Lorenzo Bono
Chiara Agrosì
INTRODUCTION
Psilocybin is natural psychedelich compound, extractable from a large variety of mushrooms, usually known as psilocybin mushrooms. The most powerfull belongs to Psilocybe family, first of all Psilocybe Azurescens, and they are able to distort human mind and thoughts actin in a similar way to LSD and mescaline. Efects include heuforia, mental and visive delusions, distorted percection of time, spiritual experiences and even some side effects like nausea and panic attacks.
First knowledge about so called "magic mushrooms" go further to 16th century, but is very probable that their abituale usage is common since prehistirical ages.
Psilocybin otherwise was discovered as a psycotropic drug in 1957 by Albert Offman , purified and then commercialized by a Hoffman emploiee until 1960, year when it was declared illegal all over the world. Still, during the '90s and 2000s country like UK allowed it's selling over their national territory, lije is still happenig in Netherlands.
CHEMISTRY
Psilocybin, also known as O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine with IUPAC classification is the fosforyloxy derivate of psilocin (4-hydroxy-N,N-dimnethyltrytamine in the IUPA classification). It is known to be a prodrug, that means that the chemical substance, originally inactive, needs to be biochemically converted in the body before it can produce it's effect on human organism.
The biosinthetic path that allow Psilocybin to be produced by mushrooms is as follow:
The several analogyes with triptophan aminoacid, with whom psilocybin has common origines are probably at the base of psilocybin ability to induced psychedelich alteration on humans.
For many organisms (including humans), tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. Amino acids, including tryptophan, act as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for many compounds like serotonin
Serotonin (a neurotransmitter), synthesized via tryptophan hydroxylase. Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase activities
PHARMACOLOGY AND PHISIOLOGY
After assumption, psilocybin in the body is dephosphorilated to his active form (psilocin) by alkaline phosphatase. The enzimatic reaction is helped by acid environment, so the reaction can occur even in the stomac, increasing drug biodisponibility. Psilocin is able to bind, even if with less strength, serotonin receptors, behaving as a partial agonist of the phisiological hormon, miming is natural action on brain cortex (anterior and posterior cingulate cortex) and thalamus
In the following picture are shown 5-HT and Psilocin to demonstrate high grade of similarity in their chemical composition: serotonin is shown on the lesft, psilocybin on the right:
5-HT receptors are located in several brain parts, cerebral cortex included and are involved ina large number of fuction, first of all mood regulation and emotivity control. There are many kind of serotonin receptors, 5-HT1A, 5-HT1D, 5-HT2 e 5-HT2A.Psilocybin chemical structure have been used for years in computational biology as amodel to better understedn 5.HT receptors structure.
Between the other, 5-HT2A receptor is the most interesting one; psilocybin in the brain has its highest affinity for serotoninergic 5-HT2A receptor and for this reason is capable of miming serotonin aminoacid well known effects; otherwise the interaction and action on the other receptor of this family is very weak and for this reason it's not interesting for a physiological study.
The psychotomimetic (psychosis-mimicking) effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT2A antagonist drugs ketanserin and risperidone, often used for the treatment of unwanted ingestion.
Even if it's known that the priciple responsable for psilocyin effects on the organism is 5-HT2A receptor, studies have demonstrated that interation with other receptors have to be watch up, because they can help to increase some of the drug behaveural aspects, even if this happends in different way sdependind on the patient.
For example, even if psilocybin e psilocyn have no affinity for dopaminergic receptors, wether LSD has a very good binding ability with the whole family of receptors, it's been noticed that psilocyn can indirectly raise dopamine concentration withing the basal ganglia. That suggest that could exist a dopaminergic action depending on psilocyn action. For that reason, and this conferm this kind of action, we can use Aloperidol to reduce and stop some of the psychotomimetic effects of the drug
Looking at the strong interaction between psilocybin and astrocites, due to the high numbered 5-HT receptors expressed on these cells, is assumable, while waiting for experimental dates, that are these cells, peculiarly responsable for the regulation of neural nutritional income, to determinate the higher use of glucose that usually follows assumption of the drug in study
BIODISPONIBILITY
Almost 50% of oral psilocybin is absorbed by stomach and gut; from here is lead to liver, where it's converted in psilocin, pharmacologically active form, that can furtherly be glucoronated and escreted with urine or converted in other psilocinics metabolites.
After psilocin gets its ative form, it is cut by the monoaminoxidase enzime (MAO), with the production of many metabolites that can simply run in the blood flow, including 4-hydroxyindole-3-acetaldehyde, 4-hydroxytryptophol, and 4-hydroxyindole-3-acetic acid; according to these reactions psilocin biodisponibility reduces befor the drug can reach the sistemic circulation. As it were said before, some of the drug can be glucoronated forming glucoronide. This is the principal biochemical mechanism that allows animals to eliminate toxics, that bound to glucuronic acid are easily escreted by urine. This process is granted by the action of two kind of enzime: the glucuronosyltransferase enzymes UGT1A9 in the liver, and by UGT1A10 in the small intestine.
Within 24 hours from administration 65% of the alucinogen is escreted by urine, while another 15-20% is excreted by bile and feces. Even if varius physiolocical mechanism are able to eliminate most of the compound in a very short time (after 8 hours drug effects are not feelable animore), traces of the compund can be detected in unine even after 7 days.
Clinical studies show that psilocin concentrations in the plasma of adults average about 8 µg/liter within 2 hours after ingestion of a single 15 mg oral psilocybin dose; psychological effects occur with a blood plasma concentration of 4–6 µg/liter. Psilocybin is about 100 times less potent than LSD on a weight per weight basis, and the physiological effects last about half as long.
Tolerance to psilocybin builds and dissipates quickly; ingesting psilocybin more than about once a week can lead to diminished effects. Tolerance dissipates after a few days, so doses can be spaced several days apart to avoid the effect. A cross-tolerance can develop between psilocybin and the pharmacologically similar LSD , and between psilocybin and phenylethylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine.
Monoamine oxidase inhibitors (MAOI) have been known to prolong and enhance the effects of psilocybin. Alcohol consumption may enhance the effects of psilocybin, because acetaldehyde, one of the primary breakdown metabolites of consumed alcohol, reacts with biogenic amines present in the body to produce MAOIs related to tetrahydroisoquinoline and β-carboline. Tobacco smokers can also experience more powerful effects with psilocybin, because tobacco smoke exposure decreases levels of MAO in the brain and peripheral organs.
TOXICITY
The toxicity of psilocybin is low. In rats, the median lethal dose (LD50) when administered orally is 280 milligrams per kilogram (mg/kg), approximately one and a half times that of caffeine. When administered intravenously in rabbits, psilocybin's LD50 is approximately 12.5 mg/kg
Psilocybin comprises approximately 1% of the weight of Psilocybe cubensis mushrooms, and so nearly 1.7 kilograms (3.7 lb) of dried mushrooms, or 17 kilograms (37 lb) of fresh mushrooms, would be required for a 60-kilogram (130 lb) person to reach the 280 mg/kg LD50 value.
To induce psychedelich effects is needed at least a minimal dose of 4-10mg, corresponding to 50-300microg per kilo. Tipical recreative dose is about 10-50mg of psilocybin, that means about 10-50g of fresh mushrooms or 1-5g of dried mushroms.
Latency is quite short, effects are shown after 10-40 minuits after oral administration and last from 2 to 6 hours, depending on the dose, individual metabolism and mushroom kind. Psilocybin half-life is about 163 ± 64 minutes for an oral administration and 74.1 ± 19.6 for an intravenous injection administration.
Repeated use of psilocybin does not lead to physical dependence
PSYCHIC EFFECTS
A 2011 prospective study by Roland R. Griffiths and colleagues suggests that a single high dosage of psilocybin can cause long-term changes in the personality of its users. About half of the study participants—described as healthy, "spiritually active", and many possessing postgraduate degrees—showed an increase in the personality dimension of openness (assessed using the Revised NEO Personality Inventory), and this positive effect was apparent more than a year after the psilocybin session.
The ability of psilocybin to cause perceptual distortions is linked to its influence on the activity of the prefrontal cortex.
Psilocybin is known to strongly influence the subjective experience of the passage of time. Users often feel as if time is slowed down, resulting in the perception that "minutes appear to be hours" or "time is standing still"
Recent studies, (Carthan Harris, 2012 PNAS) tried to demonstrate a very stricht correlation between cerebral blood flow and the psichedelyc state induce by psilocybin. It’ now proved that this particolar kind of drug is capable of reduce (in comparation with placebo injection) CBF in many brain areas, causing a lower oxigen partial pression in analized venous blood. This could lead to a lower usage o f glucose, but the same study admitted an increase glucose usage by the whole brain cell, meaning a differente use of this sugar while the drug is having effects.
Usually clinics and researchers thought that psychedelic state induce by drugs results of an increate brain function. Though hte use of MRI (functional magnetic resounance) showed that the decresed blood flow associate with decreasing in neural activity.
A simple explanation for this unexpected situation could be the serotoning agonist action of psilocybin, action that seems to be focused more on 5-HT receptors than on 5-HT2A.
Quite elementary explenation for this unexpected situation is researcheable in the fact that psilocibyn is able to act as a 5-HT agonist binding directly its receptors.
It seams that these receptors are able, after a stimulation, to induce brain blood vessel constriction
By applying molecular and pharmacological issues, 5-HT receptors have tried to be found inside the brain microvascular system; particular efforts have been done for detecting them on endothelial tissue, smooth muscle and astroglia in human cell culture.
As expected, these studies confermed the presence of 5-HT2A family receptors that are first target for psilocybin expecially when presented on isolated capillar blood vessels and astrocitary cells.
Actually, the study showed that the most interested brain areas during recuded blood flow psilocybin dependt was thalamus, anterior cingulate cortex and posterior cingulate cortex as weel. PCC is well known by phisiology because of his partuclarly high rest blood flow, usually higher about the 20%. The strong inibition of the PCC is now thought to be most significant action of psilocybin on neural disaccoppiation, leading to a different percection of reality.
A differential pcr assessed ona atrocitary population clearely shows a high expression level of 5-HT2A receptor on this population; this confirm it's envolvement in brain blood flow changes induce by psilocibyn infusion. This hipothesys is also validated from the fact that astrocites are able to change microvscular tone even in phisiological situations.
All said before could lead to think that cells after psilocybin assumption would have a lesser glucose uptake and use; actually, further studies highlighted a augmented glucose consumption in several brain regions; this lead to the conclusion that psilocybin is some way able to modify the physiological glucosal metabolic rate of our body, most for the brain
Looking at the strong interaction between psilocybin and astrocites, due to the high numbered 5-HT receptors expressed on these cells, is assumable, while waiting for experimental dates, that are these cells, peculiarly responsable for the regulation of neural nutritional income, to determinate the higher use of glucose that usually follows assumption of the drug in study
SIDE EFFECTS
The physical side effects resulting from psilocybin usage are generally not considered significant. Common responses include: pupil dilation (93%); changes in heart rate (100%), including increases (56%), decreases (13%), and variable responses (31%); changes in blood pressure (84%), including hypotension (34%), hypertension (28%), and general instability (22%); changes in stretch reflex (86%), including increases (80%) and decreases (6%); nausea (44%); tremor (25%); and dysmetria (16%) (inability to properly direct or limit motions). The temporary increases in blood pressure caused by the drug can be a risk factor for users with pre-existing hypertension
However, psilocybin can cause anxiety and increased heart rate and BP which is very counter- productive for someone on metoprolol and micardis.
Drug interactions are done through controlled studies or doctors reports. There are very few reports on psilocybin because it has no legal uses. There is no information available about drug-drug interactions.
THERAPEUTIC AND CLINICAL USES
Nowaday psilocybin is again matter of discussion in the scientific and academic wordl, and many studies have been made on his therapeutical efects. The first FDA-approved clinical study of psilocybin since 1970 led by Francisco Moreno at the University of Arizona.
According to a very recent paper (Griffiths, Journal of phsycopharmacol, 2006) psilocybin administration to psycologically instable or miserable patients should be able to benefit , improving their perception of their own "io", of the reality in whom they're living e leading to a a generalized sense of subjective well beiing and serenity.
After considering the ability of psilocibyn of inibiting mesofrontal cortex, as well capable of inibiting the limbic emotional system, a newer paper] propose the hypothesis that this drug could be used to induce the spontaneus recover of asleeped memories from a patient, in order to augment his feeling of gratification about his own himself
This theory follows the idea of using LSD in the alcoholism therapy: causing to the patient an alterated state of mind and sensorial and emotive altered perception is possible to induce him to reconsider about his pathological dependance from a different pooint of view, leading him to stop drinking on his own; however, the illegality of these substances makes human research in this field particularly difficult, thus most of the information about it have been desumed from muring models tests and from psycological analysis of treated drug-addicted patient, or from reasearch and studies review from years befor the 70s.
Concerning to this is very interesting to note the continuous and spontaneous proliferation during the last few years of studies and researches on this topic: for example we can remember all the new papers written by Dr. Harris, or the most recent Pilot Study for Anxiety in Patients With Cancer that propose the possibility to use psilocybin as a palliative therapy for terminal illness like cancer but also as a real antidepressive active principle available for the family of the patient. The rational is foundable in the fact that we usually administer SSRI as antidepressive agents, so psilocibyn sholud be useful in this purpose for its selective agonist action on 5-HT2A receptors
