action of psilocybin - unm biology department home...

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

BRIEF HISTORY OF PSILOCYBIN

• Ritualistic use of hallucinogenic mushrooms dates back 3000 years in Mexico

A.D.

• Psilocybin was first isolated and identified by Albert Hofmann

1958 • Psilocybin was

first synthesized by Albert Hofmann

1959

• Psilocybin widely used in the experimental research of mental disorders and psychotherapy

1960

• Psilocybin classified as a schedule I drug

1970

• Interest in human experimental research into Psilocybin and other psychedelics revived

1990

CHEMICAL STRUCTURES

PSILOCYBIN IS RAPIDLY DEPHOSPHORYLATED TO PSILOCIN IN THE INTESTINAL MUCOSA BY ALKALINE PHOSPHATASE AND NONSPECIFIC ESTERASE.

INGESTED MOLECULE FROM MUSHROOM

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

METABOLIZED FORM (TOXIN)

Mechanism of Action

Psilocin is glucuronidated by endoplasmic enzymes UDP-glucuronosyltransferase to psilocin-O-glucuronide.

80% of psilocin-O-glucuronide is excreted from the body.

MECHANISM OF PSILOCYBIN

Only about 50% of the total volume of psilocybin taken orally is absorbed from the digestive tract.


If dephosphorylation of Psilocybin is inhibited no psychotropic effects

are perceived, thus Psilocin is the main active metabolite of

Psilocybin.

Psilocin undergoes a demethylation and deamination to 4-hydroxyindol-3-yl-acetaldehyde (4-HIA).

MECHANISM OF PSILOCIN

4-HIA gets oxidized, believed to be by hepatic aldehyde dehydrogenase and

monoamine oxidase, to 4-hydroxyindol-3-acetic acid (4-HIAA) and 4-hydroxytryptofol (4-HT). However, only about 4% of psilocin

gets degraded in this way.

Another possible pathway for psilocin is

oxidation by hydroxyindol oxidases to a product with an o-

quinone 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

• 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

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.

PHARMACOKINETICS

Subjective impressions from individuals

Plasma concentration after initial dose of 0.224 mg/kg

Using the same dose as the last graph, this graph shows the excretion rate of Psilocin. After 3 hours, about two-thirds 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

• However the only victims were not linked to toxicity of psilocybin but due to suicide

• A human would have to 19 g of the pure drug to bring about death

9637 Vitamin A

4816 LSD

641 Psilocybin

199 Aspirin

21 Nicotine

Therapeutic Index Comparison LD50/ED50


BIOCHEMICAL EFFECTS Symptoms

Dizziness

Weakness/ Drowsiness

Tremor

Nausea/ Vomiting

Tendon Reflexes

Increase in levels of cortisol

No Effect

Heart Rate

Body Temperature

Ionic Balance

Blood Glucose

Cholesterol Levels

Plasma Concentration

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

• 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)

SIMILAR 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?

Scientists suggest the brain may temporarily rearrange itself by inhibiting normal brain activity and immediately creating new, biologically stable brain connections

Normal Neural Network

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

• Well-ordered correlation state • Not much cross-linking between

networks

The dots and colors correspond to connection-rich networks

• Substantial increase in number of network cross-links

• Newly wired neural pathways emerge

Non-Psychedelic Compound Psilocybin

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.

http://www.livescience.com/18067-psychedelic-mushrooms-brain-activity.html

PSILOCYBIN AND PSILOCIN SEROTONIN RECEPTORS

PSILOCYBIN

Psilocybin interacts mainly with serotonergic neurotransmission

5-HT1A, 5-HT1D, 5-HT2A and 5-HT2C receptor subtypes.

PSILOCIN

Psilocin binds to many different receptors including dopamine in the following order:

5HT2B>5HT1D>D1>5HT1E>5HT1A>5HT5A>5HT7>5HT6>D3>5HT2C>5HT1B>5HT2A.

Both psilocybin and psilocin have agonist activity on serotonin 5HT2A/C and 5HT1A receptors.

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.”

These MRI scans illustrate the decrease in DMN 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.”

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.


[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

REFERENCES

http://www.wired.com/2014/10/magic-mushroom-brain/






https://www.youtube.com/watch?v=F5kqThVON18

http://www.maps.org/research-archive/w3pb/2002/2002_Passie_22704_1.pdf




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