Molecules: Psilocybin

August 01, 2023

Molecules: Psilocybin

KNOW THE MOLECULES

Here is a brief overview of some key psychedelic tryptamines:

Psilocybin - The main psychoactive compound in magic mushrooms. Produces mystical-type experiences, euphoria, altered thinking and perception of time. Found naturally in various mushroom species.
DMT (N,N-Dimethyltryptamine) - A powerful psychedelic compound found in many plants and animals. Produces intense, short-lived psychedelic effects when smoked, injected or consumed orally with an MAOI. Endogenously produced in small amounts in the human body.
5-MeO-DMT - A potent psychedelic tryptamine found in various plants and in the Sonoran desert toad. Causes mystical experiences, ego dissolution and strong physical effects when smoked.
Ibogaine - A psychedelic found in the iboga plant. Used to treat addictions and trauma. Causes visions, introspection and can last up to 24 hours. Illegal in some countries.
AMT (alpha-methyltryptamine) - A synthetic psychedelic and entactogen related to DMT. Produces LSD-like psychedelic effects lasting 6-10 hours. Originally developed as an antidepressant.
5-HO-DMT - The active psychedelic in various plants like Virola. Also found in bufotenin-containing toads. A potent and fast-acting tryptamine sometimes called the "God molecule."
4-AcO-DMT - A semi-synthetic psychedelic prodrug of psilocin and analog of psilocybin. Reportedly similar effects to magic mushrooms but more potent.

The tryptamine psychedelics share similarities but produce unique psychoactive effects ranging from mystical to entheogenic to recreational. Most act as serotonin receptor agonists.

1. Psilocybin

There are a few key ways psilocybin-containing mushrooms are believed to "free the mind":

Altering brain network connectivity - Psilocybin disrupts entrenched patterns of brain activity and increases flexibility, helping break cognitive and emotional ruts.
Dampening ego/default mode network - Quieting the dorsomedial prefrontal cortex reduces the influence of the ego, allowing more unconstrained cognition.
Changing perspective - Users experience fresh perspectives, mental agility and novel thoughts, allowing more open worldviews.
Loosening cognitive filters -Psilocybin disables certain cognitive filters that constrain imagination and mental constructs. Thinking becomes more unbounded.
Flexible attention - Users can rapidly shift attention between different subjects and perspectives, seeing connections.
Enhanced imagination - Visualization, divergent thinking and ideation are enhanced as executive control is relaxed.
Emotional release - By bringing subconscious feelings/fears to the surface, psilocybin allows cathartic emotional releases.
Sense of expanded consciousness - Users feel elevated beyond ordinary consciousness, providing a broader vantage point.
Mystical awareness - Some experience a sense of sacred interconnectedness and unity that transcends ego boundaries.

By recalibrating brain networks, psilocybin seems to unleash cognition and perception from their usual neurologic constraints, enabling refreshing new insights and outlooks for many users. The mind feels more free.

Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms. Some key facts about psilocybin:

It is a prodrug that gets converted into the active compound psilocin in the body. Psilocin produces the psychedelic effects.
Chemically, it is a tryptamine compound, specifically 4-phosphoryloxy-N,N-dimethyltryptamine.
It acts as a serotonin 2A receptor agonist, producing alterations in perception, mood, and cognitive processes.
Psilocybin was first isolated from Psilocybe mushrooms in 1958 by Dr. Albert Hofmann.
It produces effects similar to LSD but shorter-acting, lasting about 4-6 hours.
Common effects include euphoria, visual and auditory hallucinations, spiritual experiences, synesthesia, changed sense of time.
It occurs naturally in over 200 species of mushrooms, commonly known as "magic mushrooms" or "shrooms."
Psilocybin mushrooms have been used for centuries for religious, divinatory, and healing purposes by indigenous cultures.
Recent research indicates psilocybin may have therapeutic potential for depression, anxiety, addiction, and other conditions.

Magic mushrooms have a vast molecular profile. Psilocybin is only one found in them. They have done studies where they have blocked psilocybin in mushrooms and looked at the brain and it behaves differently even without psilocybin. The mushrooms work in the brain in many ways we have not discovered.

There are no known overdoses from magic mushrooms. People have taken up to 64 grams and not overdosed. The molecule itself is being patented in different forms; changing a bond here and there. As a patented substance psilocibyn is tracked to be a breakthrough for treatment resistant depression. That should happen by the FDA in the next 3-4 years if all the studies come back they way they are expected.

Tryptamines are a family of psychedelic compounds that share a similar chemical structure to the neurotransmitter serotonin. Here are some key facts about tryptamines:

Chemically, they contain a tryptamine core structure, which is made up of an indole ring attached to an ethylamine group.
Many, but not all, tryptamines act as serotonin receptor agonists, particularly at 5-HT2A receptors.
They are derived from the amino acid tryptophan and biosynthesis involves the amino acid decarboxylase enzymes.
Tryptamines are widespread throughout nature and found in plants, animals, fungi and microbes.
Well-known tryptamines with psychedelic effects include psilocin and DMT. Others like melatonin are hormones.
Common effects of psychedelic tryptamines include visual hallucinations, changes in sensory perception, euphoria, mystical experiences, ego dissolution.
Some tryptamines like bufotenin and DiPT act as serotonin reuptake inhibitors rather than direct agonists.
Synthetic tryptamines have also been developed such as the psychedelic AMT and recreational 5-MeO-AMT.
While chemically similar, each tryptamine produces distinct psychoactive properties depending on its specific pharmacological activity.

In summary, tryptamines are a large class of compounds derived from tryptophan with a range of functions, but many act as potent serotonergic psychedelics with mind-altering effects. Exploring tryptamine chemistry and neuropharmacology continues to reveal therapeutic insights.

When Psilocybin reaches the brain is is mostly psilocyn (the little Phosphorus is stripped off). Notice the similarities between psilocybin, DMT, 5-MeO-DMT, LSD. DMT is very similar to serotonin. DMT is in your brain. It is found in the neurons. The actual matter of your brain is the neurons themselves and DMT is all in the inner cells, but to be a neurotransmitter they have to find it in the synaptic cleft (between cells). It has to get out of the cells to be in between the cells to be transferred. DMT is not usually found in the synaptic clefts, it is found in the neurons. So we are looking at: when does it leave the cell, under what conditions. It has been found to leave under transcendent experiences, NDE, while dreaming.

DMT binds to the 5HT receptors and activates the psychedelic related signaling.

Here are some general dosage guidelines for psilocybin:

Threshold dose - 0.2-0.5 g dried mushrooms. Mild effects but no hallucinations. Good starter dose.
Light dose - 0.5-1 g dried mushrooms. Some sensory changes without compromising ability to move around.
Moderate dose - 1-2 g dried mushrooms. Altered headspace, vibrant visuals, mood lift, incapacitation.
Strong dose - 2-3 g dried mushrooms. Strong hallucinations, mystical effects, ego dissolution. Use caution.
Heavy dose - 3-5+ g dried mushrooms. Complete disassociation from reality possible. High risk of bad trips.
Microdose - 0.1-0.3 g dried mushrooms. Sub-perceptual but may boost creativity, mood. Take every 3 days.
Tea/tincture - Can reduce nausea but come on faster. Dose about 20% less compared to eating mushrooms.
Individual sensitivity varies - Best to start low and incrementally increase dosage to find sweet spot.
Space out trips - Tolerance builds quickly. Leave 2-4 weeks between sessions to reset.

Proper dosing of psilocybin requires knowing the mushroom potency, your own tolerance, and carefully titrating over time for desired effects. Responsible use requires patience.

Here is a brief overview of how psilocybin works in the brain and body:

Absorption: When psilocybin mushrooms are ingested, the psilocybin is absorbed through the stomach and intestine.
Metabolism: In the liver, psilocybin is quickly metabolized into the active compound psilocin.
Blood-brain barrier: Psilocin easily crosses the blood-brain barrier and reaches the central nervous system.
Serotonin receptor binding: Psilocin has a similar structure to serotonin and acts as a partial agonist for several serotonin receptors, primarily 5-HT2A receptors. It fits into the receptor sites and mimics serotonin effects.
Neuronal excitability: Activation of 5-HT2A receptors triggers a signaling cascade that increases neuronal excitability and alters activity in key brain networks involving the frontal cortex, limbic system, and visual areas.
Psychedelic effects: This altered neuronal activity produces changes in mood, perception, cognition, sense of self, and overall consciousness. Users experience visual hallucinations, psychological insights, mystical states, creativity, and more.
Metabolism & excretion: The psychedelic effects last 4-6 hours until psilocin is broken down by the liver enzyme MAO and excreted out of the body through urine.

In summary, when ingested, psilocybin enters the brain where it mimics serotonin and causes temporary changes in brain signaling and activity. This induces an altered state of consciousness known as a psychedelic "trip".

Higher goverening systems is referring to the prefontal cortex. Everything that makes humans humans is in the pre-frontal cortex. Tryptamines love the prefrontal cortex. There are tons of 52HT (seratonin) receptors in the prefrontal cortex. They are primary there. Psilocybin will link to these receptors to create a disorganized firing pattern in the brain. The prefrontal cortex does not know what to do with that pattern. It can't take the pattern and use it to govern the systems of the brain because it does not know what the patterns mean. So, they disconnect and stop functioning and pressing the lower systems in the brain. When that happens the limbic system, the ancient brain deep inside the center of your head where memories and emotions are stored. Long term filing system. When that system is released because the governing systems can't suppress it, it gets to upload the higher systems with all this beautiful ancient wisdom of the collective unconscious. Generational, epigenetic and trauma...in our DNA we get coded with ancient codes. It is the codes of our ancestry.

When we take them the limbic opens and really gets to upload into the frontal cortex all these new constructs. At the same time that is happening you get a neuroplastic effect. Dendritogenesis is the word that describes what is actually happening to create neuroplastic effect. The neurons, the cells themselves, in the prefrontal cortex is....as the limbic system is uploading information. A beautiful epigentic thing happens where instructions are given to the neurons to grow single cell threads. Very tiny delicate threads a lot like mycillium. They branch out from the neurons and start to spread horizontally. So, the limbic system wakes up and it sends signals to the neurons in the prefrontal cortex and those neurons just spread threads all through out the prefrontal cortex and interconnect.

These new connections can be kept or reabsorbed. You can utilize them or let them go to waste. The way we utilize them is by integrating, giving them energy. We literally feed them energy with glucose from the blood. Every time we use them we teach the brain to keep them.

Psilocin is the primary psychoactive compound in magic mushrooms. It is structurally similar to serotonin and acts as a partial agonist on 5-HT2A receptors.

5-HT2A receptors are located on the dendrites of pyramidal neurons and are key mediators of cortical excitability. When psilocin binds to these receptors, it mimics the effects of serotonin and triggers a cascade of intracellular signaling.

Specifically, psilocin binding causes the G-protein coupled 5-HT2A receptors to activate phospholipase C, which cleaves PIP2 into IP3 and DAG. IP3 causes the release of calcium from intracellular stores, while DAG activates protein kinase C.

This enhanced signaling via the phospholipid pathway leads to increased neuronal excitability and alters the information processing in the cortex. Downstream effects include visual hallucinations, changes in sensory perception, mood elevation, cognitive alterations, and mystical-type experiences.

The psychedelic effects of psilocin result from its agonist activity at 5-HT2A receptors and the subsequent stimulation of phospholipase C signaling. This produces profound changes in cortical activity and subjectivity. The effects typically last 4-6 hours before psilocin is metabolized and excreted.

This is what it looks like between the neurons and the synaptic cleft. Neurons in the brain are separated by gaps called the inter synaptic cleft. The neurotransmitters (VMAT2) is a protein. It attached to a vesicle (bubble in the neuron), lets out the neurotransmitters (5HT) to move to the edge of the cell to SERT. SERT will mediate whether or not neurotransmitters can come into the cell and the bubble just merges to the end of the cell and release the neurotransmitter.

On the other side is a receiving end neuron (axon). The neurotransmitters link to those proteins (5HT2a proteins). The red is psilocybin. The blue is serotonin. When you have psilocybin in the synaptic cleft it will link to the same neuron that serotonin links to. There is a misconception that psilocybin increases synaptic serotonin, it doesn't do anything to the serotonin. It only links to the receptor.

There are cascading effects, but no direct affects of psilocybin on serotonin.

Psilocybin is a potent psychedelic compound that must be used responsibly and carefully. Here are some guidelines for proper use:

Use in a safe, comfortable environment - Ideally at home or in nature, with soft lighting and minimal disruptions. Have a trusted, sober guide if taking a high dose.
Start low, go slow - Begin with a modest dose (0.5-1g dried mushrooms) to assess sensitivity. Increase slowly over time. Doses over 3g are considered high.
Proper set and setting - Mindset and environment greatly influence the experience. Be in a stable frame of mind before taking psilocybin.
Avoid mixing with other drugs - Interactions with antidepressants, cannabis, and other substances can be unpredictable.
Respect the mushroom - Treat psilocybin mushrooms as a teacher plant that can provide healing or spiritual insights when used wisely. Stay hydrated and focused.
Practice safety - Since psilocybin can impair judgment, avoid hazardous activities or going out in public while under the influence. Have a trip sitter.
Integrate the experience - Reflect on your journey afterward through meditation, journaling or creative activities. Implement any insights into daily life.
Allow tolerance - Space out uses to 1-2 weeks minimum for the body to reset tolerance. Frequent use dulls effects.

With careful intention and planning, psilocybin can be an enlightening tool for personal growth. But respect its power and use discretion to minimize any risks.

There is not a ton of data about how to take psilocybin, but these above work to shorten onset and intensity. Tea takes it out of the molecular profile of the mushroom and puts it in water, and drinking it makes it go through the system quicker. The citrus strips of the phosperos and makes it work faster as well. It is metabolized in the liver and elimated by the kidney. This is important to know.

Users of psilocybin mushrooms often report having profound mystical or spiritual experiences. Some common features of these mystical-type experiences include:

Feeling of unity or interconnectedness - A dissolving of boundaries between the self and external world. A sense of merging with nature, others, or the universe.
Sacredness or awe - Deep feelings of reverence, amazement, humility and wonder at the profound mysteries of existence.
Transcendence of time and space - The normal constraints of time and space are loosened; experiencing visions of future or past events.
Ineffability - Difficulty articulating or describing the experience in words. Feelings of being in touch with a greater intelligence.
Paradigm shift - Radically shifted perspectives or worldviews regarding life, death, reality, human consciousness. Seeing the world in a new way.
Intuitive insights - Gaining sudden intuitive realizations about life's big questions or one's personal issues. Deeper understanding of self.
Ego dissolution - The normal sense of self and personality melts away. Often leads to feelings of rebirth, renewal, and interconnectedness.
Feeling of sacredness - Even ordinary objects or events take on a deep spiritual significance or energy.

While the exact nature varies considerably, mystical-type experiences are reported across cultures and eras among users of psilocybin as well as other psychedelics like LSD or DMT. They are often described as highly meaningful.

Facilitators or guides play an important role in providing safe and nurturing environments for people having psilocybin experiences. Here are some key responsibilities:

Set and setting - Help create a comfortable, inviting space. Ensure the user feels at ease and supported. Provide soft lighting, peaceful music, comfy seating.
Emotional support - Be a grounded, caring presence. Reassure the user during challenging moments. Validate emotional responses.
Physical safety - Protect the user from harming self or others. Gently redirect from hazardous behaviors. Ensure proper hydration/nutrition.
Remain sober - Refrain from consuming psilocybin to monitor the user's state and meet needs. Be clear-headed.
Active listening - Allow the user to articulate the experience without judgment. Ask open-ended questions if appropriate.
Trust in the process - Understand that difficult phases are often part of the journey. Allow the experience to unfold organically.
Integrate experiences - Discuss insights gained after the effects have subsided. Help incorporate lessons into daily life.
Confidentiality - Respect privacy and maintain confidentiality regarding the session details.
Prepare information - Educate user beforehand on the range of possible effects. Share coping strategies.

With training and compassion, facilitators can provide users with inner travels that are profoundly meaningful and psychologically beneficial.

Psilocybin can have therapeutic benefits even without inducing full-blown mystical experiences:

Mood enhancement - Many users report pronounced improvements in mood, optimism and sense of well-being, even from lower doses.
Creative thinking - Psilocybin is shown to enhance divergent thinking, imagination and problem-solving, expanding perspectives.
Personal insights - Can catalyze new self-awareness around relationships, habits, emotions without a "mystical" trip.
Appreciation - Often leads to greater appreciation of life, nature, loved ones, arts, and a curiosity for new experiences.
Behavior change - Some adopt healthier lifestyles after using psilocybin due to shifted outlooks or priorities.
Depression/anxiety relief - Low doses may lift mood and reduce anxiety by altering brain networks temporarily.
Connection - Can make people feel more connected with humanity, nature, or spirituality without profound mysticism.
Neuroplasticity - May stimulate growth of new neural connections that persist beyond the trip.
Overview effect - Some get a broadened cosmic perspective on life on Earth without deep mystical renewal.
Microdosing - Sub-perceptual doses may improve wellbeing, creativity, focus when taken regularly.

While mystical trips can be insightful, not everyone needs or desires such intense experiences. Mild psychedelic effects of psilocybin alone may improve mental health.

Psychedelic states induced by psilocybin are often described as "non-literal" experiences, meaning they do not correspond directly to physical reality. Here are some key reasons why they are considered non-literal mental states:

Hallucinations - Users frequently report seeing, hearing and feeling phenomena that are not objectively real, such as geometric visuals, perceived energy fields and synesthesia.
Dreamlike cognition - Thought patterns become less logical and dominated more by loose associations, imagination and symbolic thinking reminiscent of dreams.
Metaphorical thinking - Users understand their thoughts and visions are symbolic representations of feelings and abstract concepts rather than actual things.
Non-rational insights - Feelings of intuitive epiphanies, precognition or communicating with spirits reflect accessing cognitive domains separate from rational analysis.
Sense of self - The breakdown of ordinary ego boundaries can feel like merging into a collective consciousness or abandoning a literal individual self.
Ineffability - The inability to accurately describe or contextualize the experience in concrete terms indicates it transcends literal language and meaning.
Transformative - By showing reality can be perceived in profoundly different ways, users often feel psilocybin reveals the constructivist nature of normal consciousness.
Temporary effects - The non-literal experiences reliably give way to baseline perception of physical world again, confirming their subjective quality.

So while felt as powerfully meaningful, the psychedelic headspace induced by psilocybin is recognized as an alternate mode of consciousness distinct from everyday material reality.

Here are some recent studies that demonstrate psilocybin's potential to help with certain mental health conditions:

Depression - Several trials have found psilocybin (along with therapy) quickly reduces depression symptoms for up to several months after treatment.
Anxiety - Studies show psilocybin decreases anxiety in cancer patients and those with life-threatening diseases leading to improved quality of life.
Addiction - Small studies indicate psilocybin can help break addiction, increase abstinence, and reduce cravings from tobacco, alcohol and opioids.
OCD - A small pilot study in 2021 found psilocybin helped reduce OCD symptoms significantly for people with treatment-resistant OCD.
PTSD - Researchers found marked improvements in PTSD patients after MDMA-assisted therapy, with ongoing trials using psilocybin.
Eating disorders - An open-label study in 2021 reported psilocybin contributed to full or partial remission of eating disorder symptoms for most participants.
Existential distress - Studies show psilocybin can decrease anxiety, depression, hopelessness, and demoralization in terminal illness patients.
Cluster headaches - A few reports demonstrate psilocybin eliminating chronic cluster headaches where other treatments failed.

While still early, these promising results justify continued research into psilocybin as an adjunct treatment for an array of mental health conditions that are often resistant to standard therapies.

Here is a quick overview of some ongoing studies investigating psilocybin:

Psilocybin for treatment-resistant depression - Large randomized trials by Compass Pathways, Usona Institute, Imperial College London.
Psilocybin-assisted therapy for anxiety, depression - Research by Johns Hopkins, NYU, Mount Sinai Health System.
Neuroimaging studies on effects of psilocybin - Brain scanning research at Imperial College, Yale.
Psilocybin for smoking cessation - Pilot studies at Johns Hopkins, University of Alabama.
Microdosing psilocybin for cognitive enhancement - Studies by Imperial College, University of Toronto.
Psilocybin for alcohol use disorder - Trial by NYU and University of New Mexico.
Psilocybin for obsessive-compulsive disorder - Study by University of Arizona.
Psilocybin for anorexia nervosa - Feasibility study at Johns Hopkins.
Psilocybin for cluster headaches - Research by Yale, Harvard, and King's College London.
Psilocybin for palliative care - Studies at Johns Hopkins, NYU.
Safety, pharmacology, mechanism of action - Ongoing work by institutions like NIMH, University of California.

This psychedelic renaissance is generating valuable evidence on psilocybin's therapeutic mechanisms and safety profile to support its potential medical use. More rigorously designed clinical trials are underway.

Psilocybin use is not recommended for certain individuals or situations given the potential risks:

Those under 18 or 21 - The developing adolescent brain may be more vulnerable to negative impacts. Psilocybin use should be postponed until adulthood.
History of serious mental illness - People with schizophrenia, bipolar disorder, severe depression may worsen symptoms or have adverse reactions.
Psychosis risk - Individuals with a family history of psychotic disorders should avoid use due to increased vulnerability.
Medication interactions - Psilocybin can interact dangerously with SSRIs, MAOIs, lithium and other psychiatric medications.
Pregnancy/breastfeeding - Potential risks to fetal or infant development have not been sufficiently studied, so it is best avoided.
High blood pressure or heart conditions - Psilocybin elevates blood pressure and heart rate, which could be dangerous.
During emotionally difficult periods - Use during times of life crisis or severe stress can exacerbate issues or cause bad trips.
Lack of preparation - Proper set and setting essential for safe, productive trips. Use should be carefully planned.

While a powerful tool, psilocybin use requires caution. Those with pre-existing medical/mental health conditions or in vulnerable life stages should abstain or seek medical advice before considering use.