ejpmr, 2019,6(7), 125-130 SJIF Impact Factor 4.897 EUROPEAN JOURNAL OF PHARMACEUTICAL Review Article Singh et al. AND MEDICAL E uropeanRESEARCH Journal of Pharmaceutical and Medical ReISSNsearch 2394 -3211

www.ejpmr.com EJPMR

MAGIC MUSHROOM A POTENT HALLUCINOGEN: A CRITICAL REVIEW

Ritika Singh*, Trilochan Satapathy, Jhakeshwar Prasad and Mahendra Kumar Verma

Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Raipur, Chhattisgarh-493111, India.

*Corresponding Author: Ritika Singh Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Raipur, Chhattisgarh-493111, India.

Article Received on 12/05/2019 Article Revised on 02/06/2019 Article Accepted on 23/06/2019

ABSTRACT Hallucinogen, the substance which can alter a person's perception of reality. Some naturally occurring substances proved their potential to act as a hallucinogen. Amongst, Psilocybin (4-phosphorylox-N, N-dimethyltryptaminic acid) is one which exerts its effects by initially disrupting the interaction of nerve cells and the neurotransmitter serotonin. Serotonin system in brain is involved in many activities such as control of the behavior, perceptual, and regulatory systems etc. After consumption, this is transformed into the pharmacologically vigorous form psilocin and psilocybin are equally indole alkyl amines and structurally comparable to the neurotransmitter serotonin (5- HT). Pharmacokinetic studies in animals showed that only 60% of 13C-labelled psilocin is absorbed subsequent oral administration and is about uniformly dispersed throughout the body, as well as the brain, where it exerts its psychiatric properties. In humans, psilocybin is obvious in large amounts in the plasma within 30-40 minutes after per oral administration and highest concentrations are reached behind roughly 70-90 min. the greatest plasma level of Psilocybin is extra metabolized by monoamine oxidase (MAO) most important to arrangement of 2- hydroxyindole-4-acetic acid. In vivo studies in rats have exposed that psilocybin is eliminated in urine (75%) and feces and bile (20-30%) within 7 hours after oral administration. About 20-30% remained in the individual for a longer time with metabolites of psilocybin being detected in urine 8 days after oral administration. Psilocin and psilocybin create mostly pharmacological effects comparable to those of LSD and mescaline; activation of central serotonin receptors and obstruction of peripheral serotonin receptors.

KEYWORDS: Hallucinogen; serotonin (5-HT); psilocin; psilocybin; LSD.

INTRODUCTION been utilized in beneficial settings to care for an Mushrooms have possible been used while ancient times extensive multiplicity of ailments and disorders to supply shamanistic and spiritual visions, as well as to including huddle headaches, obsessive-compulsive make available relaxation.[1] Habitually referred to as disorders, nervousness, hopelessness, and dependence.[3] “Hallucinogenic mushroom” these can be establishing Since plant drugs, psychedelic hallucinogens have an increasing all through the world, and cause vibrant extended and colorful history. Because of their capability hallucinations. „Magic mushrooms‟ it is the name usually to create a futurist and delighted state, they were known to psychoactive fungi, containing hallucinogenic frequently credited supernatural or spiritual properties. compounds, most commonly used as psilocybin and With the finding of the hallucinogenic properties of the psilocin. At short doses, hallucinogenic drugs contain artificial ergo line d-lysergic acid diethylamide their main effects perceptual distortions and alterations hallucinogens and connected compounds have turn into of thinking, or disposition, with the occurrence of logical the center of current scientific research. The LSD- alertness and least effects on memory and direction. induced psychosis-like disease and the structural Regardless of their name, the utilize of hallucinogenic resemblance between LSD and serotonin (5- drugs hardly ever consequences in true hallucinations. hydroxytryptamine [5-HT]) encouraged the theory that The hallucinogens are a chemically miscellaneous class. 5-HT is concerned in the patho physiology of Group of hallucinogens based on their chemical structure schizophrenia.[4] includes, but is not incomplete to, three major classes: phenethylamines, methylenedioxymethamphetamine Chemistry (MDMA); indolealkylamines or tryptamines, (e.g. LSD, Hallucinogenic mushrooms present in major type of psilocybin and psilocin), including mescaline and methyl standard compound like Psilocybin (4-phosphorylox-N, and cannabinoids.[2] The first state of a hallucinogenic N-dimethyltryptaminic acid). After eating, this knowledge was recorded in London in 1799, the utilize mushroom is transformed into the pharmacologically of mushrooms exploded in the 1970s, mainly vigorous form psilocin. Psilocin and psilocybin are after LSD became available. Psilocybin mushrooms have equally indole alkyl amines and structurally comparable

www.ejpmr.com 125 Singh et al. European Journal of Pharmaceutical and Medical Research

to the neurotransmitter serotonin (5-HT).[5] In addition behavioral actions of sensory motor acting functions, like both tryptamines norbaeocystin and baeocystin can also PPI of the frighten retort. The opposite species revise of be present but are consideration to be fewer active than homologue gating functions such as PPI in human and the former two. Psilocybine (psilocybin, psilocibinic, animal models of neurosis offers a exceptional psilocybina, psylosybiinim) is 4-phosphorylox-NN- opportunity for the examination of neurobiological dimethyltryptamine. And IUPAC, name contains the substrates applicable to schizophrenia.[8] Indicative completely order chemical name is [2-(3-dimethyl amino schizophrenia and without medicated first episode ethyl)-1H-indol-4-yl] dihydrogen phosphate. schizophrenic patients show deficits in PPI, which have Psilocybinim is the dihydrogen phospate of psilocybin. been optional to be center to the psychosis Psilocin is soluble in water, fairly soluble in methanol symptomatology of the disease. Extensive and ethanol, and unsolvable in most organic solvents. pharmacological studies in animals reveal that PPI is Psilocin is a prod rug of psilocybin, in vivo the particle is modulated by numerous interacting neurotransmitters, metabolized into psilocibina by dephosphorylation.[6] including the dopamine, serotologic, cholinesterase, GABAminergic, and glutamatergic systems within CSPT pathways.

Role of dopamine In care through the Dopamine hyperactivity theory of schizophrenia, we hypothesized that augmented striatal Dopamine activity might also be give to the S-ketamine and psilocybin in induced symptom autology in humans, even though S-ketamine and psilocybiin have no similarity for Dopamine-2 receptors.[9] Diminution in compulsory potential (BP) has been vigorous recognized as a roundabout determine of the change in synaptic Dopamine attentiveness in human and animal studies. Certainly, both psilocybin and S-ketamine considerably lower BP in ventral striatum reliable with an augment in striatal Dopamine concentration. Furthermore, these Fig. 1: Molecular structure of psilocybin. changes in BP appreciably associated with

depersonalization, underneath the sight that extreme Dopamine spread at Dopamine-2 receptors contributes to the creation of positive psychotic symptoms in S- ketamine- and psilocybin treated subjects.[10] Though, the Dopamine mediated change in BP at Dopamine-2 receptors explained. Simply regarding 37% of the difference of positive symptoms, representative that additional neurotransmitter systems supply to the pathophysiology of S-ketamine and psilocybin induced symptomatology. In hold of this view, we establish that the Dopamine-2 antagonist haloperidol has almost no result on psilocin induced cognitive impairments and lowers psychotic symptoms by only about 31% in psilocybin-treated subjects. Correspondingly; current outcome in healthy subjects display that S-ketamine Fig. 2: Molecular structure of psilocin. neurosis be not ameliorated by haloperidol pretreatment.

MECHANISM FOR HALLUCINOGENS Role of serotonin Serotonergic hallucinogens and NMDA antagonists Throughout the final decade, accumulating confirmation The hyperfrontality ordinary to the psilocin and ketamine from required, electrophysiological, and behavioral models supports the thought that psychotic studies in animals recommended that indoleethyleamine hallucinogenetic and psychotomimetic N-Methyl, D- and phenyl ethylamine hallucinogens can create their Aspartate antagonists might arbitrate an amount of their psychosomatic effects using the 5-Hydroxytryptamine- possessions during an ordinary ultimate neurotransmitter [11] [7] 2A receptors in the brain. still, though the prevalence system. In exacting, the comparison of the property of of confirmation recommended that hallucinogens are ketamine and psilocybin on ego functions, cognition, and agonists at 5-Hydroxytryptamine-2A receptors, this awareness emphasize current human and animal matter was steamed up by studies that established LSD to conclusion signifying a junction in their behavioral be a fractional agonist or even an antagonist at 5- effects, regardless of the differences in their most Hydroxytryptamine-2A receptors. in addition, ever since important mode of action. Particular significance to LSD, 5-methoxy-DMT, and psilocybin have been sensory excess statements of drug-induced AnSC are

www.ejpmr.com 126 Singh et al. European Journal of Pharmaceutical and Medical Research

exposed to present high resemblance and to act as contributes to the higher-level of cognitive, perceptual, agonists at,5-Hydroxytryptamine-1A receptors, the role and moving effects of serotominergic hallucinogen and of 5-Hydroxytryptamine-1A and 5-Hydroxytryptamine- N-Methyl-D-Aspartate antagonists warrants extra 2A receptors in the production of hallucinogens in man exploration. Taken collectively, serotominergic ruins indefinable.[12] hallucinogens and psychotomimetic N-Methyl-D- Aspartate antagonists generate schizophrenia.[14] Role of glutamate Regardless of their diverse main mechanisms and sites of Current electro-physiological studies have formed new accomplishment, though, a common denominator of the confirmation that both psychosis hallucinogenetics and property of this drug program is that they modify the N-Methyl-D-Aspartate antagonists turn on the dynamics of the included CSPT circuitry such that serotonergic arrangement and improve glutaminergic standard information giving out is indistinct by deficits program via non-N-Methyl-D-Aspartate receptors in the in basic forms of sensory motor gating. anterior cortex.[13] Whether this ordinary method

Fig. 3: CSTC feedback loops.

Psychological effects soluble in methanol and ethanol. Pharmacokinetic studies Surrounded by the enter psychological functions that are in animals showed that only 60% of 13C-labelled distorted by hallucinogens or N-Methyl-D-Aspartate psilocin is absorbed subsequent oral administration and antagonists are: (i) psychotic like symptoms; (ii) alter in is about uniformly dispersed throughout the body, as mood; and (iii) changes in awareness of time, well as the brain, where it exerts its psychiatric personality, and situation, including both bullying or properties.[17] furthermore, In vivo studies in rats enjoyable experiences of de-realization and indicated that psilocin is rapidly hydrolyzed in the depersonalization phenomena. These psychological intestine to psilocybin, significance that psilocin is functions split a lot of aspects of famous psychotic absorbed mostly or even all as psilocybin.[18] In humans, symptoms of disorders such as schizophrenic or psilocybin is obvious in large amounts in the plasma delusional confusion, and can be accessed by typical within 30-40 minutes after per oral administration and psychotic or psychological ranking scales. highest concentrations are reached behind roughly 70-90 min. This property completely evaporates within about ADME OF PSILOCYBIN 3-7 hours.[19] Absorption and Distribution Magic mushrooms are characteristically administered per Metabolism oral. While it is a zwitterionic alkaloid and owing to the The greatest plasma levels of psilocybin appearing occurrence of a extremely polar phosphate group, within a very small period after total administration psilocin is extra soluble in water than psilocybin.[15] indicates a quick dephosphorylation of psilocin inside the Consequently, psilocybin is further easily absorbed from human body.[20] Psilocybin is extra metabolized by the rat colon and jejunum GIT tract, signifying also monoamine oxidase (MAO) most important to better CNS system bioavailability.[16] Together are quite arrangement of 2- hydroxyindole-4-acetic acid.[21]

www.ejpmr.com 127 Singh et al. European Journal of Pharmaceutical and Medical Research

Excretion studies are old and do not assemble modern standards for The metabolite 3-hydroxyindole-2-acetic acid (3HIAA) safety estimation and consequently more prohibited is excreted in urine. Psilocin and psilocybin have an studies are wanted to determine the beneficial role in exclusion half-life in plasma of around 150 and 60 confident diseases, particularly those psychiatric minutes, correspondingly.[22] In vivo studies in rats have related.[32] Though exhibiting diverse potencies and exposed that psilocybin is eliminated in urine (75%) and instance course, it is known that psilocin and psilocybin feces and bile (20-30%) within 7 hours after oral create mostly pharmacological effects comparable to administration. About 20-30% remained in the individual those of LSD and mescaline; activation of central for a longer time with metabolites of psilocybin being serotonin receptors and obstruction of peripheral detected in urine 8 days after oral administration.[23] serotonin receptors.[33] They attach with high Regarding 35% of the complete dose was exposed to be resemblance at 5-hydroxytryptamine (5-HT)-2A and to a eliminated unaffected. A forbidden study in humans slighter extent at 5-Hydroxytryptamin-1A, 5- showed that within 24 h, 2.4 ± 0.8% of the useful dose of Hydroxytryptamine-1D, 5Hydroxytryptamine-2C psilocin was eliminated in urine as free psilocybin. subtype receptors. In difference, they show no obvious similarity for dopamine D2 receptors.[34] Though, Treatment of psilocybin toxicity consequences are opposing while the administration of Wide-ranging investigate on the use of LSD and other haloperidol (i.e., Dopamine antagonist) also reduces classic (5 Hydroxytryptamin-2A agonist or fractional psilocin and psilocybin-induced psychotomimetic, agonist) hallucinogens in the healing of addiction.[24] raising the opportunity of dopaminergic neuronal Existential suffering in failing patients,[25] pain and conduction participation.[35] further conditions.[26] Biological method exposed that even though typical hallucinogens bind to numerous This result is well-suited with an augment in serotonin receptor subtypes and new receptors[27], the extracellular dopamine that competitively displaces the psychiatric property of all classic hallucinogens emerge antagonist. Still though psilocin does not demonstrate to depend mainly on their actions at any similarity to dopamine receptor of D2 subtype, 5Hydroxytryptamine-2A receptor.[28] Management of modulating interactions between serotonergic and classic hallucinogens in rat models has been exposed to dopaminergic neuronal systems are known to exist. Since induce down-regulation of 5Hydroxytryptamine-2A the Pharmacodynamics and the mechanisms original the receptors, mainly those in the frontal cingulated and appearance of psychiatric changes are not fully unstated, frontage medial cortex, expected secretarial for the quick metabolomic studies can supply addition insights to help growth and exchange of behavioral lenience to the scientific and forensic toxicologists in the understanding majority classic hallucinogens. Clinical effort with of toxicological results. Remarkable is the current classic hallucinogens has emphasized the middle role of rehabilitated attention of psilocybin in the healing of the changed situation of perception practiced through the resistant despair, irrational compulsive disease, cancer drug‟s acute effects.[29] The “psychiatric” treatment anxiety, and alcohol and tobacco accumulation.[36] In model on the further hand emphasized the use of these pathologies, clinical trials with sufficient control of comparatively elevated doses of typical Hallucinogens metabolic profile and metabolome (e.g., strain hormones (usually LSD) to instance a “peak-psychiatric” or such as cortisol) can help to expect if psilocin outweighs spiritual knowledge of character loss, frequently likened its unfavorable effects. Finally, imperfect data is to psychosomatic death and regeneration.[30] The final accessible concerning other vigorous hallucinogen model was utilized in mainly of the clinical studies using compounds found in mushrooms. Moreover psilocin and LSD in the management of addiction or existential psilocybin, magic mushrooms also include baeocystin (3- nervousness in the disappearing. phosphoryloxy-N-methyltryptamine) and nor baeocystin (4-phosphoryloxytryptamine), which are mono and di-N- CONCLUSION AND FUTURE PROSPECTUS demethylated equivalents of psilocybin, Utilize the hallucinogens residue a major problem for correspondingly.[37] It is also recognized that there are inhabitants of drug abusers. These drugs have an additional psychoactive compounds establish in other extensive history and their reputation comes and goes mushrooms species such as aeruginaescin (N, N, N- with time, but they continue a steady existence in the trimethyl-4-phosphoryloxytryptaminic acid), a drug civilization, typically by young people looking for trimethylene analog of psilocin, and bufotanine (N, N- psychiatric experiences. While unpolluted synthetic dimethyl-4-hydroxytryptamine), a positional isomer of psilocin (Indocin was marketed for investigational and psilocin. Collectively these compounds are fewer psychiatric treatment in the 1970s, only partial explored than psilocin and psilocybin and pharmacokinetic and pharmacodynamic information are dephosphorylation is also predictable for psilocybin accessible. additional studies are required to recognize analogues to create psychoactive metabolites. extra metabolites, and the power of drug relations and polymorphisms in pharmacokinetics and pharmacodynamics.[31] Literature data suggests that psilocin and psilocybin reveal minor toxicity and can be seen as physiologically well tolerated. Though, the most

www.ejpmr.com 128 Singh et al. European Journal of Pharmaceutical and Medical Research

REFERENCES 15. Ballesteros S, Ramón. Natural sources of drugs of 1. Leung, A. Y. and Paul, A. G. „Baeocystin and abuse: magic mushrooms, in: New research on street norbaeocystin: new analogs of psilocybin from drugs (Cole SM ad), 2006; 55(1): 167–186, Psilocybe baeocystis‟. Journal of Pharmaceutical 16. Eivindvik K, Rasmussen KE. Handling of psilocybin Sciences, 1968; 57(10): 1667–1671. and psilocin by sacs of rat jejunum and colon. Acta 2. Beck, O., Helander, A., Karlson-Stiber, „Presence of Pharmacology Nord, 1989; 55(1): 295-302. phenyl ethylamine in hallucinogenic Psilocybe 17. Hopf A and Eckert H. Distribution patterns of 14-C- mushroom: possible role in adverse psilocin in the brains of various animals. Activitas reactions‟, Journal of Analytical Toxicology, 1998; nervosa superior, 1974; 16(5): 64-66. 22(1): 45–49. 18. Passie T, Seifert J. the pharmacology of psilocybin. 3. Hallock, R. M., Dean, A., Knecht, Z. A., Spencer, J., Addiction biology, 2002; 7(1): 357-364. & Taverna, E. C. A survey of hallucinogenic 19. Shulgin AT. Profiles of psychedelic drugs, mushroom use. Drug & Alcohol Dependence, psilocybin. Journal of psychedelic drugs, 1998; 2013; 130(1): 245–248. 12(7): 79. 4. Franz X. Vollenweider, MD. Brain mechanisms of 20. Hasler F, Bourquin D. Determination of psilocin and hallucinogens and entactogens. Dialogues in Clinical 4-hydroxyindole-3-acetic acid plasma by HPLC- Neuroscience, 2001; 3(4): 265-268. ECD and pharmacokinetic profiles of oral and 5. Horita, A. and Weber, L. J.„The enzymic intravenous psilocybin in man. Pharm Acta Helv, dephosphorylation and oxidation of psilocybin and 1997; 72(5): 175-84. psilocin by mammalian tissue 21. Beck O, Helander A. Presence of phenylethylamine homogenates‟. Biochemical Pharmacology, 1961; 7: in hallucinogenic psilocybe mushroom:Possible role 47–54. in adverse reactions. Journal of Analysis 6. Repke, D. B., Leslie, D. T. „Baeocystin in psilocybe, Toxicology, 1998; 22(3): 45-49. conocybe and panaeolus‟. Lloydia, 1977; 40(6): 22. Martin R, Schurenkamp J. Determination of 566–578. psilocin, bufotenine, LSD and its metabolites in 7. Gouzoulis E, Hermle L. History, rationale and serum, plasma and urine by SPE-LC-MS/MS. potential of human experimental hallucinogenic International journal of legal medicine, 2013; drug research in psychiatry. Pharmacopsychiatry, 127(8): 593-601 1998; 31(8): 63-68. 23. Kalberer F, Kreis W. the fate of psilocin in the rat. 8. Vollenweider FX. Advances and pathophysiological Biochemical Pharmacology, 2012; 11(7): 261-269. models of hallucinogen drug actions in humans: a 24. Abuzzahab FS, Sr. and Anderson. A review of LSD preamble to schizophrenia research. treatment in alcoholism. International Pharmacopsychiatry, 1998; 31(2): 92-103. Pharmacopsychiatry, 1971; 6(2): 223–235. 9. Vollenweider FX, Leenders KL. Metabolic 25. Grof S, Goodman LE. LSD-assisted psychotherapy hyperfrontality and psychopathology in the ketamine in patients with terminal cancer. International model of psychosis using positron emission Pharmacopsychiatry, 1973; 8(5): 129–144. tomography. European Neuropsychopharmacol, 26. Grinspoon L and Balkan JB. Psychedelic Drugs 1997; 7(2): 9-24. Reconsidered. New York: The Lindesmith Center, 10. Vollenweider FX, Vogel H, Hell D. Psilocybin 1997; 88(4). induces schizophrenia-like psychosis in humans via 27. Ray TS. Psychedelics and the human receptor me. a serotonin-2 agonist action. Neuroreport, 1998; PLoS ONE, 2010; 5(1): 9019. 9(4): 3897-3902. 28. Nichols DE. Hallucinogens. Pharmacology and 11. Nichols DE. Role of serotonergic neurons and 5- Therapeutic, 2004; 101: 131–181. HT2A receptors in the action of hallucinogens. 29. Hoffer A. A program for treatment of alcoholism: Springer Verlag, 1997; 30(2): 563-585. LSD, malvaria, and nicotinic acid. Indianapolis: 12. Vollenweider FX. Effects of NMDA antagonists and Bobbs-Merrill, 1967; 56(2): 343–406. 5-HT2A-agonists on prepulse inhibition in human 30. Kurland AA, Unger S, Psychedelic therapy utilizing volunteers. Schizophrenia Research journal, 2000; LSD in the treatment of the alcoholic patient: A 7(1): 41-147. preliminary report. Journal of Psychiatry, 1967; 13. Anand A, Charney DS. Attenuation of the 123(7): 1202–1209. neuropsychiatric effects of ketamine with 31. Lindenblatt H, Kramer E. Quantitation of psilocin in lamotrigine: support for hyperglutamatergic effects human plasma by high-performance liquid of N-methyl-D-aspartate receptor antagonists. Arch chromatography and electrochemical detection: Generation Psychiatry, 2000; 57(8): 270-276. comparison of liquid-liquid extraction with 14. Vollenweider FX, Bachle D. 5-HT receptor automated on-line solid-phase extraction. Journal of activation: a common denominator of the NMDA chromatography B, Biomedical sciences and antagonist and 5HT2A agonist models of psychosis. applications, 1998; 709: 255-263. Biological Psychiatriatic, 2000; 47(6): 129S-130S. 32. Passie T, Seifert. The pharmacology of psilocybin. Addiction biology, 2002; 7(2): 357-364.

www.ejpmr.com 129 Singh et al. European Journal of Pharmaceutical and Medical Research

33. Wolbach AB, Jr. Comparison of psilocin with psilocybin, mescaline and LSD-25. Psychopharmacologia, 1962; 3(1): 219-223. 34. Creese I, Burt DR. The dopamine receptor: differential binding of d-LSD and related agents to agonist and antagonist states. Life Science, 1975; 17(3): 1715-1719. 35. Vollenweider FX, Vontobel P. 5-HT modulation of dopamine release in basal ganglia in psilocybin- induced psychosis in man, Neuropsychopharmacology, official publication of the American College of Neuropsychopharmacology, 1999; 20(5): 424-433. 36. de Veen BT, Schellekens AF. Psilocybin for treating substance use disorders. Expert Rev Neurotherapeutic, 2016; 45(3): 1-10. 37. Franke AA, Custer LJ. Liquid chromatographic- photodiode array mass spectrometric analysis of dietary phytoestrogens from human urine and blood. Journal of Chromatography Analytical Technology Biomed Life Science, 2002; 777(5): 45-59.

www.ejpmr.com 130