REVIEWPsilocybin – Summary of knowledge and new perspectives
Introduction
Psilocybin and psilocin, the main psychedelic ingredients of hallucinogenic mushrooms (Guzman et al., 1998, Laussmann and Meier-Giebing, 2010) (Table 1), have recently been given a lot of attention as a research tools (Geyer and Vollenweider, 2008) as well as a potential therapeutic agents (Grob et al., 2011, Moreno et al., 2006, Sewell et al., 2006). History of the ritual use of hallucinogenic mushrooms dates back 3000 years in Mexico and regionally its use is still conventional practice today (Carod-Artal, 2011, Hofmann, 2005). Western science was introduced to these mushrooms in 1957 by Robert G. Wasson and they were later systematically ranked by Roger Heim (Aboul-Enein, 1974). Psilocybin was first isolated and identified in 1958 and synthesized in 1959 by Albert Hofmann (Hofmann et al., 1958). The content of psilocybin and psilocin in hallucinogenic mushrooms varies in the range from 0.2% to 1% of dry weight (Table 2.).
In the 1960s psilocybin was widely used in the experimental research of mental disorders and even in psychotherapy (Metzner, 2005). 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 (Nichols, 2004) 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 1). 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 (Hasler et al., 2004, Johnson et al., 2008).
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.
Section snippets
Structural and chemical characteristics of psilocybin
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 (Hasler et al., 1997, Horita and Weber, 1961a) (Figure 1). An equimolar dose to 1 mol of psilocin is 1.4 mol of psilocybin (Wolbach et al., 1962). Substitution of the indole nucleus in position 4 probably plays a substantial role in its hallucinogenic
Metabolism and pharmacokinetics of psilocybin
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 (Kalberer et al., 1962). After systemic parenteral administration of psilocybin tissue phosphatases play the same role with the kidneys being among the most active (Horita and Weber, 1961b, Horita and Weber, 1962). Given that the competitive blockade of
Pharmacodynamics
Psilocybin and psilocin are the substances with predominant agonist activity on serotonin 5HT2A/C and 5HT1A receptors (for specific affinities see Table 3). Interestingly, psilocybin's affinity to human 5HT2A receptors is 15-fold higher than in rats (Gallaher et al., 1993). While the 5HT2A receptor agonism is considered necessary for hallucinogenic effects (Nichols, 2004), the role of other receptor subtypes is much less understood. Contrary to the previous report (Creese et al., 1975), a
Behavioral effects of psilocybin/psilocin in animals
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 (Passie et al., 2002). Characteristic effect of psilocybin is enhancement of monosynaptic spinal reflexes in cats (Hofmann, 1968).
Peak of behavioral changes are typically observed within 30–90 min after drug administration.
Dosage and time course of effects
In terms of efficacy, psilocybin is 45 times less potent than LSD and 66 times more potent than mescaline (Isbell, 1959, Wolbach et al., 1962). 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 4). Psychedelic effects occur at doses above 15 mg of oral psilocybin (Hasler et al., 2004) or plasma psilocin levels of 4–6 ng/ml (Hasler et al., 1997). Safety guidelines for the experimental use of hallucinogens
Acute somatic toxicity of psilocybin
According to a number of toxicological and clinical studies psilocybin has a very low toxicity (Nichols, 2004, Passie et al., 2002). Psilocybin showed no specific signs of toxicity in the isolated organs (intestine, heart) of rats and pigs (Cerletti, 1958), it is also not neurotoxic (Johnson et al., 2008). Psilocybin LD50 for rats and mice is 280–285 mg/kg, and for rabbits it is 12.5 mg/kg. Psilocin LD50 is significantly lower for mice and rats 75 mg/kg and for rabbits 7 mg/kg (Usdin and Efron, 1972
Risks and side effects of psilocybin, long-term toxicity
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 (Nichols, 2004). Due to the altered perception, hallucinations and intensified emotions, dangerous behavior may occur during non-medical administration (Johnson et al., 2008). These complications can be significantly reduced by educating an individual, creating a safe environment and building rapport with
Electroencephalography (EEG), Magnetoencephalography (MEG)
Early electrophysiological studies (limited to a visual assessment) documented increases of fast activity, reduction of amplitude and desynchronization in both primates and humans (Fink, 1969, Horibe, 1974, Meldrum and Naquet, 1971). Changes in visually evoked potentials and a decrease in alpha and theta activity were also described in humans (Da Fonseca et al., 1965, Rynearson et al., 1968).
Recent findings with psilocin and other hallucinogens in rats showed an overall reduction in EEG
Psilocybin as a model of psychosis
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 (Gonzalez-Maeso and Sealfon, 2009, Nichols, 2004, Palenicek and Horacek, 2008, Vollenweider, 2001).
Psilocybin is used as one of the major acute serotonergic models of psychosis/schizophrenia (Geyer and Vollenweider, 2008, Hanks and Gonzalez-Maeso, 2013) due to its phenomenological and
Therapeutic uses and recent clinical studies
Most clinical studies with psilocybin were performed in the 1960s, often using synthetic Sandoz's Indocybin® (Passie et al., 2002). 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
Conclusion
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
Role of funding source
Funding for this study was provided by IGA MHCR no. NT/13897; the IGA MHCR had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Author Filip Tylš designed the layout of the article and collected the relevant literature. He contributed to all parts of the text.
Author Tomáš Páleníček supervised the layout and wrote the abstract. He also greatly contributed to the pharmacokinetic and pharmacodynamic parts of the text.
Author Jiří Horáček supervised the whole article and contribute mainly to the discussion about imaging studies with psilocybin.
Conflict of interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that we have given due consideration to the protection of intellectual properly associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the
Acknowledgements
This work was supported by the research Grant IGA MHCR no. NT/13897.
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