Psilocybin and the brain

Psilocybin-containing mushrooms have been used for centuries throughout history, mainly used by Aztecs as a medicine. Once the Spaniards conquerors arrived in Mexico, they saw this practice as a pagan deity as it wasn’t practiced in the Christian religion, however this practice remained until today.

In the 50’s Psilocybe mushrooms were firstly introduced to the western botany by Robert G. Wasson with the help of the Oaxaca native curandera (healer) Maria Sabina.

Sabina was born in 1894, born in a poor family of campesinos (farmers) her father died when she was only three years old. Maria Sabina had to face poverty, malnutrition, and no education as she had to help her family with the farm.


Still from the 1978 documentary María Sabina, mujer espíritu

Maria Sabina and her sister Maria Ana once saw several little mushrooms and remembered the way their grandparents, curanderos themselves, spoke about them with great respect and called them “little things”. This was Sabina’s first interaction and experience with the Psilocybe mushrooms.

After becoming a widow for the second time Maria Sabina saw it as a way to embrace her faith, a faith she claimed to be traced even before she was born, the faith of becoming a curandera. Her connection with mushrooms together with the will to help Oaxaca made Sabina the first shaman to introduce mushrooms to non-Mazatec’s, unraveling the potentiality of psilocybin we know today, this brought tourist value to the region. Nowadays, Oaxaca one of the poorest indigenous regions in Mexico has hot water, internet and electricity.

Psilocybin {systematic name: 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate} was later isolated and synthesized by Albert Hofmann and his co-worker Franz Troxler in 1963. Forty years later, a new synthesis for large-scale production was introduced by Osamu Shirota and his colleagues at National Institute of Health Sciences (Tokyo). Despite the various synthesis routes introduced, the true crystal form of pharmaceutical psilocybin was yet to be unveiled by the revolutionary research conducted by the Usona Institute in 2021. The research focused on experimental challenges to solve the crystallographic puzzle and bring clarity to polymorphs, unique crystalline arrangements that arise naturally from the production of synthetic psilocybin. The study observed that three psilocybin polymorphs were repeatedly present in the well-known crystallization process, these same polymorphs have been present in various psilocybin syntheses since 1959.

Representation of the exact atom locations in a psilocybin Polymorph A crystal

Once psilocybin enters our body is broken down by the liver into psilocin, binding to our serotonin receptors (5-HT2A), this binding results in a change in the mood cognition and perception, causing hallucinations, faulty perception of color, time, and objects, being these results noted around 30 to 40 minutes and lasting up to 4 to 6 hours.

If psilocybin is consumed in a botanical form, Psilocybe mushrooms (magic mushrooms), the dosage can be variable and nearly impossible to determine as the results can be interchangeable depending on:

  • Species
  • Growing conditions
  • Harvest Period
  • Method of consumption (dried mushrooms of fresh) being the dried version more potent than the fresh as when dried the mushrooms solemnly retain psilocybin meanwhile when fresh the mushrooms contain various alkaloids naturally formed

If one consumes the substance synthetically the dosage can be:

  • Microdose: < 4 mg
  • Low dose: 4 – 8 mg
  • Average dose: 6 – 20 mg
  • High dose: 20 – 35 mg
  • Very high dose: > 35 mg

Once psilocybin is consumed generally effects such as:

  • Euphoria
  • Depersonalization
  • Uncontrollable laughter
  • Spiritual Awakening
  • Dizziness
  • Lack of coordination
  • Visual and auditory hallucinations Tingling on the body
  • A state of bliss

Can be observed, such effects can be variable depending on the state of mind, set and setting, and dosage.

Since the Psilocybe genus was introduced to the western community various differentiations in-between specimens were observed. Not only visual differentiations but chemical differentiation in between strains. Being the most sought for the Penis Envy strain. This genetically engineered strain has been sought for not only for its irregular phallic shape but also for being known as the strongest strain in the genus.

Penis envy strain- Source Blue Goba


Today we currently have 84 registered strains in the data bank Psilocydia, however, some strains remain in the dark.

Willsolvem’s Peyote Strain- Source: Shroomery


One particular strain, spread under the name Willsolvem’s Peyote strain in 2014, named after its creator, Shroomery user Willsolvem brings interest to various mushroom aficionados not only for its potency but for its distinct look similar to a Lophophora crest.  

This variation is in fact a mutated KSSS strain isolate (Koh Samui Super Strain), a strain first discovered by John Allen in the Koh Samui islands, Thailand (1989–90). Today the available KSS strains are a result of several years of refinement.

As a mutation of the KSSS strain, few attributes are present in the Willsolvem Peyote Strain, the mushrooms are dense, have a high yield, and their potency would be equally strong. Unlike the KSSS strain, the fruiting speed of this strain would be very fast, resulting in equally strong mushrooms with a higher yield.

Despite its unusual form, the mushrooms formulated and released spores, allowing a user under the name blojo02184, to fully colonize an official WillSolvem Peyote strain, sadly not many results were successful, and the strain remained without much recognition and unstable.

Along with the popularization of Psilocybe species, various clinical studies were submitted for the clinical use of psilocybin in mental illnesses, particularly, depression, ADHD and anxiety as well understanding what the substance can do to our mind and explore the hypothesis that magic mushrooms can alter in our gut microbiome.

Previous studies using fMRI scans (functional magnetic resonance imaging scan) have shown that psilocybin seemingly reduced the activity in the medial prefrontal cortex, known for regulating cognitive functions like memory, habits, and attention. During the study, a decreased connection between the medial prefrontal cortex and the posterior cingulate cortex (part of the brain that might take a role in regulating memory and emotions) was also noticed.

This connection is considered to be a feature of the brain’s default mode network, a network that is active even when one is resting or focusing internally. By reducing this activity psilocybin might be able to remove the constrains of the internal self as users reported to have a open mind and an increased perception of the world around them once they are under the influence of the substance.

The state of constantly facing negative thoughts is usually considered a hallmark of depression, it is known that patients with a higher level of negative rumination show increased activity on the default mode network compared to other networks while resting making these patients less responsive to the world around them. However, is yet to be proven that the symptoms of depression are the root cause of such altered activity or if those with a more active default network are more likely to be prone to depression.

Despite all the mystery surrounding how psilocybin acts in the brain, the most captivating evidence was obtained from a double-blind randomized controlled trial.

This trial compared a group of patients taking psilocybin to a patient group taking the antidepressant Escitalopram. The trial was then analyzed using fMRI scans and compared to previous studies.

It was observed that a day after the first dosage of psilocybin, the fMRI measures revealed increased connectivities in various brain networks which are typically reduced in patients with severe depression. The connectivity of the areas was dose-dependent in certain patients, consequently, the study observed that patients who had a bigger boost in the connections between networks had a greater improvement in their symptoms.

On the other hand, patients who took Escitalopram presented no change in the connectivity between the default mode and other brain networks after six weeks of treatment. The possibility of future changes caused by Escitalopram remains on the table, however, the rapid onset effect of psilocybin hypothesizes the substance to be an ideal tool for people who don’t respond to existing antidepressants.

The study proposes that the observed effect may be due to psilocybin having more concentrated action on serotonergic 5-HT2A receptors than Escitalopram. These receptors are activated by serotonin and are active throughout network brain areas, including the default mode network. Exactly how their activation leads to changes in network connectivity is still to be explored.

Researchers conducting the study propose that the observed results might be due to the concentrated action in the 5-HT2A receptors of psilocybin in comparison to Escitalopram. These receptors are activated by serotonin and are active throughout network brain areas including the default mode network. The binding to the 5-HT2A is also probably connected to the psychoactive effects of the substance, however, how the activation of these sites lead to change the network connectivity is yet to be explored.

Psilocybin occupancy of 5-HT2AR Source: Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels


The positive results of psilocybin in the treatment of depression have also been obtained by Johns Hopkins as 71% of the participants in Phase II clinical trial reported a decrease in symptoms 4- weeks after treatment. Alongside with Psilocybin is its analog CYB003, is believed to hold the potential to treat major depressive disorder (MDD) and alcohol disorder. This analog is designed to have less variability in the plasma levels, a faster onset of action, shorter duration, and potentially be more tolerable versus oral psilocybin. Thus, Cybin summited IND applications to FDA for the Phase1/2a first human trial for the treatment of MDD. Opening doors to various new psilocybin analogs with possible value in future clinical trials.


Such data have brought to light various projects regarding the research of psilocybin for the treatment of depression as well as various psilocybin clinics. Together with these clinics, a movement of micro dosing can also be observed to ameliorate symptoms of anxiety, social interaction and to enhance general performance.


Adding up to the physiological effects of psilocybin a recent thesis by Nicholas Alexander Anas presented psilocybin as a strong candidate for alleviating gut dysbiosis and producing positive downstream effects.

According to the research, psilocybin treatment showed a significant difference in gut microbiome diversity as well as a change in Firmicutes and Bacteroidetes at the phylum level, increasing and decreasing respectively.

Both Firmicutes and Bacteroidetes have been a center of discussion on gut health. High levels of Firmicutes have been associated with various health benefits from the reduction of G.I inflammation to alleviate symptoms of depression in patients with Major Depressive Disorder (Huang, Shi et al. 2018). Correspondently high levels of Bacteriodetes have been associated with many disorders such as obesity and weakened immune system(Johnson, Heaver et al. 2017).

The alteration of the gut microbiome might explain the reasoning behind the reduction of depressive symptoms up to six months after treatment (Grob, Danforth, et al. 2011). Unlike a conventional antidepressant which requires various doses over a long period, the possibility that psilocybin works by modulating microbe populations in the gut, potentially targeting a component of the disease instead of treating symptoms remains a hypothesis.

Such alteration in the gut microbiome presents promise in the ability of psilocybin to affect the gut-brain axis positively, hence paving the way for future research to understand how can psilocybin be used to modulate the gut microbiota to treat dysbiosis and similar disorders, to achieve such results it is needed to comprehend and determine the mechanism of action of psilocybin, how the substance affects the body physiology and behavior

The research presented by Hesselgrave, Troppoli displays the first known dose-dependent response curve for psilocybin in a rat model. The study presented in Nicholas Alexander Anas thesis provides a basis for future treatments at more effective doses. In addition prior to the thesis presented the effects of psilocybin in the gut microbiome were unknown. Creating a potential avenue for new pharmaceutical tools targeting the gut-brain axis.


María Sabina, mujer espíritu – Nicolás Echevarría 1978

Psilocybin: crystal structure solutions enable phase analysis of prior art and recently patented examples.
Alexander M. Sherwood,a Robert B. Kargbo,a Kristi W. Kaylo,a Nicholas V.
Cozzi,b,c Poncho Meisenheimera and James A. Kadukd –

Madsen, M.K., Fisher, P.M., Burmester, D. et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol. 44, 1328–1334 (2019).

Ricardo Jorge Dinis-Oliveira (2017): Metabolism of psilocybin and psilocin:  clinical and forensic toxicological relevance. DOI: 10.1080/03602532.2016.1278228

WilSolvem Strain:

Clare Tweedy: Psychedelics: How They Act on the Brain to Relieve Depression

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin
Robin L. Carhart-Harris, David Erritzoe, Tim Williams, James M. Stone, Laurence J. Reed, Alessandro Colasanti, Robin J. Tyacke, Robert Leech, Andrea L. Malizia, Kevin Murphy, Peter Hobden, John Evans, Amanda Feilding, Richard G. Wise, and David J. Nutt

Zachary T Goodman, Sierra A Bainter, Salome Kornfeld, Catie Chang, Jason S Nomi, Lucina Q Uddin, Whole-Brain Functional Dynamics Track Depressive Symptom Severity, Cerebral Cortex, Volume 31, Issue 11, November 2021, Pages 4867–4876,

Robin Carhart-Harris, Ph.D., Bruna Giribaldi, B.Sc., Rosalind Watts, D.Clin.Psy., Michelle Baker-Jones, B.A., Ashleigh Murphy-Beiner, M.Sc., Roberta Murphy, M.D., Jonny Martell, M.D., Allan Blemings, M.Sc., David Erritzoe, M.D., and David J. Nutt, M.D: Trial of Psilocybin versus Escitalopram for Depression

The Pharmacology and Clinical Applications of Psychedelic Medicines Within Midwifery Practice
Cindy A. Stein CNM, PhD, MPH,Andrew Penn MS, NP, PMHNP-BC,Stephanie Van Hope DNP, RN, NC-BC,Caroline G. Dorsen PhD, FNP-BC,Mariavittoria Mangini CNM, PhD, FNP – DOI:

Whole-Brain Functional Dynamics Track Depressive Symptom Severity Get access Arrow
Zachary T Goodman, Sierra A Bainter, Salome Kornfeld, Catie Chang, Jason S Nomi, Lucina Q Uddin
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Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms
Robin L Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J Nienke Pannekoek, Matthew B Wall, Mark Tanner, Mendel Kaelen, John McGonigle, Kevin Murphy, Robert Leech, H Valerie Curran & David J Nutt

Natalie Gukasyan, Alan K Davis , Frederick S Barrett, Mary P Cosimano, Nathan D Sepeda, Matthew W Johnson and Roland R Griffiths: Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up

By Nicholas Alexander Anas –

Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2022489118. doi: 10.1073/pnas.2022489118. PMID: 33850049; PMCID: PMC8092378.

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