Psilocybin – Summary of knowledge and new perspectives

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

[1]  N. Malleson Acute Adverse Reactions to Lsd in Clinical and Experimental use in the United Kingdom , 1971, British Journal of Psychiatry.

[2]  G. Moore,et al.  Evidence for Coupling between Glucose Metabolism and Glutamate Cycling Using FDG PET and 1H Magnetic Resonance Spectroscopy in Patients with Epilepsy , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  F. Vollenweider,et al.  Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. , 1997, Pharmaceutica acta Helvetiae.

[4]  R. Collins,et al.  Psilocin: Effects on Behaviour and Brain Serotonin in Mice , 1966, Nature.

[5]  Mathias Schreckenberger,et al.  Neurometabolic Effects of Psilocybin, 3,4-Methylenedioxyethylamphetamine (MDE) and d-Methamphetamine in Healthy Volunteers A Double-Blind, Placebo-Controlled PET Study with [18F]FDG , 1999, Neuropsychopharmacology.

[6]  I. Creese,et al.  The dopamine receptor: differential binding of d-LSD and related agents to agonist and antagonist states. , 1975, Life sciences.

[7]  M. Okuda,et al.  Dopamine Receptor , 2020, Definitions.

[8]  Aboul-Enein Hy,et al.  Psilocybin: a pharmacological profile. , 1974, American journal of pharmacy and the sciences supporting public health.

[9]  F. Vollenweider,et al.  Positron Emission Tomography and Fluorodeoxyglucose Studies of Metabolic Hyperfrontality and Psychopathology in the Psilocybin Model of Psychosis , 1997, Neuropsychopharmacology.

[10]  J. Gartz,et al.  Analysis and cultivation of fruit bodies and Mycelia of Psilocybe bohemica , 1989 .

[11]  J. Bonnardeaux The Effects of Psychotropic Drugs. , 1984 .

[12]  M. Beug,et al.  Psilocybin and psilocin levels in twenty species from seven genera of wild mushrooms in the Pacific Northwest, U.S.A. , 1982, Journal of ethnopharmacology.

[13]  Felix Hasler,et al.  Effects of psilocybin on time perception and temporal control of behaviour in humans , 2007, Journal of psychopharmacology.

[14]  J. C. Winter,et al.  Psilocybin-induced stimulus control in the rat , 2007, Pharmacology Biochemistry and Behavior.

[15]  M. Nishikawa,et al.  Direct detection of serum psilocin glucuronide by LC/MS and LC/MS/MS: time-courses of total and free (unconjugated) psilocin concentrations in serum specimens of a “magic mushroom” user , 2006, Forensic Toxicology.

[16]  Richard G. Wise,et al.  Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin , 2012, Proceedings of the National Academy of Sciences.

[17]  Franz X Vollenweider,et al.  Serotonin research: contributions to understanding psychoses. , 2008, Trends in pharmacological sciences.

[18]  F. Pfeffer,et al.  Investigation into the temporal stability of aqueous standard solutions of psilocin and psilocybin using high performance liquid chromatography. , 2006, Science & justice : journal of the Forensic Science Society.

[19]  R. Naquet,et al.  Effects of psilocybin, dimethyltryptamine, mescaline and various lysergic acid derivatives on the EEG and on photically induced epilepsy in the baboon (Papio papio). , 1971, Electroencephalography and clinical neurophysiology.

[20]  R. Strassman ADVERSE REACTIONS TO PSYCHEDELIC DRUGS. A REVIEW OF THE LITERATURE , 1984, The Journal of nervous and mental disease.

[21]  P. Delgado,et al.  Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. , 2006, The Journal of clinical psychiatry.

[22]  Hollister Le Clinical, biochemical and psychologic effects of psilocybin. , 1961 .

[23]  Stuart C. Sealfon,et al.  Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior , 2007, Neuron.

[24]  B. Levine,et al.  The detection of psilocin in human urine. , 2001, Journal of forensic sciences.

[25]  Graeme Milligan,et al.  Identification of a serotonin/glutamate receptor complex implicated in psychosis , 2008, Nature.

[26]  L. Herlihy,et al.  Conditioned fear inhibits c-fos mRNA expression in the central extended amygdala , 2008, Brain Research.

[27]  D. Nutt,et al.  The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability , 2011, Journal of psychopharmacology.

[28]  M. Tuda,et al.  A New Species Megabruchidius sophorae (Coleoptera, Bruchidae), Feeding on Seeds of Styphnolobium (Fabaceae) New to Bruchidae , 2004, Zoological science.

[29]  A. Horita,et al.  Dephosphorylation of psilocybin in the intact mouse. , 1962, Toxicology and applied pharmacology.

[30]  H. Pope,et al.  Response of cluster headache to psilocybin and LSD , 2006, Neurology.

[31]  W. Kreis,et al.  The fate of psilocin in the rat. , 1962, Biochemical pharmacology.

[32]  C. E. Becker,et al.  Coma, hyperthermia, and bleeding associated with massive LSD overdose, a report of eight cases. , 1974, Clinical toxicology.

[33]  Franz X Vollenweider,et al.  The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval , 2007, Neuropsychopharmacology.

[34]  D. Picart,et al.  Intoxication mortelle à la suite de la consommation volontaire et en groupe de champignons hallucinogènes , 1996 .

[35]  R. Strassman Human psychopharmacology of N,N-dimethyltryptamine , 1995, Behavioural Brain Research.

[36]  M. F. Sugrue,et al.  A study of the role of noradrenaline in behavioural changes produced in the rat by psychotomimetic drugs , 1969, British journal of pharmacology.

[37]  Matthew W. Johnson,et al.  Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects , 2011, Psychopharmacology.

[38]  M. Geyer,et al.  A characteristic effect of hallucinogens on investigatory responding in rats , 1979, Psychopharmacology.

[39]  Adam L. Halberstadt,et al.  Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens , 2011, Neuropharmacology.

[40]  F. Vollenweider,et al.  Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia , 2003, Neuropsychopharmacology.

[41]  H. Pope,et al.  Hallucinogen persisting perception disorder: what do we know after 50 years? , 2003, Drug and alcohol dependence.

[42]  H. Sass,et al.  [Psychedelic experiences at the onset of productive episodes of endogenous psychoses]. , 1994, Der Nervenarzt.

[43]  J. B. Appel,et al.  Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline. , 1989, European journal of pharmacology.

[44]  U. Et Effects of mescaline and psilocybin on dominance behavior of the rat. , 1967 .

[45]  Stuart C. Sealfon,et al.  Psychedelics and schizophrenia , 2009, Trends in Neurosciences.

[46]  B. Sessa Can psychedelics have a role in psychiatry once again? , 2005, The British journal of psychiatry : the journal of mental science.

[47]  J. Suvisaari,et al.  Lifetime prevalence of psychotic and bipolar I disorders in a general population. , 2007, Archives of general psychiatry.

[48]  Sempere Áp,et al.  Respuesta de la cefalea en racimos crónica a la psilocibina , 2006 .

[49]  Tomas Palenicek,et al.  Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia , 2006, CNS drugs.

[50]  F. Hoffmeister Negative reinforcing properties of some psychotropic drugs in drug-naive rhesus monkeys. , 1975, The Journal of pharmacology and experimental therapeutics.

[51]  M. Horibe The effects of psilocybin on EEG and behaviour in monkeys. , 1974, Activitas nervosa superior.

[52]  P. Kovacic Unifying electron transfer mechanism for psilocybin and psilocin. , 2009, Medical hypotheses.

[53]  M. Spitzer,et al.  Effects of the Hallucinogen Psilocybin on Covert Orienting of Visual Attention in Humans , 2002, Neuropsychobiology.

[54]  A. Horita,et al.  Dephosphorylation of Psilocybin to Psilocin by Alkaline Phosphatase , 1961, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[55]  M. Geyer,et al.  Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice , 2011, Journal of psychopharmacology.

[56]  S. Peroutka,et al.  Differential interactions of indolealkylamines with 5-hydroxytryptamine receptor subtypes , 1990, Neuropharmacology.

[57]  E. Gouzoulis-Mayfrank,et al.  Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers Results of an experimental double-blind placebo-controlled study , 1999, Psychopharmacology.

[58]  S. Sealfon,et al.  Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists , 2011, Neuroscience Letters.

[59]  N. Peden,et al.  HALLUCINOGENIC FUNGI , 1982, The Lancet.

[60]  A. Lawson,et al.  New Species , 1897, Botanical Gazette.

[61]  D. Barceloux Book Review: Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants , 2012 .

[62]  Matthew W. Johnson,et al.  Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later , 2008, Journal of psychopharmacology.

[63]  Peter Vontobel,et al.  5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride , 1999, Neuropsychopharmacology.

[64]  W. Hörl,et al.  Magic mushrooms: hope for a 'cheap high' resulting in end-stage renal failure. , 1996, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[65]  Felix Hasler,et al.  Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies , 2011, Journal of psychopharmacology.

[66]  F. Vollenweider,et al.  Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man. , 2002, Journal of pharmaceutical and biomedical analysis.

[67]  E. Uyeno Relative potency of amphetamine derivatives and N,N-dimethyltryptamines , 2004, Psychopharmacologia.

[68]  T. Laussmann,et al.  Forensic analysis of hallucinogenic mushrooms and khat (Catha edulis Forsk) using cation-exchange liquid chromatography. , 2010, Forensic science international.

[69]  Michael Kometer,et al.  The neurobiology of psychedelic drugs: implications for the treatment of mood disorders , 2010, Nature Reviews Neuroscience.

[70]  M. Finel,et al.  Glucuronidation of Psilocin and 4-Hydroxyindole by the Human UDP-Glucuronosyltransferases , 2010, Drug Metabolism and Disposition.

[71]  C. Mundi,et al.  Triptans: over the migraine , 2012, Neurological Sciences.

[72]  Michael Davis,et al.  Psilocybin: Biphasic dose-response effects on the acoustic startle reflex in the rat , 1977, Pharmacology Biochemistry and Behavior.

[73]  Thomas S. Ray,et al.  Psychedelics and the Human Receptorome , 2010, PloS one.

[74]  D. Sharp,et al.  Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. , 2012, The British journal of psychiatry : the journal of mental science.

[75]  A. Meijer,et al.  Macromycetes from the state of Parana, Brazil . 4. The psychoactive species , 1993 .

[76]  Wim van den Brink,et al.  Harm potential of magic mushroom use: a review. , 2011, Regulatory toxicology and pharmacology : RTP.

[77]  F. Vollenweider,et al.  The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions , 2012, Psychopharmacology.

[78]  J. Hampson,et al.  Shared care: a review of the literature. , 1996, Family practice.

[79]  Andreas Bäbler,et al.  Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action , 1998, Neuroreport.

[80]  J. Rapoport,et al.  Relief of obsessive-compulsive symptoms by LSD and psilocin. , 1987, The American journal of psychiatry.

[81]  David Alais,et al.  Psilocybin impairs high-level but not low-level motion perception , 2004, Neuroreport.

[82]  H. Aboul‐Enein Psilocybin: a pharmacological profile. , 1974, American journal of pharmacy and the sciences supporting public health.

[83]  G. Aghajanian,et al.  Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors. , 1975, Psychopharmacology communications.

[84]  D. Barceloux Psilocybin and Hallucinogenic Mushrooms , 2012 .

[85]  R. Doblin PAHNKE'S "GOOD FRIDAY EXPERIMENT' A LONG-TERM FOLLOW-UP AND METHODOLOGICAL CRITIQUE , 1991 .

[86]  J. González-Maeso,et al.  Animal models of serotonergic psychedelics. , 2013, ACS chemical neuroscience.

[87]  Karl J. Friston,et al.  Schizophrenia: a disconnection syndrome? , 1995, Clinical neuroscience.

[88]  A Dittrich,et al.  The Standardized Psychometric Assessment of Altered States of Consciousness (ASCs) in Humans , 1998, Pharmacopsychiatry.

[89]  B. Roth,et al.  Serotonin 5-HT2A receptors: molecular biology and mechanisms of regulation. , 1998, Critical reviews in neurobiology.

[90]  Karl J. Friston,et al.  Broadband Cortical Desynchronization Underlies the Human Psychedelic State , 2013, The Journal of Neuroscience.

[91]  J. Woods,et al.  Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys , 2004, Behavioural pharmacology.

[92]  G. Went Mutagenicity testing of 3 hallucinogens: LSD, psilocybin and‡ 9-THC using the micronucleus test , 1978, Experientia.

[93]  P. Anderer,et al.  Effects of the South American Psychoactive Beverage Ayahuasca on Regional Brain Electrical Activity in Humans: A Functional Neuroimaging Study Using Low-Resolution Electromagnetic Tomography , 2004, Neuropsychobiology.

[94]  S. Sealfon,et al.  Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex , 2003, The Journal of Neuroscience.

[95]  osé Morenoa,et al.  etabotropic glutamate mGlu 2 receptor is necessary for the pharmacological nd behavioral effects induced by hallucinogenic 5-HT 2 A receptor agonists , 2011 .

[96]  J. González-Maeso,et al.  Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects , 2013, European Neuropsychopharmacology.

[97]  Parashos Aj The psilocybin-induced "state of drunkenness" in normal volunteers and schizophrenics. , 1976 .

[98]  A. Frey,et al.  Psilocybin und Psilocin, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen , 1959 .

[99]  Rae M. Morgan,et al.  Drugs Affecting the Central Nervous System , 2008 .

[100]  Franz X Vollenweider,et al.  A systems model of altered consciousness: integrating natural and drug-induced psychoses , 2001, Brain Research Bulletin.

[101]  A. Hill The Pharmaceutical Society of Great Britain. , 1930, British medical journal.

[102]  E. Clarke Clarke's Isolation and Identification of Drugs: In Pharmaceuticals, Body Fluids and Post Mortem Material , 1970 .

[103]  Hongmei Zhu,et al.  Determining the pharmacokinetics of psilocin in rat plasma using ultra-performance liquid chromatography coupled with a photodiode array detector after orally administering an extract of Gymnopilus spectabilis. , 2011, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[104]  J. Gartz Extraction and analysis of indole derivatives from fungal biomass , 1994, Journal of basic microbiology.

[105]  K. Murnane,et al.  The behavioral pharmacology of hallucinogens. , 2008, Biochemical pharmacology.

[106]  S. Cohen LYSERGIC ACID DIETHYLAMIDE: SIDE EFFECTS AND COMPLICATIONS , 1960, The Journal of nervous and mental disease.

[107]  T. Kuyper,et al.  Occurrence of psilocybin in various higher fungi from several European countries. , 1985, Planta medica.

[108]  H. Isbell Comparison of the reactions induced by psilocybin and LSD-25 in man , 2004, Psychopharmacologia.

[109]  D. E. Nichols,et al.  Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines. , 2001 .

[110]  F. Vollenweider,et al.  Prediction of Psilocybin Response in Healthy Volunteers , 2012, PloS one.

[111]  M. Geyer,et al.  Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans , 1998, Behavioural pharmacology.

[112]  A. Hofmann,et al.  LSD, my problem child , 1980 .

[113]  M. Fink EEG and human psychopharmacology , 1963 .

[114]  Petr Zach,et al.  Behavioral, neurochemical and pharmaco-EEG profiles of the psychedelic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats , 2012, Psychopharmacology.

[115]  W. Kostowski,et al.  II. The effects of some hallucinogens on aggressiveness of mice and rats. , 1972, Pharmacology.

[116]  D. B. Repke,et al.  Baeocystin in psilocybe, conocybe and panaeolus. , 1977, Lloydia.

[117]  F. Vollenweider Brain mechanisms of hallucinogens and entactogens , 2001, Dialogues in clinical neuroscience.

[118]  R. Kellner,et al.  Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. , 1994, Archives of general psychiatry.

[119]  A. Hofmann,et al.  [Elucidation of the structure and the synthesis of psilocybin]. , 1958, Experientia.

[120]  R. Griffiths,et al.  Human hallucinogen research: guidelines for safety , 2008, Journal of psychopharmacology.

[121]  Matthew W. Johnson,et al.  Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness , 2011, Journal of psychopharmacology.

[122]  C. Grob,et al.  Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. , 2011, Archives of general psychiatry.

[123]  A. Horita Some biochemical studies on psilocybin and psilogin. , 1963, Journal of neuropsychiatry.

[124]  R. Griffiths,et al.  Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance , 2006, Psychopharmacology.

[125]  D. Adams,et al.  Histocompatibility antigen gene theory of inherited autoimmune disease. , 1980 .

[126]  Felix Hasler,et al.  Acute psychological and physiological effects of psilocybin in healthy humans : a double-blind , placebo-controlled dose – effect study , 2004 .

[127]  H. Isbell,et al.  Comparison of psilocin with psilocybin, mescaline and LSD-25 , 2004, Psychopharmacologia.

[128]  Lutz Jäncke,et al.  Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on α Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations , 2013, The Journal of Neuroscience.

[129]  C. Nichols,et al.  An animal model of schizophrenia based on chronic LSD administration: Old idea, new results , 2011, Neuropharmacology.

[130]  K. Neve,et al.  Dopamine Receptors , 2008 .

[131]  E. Usdin,et al.  Psychotropic Drugs and Related Compounds , 1979 .

[132]  J. Bakalar,et al.  The psychedelic drug therapies. , 1981, Current psychiatric therapies.

[133]  A. Hopf,et al.  Distribution patterns of 14-C-psilocin in the brains of various animals. , 1974, Activitas nervosa superior.

[134]  F. Troxler,et al.  Abwandlungsprodukte von Psilocybin und Psilocin. 2. Mitteilung über synthetische Indolverbindungen , 1959 .

[135]  G. H. Litwin,et al.  REACTIONS TO PSILOCYBJN ADMINISTERED IN A SUPPORTIVE ENVIRONMENT , 1963, The Journal of nervous and mental disease.

[136]  H. Käferstein,et al.  Detection of psilocin in body fluids. , 2000, Forensic science international.

[137]  A. Horita,et al.  The enzymic dephosphorylation and oxidation of psilocybin and psilocin by mammalian tissue homogenates. , 1961, Biochemical pharmacology.

[138]  Aghajanian Gk,et al.  Hallucinogenic indoleamines: Preferential action upon presynaptic serotonin receptors. , 1975 .

[139]  F. J. Carod-Artal Hallucinogenic drugs in pre-Columbian Mesoamerican cultures☆ , 2015 .

[140]  L. Hollister Clinical, biochemical and psychologic effects of psilocybin. , 1961, Archives internationales de pharmacodynamie et de therapie.

[141]  H. Emrich,et al.  The pharmacology of psilocybin , 2002, Addiction biology.

[142]  M. Beug,et al.  A new species and a new variety of Psilocybe from North America. , 1980 .

[143]  E. Gouzoulis-Mayfrank,et al.  Quantitation of psilocin in human plasma by high-performance liquid chromatography and electrochemical detection: comparison of liquid-liquid extraction with automated on-line solid-phase extraction. , 1998, Journal of chromatography. B, Biomedical sciences and applications.