This review (2014) provides a history of psilocybin and a summary of its pharmacology within humans and animals, its psychedelic effects as measured via neuroimaging and psychometric assessments, whilst highlighting its potential for both therapy and abuse.
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.
Psilocybin and its active metabolite psilocin, the principal psychoactive constituents of hallucinogenic mushrooms, have been investigated both as experimental tools for modelling psychosis and as candidate therapeutic agents. Historical use stretches back millennia in ritual contexts, and the compounds were introduced to Western science in the mid-20th century; however, widespread recreational use led to restrictions and a long hiatus in human research. Recent decades have seen a revival of experimental work because psilocybin combines relatively well characterised pharmacology with oral bioavailability and a tolerable safety profile in controlled settings. Tylš and colleagues set out to assemble a comprehensive, up-to-date synthesis of knowledge about psilocybin. The paper reviews chemical structure, metabolism and pharmacokinetics, receptor pharmacodynamics, animal and human behavioural effects, neurophysiological and neuroimaging findings, toxicity and safety issues, and emerging clinical applications. The stated aim is to bring together past and contemporary findings to clarify both the research utility and therapeutic potential of psilocybin.
Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
Carhart-Harris, R. L., Williams, T. M., Sessa, B. et al. · Journal of Psychopharmacology (2010)
Cohen, S. · Journal of Nervous and Mental Disease (1980)
Doblin, R. · Journal of Transpersonal Psychology (1991)
The extracted text does not present a dedicated Methods section detailing search strategy, inclusion criteria or systematic review procedures. From the content it is apparent that the paper is a narrative review that integrates historical reports, preclinical experiments, human experimental studies, electrophysiology and neuroimaging work, and clinical case reports and pilot trials. Material summarised includes chemical and pharmacokinetic data, receptor-binding and functional pharmacology, behavioural pharmacology in animals, controlled human psychopharmacology experiments (including psychometric scales), electrophysiological (EEG/MEG) and neuroimaging (PET/fMRI) investigations, toxicological findings, and small clinical and case-series reports of therapeutic applications. Where relevant, numerical values (for doses, timing, plasma levels, toxicology indices and prevalence estimates of adverse psychiatric outcomes) are reported from primary studies cited in the review; however, the paper does not state that meta-analytic pooling or formal risk-of-bias assessment was performed.
Chemical and pharmacokinetic findings: Psilocybin (O‑phosphoryl‑4‑hydroxy‑N,N‑dimethyltryptamine) is a prodrug rapidly dephosphorylated to the active psilocin by phosphatases in gut and tissues. Psilocybin content in mushrooms ranges about 0.2–1% of dry weight. After oral administration in humans, psilocybin/psilocin appear in plasma within 20–40 minutes, with peak psilocin at 80–105 minutes; oral effects onset 20–40 minutes, peak at 60–90 minutes and typically last 4–6 hours. Psilocin plasma half‑life is reported as ~2.5 hours after oral dosing and ~1.23 hours after intravenous administration. Metabolism includes glucuronidation (UGT1A10 in intestine, UGT1A9 in liver) and oxidative pathways; about 80% of psilocin is excreted as glucuronide and most elimination occurs within 3 hours, complete by 24 hours. Receptor pharmacology and cellular effects: Psilocin acts primarily as an agonist at serotonin 5‑HT2A/C and 5‑HT1A receptors, with much higher affinity at human 5‑HT2A receptors than in rats. The 5‑HT2A agonism is considered necessary for hallucinogenic effects; other receptor interactions (including weak binding at dopamine and other receptors) have also been reported. In neuronal systems expressing 5‑HT2A, psilocybin increases immediate early gene expression (eg c‑fos and egr family), a pattern the authors discuss in the context of biased/heteromeric receptor signalling (5‑HT2A/mGlu2 complex) as a possible mechanism distinguishing hallucinogenic from non‑hallucinogenic 5‑HT2A agonists. Animal and behavioural pharmacology: Doses used in animal studies vary widely (0.25–10 mg/kg typical, up to 80 mg/kg in some experiments). In rodents and other species psilocybin/psilocin produce dose‑dependent locomotor inhibition, signs of serotonergic behavioural syndrome (eg head‑twitch), altered sensorimotor gating (prepulse inhibition, with dose and species dependence), impaired performance on certain conditioned tasks, and reduced aggression/dominance behaviours. In primates, high doses produce stereotyped scanning and behaviours suggestive of altered perception, consistent with visual hallucination‑like phenomena. Human psychotropic and neuropsychological effects: Psychedelic effects typically emerge above ~15 mg oral psilocybin (corresponding to plasma psilocin 4–6 ng/ml); the drug is ~45× less potent than LSD and ~66× more potent than mescaline. Low doses accentuate pre‑existing mood, medium doses induce controllable altered states, and higher doses produce strong psychedelic experiences including altered perception, synaesthesia, derealisation/depersonalisation, time distortions, thought disturbances and marked emotional variability. Psychometric instruments (eg Altered States of Consciousness scales, Adjective Mood Rating Scale) document increased visual phenomena, altered affect and transient cognitive/perceptual impairments; some effects persist for hours but generally resolve within 24 hours. Longer‑term subjective changes: Several controlled and follow‑up studies report that a single psilocybin session can produce enduring positive changes in attitudes, mood and life priorities, including increased ratings of personal meaning and spirituality and, in some participants who had mystical‑type experiences, sustained increases in the personality trait openness lasting longer than one year. Physiological and endocrine effects: Sympathetic stimulation is typically mild—mydriasis, modest rises in systolic/diastolic blood pressure (~10–30 mmHg) and heart rate increases (average 82–87 bpm, peaks reported up to 140 bpm). Psilocybin has minimal acute effects on ECG or body temperature. It transiently elevates prolactin and, at high doses, corticotropin, cortisol and thyrotropin, with hormones returning to baseline within about five hours. Toxicity, safety and dependence potential: Acute somatic toxicity is low. Reported LD50 values are high in rodents (psilocybin LD50 ~280–285 mg/kg; psilocin LD50 lower at ~75 mg/kg for rodents). The LD50/ED50 ratio cited is 641. Clinical trial doses have not exceeded 0.429 mg/kg. Fatalities following mushroom ingestion have typically resulted from hazardous behaviour rather than direct pharmacological toxicity. Psychologically, adverse outcomes include transient anxiety, panic, prolonged unpleasant experiences, rare psychotic reactions and very rare hallucinogen persisting perception disorder (HPPD). Prevalence estimates from pooled serotonergic hallucinogen exposures suggest prolonged psychiatric symptoms occur in ~0.08–0.09% of healthy subjects and ~0.18% of psychiatric patients; suicide attempts in psychiatric patients were reported at 0.12% with fatalities in ~0.04% in the sources summarised. Tolerance develops rapidly with repeated dosing, and evidence for physical dependence or craving is lacking; primate self‑administration data do not indicate rewarding effects. Direct mutagenicity/genotoxicity was not observed in one cited study, but teratogenicity data are lacking. Electrophysiology and neuroimaging: EEG/MEG studies report reduced absolute power and coherence (especially fronto‑temporal), decreased alpha power and desynchronisation; MEG shows broadband reductions in spontaneous cortical oscillatory power with large decreases in default mode network (DMN) regions. FDG‑PET studies at peak effect (15–25 mg p.o.) reported increased metabolism in lateral and medial prefrontal cortex (including anterior cingulate), temporomedial cortex and basal ganglia, and reduced uptake in thalamus; these metabolic increases correlated with positive psychotic‑like symptoms. In contrast, intravenous psilocybin fMRI studies documented decreases in BOLD and perfusion in subcortical and high‑level association regions and reduced connectivity among key hubs (eg posterior cingulate–mPFC), with subjective intensity predicted by decreases in anterior cingulate and mPFC activity. The authors discuss several possible reasons for PET/fMRI discrepancies, including timing relative to peak effects and vasoactive actions of psilocybin. Clinical applications: Historical clinical use in the 1950s–1960s included psycholytic/psychedelic psychotherapy across a range of conditions. Recent pilot and controlled studies summarised include low‑dose psilocybin (0.2 mg/kg) showing anxiolytic and antidepressant effects in terminal cancer patients, reports of transient benefit in obsessive‑compulsive disorder, and preliminary support for facilitation of smoking cessation and alcohol dependence through enhancement of spirituality and motivation. Case reports also suggest benefit in cluster headache. The review notes these findings are preliminary and further research is needed.
Tylš and colleagues interpret the assembled evidence as indicating that psilocybin is a well characterised psychedelic with considerable value both as an experimental probe of brain function and as a candidate therapeutic agent. They emphasise that the drug's primary action at 5‑HT2A receptors, its downstream effects on cortical excitability and connectivity, and its relatively favourable acute safety profile make it useful for investigating perception, emotion and the neurobiology of psychosis. The authors acknowledge important caveats and unresolved issues. They note discordant neuroimaging findings (PET versus fMRI), which may reflect differences in timing, vascular effects and the relationships between neuronal excitability, oscillatory desynchronisation and metabolic measures. The limits of serotonergic models of psychosis are discussed: while psilocybin reproduces many positive symptoms and some processing abnormalities, it lacks the negative symptom and cognitive deficit profile typical of chronic schizophrenia, and clinical antipsychotic efficacy crucially relies on D2 antagonism. Practical constraints are highlighted—rapid tolerance to psilocybin precludes chronic modelling in humans, and ethical and legal restrictions have historically limited clinical research. Safety uncertainties are also identified. Although controlled studies report low rates of serious adverse events, the reviewers point to sparse data on teratogenicity and a small but non‑zero incidence of prolonged psychiatric sequelae and HPPD. The Schedule I legal status is criticised as inconsistent with the accumulated evidence of potential medical utility and acceptable safety under supervision. Finally, the authors call for further controlled clinical trials to define therapeutic indications and mechanistic studies to reconcile imaging and electrophysiological findings.
The authors conclude that psilocybin has substantial research and therapeutic potential. They highlight the drug's well understood pharmacokinetics and pharmacodynamics, its favourable safety profile in controlled settings and an absence of evidence for addiction liability. Psilocybin is presented as a valuable tool for probing serotonergic contributions to perception and emotion, a useful experimental model with translational validity, and a promising candidate for clinical development in several psychiatric and neurological conditions, pending further rigorous research.
Psilocybin and psilocin, the main psychedelic ingredients of hallucinogenic mushrooms) (Table), have recently been given a lot of attention as a research toolsas well as a potential therapeutic agents. History of the ritual use of hallucinogenic mushrooms dates back 3000 years in Mexico and regionally its use is still conventional practice today. Western science was introduced to these mushrooms in 1957 by Robert G. Wasson and they were later systematically ranked by Roger. Psilocybin was first isolated and identified in 1958 and synthesized in 1959 by Albert Hofmann. The content of psilocybin and psilocin in hallucinogenic mushrooms varies in the range of 0.2 to 1% of dry weight (Table.). In the 1960s psilocybin was widely used in the experimental research of mental disorders and even in psychotherapy. Soon, however, psilocybin containing mushrooms spread amongst the general public and became a popular recreational drug. Consequently, psilocybin (and psilocin) was classed as a schedule I drug in 1970) and all human experiments were gradually discontinued. Since the late 1990s, interest in human experimental research into psilocybin and other psychedelics has become revived (Figure). Nowadays, psilocybin is one of the most used psychedelics in human studies due to its relative safety, moderately long duration of action and good absorption after oral administration. The aim of this paper is to bring together the most detailed and up to date list of known properties and effects of psilocybin, starting with its chemical characteristics, metabolism, pharmacokinetics and ending with the use of psilocybin in human research and therapy.
Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active dephosphorylated metabolite psilocin (N,N-dimetyltryptamine) structurally belong to the group of tryptamine/indolamine hallucinogens and are structurally related to serotonin) (Figure). An equimolar dose to 1 mol of psilocin is 1.4 mol of psilocybin. Substitution of the indole nucleus in position 4 probably plays a substantial role in its hallucinogenic effects. Psilocybin and psilocin in their pure forms are white crystalline powders. While psilocybin is soluble in water, psilocin on the other hand is more lipid-soluble. However, psilocin can be also diluted in an acidified aqueous solution and in dimethylsulfoxide (DMSO; up to 100mM). Furthermore, both substances are soluble in methanol and ethanol, but almost insoluble in petroleum ether and chloroform. Both drugs are unstable in light (in particular in the form of solutions), their stability at low temperatures in the dark under an inert atmosphere is very good.
Psilocybin is rapidly dephosphorylated to psilocin in the intestinal mucosa by alkaline phosphatase and nonspecific esterase. After ingestion, about 50% of the total volume of psilocin is absorbed from the digestive tract of the rat. After systemic parenteral administration of psilocybin tissue phosphatases play the same role with the kidneys being among the most active. Given that the competitive blockade of dephosphorylation (beta-glycerolphosphate) blocks the psychotropic effects of psilocybin, it is clear that psilocin is the main active metabolite of psilocybin. Psilocin is further glucuronidated by endoplasmic enzymes UDPglucuronosyltransferase (UGTs) to psilocin-O-glucuronideand in this form 80% of it is excreted from the body. Of the 19 tested recombinant UGTs (from the families 1A, 2A and 2B) UGT1A10 in the small intestine and UGT1A9 in the liver have the greatest activity. In addition to the above-described metabolic pathway, psilocin itself is subject to oxidative metabolism. This is a demethylation and deamination of 4-hydroxyindol-3-ylacetaldehyde (4-HIA) and subsequent oxidation (presumably by hepatic aldehyde dehydrogenase and monoamine oxidase) to 4-hydroxyindol-3-acetic acid (4-HIAA) and 4hydroxytryptofol (4-HT). These minor metabolites (about 4% psilocin being degraded in this way) can also be detected in vivo in human plasma. The third possible pathway is the oxidation of psilocin by hydroxyindol oxidases to a product with an o-quinone or iminochinon structure. In rats and mice after oral administration of extracts from mushroomsmaximum plasma levels are achieved after approximately 90 minutes. Psilocin is distributed to all tissues, including the brain, and is excreted within 24 hours -the majority in the first 8 hours (65% in the urine and 15-20% in the bile and feces); small amounts can be detected in the urine even after a week). The highest levels of psilocin in various animals were detected in the neocortex, hippocampus, extrapyramidal motor system and reticular formation. In mice, preceding the brain, psilocin accumulates in the kidneys, and the liver. In humans, psilocybin and psilocin can be found in blood plasma 20-40 min after oral administration of psilocybin, maximum levels of psilocin are achieved between 80 and 105 min and can be detected for up to 6 hours. The halflife of psilocin in plasma is 2.5 hours after oral ingestion of psilocybin, following intravenous administration the half-life is 1.23 hours. 80% of psilocin in plasma was found to be in a conjugated form. Both psilocin (at 90-97%) and psilocybin (3-10%), are detectable in human urine, unmodified (only 3-10%) and in particular conjugated with glucoronic acid. The elimination half-life of psilocybin is 50 min, the elimination constant is 0.307/h. The majority is excreted within 3 hours after oral administration and is completely eliminated from the body within 24 hours.
Psilocybin and psilocin are substances with predominant agonist activity on serotonin 5HT 2A/C and 5HT 1A receptors (for specific affinities see Table.). Interestingly, psilocybin's affinity to human 5HT 2A receptors is 15-fold higher than in rats. While the 5HT 2A receptor agonism is considered necessary for hallucinogenic effects, the role of other receptor subtypes is much less understood. Contrary to a previous report, a recent study found that psilocin binds to many different receptors including dopamine in the following order: According to this data it also weakly binds to the receptors for Imidazoline 1 , Alpha 2A/B/C and 5HT transporters. Using selective agonists and antagonists 5HT 1A and 5HT 2A activity has also been confirmed in rodents in discrimination studies with hallucinogensand in studies on head twitch behavior and wet dog shakes (typical signs of the stimulation of the 5-HT 2A receptor). On the other hand, psilocybin/psilocin-induced locomotor inhibition was restored by antagonists 5-HT 1A and 5-HT 2B/C receptors. Finally, inhibition of dorsal raphe nucleus activity by psilocybin was shown to be mediated via agonism at 5-HT 1A autoreceptorsand electroencephalographic changes induced by psilocin were partly normalized by antagonists of 5-HT 1A, 5HT 2A/C as well as dopamine D 2 receptors. The effects of psilocybin in humans are also blocked by the 5-HT 2A/C antagonists. The role of 5-HT 1A receptors in human psilocybin studies has also yet to be investigated, certain clues can be derived from a study of a related hallucinogen N,N-dimethyltryptamine (DMT). Here the 5-HT 1A partial antagonist pindolol magnified the hallucinogenic effects by two to three times. Psilocybin also indirectly increased (via 5HT receptors) the release of dopamine in the ventral striatum in humans, an effect that correlated with symptoms of depersonalization and euphoria. In neurons expressing the 5HT 2A receptor, but not in 5HT 2A knockouts, psilocybin increases the expression of early genes and reduces the expression of sty-kinase. Needless to say, the precise signaling pathway leading from the receptor to the activation of early genes is not yet known. Given that a non-hallucinogenic lisuride also activates the c-fos, it is likely that the expression of c-fos only reflects increased neuronal activity, while the expression of egr-1/ egr-2 is specific for the hallucinogenic effect. Gonzales-Meaeso explained this selectivity with the "agonist trafficking of receptor signaling theory", where hallucinogens activate the 5HT 2A /mGlu 2 receptor heterocomplex and different G proteins compared to nonhalucinogenic 5-HT2A agonists. This hypothesis is supported in a study where mice with the knockout gene for the mGlu 2 receptor do not display any head twitch behavior.
Psilocybin and psilocin are used in animal behavioral experiments in the range of 0.25-10 mg/kg; however doses up to 80 mg/kg have also been used. Psilocybin dose of 10 mg/kg has mild sympathomimetic effects (piloerection and hyperventilation) in rodents and small carnivores. Characteristic effect of psilocybin is enhancement of monosynaptic spinal reflexes in cats. Peak of behavioral changes are typically observed within 30-90 min after drug administration. Locomotor behavior of rodents is dose-dependently inhibited by the drug with signs of ataxia. Psilocin also suppresses exploration and habituation elements and induces manifestations of behavioral serotonin syndrome (e.g. head twitch behavior) and in a very high doses (80 mg/kg) also atypical behavioral of backward walking. Behavioral excitation was observed anecdotally. Furthermore, psilocybin decreases aggressive behavior in rodentsand inhibits normal dominance behavior. Psilocybin has increased prepulse inhibition of acoustic startle response (PPI) a up to doses of 4.5 mg/kg in mice. Using a lower dose of psilocin (1 mg/kg), it attenuated PPI (via 5-HT 2A agonism predominantly) and with 4 mg/kg had no effect in Wistar rats. Psilocin also seems to have biphasic effects on startle reaction per se, with lower doses slightly increasing and higher doses (4-8 mg/kg) decreasing startle. Psilocybin also increased the starting latency in a special conditioned task (swimming through an underwater tube)and attenuated responses in a passive avoidance task. It is probable that the attenuation of startle response as well as altered performance in cognitive tasks could be related to the motor inhibition and ataxia produced by the drug as well as to an altered perception of the environment. In psilocybin self-administration experiments with macaques at sufficiently high doses the drug provoked stereotypical visual scanning, head shaking, bizarre postures, hyperactivity and focusing on an empty spot in a room with catching non-existent flies. It is therefore very likely that this is a direct manifestation of an altered perception, especially visual hallucinations.
In terms of efficacy, psilocybin is 45 times less potent than LSD and 66 times more potent than mescaline. Clinical studies indicate that the effective dose of oral (p.o.) psilocybin is 0.045-0.429 mg/kg and 1-2 mg per adult intravenously (i.v.) (Table). Psychedelic effects occur at doses above 15 mg of oral psilocybinor plasma psilocin levels of 4-6 ng/ml. Safety guidelines for the experimental use of hallucinogens state high but not dangerous oral doses of psilocybin as being anything higher than 25 mg. The psilocybin onset of action is between 20-40 minutes, maximum is 60-90 minutes and the duration is 4-6 hours after oral administration. The main effects disappear entirely within 6-8 hours, completely in 24 hours. For i.v. application, the effect starts after 1-2 minutes, peaks at 4-5 minutes and lasts for about 20 minutes. Evaluation of the effects of psilocybin after one week of administration did not confirm any breach of perception or cognition.
Analogously as in animals, in humans psilocybin slightly stimulates sympathetic activity (mydriasis, mild increase in blood pressure and increased heart rate) at doses higher than 3-5 mg p.o. with the full effect at 8-25 mg p.o.. The increase of systolic and diastolic pressure is approximately 10-30 mmHg each. The average heart rate was in the range of 82-87, maximal values reached 140 beats per minute. Furthermore, psilocybin had no effect on electrocardiograph (ECG) or body temperature. Other common somatic symptoms are: dizziness, weakness, tremor, nausea and vomiting (mainly after ingestion of psilocybin-containing mushrooms, drowsiness, yawning, paresthesia, blurred vision, and increased tendon reflexes. Psilocybin does not acutely affect the ionic balance, blood glucose or cholesterol, and even in high doses has only a negligible effect on plasma concentration or the activity of various enzymes (lactate dehydrogenase, alanine transaminase, alkaline phosphatase and cholinesterase, mild elevation of aspartate aminotransferase and γ-glutamyl transferase). However, psilocybin increases levels of prolactin, and in high doses also corticotropin, cortisol and thyreotropin. Hormone levels have returned to normal within five hours.
Very low doses cause drowsiness and emphasize the pre-existing mood. Medium doses induce a well controllable altered state of consciousnessand higher doses evoke a strong psychedelic experience. The phenomenology of psilocybin intoxication includes changes in perception (dream-like states, illusions, hallucinations, synesthesiae) including changes in body image (e.g. paraesthesia in the form of a tingling, dreaminess or somatic hallucinations), altered self-perception, derealization and depersonalization, impaired perception of time and space, impaired attention, thought content disorder (magical thinking, unusual ideas or delusions), change of intuition and sometimes also mood swings, symptoms of anxiety or elation, impaired concentration, and nervousness. Emotions during intoxication can vary greatly from ecstatic and pleasant feelings to anxiety. The effects of psilocybin as with other hallucinogens are quantified with five subscales of the Altered States of Consciousness scale (ASCs) (Table.). Comparing psilocybin with the dissociative anesthetic ketamine it was found that psilocybin has greater visual hallucinatory effects (VUS scale) but feelings of loss of physical integrity (AED scale) are more pronounced in ketamine. Psilocybin-induced changes were uniformly normalized by ketanserin (5-HT 2A/C antagonist) and risperidone (mixed 5-HT 2A/C and D 2 antagonist). On the other hand, an antagonist of the D 2 receptor, haloperidol, normalized only euphoric symptoms, derealization and depersonalization (OSE scale) and had no effect on the visual hallucinations (VUS scale) and even slightly potentiated the feeling of a loss of self-control (AIA scale). A positive correlation between psilocybin-induced reduction of visually evoked potentials and score on the VUS scale was also described. According to the Adjective Mood Rating Scale (AMRS) bpsilocybin induced an overall inactivation and tiredness, dazed state, introversion, increased emotional excitability, increased sensitivity and persisting dreaminess for up to 24 hours. Psilocybin altered several domains of cognitive function and information processing. It selectively reduced the ability to visually distinguish between faces with negative and neutral expressions but not positive-neutral faces, disrupted sustained attentionand altered visual information processing. Interestingly, some of the alterations in a binocular rivalry test (visual processing) were also observed during deep meditative states realized by experienced meditation practitioners. Effect of psilocybin on sensorimotor gating (PPI) was found to be dependent on the parameter "prepulse-pulse interval", with PPI disruption for short intervals (30 ms) and PPI increase in longer intervals (120-2000 ms). Psilocybin intoxication also brings about numerous spiritual and mystical experiences, as first documented in the famed Good Friday Experiment c. Positive longterm changes in life attitudes of participants were reported 25 years later. These pioneering experiments have recently been confirmed by double-blind placebo and active comparator controlled studies. Volunteers without any previous experience with psychedelics, two months after taking psilocybin rated the experience as having substantial personal meaning and spiritual significance with sustained positive changes in attitudes and behavior. A 14 months follow-up revealed it as being one of the most significant spiritual experiences. In another follow-up survey with subjects from studies carried out in Switzerland between 1999-2008, most described the experience as pleasurable, enriching and non-threatening. A third of subjects positively evaluated their experience 8-16 months after the session (positive change in world view, values, awareness of personal problems, relationships to one's body as well as to other people, relationships to nature, aesthetic experiences and their attitude to altered states of consciousness). Only 8% of the subjects reported moderate negative changes in their psychological well-being, however no subsequent long-term impairment of functioning was detected. Another recent study, assessing domains of personality in order to objectify long term subjective changes, found a significant increase in "openness" after psilocybin in participants who had mystical experiences during the session which remained for more than one year.
According to a number of toxicological and clinical studies psilocybin has a very low toxicity. Psilocybin showed no specific signs of toxicity in the isolated organs (intestine, heart) of rats and pigs, it is also not neurotoxic. Psilocybin LD 50 for rats and mice is 280-285 mg/kg, and for rabbits it is 12.5 mg/kg. Psilocin LD 50 is significantly lower for mice and rats 75 mg/kg and for rabbits 7 mg/kg. The LD 50 /ED 50 ratio is 641 according to the National Institute for Occupational Safety and Health Registry of Toxic Effects (compare this with 9637 for vitamin A, 4816 for LSD, 199 for aspirin and 21 for nicotine). Fatalities associated with ingestion of psilocybin containing mushrooms have been described, however these were not linked to direct toxicity of psilocybin but most victims died after jumping out of the window or committing suicide. The only reported fatality was described after ingestion of an extreme dose (psilocin plasma level was 4μg/ml) of Psilocybe semilanceata. A human lethal dose of psilocybin is difficult to estimate, it is clear that it is much higher than the psychoactive dose. One would have to eat approximately 19 grams of the pure drug or consume their body weight in fresh psilocybin containing mushrooms to bring on death (www.erowid.org). Doses have not exceeded 0.429 mg/kg in clinical trials, which is approximately 30× less than the LD 50 for rabbits. Theoretically, hypertension and tachycardia may affect predisposed individuals and extremely high doses of psilocybin (several times higher than in clinical trials) can cause coma, hyperthermia, and respiratory failure (symptoms of serotonin syndrome), similar to high doses of LSD. However, no such case has been reported to-date. During the long history of psilocybin use in the form of hallucinogenic mushrooms there have been no documented cases of somatic toxicity. Organ damage (e.g. renal failure) only occurs due to confusion between psilocybin mushrooms and other morphologically similar mushrooms.
The safety of psilocybin use is given mainly by personal expectations (set) and the nature of the environment (setting), which is the cause of the great variability of the subjective effects. Due to the altered perception, hallucinations and intensified emotions, dangerous behavior may occur during non-medical administration. These complications can be significantly reduced by educating an individual, creating a safe environment and building rapport with an experienced intoxication guide (sitter).. Thus well-prepared hallucinogen-naïve participants can safely take higher doses of psilocybin (over 25 mg)and experienced volunteers can be administered with psilocybin even in magnetic resonance. Approximately 2,000 subjects had received psilocybin under controlled experimental conditions during psychological and psychiatric research by 2005, without causing any serious side effects. Anxiety, paranoid experiences, derealization, depersonalization, long lasting unpleasant experiences (bad trips), psychotic reactions and rare hallucinogen persisting perception disorder (HPPD) d are the main side effects describedand are more likely than any physical risks. Psychological interventions are mostly sufficient, anxiolytics and/or atypical antipsychotics can be used in extreme cases, and commitment is only very rarely required. Generally, although the use of hallucinogens can trigger nonspecific psychotic episodes or accentuate psychotic symptoms in patients, these substances are not the etiological agents. The risk of prolonged psychosis (lasting longer than 48 hours) in otherwise healthy subjects after a single dose of psilocybin is rare and in most cases it is associated with personality predisposition. The prevalence of prolonged psychiatric symptoms after serotonergic hallucinogens in thousands of healthy subjects and psychiatric patients was 0.08-0.09% and 0.18%, respectively. Attempts to commit suicide occurred in psychiatric patients only (in 0.12%) with few (0.04%) succeeding. Finally, incidence of HPPD is estimated to be in only a few cases per million users. Since chronic administration of hallucinogens reduces the number of 5HT 2A receptors leading to a rapid onset of short-lasting tolerancethe risk of addiction to hallucinogens, including psilocybin is very low. Furthermore, monkeys did not seek psilocybin as a reward, and in the case of LSD they even reacted aversely. In humans, psilocybin does not cause craving or withdrawaland it does not directly affect the mesolimbic dopaminergic pathway and therefore does not activate the reward system. Psilocybin is very likely to have no genotoxic effects. One study that directly focused on the mutagenic potential of psilocybin did not prove this type of toxicity. However, due to the lack of direct data on the teratogenicity of psilocybin, this substance should not be administered to pregnant women. Despite the high level of safety and absence of risk of addiction psilocybin is included in the U.S. list of "Schedule I" controlled substances. However, substances on this list must have the following three characteristics: the drug or other substance has no currently accepted medical use in treatment, there is a lack of accepted safety for use of the drug or other substance under medical supervision, the drug or other substance has a high potential for abuse. It is clear from this text that psilocybin does not meet the first two criteria and the third point is disputable.
Early electrophysiological studies (limited to a visual assessment) documented increases of fast activity, reduction of amplitude and desynchronization in both primates and humans. Changes in visually evoked potentials and a decrease in alpha and theta activity were also described in humans (Da). Recent findings with psilocin and other hallucinogens in rats showed an overall reduction in EEG absolute power and coherence (fronto-temporal mainly); relative power was decreased in the delta and theta bands and increased in the alpha, beta, high beta and gamma bands. Since the theta band in rats is the main basic activity, this may be analogous to the aforementioned EEG desynchronization in primates and humans. As similar patterns of coherence were also observed for dissociative anestheticswe hypothesize that the reduction of coherence might nonspecifically reflect the hallucinogenic effects. Observed fronto-temporal disconnection is also a characteristic finding correlating with the distortion of several cognitive parameters and might also reflect sensorimotor processing deficits that are typically induced by hallucinogens. Recent quantitative EEG analysis in healthy volunteers revealed that psilocybin (0.215 mg/kg p.o.) decreased basal alpha power precluding a subsequent stimulus-induced α-power decrease and attenuated VEP N170 in the parieto-occipital area. Psilocybin (2 mg i.v.) also decreased broadband spontaneous cortical oscillatory power during resting state in MEG, with large decreases being in the areas of the default-mode network (DMN) and other resting state networks. On the other hand, visually and motor-induced gamma activity remained unchanged. Subsequent effective connectivity analysis revealed that posterior cingulate (central hub of DMN) desynchronization can be explained by increased excitability of deep-layer pyramidal neurons. The assumption that all these findings could be generalized to hallucinogens is supported by a human Ayahuasca e study with low-resolution brain electromagnetic tomography (LORETA), where a global current density reduction was observed.
In an 18 fluorodeoxyglucose ( 18 FDG) PET study psilocybin 15-25 mg p.o. increased metabolism in both the lateral and medial prefrontal cortex (mPFC) including the anterior cingulum (ACC), temporomedial cortex and basal ganglia. Interestingly, the 18 FDG uptake positively correlated with psychotic positive symptoms (especially ego disintegration) and mirrored the metabolic pattern typical for acute psychotic episodes. Analogously, other PET studies have demonstrated increased metabolism in the frontotemporal cortex and ACC, and a reduction of 18 FDG uptake in thalamus. In addition, the same study documented a blunted metabolic increase during cognitive activation in the left frontal cortex. On the contrary, a recent fMRI study with psilocybin (2 mg i.v.) documented only a decrease of both BOLD (blood-oxygen-level-dependent) and perfusion (arterial spin labeling) in a variety of subcortical regions, high-level association between fronto-temporo-parietal regions and in the important connectivity hubs of thalamus and midline cortex (anterior and posterior cingulum and precuneus). The intensity of the subjective effects was predicted by decreased activity in the anterior cingulate and mPFC. The subsequent mPFC seed connectivity analysis revealed that psilocybin induced reduction of connectivity between the posterior cingulate and mPFC, indicating that subjective effects of psilocybin could be caused by decreased activity and connectivity in the brain's key hubs of functional connectivity. There are several explanations for the substantial discrepancy between PET and fMRI findings in a resting state. Firstly, the individuals in the PET study were at the peak of the effect (90 min after p.o.), whilst the fMRI study may have captured the onset of effect, thus the findings may correlate with anxiety rather than the psychedelic experience. Secondly, psilocybin as a 5-HT 1B/D agonist induces the vasoconstriction (like triptans, antimigraine drugs). This vasoactive reaction could directly influence the fMRI signal but not the resting 18 FDG uptake. Finally, the above-mentioned reduced power and desynchronization in MEG may be congruent with the fMRI as well as PET results. The MEG study describes an increased excitability of deep-layer pyramidal neurons rich in 5-HT 2A receptors. These glutamatergic neurons could induce both desynchronization of ongoing oscillatory rhythms (a decrease in resting connectivity and fMRI signal) and an increase in glutamate turnover which leads to an increase in glial metabolism reflected by an increase in 18 FDG uptake. Recent fMRI activation studies verifying the psychotherapeutic effectiveness of psilocybin revealed a robust increase in the BOLD signal in the early phases of autobiographical memory recollection (within 8 s) in the striatum and limbic areas, and in the later phases also in the medial prefrontal cortex and sensory areas of the cortex. The most recent fMRI studies by the same group documented the increased functional connectivity after 2 mg i.v. of psilocybin between the two specific neuronal networks. The first, DMN, is typically activated during a resting state and introspection, whilst the second, task-positive network, is activated during focused attention. These two networks reciprocally alternate in their activity under physiological circumstances but under meditation, psychosis, propofol sedation or under the influence of psilocybin they closely interact. However, unlike propofol, thalamo-cortical connectivity was preserved after the administration of psilocybin and it would discriminate in a substantial way the psychedelic experience from sedation.
Hallucinogens including psilocybin induce complex changes at various levels of the brain which lead to altered states of consciousness. The neurobiology of the hallucinogenic effect was described elsewhere. Psilocybin is used as one of the major acute serotonergic models of psychosis/schizophreniadue to its phenomenological and construct validity characterized by: induction of positive psychotic symptoms (alterations in perception, thinking and emotivity), changes in information processing, changes of brain metabolism and/or activity and induction of a hyperdopaminergic state in the striatum. Further support follows from the mechanism of action of atypical antipsychotics, of which most of them show antagonist properties at 5-HT 2A/C receptors and congruently also restored changes induced by psilocybin. More evidence of the role of these receptors in psychosis is given by the fact that an increased amount of 5-HT 2A receptors was described in the cortex of young untreated subjects with schizophrenia postmortem. The validity of serotonin models of psychosis, however, is hampered by the fact that antagonism at dopamine D 2 receptors but not 5-HT 2A antagonism is essential to treat psychotic symptoms in patients, whereas 5-HT 2A antagonism might be important for amelioration of negative symptoms. Further on, unlike auditory hallucinations typical in schizophrenia, hallucinations after psilocybin intoxication are primarily visualand there is an absence of negative symptoms and cognitive deficits, otherwise typical for schizophrenia. However, psilocybin intoxication may be phenomenologically more similar to the early stages of the psychotic process in which the serotonin system may be crucial. The lack of negative symptoms can be attributed to the chronification of the disease related to the adaptation of the brain to information overload. In relation to this, however, theoretical modeling of psychosis using the chronic administration of psilocybin is not possible due to the rapid development of shortly lasting tolerance to the drug and to ethical issues. On the other hand, a chronic animal model with LSD has already been created.
Most clinical studies with psilocybin were performed in the 1960s, often using synthetic Sandoz's Indocybin®. Hallucinogens were considered as key tools for understanding the etiopathogenesis of some mental illnesses and to have some therapeutic potential. In spite of often being considered as methodologically inaccurate from a current perspective, thousands of scientific papers published by 1965 described positive results in more than 40,000 patients who had taken psychedelics with minimal side effects and a high level of safety. By 2005, approximately 2,000 subjects had undergone psycholytic and psychedelic psychotherapy f in clinical studies with psilocybin. Use of psychedelic psychotherapy encountered varying degrees of success in neurotic disorders, alcohol dependence and psychotherapeutic adjunct to the dying. There are also records of the successful application of psycholytic therapy with repeated administration of psilocybin in treatment resistant autistic and schizophrenic children. For decades, due to law restrictions, the use of psychedelics including psilocybin in the treatment was considered a closed chapter, however the idea has been recently revived. In a recent pilot study psilocybin at low doses (0.2mg/kg) acted as an anxiolytic and antidepressant in terminally ill cancer patients without clinically significant side effects. This study follows on from another three where effects on psychosocial distress/inner psychological well-being, anxiety and depression, attitudes to the disease and towards death, quality of life and spiritual/mystical states of consciousness, secondarily changes in the perception of pain and plasma markers of stress and immune system function are evaluated. Case reports and clinical trials have also reported improvement of obsessivecompulsive disorder (OCD) symptoms after psilocybin. In one patient the effect persisted for five months. In studies devoted to the treatment of alcohol dependenceand smoking cessationit is suggested that psilocybin deepens spiritualityand stimulates motivation to overcome the addiction. Further on, a potential future use of psilocybin in the treatment of anxiety depressive disorder is also emerging. The last reported effect of psilocybin is in the treatment of cluster headaches: mushrooms containing psilocybin improved individual attacks but also stopped the cycle of otherwise intractable cluster headache attacks. A possible explanation is a reduction in blood flow to the hypothalamus induced by the psilocybinor the activity of psilocybin at 5-HT 1B/D receptors, similar to triptans. Further research, however, will be necessary in the future in order to clarify the above.
In summary, psilocybin has a strong research and therapeutic potential. Due to the good knowledge of its pharmacodynamics and pharmacokinetics, beneficial safety profile and zero potential to cause addiction it is frequently used both in animal and human research. It brings a number of key findings regarding the functioning of the human brain, in particular the role of the serotonergic system in complex functions such as perception and emotions. It also serves as a useful tool for the study of the neurobiology of psychoses. Due to its considerable degree of translational validity of animal and human studies, a psilocybin model of psychosis plays a key role in the development of new treatments for psychotic disorders. Finally, the most recent human studies also suggest its potential therapeutic use in the treatment of several psychiatric and neurological disorders.
a. PPI is a commonly evaluated parameter, which reflects sensorimotor processing. It is the evaluation of the startle response to a sudden unexpected stimulus (usually tactile or audio) and the prepulse inhibition of startle response. The principle of prepulse inhibition relies on the ability of slightly supraliminal stimulus (prepulse; cannot be consciously processed) preceding in an order of milliseconds the startle stimulus (pulse) to reduce the extent of the startle response. These measurements can be used to evaluate a number of parameters, such as latency response and amplitude. A frequently evaluated parameter is the habituation to a startle response and PPI. b. AMRS: This subjective scale, allowing repeated assessment of the current state of mind, is based on the principle of assigning the degree of conformity to various adjectives that are typical for a certain mental disposition. HPPD manifests itself as persistent changes in visual perception after the pharmacological effects of the substance have worn off. e. Ayahuasca, a hallucinogenic beverage used by indigenous tribes in Amazonia, contains the hallucinogen N,N-Dimethyltryptamine (DMT; structurally and pharmacologically very close to psilocybin) and harmine and harmaline with monoaminooxidase inhibiting activity. f. In psycholytic therapy a low dose is given and analysis and interpretation are performed during the course of its effects, psychedelic therapy uses high doses of psilocybin and the processing of experiences and their interpretation takes place after the effects have worn off.
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