Understanding the Molecular Mechanisms of Psilocybin

Psilocybin, the psychoactive component of magic mushrooms, has been used throughout recorded history in various cultural and spiritual contexts and rituals. With a growing social acceptance of previously forbidden natural medicines, such as cannabis, conversations surrounding medicinal mushrooms are spawning throughout the scientific and medical community.

Recent advancements in neuroscience and pharmacology have enabled a deeper understanding of how psilocybin interacts with the human body. By increasing mycological research, scientists will continue to shed light on the molecular and biological mechanisms responsible for its psychedelic and therapeutic effects.

In the article below, we will investigate how psilocybin interacts with the human body, including:

  • The tryptamine’s characteristics
  • Its absorption and conversion to psilocin
  • The impact on neurotransmitter systems

Let’s get started, mycology fans. It’s time to unlock the magic behind “magic mushrooms.”

What Is Psilocybin?

Psilocybin is a naturally occurring psychedelic derivative found in over 200 species of Psilocybe (magic mushrooms). The compound has been revered for its ability to induce an altered state of consciousness. Although usually found in humid tropical regions such as South America, the only place on earth where we have yet to discover any species of Psilocybe mushrooms is Antarctica. Very few species of fungi can survive there, and Psilocybe mushrooms are not one of them.

Human brain neurons and neurotransmitters
When psilocybin becomes psilocin, it interacts with the brain’s serotonin receptors. This is why a psychedelic experience affects emotions, mood, and even digestion.

What are Tryptamines?

Tryptamines are a fascinating class of psychoactive compounds. They are found in nature, synthesized in laboratories, and exhibit unique effects on the human mind and consciousness. Tryptamines are characterized by their core chemical structure, which includes a double-ring system with a side chain.

The psychoactive effects of tryptamines are primarily attributed to their interaction with serotonin receptors in the brain (which we’ll review later.) This interaction leads to alterations in perception, mood, and cognition. The well-known tryptamine, psilocybin, is commonly found in various species of “magic mushrooms” and is known for its mind-expanding effects and potential therapeutic applications.

Recent scientific interest in psilocybin has focused on elucidating the tryptamine’s interaction with various biological systems within the human body. In doing so, researchers hope to further their understanding of the mechanisms underlying its profound psychedelic effects. In fact, psychedelics show promise in treating the deep-seated causes of many mental illnesses, rather than simply treating the symptoms.

Absorption and Metabolism

Upon ingestion, psilocybin is rapidly absorbed in the gastrointestinal tract, allowing the compound to enter our bloodstream. When psilocybin enters our liver, it is dephosphorylated (has a phosphate group removed) through an enzymatic conversion to psilocin. This process uses alkaline phosphatase enzymes to facilitate the transformation of psilocybin into psilocin.

psilocybin and psilocin molecules
Psilocybin, the compound found in “magic mushrooms,” transforms into the active compound psilocin. This process takes place after dephosphorylation occurs in the liver, removing one of psilocybin’s phosphate groups.

Psilocin, the pharmacologically active metabolite from Psilocybe mushrooms, has a molecular structure like serotonin. This, in part, allows the compound to easily cross the blood-brain barrier, facilitating its interaction with serotonin receptors. And this is when the fun begins.

Serotonin Receptor Agonism

Once psilocybin dephosphorylates (loses a phosphate group, see image above) into its active compound, psilocin, the compound can interact with the 5-HT receptors found abundantly throughout our cortex. And just as serotonin interacts with our 5-HT3 receptors, psilocin targets our 5-HT2A receptor. Psilocin acts as a partial agonist at the 5-HT2A receptor, leading to a cascade of intracellular events.

psilocin and serotonin molecules
Psilocin’s molecular structure is similar to that of the neurotransmitter, serotonin. This, in part, allows psilocin to act as a partial agonist to the 5-HT2A receptors found largely in the outer layer of the brain (the cortex.)

The activation of the 5-HT receptor modulates neuronal firing patterns (altering neurotransmitter release) and induces changes in synaptic plasticity. Collectively, these chemical interactions within the brain contribute to the characteristic psychedelic experience.

Neuroplasticity and Synaptic Remodeling

Emerging evidence suggests that psilocybin may exert neuroplastic effects, promoting structural changes in the brain. Animal studies indicate that psychedelics, including psilocybin, can enhance neurogenesis and stimulate synaptic plasticity. As described by the National Library of Medicine,

Synaptic plasticity refers to the ability of neurons to modify the strength of their connections and is an important neurophysiological process involved in brain networks development and reorganization after damage.”

Stampanoni Bassi M, Iezzi E, Gilio L, Centonze D, Buttari F. Synaptic Plasticity Shapes Brain Connectivity: Implications for Network Topology. Int J Mol Sci. 2019 Dec 8;20(24):6193. doi: 10.3390/ijms20246193. PMID: 31817968; PMCID: PMC6940892.

These changes may underlie the observed therapeutic potential of psilocybin in conditions such as depression and post-traumatic stress disorder. Neuroplasticity is also an important component of psychedelic-assisted therapy, allowing a therapist to help their patient heal from deep-seated memories and experiences by temporarily creating a buffer between their cognitive processing and their ego.

Neurotransmitter Modulation

In addition to its interactions with serotonin receptors, psilocybin influences other neurotransmitter systems, including dopamine and glutamate. This is because psilocybin acts as a neuromodulator, affecting how neurons in the brain communicate (or don’t.) The modulation of these neurotransmitters is implied by a subject’s change in mood, perception, and cognition.

Recent studies suggest that the effects of psilocybin extend beyond traditional serotonin pathways, highlighting the complexity of its neuropharmacological profile. Psilocybin is only one of many tryptamines. The more scientists research and uncover how the compound interacts with our physiology, the more we can leverage these psychedelics for mental health therapy and exploring different states of consciousness.

Default Mode Network (DMN) Disruption

Functional neuroimaging studies have revealed that psilocybin induces a transient disruption of the default mode network (DMN.) This is a neural network in our brains that allows humans to associate self-referential thinking and the ego. In short, it is believed that our “ego” (sense of self) is the primary component of our waking consciousness. For most individuals, the “id” (the subconscious, instinctive component) lies buried in our minds while the DMN is functioning properly.

When certain psychedelics such as psilocin disrupt the two psychological components of the subject’s personality (the ego and the id,) the ego-dissolving and introspective nature of the experience fosters a sense of interconnectedness and altered perception of time. During and after the experience, the brain is more flexible and open to new perspectives and paths to psychological healing.

Conclusion

Understanding the molecular interactions of psilocybin with the receptors in our brain is essential for unraveling the mechanisms behind its psychedelic effects and therapeutic potential. Ongoing research in this field holds promise for the development of targeted treatments for mental health disorders and provides valuable insights into the complex interplay between neurotransmitter systems and neural circuits in the human brain during altered states of consciousness.

As the scientific community continues to delve into the intricacies of psychedelic pharmacology, a more comprehensive understanding of its effects on the human mind, brain, and body will likely emerge, paving the way for novel therapeutic applications and a deeper understanding of the mind-brain relationship.

If you have questions surrounding commercial fungiculture, feel free to reach out to our team. Whether you have experienced psychedelic-assisted therapy or are looking to design and build a commercial fungi facility — establishing a medicinal mycology business is a trip we’ll take together.

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