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Metabolism of Psilocybin and Psilocin: Clinical and Forensic Toxicological Relevance

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Metabolism of Psilocybin and Psilocin: Clinical and Forensic Toxicological Relevance Drug Metabolism Reviews ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: http://www.tandfonline.com/loi/idmr20 Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance Ricardo Jorge Dinis-Oliveira To cite this article: Ricardo Jorge Dinis-Oliveira (2017): Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance, Drug Metabolism Reviews, DOI: 10.1080/03602532.2016.1278228 To link to this article: http://dx.doi.org/10.1080/03602532.2016.1278228 Accepted author version posted online: 11 Jan 2017. Published online: 31 Jan 2017. Submit your article to this journal Article views: 39 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=idmr20 Download by: [b-on: Biblioteca do conhecimento online CESPU] Date: 08 February 2017, At: 02:51 DRUG METABOLISM REVIEWS, 2017 http://dx.doi.org/10.1080/03602532.2016.1278228 REVIEW ARTICLE Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance Ricardo Jorge Dinis-Oliveiraa,b,c aDepartment of Sciences, IINFACTS – Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal; bDepartment of Biological Sciences, UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Porto, Portugal; cDepartment of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal ABSTRACT ARTICLE HISTORY Psilocybin and psilocin are controlled substances in many countries. These are the two main hal- Received 1 November 2016 lucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists Revised 21 December 2016 Accepted 27 December 2016 at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This KEYWORDS review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor Psilocybin; psilocin; psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline metabolomics; metabolism; phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucur- toxicity; toxicokinetics onide being the main urinary metabolite with clinical and forensic relevance in diagnosis. Introduction 5-hydroxytryptamine [5-HT]) like such as psilocybin, psilocin and lysergic acid diethylamide [LSD]; and (ii) Hallucinogens are compounds that in low doses alter a catecholamines (i.e., dopamine, noradrenaline and person’s perception of reality often in dramatic and unpredictable ways, thought, or mood, without causing adrenaline) like such as mescaline (Figure 1). Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyl- marked psychomotor stimulation or depression and N N preserving alertness, attentiveness, memory and orien- tryptamine; Figure 2) and psilocin (4-hydroxy- , -dime- tation (Cody, 2008). Although they mainly cause audi- thyltryptamine) are tryptophan indole-based alkaloids tory, visual and tactile distortions, gustatory and distributed worldwide in mushrooms of the genus Psilocybe Panaeolus Conocybe Gymnopilus Stropharia olfactory alterations may also be present. These sensory , , , , , Pluteus Panaeolina distortions are referred to as synesthesia, meaning that and (Cody, 2008; Derosa & Maffioli, sounds are “seen” or colors are “heard”, etc. (Chan & 2014; Tyls et al., 2014). Both are tryptamines, i.e., Mendelson, 2014). Although called hallucinogens, hallu- have an indole ring structure, a fused double ring com- cinations (i.e., such as manifestations of something non- prising of a pyrrole ring and a benzene ring, joined existent or dream-like episodes in awake humans) are to an amino group by a two carbon side chain not always present and therefore psychedelics (“mind (Tittarelli et al., 2015). They are commonly referred as revealing”)or“psychotomimetics” (psychosis mimick- “magic”, “hallucinogenic”, “psychedelic”, “entheogenic”, ing) are alternative preferred designations (Nichols, “medicinal”, “neurotropic”, “psychoactive”, “sacred” or 2004; Osmond, 1957). These compounds differ from “saint” mushrooms (Guzman, 2008). Psilocin and psilo- most other psychoactive drugs since they induce nei- cybin are typically used as recreational drugs by eating ther dependence nor addiction nor are used for pro- the mushrooms, which contains them at concentrations longed periods; in other words, these drugs do not of up to 0.5% and 2% (m/m), respectively (Pedersen- interfere with the mesolimbic rewarding system and are Bjergaard et al., 1997). Nevertheless, these concentra- considered physiologically safe (Katzung et al., 2012; tions show a large variation depending on the species, Nichols, 2004). One of the possible classification origin, mushroom sizes, growing and drying conditions, schemes divide hallucinogens as (i) serotonin (i.e., and age (van Amsterdam et al., 2011). Although both CONTACT Ricardo Jorge Dinis-Oliveira [email protected] Department of Sciences, University Institute of Health Sciences (IUCS)-CESPU, Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal ß 2017 Informa UK Limited, trading as Taylor & Francis Group 2 R. J. DINIS-OLIVEIRA H H H N N N HO OOHH NNHH2 N N Serotoninin oror 5-5- PsilocPsilocinin N,N-Di-Dimethyltryptaminemethyltryptamine 5-methoxy-5-methoxy-N,N- hydroxytryptaminemine (5-(5-HT)HT) ((4-hydroxy-4-hydroxy-N,N- ((DMT)DMT) dimethyltryptaminedimethyltryptamine didimethyltryptamine)methyltryptamine) ((5-methoxy-DMT)5-methoxy-DMT) Simple triptamines Indolylalkylamines Lysergic acid diethylamidehylamide Ergoline OH NH2 HO OH Noradrenaline MescalineMescaline 2,5-Dimethoxy-4-2,5-Dimethoxy-4- 2,5-Dimethoxy-4-2,5-Dimethoxy-4- 2,5-Dimethoxy-4- mmethylamphetamineethylamphetamine iodoamphetamineiodoamphetamine bromoamphetamine (DOM) (DOI) (DOB) Phenylethylamines Figure 1. Chemical structures of hallucinogens. This class is divided in two major groups: (i) indolylalkylamines or triptamines or serotonin like and (ii) phenylethylamines or phenethylamine or b-phenylethylamine (2-phenylethylamine) or catecholamines (i.e., dopamine, noradrenaline and adrenaline) like such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy- 4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-bromoamphetamine (DOB). Indolylalkylamines include two subgroups: simple tryptamines with considerable conformational flexibility such as N,N-dimethyltryptamine (DMT), 5-methoxy-DMT, psilocybin and psilocin, and the relatively rigid analogs ergolines such as lysergic acid diethylamide (LSD). are naturally occurring compounds, psilocin and psilo- mainly supportive. Most probably, the higher risk cybin can also be chemically synthesized (Hofmann associated with hallucinogen administration is “bad et al., 1958, 1959; Shirota et al., 2003). trip”, which is characterized by anxiety, fear, panic, Although generally considered of low toxicity dysphoria and paranoia (Johnson et al., 2008). Early (LD50 ¼280 and 285 mg/kg for rats and mice, respect- single-blind experiments showed cross-tolerance of ively; a 60-kg person would need to ingest up to 1.7 kg psilocybin and LSD (Isbell et al., 1961). More recently, of fresh mushrooms to reach this dose), several acute and due to its safety profile (little or no affinity for toxic effects have been reported to be related to psilo- receptors that mediate vital functions) and non-addict- cybin and psilocin exposure is all organ systems (Isbell, ive effects, psilocin has emerged as having therapeutic 1959; Lim et al., 2012; van Amsterdam et al., 2011): (i) potential namely in psychotherapy as an anxiolytic, anti- cardiovascular (tachycardia, hypertension and hypoten- depressant and to control symptoms of the obsessive– sion); (ii) neurological (headache, confusion, euphoria, compulsive disorder, and in the treatment of head- muscle weakness, hallucinations, panic attacks, dereal- aches, alcohol dependence and smoking cessation ization, illusions, synesthesia, convulsions, alterations of (Grob et al., 2011; Moreno et al., 2006; Sewell et al., thought and time sense, vertigo, anxiety, agitation and 2006; Tyls et al., 2014). significant tolerance with repeated use without causing One of the objectives of metabolomics is the charac- dependence); (iii) respiratory (transient hypoxemia); terization of all xenobiotic metabolites and their qualita- (iv) gastrointestinal (nauseas); (v) acute renal failure; tive and quantitative changes over time (Barbosa et al., (vi) ocular (mydriasis); (vii) hematological; and (viii) fatal 2016; Dinis-Oliveira, 2014, 2015, 2016a, c, d). The focus accidental cases due to a strong emotional destabiliza- of this manuscript is to present all the available meta- tion or hallucinations that predisposed to risky behav- bolic data regarding psilocybin and psilocin focusing on iors such as the belief of the ability to fly (Muller et al., major and minor metabolites and discussing their 2013). No specific antidote is available, and treatment is pharmacological and toxicological relevance. DRUG METABOLISM REVIEWS 3 H N O O N Psilocin o-quinone H N O H N OH N OH Psilocin iminoquinone OH O Ceruloplasmin, 4-hydroxy-indole-3-acetic acid cytochrome oxidase Alkaline Fe3+ phosphatase, 7 H nonspecific H ALDH,
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