Pharmacokinetics and Pharmacodynamics of Dextromethorphan: Clinical and Forensic Aspects

Home , Acetylcysteine, Dextromethorphan, Dextrorphan, Dimemorfan, Ketamine, Lean (drug)

ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: https://www.tandfonline.com/loi/idmr20

Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects

Ana Rita Silva & Ricardo Jorge Dinis-Oliveira

To cite this article: Ana Rita Silva & Ricardo Jorge Dinis-Oliveira (2020) Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects, Drug Metabolism Reviews, 52:2, 258-282, DOI: 10.1080/03602532.2020.1758712 To link to this article: https://doi.org/10.1080/03602532.2020.1758712

Published online: 12 May 2020.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=idmr20 DRUG METABOLISM REVIEWS 2020, VOL. 52, NO. 2, 258–282 https://doi.org/10.1080/03602532.2020.1758712

REVIEW ARTICLE Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects

Ana Rita Silvaa and Ricardo Jorge Dinis-Oliveiraa,b,c aDepartment of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal; bDepartment of Sciences, IINFACTS – Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal; cDepartment of Biological Sciences, Faculty of Pharmacy, Laboratory of Toxicology, UCIBIO, REQUIMTE, University of Porto, Porto, Portugal

ABSTRACT ARTICLE HISTORY Dextromethorphan (DXM) is a safe and effective antitussive agent present in several over the Received 27 December 2019 counter cough and cold medications. At higher doses, it causes psychoactive effects, making it Accepted 7 April 2020 appealing for abuse. In this work, the pharmacokinetics and pharmacodynamics of DXM with KEYWORDS clinical and forensic relevance were extensively reviewed. DXM and related known metabolizing Dextromethorphan; metab- enzymes and metabolites were searched in books and in PubMed (U.S. National Library of olism; pharmacokinetics; Medicine) without a limiting period. Major metabolic pathways include sequential O-demethyla- clinical and forensic tion and N-demethylation of DXM, yielding dextrorphan (DXO), the major active metabolite, and aspects; abuse 3-hydroxymorphinan, the bi-demethylated product, respectively. The demethylation order described may reverse being the resultant mid product 3-methoxymorphinan. UDP-glucuronosyltranferase produces glucuronide conjugates. Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxicological effects produced. Knowing the metabolism of DXM may help to better understand the inter-individual variability in the pharmacokinetics and pharmacodynamics and to avoid adverse effects.

Introduction stimulation and N-methyl-D-aspartate (NMDA) antagonism (Brown et al. 2004). Moreover, especially in doses Dextromethorphan (DXM; d-methorphan) is a non-nar- higher than 100–200 mg, DXM has the potential to pro- cotic synthetic analog of codeine (Aumatell and Wells 1993), widely used as an antitussive agent in over-the- duce clinical signs and symptoms similar to those of counter (OTC) cough and cold medications (El-Naby phencyclidine (PCP) and ketamine, such as euphoria and Kamel 2015) and is considered safe and effective and dissociative hallucinations, effects that are probably when taken at therapeutic doses (Spangler et al. 2016). mediated by a rather nonselective action on serotonin r a b In 2015, in the USA, OTC medicines containing DXM reuptake inhibition and 1 opioid, 3 4 nicotinic, and comprised 85–90% of all medicines containing a cough NMDA receptors (Logan 2009; Logan et al. 2009, 2012). suppressant that were sold, in a total of 235 million Although structurally related to opioid agonists, DXM packages (Spangler et al. 2016). Codeine, levopropoxy- does not have relevant pharmacological activity at opi- phene, and noscapine are other opioids derivatives also oid receptors (Chen et al. 2005). DXM also is a seroto- used as antitussive agents (Dinis-Oliveira 2019). DXM nergic drug having a potential risk for serotonin may have several other medical uses, such as pain man- syndrome (Chyka et al. 2007; Dilich and Girgis 2017), agement, treatment of pseudobulbar affect, and psy- and enhances the analgesic action of morphine and chological applications (El-Naby and Kamel 2015). It is presumably other l-receptor agonists. purported to produce less constipation than codeine. Regarding metabolism, DXM is primarily metabolized DXM has a wide range of pharmacodynamic effects by cytochrome P450 (isoenzyme CYP2D6) producing its as consequence of its activity on numerous channels major active metabolite dextrorphan (DXO). and receptors. DXMs popular antitussive effects are Nevertheless, DXM is also a pharmacological active believed to result from its sigma-1 receptors (r1R) compound (Pechnick and Poland 2004). The expression

CONTACT Ricardo Jorge Dinis-Oliveira [email protected], [email protected] Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Alameda Prof. Hern^ani Monteiro, Porto 4200-319, Portugal ß 2020 Informa UK Limited, trading as Taylor & Francis Group DRUG METABOLISM REVIEWS 259 of CYP2D6 is genetically controlled and this enzyme This review aims to gather as much information as pos- polymorphism contributes to a variability in drug sible available in the literature concerning its chemical response and toxicity (Meyer et al. 1990; Burton et al. structure, pharmacokinetics, pharmacodynamics, 2006; Gaedigk 2013). This is even more relevant since pharmacogenomics and abuse potential, as well as clin- DXM is widely consumed and usually ingested licitly ical effects, toxicological analysis and treatment of when combined with other drugs, or illicitly as mixtures acute intoxications, with special focus on DXM metabol- of uncertain composition (Chyka et al. 2007; Banken ism and its implications in clinical and forensic and Foster 2008; Brown et al. 2018). interpretations. Even though DXM has been used as a nonprescription drug since 1958, only recently it has been consid- Methodology ered as a seriously emerging substance of abuse, with its recreational use becoming more frequent and wide- A narrative review was performed by searching articles spread since the 1990s (Banken and Foster 2008; in English, French, Spanish, and Portuguese in PubMed, Spangler et al. 2016). The availability of DXM, either in Scopus, Web of Science, and PsycINFO concerning legal, OTC formulations or as illicitly manufactured powder or laboratorial, clinical, ethical, forensic, and safety con- tablets containing DXM, alone or with other drugs, and cerns related to DXM and its known metabolizing the easy access through the internet may facilitate the enzymes and metabolites, without a limiting period. abuse and fatalities (Brown et al. 2018). The reports of Furthermore, electronic copies of the full papers were abuse involve most commonly teenagers, but also obtained from the retrieved journal articles and books young adults (Spangler et al. 2016). Data from related to this topic, which were further reviewed for pos- American Association of Poison Control Centers from sible additional publications related to pharmacokinetics 2000 to 2015 show a total number of 72,260 calls and pharmacodynamics aspects of DXM. Besides these reporting intentional abuse of a DXM cough and cold inclusion criteria, the World Health Organization (WHO) product, with a peak in 2006 (Karami et al. 2018). Since pre-review report on DXM was also reviewed to identify antitussive OTC medications that contain DXM are safe possible additional publications related to human and and effective, and acute bothersome coughing can non-human in vivo and in vitro studies. impair daily life, self-medication with these products, can contribute to make them about 85–90% of all med- Chemistry of dextromethorphan and analogs icines sold as cough suppressants and a total accounted of around 235 million of packages purchased in 2015 DXM (3-methoxy-N-methylmorphinan; Figure 1)isthe (Spangler et al. 2016). dextrorotatory [d-or(–)] enantiomer of levomethorphan Therefore, it is important to understand how DXM [l-or(þ)], which is the methyl ether of DXO (3-hydroxy-N- produces its pharmacological and toxicological effects. methylmorphinan) and levorphanol, respectively (Sromek

Racemethorphan Dromoran®

O HO O H N H N H H Dextromethorphan Dextrorphan O H (DXM; antitussive and (DXO; antitussive and hallucinogen) hallucinogen) N HO O HO Codeine H N H N H H Levomethorphan Levorphanol (analgesic) (Levo-Dromoran®; analgesic)

Figure 1. Chemical structure of dextromethorphan and analogs. 260 A. R. SILVA AND R. J. DINIS-OLIVEIRA et al. 2014). Although former levorotatory compounds are DXM has been synthesized from a benzylisoquino- both opioid analgesics, only levorphanol was clinically line by a process known as Grewe’s cyclization to give developed (Gudin et al. 2016;LeRouzicetal.2019). the corresponding morphinan with a three-dimensional Moreover, levorphanol is the levorotatory isomer of structure. The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1- racemic 3-hydroxy-N-methylmorphinan (DromoranVR )and (4-methoxybenzyl) isoquinoline (there is just one V named as Levo-Dromoran R . DXM is named according to residual double bond at the fusion position of the two IUPAC rules as (þ)-3-methoxy-17-methyl-9a,13a,14a-mor- rings of the isoquinoline) and it is converted into the N- phinan. It is also the d-isomer of methorphan (racemic formyl derivative, cyclized to the N-formyl normor- mixture), but unlike the l-isomer, it does not have opioid phinan, and the formyl group reduced to an N-methyl activity. Methorphan presents as two isomeric forms, each group, to give 3-methoxy-17-methylmorphinan, or race- with differing pharmacology and effects with respect to methorphan (WHO 2012). its two enantiomers. The DXM is used as an antitussive drug in cough medicines (and in high doses, it is a dis- Licit and illicit formulations sociative hallucinogen), whereas the levorotatory enantiomer levomethorphan, a prodrug of levorphanol, is a Accordingly to PubChem Database (CID ¼ 5360696), in strong opioid analgesic that is listed as a schedule II drug its pure form, DXM exists as an odorless, opalescent in the USA (Wong and Sunshine 1996; Bortolotti et al. white powder, freely soluble in ethanol 96% and poorly 2013;Gudinetal.2016). Levorphanol binding affinity for water soluble. It is available most often as the monohy- the mu (MOR; m) opioid receptor, 0.42 nM, is greater than drated hydrobromide salt, making it water soluble the affinity of morphine, 1.24 nM and also presents longer (Loyd et al. 2014; Jayachandra et al. 2018). The monohy- t1/2 (Bortolotti et al. 2013). As DXM is approved for use in drated hydrobromide salt is water-soluble up to 1.5 g/ OTC drugs, accurate control of enantiomeric purity is 100 mL at 25 C. Some formulations, as extended- essential to assure that commercial DXM preparations do release ones, can present DXM bound to an ion- not contain the l-enantiomer. exchange resin based on polystyrene sulfonic. Therefore, DXM is chemically an opium alkaloid Licit DXM is typically available as an oral drug in derivative but since it does not act pharmacologically liquid, tablet, lozenges, and capsule formulations of at opioid receptors, it is not an opioid and does not cough and cold (and other pathologies) OTC medicines. have analgesic, euphoriant, and respiratory depression These products can contain DXM alone or in combin- effects, such as codeine and morphine (Bem and Peck ation with guaifenesin, brompheniramine, pseudoephe- 1992; Jasinski 2000; Pechnick and Poland 2004). In other drine, phenylephrine, promethazine, codeine, V words, DXM and DXO, both dextrorotatory enantiom- acetaminophen, and/or chlorpheniramine. Benylin R , V V V V ers, are non-opioid opium alkaloid derivatives. Delsym R , Sucrets R , Bromfed-DM R , Robitussin R , Vicks V V V V Racemethorphan is the racemic mixture composed by Formula 44-D R , Coricidin R , Bisoltussin R , Tylenol-DM R , V V the two enantiomers DXM and levomethorphan (Wong Tussilene R , Romilar R , Dr. Rentschler tuss hustenstiller V V V V and Sunshine 1996). Racemorphan or morphanol refers retard kapseln R , Comtrex R , Sucrets DM R , Vicks Nyquil R , V to the racemic mixture of DXO and levorphanol, both Medicon R are the most common trade names in differ- with pharmacological and toxicological effects similar ent countries. OTC cough products containing DXM to their correspondent methyl ether derivatives alone have been discontinued as a response to the per- (Aumatell and Wells 1993). This enantiomeric behavior ceived abuse risk. is characteristic of other opioids. Indeed, dextrorotatory Traditionally, DXM is abused in the form of the OTC opioids have very different pharmacological profiles liquid cough preparations. Nevertheless, nowadays, it than their levorotatory isomers. Unlike the levorotatory can be seen in other presentation forms such as tablet opioids, dextrorotatory generally have little or no affin- and gel capsule preparations, illicitly manufactured ity to the mu (MOR; m), delta (DOR; d), or kappa (KOR; K) DXM powder and tablets of DXM alone or in combin- opioid receptors, and thus do not carry the same abuse ation with other drugs for recreational purposes such and addiction potential as their levorotatory enantiom- as 3,4-methylenedioxymethamphetamine (MDMA; ers (Sromek et al. 2014). Dextrorotatory enantiomers ecstasy), methamphetamine, and cocaine (Banken and typically act as weak to moderate noncompetitive Foster 2008; El-Naby and Kamel 2015; Brown et al.

NMDA receptor antagonists and have affinity to the r1 2018), which composition and dose are uncertain. and a3b4 nicotinic receptors (Glick et al. 2001). Both ‘CCC’, ‘triple C’, ‘rojos’, ‘red devils’, ‘skittles/skittling’, dextrorotatory and levorotatory opioids have antitus- ‘dexing’, ‘robo-tripping’, ‘ro-bowing’, ‘robo-copping’, sive properties. ‘robo’, ‘velvet’, ‘poor man’s PCP’ are common street DRUG METABOLISM REVIEWS 261 names that come from the most abused products ingest up to three or four bottles per day (Wolfe and RobitussinVR and the red tablet formulation in CoricidinVR Caravati 1995). Alternatively, powders and tablets have cough & cold products (Banken and Foster 2008; Logan been used since they produce an effect similar to sirups 2009; Logan et al. 2009, 2012; Ritter et al. 2019). without the need to consume large quantities of the Nevertheless, color pink due to dilution of other bever- substance in a short time period (Banerji and Anderson ages, have also been described, making it difficult to 2001; Chyka et al. 2007; Romanelli and Smith 2009). ascertain what dose is being administered. Lean also Besides ingestion, DXM snorting has also been reported known as purple drank and other street names (Agnich among abusers (Banken and Foster 2008). In a retro- et al. 2013; Hart et al. 2014), is a recreational drug, cre- spective review of 47 patients admitted in an adoles- ated by combining prescription-grade cough sirup with cent inpatient psychiatric unit for depression and/or V a soft drink (e.g. Sprite, Mountain Dew, or grape-fla- psychosis related to Coricidin HBP R abuse, the number vored Fanta) and hard candy. The term ‘lean’ refers to of tablets used per episode ranged from 2 to 42 with the posture that abusers assume when intoxicated, 14% of the patients abusing this product daily namely difficulty in standing up straight. The term (Dickerson et al. 2008). ‘purple drank’ is a nod to its purple hue, as most cough DXO is almost completely absorbed by the gastro- sirups are purple in color, and drank is an informal term intestinal tract and its brain-to plasma ratio ranges from for a beverage, especially an intoxicating drink. 25 to 500 (Desmeules et al. 1999). Kanaan et al. (2008) Although, traditionally, the base for lean has been demonstrated in vitro Caco-2 cell monolayer model that cough sirup, containing promethazine and codeine, neither DXM and DXO are P-glycoprotein (P-gp) sub- DXM has also been used, as it can produce similar strates, but pH-mediated efflux mechanisms, probably þ þ effects, is cheaper and eliminates the need for a doc- Na /H exchangers, may be involved in limiting DXM tor’s visit (Schwartz 2005). Nevertheless, hallucinogenic gastrointestinal absorption and DXO transmembrane effects are more prevalent, rather than the sedative passage when a pH gradient is present. Another study effects of the traditional form of purple drank contain- showed an enhanced cerebral uptake of DXM in rats by ing codeine and promethazine. concomitant administration of the P-gp inhibitor verap- Experienced DXM abusers extract the DXM from the amil but no effect on its systemic biodisposition (Uhr sirup and offer it as a powder in capsules. Two extrac- et al. 2004; Marier et al. 2005). As suggested by Kanaan tion techniques are widely described in the internet et al. (2008), DXM might possibly interact with trans- aiming to purify the DXM and therefore to avoid co- porters other than P-gp, possibly present at the blood–- ingestant toxicity (e.g. ethanol, guaifenesin, saccharin, brain barrier but not at the intestinal barrier. But several propylene glycol, coloring agents, sweeteners) present contradictory results exist, since grapefruit juice (i.e. an in combination cold preparations (Hendrickson and CYP3A4 and efflux transporters inhibitor in the small Cloutier 2007): (i) a single-phase acid–base extraction intestine) can in some concentrations decrease DXM with sodium hydroxide that yields a freebase crystalline bioavailability by delaying the gastric emptying powder (i.e. ‘crystal dex’) and (ii) a two-phase acid–base (Strauch et al. 2009). Therefore, it is obvious that further extraction with ammonia resulting in a liquid (i.e. studies are needed to explore the role of these efflux ‘DXemon juice’ or ‘agent lemon’). This last technique transporters in the transepithelial transport of DXM and has become more popular because it yields a more pal- its active metabolite DXO. atable liquid product, it avoids the use of lye, and it The first pass effects in the gastrointestinal tract and eliminates the hazards of heating flammable solvents in in the liver limit oral bioavailability (Wu et al. 1995). enclosed spaces. Most published results regarding the bioavailability and disposition of DXM are based on analysis of DXO, in plasma and urine. In humans, it has been suggested to Absorption be in the order of 1–2% in extensive metabolizer (EM) DXM is usually administered per os, the typical dose as subjects and would arise to 80% in poor metabolizer antitussive being in patients over 12-years-old, (PM) subjects, expressing a large variation in the intrin- 10–30 mg taken three to six times per day or extended sic clearance of DXM (Capon et al. 1996). Moreover, the release formulations 60 mg twice per day, in a max- plasma concentrations of DXM were reported to be imum of 120 mg per day, without concern with meals greater for the slow metabolizers when compared to (Collins 2018). On the other hand, a single dose for rec- the immediate metabolizers, due to the greater meta- reational users can range from 240 to 1500 mg (Banken bolic capability of the intermediate metabolizers (IMs) and Foster 2008). Heavier users have been known to (Woodworth et al. 1987). Furthermore, since DXM is 262 A. R. SILVA AND R. J. DINIS-OLIVEIRA usually administered in combination with other sub- of DXO, suggesting a poor brain bioavailability of DXO. stances, its bioavailability may depend on the drug for- In comparison to DXM, the lower liposolubility of DXO mulation. Indeed, DXM bioavailability can increase may contribute to a lower cerebral bioavailability and approximately 20-fold when administered with quini- anti-NMDA neuromodulatory effect. Even though DXM dine, a potent inhibitor of hepatic CYP2D6 (Chez et al. probably crosses the placental barrier due to its low 2018; Fralick et al. 2019). Other authors also demon- molecular weight, it has no teratogenic effect. strated that the coadministration of DXM with a low dose of quinidine inhibits DXM metabolism, yielding Metabolism greater bioavailability (Taylor et al. 2016). Pathological conditions can also influence bioavailability (Gao et al. The metabolic pathways of DXM are shown in Figure 2. 2015). Indeed, besides genetic factors, drug oxidation DXM is primarily rapid and extensively O-demethylated may depend on liver function, and particularly cirrhosis by CYP2D6 to DXO, its major active metabolite (Nagai is associated with approximately a 50% decrease in et al. 1996; Zhou and Meibohm 2013). Nevertheless, the hepatic cytochrome P450 (Howden et al. 1989). Larrey therapeutic activity is believed to be caused by both et al. (1989) have demonstrated that DXM oxidation DXM and DXO (Braga et al. 1994). Indeed, in vitro stud- capacity is impaired in patients with chronic liver dis- ies showed that DXM was a more potent NMDA antag- ease. Moreover, in inflammation and infection, CYP onist than DXO (Szekely et al. 1991; Dematteis et al. enzyme activities are also downregulated. The compari- 1998; Nicholson et al. 1999). Additionaly, experimental son between human immunodeficiency virus (HIV)- and clinical evidence suggests that the antinocicep- infected patients and healthy people evidenced that tive, neuromodulatory and neuroprotective in vivo overall CYP3A activity was approximately 50% lower in effects of DXM result mainly from a central action of HIV-infected patients than in healthy volunteers. The unchanged DXM rather than from its more active CYP2D6 activity was highly variable, but on average metabolite DXO (Steinberg et al. 1993;Desmeules was not different between groups (Jetter et al. 2010). In et al. 1999). This metabolic reaction can also be, at another study, aimed to quantify the inhibition of lower extent, catalyzed by CYP2C9 and CYP3A4/5 CYP3A, CYP2D6, and P-gp in HIV-infected patients (Takashima et al. 2005). CYP3A4 and CYP3A5 are the receiving an antiretroviral therapy containing ritonavir major enzymes (with certain contribution from boosted lopinavir, it was demonstrated that in CYP2D6 CYP2D6) implicated in the N-demethylation of DXM to EM, the AUC plasma ratio DXM/DXO increased to 2.92- 3-methoxymorphinan and DXO to 3-hydroxymorphinan fold (Wyen et al. 2008). Nevertheless, in other study, it (Jacqz-Aigrain et al. 1993; Yu and Haining 2001; was claimed that the effect of low-dose ritonavir on Takashima et al. 2005). 3-Methoxymorphinan undergoes CYP2D6 will not require standard dose reductions for further O-demethylation mediated by CYP2D6 to 3- CYP2D6 substrates (Aarnoutse et al. 2005). hydroxymorphinan (Strauch et al. 2009). Subsequently, DXO and 3-hydroximorphinan are subjected to glucuronide and sulfate conjugation and then excreted (Nagai et al. Distribution 1996). In fact, the major urinary excretion products are the DXM has a higher liposolubility (Log P: 4.11 ± 0.4) than glucuronide conjugates of DXO and 3-hydroxymorphinan, DXO (Log P: 3.46 ± 0.3) and a blood/plasma ratio of 1.5, dextrorphan-O-glucuronide and 3-hydroxymorphinan-O- resulting in a volume of distribution of 5–6 L/kg (Roos glucuronide (Strauch et al. 2009). et al. 1991; Wu et al. 1995). Its plasma protein binding is Using human liver microsomes, differences between approximately 60–70% (Taylor et al. 2016) and follow- PM and EM subjects in N-demethylation of either DXM ing oral administration DXM achieves peak serum con- to 3-methoxymorphinan and DXO to 3-hydroxymor- centration in 2–3 hours, whereas peak serum phinan were not obtained; hence it was concluded that concentrations of DXO occur within approximately CYP2D6 is not significantly involved in these reactions 1.5–3 hours, independently if it is a liquid, tablet, or an (Kerry et al. 1994). Indeed, when grapefruit juice was extended-release formulation (Barnhart and Massad co-administered with DXM, accumulation of the 1979; Chyka et al. 2007). Steinberg et al. (1993) showed CYP3A4 substrates, DXM and DXO, and a diminished a good intestinal absorption and brain accumulation of production of 3-methoxymorphinan, 3-hydroxymor- DXM in a clinical trial involving neurosurgical patients phinan, and hydroxymorphinan-O-glucuronide were receiving high oral doses of DXM. DXM brain levels obtained (Strauch et al. 2009). Particularly, 3-hydroxy- were more than 13-fold higher than those of DXO and morphinan, which formation depends also on the DXO brain-to-plasma ratio was fivefold lower than that CYP2D6 activity, had a dose-dependent decrease. The DRUG METABOLISM REVIEWS 263

OO S HO N O CH3 Dextrorphan sulfate

SULT

CYP2D6 O CYP2C9 O O CYP3A4/5 UGT2B HO O N HO CH HO OH 3 H N H N OH H H Dextromethorphan Dextrorphan Dextrorphan O-glucuronide CYP3A4/5 CYP2B6 CYP3A4/5 CYP2C9 CYP2C19 CYP2D6 O O O HO CYP2D6 O HO UGT2B NH H C 3 NH NH HO OH OH 3- Methoxymorphinan 3-Hydroxymorphinan 3-Hydroxymorphinan O-glucuronide

SULT

O O S HO NH O

3-Hydroxymorphinan sulfate Figure 2. Metabolic pathway of dextromethorphan (DXM). Dextromethorphan in extensive metabolizers is rapidly metabolized (mostly in liver) to its active metabolite dextrorphan (DXO). In poor metabolizers or in patients treated with the combination of quinidine, this metabolism is mostly blocked. Subsequently, most DXO is rapidly glucuronide or sulfonated. Demethylation by CYP3A4 to form 3-methoxymorphinan is a relatively minor pathway. The biological activities of 3-methoxymorphinan and 3- hydroxymorphinan are unknown. Both 3-methoxymorphinan and DXO are further metabolized to 3-hydroxymorphinan. DXO has significant pharmacological activity, particularly at N-methyl-D-aspartate receptor. P450 isoform is indicated for each metabolic route. UGT: uridine 50-diphospho-glucuronosyltransferase; SULT: sulfotransferase. excretion of the glucuronides suffered also a significant ingredients (Tassaneeyakul et al. 2000; Vanamala et al. decrease only at the top grapefruit juice concentration 2005). In contrast, Di Marco et al. (2002) observed an (Strauch et al. 2009). Interestingly, there was no increase of DXM bioavailability following the administra- increase of DXM systemic availability, since the inhib- tion of grapefruit and Seville orange juice as conse- ition of CYP3A4 was counterbalanced by the short-term quence of the inhibition effect on CYP3A activity as well decrease in DXM absorption from the gastrointestinal as on P-gp efflux transport. Finally, in PM and fetuses tract, both effects attributed to grapefruit juice (Strauch (i.e. human fetal microsomes, CYP2D6 protein and activity et al. 2009). Moreover, a massive effect on CYP3A4 are not detectable until birth), N-demethylation catalyzed dependent metabolites was not registered, since 3- by CYP3A4/5 emerges as an alternative and predominant methoxymorphinan can be produced in minor fractions metabolic pathway, being 3-methoxymorphinan the by other enzymes such as CYP2B6, CYP2C9, CYP2C19, major metabolite (Jacqz-Aigrain et al. 1993;Takashima and CYP2D6 (Strauch et al. 2009). Several compounds et al. 2005). DXM is not considered a sensitive CYP3A4 in the grapefruit juice were identified as inhibitors of substrate (Zhou and Meibohm 2013). CYP3A4 activity, namely the furanocoumarins berga- To identify the UDP-glucuronosyltranferase (UGT) mottin and 60,70-dihydroxybergamottin and the flavo- isoforms responsible for DXO glucuronidation, DXO was noids naringin and naringenin, and the storage and incubated with a panel of 12 recombinant UGT iso- treatment of grapefruits affect the amount of these forms. All four UGT2B isoforms studied (2B4, 2B7, 2B15, 264 A. R. SILVA AND R. J. DINIS-OLIVEIRA and 2B17), but none of the eight UGT1A isoforms Therefore, it is possible to measure the activity of studied (1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, and 1A10), CYP2D6 through DXM O-demethylation by measuring formed DXO-O-glucuronide, suggesting that DXO glu- urinary metabolic ratios after DXM ingestion (Burton curonidation is catalyzed mainly by the UGT2B subfam- et al. 2006). This analysis can also be done on the basis ily in vivo (Lutz and Isoherranen 2012), similarly to other of saliva samples and obtaining a salivary metabolic related opioids such as morphine and codeine (Dinis- ratio, although it requires a higher dose of DXM with Oliveira 2019). DXM-O-glucuronide is permanently the higher risk for side effects (Hou et al. 1991). The charged and less permeable to the blood–brain barrier phenotype identification has also been performed by than unconjugated DXM, and therefore is unlikely to plasma metabolite analysis (Mortimer et al. 1989), that produce significant pharmacological effects in the brain would be more rapid and accurate (Yeh et al. 2003). at clinically used doses even though it may be present Nevertheless, it should be born in mind that although at higher total (bound and unbound) plasma concentra- DXM is not a sensitive CYP3A4 substrate, most of the tions than DXM. Furthermore, glucuronide compounds routinely used CYP2D6 substrates (e.g. desipramine, are usually rapidly eliminated by the kidneys (Wu metoprolol, tolterodine) do show clinically significant et al. 1995). CYP3A4 effects (Tornio et al. 2019). Indeed, in this interesting review, it is made clear that an optimal index inhibitor would be selective (i.e. only inhibits one The relevance of CYP2D6 in enzyme), meaning that direct mechanistic conclusions dextromethorphan metabolism could be drawn from the result with reasonable confi- CYP2D is expressed in hepatic and brain microsomes, dence. In opposition, if the index inhibitor inhibits sev- both in humans and rats, and although the expression eral enzymes and/or transporters, the observed effects in the brain being approximately 1–4% of the liver on victim drug pharmacokinetics cannot be attributed expression, its activity can alter the pharmacologic to a single pathway without further studies (Tornio responses of a centrally acting drug (DuBois and et al. 2019). Mehvar 2018). Particularly, the genetic polymorphism of A study conducted in Swiss subjects showed a CYP2D6 is one of the best studied examples of a gen- bimodal distribution of the metabolic ratio of DXM/ etic variability that determines susceptibility to the DXO for the first eight hours, expressing the rates of O- drug effects, adverse reactions and different potential demethylation of DXM, which indicated that there were for drug interactions (Burton et al. 2006). The cyto- two phenotypes (i.e. PM and EM) for the DXM metabol- chrome P450 2D6 gene, located on chromosome ism (Schmid et al. 1985). The threshold of 0.3 for the 22q13, is currently one of the most extensively charac- metabolic ratio of DXM/DXO was used as a criteria to terized P450 isoenzymes in part due to its intrinsic role differentiate PM (<0.3; the antimode) and EM (>0.3) in the metabolism of 25% of all clinically relevant drugs (Schmid et al. 1985). However, this test is sensitive to and due to its highly polymorphic nature (Zanger et al. co-medications which inhibit CYP2D6 and may yield a 2004; Zhou 2009a, 2009b; Gaedigk et al. 2017). Indeed, phenoconversion from an EM to a PM phenotype. In more than 100 variant alleles have been identified to the context of DXM, an EM might be more likely to date by the Pharmacogene Variation Consortium achieve the dissociative effects at lower doses. Indeed, (https://www.pharmvar.org/gene/CYP2D6) (Burton et al. DXO, besides anticonvulsant, sedative, and antitussive 2006; Gaedigk 2013; Gaedigk et al. 2018). As result, four properties, has an affinity for the ligand-gated channel phenotypes were identified based on CYP2D6 activity: of the NMDA receptor complex similar to ketamine PMs, IMs, normal/EMs (NM/EMs), or ultrarapid metabo- (Wong et al. 1988). lizers (UMs). These polymorphisms can justify inad- Similarly to the above described Caucasian study, a equate treatment response, increased risk of adverse population of 75 healthy Japanese subjects was pheno- effects and resistance in the use of CYP2D6 metabo- typed using the metabolic ratio to determine the per- lized drugs (Burton et al. 2006; Gaedigk 2013; Gaedigk centage of PM. The study concluded 1–3% of the et al. 2018). population were PM (Nagai et al. 1996). Moreover, dif- Even though it is not catalyzed by only one enzyme, ferences in the pharmacokinetics between European DXM is considered a relatively selective substrate for Caucasians and Japanese EM were identified, namely P450 isoenzyme CYP2D6 (Capon et al. 1996; Nagai et al. larger 3-hydroxymorphinan formation in the Japanese 1996). Moreover, since it is safe and readily available, population (Nagai et al. 1996). East Asian populations DXM might be used as a phenotyping probe to differ- present the lowest incidence of poor metabolism entiate CYP2D6 genotypes (Gutierrez Rico et al. 2020). (0–2%) (Gaedigk 2013). For Caucasians, this value was DRUG METABOLISM REVIEWS 265 first obtained using sparteine or debrisoquine as the be fully clarified (Glass et al. 2019). Nevertheless, a sig- test compound and was estimated to be 3–10% (Kupfer€ nificant increase of DXM systemic exposure with clinical and Preisig 1983). Subsequently, using DXM as a relevance was reported after a single oral dose of rola- CYP2D6 O-demethylation probe, the frequency of PM in pitant 180 mg (Wang et al. 2019). a white French population was 3.9%, meaning that Quinidine can be used to inhibit the rapid DXM Caucasians Europeans are the group with higher inci- metabolism and consequently increase its serum con- dence (3–10%) for the PM phenotype (Larrey et al. centrations and its t1/2 (Pope et al. 2004; Garnock-Jones 1987; Gaedigk 2013). Indeed, Black Africans and African 2011; Taylor et al. 2016; Collins 2018). In other words, Americans have a 2–7% incidence of PM quinidine has the potential to temporarily transform a (Gaedigk 2013). CYP2D6 phenotypic EM into a PM subject. Indeed, a sin- In PM, the area under the plasma concentration–time gle dose of 50 mg of quinidine caused a partial inhib- curve (AUC) and urinary recovery of 3-methoxymorphinan ition of the formation of DXO in the EM group (Capon were increased, and a decrease of O-demethylation to et al. 1996) and increased DXM elimination t1/2 from 3-hydroxymorphinan via CYP2D6 was described (Nagai approximately four hours (Kazis et al. 2009) to approxi- et al. 1996). On the other hand, in EM, there was almost mately 13 hours (Pope et al. 2004) in volunteers with an nonexistent quantification of 3-methoxymorphinan due to EM phenotype, allowing a twice-daily administration to the rapid conversion to 3-hydroxymorphinan catalyzed by maintain adequate DXM plasma concentrations. This V CYP2D6. Still in the Japanese population, the ratios of the DXM plus quinidine sulfate association (Nuedext R ) has a cumulative amounts of free and conjugated DXO to DXM therapeutic effect on pseudobulbar affect in patients excreted in the urine suffered extensive inter-subject with amyotrophic lateral sclerosis by diminishing its variation,mostprobablyrelatedtothefactthatthe manifestations (Pope et al. 2004; Garnock-Jones 2011; catalysis of DXM to DXO is mediated by CYP2D6; the Taylor et al. 2016; Collins 2018). It is also important to ratios of DXO to 3-hydroxymorphinan were almost note that the daily dose of quinidine in this combin- constant, as this reaction is CYP3A4 dependent. The ation (20 mg of DXM and 10 mg of quinidine) is much percentages of conjugate metabolites to total metabo- lower than the antiarrhythmic dose of quinidine that is lites (free and conjugated) were around 86.3–98.9% for used to block cardiac sodium channels. In another both DXO and 3-hydroxymorphinan conjugates, in study, DXM 50 mg plus quinidine sulfate 50 mg pro- accordance with data from a French population. duced, in PM, an increase in DXM concentrations DXO and 3-hydroxymorphinan conjugative capacities accompanied with a subjective and objective increase were similar (mean of 95.7% and 96.7%, respectively), in pain threshold of 35% and 45%, respectively; in EM allowing to infer that this step might not be the only a slight and short-lasting increase in the subjective rate limiting step in the DXM metabolic pathway threshold was seen (Desmeules et al. 1999). This high- (Nagai et al. 1996). lights the importance of CYP2D6 polymorphisms in the effect of DXM as well as its role in the balance between the analgesic effect of DXM and the hallucinogenic Metabolic interactions effect of DXO. Authors concluded that the use of Besides grapefruit juice, several other metabolic interac- CYP2D6 inhibitors combined with DXM interferes with tions have been described. Curcuma longa is used as a this balance contributing to a higher risk for serotoni- traditional medicine and can significantly inhibit human nergic and narcotic related adverse effects (Desmeules CYP2D6 and CYP3A4 activities. As a result, it was shown et al. 1999). that Curcuma longa extracts inhibited the enzyme Amiodarone and selective serotonin reuptake inhibi- CYP2D6 and CYP3A4 mediated O- and N-demethylation tors may as well interfere with DXM metabolism leading of DXM into DXO and 3-methoxymorphinan, respect- to toxicity (Collins 2018). Clinical interactions of DXM/ ively, in a dose-dependent and linear fashion (Al- quinidine with paroxetine have been observed in Jenoobi et al. 2015). healthy subjects (Schoedel et al. 2012). The combin- Rolapitant is a potent selective and competitive sub- ation increases the AUC of paroxetine by 30% and stance P/neurokinin-1 (NK-1) receptor antagonist indi- paroxetine increases the AUC of DXM and quinidine by cated in combination with other antiemetic agents in 50% and 40%, respectively (Schoedel et al. 2012). There adults for the prevention of delayed chemotherapy- is a decrease of 12.3% for the AUC of DXO. The side induced nausea and vomiting. In vivo rolapitant moder- effect events are increased. Therefore, paroxetine ately inhibits CYP2D6 for at least seven days after one should not be used with DXM/quinidine, patients 180 mg dose, but the relevance of this finding is yet to should be monitored for potential side effects and 266 A. R. SILVA AND R. J. DINIS-OLIVEIRA dosage adjustment considered when combining these MAOIs and DXM concurrent use, or if at least two two agents. Otton et al. (1996) have compared the weeks of MAOIs discontinuation are not respected, may inhibitory potency of several selective serotonin cause psychosis, serotonin syndrome, with hyperten- reuptake inhibitors for CYP2D6-catalyzed DXM O-deme- sion or hyperpyrexia, and even death, since DXM also thylation. The authors have found that paroxetine, flu- blocks serotonin neuronal uptake (Meoni et al. 1997;Dy oxetine, norfluoxetine, fluvoxamine, and sertraline are et al. 2017; Kongpakwattana et al. 2018; Ahmed et al. potent inhibitors of CYP2D6-catalyzed DXM O-demethy- 2019). Co-ingestion with SSRIs, tricyclic antidepressants, lation with Ki values of 0.065–1.8 lM (Otton et al. 1996). meperidine, clonazepam, sibutramine, lithium, and anti- Lansoprazole proved to be more potent (Ki ¼ 44.7 lM) histamines such as chlorpheniramine and, to a lesser than omeprazole (Ki ¼ 240.7 lM) as an inhibitor of extent, diphenhydramine (Logan 2009; Logan et al. CYP2D6-mediated conversion of DXM to DXO (Ko 2009, 2012), can as well increase the risk of inducing a et al. 1997). serotonin syndrome (Chyka et al. 2007; Collins 2018). DXM has been suggested as an adjuvant for the Clinical effects associated with the serotonin syndrome methadone maintenance therapy for the treatment of are dose-related and include signs of autonomic opioid dependence (Lee et al. 2015; Fluyau et al. 2020), instability (hypertension, hyperpyrexia, diaphoresis, aiming at reducing methadone tolerance and needed tachycardia), muscular hypertonicity (tremor, clonus, dose, withdrawal symptoms from acute opioid detoxifi- myoclonus, hyperreflexia), and mental status changes cation and inhibiting ‘conditioned reactions to drug- (agitation, disorientation, confusion). SSRIs, such as flu- related cues’ (Cornish et al. 2002). There would be a oxetine, can also inhibit CYP2D6 enzyme (Cazet potential interaction between these two drugs, since et al. 2018). methadone is both a substrate and a CYP2D6 inhibitor In another study, the inhibition and recovery half-life (Dinis-Oliveira 2016; Dilich and Girgis 2017). of CYP2D6 and CYP3A4 activity was assessed in female Investigators propose that the beneficial effects from subjects by administering the probe drug DXM before this combination would come from the increase of and repeatedly after MDMA administration, which is a plasma methadone concentration, although further potent mechanism-based inhibitor of CYP2D6 (de la research is necessary (Lee et al. 2015; Dilich and Girgis Torre et al. 2004). Results evidence that in women the 2017). An 83-year-old woman on methadone 20 mg pretreatment with MDMA resulted in a decrease in daily, developed delirium, hypersomnia, confusion, leth- DXM clearance. CYP2D6 activity recovered after 10 days argy, impaired concentration, and poor food intake to 90% of baseline activity. Regarding CYP3A4 activity, after taking DXM at therapeutic doses of 60 mg per day there is an apparent decrease in its activity after MDMA for cough. Her symptoms resolved soon after discontin- use. These results also highlight that physicians should uing of DXM (Lotrich et al. 2005). be criterious when prescribing drugs metabolized by

Amitriptyline is a tricyclic antidepressant, for what CYP2D6 (Yubero-Lahoz et al. 2011). In men, DXM Cmax inhibits serotonin and norepinephrine uptake. It is an and AUC increased approximately 10-fold with corre- important substrate of CYP2D6 (Coutts et al. 1994)and sponding decreases in DXO pharmacokinetic parame- has been proven to inhibit CYP2D6 competitively (Forget ters. The metabolic ratio also increased almost 100-fold et al. 2008). Moreover, it competes with DXM at r1Rbut after MDMA administration, with 67% of the subjects with a lower affinity (Werling et al. 2007)andmayblock having a value greater than the antimode of 0.3 for NMDA receptors (Sawynok and Reid 2003). Given this assigning the PM phenotype (O’Mathuna et al. 2008). pharmacodynamics, amitriptyline interacts with DXM and Interactions with ethanol were also reported. Indeed, may even have a therapeutic adjuvant effect (Sawynok acute ethanol exposure had the largest effect on the and Reid 2003). A case was described of a possible life- pharmacokinetics of DXM (was doubled), of all studied threatening DXM intoxication related with an interaction compounds clearly indicating an inhibitory effect on withamitriptylineinaPM(Forgetetal.2008). CYP2D6 (Gazzaz et al. 2018). DXM use is not recommended in children younger than 4-years-old, for the doses that would be safe in Pharmacological interactions this age range are not known (Chyka et al. 2007; Collins 2018). There has not been noted any age-related pre- There are some drugs that should not be administered caution concerning DXM use in the elderly (Collins with DXM due to the potential of interactions, namely 2018). DXM is considered safe for use during pregnancy monoamine oxidase inhibitors (MAOIs), SSRIs, central within recommended doses and is commonly used in nervous system depressants, and the CYP2D6 inhibitors this context (Chyka et al. 2007). amiodarone and quinidine (Collins 2018). DRUG METABOLISM REVIEWS 267

Elimination HT1 agonist activity (Kamei 1996). Major pharmacodynamic aspects of DXM are resumed in Figure 3. Even DXM onset of action is about 15–30 minutes and has a though it is structurally similar to other morphine deriv- half-life (t )of1.4–3.9 hours as a parent compound and 1/2 atives it is devoid of narcotic proprieties (Spangler et al. as DXO of 3.4–5.6 hours (Collins 2018). The duration of 2016). Indeed, DXM does not show any significant affin- action is 5–6 hours and is influenced by the individuals ity for the l and r opioid receptors, which are respon- CYP2D6 enzyme activity (Brown et al. 2018). DXM is pri- 1 sible for analgesic and central nervous system marily excreted in urine, mostly as conjugates metabo- depressant effects, except in overdoses (Wang lites of DXO and 3-hydroxymorphinan, dextrorphan-O- et al. 1977). glucuronide, and 3-hydroxymorphinan-O-glucoronide. DXM also blocks voltage-activated Ca2þ and Naþ Traces of the unmetabolized drug were found in urine channels (Netzer et al. 1993), being the last involved in after oral administration (Ramachander et al. 1977;Pfaff local anesthetic effect. Indeed, DXM was found to pro- et al. 1983). In the first four hours post DXM administra- duce a dose-dependent local anesthetic effect on the tion, approximately one-third of the ingested dose was sciatic nerve blockades of motor function, propriocep- recovered in urine, mostly as glucuronides conjugates (Strauch et al. 2009); this fraction had been reported to tion, and nociception. The same is true for DXO and 3- rise to 55% in 12 hours (Schadel et al. 1995) and more hydroxymorphinan, and therefore these three com- than 85% of the dose is excreted in urine within 24 hours pounds may potentially be the novel local anesthetics (Pfaff et al. 1983). Both DXO and 3-hydroxymorphinan for peripheral neural blockade (Hou et al. 2006). conjugates were found to have a lower mean renal clear- Another study indicates that DXM induces anti-hyper- ance value than the mean glomerular filtration rate, sug- algesia through NMDA receptors antagonism and that gesting that renal reabsorption might take a part in the DXO would play a weaker role; they can prevent the overall excretion process for conjugated metabolites induction of neuronal hyper-excitability and also (Nagai et al. 1996). Also, urinary pH is considered a sig- reverse established neuronal sensitization, but has no nificant covariate for DXM renal clearance (Abduljalil effect on acute pain (Duedahl et al. 2005). Some studies et al. 2010). Moreover, mean plasma concentrations of suggest that combining NMDA receptor antagonists dextrorphan-O-glucuronide increased by approximately such as DXM, especially with gabapentin could provide 45% following concomitant administration of DXM and synergistic effect to alleviate neuropathic pain and verapamil. Since DXO is mainly eliminated in its glucuro- reduce side effects (Pickering et al. 2014; Aiyer et al. nide form in the urine (Zysset et al. 1988), the increase in 2018; Shi et al. 2018). plasma concentrations of dextrorphan-O-glucuronide The mechanism of DXMs cough suppressant propri- may be attributed to an inhibitory effect of verapamil on eties is not completely clarified but it is thought to the P-gp-mediated renal excretion of dextrorphan-O-glu- result from depressing the medullary cough center r curonide. Another study pointed out that the urinary through 1R stimulation and NMDA receptors antagon- recovery in the form of either DXM or its metabolites ism (Brown et al. 2004), thus decreasing the cough would not be complete, suggesting that a small percent- reflex sensitivity (Ramsay et al. 2008) and elevating the age could be excreted in feces, as already reported in threshold for cough initiation (Bolser 2006; Spangler rats. Moreover, enterohepatic recirculation of DXO has et al. 2016). been described (Zysset et al. 1988; Schadel et al. 1995). Fast-acting antidepressant activity is also associated r Furthermore, in PM, in comparison to EM, the urinary to 1R signaling by DXM, hypothesis that was raised recovery was increased, since there was an higher frac- because of the drug pharmacodynamics similarities to tion of DXM and 3-methoxymorphinan as excretion the NMDA antagonist ketamine (Dinis-Oliveira et al. products, of which fecal excretion in rats was minimal 2010; Dinis-Oliveira 2017). Moreover, it was shown that (Capon et al. 1996). DXM itself would sufficiently produce this antidepressant-like effect, not requiring conversion to the metabolite DXO (Nguyen et al. 2014). It has been suggested Pharmacodynamics and therapeutic actions that, when at higher doses namely if over 1500 mg/day,

DXM has several pharmacodynamic mechanisms being, DXM r1R activation could induce a schizophrenic-like a r1R agonist (Chou et al. 1999), a a3b4 nicotinic recep- mental state (Martinak et al. 2017). tor antagonist, a noncompetitive NMDA receptor antag- Also, in mice, DXM shown to elicit stimulant actions onist, a NAPDH oxidase inhibitor, a serotonin reuptake (namely locomotor activity) by r1R dependent mecha- inhibitor (Kaplan et al. 2011) and also stimulates its nisms, which would be independent of the antidepres- release (Gaikwad et al. 2005), and has competitive 5- sant-like effects of DXM and would not be increased by 268 A. R. SILVA AND R. J. DINIS-OLIVEIRA

3-hydroxymorphinan DXO DXM

Local anesthec eﬀect; Voltage-acvated Ca2+ and Na+ Peripheral neural blockade channels inhibitor Hallucinogenic and dissociave eﬀects

Adrenergic effect NMDA receptor antagonist An-hyperalgesic effect Nausea, voming Diaphoresis Antussive effect Hyperthermia Anconvulsant effect Tachycardia Neuroprotecve effect Hypertension Sigma-1 receptor agonist Hyperexcitability Andepressant-like effect Increased sense of perceptual awareness Altered me percepon Schizophrenic-like mental state Respiratory depression Increases in locomotor acvity Lethargy, stupor and coma Serotonin reuptake inhibitor Abuse potenal Increases serotonin release Risk of serotoninergic syndrome

Niconic and acetylcholine receptor antagonist

NAPDH inhibitor

Figure 3. Major pharmacodynamic aspects of dextromethorphan. DXM: Dextromethorphan; DXO: Dextrophan; NMDA: N-methyl- D-aspartate; NADPH: Nicotinamide Adenine Dinucleotide Phosphate. the addition of the CYP2D6 inhibitor quinidine (Wang binding domain of the NMDA receptor (Franklin and et al. 2007). Both Food and Drug Administration and Murray 1992), and electrophysiological data show that European Medicines Agency have approved in 2010 DXO is a more potent NMDA receptor antagonist than and 2013, respectively, this DXM plus quinidine scheme DXM both in vitro and in vivo (Church et al. 1985, 1989; for the treatment of pseudobulbar affect, whose main Ishmael et al. 1998; Pechnick and Poland 2004). DXM as symptom is emotional lability (Nguyen et al. 2014). a weak inhibitor of NMDA receptors, blocks the effect Anticonvulsant and neuroprotective effects in several of excess glycine, and can decrease the associated seiz- experimental models have also been attributed to DXM ures, combined with benzoate to reduce the glycine probably associated with its proprieties as a low-affinity levels (Bjoraker et al. 2016). noncompetitive NMDA receptors antagonist and/or high-affinity r R agonist in the brain (Chou et al. 1999; 1 Abuse and tolerance potential Shin et al. 2005). DXM has been proposed for the treatment of nonke- Reports of DXM abuse, especially among teenagers and totic hyperglycinemia. Nonketotic hyperglycinemia is a to a lesser extent by young adults, have been described genetic defect of glycine metabolism, in which defi- (Spangler et al. 2016). It is interesting to note that DXM ciency of glycine cleavage system leads to increased abuse is consistent with the finding that hallucinogens levels of glycine in all tissues, including the brain use peaks at 19-years-old and rapidly decreases after (Bjoraker et al. 2016). Among other effects, and because (Karch 2008; Karch and Drummer 2016). DXM was glycine is an allosteric co-activator of the NMDA recep- approved by the FDA for OTC sale in 1958 and its pat- tor, the high levels of glycine over-stimulate these tern of abuse was not reported at that time (Kaplan NMDA receptors, causing an excitotoxic response et al. 2011). This could be because these participants (Bjoraker et al. 2016; McQueen 2017). Progressive neu- were not abusers of m-agonist opioids and the meas- rodegeneration and recurrent uncontrollable seizures ured outcomes were centered on its potential to pro- are usually present in this syndrome (McQueen 2017). duce liking or euphoria and ascertain if it had DXO has a higher affinity for the noncompetitive morphine-like proprieties. Indeed, even if dissociative DRUG METABOLISM REVIEWS 269 effects had appeared, the outcome instruments may intoxicating effect (Karch 2008; Karch and Drummer not have been capable of identifying them. In oppos- 2016). These effects, combined with being relatively ition, these studies reported drowsiness after a large inexpensive and easily available for consumption and oral single dose up to 800 mg and some ‘confusion’ since extensive information on how safely abuse DXM and ‘loss of memory’ when chronic dosage, symptoms over the internet, may explain its widespread popularity stated as ‘frightening’ by the participants; increases in (Banken and Foster 2008; Spangler et al. 2016). the pentobarbital-chlorpromazine and alcohol-like However, it shows little recurrence of abuse when drugs (PCAG) and lysergic acid-like drugs (LSD) scales of researched with other psychoactive substances such as the Addiction Research Center Inventory were cocaine and heroin (El-Naby and Kamel 2015; Spangler found, measuring sedative-like effects and dysphoric et al. 2016). In opposition to DXM and DXO, their enan- experiences, respectively (Karch 2008; Karch and tiomers levomethorphan and levorphanol, respectively, Drummer 2016). are potent narcotic analgesics and have much greater Especially since the mid-1990s, its abuse has been abuse potential and are both Class A controlled drugs. found to be more frequent and widespread, probably DXM and DXO both act as antagonists of the NMDA related to the easy and rapid spread of information receptor, reducing neural activation (Logan 2009; made possible by the internet (Karch 2008; Karch and Logan et al. 2009, 2012). These differ biochemically Drummer 2016). In the first 30 years, just 15 cases of from high-affinity NMDA antagonists such as PCP and fatal outcomes involving DXM were reported to the ketamine (Spangler et al. 2016), but when administered manufacturer, and only one refers therapeutic doses in high doses, the pharmacology of DXM is similar to however in concomitant administration with antide- these controlled substances and hallucinogenic and dis- pressants (Bem and Peck 1992); from 1999 to 2004, the sociative effects may appear (Logan 2009; Logan et al. California Poison Control System data identified a 10- 2009, 2012). This NMDA antagonism might also be fold increase in DXM abuse cases among all age groups, related to the adrenergic effects accompanying a high and in children aged 9–17-years-old this increase was dose intake of DXM due to an inhibition of catechol- of 15-fold (Bryner et al. 2006). Similar data from amine reuptake (Chyka et al. 2007). DXM is a stronger

American Association of Poison Control Centers from r1R agonist than DXO and DXO is a stronger NMDA 2000 to 2015 show a total number of 72,260 calls receptor antagonist than DXM. Both these compounds reporting intentional abuse of a DXM cough and cold are capable of inducing psychoactive effects; however, product, with a peak in 2006 and with the highest fre- it may be DXO, the major responsible compound for quency among 15- and 16-year-olds (Karami et al. the psychotic and dissociative states (Miller 2005; 2018), being the subsequent reduction possibly related Logan 2009; Logan et al. 2009, 2012). to the ‘Paper Talk’ by the Food and Drug Even though DXM has no significant addiction liabil- Administration in 2005 that notified the public about ity (El-Naby and Kamel 2015), as with most opioids, the abuse on DXM (Desai et al. 2006). Even though this long-term users can develop tolerance and in few cases abuse has been decreasing since 2006, a significant dependence (Chyka et al. 2007). Regarding DXM toler- reduction in OTC cold medications abuse was regis- ance, there seems to be a correlation with the individu- tered since 2010. Although the cause is not absolutely al’s metabolizer phenotype. One pilot study clear, it is thought to be related to the increased aware- demonstrated that EM tolerated 3–6 mg/kg of DXM, ness resulted from 2010 Food and Drug Administration while PM barely tolerated 3 mg/kg without significantly Advisory Committee meeting, followed by implementa- undesirable symptoms emerging justifying lower doses tion of the mitigation plan targeting decisive factors in (Zawertailo et al. 1998). Authors also demonstrated that youth behavior (Spangler et al. 2016). In Korea, zipeprol PM had greater psychomotor impairment, as measured is another centrally acting cough suppressant that is by a joystick tracking task, compared with EM. At this abused with DXM for stronger hallucinogenic effects, dose, EM also reported greater abuse potential com- predominantly by teenagers (Chung et al. 1998). pared with PM, and PM reported greater sedation and Currently, DXM is not scheduled under the dysphoria compared with EM. These data provide pre- Controlled Substances Act (CSA), nonetheless along the liminary evidence that DXO contributes to DXM abuse years there has been some controversy on whether liability, and therefore PM may be less likely to abuse DXM should be or not a scheduled substance (Banken DXM. Indeed, since PM produces less DXO, maintaining and Foster 2008; Spangler et al. 2016). DXM can be DXM level elevated, experience more pronounced side used recreationally since at higher doses produces a effects, such as nausea, vomiting, dysphoria, and subse- dissociative/hallucinogenic experience or simply an quently having less tendency for abuse. On the other 270 A. R. SILVA AND R. J. DINIS-OLIVEIRA hand, since EM produces more DXO, which has higher formulations containing antihistamines (chlorphenir- affinity for the NMDA receptor than the parent com- amine, brompheniramine, pheniramine), analgesics pound, experiences the ‘desirable’ psychoactive and (paracetamol, acetyl salicylic acid), decongestants euphoric effects, presenting with a higher risk for abuse (phenylephrine, pseudoephedrine), and/or expectorant (Zawertailo et al. 1998). Other reports also demon- mucolytic agents; additional toxicity of these com- strated the relationship between CYP2D6 activity and pounds is a concern and predisposes to fatal overdoses the plasma drug levels, the psychoactive drug effects (Karch 2008; Karch and Drummer 2016). Some liquid and the abuse liability and therapeutic utility of DXM DXM preparations also contain ethanol concentrations (Zawertailo et al. 2010). up to approximately 25% (Bisaga and Popik 2000). Thus, a high level of suspicion is needed when detected an increase in blood pressure possibly due to pseudoe- Clinical signs and symptoms phedrine, a delayed liver damage related to high doses DXM is widely available on OTC products and its of paracetamol or central nervous system depression, adverse effects are rarely observed if it is taken within cardiovascular and anticholinergic toxicity from antihist- recommended dosing parameters (Spangler et al. amines (Gunn et al. 2001; Banken and Foster 2008; Woo 2016). Occasionally, drowsiness, dizziness, nausea and and Hanley 2013). abdominal discomfort, flatulence, diarrhea or constipation are observed (Collins 2018). However, constipation, Dose-dependent signs of intoxication by a frequent opioid side-effect, is much less pronounced dextromethorphan since DXM has no relevant activity on m-opioid receptor and r1R (Grattan et al. 1995; Farmer et al. 2018). DXM clinical signs of intoxication are dose-dependent Given its potential for abuse, it is important to be and manifest classically in four separate stages or pla- aware to the overdose risk by DXM and the resulting teaus (Table 1) and once the next is reached the effects visual and auditory hallucinations, dissociative effects, may completely change (Logan 2009; Logan et al. 2009, mania, delusions, aggression, euphoria, and dysphoria 2012; Brown et al. 2018). Also, for each plateau, effects effects (Banken and Foster 2008; Brown et al. 2018), can often vary and recreational effects may be different similarly to what is observed in ketamine or PCP abuse depending on the relative quantity of DXM and DXO, (Logan 2009; Logan et al. 2009, 2012). In these cases, since they produce different effects, with DXMs being some physiological changes can often be noticed, such more subtle (Logan et al. 2012; Brown et al. 2018). The as diaphoresis, hyperthermia, and tachycardia, requiring comedown can start suddenly and is noticeable by the early and appropriate recognition and management user by the return of normal sensory processing; how- (Brown et al. 2018). In overdoses, ataxia, nystagmus, ever, it may be prolonged in time (Logan 2009; Logan mydriasis, muscle spasticity, increase or decrease in et al. 2009, 2012; Brown et al. 2018). During the first blood pressure, blurred vision, blue fingernails and lips, plateau, ingestion of approximately 100–200 mg DXM nausea, vomiting, respiratory depression, seizure, stu- produces mild stimulant effects similarly to methylene- por, and coma have also been described (Banken and dioxyamphetamine (MDA), whereas mild hallucinations Foster 2008; Kaplan et al. 2011; Spangler et al. 2016). develop during the second level following the ingestion QT interval prolongation in DXM overdose with ethanol of about 200–400 mg DXM, similarly to a combination (Kaplan et al. 2011), myoclonus after therapeutic DXM of alcohol and marijuana intoxication. Dysphoria can use in a patient on peritoneal dialysis with chronic renal occur when DXM doses exceed 200–250 mg. The third failure (Tanaka et al. 2011), and a serotonin syndrome plateau is the ‘out of body’ experience, with physical with therapeutic doses of DXM in a 77-years-old patient distortion and hallucinations for DXM doses of with chronic hepatitis (Chyka et al. 2007; Kinoshita et al. 300–600 mg; the ingestion of doses > 600 mg is associ- 2011) were also reported. If symptoms are not devel- ated with complete dissociation similarly to ketamine. If oped within the first four hours after DXM ingestion, doses exceed the ‘fourth plateau dosage’ full anesthe- those are unlikely to appear later, unless it comes from sia, psychosis, coma, and/or death can occur (Aytha toxicity related to a concomitantly ingested drug like et al. 2013). Another interesting effect is that music paracetamol. enhances DXM sense of euphoria, something that is not DXM abuse can cause several other serious health quite true with other dissociative drugs, being listening complications not directly related to DXM itself, but to music probably the most common fun thing to do due to other drugs found in OTC medications (Woo and on DXM (Logan 2009; Logan et al. 2009, 2012; Brown Hanley 2013). Indeed, when abuse occurs using the et al. 2018). Given this euphoria specifically linked to DRUG METABOLISM REVIEWS 271

Table 1. Dose-dependent signs of intoxication by dextrome- rash mimicking a pyoderma gangrenosum (Kunze 1976; thorphan classically manifested in four separate stages Battin and Varkey 1982; Hung 2003; Maffeis et al. 2008; or plateaus. Oda et al. 2016). Stage 1 (1.5–2.5 mg/kg) Increased alertness Restlessness Altered sense of movement and position, disturbances in balance and Dextromethorphan DNA interaction body position Mood enhancement and intensified emotions The first study aiming to evaluate the interaction Visual and auditory sensitization between DXM hydrobromide and DNA was published Altered motion and motor skills Impaired short-term memory very recently (Bi et al. 2018). The results showed a spon- Generalized euphoria, specifically linked to music and motion taneous DXM–DNA interaction, through van der Waals No mental confusion Stage 2 (2.5–7.5 mg/kg) force or hydrogen bond, with a static fluorescence Music and motion linked euphoria may diminish or stop quenching process between the two; DXM binding Disturbed time-continuous sensory input (‘Flanging’) Exaggerated auditory and visual sensations followed by periods of affected DNA structure and the stability of the complex deprivation DXM–DNA decreased when increasing in temperature Disrupted sense of balance, body position and kinetic sense Hallucinations and eidetic imagery occurred (Bi et al. 2018). The preferred binding mode of Impaired working and intermediate-term memory DXM to DNA was intercalation binding, indicated by Increased energy and excitability Stage 3 (7.5–15 mg/kg) UV/VIS absorption and CD spectroscopy and further Visual and auditory disturbances confirmed by the effect of ionic strength, the increase Hallucinations Periods of semiconsciousness in DNA viscosity and stability in the presence of DXM, a Delayed reaction and response time smaller binding constant of DXM with dsDNA than with Impaired cognitive ability Impaired short-term memory, and working memory to a lesser extent ssDNA, cyclic and differential pulse voltammogram, and Mania and/or panic molecular docking that suggests that the chromophore Partial disassociation of DXM could slide into the DNA enriched G-C region Stage 4 (>15 mg/kg) Complete disassociation (Bi et al. 2018). Hallucination/delusions Ataxia Adapted from Brown et al. (2018), Logan (2009), Logan et al. (2009), Interpretation of toxicological analysis, results, Logan et al. (2012), Romanelli and Smith (2009). and forensic aspects DXM is not usually contemplated in the basic immuno- assays toxicological screenings. Moreover, since these music, which is set and setting dependent, DXM analysis can result in false positive results for PCP, more presents as a popular drug within the rave culture frequently, but also for opiates, confirmation and quan- (Abanades et al. 2004; Parks and Kennedy 2004; Logan 2009; Logan et al. 2009, 2012; Brown et al. 2018). tification by other specific techniques such as high-per- After discontinuation of use, rapid and complete formance liquid chromatography coupled to mass – – remission of symptoms is expected (Miller 2005). DXM spectrometry (LC MS) and gas chromatography mass withdrawal can occur, manifesting both psychological spectrometry, and less commonly by electrophoresis, and physical signs, and is usually long and accompa- fluorimetry, ELISA, and spectrophotometry, are required nied by nausea, vomiting, diaphoresis, myalgias, and (El-Naby and Kamel 2015). Also, the use of potentiomet- diarrhea, especially during the first three days after dis- ric sensors for determination of DXM has been investi- continuation of use. Also, anxiety, dysphoria, insomnia, gated (El-Naby and Kamel 2015) and different samples nonspecific malaise, and suicidal ideation have been tested such as urine, blood, and oral fluid (Rodrigues described as part of DXM withdrawal (Miller 2005; et al. 2008). Cross reactivity is also obtained for the Stanciu et al. 2016). DXM enantiomer levomethorphan that presents potent Since DXM can be found in the form of a bromide narcotic proprieties (Wong and Sunshine 1996). salt, bromide poisoning may occur if large quantities Therapeutic dosing regimens generally produce are taken. Bromide poisoning, known as bromism, is DXM blood concentrations below 50 ng/mL. Generally, primarily a chronic neuropsychiatric disorder mani- plasma concentration range of 0.5–5.9 ng/mL (mean fested by behavior changes, headaches, apathy, irrita- 2.4) for EM and 182–231 ng/mL (mean 207) for PM has tion, slurred speech, psychosis, tremors, ataxia, been described (Cochems et al. 2007). The reference hallucinations, and coma (James et al. 1997; Frances blood level list of therapeutic and toxic substances of et al. 2003; Hsieh et al. 2007). It can also cause weight The International Association of Forensic Toxicologists loss and bromoderma characterized as an acneiform and provided by other comprehensive collection of 272 A. R. SILVA AND R. J. DINIS-OLIVEIRA data report serum concentrations of 10–40 ng/mL mechanisms of death are serotonin syndrome and gen- (Repetto and Repetto 1998, 1999; Bailey et al. 2000; eralized CNS depression (Logan 2009; Logan et al. Schulz et al. 2012). Due to extensive metabolism of 2009, 2012). DXM to DXO, the first is found in low concentrations The diagnosis of a dissociative condition should not and the second in high concentrations in the blood, only take into account the elevated blood concentra- resulting in a blood DXM/DXO ratio of less than 0.11; tions of the DXM and DXO, but should also consider a however, in PM subjects, this ratio can invert and rise DSM-V psychiatric criteria (Logan 2009; Logan et al. up to 2.5 or higher (Mortimer et al. 1989). Blood con- 2009, 2012). Although evaluation by drug recognition centrations were described to be toxic at 0.1–2.8 mg/L experts indicated that drivers had poor psychomotor and lethal at 1.8–18 mg/L; for humor vitreous and liver, performance on standardized field sobriety tests, hori- concentrations of 0.7 mg/L and 19–230 mg/kg were zontal gaze nystagmus, vertical gaze nystagmus, and obtained, respectively (Repetto and Repetto 1998, 1999; overall signs of central nervous system depression, 96% Logan 2009; Logan et al. 2009, 2012; Schulz et al. 2012). of these samples contained other drugs (Cochems et al. Several deaths were reported in Pakistan after consum- 2007). Logan (2009) and Logan et al. (2009) described ing cough sirups containing DXM. In an important casu- cases of eight drivers arrested for driving under the istic of 30 deaths caused by DXM, toxicological analysis influence of the combined effects of DXM and chlor- revealed concentrations ranging from 7.3 to 41.7 mg/L pheniramine, and a further four drivers under the influ- in the peripheral blood, 4.2–92.6 mg/kg in the liver and ence of DXM alone. Drivers generally displayed 9.9–349.6 mg/L in the gastric content. All subjects symptoms of CNS depression, gross evidence of impair- tested positive for the presence of opiates, eight for ment in their driving, including weaving, leaving the cannabinoids, and two for benzodiazepines. Gastric lane of travel, failing to obey traffic signals, and involve- contents of one deceased also contained 1.1 g/dL etha- ment in collisions. To evaluate DXM related-deaths, it is nol. Table 2 provides a compilation of toxic and lethal relevant to consider the potential significance of a co- concentrations in several reported cases. administrated or co-ingested drug, since DXM is fre- A study in rats showed that some postmortem redis- quently abused combined with other substances, and tribution of DXM can occur, characterized by a mean of some of the effects following that DXM abuse might be sixfold increase and maximum of 15-fold; this was not caused or exacerbated by those other concomitant sub- studied for DXO, but previous studies with other drugs stances (Chyka et al. 2007). Several DXM-related deaths show a tendency for the metabolites to undergo the had been reported in impaired drivers (Cochems et al. same extent of postmortem redistribution as the corre- 2007), where whole blood DXM concentrations aver- sponding parent drug (Bailey et al. 2000). The relative aged 51 lg/L (range 5–1800 lg/L). In another incident, distribution of DXM and DXO in skeletal tissues of rats five drivers died after consuming 1500 mg DXM (Logan having undergone acute or repeated exposure to DXM 2009; Logan et al. 2009). All of them had documented in different microclimate environments was assessed abuse histories of recreational DXM abuse and their (Unger and Watterson 2016; Morrison et al. 2017). In blood DXM concentration averaged 790 lg/L (range this study, the drug exposure patterns were shown to 470–1220 lg/L). It is also important to highlight that be distinguishable from bone drug levels after decom- that toxicological analysis should also include metabol- position, in other words, it was possible to discern ite DXO levels, since as mentioned above, DXO has a acute from repeated drug exposure. Both DXM levels longer half-life than DXM and it also has increased and the ratio of the levels of DXO to DXM were useful pharmacological action and potentially increased in discriminating acute from repeated drug exposure. impairment effects in relation to driving. Moreover, analyte levels and analyte ratios did not dif- In another study, cannabidiol e-liquids used in elec- fer significantly between different microclimates during tronic cigarettes (e-cigarettes) revealed unexpectedly 5- bone decomposition. Further investigation is necessary fluoro MDMB-PINACA (5F-ADB) in four of the products to evaluate physiochemical differences during differen- and DXM in one of the products. The analysis of these tial decomposition (Morrison et al. 2017). products illustrates the potential quality control issues The postmortem findings in individuals dying from that can occur in an unregulated industry (Poklis et al. DXM intoxications are nonspecific, and similar to other 2019). DXM has also been used as cutting agent of her- opioid intoxications, namely cerebral edema, pulmon- oin, increasing the risk of adverse health effects on con- ary edema, and frothy foam in the major airways with- sumers, possibly due to the synergistic effect of the out evidence of trauma or antecedent natural disease adulterants laced with substances of abuse (Solimini (Logan 2009; Logan et al. 2009, 2012). The most likely et al. 2017). DRUG METABOLISM REVIEWS 273

Table 2. Therapeutic, toxic, and lethal concentrations of dextromethorphan (DXM) in different biological samples. Biological samples [Dextromethorphan] and additional toxicological data References Serum 0.1 mg/L toxic (Repetto and Repetto 1998, 1999) 3 mg/L lethal Blooda 3 mg/L lethal 0.15 mg/L lethal (infant; age not described) Blooda 0.15–1.22 mg/L toxic (Logan 2009; Logan et al. 2009) Association with chlorpheniramine and in one case temazepam, lorazepam, oxazepam, clonazepam, trazodone, venlafaxine, and bupropion at therapeutic or sub therapeutic concentrations were also found Blooda 0.67 mg/L toxic Association with chlorpheniramine, Nor-9-carboxy-D9- tetrahydrocannabinol and fluoxetine 20-years-old Blooda 0.19–1 mg/L toxic Association with ethanol Blooda 1 mg/L toxic, plus guaifenesin and Nor-9-carboxy-D9- tetrahydrocannabinol 22-years-old Heart blood 3.23 mg/L lethal, association with cannabinoids; 17-years-old 1.89 mg/L lethal, association with diphenhydramine and cannabinoids; 19-years-old Iliac blood 1.3 mg/L lethal Vitreous humor 0.7 mg/L lethal Liver 19 mg/kg lethal Urine >20 mg/L lethal Association with alprazolam; 19-year-old Iliac blood 0.95 mg/L lethal 3.08 mg/L lethal Association with diphenhydramine; 19-year-old Blooda 5.09 mg/L, 1.4 mg/L DXO lethal (Kintz and Mangin 1992) Urine 3.29 mg/L, 3.09 mg/L DXO lethal Bile 3.48 mg/L, 1.86 mg/L DXO lethal Liver 10.74 mg/kg, 4.81 mg/kg DXO lethal Heart 2.38 mg/kg, 1.72 mg/kg DXO lethal Kidney 4.27 mg/kg, 2.09 mg/kg DXO lethal Brain 3.47 mg/kg, 1.58 mg/kg DXO lethal Association with terfenadine; 22-years-old Blood from femoral vein 9.2 mg/g, 2.9 mg/g DXO lethal (Rammer et al. 1988) Liver 31.2 mg/g, 11.5 mg/g DXO lethal 18-years-old Blood from femoral vein 3.3 mg/g, 1.5 mg/g DXO lethal Liver 230 mg/g, 29.2 mg/g DXO lethal 27-years-old Blooda 2.6 mg/L lethal (Yoo et al. 1996) Gastric contents 25.5 mg/g lethal Association with zipeprol; 21-years-old Blooda 1.2 mg/L lethal Gastric contents 243.7 mg/g lethal Association with zipeprol; 20-years-old Blooda 4.1 mg/L lethal Association with zipeprol; 19-years-old Blooda 1.8 mg/L lethal Gastric contents 2.1 mg/g lethal Association with zipeprol; 21-years-old Blooda 1.4 mg/L lethal Gastric contents 3.4 mg/g lethal Association with zipeprol; 19-years-old Blooda 1.8 mg/L lethal Gastric contents 15 mg/g lethal Association with zipeprol; 29-years-old Blooda 18.3 mg/L lethal Association with zipeprol; 22-years-old Blooda 2.9 mg/L lethal Association with zipeprol; 21-years-old Blooda 1.1 mg/L lethal Association with zipeprol and ethanol; 22-years-old Peripheral blooda 4.74 mg/L lethal (Logan et al. 2012) 31-years-old Blooda 0.3 mg/L toxic 23-years-old Blooda 1.05 mg/L toxic (continued) 274 A. R. SILVA AND R. J. DINIS-OLIVEIRA

Table 2. Continued. Biological samples [Dextromethorphan] and additional toxicological data References Association with chlorpheniramine and Nor-9-carboxy-D9- tetrahydrocannabinol; 18-years-old Peripheral blooda 2.42 mg/L toxic Association with pseudoephedrine, chlorpheniramine, sertraline, caffeine, cannabinoids, and desmethylsertraline; 15-years-old Peripheral blooda 19.5 mg/L lethal Association with chlorpheniramine 13-years-old Blooda 0.5 mg/L lethal (Boland et al. 2003) Liver 0.57 mg/kg lethal Association with brompheniramine and pseudoephedrine; 2- months-old Cavity blooda 0.55 mg/L toxic (Marinetti et al. 2005) Brain 1.3 mg/kg toxic Urine 2.9 mg/L toxic Association with ephedrine, pseudoephedrine, acetaminophen, ethanol; 12-months-old Peripheral blooda 0.08 mg/L toxic Brain 0.58 mg/kg toxic Liver 0.90 mg/kg toxic Association with ephedrine, pseudoephedrine, acetaminophen, and ethanol; 8-months-old Heart blood 0.04 mg/L lethal Liver 0.29 mg/kg lethal Association with ephedrine, pseudoephedrine, carbinoxamine, acetaminophen, and levorphanol; 2-months-old Heart blood 0.03 mg/L toxic Association with ephedrine, pseudoephedrine, acetaminophen, and levorphanol; 3-months-old Cavity blood 0.09 mg/L lethal Liver 0.55 mg/kg lethal Association with ephedrine, pseudoephedrine, carbinoxamine, acetaminophen, metoclopramide, and levorphanol; 5-months-old Peripheral blood 7.3–41.7 mg/L (Shafi et al. 2016) All subjects tested positive for the presence of opiates, 8 were tested positive for cannabinoids, and 2 were tested positive for benzodiazepines. Gastric contents of one deceased also contained 1.1 g/dL ethanol 18- to 45-years (30 fatal cases) Liver gastric contents 4.2–92.6 mg/kg 9.9–349.6 mg/L 17- to 45-years-old (7 cases) All subjects also tested positive for the presence of opiates, 3 were tested positive for cannabinoids and 2 were tested positive for the presence of benzodiazepines by immunoassay. In 5 deceased, 0.02–0.43 g/dL ethanol was also found in the gastric contents aThe anatomic place of collection is not described.

Interestingly, Olives et al. (2019) reported a patient Treatment of acute intoxications with persistent DXM hydrobromide abuse at escalating Recognition of DXM abuse is difficult in emergency doses whose mean serum chloride concentration context, since the signs and symptoms are not specific increased, on average, by 0.00232 mEq/L every day for DXM and can even precipitate a psychiatric diag- over a 110-month period. This case demonstrates pro- nose, and because DXM is not routinely tested in stand- gressive spurious hyperchloremia secondary to bromide ard toxicological urine drug assays (Dilich and Girgis interference in hospital-based ion-selective chloride 2017). Thereby, the early identification of its use and assays, supporting the patient’s reported need to dose whether other drugs were co-ingested may be chal- escalate to the same desired effect. Although this arte- lenging. Careful anamnesis collected either from the factual hyperchloremia laboratory finding is a well- patient or other people who may have essential infor- documented result of bromide ingestion (Emancipator mation or inspection of the patient’s belongings can and Kroll 1990; Ng et al. 1992; Hsieh et al. 2007), help on the identification of the drug causing the acute authors claimed that this artifact may be useful in iden- intoxication (Chyka et al. 2007). tifying patterns of DXM hydrobromide use that sug- When addressing a DXM acute intoxication, monitor- gest tolerance. ing of vital signs and respiratory, cardiovascular, and DRUG METABOLISM REVIEWS 275 neurological status are essential. Additionally, support- Foster 2008), and it is thought that restrictions over ive and symptomatic care should be provided accord- these OTC formulations access would mostly interfere ing to the needs (Chyka et al. 2007), followed by with its legitimate use (Spangler et al. 2016). identification and treatment of any psychiatric or med- When intoxication occurs, effects on central nervous ical conditions that may be simultaneous (Logan 2009; system are predominant (Chyka et al. 2007), with other Logan et al. 2009). Particularly, the treatment of anxiety, important symptoms emerging, such as nausea, vomit- agitation, seizures, and psychosis by the administration ing, tachycardia, and hypertension (Kaplan et al. 2011; of short-action benzodiazepines or a low-dose of short- Spangler et al. 2016). Since DXM is usually not detected term antipsychotics, should be considered. Many by routine toxicological screens, a high suspicion is patients may benefit from pharmacological aid for required for its identification (El-Naby and Kamel 2015), insomnia or sleep cycle dysregulation (Logan 2009; thus enabling appropriate patient management, includ- Logan et al. 2009, 2012). External cooling measures can ing supportive and symptomatic care (Chyka et al. be used for hyperthermia that may result from sero- 2007). Also, these patients should be checked for intoxi- tonin syndrome. cation by other drugs that can have been co-ingested The benefit of using naloxone in a DXM intoxication with DXM, such as acetaminophen or antihistamines is not clear; however, if the patient is sedated or coma- (Woo and Hanley 2013), providing treatment tose, particularly if there is respiratory depression, its accordingly. use may be considered, given its low risk for adverse DXM has a wide range of effects and its pharmaco- effects. Likewise, although the benefit of charcoal use is kinetics and pharmacodynamics are complex. The not proven, it can be considered in specific circumstan- metabolism of DXM is affected by inter-individual vari- ces, especially if less than one hour since ingestion ability, namely polymorphisms in genes encoding (Chyka et al. 2007). Intravenous fluids should be given enzymes involved, as is the case for CYP2D6, the main as indicated. enzyme involved (Meyer et al. 1990; Takashima et al. Since DXMs abuse can occur using co-formulated 2005), and by other drugs that cause metabolic interac- preparations of cough sirup, checking for intoxication tions with DXM, usually as substrates or inhibitors of by these other drugs should be done and treatment the metabolic pathways (Coutts et al. 1994; Pope et al. should be directed according to the findings (Gunn 2004; Garnock-Jones 2011; Taylor et al. 2016; Collins et al. 2001; Woo and Hanley 2013); for example, if sus- 2018). Other, non-metabolic interactions have also pected co-ingestion of paracetamol, its levels should be been described and are relevant once DXM is usually measured and toxicity treated appropriately, with N- not ingested alone (Chyka et al. 2007; Banken and acetylcysteine (Brown et al. 2018). Foster 2008; Brown et al. 2018), as they can precipitate a serotonin syndrome or a central nervous system depression (Dy et al. 2017; Baldo 2018; Moss Conclusions and future perspectives et al. 2019).

DXM is widely available, present in approximately 140 DXM stimulates r1R and blocks NMDA receptors, prescription and nonprescription cough and cold medi- mechanism that may be underlying its cough suppres- cations (Chyka et al. 2007), and it is known to be safe sant properties (Brown et al. 2004), and may also be the and effective at therapeutic doses (Spangler et al. basis for its anticonvulsant and neuroprotective effects

2016). DXM has little recurrence of abuse (Spangler (Chou et al. 1999; Shin et al. 2005). Additionally, r1R et al. 2016), has no significant addiction liability (El- activation is associated with antidepressant-like activity Naby and Kamel 2015), and follows other hallucinogen (Nguyen et al. 2014) and, when high doses of DXM are abuse pattern with a peak of use at 19-years-old and a present, may induce a schizophrenic-like mental state rapid decrease afterwards (Karch 2008; Karch and (Martinak et al. 2017); these elevated DXM doses act on Drummer 2016). Nevertheless, reports show a decrease NMDA receptors, and can induce euphoria and hallu- of abuse of OTC cough and cold medication containing cinogenic and dissociative effects, as seen with PCP and DXM since 2006, and quite markedly since 2010, pos- ketamine (Logan 2009; Logan et al. 2009, 2012). Some sible due to an increased awareness with FDA ‘Talk of these effects are also carried by DXM’s metabolites, Paper’ issued in 2005 (Desai et al. 2006) and to a variety and DXO, its main active metabolite, may be the major of education initiatives in the form of a mitigation plan responsible compound for the psychotic and dissocia- lead by CHPA in 2010 (Spangler et al. 2016). Currently, tive states (Miller 2005; Logan 2009; Logan et al. 2009, DXM is not scheduled under the CSA (Banken and 2012). Serotonin enhancement contributes to its abuse 276 A. R. SILVA AND R. J. DINIS-OLIVEIRA potential and to the risk of serotonin syndrome, that longa on CYP2D6-and CYP3A4-mediated metabolism of can increase with certain drug interactions (Chyka et al. dextromethorphan in human liver microsomes and 2007), as pointed above. healthy human subjects. Eur J Drug Metab Pharmacokinet. – Taken together all these issues contribute concur- 40(1):61 66. Aumatell A, Wells RJ. 1993. Chiral differentiation of the rently to a diversity in DXM clinical and toxicological optical isomers of racemethorphan and racemorphan in aspects, and better understanding these may help urine by capillary zone electrophoresis. J Chromatogr Sci. delineate strategic uses of this drug, considering its 31(12):502–508. potential applications, allowing a more efficient and Aytha SK, Dannaram S, Moorthy S, Sharma A. 2013. A case of safe use of DXM (Gaedigk 2013). Moreover, CYP2D6 acute psychosis secondary to coricidin overdose. Prim genotype analysis would be clinically very useful; how- Care Companion CNS Disord. 15(6): PCC.13l01549. DOI:10. 4088/PCC.13l01549 ever, it is not so simple given the big number of allelic Bailey B, Daneman R, Daneman N, Mayer JM, Koren G. 2000. variants and presence of structural and copy number Discrepancy between CYP2D6 phenotype and genotype variation. 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