Addiction Biology (2002) 7, 357–364
`
`INVITED REVIEW
`
`The pharmacology of psilocybin
`
`TORSTEN PASSIE, JUERGEN SEIFERT, UDO SCHNEIDER &
`HINDERK M. EMRICH
`
`Department of Clinical Psychiatry and Psychotherapy, Medical School Hannover, Hannover,
`Germany
`
`Abstract
`Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamin e) is the major psychoactive alkaloid of some species of
`mushrooms distributed worldwide. These mushrooms represent a growing problem regarding hallucinogenic drug
`abuse. Despite its experimental medical use in the 1960s, only very few pharmacological data about psilocybin
`were known until recently. Because of its still growing capacity for abuse and the widely dispersed data this
`review presents all the available pharmacological data about psilocybin.
`
`Introduction
`Psilocybin-containing mushrooms are one of the
`major hallucinogenic drugs of abuse today. These
`mushroom species are distributed worldwide1
`and their abuse potential produces partially
`harmful effects in a growing population of psy-
`chedelic drug users.2 No physical damage but
`many psychiatric complications have been repor-
`ted worldwide.3 Recent research has been repor-
`ted on the treatment of compulsive disorders in
`humans with psilocybin; 4 therefore, it is impor-
`tant to know the essential pharmacological data
`about psilocybin.
`Despite the fact that pure synthetic psilocybin
`(Indocybin® Sandoz) was used and marketed for
`experimental and psychotherapeutic purposes in
`the 1960s, until recently only limited pharmaco-
`logical data were available. In recent years some
`experimental psychophysiological studies were
`performed in which human pharmacokinetic and
`
`pharmacodynamic data of psilocybin were
`explored further.5 –10 Because of the widely dis-
`persed material about the pharmacological prop-
`erties of psilocybin, old and new data are
`reviewed here. It should be noted that character-
`ization of the complex psychopathological phe-
`nomena inudced is not in the focus of this
`review.
`
`Pharmacology of psilocybin
`Psilocybin (4-phosphoryloxy-N,N-dimethyltryp-
`tamine) is a substituted indolealkylamine and
`belongs to the group of hallucinogenic trypta-
`mines. Psilocybin was isolated from Central
`American mushrooms (Psilocybe mexicana) by the
`renowned Swiss chemist Albert Hofmann in
`1957, and in 1958 was produced synthetically for
`the first time.11 It has been found in many species
`of mushrooms worldwide1 (Fig. 1).
`
`Correspondence to: Torsten Passie, Medical School Hannover (Germany), Department of Clinical Psychiatry
`and Psychotherapy, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel: 0049 511 5323517; Fax: 0049 511
`5322415; E-mail: dr.passie@gmx.de
`Received for publication 15th October 2001. Accepted 30th May 2002.
`
`ISSN 1355-6215 print/ISSN 1369-1600 online/02/040357-08
` Society for the Study of Addiction to Alcohol and Other Drugs
`DOI: 10.1080/1355621021000005937
`
`Taylor & Francis Ltd
`
`EXHIBIT K
`
`

`

`358
`
`T. Passie et al.
`
`Figure 1. Molecular structures of psilocybin and psilocin.
`
`Psychic effects
`In a medium dosage (12–20 mg p.o.), psilocybin
`was found to produce a well-controllable altered
`state of consciousness. This state is marked by
`stimulation of affect, enhanced ability for intro-
`spection and altered psychological functioning in
`the direction of Freudian primary processes,
`known otherwise as hypnagogic experience and
`dreams.12 Especially noteworthy are perceptual
`changes such as illusions, synaestesias, affective
`activation, and alterations of thought and time
`sense. The effects last from 3 to 6 hours.
`After extensive tests in animals and humans,
`psilocybin was distributed worldwide under the
`name Indocybin® (Sandoz) as a short-acting and
`more compatible substance (than, for example,
`LSD)
`to support psychotherapeutic proce-
`dures.13 Experimental and therapeutic use was
`extensive and without complications.14
`
`Somatic effects
`Cerletti15 reported an LD50 for mice with intra-
`venous application of 280 mg/kg which may imply
`an LD50 of some grams of psilocybin in humans.
`In some in vitro experiments, except for an
`inhibitory effect on the neurotransmitter ser-
`otonin, psilocybin showed no specific effects on
`isolated organs (intestines, heart) of guinea pigs
`and rats.15 Characteristic autonomic effects of the
`neurovegetative system that were notable for the
`whole animal (mice, rats, rabbits, cats and dogs)
`with doses of 10 mg/kg s.c. included: mydriasis,
`piloerection, irregularities in heart and breathing
`rate and discrete hyperglycaemic and hypertonic
`effects.15 Cerletti interpreted these effects as an
`
`excitatory syndrome caused by central stimula-
`tion of the sympathetic system. In contrast to an
`autonomic excitatory syndrome, motor behaviour
`was muted.16 –18 Experiments with Rhesus mon-
`keys (2–4 mg/kg i. p.) confirmed the above
`changes of physiological parameters and a central
`excitatory syndrome. After 20–40 minutes the
`EEG showed a disappearance of alpha activity
`and an increase of beta activity in the neo-
`cortex.19 In two early non-blind studies in healthy
`volunteers (n = 12, 0.12–0.15 mg/kg p.o.),20
`(n = 22, 10 mg p.o.)21 the EEG showed variations
`of visual evoked potentials and decrease in alpha
`and theta frequencies. There were no changes in
`the electroretinogram. 21
`The somatic effects in humans were investi-
`gated first by Quetin22 in a non-blind study in
`healthy volunteers (n = 29, 8–12 mg p.o., i.m.).
`The physiological changes which were noted
`regularly are listed in Table 1. These effects were
`confirmed qualitatively by another early non-
`blind study (n = 16, 0.11 mg/kg p.o.).33 Discrete
`changes of RR and pulse were also confirmed in a
`recent double-blind placebo-controlled study
`(n = 8, 0.2 mg/kg p.o.), as shown in Table 2.9 The
`effects described were barely noticeable and
`should be interpreted as secondary pharmaco-
`logical effects, induced mainly by the sympatho-
`mimetic excitation syndrome.24 Hollister et al.25
`found no significant aberrations of the afore-
`mentioned parameters
`in one subject after
`adminstration of psilocybin for 21 consecutive
`days with increasing dosages (1.5 mg increased to
`25 mg p.o. in three doses per day). Electrolyte
`levels, liver toxicity tests and blood sugar levels
`remained unaffected.23 – 25 Human leucocytes
`
`

`

`Table 1. Somatic symptoms
`
`Table 2. Blood pressure and heart rate changes
`
`Pharmacology of psilocybin
`
`359
`
`Percentage of subjects
`
`Midriasis
`Heart frequency
`Accelerated
`Slowed
`Variable
`No change
`Arterial blood pressure
`Hypotension
`Hypertension
`Instability
`No change
`Nausea
`Reflexes tendineae
`Increased
`Decreased
`No change
`Dysmetry
`Tremor
`
`93%
`
`56%
`13%
`31%
`0%
`
`34%
`28%
`22%
`16%
`44%
`
`80%
`6%
`13%
`16%
`25%
`
`Modified from ref. 22. N = 30, 8–12 mg psilocybin i.m.,
`p.o.
`
`were found by Quetin23 (n = 29, 8–12 mg p.o.,
`i.m.) and Hollister et al.25(n = 16, 0.06–0.2 mg/
`kg p.o., s.c.) to be reduced in number temporarily
`between the second and fourth hour after psilocy-
`bin. In a recent double-blind placebo-controlled
`study (n = 8, 0.2 mg/kg p.o.) endocrine activity
`(cortisol, prolactin, growth hormone) was found
`not to be affected significantly by psilocybin. 9
`Experiments in mice (4, 8 and 16 mg/kg) with
`the micronucleus test, highly sensitive to the
`chromosome-breaking potential of substances,
`found no evidence
`for genetic aberrations
`through psilocybin.26 In mutagenicity testing it is
`not possible at present to prove the mutagenic
`potential of a compound in a single test system.
`Results of other tests are required to confirm
`these negative results.
`
`Pharmacokinetics
`Pharmacokinetic studies showed that 50% of
`14C-labelled psilocybin was absorbed following
`oral administration. The isotope is distributed
`almost uniformly
`throughout
`the whole
`body.27,28 As part of a recent double-blind
`placebo-controlled psychopathological
`study
`(n = 13, 0.2 mg/kg p.o.), Holzmann5 assayed psi-
`locybin metabolites in human plasma and urine
`by HPLC as part of an investigation of the
`
`Systolic blood pressure (mmHg)
`Diastolic blood pressure (mmHg)
`Heart rate
`
`Mean/SD
`
`25.9 ± 11.7
`10.0 ± 7.6
`10.4 ± 12.6
`
`From ref. 9. N = 8, 0.2 mg/kg psilocybin p.o.
`
`pharmacokinetics of psilocybin and psilocin. In
`another recent double-blind placebo-controlled
`study (n = 6, 0.5–3 mg i.v.; n = 6 0.22mg/kg p.o.)
`Hasler et al.6 used HPLC with column-switching
`coupled with the electrochemical detection pro-
`cedure for reliable quantitative determination of
`psilocybin metabolites. Altogether, four metabo-
`lites of psilocybin have been identified (Fig. 2):
`
`4-hydroxy-N,N-dimethyltrypt-amine
`(Psilocin);
`4-hydroxyindole-3-yl-acetaldehyde (4H1A);
`(41-IIAA);
`4-hydroxyindole-3-yl-acetic-acid
`and
`4-hydroxytryptophol (41-IT).
`
`According to the two above-mentioned phar-
`macokinetic studies in humans it was found that
`after oral administration (on an empty stomach),
`psilocybin is detectable in significant amounts in
`the plasma within 20–40 minutes. Psychological
`effects occur with plasma levels of 4–6 mg/ml.5,6
`The threshold dose depends on interindividual
`differences, but may be in the range of 3–5 mg
`p.o. for a subjectively detectable sympathomi-
`metic, but not hallucinogenic, effect as found in
`double-blind placebo-controlled trials.29 The full
`effects occur with doses of 8–25 mg p.o. within
`70–90 minutes. Psilocin appears in the plasma
`after 30 minutes. A significant first-pass effect
`with the vast majority of psilocybin converted
`into psilocin mainly by hepatic metabolism can
`be assumed.29 Another early biochemical study
`showed psilocin to be the main, if not the solely
`pharmacologically active substance by decreasing
`the dephosphorylation of psilocybin to psilocin
`using a competetive substrate (beta-glycerophos-
`phate) for blocking the alkaline phosphatase.30
`Recent experimentation on rodent tissue pre-
`sented more evidence for complete conversion of
`psilocybin to psilocin before entering systemic
`circulation.31 This assumption is also supported
`
`d
`d
`d
`d
`

`

`360
`
`T. Passie et al.
`
`Figure 2. Metabolism of psilocybin.
`
`by the finding that equimolar amounts of psilocy-
`bin and psilocin evoke qualitatively and quantita-
`tively similar psychotropic effects in humans.32
`Psilocybin could therefore be referred to as a
`prodrug. However, because of the lack of reliable
`analytical methods for the determination of psilo-
`cybin in human plasma, it was not possible to
`prove this assumption by showing the absence of
`the parent drug in plasma after psilocybin admin-
`istration. After a rapid increase of psilocin plasma
`levels a plateau of about 50 minutes follows, after
`which there is a relatively slow decline of the
`curve, ending at about 360 minutes. This is
`confirmed by the subjective impressions of the
`subjects and Leuner’s diagram of the clinical
`course (Fig. 3).13 An interesting fact may be the
`much shorter half-life (mean 74.1 ± 19.6 minutes
`
`i.v. compared to 163 ± 64 minutes p.o.) and
`duration of action (subjective effects lasting only
`15–30 minutes) when psilocybin is given intra-
`venously, as performed in a recent double-blind
`placebo controlled trial.29
`Despite weight-specific dosage used in recent
`human studies, the plasma concentration-time
`curves indicate highly variable plasma concentra-
`tions. However, the timing of the maximum
`plasma concentration is after approximately 80
`minutes (Fig. 4).6
`The elimination of glucuronidated metabolites
`as well as unaltered psilocybin (3–10%) was
`found to occur through the kidneys. Approx-
`imately two-thirds of the renal excretion of
`psilocin is completed after 3 hours, but with great
`interindividual differences. The mean elimination
`
`

`

`Pharmacology of psilocybin
`
`361
`
`Figure 3. Course of clinical effects of LSD, psilocybin and CZ-74 (a psilocybin-derivative).13
`
`Figure 4. Time-course of plasma levels for psilocin after 0.224 mg/kg body weight psilocybin p.o. (n = 6).6
`
`half-life of psilocin is 50 minutes (Fig. 5, Table
`3).5
`In two early single-blind randomized compar-
`ative studies a dose of 100 mg psilocybin was
`reported as equivalent to 1 mg LSD and 1000 mg
`mescaline.33,34 Even though significant tolerance
`is known to occur with repeated use of psilocybin,
`the development of physical dependence does not
`occur.35,36 Other early single-blind experiments
`showed cross-tolerance of psilocybin and
`LSD.37,38
`
`Pharmacodynamics
`Two recent double-blind placebo controlled PET
`(positron emission tomography) studies using
`[F-18]-fluorodeoxyglucose showed brain meta-
`bolic activation under the influence of psilocybin.
`Gouzoulis et al.8 (n = 8, 0.20 mg/kg p.o.) found
`no increase of global brain metabolism, while
`Vollenweider et al.7 (n = 15, 0.26 mg/kg p.o.)
`found a general increase of cortical metabolism.
`Vollenweider et al. found increased metabolism
`bilaterally in the frontomedial and frontolateral
`
`

`

`362
`
`T. Passie et al.
`
`Figure 5. Mean urine excretion rate of psilocin after 0.224 mg/kg psilocybin p.o. (n = 8).6
`
`cortex (24%), as well as in the anterior cingulate
`gyrus (25%), the temporal-medial cortex (25%)
`and the basal ganglia (19%). The smallest increa-
`ses were found in the sensorimotor (15%) and the
`occipital cortex (14%). Furthermore, an increase
`of
`the
`frontal-occipital metabolic gradient
`occurs.7 Regional activation was especially high
`in the right hemispheric frontotemporal cortical
`regions and decreased in the thalamus.8
`Psilocybin interacts mainly with serotonergic
`neurotransmission (5-HT1A, 5-HT1D, 5-HT2A
`and 5-HT2C receptor subtypes). It binds with
`high affinity at 5-HT2A (Ki = 6 nM) and to a
`lesser extent at 5-HT1A (Ki = 190 nM) recep-
`tors.39 It should be noted that psilocybin and its
`active metabolite psilocin have— in contrast to
`the indoleamine LSD—no affinity for dopamine
`D2 receptors.40 A recent double-blind placebo-
`controlled study (n = 15, 0.25 mg/kg p.o.) with
`ketanserin pre-treatment (20 mg/40 mg p.o.)
`showed that the psychotomimetic effects of psilo-
`cybin can be blocked completely using the
`preferential 5HT2A receptor antagonist ketan-
`serin.41 It is probable, therefore, that the effects
`of psilocybin are mediated mainly via activation
`
`of presynaptic 5HT2A receptors. However, pre-
`treatment with the D2 receptor antagonist halo-
`peridol also reduces psilocybin-induced psycho-
`tomimesis, which raises the possibility that
`psilocybin-induced psychotomimesis is a second-
`ary response to increased dopaminergic transmis-
`sion, as demonstrated recently in a double-blind
`placebo-controlled PET study in humans (n = 7,
`0.25 mg/kg p.o.) using the D2-receptor ligand
`[11C] raclopride.42 Functional interactions of
`central dopaminergic and serotoninergic systems
`have been well demonstrated.43,44
`In experiments with rats, Aghajanian 45 showed
`psilocybin to interact mainly with serotonin
`receptors of the dorsal raphe nucleus. Because of
`its inhibiting influence on neurones of the dorsal
`raphe nucleus an activation of noradrenergic
`neurones of the nearby
`locus coeruleus
`is
`induced. The locus coeruleus represents a major
`center for the integration of sensory input. This
`may explain some forms of perceptual alterations
`such as synaesthesias. Another hypothesis gen-
`erated in the course of recent human studies with
`psilocybin assumed that alterations of different
`feedback-loops between cortex and thalamus are
`
`Table 3. Pharmacokinetic parameters of psilocin, the active metabolite (N = 8, 0.224 mg/kg psilocybin p.o.)6
`
`Cmax[ng/ml plasma]
`
`tmax[min]
`
`AUCo-` [ng min/ml]
`
`t1/2
`
`Fabs[%]
`
`Mean(SD)
`
`8.2 (2.8)
`
`105 (37)
`
`1963 (659)
`
`163.3 (63.5)
`
`52.7 (20.4)
`
`

`

`responsible for an “opening of the thalamic filter
`for sensory input” as the cause of the psilocybin
`induced frontal hyperfrontality, as shown in PET
`studies.7
`The evidence reviewed suggests psilocybin to
`exhibit low toxicity and may be seen as physio-
`logically well tolerated. However, most studies
`are old and do not meet contemporary standards
`for safety studies. In particular, properly con-
`ducted safety pharmacology studies are lacking.
`Complications may result mainly from its psy-
`chotomimetic effects in vulnerable individuals,
`especially under uncontrolled conditions.
`
`Acknowledgements
`We should like to thank Felix Hasler, PhD, for
`permitting the use of some of the figures in the
`text.
`
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