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Psilocybin, Its Effect on Neuroplasticity,

and Its Role as an Antidepressant
Eftyhia Fillas
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“Flesh of the Gods,” was an early nickname for magic mushrooms, as its ceremonial and

religious uses date back to prehistoric times. The Aztecs mixed mushrooms with other

ingredients to induce a trance and allow communication with the gods. The Selva Pascuala mural

depicts fungoid features which are believed to be referencing magic mushrooms, dating back to

4,000 BCE (Akers et al., n.d.). Siberians belonging to indigenous tribes utilized dissociative

characteristics of hallucinogenic mushrooms to allow the body to endure harsh weather

conditions when traveling (Dorr, n.d.). During ritual ceremonies praising the goddess Demeter,

Ancient Greeks ingested mushrooms through home-made psychoactive concoctions (Dorr, n.d.).

Magic mushrooms soon found their way into the United States, after Robert Gordon Wasson and

his wife, Valentina Pavlovna Wasson partook in an indigenous ceremony involving magic

mushrooms and publicized this experience with the substances in the 1950s. The term “magic

mushroom” was coined in the couple’s article (Scott Houghton, n.d.). Psilocybin mushrooms

swiftly grabbed the attention of academia and research was conducted testing the effects of

psilocybin on mental health and human consciousness. Timothy Leary established the Harvard

Psilocybin Club to study magic mushrooms and, along with his colleagues, test their effects

firsthand (Scott Houghton, n.d.). Research helped gain a better understanding of the effects of

mushrooms. Psilocybin mushrooms escaped outside the walls of academia and made their way

into the art and music industry. The counterculture hippie movement of the late 1960s

romanticized the power of psychedelic mushrooms and promoted a liberal and ‘free’ outlook on

life. This liberal way of thinking was called the “Free Love” movement. Hippies believed that

magic mushrooms could “transform” both individuals and society by expanding consciousness

and self identity (Rorabaugh, n.d.). Recreational use of psilocybin mushrooms became

popularized and their perception altering effects became glamorized. In 1970, the Control
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Substance Act of 1970 began the war on drugs and mushrooms were made illegal. Now, 50 years

later, the legality of psilocybin mushrooms has opened the doors to better understand psilocybin

and its effect on the brain, while also providing an opportunity to use magic mushrooms for

medicinal treatment of depression.

Magic mushrooms are natural substances that contain the psychedelic substances

psilocybin and psilocin. Different species contain varying concentrations of psilocybin and

psilocin, depending on the type of plant, origin, and growing conditions. The most potent

mushrooms are the members of the Psilocybe genus (Pravesh Sharma et al., n.d.). The reason for

the mushroom’s popularity is its ability to induce psychosis-like symptoms including distortions

in one’s perception, cognition, and emotions (Pravesh Sharma et al., n.d.). Oral administration of

psilocybin allows for the tryptophan indole-based alkaloid to be metabolized into psilocin, which

produces the hallucinations associated with magic mushrooms (Pravesh Sharma et al., n.d.). In

order to experience such psychedelic sensations, a relatively small dose must be administered,

around 8-25 mg (Pravesh Sharma et al., n.d.).

The activity of psilocybin on the 5-HT2A serotonin receptor allows the mushroom to

produce these alterations in cognition, perception, and consciousness (Lopez-Gimenez & Maeso,

n.d.). Activation of the 5-HT2A serotonin receptor is critical in producing hallucinations

(Lopez-Gimenez & Maeso, n.d.). The receptor contains four specific amino acids on its carboxyl

terminus that comprise a unique binding domain- PDZ. Subsequent to the activation of the

serotonin receptor, this binding domain interacts with a secondary binding domain PSD-95, a

protein that regulates synaptic activity (Coley & Gao, n.d.). Studies suggest that the PSD-95

protein is vital to elicit hallucinogenic effects at the level of the serotonin receptor

(Lopez-Gimenez & Maeso, n.d.). The 5-HT2A receptors are also highly expressed in the visual
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cortex, which explains its ability to produce visual hallucinations (Susan Ling et al., n.d.).

Psilocybin activation of the 5-HT2A serotonin receptors are detected in the hippocampus,

thalamic nuclei, mammillary bodies in the hypothalamus, various midbrain nuclei, and the

neocortex, which contains the highest density of these serotonin receptors (Lopez-Gimenez &

Maeso, n.d.).

The major symptoms of major depressive disorder are reduced motivation, anhedonia,

irritability, disrupted sleep, appetite and cognition, and tendency to suicide (Yang et al., n.d.).

The death of cortical neurons and neural connections is a key characteristic in the

pathophysiology of depression (Ly et al., n.d.). The degeneration of neural circuitry by

depression is only exacerbated by stress. In response to stress, neurotransmitters such as

serotonin, norepinephrine, and acetylcholine are released and the paraventricular nucleus is

activated, resulting in the secretion of corticotropin releasing factor (CRF) (Yang et al., n.d.).

Through a series of neurons, CRF stimulates the release of adrenocorticotropic hormone, which

projects to the adrenal cortex to release glucocorticoids, and with catecholamine, are the main

stress hormones (Yang et al., n.d.). The glucocorticoid hypothesis focuses on the effects stress

has on the structure and function of the brain. Depressed patients exhibit high CRF release and

excess cortisol, causing neuron atrophy and the shrinking of dendritic spines. Death of neurons in

the hippocampus reduces cortical level response and impedes feedback inhibition. By the

neurotrophic hypothesis, depression is understood as reduced levels of brain derived

neurotrophic factor (BDNF), which causes a significant loss of dendritic spines in both the

hippocampus and the prefrontal cortex, as well as diminished neurogenesis in the hippocampus.

Stress aggravates these functional changes that occur in depression, by decreasing BDNF,

resulting in a further loss of dendritic spines in the hippocampus. Antidepressants essentially

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work as antistress drugs, reversing this atrophy and promoting neuroplasticity, the development

of new neurons, and strengthening of neural circuitry. Recent evidence highlights the ability of

psychedelics to more rapidly and effectively promote neuroplasticity in hopes of relieving the

neuro-degeneration caused by depression.

Standard treatment for Major Depressive Disorder (MDD) include selective serotonin

reuptake inhibitors, (SSRIs), norepinephrine reuptake inhibitors (NRIs), and

serotonin-norepinephrine reuptake inhibitors (SNRIs). Patients on such treatment experience

adverse side effects such as sexual dysfunction, sleep disturbance, and weight fluctuation

(Ferguson, n.d.). After the termination of prolonged use of SSRIs, withdrawal symptoms may be

experienced, making it difficult to cease administration of the medication. SSRIs are not as

robust, typically do not work after the first administration, and have an increased risk of relapse.

One third of patients do not respond to antidepressants and do not experience benefits until after

4 weeks of treatment (Ly et al., n.d.). Psilocybin provides a more rapidly acting medication that

increases risk of remission, without the presence of side effects (Susan Ling et al., n.d.).

Psilocybin’s fast acting and low toxicity characteristics make it a, possibly, more favorable

method of treatment (Susan Ling et al., n.d.). What makes psychedelics, like psilocybin, better

candidates for first-line treatment of depression is their ability to promote neural plasticity and

alter the functional and structural basis of the brain within seconds of administration.

BDNF plays a major role in the effectiveness of the treatment of depression (Björkholma

& Monteggiab, n.d.). BDNF is a neurotrophin that regulates neural maturation, neuroplasticity,

and neuronal growth (Calder & Hasler, n.d.). By increasing the expression of BDNF in the

hippocampus and cortex, the symptoms of depression are reversed (Björkholma & Monteggiab,

n.d.). SSRIs and psychedelics both affect the expression of BDNF in the brain. Antidepressants
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activate the BDNF pathway through neurotransmitters serotonin and norepinephrine, which then

enable the release of BDNF. Psilocybin, and other psychedelics, bind to the TrkB receptor of

BDNF itself and directly increase the release of BDNF. Through this direct activation,

psychedelics have the ability to promote structural and functional remodeling in the brain and

increase neurogenesis and synaptogenesis, the growth of new neurons and new dendritic spines,

in a much more efficient and rapidly acting way (Susan Ling et al., n.d.). By advancing the

plasticity of the neural system, psychedelics increase the number of dendritic spines and

strengthen neural connections. By increasing the amount of synaptic connections in the brain, the

effects of chronic stress are reversed and thus, effects of depression are undone. Similar to

ketamine, psychedelics have long lasting beneficial neural alterations that occur just after a

single dose (Susan Ling et al., n.d.).

Around 3.8% of the world’s population is affected by depression. With a large number of

people suffering from this neural disorder, there must be a better first line treatment that works

robustly after minimal administrations. SSRIs have minimal benefits and low success rates.

Psychedelics are better agents at reversing the effects of depression by enhancing neuroplasticity

and neuron maturation through the increased release of BDNF. Though a negative stigma from

the Free Love movement has remained, it has been proven that psychedelics, in controlled

environments and doses, can be medicinally and therapeutically beneficial. Psychedelics may,

again, escape the walls of academia and make their way into the world of medicine, allowing for

a more effective and rapid treatment of major depressive disorder.

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Work Cited

Akers, B. P., Ruiz, J. F., Piper, A., & Ruck, C. A. P. (n.d.). A Prehistoric Mural in Spain

Depicting Neurotropic Psilocybe Mushrooms? Economic Botany, 65, 8.

Björkholma, C., & Monteggiab, L. M. (n.d.). BDNF — a key transducer of antidepressant

effects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763983/

Calder, A. E., & Hasler, G. (n.d.). Towards an understanding of psychedelic-induced

neuroplasticity.

Coley, A. A., & Gao, W.-J. (n.d.). PSD95: A synaptic protein implicated in schizophrenia or

autism?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801047/#:~:text=Postsynaptic%20densi

ty%20protein%2D95%20(PSD,AMPARs)%20to%20the%20postsynaptic%20membrane.

Dorr, A. (n.d.). The History of Psilocybin: Magic Mushroom Use Through the Ages.

https://www.mushroomrevival.com/blogs/blog/the-history-of-psilocybin-magic-mushroo

m-use-through-the-ages

Ferguson, J. M. (n.d.). SSRI Antidepressant Medications: Adverse Effects and Tolerability.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC181155/

Lopez-Gimenez, J. F., & Maeso, J. G.-. (n.d.). Hallucinogens and Serotonin 5-HT 2A

Receptor-Mediated Signaling Pathways.

https://link.springer.com/chapter/10.1007/7854_2017_478

Ly, C., Greb, A. C., Cameron, L. P., & Wong, J. M. (n.d.). Psychedelics Promote Structural and

Functional Neural Plasticity. https://doi.org/10.1016/j.celrep.2018.05.022.

Pravesh Sharma, Quang Anh Nguyen, & Hammond, C. J. (n.d.). Psilocybin history, action and

reaction: A narrative clinical review. Sage Journals, 37.

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https://journals.sagepub.com/doi/10.1177/02698811231190858

Rorabaugh, W. J. (n.d.). American Hippies. Cambridge University Press.

https://www.cambridge.org/core/books/abs/american-hippies/drugs-music-and-spiritualit

y/1BA131FA9915F651C886A6D41B9B60B8

Scott Houghton. (n.d.). From Medicine to Poison: The Magic Mushroom in 1960s America. The

Collector. https://www.thecollector.com/magic-mushrooms-1960s-america/

Susan Ling, Felicia Ceban, W, L., Leanna M., & Lee, Y. (n.d.). Molecular Mechanisms of

Psilocybin and Implications for the Treatment of Depression.

https://www.proquest.com/docview/2618817902?accountid=10796&pq-origsite=primo&

parentSessionId=E2gcDquSvauIs2813OXWfFhVrFY8yRyAIDQNPXw6%2BBE%3D

Yang, L., Zhao, Y., Wang, Y., & Liu, L. (n.d.). The Effects of Psychological Stress on Depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790405/
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