlations of dextromethorphan metabolism in rat models. Biochem Pharmacol. 41(10):1513–1519.
  • Sawynok J, Reid A. 2003. Peripheral interactions between dextromethorphan, ketamine and amitriptyline on formalin-evoked behaviors and paw edema in rats. Pain. 102(1–2):179–186.
  • Schadel M, Wu D, Otton SV, Kalow W, Sellers EM. 1995. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol. 15(4):263–269.
  • Schmid B, Bircher J, Preisig R, Küpfer A. 1985. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther. 38(6):618–624.
  • Schoedel KA, Pope LE, Sellers EM. 2012. Randomized open-label drug-drug interaction trial of dextromethorphan/quinidine and paroxetine in healthy volunteers. Clin Drug Investig. 32(3):157–169.
  • Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. 2012. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 16(4):R136.
  • Schwartz RH. 2005. Adolescent abuse of dextromethorphan. Clin Pediatr (Phila). 44(7):565–568.
  • Shafi H, Imran M, Usman HF, Sarwar M, Tahir MA, Naveed R, Ashiq MZ, Tahir AM. 2016. Deaths due to abuse of dextromethorphan sold over-the-counter in Pakistan. Egypt J Forensic Sci. 6(3):280–283.
  • Shi T, Hao J-X, Wiesenfeld-Hallin Z, Xu X-J. 2018. Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain. Scand J Pain. 18(4):687–693.
  • Shin EJ, Nah SY, Kim WK, Ko KH, Jhoo WK, Lim YK, Cha JY, Chen CF, Kim HC. 2005. The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via σ1 receptor activation: comparison with the effects of dextromethorphan. Br J Pharmacol. 144(7):908–918.
  • Solimini R, Rotolo MC, Pellegrini M, Minutillo A, Pacifici R, Busardò FP, Zaami S. 2017. Adulteration practices of psychoactive illicit drugs: an updated review. Curr Pharm Biotechnol. 18(7):524–530.
  • Spangler DC, Loyd CM, Skor EE. 2016. Dextromethorphan: a case study on addressing abuse of a safe and effective drug. Subst Abuse Treat Prev Policy. 11(1):22.
  • Sromek AW, Provencher BA, Russell S, Chartoff E, Knapp BI, Bidlack JM, Neumeyer JL. 2014. Preliminary pharmacological evaluation of enantiomeric morphinans. ACS Chem Neurosci. 5(2):93–99.
  • Stanciu CN, Penders TM, Rouse EM. 2016. Recreational use of dextromethorphan, “Robotripping”—a brief review. Am J Addict. 25(5):374–377.
  • Steinberg GK, Kunis D, DeLaPaz R, Poljak A. 1993. Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile. Neurol Res. 15(3):174–180.
  • Strauch K, Lutz U, Bittner N, Lutz WK. 2009. Dose-response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles. Food Chem Toxicol. 47(8):1928–1935.
  • Szekely JI, Sharpe LG, Jaffe JH. 1991. Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav. 40(2):381–386.
  • Takashima T, Murase S, Iwasaki K, Shimada K. 2005. Evaluation of dextromethorphan metabolism using hepatocytes from CYP2D6 poor and extensive metabolizers. Drug Metab Pharmacokinet. 20(3):177–182.
  • Tanaka A, Nagamatsu T, Yamaguchi M, Nomura A, Nagura F, Maeda K, Tornino T, Watanabe T, Shimizu H, Fujita Y, et al. 2011. Myoclonus after dextromethorphan administration in peritoneal dialysis. Ann Pharmacother. 45(1):123.
  • Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y. 2000. Inhibition selectivity of grapefruit juice components on human cytochromes P450. Arch Biochem Biophys. 378(2):356–363.
  • Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. 2016. Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta(R)) clinical use. Pharmacol Ther. 164:170–182.
  • Tornio A, Filppula AM, Niemi M, Backman JT. 2019. Clinical studies on drug–drug interactions involving metabolism and transport: methodology, pitfalls, and interpretation. Clin Pharmacol Ther. 105(6):1345–1361.
  • Uhr M, Namendorf C, Grauer MT, Rosenhagen M, Ebinger M. 2004. P-glycoprotein is a factor in the uptake of dextromethorphan, but not of melperone, into the mouse brain: evidence for an overlap in substrate specificity between P-gp and CYP2D6. J Psychopharmacol. 18(4):509–515.
  • Unger KA, Watterson JH. 2016. Analysis of dextromethorphan and dextrorphan in skeletal remains following decomposition in different microclimate conditions. J Anal Toxicol. 40(8):669–676.
  • Vanamala J, Cobb G, Turner ND, Lupton JR, Yoo KS, Pike LM, Patil BS. 2005. Bioactive compounds of grapefruit (Citrus paradisi Cv. Rio Red) respond differently to postharvest irradiation, storage, and freeze drying. J Agric Food Chem. 53(10):3980–3985.
  • Wang SC, Chou DT, Wallenstein MC. 1977. Studies on the potency of various antitussive agents. Agents Actions. 7(3):337–340.
  • Wang J, Mack AL, Coop A, Matsumoto RR. 2007. Novel sigma (σ) receptor agonists produce antidepressant-like effects in mice. Eur Neuropsychopharmacol. 17(11):708–716.
  • Wang J, Zhang ZY, Lu S, Powers D, Kansra V, Wang X. 2019. Effects of rolapitant administered orally on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. Support Care Cancer. 27(3):819–827.
  • Werling LL, Keller A, Frank JG, Nuwayhid SJ. 2007. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol. 207(2):248–257.
  • WHO. 2012. Dextromethorphan: pre-review report. Hammamet: World Health Organization.
  • Wolfe TR, Caravati EM. 1995. Massive dextromethorphan ingestion and abuse. Am J Emerg Med. 13(2):174–176.
  • Wong BY, Coulter DA, Choi DW, Prince DA. 1988. Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-d-aspartate in brain slices. Neurosci Lett. 85(2):261–266.
  • Wong SHY, Sunshine I. 1996. Handbook of analytical therapeutic drug monitoring and toxicology. New York: Taylor & Francis.
  • Woo TM, Hanley JR. 2013. “How high do they look?”: identification and treatment of common ingestions in adolescents. J Pediatr Health Care. 27(2):135–144.
  • Woodworth JR, Dennis SR, Hinsvark ON, Amsel LP, Rotenberg KS. 1987. Bioavailability evaluation of a controlled-release dextromethorphan liquid. J Clin Pharmacol. 27(2):133–138.
  • Wu D, Otton SV, Kalow W, Sellers EM. 1995. Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat. J Pharmacol Exp Ther. 274:1431–1437.
  • Wyen C, Fuhr U, Frank D, Aarnoutse RE, Klaassen T, Lazar A, Seeringer A, Doroshyenko O, Kirchheiner JC, Abdulrazik F, et al. 2008. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther. 84(1):75–82.
  • Yeh G-C, Tao P-L, Ho H-O, Lee Y-J, Chen J-R, Sheu M-T. 2003. Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes. J Biomed Sci. 10(5):552–564.
  • Yoo Y, Chung H, Kim E, Kim M. 1996. Fatal zipeprol and dextromethorphan poisonings in Korea. J Anal Toxicol. 20(3):155–158.
  • Yu A, Haining RL. 2001. 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? Drug Metab Dispos. 29:1514–1520.
  • Yubero-Lahoz S, Pardo R, Farré M, O'Mahony B, Torrens M, Mustata C, Pérez-Mañá C, Carbó ML, de la Torre R. 2011. Sex differences in 3,4-methylenedioxymethamphetamine (MDMA; ecstasy)-induced cytochrome P450 2D6 inhibition in humans. Clin Pharmacokinet. 50(5):319–329.
  • Zanger UM, Raimundo S, Eichelbaum M. 2004. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn-Schmiedeberg’s Arch Pharmacol. 369(1):23–37.
  • Zawertailo LA, Kaplan HL, Busto UE, Tyndale RF, Sellers EM. 1998. Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol. 18(4):332–337.
  • Zawertailo LA, Tyndale RF, Busto U, Sellers EM. 2010. Effect of metabolic blockade on the psychoactive effects of dextromethorphan. Hum Psychopharmacol Clin Exp. 25(1):71–79.
  • Zhou SF. 2009a. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 48(11):689–723.
  • Zhou SF. 2009b. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 48(12):761–804.
  • Zhou H, Meibohm B. 2013. Drug–drug interactions for therapeutic biologics. New York: John Wiley & Sons Inc.
  • Zysset T, Zeugin T, Küpfer A. 1988. In-vivo and in-vitro dextromethorphan metabolism in SD and DA rat. An animal model of the debrisoquine-type polymorphic oxidation in man. Biochem Pharmacol. 37(16):3155–3160.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.