Pam Conboy
In Part 2 of this series, I will be diving into the neurobiological mechanisms of psilocybin, or more accurately, its active metabolite: psilocin. We will explore how psilocybin is converted to psilocin in the body and how that active ingredient, along with a host of other biologically active molecules, serves to induce neuroplasticity, reduce neuroinflammation, balance neurotransmitters, and contribute to a host of other whole health-supportive benefits.
Psilocybin to Psychedelic | Prodrug to Active Compound
Psilocybin occurs naturally in so-called “magic” mushrooms. It is, however, classified as a biologically inactive “pro-drug”– one that is converted into an active drug via human metabolic processes. Although Psilocybe cubensis is far and away the most common psilocybin-containing species, there are many others. Indeed, the various strains of P. cubensis themselves have quite unique personalities: a deeply interesting discussion better left for a future article.
Today, I’ll speak in more general terms about how psilocybin is converted to its active metabolite and how that metabolite and other fungi components interact with the human brain and body to positively impact our mental processes and overall wellness.
The Biochemistry
This section is a bit on the nerdy side, but it serves to illustrate how our bodies metabolize psilocybin into psilocin. For those of you with an interest in biochemistry, links for additional reading are included throughout.
Dephosphorylation
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The psilocybin molecule (4-phosphoryloxy-DMT) is rapidly stripped of its phosphate group after ingestion, a process which is catalyzed by enzymes (alkaline phosphatase and other esterases) in the liver and the small intestinal tract lining. The resulting compound is psilocin (4-hydroxy-N, N-dimethyltryptamine or 4-HO-DMT). For a deep dive into this biochemical cascade, I refer you to: In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin.
Psilocin is structurally similar to serotonin, or 5-hydroxytryptamine (5-HT), our primary calming neurotransmitter. Although the serotonergic pathways explain much of its effect, it is not the only tool in the toolbox.
Key Psilocin Mechanisms: N3
Neurotransmitters.Neuroplasticity.Neuroinflammation
The psilocin molecule fits like a key in receptors for serotonin (5-HT), which is the same target for many antidepressant medications (e.g., selective serotonin reuptake inhibitors, or SSRIs). Psilocin has a particular affinity for 5-HT2A receptors, which dominate in the executive functioning area of the brain, the prefrontal cortex. Once bound, psilocin activates the receptors, increasing the excitability of brain cells, especially pyramidal neurons, which shift functional connectivity in the brain. One of the primary networks impacted is the Default Mode Network (DMN), which is associated with introspection, rumination (negative thought loops), and self-referential thinking. Psilocin acts to decrease DMN activity and increase a state of neural entropy, which can lead to the feeling of ego dissolution, enhanced feelings of connection, and a higher level of processing flexibility, allowing for release from “stuck” thought patterns.
Psilocin-bound serotonin receptors also facilitate the release of glutamate (GLU) and downstream release of gamma-aminobutyric acid (GABA). Increased GABA reduces stress and anxiety and is thought to play a foundational role in psilocin’s anti-depressive effect. Psilocin’s interaction with the glutamatergic (GLU) pathway also encourages new brain cell growth and connectivity (neuroplasticity) via elevated brain-derived neurotropic factor (BDNF) production.
Psilocin is also able to modulate dopamine, our primary reward neurotransmitter. This activity can play a significant role in mitigating depressive symptoms and potentially resetting dysfunctional reward circuits in the brain, which is thought to be a key mechanism for the successful disruption of addictive behaviors.
As mentioned above, psilocin influences our GABA neurotransmitter pathways, resulting in increased brain-derived neurotropic factor: the growth elixir for our brains. The resulting neurogenesis (new brain cells), synaptogenesis (new brain cell connections), and dendritogenesis (new brain cell branches which strengthen connections) are collectively referred to as neuroplasticity. Enhanced neuroplasticity is an integral component of the cognitive shifts that result from a psilocybin/psilocin experience.
Psilocin-induced neuroplasticity offers a root cause approach to addressing common mental health challenges, including depression, anxiety, trauma, and addiction, in addition to other neurocognitive disorders. Because the brain is a highly metabolically demanding organ, efficiency is its go-to. Habitual patterns of thinking can therefore become rigid and intransigent: not a good situation if you are stuck in chronic ruminative thinking and post-traumatic stress. It is well established that individuals suffering from these conditions are impacted by deleterious changes in neuroplasticity and functional connectivity, which work to keep them stuck in negative thought loops. Fortunately, psilocin can help break up those entrenched neural pathways that do not serve us and lay the foundation for new connections, insights, interpretations, and outlook. Since the FDA’s designation as a breakthrough therapy for depression (2018, 2019), scientific investigation into these areas has skyrocketed in our most prestigious universities–clearly demonstrating the therapeutic promise. An overview of the research to date will be the topic of my next article.
As we now understand, chronic inflammation is a causal component of essentially all chronic diseases, including neurocognitive disorders and mental health challenges such as depression.
Microglia are the heavy lifters of the immune defense network for the central nervous system, including the brain, and play a direct role in the modulation of neuroinflammation. These cells maintain neural networks, repair injury, and regulate brain development overall. Recent research has demonstrated that psilocin reduces inflammatory signals and facilitates microglia in their neuroimmune maintenance (e.g., clearance of harmful substances and cytokines [pro-inflammatory proteins] such as tumor necrosis factor alpha [TNFɑ] and interleukin-6 [IL-6], as well as cytotoxins, including reactive oxygen species [ROS] and nitric oxide [NO]). Moreover, the unique properties of psilocin in support of microglia activity highlight its potential efficacy as a therapeutic agent for neurocognitive disorders such as Alzheimer’s Disease and Parkinson’s Disease, Huntington’s Disease, and others.
But Wait – There’s More
In addition to all the magical mechanisms outlined above, benefits are multiplied with whole, organic psilocybin-containing mushrooms. The fruiting body of these mushrooms contains a wealth of health-promoting constituents that I would be remiss not to mention here.
These complex carbohydrates are a component of fungal cell walls, which offer both supportive immunomodulatory and anti-inflammatory effects. They enhance adaptive immune response (e.g., stimulation of immune system cell activation, including macrophages, natural killer [NK] cells, and dendritic cells) and protect against cardiovascular disease and cancer cell proliferation. Moreover, the insoluble fiber is a robust source of prebiotic sustenance for a healthy gut microbiome.
Similar to beta-glucans, the polysaccharide chitin and chitosan found in fungi cell walls act as a prebiotic to support digestion and gut motility, as well as binding to dietary fat to promote excretion while supporting a feeling of fullness (satiety)–a great tool for any weight loss program.
One of the most compelling non-psychedelic, health-promoting components of mushrooms is the highly bioactive terpenes and terpenoids they contain. These substances have been found to offer antioxidant, anti-inflammatory, antitumor, antiviral, and antimicrobial activity. In the context of this discussion, however, their efficacy in countering neurodegenerative diseases is of primary interest.
Mushrooms are truly nutritional powerhouses, including vitamins, minerals, antioxidants, micronutrients, phenols, flavonoids, organic acids, biological catalysts, and many others. Although a thorough discussion of the pro-health constituents is beyond the scope of this article, you may click the link above to dive more deeply.
Coming Next
In the next two articles in this series, I will explore the psilocybin research landscape in the United States presently and what lies on the horizon. We will investigate the leading research institutions as well as some of the most exciting therapeutic foci, including: treatment-resistant depression, anxiety, ADHD, PTSD, addiction, Alzheimer’s disease, Parkinson’s disease, and other neurocognitive disorders. I think you’ll be amazed!
Pam Conboy has an undergraduate degree in biology and began her career in medical technology(clinical laboratory). A certified IIN health coach, she is currently completing a non-US-accredited doctoral degree in naturopathic medicine. Pam has worked most of her career in medical marketing in both conventional and integrative channels.
