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

Metabolism of and : 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, 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.

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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 ” and both act as 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 -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- ; 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 diethylamide [LSD]; and (ii) are compounds that in low doses alter a catecholamines (i.e., , noradrenaline and person’s of reality often in dramatic and unpredictable ways, thought, or , without causing adrenaline) like such as (Figure 1). Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyl- marked psychomotor stimulation or and N N preserving alertness, attentiveness, memory and orien- ; Figure 2) and psilocin (4-hydroxy- , -dime- tation (Cody, 2008). Although they mainly cause audi- thyltryptamine) are -based tory, visual and tactile distortions, gustatory and distributed worldwide in mushrooms of the genus Stropharia olfactory alterations may also be present. These sensory , , , , , Panaeolina distortions are referred to as , meaning that and (Cody, 2008; Derosa & Maffioli, sounds are “seen” or colors are “heard”, etc. (Chan & 2014; Tyls et al., 2014). Both are , 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 ring, joined existent or -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” ( 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 since they induce nei- cybin are typically used as recreational drugs by eating ther dependence nor 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, sizes, growing and drying conditions, schemes divide hallucinogens as (i) (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- PsilocinPsilocin N,N-Dimethyltryptamine-Dimethyltryptamine 5-methoxy-5-methoxy-N,N- hydroxytryptaminemine (5-(5-HT)HT) (4-hydroxy-(4-hydroxy-N,N- (DMT)(DMT) didimethyltryptaminemethyltryptamine dimethyltryptamine)dimethyltryptamine) ((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 iiodoamphetamineodoamphetamine 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 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 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 administration is “bad et al., 1958, 1959; Shirota et al., 2003). trip”, which is characterized by , fear, panic, Although generally considered of low toxicity and (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 as an , anti- cardiovascular (, and hypoten- and to control symptoms of the obsessive– sion); (ii) neurological (, , , compulsive disorder, and in the treatment of head- muscle weakness, , panic attacks, dereal- aches, dependence and smoking cessation ization, illusions, synesthesia, , 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 (); (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, H 7a N 1 N N 6 2 esterases MAO 5 3a 4 3 OH β HO O 1' 2' OH OH P α N N O O [3-(2-Dimethylaminoethyl)-1H-indol-4-yl] 3-[2-(Dimethylamino)ethyl]-4-indolol 4-hydroxy-indole-3- (psilocybin) (psilocin) UGT1A10, UGT1A9, UGT1A6, UGT1A7, H UGT1A8 HO H N N

O O O HO OH N HO OH 4-hydroxytryptophole OH Psilocin-O-glucuronide Figure 2. Metabolism of psilocybin. The structure of tryptamine is indicated in red.

Methodology gastrointestinal tract, suggesting also greater central nervous system bioavailability (Eivindvik et al., 1989). An English extensive literature search was carried out Both are moderately soluble in and in PubMed (U.S. National Library of Medicine) without (Ballesteros et al., 2006). Pharmacokinetic studies in ani- a limiting period to identify relevant articles on mals showed that only 50% of 14C-labelled psilocybin is psilocybin, psilocin and related known metabolizing absorbed following oral administration and is almost and metabolites. Electronic copies of the full uniformly distributed throughout the body, including papers were obtained from the retrieved journal articles the brain, where it exerts its psychedelic properties “ ” as well as books on magic mushrooms and hallucino- (Hopf & Eckert, 1974). Moreover, the in vivo studies in gens, and then further reviewed to find additional pub- rats showed that psilocybin is rapidly hydrolyzed in lications related to human and non-human studies. the intestine to psilocin, meaning that psilocybin is absorbed mostly or even all as psilocin (Eivindvik et al., , distribution and 1989). In humans, psilocin is detectable in significant amounts in the plasma within 20–40 minutes after per “Magic mushrooms” are typically administered per os os administration (Passie et al., 2002), and maximum (drink or in the form of bar of chocolates due to the concentrations are reached after approximately unpleasant flavor) or smoked. Since it is a zwitterionic 80–100 min (Hasler et al., 1997; Lindenblatt et al., 1998). and due to the presence of a highly polar phos- The effects completely disappear within about 4–6h phate group, psilocybin is more soluble in water than (Shulgin, 1980). psilocin (Ballesteros et al., 2006). Therefore, psilocin is Psilocybin and psilocin have an elimination half-life more easily absorbed from the rat jejunum and colon in plasma of approximately 160 and 50 min, respectively 4 R. J. DINIS-OLIVEIRA

(Hasler et al., 1997; Martin et al., 2013a). In vivo studies dehydrogenase, via a presumed intermediate metabol- in rats have shown that psilocin is excreted in urine ite, 4-hydroxyindole-3-acetaldehyde, to 4-hydroxy- (65%) and and feces (15–20%) within 8 h after oral indole-3-acetic acid, 4-hydroxy-indole-3-acetaldehyde administration (Kalberer et al., 1962). About 10–20% and 4-hydroxytryptophole (Kalberer et al., 1962; remained in the organism for a longer time with metab- Lindenblatt et al., 1998). Therefore, MAO inhibitors are olites of psilocin being detected in urine seven days also co-consumed by psilocin abusers to intensify its after oral administration (Hofmann, 1968; Kalberer et al., hallucinogenic effects (Halpern, 2004). Indeed, ethanol 1962). About 25% of the whole dose was shown to be may enhance the trip since its primary metabolite acet- excreted unaltered (Kalberer et al., 1962). A controlled aldehyde reacts in vivo with endogenous biogenic study in humans showed that within 24 h, 3.4 ± 0.9% of producing the MAO-inhibitors tetrahydroisoqui- the applied dose of psilocybin was excreted in urine as nolines and b-carbolines. use is also associated free psilocin (Hasler et al., 2002). Later pharmacokinetic with lowered levels of MAO in the brain and peripheral and forensic studies revealed that psilocin is mostly tissues and therefore extended effects of “magic mush- (approximately 80%) eliminated as psilocin-O-glucuro- rooms” are likely (Fowler et al., 1996). Moreover, since nide (Grieshaber et al., 2001; Sticht & Kaferstein, 2000). psilocin may cause competitive inhibition of MAO and The enzymatic hydrolysis of this conjugate during ana- this also metabolizes serotonin, brain levels of lysis extends the time of detectability for psilocin in serotonin may be elevated and simultaneously 5-HIAA urine samples, namely due to the higher stability of this may decrease (Freedman et al., 1970). It was also metabolite compared to psilocin, especially at room described a minor oxidation metabolic pathway of psi- temperature (Hasler et al., 2002; Martin et al., 2014). locin to a deep blue color product with an o-quinone or iminoquinone structure. This pathway was claimed to be catalyzed by hydroxyindol oxidases (e.g., ceruloplas- Metabolism min, the copper containing oxidase of mammalian The metabolism of psilocybin and psilocin is presented plasma and cytochrome oxidase) or non-enzymatically in Figure 2. After oral administration, psilocybin is rap- by Fe3þ (Blaschko & Levine, 1960; Horita & Weber, idly dephosphorylated under acidic environment of the 1961a; Kovacic, 2009). Although these metabolites may

stomach or by (and other nonspe- present physiological activity related to production of cific esterases) in intestine, and perhaps in the reactive species during catalytic cycling, data blood to generate the phenol compound psilocin, are yet limited (Kovacic & Cooksy, 2005). Additionally, which easily crosses the blood-brain barrier (Hasler the oxidation to the bluish products also appears when et al., 1997; Horita & Weber, 1961b, 1962). Other rodent mushrooms are handled or damaged. tissue studies presented more evidence for complete The analysis of samples collected 5 h after conversion of psilocybin to psilocin before entering the “magic mushrooms” intoxication showed that up to systemic circulation (Eivindvik et al., 1989). This assump- 80% of the psilocin was present as the O-glucuronide tion is also supported by the observation that equimo- conjugate and is eliminated by urine in this form lar amounts of psilocybin and psilocin evoke (Kamata et al., 2006). Glucuronidation of hydroxyl group qualitatively and quantitatively similar psychotropic to psilocin O-glucuronide seems to be an important effects in humans (Passie et al., 2002). Psilocybin could detoxification step. Indeed, the same occurs in the for- therefore be referred to as a and whenever a mation of 5-hydroxytryptamine O-glucuronide during reference is made to the in vivo effects of psilocybin, it serotonin metabolism (Eivindvik et al., 1989; Sticht & should be understood that it is psilocin the responsible Kaferstein, 2000). Therefore, enzymatic hydrolysis for the effects. Noteworthy is the relative of extends the detection time for psilocibin in urine sam- psilocin to psilocybin (1.48); almost identical to the ples (Hasler et al., 2002). Whereas psilocin may be sub- molecular weight ratio between the two compounds jected to extensive glucuronidation by UDP- (Wolbach et al., 1962). Moreover, blockage of alkaline (UGT)1A10 in the small intes- phosphatase by means of competitive substrates tine, UGT1A9 is likely the main contributor to its glucur- (b-glycerophosphate) prevents the symptoms of intoxi- onidation once it has been absorbed into the cation (Horita, 1963). Since psilocin is structurally related circulation (Manevski et al., 2010). N-glucuronidation to the serotonin (Figures 1 and 2), it was not observed (Manevski et al., 2010). undergoes comparable human metabolism (Helsley The analysis of psilocybin and psilocin in body fluids et al., 1998). Indeed, psilocin is then further metabolized is challenging since the analytes are rapidly metabo- by a demethylation and oxidative deamination cata- lized and are unstable under the influence of light and lyzed by (MAO) or aldehyde air, especially when in solution (Hasler et al., 1997). DRUG METABOLISM REVIEWS 5

Blood samples stored at room temperature evidenced a and mescaline; stimulation of central serotonin recep- continuous decrease of about 90% of the analyte within tors and blockade of peripheral serotonin receptors one week (Martin et al., 2012). Storage at 4 C improved (Wolbach et al., 1962). They bind with high affinity at stability to almost seven days if fluoride was added. 5-hydroxytryptamine (5-HT)2A and to a lesser extent at Surprisingly, freezing blood samples led to an unrepro- 5-HT1A, 5-HT1D and 5-HT2C subtype receptors (McKenna ducible and uncontrollable loss of psilocin. The authors et al., 1990). In contrast, they exhibit no apparent affin- suggested that enzymes involved in psilocin metabol- ity for dopamine D2 receptors (Creese et al., 1975). ism are released from hemolysis that occurs during However, results are contradictory since the administra- freezing (Martin et al., 2012). Therefore, if psilocin needs tion of (i.e., D2 ) also to be analyzed, whole blood samples should not be reduces psilocybin-induced psychotomimesis, raising stored at room temperature or frozen. It is preferable the possibility of a neuronal transmission that blood samples be cooled until they reach the involvement. Indeed, the administration of psilocybin to laboratory and then centrifuged to freeze the serum healthy human volunteers, decreased the binding of 11 (Martin et al., 2012). the dopamine D2 antagonist [ C] raclopride in both caudate nucleus and putamen (Vollenweider et al., 1999). This effect is compatible with an increase in Conclusion and future perspectives extracellular dopamine that competitively displaces the Use of hallucinogens remains a significant problem for antagonist. Therefore, the probability that the inter- a population of drug abusers. These drugs have a long action of indolylalkylamines with non-5-HT2 receptors history and their popularity comes and goes with time, with psychopharmacological and behavioral conse- but they remain a constant presence in the drug com- quences should not be excluded (Halberstadt & Geyer, munity, mainly by young people seeking psychedelic 2011). Although psilocybin does not show any affinity . Although pure synthetic psilocybin to dopamine receptor of D2 subtype, interactions V (Indocybin R ) was marketed for experimental and psychi- between and dopaminergic neuronal sys- atric therapy in the 1960s, only limited pharmacokinetic tems are known to exist (Vollenweider et al., 1999). and pharmacodynamic data are available. Since the pharmacodynamics and the mechanisms

In this work, the metabolism of psilocybin and psilo- underlying the emergence of psychedelic alterations cin was fully reviewed. Psilocybin is predominately are not fully understood, metabolomic studies may pro- dephosphorylated in the intestine and liver by alkaline vide addition insights to help clinical and forensic toxi- phosphatase to psilocin, which is the main psychoactive cologists in the interpretation of toxicological results. compound. More studies are needed to identify add- Noteworthy is the recent renewed interest of psilocin in itional metabolites, and the influence of drug interac- the treatment of resistant depression, obsessive com- tions and polymorphisms in and pulsive disorder, cancer anxiety, and alcohol and pharmacodynamics. Indeed, Lindenblatt et al. (1998) tobacco addition (de Veen et al., 2016; Hendrie & revealed a large interindividual variation as regards psi- Pickles, 2016; Nichols, 2016). In these pathologies, clin- locin plasma concentrations in healthy volunteers after ical trials with adequate control of metabolic profile and oral administration of psilocybin. The identification of metabolome (e.g., stress hormones such as cortisol) can additional metabolites is also important for qualitative help to predict if psilocybin outweighs its adverse and quantitative toxicological analysis (Dinis-Oliveira, effects. 2016b). Particularly, further sensitive analytical methods Finally, scarce data is available regarding other active will prove consumption in a wider detection window, hallucinogen compounds found in mushrooms. Indeed, especially if hydrolysis of glucuronide conjugates is besides psilocybin and psilocin, magic mushrooms also performed. contain (4-phosphoryloxy-N-methyltrypt- Literature data suggests that psilocybin and psilocin ) and (4-phosphoryloxytryptamine), exhibit low toxicity and may be seen as physiologically which are mono- and di-N-demethylated equivalents of well tolerated. However, most studies are old and do psilocybin, respectively (Figure 3) (Franke et al., 2002; not meet contemporary standards for safety assessment Mahmood et al., 2010). It is also known that there and therefore more controlled studies are needed to are further psychoactive compounds found in ascertain the therapeutic role in certain diseases, espe- other mushrooms species such as aeruginascin (N,N,N- cially those psychiatry-related (Passie et al., 2002). trimethyl-4-phosphoryloxytryptamine), a trimethyl Although exhibiting different potencies and time analog of psilocybin, and bufotenine (N,N-dimethyl- course, it is known that psilocybin and psilocin produce 5-hydroxytryptamine), a positional isomer of psilocin mainly pharmacological effects similar to those of LSD (Figure 3) (Jensen et al., 2006; Franke et al., 2002; 6 R. J. DINIS-OLIVEIRA

H H Blaschko H, Levine WG. (1960). Enzymatic oxidation of N N psilocine and other hydroxyindoles. Biochem Pharmacol 3:168–169. – OH OH Chan RHA, Mendelson JE. (2014) Chapter seventeen HO O HO O Hallucinogens. In: The effects of drug abuse on the human P P – NH NH2 nervous system. Boston: Academic Press, 533 552. O O Cody JT. (2008). Chapter 4 Hallucinogens. In: Bogusz MJ, ed. Baeocystin Norbaeocystin Handbook of analytical separations. Amsterdam, H Netherlands: Elsevier Science B.V., 175–201. N H N Creese I, Burt DR, Synder SH. (1975). The dopamine receptor: differential binding of d-LSD and related agents to – OH HO and antagonist states. Life Sci 17:1715 1719. HO O de Veen BT, Schellekens AF, Verheij MM, Homberg JR. (2016). P N+ N Psilocybin for treating substance use disorders? Expert Rev O Neurother 17:203–212. Aeruginascin Bufotenine Derosa G, Maffioli P. (2014). Alkaloids in the nature: pharma- Figure 3. Chemical structures of other hallucinogens present cological applications in clinical practice of berberine and in “magic mushrooms”. mate tea. Curr Topics Med Chem 14:200–206. Dinis-Oliveira RJ. (2014). Metabolomics of drugs of abuse: a Martin et al., 2013b). Together these compounds are more realistic view of the toxicological complexity. – less explored than psilocybin and psilocin and dephos- Bioanalysis 6:3155 3159. Dinis-Oliveira RJ. (2015). Metabolomics of : implica- phorization is also expected for psilocybin analogs to tions in toxicity. Toxicol Mech Methods 25:494–500. produce psychoactive metabolites. Dinis-Oliveira RJ. (2016a). Metabolomics of Delta9-tetrahydro- cannabinol: implications in toxicity. Drug Metab Rev 48:80–87. Acknowledgements Dinis-Oliveira RJ. (2016b). Metabolomics of delta(9)-tetra- hydrocannabinol: implications in toxicity. Drug Metab Rev ~ ^ Ricardo Dinis-Oliveira acknowledges Fundac¸ao para a Ciencia 48:80–87. e a Tecnologia (FCT) for his Investigator Grant (IF/01147/ Dinis-Oliveira RJ. (2016c). Metabolomics of methadone: clin- 2013). This work was supported by FEDER under Program ical and forensic toxicological implications and variability

– PT2020 (project 007265 UID/QUI/50006/2013). of dose response. Drug Metab Rev 48:568–576. Dinis-Oliveira RJ. (2016d). Oxidative and non-oxidative metab- olomics of ethanol. Curr Drug Metab 17:327–335. Disclosure statement Eivindvik K, Rasmussen KE, Sund RB. (1989). Handling of psilocybin and psilocin by everted sacs of rat jejunum and The author has no relevant affiliations or financial involve- colon. Acta Pharm Nord 1:295–302. ment with any organization or entity with a financial interest Fowler JS, Volkow ND, Wang GJ, et al. (1996). Inhibition of in or financial conflict with the subject matter or materials monoamine oxidase B in the brains of smokers. Nature discussed in the manuscript. This includes employment, con- 379:733–736. sultancies, honoraria, stock ownership or options, expert tes- Franke AA, Custer LJ, Wilkens LR, et al. (2002). Liquid chroma- timony, grants or patents received or pending, or royalties. tographic-photodiode array mass spectrometric analysis No writing assistance was utilized in the production of this of dietary phytoestrogens from human urine and blood. manuscript. J Chromatogr B Analyt Technol Biomed Life Sci 777:45–59. Freedman DX, Gottlieb R, Lovell RA. (1970). drugs and brain 5-hydroxytryptamine metabolism. Funding Biochem Pharm 19:1181–1188. Ricardo Dinis-Oliveira acknowledges Fundac¸~ao para a Ciencia^ Grieshaber AF, Moore KA, Levine B. (2001). The detection of – e a Tecnologia (FCT) for his Investigator Grant (IF/01147/ psilocin in human urine. J Forensic Sci 46:627 630. 2013). This work was supported by FEDER under Program Grob CS, Danforth AL, Chopra GS, et al. (2011). Pilot study of PT2020 (project 007265 – UID/QUI/50006/2013). psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 68:71–78. Guzman G. (2008). Hallucinogenic mushrooms in : an References overview. Econ Bot 62:404–412. Halberstadt AL, Geyer MA. (2011). Multiple receptors contrib- Ballesteros S, Ramon MF, Iturralde MJ, Martınez-Arrieta R. ute to the behavioral effects of indoleamine hallucinogens. (2006). Natural sources of drugs of abuse: magic mush- 61:364–381. rooms. In: Cole SM, ed. New research on street drugs. New Halpern JH. (2004). Hallucinogens and agents York, 167–186. naturally growing in the United States. Pharmacol Ther Barbosa J, Faria J, Queiros O, et al. (2016). Comparative 102:131–138. metabolism of and : a toxicological Hasler F, Bourquin D, Brenneisen R, et al. (1997). perspective. Drug Metab Rev 48:577–592. Determination of psilocin and 4-hydroxyindole-3-acetic DRUG METABOLISM REVIEWS 7

acid in plasma by HPLC-ECD and pharmacokinetic profiles Kovacic P. (2009). Unifying electron transfer mechanism for of oral and intravenous psilocybin in man. Pharm Acta psilocybin and psilocin. Medical Hypotheses 73:626. Helv 72:175–184. Kovacic P, Cooksy AL. (2005). Unifying mechanism for Hasler F, Bourquin D, Brenneisen R, Vollenweider FX. (2002). toxicity and addiction by abused drugs: electron Renal excretion profiles of psilocin following oral adminis- transfer and reactive oxygen species. Med Hypotheses tration of psilocybin: a controlled study in man. J Pharm 64:357–366. Biomed Anal 30:331–339. Lim TH, Wasywich CA, Ruygrok PN. (2012). A fatal case of Helsley S, Fiorella D, Rabin RA, Winter JC. (1998). A compari- 'magic mushroom' ingestion in a heart transplant recipient. son of N,N-dimethyltryptamine, , and selected Intern Med J 42:1268–1269. congeners in rats trained with LSD as a discriminative Lindenblatt H, Kramer E, Holzmann-Erens P, et al. (1998). stimulus. Prog Neuro-Psychopharmacol Biol Psychiatry Quantitation of psilocin in human plasma by high- 22:649–663. performance liquid and electrochemical Hendrie C, Pickles A. (2016). Psilocybin: panacea or ? detection: comparison of liquid-liquid extraction with auto- Lancet Psychiatry 3:805–806. mated on-line solid-phase extraction. J Chromatogr B Hofmann A. (1968) Psychomimetic agents. In: Burger A, ed. Biomed Sci Appl 709:255–263. Drugs affecting the central nervous system, medicinal Mahmood ZA, Ahmed SW, Azhar I, et al. (2010). Bioactive research series 2. New York: Dekker, 169–235. alkaloids produced by fungi. I. Updates on alkaloids from Hofmann A, Heim R, Brack A, Kobel H. (1958). Psilocybin, the species of the genera Boletus, Fusarium and psilocybe. ein psychotroper Wirkstoff aus dem mexikanischen Pak J Pharm Sci 23:349–357. RauschpilzPsilocybe mexicana Heim. Experientia Manevski N, Kurkela M, Hoglund C, et al. (2010). 14:107–109. Glucuronidation of psilocin and 4-hydroxyindole by the Hofmann A, Heim R, Brack A, et al. (1959). Psilocybin human UDP-glucuronosyltransferases. Drug Metab Dispos und Psilocin, zwei psychotrope Wirkstoffe aus mexikani- 38:386–395. schen Rauschpilzen. Helvetica Chimica Acta Martin R, Schurenkamp J, Gasse A, et al. (2013a). 42:1557–1572. Determination of psilocin, bufotenine, LSD and its metabo- Hopf A, Eckert H. (1974). Distribution patterns of 14-C-psilo- lites in serum, plasma and urine by SPE-LC-MS/MS. Int J cin in the brains of various animals. Act Nerv Super Legal Med 127:593–601. 16:64–66. Martin R, Schurenkamp€ J, Gasse A, et al. (2013b). Horita A. (1963). Some biochemical studies on psilocybin and Determination of psilocin, bufotenine, LSD and its metabo- psilogin. J Neuropsychiatry 4:270–273. lites in serum, plasma and urine by SPE-LC-MS/MS. Int J

Horita A, Weber LJ. (1961a). The enzymic Legal Med 127:593–601. and oxidation of psilocybin and pscilocin by mammalian Martin R, Schurenkamp J, Pfeiffer H, Kohler H. (2012). A vali- tissue homogenates. Biochem Pharmacol 7:47–54. dated method for quantitation of psilocin in plasma by Horita A, Weber LJ. (1961b). The enzymic dephosphorylation LC-MS/MS and study of stability. Int J Legal Med and oxidation of psilocybin and psilocin by mammalian 126:845–849. tissue homogenates. Biochem Pharmacol 7:47–54. Martin R, Schurenkamp J, Pfeiffer H, et al. (2014). Synthesis, Horita A, Weber LJ. (1962). Dephosphorylation of psilo- hydrolysis and stability of psilocin glucuronide. Forensic cybin in the intact mouse. Toxicol Appl Pharmacol Sci Int 237:1–6. 4:730–737. McKenna DJ, Repke DB, Lo L, Peroutka SJ. (1990). Isbell H. (1959). Comparison of the reactions induced by Differential interactions of indolealkylamines with 5- psilocybin and LSD-25 in man. Psychopharmacologia hydroxytryptamine receptor subtypes. Neuropharmacology 1:29–38. 29:193–198. Isbell H, Wolbach AB, Wikler A, Miner EJ. (1961). Cross toler- Moreno FA, Wiegand CB, Taitano EK, Delgado PL. (2006). ance between LSD and psilocybin. Psychopharmacologia Safety, tolerability, and efficacy of psilocybin in 9 patients 2:147–159. with obsessive-compulsive disorder. J Clin Psychiatry Jensen N, Gartz J, Laatsch H. (2006). Aeruginascin, a trimethy- 67:1735–1740. lammonium analogue of psilocybin from the hallucino- Muller K, Puschel K, Iwersen-Bergmann S. (2013). genic mushroom aeruginascens. Planta Medica under the influence of “magic mushrooms”. Arch Fur 72:665–666. Kriminol 231:193–198. Johnson M, Richards W, Griffiths R. (2008). Human hallucino- Nichols DE. (2004). Hallucinogens. Pharmacol Ther gen research: guidelines for safety. J Psychopharmacol 101:131–181. (Oxford) 22:603–620. Nichols DE. (2016). Psychedelics. Pharmacol Rev 68:264–355. Kalberer F, Kreis W, Rutschmann J. (1962). The fate of psilocin Osmond H. (1957). A review of the clinical effects of in the rat. Biochem Pharmacol 11:261–269. psychotomimetic agents. Ann New York Acad Sci Kamata T, Katagi M, Kamata HT, et al. (2006). Metabolism of 66:418–434. the psychotomimetic tryptamine derivative 5-methoxy- Passie T, Seifert J, Schneider U, Emrich HM. (2002). The N,N- in humans: identification and of psilocybin. Addict Biol 7:357–364. quantification of its urinary metabolites. Drug Metab Pedersen-Bjergaard S, Sannes E, Rasmussen KE, Tonnesen F. Dispos 34:281–287. (1997). Determination of psilocybin in Psilocybe semilan- Katzung BG, Masters SB, Trevor AJ. (2012). Basic and clinical ceata by capillary zone electrophoresis. J Chromatogr pharmacology. New York: McGraw-Hill. Biomed Sci Appl 694:375–381. 8 R. J. DINIS-OLIVEIRA

Sewell RA, Halpern JH, Pope HG. Jr. (2006). Response of clus- Tyls F, Palenicek T, Horacek J. (2014). Psilocybin–summary ter headache to psilocybin and LSD. Neurology of knowledge and new perspectives. Eur 66:1920–1922. Neuropsychopharmacol 24:342–356. Shirota O, Hakamata W, Goda Y. (2003). Concise large-scale van Amsterdam J, Opperhuizen A, van den Brink W. (2011). synthesis of psilocin and psilocybin, principal hallucino- Harm potential of magic mushroom use: a review. Regul genic constituents of “magic mushroom”. J Nat Prod Toxicol Pharmacol 59:423–429. 66:885–887. Vollenweider FX, Vontobel P, Hell D, Leenders KL. (1999). Shulgin AT. (1980). Profiles of psychedelic drugs. Psilocybin. 5-HT modulation of dopamine release in basal J Psychedel Drugs 12:79 ganglia in psilocybin-induced psychosis in man – a PET Sticht G, Kaferstein H. (2000). Detection of psilocin in body study with [11C]raclopride. Neuropsychopharmacology fluids. Forensic Sci Int 113:403–407. 20:424–433. Tittarelli R, Mannocchi G, Pantano F, Romolo FS. (2015). Wolbach AB, Jr., Miner EJ, Isbell H. (1962). Comparison Recreational use, analysis and toxicity of tryptamines. Curr of psilocin with psilocybin, mescaline and LSD-25. Neuropharmacol 13:26–46. Psychopharmacologia 3:219–223.