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Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy

Published online by Cambridge University Press:  11 July 2022

Seetal Dodd Open the ORCID record for Seetal Dodd [Opens in a new window] ,
Trevor R. Norman ,
Harris A. Eyre ,
Stephen M. Stahl ,
Arnie Phillips ,
André F. Carvalho Open the ORCID record for André F. Carvalho [Opens in a new window]  and
Michael Berk
Seetal Dodd*
Affiliation:
IMPACT – The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia School of Medicine, Deakin University, Geelong, VIC, Australia University Hospital Geelong, Barwon Health, Geelong, VIC, Australia Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia
Trevor R. Norman
Affiliation:
Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia
Harris A. Eyre
Affiliation:
IMPACT – The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia School of Medicine, Deakin University, Geelong, VIC, Australia Neuroscience-Inspired Policy Initiative, Organisation for Economic Co-Operation and Development (OECD), Meadows Mental Health Policy Institute and the PRODEO Institute, Paris, France Global Brain Health Institute, University of California, San Francisco (UCSF), San Francisco, CA, USA Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile Brain Health Nexus, Cohen Veterans Network, Boston, MA, USA Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
Stephen M. Stahl
Affiliation:
Department of Psychiatry, University of California San Diego, San Diego, CA, USA
Arnie Phillips
Affiliation:
IMPACT – The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia School of Medicine, Deakin University, Geelong, VIC, Australia
André F. Carvalho
Affiliation:
IMPACT – The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia School of Medicine, Deakin University, Geelong, VIC, Australia
Michael Berk
Affiliation:
IMPACT – The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia School of Medicine, Deakin University, Geelong, VIC, Australia University Hospital Geelong, Barwon Health, Geelong, VIC, Australia Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
*
*Author for correspondence: Seetal Dodd, Email: seetald@barwonhealth.org.au
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Abstract

Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin, which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors are not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialed for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm vs the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.

Keywords

Psilocybinpsychiatryneurosciencetreatmentdepressionanxietyposttraumatic stress disordersafetyadverse events
Type
Review
Information
CNS Spectrums , Volume 28 , Issue 4 , August 2023 , pp. 416 - 426
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2022. Published by Cambridge University Press

Introduction

Psilocybin is a natural, widely occurring tryptamine alkaloid found in many species of mushroom, most notably those of the genus Psilocybe. In addition to psilocybin obtained from mushrooms, synthetic psilocybin and synthetic psilocin is widely available.Reference Geiger, Wurst and Daniels 1 Psilocybin undergoes metabolism to produce four metabolites. Psilocybin itself is not known to be pharmacologically active and its pharmacological effects are through its primary metabolite psilocin, which is the only metabolite known to be pharmacologically active.

Ritual use of Psilocybe mushrooms has an ancient history, as suggested by paleolithic cave paintings in Selva Pascuala, Spain, where mushroom pictographs have been dated to at least 7000 years before present.Reference Akers, Ruiz, Piper and Ruck 2 The best documented example of ritual or ceremonial use of Psilocybe mushroom is amongst indigenous populations in Mexico where many sites have been identified. Many populations have traditionally used and continue to use mushrooms that have attained a sacred status.Reference Guzman 3 Amongst traditional and current “recreational” users of Psilocybe mushrooms, the objective has been to ingest sufficient psilocybin to obtain an altered state of consciousness, described as hallucinogenic or to obtain marked alterations in perception, mood, and thought.Reference Geiger, Wurst and Daniels 1

Psilocybin is being investigated as a novel therapeutic agent for potential use in some neuropsychiatric disorders, including mood, anxiety, addictive disorders, and cluster headaches,Reference Geiger, Wurst and Daniels 1 , Reference Johnson and Griffiths 4 and as an adjunctive pharmacotherapy to assist psychotherapeutic interventions.Reference Reiff, Richman and Nemeroff 5 , Reference Trope, Anderson, Hooker, Glick, Stauffer and Woolley 6 Psychedelics are currently receiving increasing interest from researchers and investors, although several barriers to translating research into clinical practice have been recognized and include the need for clinical supervision of hallucinogenic experiences.Reference Weintraub 7 Other limitations include drug safety concerns. This review investigates the pharmacology, risks, and benefits of psilocybin and scope the suitability of this agent as a future pharmacological treatment for a multitude of neuropsychiatric conditions.

Pharmacology of psilocybin

Due to its designation as a controlled substance in the USA from 1970, the pharmacology of psilocybin has not been comprehensively investigated and gaps in knowledge remain.Reference Johnson, Griffiths, Hendricks and Henningfield 8 Psilocybin itself is not known to be pharmacologically active and the observed effects are mediated by its primary metabolite psilocin (vide infra). Both psilocybin and psilocin are structurally related to the indole alkylamine hallucinogen, N,N-dimethyltryptamine, which occurs naturally in a variety of animals and plants.Reference Carbonaro and Gatch 9 This group of compounds is in turn related chemically to the indoleamine neurotransmitter, serotonin. Psilocybin and psilocin were isolated and purified from the Mexican hallucinogenic fungus Psilocybe mexicana by Heim in 1958.Reference Hofmann, Heim and Brack 10 Both compounds were chemically synthesized by Hoffman, and the structure was characterized in the same laboratory.Reference Hofmann, Frey, Ott, Petr Zilka and Troxler 11

Pharmacokinetics and metabolism

Studies in rodent tissue have suggested complete conversion of psilocybin to psilocin, by loss of the phosphate moiety, before entering the systemic circulation.Reference Eivindvik, Rasmussen and Sund 17 Thus, studies of the kinetics of the drug are of its major (active) metabolite, psilocin. Indeed, following oral administration of ascending doses of psilocybin, no parent compound was observed in plasma or urine.Reference Brown, Nicholas and Cozzi 15 Few human pharmacokinetic studies have been undertaken so that detailed information of some aspects is unknown. For example, the influence of intrinsic factors on observed pharmacokinetic parameters (eg, hepatic and renal impairment, age, and gender) in addition to that of extrinsic factors are poorly studied, if at all. A summary of the known kinetic studies and their associated parameters for psilocin are presented in Table 1.

Table 1. Pharmacokinetic Parameters for Psilocin Following Administration of Psilocybin

a i.v. intravenous; p.o. oral.

b Study of Brown et al was an ascending dose study in the same subjects. Reduced numbers due to dropouts.

Following oral administration of psilocybin, psilocin appears in the plasma within 20 to 30 minutes and maximum concentrations are achieved within 2 to 3 hours of the dose.Reference Brown, Nicholas and Cozzi 15 , Reference Kolaczynska, Liechti and Duthaler 16 Conversion of the parent compound to psilocin appears to be highly variable based on the dispersion of Tmax values reported in oral administration studies (see Table 1). Maximum concentrations of psilocin were linearly dependent on dose in the only oral ascending dose study conducted to date.Reference Brown, Nicholas and Cozzi 15 Similarly, area under the plasma concentration time curve (AUC) also increased proportionally to the dose confirming linear pharmacokinetics of psilocin in the dose range 0.3 to 0.6 mg/kg.Reference Brown, Nicholas and Cozzi 15

Psilocin is extensively distributed to the tissues as the apparent volume of distribution exceeds that of total body water.Reference Brown, Nicholas and Cozzi 15 A value of 298 L was determined based on a population pharmacokinetic estimate, assuming a one-compartment model with linear clearance and linear absorption.Reference Brown, Nicholas and Cozzi 15 The model fitted estimate agrees with the volume of distribution calculated from mean published values for AUC and half-life following intravenous administration.Reference Hasler, Bourquin, Brenneisen, Bar and Vollenweider 12 In a study of N = 3 human participants, the mean absolute bioavailability of psilocin was 52.7% (±20.4%) after oral administrationReference Hasler, Bourquin, Brenneisen, Bar and Vollenweider 12 which is similar to values determined following administration of 14C labeled psilocybin to rodents.Reference Passie, Seifert, Schneider and Emrich 18

After oral administration of psilocybin, the apparent terminal elimination half-life of psilocin was variable (see Table 1). An overall mean of 3 ± 1.1 hours was determined after ascending oral doses.Reference Brown, Nicholas and Cozzi 15 Values within a similar range were observed after administration of other oral doses suggesting that elimination half-life is not dependent on the dose, that is, metabolism is not saturated within the dose ranges studied.

Psilocybin is rapidly dephosphorylated after oral administration forming psilocin in the acidic environment of the stomach or by alkaline phosphatase in the intestine and kidney.Reference Dinis-Oliveira 19 It has been suggested that psilocybin can be considered a “pro-drug” for psilocin. Psilocin is subject to extensive hepatic first-pass Phase I metabolism by demethylation and oxidation catalyzed by monoamine oxidase and aldehyde dehydrogenase to form 4-hydroxyindole-3-acetic acid (4-HIAA), 4-hydroxy-indole-3-acetaldehyde and 4-hydroxytryptophol.Reference Lindenblatt, Kramer, Holzmann-Erens, Gouzoulis-Mayfrank and Kovar 13 , Reference Kalberer, Kreis and Rutschmann 20 None of these metabolites are considered pharmacologically active. Phase II metabolism is catalyzed by the UDP-glucuronosyltransferase (UGT) family of enzymes and is the predominant route of metabolism (>80%).Reference Chen, Li and Yan 21 Extensive glucuronidation by UGT1A10 occurs in the small intestine, while UGT1A9 is the main contributor to glucuronidation once absorbed into the circulation.Reference Manevski, Kurkela and Hoglund 22 The main urinary metabolite is psilocin-O-glucuronide while 2 to 4% of psilocin is excreted unchanged in the urine.Reference Hasler, Bourquin, Brenneisen and Vollenweider 14 Both the glucuronide of psilocin and 4-HIAA are present in plasma in concentrations far exceeding those of psilocin after oral administration.Reference Hasler, Bourquin, Brenneisen, Bar and Vollenweider 12 , Reference Kolaczynska, Liechti and Duthaler 16 Similarly, the amount of psilocin glucuronide excreted renally has been shown to exceed that of psilocin over 24 hours.Reference Hasler, Bourquin, Brenneisen and Vollenweider 14

Concentrations of psilocin in plasma show a direct correlation with neocortical 5-HT2A receptor occupancy and subjective psychoactive effects.Reference Madsen, Fisher and Burmester 23 Single doses of psilocybin from 3 to 30 mg occupied up to 72% of 5-HT2A receptors in a dose dependent manner. The EC50 for receptor occupancy by psilocin was 1.97 μg/L.

Pharmacodynamics

Interaction of psilocin with various receptor subtypes has been determined using radioligand binding studies. An early study showed a rank order of affinity of binding as 5HT2A > 5HT1A > 5HT2B in rat (1A, 2A) or bovine (2B) cortex.Reference McKenna, Repke, Lo and Peroutka 24 Using cell preparations expressing 5HT2A or 5HT2C (rat) or 5HT1A (human) receptors a rank order of binding of psilocin was 5HT2C > 5HT2A > 5HT1A.Reference Blair, Kurrasch-Orbaugh and Marona-Lewicka 26 A later study showed that in addition to binding to 5HT2A receptors psilocin bound to many other receptors, the increasing order of affinity being: 5HT2B, 5HT1D, dopamine D1, 5HT1E, 5HT1A, 5HT5A, 5HT7, 5HT6, D3, 5HT2C, and 5HT1B.Reference Ray 27 Binding to the serotonin transporter (SERT) and the trace amine associated receptor (TAAR1), has also been observed but the significance of binding to this latter receptor for the subjective effects of the drug is not known.Reference Rickli, Moning, Hoener and Liechti 25 Some reported values for psilocin binding to various receptors are shown in Table 2.

Table 2. Binding Data for Psilocin to Neuronal Receptors and Transporters

Note: Ki values expressed as nM. Measured Ki values between studies generally show a lower affinity for 5HT2A than for the other subtypes although there is considerable variation, possibly reflecting different assay conditions, ligands used to define binding sites and tissue preparations and species in which the binding was determined (eg, rat vs human cloned receptors).

Abbreviation: PDSP, NIMH Psychoactive Drug Screening Program.

Psilocin acts as a partial agonist at the 5HT2A receptor with <40% efficacy (Ca2+ mobilization assay relative to 5HT as a control).Reference Rickli, Moning, Hoener and Liechti 25 , Reference Blough, Landavazo, Decker, Partilla, Baumann and Rothman 28 Intrinsic activity at the 5HT2A receptor (phospho-inositol hydrolysis relative to 5HT) was 52 ± 5.6%.Reference Blair, Kurrasch-Orbaugh and Marona-Lewicka 26 The decrease in the firing rate of the raphe nucleus has been attributed to an agonist effect at 5HT1A autoreceptors.Reference Aghajanian and Hailgler 29 The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor.Reference Vollenweider and Kometer 30 However, the 5HT1A receptor has been suggested as a potential mediator of psilocin effects, while effects at 5HT2C receptor seem less likely.Reference De Gregorio, Aguilar-Valles and Preller 31

Evidence for the mediation of psilocybin effects by the 5HT2A receptor has been examined using specific antagonists. Thus, pretreatment of subjects with the selective 5HT2 receptor antagonist, ketanserin, dose dependently blocked the perceptual disturbance and hallucinatory phenomena induced by psilocybin (0.25 mg/kg).Reference Vollenweider, Vollenweider-Scherpenhuyzen, Babler, Vogel and Hell 32 Furthermore, the atypical antipsychotic, risperidone, but not the typical agent haloperidol, was also able to block the effects suggesting a specific action at the 5HT2A receptor. Administration of ketanserin has been shown to block the effects of psilocybin on mood and emotional face recognition in healthy volunteersReference Kometer, Schmidt, Bachmann, Studerus, Seifritz and Vollenweider 33 as well as sensorimotor gating and controlled (Stroop interference) inhibition processes.Reference Quednow, Kometer, Geyer and Vollenweider 34 These findings are supported by preclinical studies in rodents which show that head twitches and wet dog shakes induced by psilocybin administration are also reversed by 5HT2A antagonists.Reference Tyls, Palenicek and Horacek 35 In addition, some behavioral effects in animals due to psilocybin are prevented by 5HT1A, 5HT2B/2C, and D2 receptor antagonists.Reference Tyls, Palenicek and Horacek 35

The head twitch response in rodents can reliably distinguish hallucinogenic and nonhallucinogenic 5-HT2A receptor agonists, with positive responses observed for hallucinogenics lysergic acid diethylamid (LSD), psilocybin and mescaline, but not for nonhallucinogenic lisuride.Reference Halberstadt, Chatha, Klein, Wallach and Brandt 36

Psilocin has been associated with changes in neuroplasticity, including neuritogenesis, mediated through tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR) and 5HT2A signaling pathways.Reference Ly, Greb and Cameron 37 Neuro-plastogenic effects of psychedelics have been proposed as a nonhallucinogenic mechanism of action that contributes to their therapeutic effect.Reference Peters and Olson 38 In addition to 5HT2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis,Reference Akin, Manier, Sanders-Bush and Shelton 39 5HT2A antagonism has been shown to activate the TrkB pathwayReference Pilar-Cuellar, Vidal and Pazos 40 and perhaps other pathways. Biasing the agonism for one vs another pathway (and thus for hallucinogens vs psychoplastic effects in theory) could be the result of numerous mechanisms under current investigation including homomeric vs heteromeric receptor complexes and ligand dependent biased signaling, leading to the prospect that future psilocybin analogues may be able to work at the 5HT2A signaling complex to cause psychoplastic effects without hallucinogenic effects, and thus antidepressant effects without behavioral toxicities.

Systemic administration of psilocin results in alterations of serotonin and dopamine concentrations in specific brain areas of the rat, as demonstrated by in vivo microdialysis.Reference Sakashita, Abe and Katagiri 41 Serotonin was increased in the medial prefrontal cortex but not the nucleus accumbens, whereas dopamine was increased in the accumbens but not the cortex. It was speculated the differential effects could be explained by activation of mesocortical 5HT2A receptors (serotonin increases) and both 5HT1A and 5HT2A activation (dopamine increases) in the accumbens. An increase in endogenous dopamine concentrations was demonstrated in the caudate nucleus and the putamen in healthy volunteers following psilocybin administration, indexed by decreased [11C]raclopride receptor binding potential.Reference Vollenweider, Vontobel, Hell and Leenders 42 Dopamine increases were correlated with euphoria and depersonalisation. Increases in both transmitters thus may explain, at least in part, the mood elevating and psychotomimetic properties associated with psilocybin administration (vide infra). These neurochemical changes are accompanied by intracellular and downstream receptor alterations, which have been associated with a proposed mechanism of action of hallucinogens in general.Reference Vollenweider and Kometer 30 It is suggested that hallucinogenic 5HT2A agonists differentially activate cortical pyramidal neurons resulting in increased expression of (erythroblast transformation-specific related gene) ERG1 and ERG2 and β-arrestin-2.Reference Gonzalez-Maeso, Weisstaub and Zhou 43 , Reference Schmid, Raehal and Bohn 44 Glutamatergic activity in pyramidal neurons of the prefrontal cortex is also increased as a result of 5HT2A activationReference Vollenweider and Kometer 30 which in turn leads to interactions of glutamate with AMPA and NMDA receptors on cortical pyramidal neurons. Systemic administration of psilocybin has been shown to increase the production of BDNF in the hippocampus, an effect related to 5HT2A agonist properties.Reference Ly, Greb and Cameron 37 , Reference Catlow, Song, Paredes, Kirstein and Sanchez-Ramos 45 Furthermore, the increase in neurogenesis was accompanied by extinction of conditioned fear related behaviors.Reference Catlow, Song, Paredes, Kirstein and Sanchez-Ramos 45 A complex interplay between serotonergic and glutamatergic systems in the prefrontal circuits may underlie the potential therapeutic effects of psilocin in depressive and anxiety states.

Imaging studies

Different brain imaging modalities have been applied to the study of psilocybin administration in human samples with some inconsistencies between them. While positron emission tomography (PET) studies have shown that psilocybin causes increased brain activity, other modalities (eg, functional magnetic resonance imaging [fMRI]) have shown decreased activity.Reference Johnson, Hendricks, Barrett and Griffiths 46

A PET study utilizing glucose metabolism (18FDG) showed that 15 to 25 mg of psilocybin increased activity in the prefrontal cortex.Reference Vollenweider, Leenders, Scharfetter, Maguire, Stadelmann and Angst 47 In these healthy subjects, glucose uptake was positively correlated with certain psychotic symptoms, in particular ego disintegration. Psilocybin (0.2 mg/kg) increased the metabolic rate of glucose in the right frontotemporal cortical regions, but particularly the right anterior cingulate cortex.Reference Gouzoulis-Mayfrank, Schreckenberger and Sabri 48 Simultaneously, metabolism in the thalamus was decreased. Increases in activity in the left fronto-cortical regions triggered by a cognitive activation task (word association) was blunted by psilocybin.

Magnetoencephalography (MEG) demonstrated reduced spontaneous cortical oscillatory power in the cortical region of male participants (N = 15) who had received an infusion of psilocybin over 60 seconds (2 mg in 10 ml of saline).Reference Muthukumaraswamy, Carhart-Harris and Moran 49 Elsewhere, global decrease or desynchronization of electroencephalography (EEG) activity was demonstrated in freely moving rats administered psilocin (4 mg/kg).Reference Vejmola, Tyls and Piorecka 50

Resting state fMRI studies have examined the effects of psilocybin on the connectivity between different brain areas and the activity of specific brain regions. The psychedelic experience with psilocybin was suggested to be caused by an impairment of connectivity between different brain regions.Reference Calvey and Howells 51 Using BOLD imaging, intravenous infusion of psilocybin decreased coupling between the medial prefrontal cortex and the posterior cingulate cortex compared to placebo.Reference Carhart-Harris, Erritzoe and Williams 52 It was suggested that the observed alterations in activity and connectivity may be responsible for the subjective effects of the drug. The data from this study were subjected to further analysis to define brain functional networks.Reference Petri, Expert and Turkheimer 53 A consequence of psilocybin administration was disruption of the normal brain organization and an emergence of strong, long range function connections which are not normally present. This increased integration of cortical regions under psilocybin possibly occurs because of stimulation of 5HT2A receptors. It was speculated that one result of such reinforced cortical connections is the phenomenon of synaesthesia.

Decreased functional connectivity between the right claustrum with the auditory cortex and default mode network (DMN) was demonstrated using BOLD fMRI after psilocybin administration.Reference Barrett, Krimmel, Griffiths, Seminowicz and Mathur 54 Concurrently increased connectivity between the right claustrum and the frontoparietal task control network was demonstrated, suggesting a potential role of the claustrum in the therapeutic and subjective effects of psilocybin.

Few neuroimaging studies have examined the effects of psychedelic drugs in patients with psychiatric conditions. An open evaluation of psilocybin was conducted in 19 patients with treatment-resistant depression who underwent BOLD fMRI scanning pre- and posttreatment.Reference Carhart-Harris, Roseman and Bolstridge 55 Patients received 2 doses of psilocybin (10 and 25 mg) 1 week apart and the post scans were conducted 1 day after the second dose of drug. A main finding was diminished cerebral blood flow in the amygdala posttreatment, which was correlated with decreased depressive symptoms. Resting state functional connectivity in the DMN was increased posttreatment. Response to treatment at a 5-week follow-up was predicted by an increased connection between the prefrontal cortex and the inferior lateral parietal cortex and by diminished para-hippocampal-prefrontal cortex connectivity. In patients with depression, imaging studies have shown a heightened amygdala response to fearful faces which is attenuated by SSRI antidepressants.Reference Ma 56 Examination of these responses in the same treatment-resistant patients showed increased amygdala reactivity after psilocybin and a reduction in amygdala, prefrontal cortex connectivity.Reference Roseman, Demetriou, Wall, Nutt and Carhart-Harris 57 , Reference Mertens, Wall, Roseman, Demetriou, Nutt and Carhart-Harris 58 These results are at odds with other data which demonstrated a decrease in amygdala reactivity to emotional processing after acute treatment with psilocybin.Reference Kraehenmann, Preller and Scheidegger 59 Furthermore, an increase in the positive mood of healthy volunteers was associated with the decreased reactivity. The differences between studies might simply be due to the investigation of healthy controls vs depressed patients. Also, the proximity of scanning times to the administration of drug might also be a factor (immediately after drug administration vs a delay of 24 hours).

A recent study of people with depression who were treated with psilocybin (25 mg) used fMRI at baseline and 3 weeks posttreatment to find enduring changes in increased global integration of brain networks. Brain networks became more functionally interconnected and flexible after psilocybin treatment.Reference Daws, Timmermann and Giribaldi 60 Previous research had associated depressive illness with reduced global integration of brain networks and the current finding suggests a possible mechanism for symptomatic improvement with psilocybin treatment.

Drug safety

Psilocybin and psilocin are considered to have a low potential for acute toxicity due to overdose. A study investigating lethal toxicity in rodents as well as human effects concluded that psilocybin has a high therapeutic index, with a therapeutic dose at 15 to 30 mg and a lethal dose 500 times greater at 6 g.Reference Gable 61 For recreational users, consuming psilocybe mushrooms to a lethal dose is nearly impossible to achieve and lethality is more likely due to misidentification of mushrooms or disrupted judgment or behavior consequent to psychosis or dissociation.Reference Coletta 62

Psilocybin and has long been known to be able to induce symptoms resembling, to some extent, those presented by schizophrenia or psychosis, but with a greater visual effects such as bright and colorful shapes and figures,Reference Geiger, Wurst and Daniels1 which appears to be mediated by serotonin type 2 agonism.Reference Vollenweider, Vollenweider-Scherpenhuyzen, Babler, Vogel and Hell 32 Concordant with this there is preclinical evidence that psilocybin has an impact on pre-pulse inhibition.Reference Gouzoulis-Mayfrank, Heekeren and Thelen 63

Adverse effects for psilocybin, psilocin or psilocybe mushrooms include; tachycardia, anxiety, nausea, vomiting, diarrhea, emotional lability, delusions, feelings of impending doom and confusion,Reference Geiger, Wurst and Daniels 1 dysphoria, derealisation, depersonalisation, and mydriasis.Reference Peden, Pringle and Crooks 64 Seizure threshold lowering has been suggested as an adverse effect,Reference Geiger, Wurst and Daniels 1 but has not been well established.Reference Zagnoni and Albano 65 Gastro-intestinal effects are more common with mushroom ingestion and may result from other components in the mushroom preparations.

Of concern, an ongoing condition called hallucinogen persisting perception disorder (HPPD) has been described amongst users of hallucinogenic substances following cessation of use, characterized by flashbacks and ongoing hallucinations of varying intensity.Reference Geiger, Wurst and Daniels 1 HPPD symptoms include geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trails of images of moving objects (palinopsia), positive afterimages, halos around objects, macropsia and micropsia. 66 HPPD has been reported in a recreational user of psilocybin, where alcohol and cannabis use were also present.Reference Skryabin, Vinnikova, Nenastieva and Alekseyuk 67 A study of data from 21 967 people who reported lifetime hallucinogen use suggested that HPPD was rare and that an association between hallucinogen use and adverse mental health outcomes was not found.Reference Krebs and Johansen 68 Elsewhere it was suggested that chronic visual disturbances in hallucinogen users may be more common, affecting up to 50% of users, with HPPD a less common severe form.Reference Orsolini, Papanti, De Berardis, Guirguis, Corkery and Schifano 69

Adverse outcomes may result from “bad trips” including a reported fatal outcome.Reference Honyiglo, Franchi and Cartiser 70 In the research environment hallucinogenic experiences are generally supported by experienced psychologists with research participants who have been carefully screened and prepared. “Bad trips” may be more common in a recreational drug use environment and it is not clear how common they would be in a routine clinical environment. In a research environment, participants administration and dosage is tightly controlled, which is less so in a routine clinical environment and even less so in a recreational environment. Given the widespread enthusiasm for this class of agent and the equally widespread recreational use, the boundaries between clinical and recreational use are likely to become rapidly very blurry.

Investigations in humans and animals

Recently, there has been a growing interest that psilocybin may be an efficacious drug as an agent for drug assisted psychotherapy and as a psychotherapeutic adjunct for the treatment of addictive disorders, anxiety and depression. Moreover, there is a suggestion that clinical usefulness may be a class effect across psychedelics.Reference Murnane 71 However, the safety and tolerability profiles as well as other pharmacological characteristics varies significantly between agents and clinical benefit remains under investigation, suggesting that further work is required.

Animal studies

A single administration of psilocybin (1 mg/kg IP) compared to saline (IP) produced antidepressant-like effects in in the forced swim test and anxiolytic-like effects in the elevated plus maze.Reference Hibicke, Landry, Kramer, Talman and Nichols 72 Psilocybin “microdosing” has been investigated in a study of rats dosed 0.03 to 10 mg/kg, with presumed serotonin mediated antidepressant-like behaviors reported for doses 0.3 mg/kg and above.Reference Higgins, Carroll and Brown 73 Anxiolytic efficacy was not supported in a study of psilocin microdosing (0.05 or 0.075 mg/kg) of rats in the elevated plus maze.Reference Horsley, Palenicek, Kolin and Vales 74 Elsewhere, psilocybin (1, 2.5, and 10 mg/kg) did not reduce relapse behavior in a rodent model of alcohol relapse.Reference Meinhardt, Gungor, Skorodumov, Mertens and Spanagel 75

Human studies

Improvement in symptoms of mood and anxiety have been reported in three small pilot randomized clinical trials (RCTs) of people with cancer treated with psilocybin. In an RCT with a cross-over design, 12 people with end-stage cancer and anxiety were administered single dose psilocybin (0.2 mg/kg) or placebo (niacin). Psilocybin treatment was well tolerated and associated with improvement on the State–Trait Anxiety Inventory trait anxiety subscale (STAI-anxiety) at 1 and 3 months posttreatment and the Beck Depression Inventory (BDI) at 6 months posttreatment.Reference Grob, Danforth and Chopra 76 Elsewhere, an RCT with a similar design randomized 29 people with cancer-related anxiety and depression to single dose psilocybin (0.3 mg/kg) or placebo (niacin), with cross-over at week 7. The psilocybin first group, but not the placebo first group, demonstrated significant within-group reductions (compared to baseline at each post-baseline assessment point) in anxiety and depression after receiving psilocybin and prior to cross over. At 6.5 months post (after both groups received psilocybin), antidepressant or anxiolytic response rates were approximately 60 to 80% measured with the Hospital Anxiety and Depression Scale (HADS) and the BDI.Reference Ross, Bossis and Guss 77 A larger RCT of people with cancer, randomized participants to low dose first (n = 27; 1 or 3 mg/70 kg) or high dose first (n = 29; 22 or 30 mg/70 kg) of psilocybin in a cross-over design with 5 weeks between treatment sessions and a 6 month follow-up. Data from at least one session was collected from 51 participants, with 46 participants providing 6 month follow-up data. High dose first was superior to low dose first following the first treatment session and second dose was superior to first dose for low dose first following the second treatment session for measures of depression (Hamilton Rating Scale for Depression [HAMD], BDI, HADS) and anxiety (Hamilton Rating Scale for Anxiety [HAM-A], STAI-anxiety), and lower measures of depression and anxiety were sustained as 6 month follow-up for both groups.Reference Griffiths, Johnson and Carducci 78

Psilocybin was superior to being randomized to a waiting list in a trial of people with major depressive disorder (N = 27) in a trial of two therapist supported psilocybin sessions (20 mg/70 kg in session 1 and 30 mg/70 kg in session 2), with reduction in HAMD and QIDS-SR-16 scores reported from week 1 to week 4 posttreatment.Reference Davis, Barrett and May 79 Wait list is a problematic control as it tends to inflate effect sizes and may even serve as a nocebo condition.Reference Furukawa, Noma and Caldwell 80 A meta-analysis of all studies where psilocybin was administered to people with elevated symptoms of depression and/or anxiety identified four studies and found a large effect size for psilocybin treatment for anxiety (Hedges’ g = 1.38) and depression (Hedges’ g = 1.47), but suggested problems with detection bias due to inadequate blinding and attrition bias.Reference Goldberg, Pace, Nicholas, Raison and Hutson 81 More recently, an RCT randomized participants with moderate to severe depression (HAMD ≥ 17 at baseline) to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group, N = 30) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group, N = 29), plus psychological support. Improvement in depression symptoms using the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16) was observed in both treatment groups at 6 weeks posttreatment. In the psilocybin group 21 of 30 participants responded and 17 of 30 participants remitted (response defined as a reduction in QIDS-SR-16 score of >50% and remission defined as a score of ≤5) whereas in the escitalopram group 14 of 29 participants responded and 8 of 29 participants remitted, however, the differences in QIDS-SR-16 scores were not significant between groups.Reference Carhart-Harris, Giribaldi and Watts 82 This trial is subject to similar issues regarding blinding and expectancy noted above. A larger, multisite RCT of psilocybin for depression is currently in progress (ClinicalTrials.gov Identifier: NCT03866174) with no results available to date.

Psilocybin with psychological support has been investigated in an open-labeled trial of patients (N = 20) with treatment-resistant depression (TRD) who received two doses (10 and 25 mg) 7 days apart. Participants were followed for 6 months and reported reductions in depressive symptoms measured using the QIDS-SR-16 at all posttreatment time points with the greatest improvement at 5-weeks posttreatment.Reference Carhart-Harris, Bolstridge and Day 83

Psychological interventions assisted by psychedelic drugs has used psycholytic and psychedelic paradigms. Psycholytic approaches are associated with psychoanalytic practice and use low dose psychedelic drugs, especially LSD, to putatively reduce psychological defenses and to release unconscious information, whereas psychedelic approaches integrate the psychedelic experience into the psychotherapy session.Reference Bravo and Grob 84 Psilocybin has been used for psychedelic assisted psychotherapy.

Psilocybin assisted psychotherapy, where psilocybin treatment is adjunctive therapy to enhance a psychotherapeutic intervention was first studied from 1961 in the context of recidivism in prison inmates released on parole, where incarcerated prisoners nearing their parole dates were offered sessions using psilocybin in addition to session(s) that did not include medications. Despite initial, possibly falsified reports of strong antirecidivist effects more recent reanalyses of the original data suggests that effects were modest and not statistically significant.Reference Doblin 85

Some evidence for efficacy of psilocybin assisted psychotherapy to treat substance use disorders was demonstrated from small open labeled trials for tobacco smoking cessation and alcohol cessation. An open-labeled pilot study (N = 15) included three sessions with moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin administration occurring in weeks 5, 7, and 13 within a 15-week course of smoking cessation treatment. Twelve of 15 participants were abstinent from smoking (confirmed by exhaled carbon monoxide and urinary cotinine) at the 6-month follow-up, however the study design does not permit discerning the contribution of the psilocybin sessions to the smoking cessation rate.Reference Johnson, Garcia-Romeu and Griffiths 86 Elsewhere, psilocybin sessions at 4 (0.3 mg/kg) and 8 (0.4 mg/kg) weeks were included in a 12 week program of 14 sessions of psychosocial treatment for alcohol dependence (N = 10). Compared to baseline, significant reduction in percent heavy drinking days and percent drinking days was observed at weeks 5 to 12 of treatment and remained low until the final follow-up visit at week 36 for the nine participants that completed all assessments.Reference Bogenschutz, Forcehimes, Pommy, Wilcox, Barbosa and Strassman 87

It is unclear from the available research designs if concomitant administration of psilocybin amplifies the benefits of psychotherapy or whether benefits, if present, are driven by either of the elements alone. Multi arm studies disentangling these variables are necessary to provide the requisite clarity. A further methodological issue that needs to be resolved is that many psychotherapy trials involve considerable face to face contact, support, and reinforcement. It is known that nonspecific therapeutic benefits are robustly associated with the quantity and enthusiasm of the available clinical support and the next generation of trials needs to ensure that these elements are matched between treatment arms.

Psilocybin microdosing has not been found to be effective. A study of psilocybin microdose vs placebo for well-being and cognition in volunteers (N = 191) demonstrated improvement from baseline in both study arms, suggesting that improvement could be attributed to the placebo effect.Reference Szigeti, Kartner and Blemings 88

Human studies are summarized in Table 3 and the mechanism of action of psilocybin is described in Figure 1.

Table 3. Clinical Trials of Psilocybin for Neuropsychiatric Disorders

Figure 1. Mechanism of action for psilocybin, describing the psychedelic, psychological, and neuroplastogenic effects.

Note: 1. Additional binding receptors include: 5HT2B, 5HT1D, dopamine D1, 5HT1E, 5HT1A, 5HT5A, 5HT7, 5HT6, D3, 5HT2C, 5HT1B, SERT, and TAARI. Reported values for psilocin binding to various receptors are shown in Table 2.

Discussion

Psilocybin has been used by several cultures for millennia, suggesting a historical experience-based knowledge of its use. Its use in traditional rituals has been documented where it has been consumed to induce altered states of consciousness often as religious or mystical experiences. However, there is little evidence of the traditional use of psilocybin containing mushrooms as treatment for medical or neuropsychiatric illness, rather psilocybin mushrooms have been sought specifically for their hallucinogenic properties. The modern pharmacopeia has many examples of pharmaceuticals that were discovered by investigating traditional plant-based remedies, although typically there has been some level of overlap between the traditional use and the modern indication for use or sought mechanism of action.

In healthy humans, psilocybin use is associated with increased emotional empathyReference Pokorny, Preller, Kometer, Dziobek and Vollenweider 89 as well as mystical and spiritual experiences that can be potent and enduring.Reference Griffiths, Richards, Johnson, McCann and Jesse 90 Improvements in mood, and pleasurable experiences of perception, thought and self-experience have also been reported, although strong dysphoria, anxiety and may also occur as adverse effects.Reference Studerus, Kometer, Hasler and Vollenweider 91 With the psychedelic effects of psilocybin being the most remarkable aspect of its pharmacology and the mood altering and anxiolytic properties less predictable and sometimes adverse, a therapeutic role for psilocybin in neuropsychiatry may be limited or elusive.

Although psychedelic experiences with guided psychotherapy have been suggested to be therapeutic, not all behavioral experiences are therapeutic. Psilocybin has also been used with limited success in attempts to brainwash subjects, as for example in the well-known MK-ULTRA project run by the U.S. CIA.Reference Dimsdale 92

While there is some evidence around dosing it is unclear if the optimal dose required has been definitively established. Evidence of efficacy of psilocybin microdosing is weak.

Furthermore, there has been a paucity of high-quality research into psilocybin due to Schedule I controlled substance status for the last five decades. Despite recent studies, the body of literature supporting the clinical efficacy of psilocybin remains preliminary. This literature is also beset by significant methodological questions which need to be addressed by the next generation of studies. Blinding and the driving of expectancy is a very important challenge. Acute administration of any overtly euphorigenic agent unblinds administration and is a powerful driver of expectancy and hence placebo effects.Reference Aday, Heifets, Pratscher, Bradley, Rosen and Woolley 93 This is particularly the case in people who have had persistent or unremitting depression and anxiety, where relief, let alone euphoria can be one of the most robust drivers of expectancy and hence nonspecific treatment effects. It is worth noting that several of the trials cited above used the QIDS-SR-16 which is a self-rated (SR) scale, which is problematic when blinding is inadequate. The next generation of studies may well require innovative solutions such as psychoactive controls to mitigate the euphoria inducing effects of medication or administration under sedation to minimize unblinding and expectancy. If psilocybin does become a pharmacotherapeutic agent, careful formal pharmacovigilance and postmarketing surveillance will be crucial.

Next generation research may even bypass psilocybin and other hallucinogens altogether, with psychoplastogens currently being developed.Reference Peters and Olson 38 These agents share neuroplastic mechanisms with classical psychedelics, but without the hallucinogenic experiences and there is preclinical data to demonstrate robust effects on structural plasticity in the prefrontal cortex.Reference Vargas, Meyer, Avanes, Rus and Olson 94 However, human trials of nonhallucinogenic psychoplastogens have not been conducted and the relationship between synaptogenesis or dendritogenesis in rodents and clinical outcomes in humans is not known.

There are three principal bridges to cross. Firstly, definitive data regarding efficacy is required arising from studies that have dealt with the major methodological problems bedeviling the field to date such as blinding and expectancy. Secondly, because most psychiatric disorders are enduring, long term data regarding both safety and efficacy is required. It is not possible to extrapolate from acute data because of tachyphylaxis associated with many recreational drugs and uncertainty about long term effects. Lastly but most importantly the pivotal issue remains safety. The small trials to date are inadequately powered to detect relatively rare risks such as psychosis which can be life changing. The opiate experience is informative in this regard because risks did not emerge in the well-controlled environment of clinical trials for pain but did so in the far less regulated clinical environment especially when it abuts into the chaotic world of recreational use. The number needed to harm (NNH) regarding risks like psychosis needs to be calibrated. Additionally other risks such as the use of one repurposed recreational drug serving as a gateway to experimentation with other recreational drugs for self-medication in the real world remains uncertain. Careful evaluation of the number needed to harm against the number needed to treat (NNT) will ultimately be needed to justify the clinical use of psilocybin. These issues need to be addressed before the field can embrace psilocybin and other psychedelics.

Conclusion

There is a paucity of research into the efficacy and safety of psilocybin. There is some evidence to suggest that it may benefit people with anxiety and depression due to cancer. Additionally, psilocybin may be a treatment option for people with treatment-resistant depression although the existing literature has significant methodological challenges that limited definitive extrapolation. Benefit seems to be obtained from doses sufficient to generate hallucinogenic experiences in participants who have been prepared for the experience with psilocybin administered in supported sessions. There is limited evidence to suggest a role for psilocybin for treating high prevalence disorders, depression and anxiety, and further research is required to identify risks and benefits as well as to identify individual patient characteristics or patient groups that may receive the greatest benefit. Further research and potential therapeutic use of psilocybin is limited by its status as a schedule 1 substance and risk of abuse and behavioral effects by recreational drug users.

Author Contributions

Conceptualization: S.D., H.A.E., A.F.C., M.B.; Investigation: S.D., T.R.N.; Methodology: S.D., T.R.N., S.M.S., M.B.; Project administration: S.D., S.M.S., M.B.; Writing—original draft: S.D., T.R.N., H.A.E., S.M.S., A.P., A.F.C., M.B.; Writing—review and editing: S.D., T.R.N., H.A.E., S.M.S., A.F.C., M.B.

Disclosures

S.D. has received grant support from the Stanley Medical Research Institute, NHMRC, Beyond Blue, ARHRF, Simons Foundation, Geelong Medical Research Foundation, Harry Windsor Foundation, Fondation FondaMental, Eli Lilly, Glaxo SmithKline, Organon, Mayne Pharma and Servier, speaker’s fees from Eli Lilly, advisory board fees from Eli Lilly and Novartis, and conference travel support from Servier. M.B. is supported by a NHMRC Senior Principal Research Fellowship (1156072). M.B has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant, and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier—all unrelated to this work. Over the past 36 months (January 2019–date), S.M.S. has served as a consultant to Acadia, Adamas, Alkermes, Allergan, Abbvie, Arbor Pharmaceutcials, AstraZeneca, Avanir, Axovant, Axsome, Biogen, Biomarin, Biopharma, Celgene, Concert, ClearView, DepoMed, EMD Serono, Eisai Pharmaceuticals, Eurolink, Ferring, Forest, Genomind, Innovative Science Solutions, Impel, Karuna, NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Jazz, Karuna, Lilly, Lundbeck, Merck, Neos, Neurocrine, Novartis, Noveida, Otsuka, Perrigo, Pfizer, Pierre Fabre, Proxymm, Relmada, Reviva, Sage Therapeutics, Servier, Shire, Sprout, Sunovion, TMS NeuroHealth, Takeda, Taliaz, Teva, Tonix, Tris Pharma, Trius, Vanda, Vertex, and Viforpharma; he holds options in Genomind, Lipidio, and Delix; he has been a board member of RCT Logic and Genomind; he has served on speakers bureaus for Acadia, Genentech, Janssen, Lundbeck, Merck, Otsuka, Servier, Sunovion, Takeda, and Teva and he has received research and/or grant support from Acadia, Alkermes, Allergan/AbbVie, AssureX, Astra Zeneca, Arbor Pharmaceuticals, Avanir, Axovant, Biogen, Braeburn Pharmaceuticals, BristolMyer Squibb, Celgene, CeNeRx, Cephalon, Dey, Eisai, Eli Lilly, Forest, GenOmind, Glaxo Smith Kline, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, ISSWSH, Janssen, JayMac, Jazz, Lundbeck, Merck, Neurocrine, Neuronetics, Novartis, Otsuka, Pear Therapeutics, Pfizer, Reviva, Roche, Sage, Servier, Shire, Sprout, Sunovion, Supernus, TMS NeuroHealth Centers, Takeda, Teva, Tonix, Torrent, and Vanda. H.A.E. has previously received consulting fees from Delix Therapeutics. He reports no other conflicts of interest. T.R.N., A.P., and A.F.C. have nothing to disclose.

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Figure 0

Table 1. Pharmacokinetic Parameters for Psilocin Following Administration of Psilocybin

Figure 1

Table 2. Binding Data for Psilocin to Neuronal Receptors and Transporters

Figure 2

Table 3. Clinical Trials of Psilocybin for Neuropsychiatric Disorders

Figure 3

Figure 1. Mechanism of action for psilocybin, describing the psychedelic, psychological, and neuroplastogenic effects.Note: 1. Additional binding receptors include: 5HT2B, 5HT1D, dopamine D1, 5HT1E, 5HT1A, 5HT5A, 5HT7, 5HT6, D3, 5HT2C, 5HT1B, SERT, and TAARI. Reported values for psilocin binding to various receptors are shown in Table 2.