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Psilocybin
Jenna Hall
Andres Garcia
Azaria Brooks
Nathan Brenner
PSILOCYBIN
Kekulé, skeletal formula of canonical Psilocybin
• Psychoactive Alkaloid
(amine-containing compound)
• Found in 10 different genera
of mushrooms
• Frequently abused natural
hallucinogen
• Potential for Therapeutic
Effects
Tyls, F., Palenicek, T., Horacek, J. (2014) Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology 24(3) 342-356​
Tyls, F., Palenicek, T., Horacek, J. (2014) Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology 24(3) 342-356​
BRIEF HISTORY OF PSILOCYBIN
• Ritualistic use
of
hallucinogenic
mushrooms
dates back
3000 years in
Mexico
A.D.
1960
1958
• Psilocybin
was first
isolated and
identified by
Albert
Hofmann
• Psilocybin was
first
synthesized by
Albert
Hofmann
1959
• Psilocybin widely
used in the
experimental
research of
mental disorders
and
psychotherapy
1990
• Psilocybin
classified as a
schedule I
drug
1970
• Interest in
human
experimental
research into
Psilocybin and
other
psychedelics
revived
CHEMICAL STRUCTURES
PSILOCYBIN IS RAPIDLY DEPHOSPHORYLATED TO PSILOCIN IN THE INTESTINAL MUCOSA BY
ALKALINE PHOSPHATASE AND NONSPECIFIC ESTERASE.
INGESTED MOLECULE
FROM MUSHROOM
METABOLIZED FORM
(TOXIN)
TORSTEN PASSIE, JUERGEN SEIFERT, UDO SCHNEIDER & HINDERK M. EMRICH. (2002, January 1). The pharmacology of psilocybin. Retrieved April 6, 2015, from
http://www.maps.org/research-archive/w3pb/2002/2002_Passie_22704_1.pdf
Mechanism of Action
MECHANISM OF PSILOCYBIN
Only about 50% of the
total volume of
psilocybin taken orally
is absorbed from the
digestive tract.
Psilocin is glucuronidated by
endoplasmic enzymes UDPglucuronosyltransferase to
psilocin-O-glucuronide.
80% of psilocin-O-glucuronide is excreted from the body.
Tyls, F., Palenicek, T., Horacek, J. (2014) Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology 24(3) 342-356​
MECHANISM OF PSILOCIN
Psilocin undergoes a demethylation and deamination to
4-hydroxyindol-3-yl-acetaldehyde (4-HIA).
4-HIA gets oxidized, believed to be by
hepatic aldehyde dehydrogenase and
monoamine oxidase, to 4-hydroxyindol-3acetic acid (4-HIAA) and 4-hydroxytryptofol
(4-HT). However, only about 4% of psilocin
gets degraded in this way.
If dephosphorylation of
Psilocybin is inhibited
no psychotropic effects
are perceived, thus
Psilocin is the main
active metabolite of
Psilocybin.
Another possible
pathway for psilocin is
oxidation by
hydroxyindol oxidases
to a product with an oquinone or
iminochinon structure.
Metabolism of Psilocin
P450 BIOTRANSFORMATION
•
•
Psilocin is an Indolealkylamine drug
(analog of serotonin)
Other Indolealklyamines use p450s in
their metabolism. For example:
• 5-MeO-DIPT aka “foxy methoxy” (a
psychedelic tryptamine)uses CYP2D6 and
for demethylation and CYP1A2, 2C8, 2C9,
2C19, and 3A4 for deisopropylation.
•
•
There are limited studies on the
metabolism of Psilocin and the specific
enzymes used to catalyze these reactions
are unknown.
It is logical to infer that since other
Indolealkylamine drugs use p450
oxidation in their metabolism, Psilocybin
utilizes its functions as well.
Yu, A. (2008) Indolealkylamines: Biotranformations and Potential Drug-Drug Interactions AAPS Journal 10(2) 242-253
PHARMACOKINETICS
• The image on the left shows the
biotransformation of Psilocybin to Psilocin
and the four other metabolites
• Psilocin is the main pharmacologically active
substance.
• Dephosphorylation of Psilocybin creates
Psilocin.
• Psilocybin is completely converted to
Psilocin before entering the blood stream.
• The first pass effect is significant, converting
the majority of psilocybin to psilocin in
hepatocytes
• In humans, Psilocin was detectable in
plasma at 20-40 minutes and had
psychological effects at plasma levels of 4-6
mg/ml
PHARMACOKINETICS
Subjective
impressions
from
individuals
Plasma
concentration
after initial
dose of 0.224
mg/kg
These graphs show a correlation
between the subjective effects and
the plasma concentrations.
The concentration and effects
increase rapidly than plateau for
almost an hour before decreasing.
After 5-6 hours, the plasma Psilocin
concentration will decrease to a level
(in this case ~2 ng/ml) in which the
effects are mostly gone.
Desired effects also depend on
individual susceptibility.
Using the same dose as the
last graph, this graph shows
the excretion rate of Psilocin.
After 3 hours, about twothirds of the toxin has been
excreted by the kidneys.
Mean elimination half-life of
Psilocin is 50 minutes.
ABSORPTION AND EXCRETION OF PSILOCYBIN
ORAL: 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
The half-life• ORAL INGESTION: 2.5 hours
• INTRAVENOUS: 1.23 hours
80% of Psilocin in plasma was found to be in
a conjugated form with glucoronic acid.
Both are detectable in human urine
• Effective Dose of oral Psilocybin is 0.045–0.429
mg/kg
Effects of Psilocin
TOXICITY OF PSILOCYBIN
•
•
•
No toxicity in heart or
intestines (mice and rabbits)
Not neurotoxic
Fatalities associated with
psilocybin ingestion have been
described
Therapeutic Index Comparison
LD50/ED50
LSD
A human would have to 19 g of
the pure drug to bring about
death
Aspirin
Vitamin A
641
Psilocybin
21
Nicotine
4816
• However the only victims were not
linked to toxicity of psilocybin but due
to suicide
•
9637
199
Tyls, F., Palenicek, T., Horacek, J. (2014) Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology 24(3) 342-356​
Symptoms
No Effect
Dizziness
Heart Rate
Weakness/
Drowsiness
Body
Temperature
Tremor
Ionic Balance
Nausea/
Vomiting
Blood Glucose
Tendon
Reflexes
Cholesterol
Levels
Increase in
levels of
cortisol
Plasma
Concentration
BIOCHEMICAL EFFECTS
Similar to LSD:
In theory, hypertension and tachycardia may
occur in predisposed individuals.
Extremely high doses of Psilocybin could
cause coma, hyperthermia and respiratory
failure (serotonin syndrome), however no
cases have been documented.
PSILOCYBIN IN YOUR BRAIN
TWO-FOLD EFFECT
SIMILAR CHEMICAL STRUCTURES
• Target: serotonin receptors in the
brain
• Only 20% of the Psilocybin actually
reaches the target
• Effect:
• Prevents reuptake of serotonin
• Binds to serotonin receptors
(due to similarity in chemical structures)
Serotonin
Psilosin
Psilocybin
PSILOCIN: TWO-FOLD EFFECT
1. Prevents the Reuptake of
Serotonin = Serotonin stays in
synapse longer, prolonging
euphoric effects
2. Psilocin has a similar
chemical structure to serotonin
so it is able to amplify
stimulation
Moffit, M., & Brown, G. (2015, March 11). Your Brain On Shrooms. Retrieved April 24, 2015, from https://www.youtube.com/watch?v=F5kqThVON18
HOW DOES PSILOCYBIN WORK?
Normal Neural Network
Scientists suggest the brain may
temporarily rearrange itself by
inhibiting normal brain activity and
immediately creating new, biologically
stable brain connections
Able to experience moments without any
actual stimuli; difficulty in determining
fantasy from reality
Activation of the anterior cingulate
cortex and hippocampus occurs- brain
regions associated with dreaming
Communication Between Brain Networks
The dots and colors correspond to connection-rich networks
Non-Psychedelic Compound
• Well-ordered correlation state
• Not much cross-linking between
networks
Psilocybin
• Substantial increase in number of
network cross-links
• Newly wired neural pathways emerge
Keim, B. (2014, October 13). Science Graphic of the Week: How Magic Mushrooms Rearrange Your Brain | WIRED. Retrieved April 24, 2015, from
http://www.wired.com/2014/10/magic-mushroom-brain/
ACTION OF PSILOCYBIN ON THE BRAIN
• A study by scientists at Johns Hopkins University found
that a single experience with psilocybin in a controlled
environment altered their personalities, making people
more open to new experiences on a long term scale.
• The Results:
• Psilocybin never increased activity in the brain
• Psilocybin only decreased activity in the thalamus
• Knocking out this key hub with Psilocybin appears
to allow information to travel more freely in the
brain, probably explaining why people's
imaginations become more vivid and animated
and the world is experienced as unusual.
Eduardo E. Icaza, M.D., George A. Mashour, M.D., Ph.D.; Altered States: Psychedelics and Anesthetics. Anesthesiology 2013;119(6):1255-1260. doi:
10.1097/01.anes.0000435635.42332.ee.
PSILOCYBIN AND PSILOCIN SEROTONIN RECEPTORS
Both psilocybin and psilocin have agonist activity on serotonin 5HT2A/C and 5HT1A receptors.
PSILOCYBIN
PSILOCIN
Psilocybin interacts
mainly with
serotonergic
neurotransmission
Psilocin binds to many
different receptors
including dopamine in the
following order:
5-HT1A, 5-HT1D, 5HT2A and 5-HT2C
receptor subtypes.
5HT2B>5HT1D>D1>5HT1E>5
HT1A>5HT5A>5HT7>5HT6>
D3>5HT2C>5HT1B>5HT2A.
Passie, T., Seifert, J., Schneider, U. and Emrich, H. M. (2002), The pharmacology of psilocybin. Addiction Biology, 7: 357–364. doi: 10.1080/1355621021000005937
Future of Psilocybin
PSILOCYBIN AS A MEDICAL/PSYCHOLOGICAL TREATMENT
•
In general psychedelics allow for more
neuroplasticity, which explains the basis
for treating the problems like addiction,
depression, and anxiety, with potential
for more.
•
The DMN (Default Mode Network),
which includes the medial prefrontal
cortex and posterior cingulate cortex, is
responsible for introspective thought,
self-reflection and ingrained patterns of
behavior. If this becomes overly engaged
with negative thoughts or cravings it can
lead to the previously mentioned
problems.
•
Psilocybin decreases over engagement
of the DMN, breaking negative patterns
like the ingrained ‘need’ to smoke.
The Pharmaceutical Journal, 1 November 2014, Vol 293, No 7834, online | URI: 20066899
DEFAULT MODE NETWORK (DMN)
“A decrease in DMN activity allows a less
constrained mode of brain activity.”
Patient testimony:
“I think psilocybin gave me the
impetus to stay abstinent. It opens
up a whole new dimension to your
personality. It is almost as though
quitting smoking is peripheral during
the experience.”
These MRI scans illustrate the decrease
in DMN activity.
The Pharmaceutical Journal, 1 November 2014, Vol 293, No 7834, online | URI: 20066899
SCHEDULE 1 DRUG
• Schedule 1 drugs are extremely regulated, making the process of researching
them difficult, tedious and expensive.
• Putting potentially useful compounds under this category is a huge disservice to
health science research.
• If the complete therapeutic effects of Psilocybin are to be harnessed and fully
understood it is essential that the classification of this drug be reconsidered.
The Pharmaceutical Journal, 1 November 2014, Vol 293, No 7834, online | URI: 20066899
REFERENCES
[1] Eduardo E. Icaza, M.D., George A. Mashour, M.D., Ph.D.; Altered States: Psychedelics and Anesthetics. Anesthesiology 2013;119(6):1255-1260. doi:
10.1097/01.anes.0000435635.42332.ee.
[2] Keim, B. (2014, October 13). Science Graphic of the Week: How Magic Mushrooms Rearrange Your Brain | WIRED. Retrieved April 24, 2015, from
http://www.wired.com/2014/10/magic-mushroom-brain/
[3] Moffit, M., & Brown, G. (2015, March 11). Your Brain On Shrooms. Retrieved April 24, 2015, from https://www.youtube.com/watch?v=F5kqThVON18
[4] Passie, T., Seifert, J., Schneider, U. and Emrich, H. M. (2002), The pharmacology of psilocybin. Addiction Biology, 7: 357–364. doi:
10.1080/1355621021000005937
[5] The Pharmaceutical Journal, 1 November 2014, Vol 293, No 7834, online | URI: 20066899
[6] TORSTEN PASSIE, JUERGEN SEIFERT, UDO SCHNEIDER & HINDERK M. EMRICH. (2002, January 1). The pharmacology of psilocybin. Retrieved April 6, 2015,
from http://www.maps.org/research-archive/w3pb/2002/2002_Passie_22704_1.pdf
[7] Tyls, F., Palenicek, T., Horacek, J. (2014) Psilocybin – Summary of knowledge and new perspectives European Neuropsychopharmacology 24(3) 342-356​
[8] Yu, A. (2008) Indolealkylamines: Biotranformations and Potential Drug-Drug Interactions AAPS Journal 10(2) 242-253