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Psilocybin
KATHARINA SCHMIDT, EDINA SIC, HORST SCHUCHMANN,
MALTE SCHUMMER
Technische Universität Darmstadt
Abstract
Psilocybin is a psychoactive alkaloid contained in hallucinogenic mushrooms. Nowadays it is used in research as a tool
for modelling psychosis. However, it is also a very popular and frequently abused natural hallucinogen. This report
summarizes the current state of knowledge on psilocybin. It briefly discusses the history, structure, synthesis, mode of
action, pharmacokinetics and pharmacodynamics of the drug.
I. History
There are about 100 types of mushrooms with
hallucinogen ingredients. Most of the
hallucinogen mushrooms contain Psilocybin
and Psilocin, which can only be differentiated
in one phosphate group.
Hallucinogen psychoactive mushrooms, known
as “magic mushrooms” were used to religious
causes in many cultures.
Gordon Wasson and Valentina Pavlovna first
figured out the hallucinogen effect of those
mushrooms.
In 1953 Wasson watched a mushroom-ritual
and in 1955 he participated at one to convince
himself about this effect.
In 1958 Albert Hofmann was able to isolate the
main components Psilocybin and Psilocin.
Psilocybin was classified as a drug in the 1970s
and because of that the human experiments
were stopped. First in the 1990s the research
was resumed and nowadays it is one of the
most used psychedelic drugs.
II. Physical Properties
The table downside shows the physical properties of
Psilocybin.
Table 1: List of physical properties
Property
CAS - Number
State
Molecular weight
Molecular formula
Lethal dose (LD50)
pKa1
pKa2
pKa3
Melting point
Solubility
Biological half-life
Value
520-52-5
solid
284,25 g/mol
C12-H17-N2-O4-P
285 mg/kg (mouse)
1,3
6,5
10,4
220-228°C
Soluble in water &
methanol; slightly in
ethanol
1-4 h
1
gets esterified with Dibenzylphosphorylchloride.
Finally the two Benzyl groups are removed through a
reduction with Hydrogen and a Palladium catalyst. The
outcome after recrystallization is pure Psilocybin ([3-(2Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen
phosphate) with a yield of about 56%.
III. Structure
Figure 1: Synthesis of psilocybin
IUPAC: [3-(2-Dimethylaminoethyl)-1H-indol-4yl] dihydrogen phosphate)
Psilocybin is a tryptamine compound
containing an indole ring linked to an
ethylamine substituent.
It is soluble in water and methanol but
insoluble in organic solvents. It exists in general
as a zwitterionic structure and its pKa values
are estimated to be 1,3 and 6,5 for the two
hydroxyl groups and 10,4 for the
dimethylamine nitrogen.
IV. Extraction
Before being able to synthesize Psilocybin,
Albert Hofmann first extracted it from
psilocybe mexicana in 1958. Therefor the
mushrooms must first be dried and pulverized.
Afterwards they get washed in chloroform and
then in acetone. The dry and washed
mushrooms are extracted three times with
methanol. The outcome is a crude extract which
is still impure. Through chromatographic
methods the crude extract can be separated into
psilocin, baeocystin and psilocybin.
V. Synthesis
In 1958 A. Hofmann first synthesized
Psilocybin. Therefor it is necessary to first
synthesize its hydrolysis product Psilocin.
Starting with 4-Acetoxyindol and
Oxalylchloride, all solved in Ethanol, it comes
to Indolglyoxylchloride which is a yellow
cristalline solid. After the reaction with
Dimethylamid, Tetrahydrofurane and
Lithiumaluminumhydride to 3-[2(dimethylamino)ethyl]-4-indolol (Psilocin), it
2
VI. Pharmacokinetics
50% of psilocybin is absorbed after oral
administration. Psilocybin is detectable in
plasma after 20-40 minutes whereas the main
metabolite psilocin appears after 30 minutes. A
significant first pass effect can be assumed.
Four metabolites have been identified, see
figure below. A shorter half-life after i.v.
administration (mean 74,1+/- 19,6 min.) is
reported compared to oral administration (163
+/- 64 min.). Maximum plasma concentrations
were observed after 80 minutes. The
elimination of the drug and its metabolites
mainly occurs through the kidneys. Most of it is
completed within 3 hours.
Figure 2: Biotransformation
5HT2A, 5HT2C and 5HT1A.
While the agonistic effect on the 5HT2A receptor is
considered necessary for hallucinogenic effects the role
of other receptor subtypes is much less understood.
Psilocin binds to many different serotonin-receptors
including dopamine and adrenergic receptors.
Psilocybin shows a wide variety of effects: Very low
doses cause drowsiness and emphasize the preexisting
mood. Medium doses induce a well controllable altered
state of consciousness and higher doses evoke a strong
psychedelic experience. Psilocybin slightly stimulates
sympathetic activity (e.g. mydriasis, increase in blood
pressure and increased heart rate).
Psilocybin related research yielded 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. Effects induced by psilocin/psilocybin are
partly normalized by antagonists of 5-HT1A, 5HT2A/C
as well as dopamine D2 receptors. So Psilocybin is a
useful research tool to develop drugs against disorders
connected to the effect of high levels of serotonin on the
brain like psychosis.
On the other hand, the substance could be directly used
as anxiolytic or antidepressant in disorders with very
low levels of serotonin in the brain. A number of clinical
studies with psilocybin exist, but were performed in the
1960s. Scientific papers found positive effects with low
side effects, a good level of safety and no drug
addiction when combined with psychotherapy.
Nevertheless, psilocybin is under control of the suppl. 1
of the Narcotics Act in Germany. The drugs on the
suppl. 1 list are illegal due to their high potential for
addiction/due to their highly addictive nature.
VII.
Mechanism of action and use in
research
Psilocybin and to a large extend also psilocin
are substances with predominant agonist
activity on serotonin receptors of the type
3
VIII. Importance
Nowadays psilocybin is given a lot of attention
in the scientific community. It induces complex
changes at various levels of the brain which
lead to altered states of consciousness.
Psilocybin is used as one of the major acute
serotonergic models of
psychosis/schizophrenia. It is able to induce
reproducible psychotic symptoms for a better
understanding of these disorders and the
development of useful drugs against psychosis.
References
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www.catbull.com/alamut/Lexikon/Mittel/Psilocin.htm
22.06.2016
Experientia November 1958, Volume 14, Issue 11, pp 397399
European Neuropsychopharmacology (2014) 24, 342-356
Addiction Biology (2002) 7, 357–364 5
www.erowid.org/lang/de/drug_reference/psilocy.shtm
l 23.06.2016
Stamets P. Psilocybin mushrooms of the world. Olympia,
WA: Ten Speed Press, 1996
The pharmacology of psilocybin; by Passie, Torsten;
Seifert, Juergen; Schneider, Udo; Emrich, Hinderk M.
from Addiction Biology (2002), 7(4), 357-364
Psilocybin – Summary of knowledge and new
perspectives; by Tyls, Filip; Palenicek, Tomas; Horacek,
Jiri from European Neuropsychpharmacology (2014),
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Figure 3: 3D model of psilocybin
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