Protocols
Science-based tools and supplements that push the needle.
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Full Notes
Introduction to Psilocybin
- Psilocybin is a psychedelic that modifies the psyche and changes our level of consciousness
- Changes perception of the outside world and internal world, memories, thoughts, and feelings
- Can fundamentally change these aspects even after the psychedelic experience
- Growing excitement for its application in treating mental health issues like depression, alcohol abuse, addiction, OCD, and eating disorders
Other Psychedelics
- LSD, DMT, 5‑MeO-DMT, and MDMA (not a classic psychedelic but considered one in a general sense)
Therapeutic Approaches
- Proper psilocybin therapeutic approaches focus on the post-experience period
- Positive changes occur after the session, including hallucinations and changes in thought patterns
- Conditions during the psilocybin journey impact the therapeutic outcome (e.g., eyes open/closed, music played, dosage level)
Safety Issues and Considerations
- Young people (25 or younger) should consider their brain’s natural neuroplasticity before using psilocybin
- Dosages for those on antidepressants
- Risk for psychotic episodes for those with a propensity for psychosis or close family members with psychiatric conditions
Psilocybin and Serotonin
- Psilocybin is a tryptamine, closely resembling serotonin in chemical structure
- Serotonin is a neuromodulator, affecting the activity of other neurons and neural circuits
- Serotonin is involved in satiety, mood regulation, pleasure, motivation, and many other functions
- Serotonin receptors have various functions, including changing neuron activity, releasing growth factors, and altering gene expression
Psilocybin vs. SSRIs
- Psilocybin has shown to outperform standard therapy and SSRIs (Selective Serotonin Reuptake Inhibitors) in providing depression relief
- SSRIs increase serotonin transmission nonspecifically, leading to side effects and mixed results
- Psilocybin’s specific binding to the serotonin 2A receptor allows for more targeted effects
Key Takeaways
- Psilocybin’s chemical similarity to serotonin and its selective binding to the serotonin 2A receptor make it a promising therapeutic tool
- Its effects on mood, pleasure, and creativity are linked to its activation of the serotonin 2A receptor
- Understanding the serotonin 2A receptor and its role in neural circuitry is crucial for optimizing psilocybin’s potential benefits
Serotonin 2A Receptors and Psilocybin
- Serotonin 2A receptors are located in multiple brain regions, including the neocortex
- High expression in the prefrontal cortex, which is involved in understanding context and adapting behavior
- Also found in areas associated with sensation and perception, such as the visual cortex
- Psilocybin binds strongly to serotonin 2A receptors, causing visual hallucinations
- Hallucinations occur even when eyes are closed
Safety Precautions and Contraindications
- Psilocybin is not for everyone
- Contraindicated for people with existing or predisposition to psychotic episodes or bipolar episodes
- Having a first-degree relative with bipolar, schizophrenia, or schizotypal issues can be a rule-out condition
- Focus on adults (25 years or older) in clinical studies
Heroic Doses and Traditional Psychonauts
- “Heroic doses” are discussed in the informal community of psychonauts
- Difficult to translate this concept to scientific dataHeroic Dose of Psilocybin
- Refers to a 5‑gram dose of mushrooms, equivalent to 50 milligrams of psilocybin
- Concentration of psilocybin in different strains of mushrooms can vary greatly (0.5% to 2%)
- Sourcing and consistency are important for accurate dosing
- Synthetic psilocybin provides more consistent dosing
Safety and Precautions
- People prone to psychotic episodes or with a family history of psychosis should not take psilocybin
- Individuals under 25 years old should avoid psilocybin
- People taking antidepressants that impact the serotonin system should not take psilocybin without consulting a physician
Music in Psilocybin Journeys
- Not just an incidental feature, but a major driver of the cognitive and emotional experience
- Can impact emotion, thought processes, and the overall journey
- Selection of music should be carefully considered for the duration of the journey (4 to 6 hours)
Psilocybin Journey and Music
- Psilocybin journey lasts about 6 hours
- Begins 30–45 minutes after ingestion
- Peak experience with intense emotions and anxiety
- Gradual tapering off towards the 6‑hour mark
- Music played during clinical studies
- Matches and drives the contour of the psilocybin journey
- Starts with low volume, classical music without vocals
- Transitions to intense, high volume percussion music during peak experience
- Softens to choral or melodic music, often with female voices
- Ends with nature sounds and less synthetic elements
Cell Biology and Chemistry of Psilocybin Effects
- Psilocybin is converted to psilocin, which crosses the blood-brain barrier
- Psilocin predominantly activates the serotonin 2A receptor
- Serotonin 2A receptors are expressed on apical dendrites of pyramidal neurons
- These neurons communicate with other neurons in their environment
- Psilocybin increases lateral communication across brain areas
- Shift from a more modular, segmented brain to a more integrated, connected brain
- Reduction in hierarchical organization of the brain
- Sensory information flows more broadly through the thalamus
- More blending of different senses, including interoception (sense of the body and its internal state)Psilocybin and Creativity
- Serotonin 2A receptor activation allows for broader, less precise, and less hierarchical activation of brain circuitry
- This can lead to blending of senses and experiences (e.g., sound linked to visual phenomena)
- Four prominent theories of brain networks activated during a psychedelic journey:
- Changes in the Default Mode Network (responsible for spontaneous imagination and daydreaming)
- [Other three theories not mentioned]
- These theories are not competing; all have been shown to be true in different studies
- Controversy lies in which network changes the most to explain therapeutic outcomes
Functional Connectivity and Psilocybin
- Psilocybin expands the functional connectivity of the brain
- This expanded connectivity persists after the effects of psilocybin have worn off
- Study: “The Effects of Psilocybin and MDMA on Between-Network Resting State Functional Connectivity in Healthy Volunteers”
- Conducted by Robin Carhart-Harris at UCSF
- Explored brain connectivity in healthy volunteers before and after taking psilocybin or MDMA
- Found more extensive connectivity, pointing to enhanced lateral connectivity and less hierarchical organization
- Adaptive rewiring of the brain is the goal of effective psychedelic therapies
- Psilocybin does not seem to cause long-term issues with memory
Psilocybin and Creativity: Music Perception
- Study: “Increased Low-Frequency Brain Responses to Music after Psilocybin Therapy for Depression”
- Took advantage of music being played during therapeutic psilocybin sessions
- Different types of music activate different brain areas (e.g., auditory cortex, ventral striatum, mesolimbic reward pathway)
- Music can be broken down into high and low frequencies
- Psilocybin may enhance the brain’s response to music, potentially increasing creativity and the experience of life outside of psychedelic journeysEffects of Psilocybin on Music Perception and Emotion
- Psilocybin changes one’s experience of music, not just during the journey, but also thereafter
- Increases positive emotions associated with music
- Diminishes the sadness of music that tends to make one sad
- Study found that psilocybin rewires connections between emotion centers in the brain and networks controlling auditory perception of music
- Allows people to experience joy in response to music again
- Reduces the capacity of sad music to make them feel sad and depressed
Key Experiences During a Psilocybin Journey
- Common phrases: letting go, ego dissolution, feelings of connectedness
- Scientific studies have explored subjective experiences that relate to positive therapeutic outcomes
- Enhanced feelings of connectedness
- Dissolution of the ego, loss of one’s sense of self, and regaining of one’s sense of self
- Studies use rating scales to measure and compare experiences between different groups and studies
- Possibility of having a frightening or negative experience during a psilocybin journey
- Important to consider and understand the risks and potential negative outcomes associated with psilocybin use
Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression
- Study involved subjects undergoing two psilocybin sessions
- First session: 10mg of psilocybin (equivalent to 1g of psychedelic mushrooms)
- Second session: 25mg of psilocybin (equivalent to 2.5g of psychedelic mushrooms)
- Subjects answered the Altered States of Consciousness Questionnaire
- Addressed the quality of experiences in the 25mg psilocybin session
- Key feature of a positive psychedelic experience: sense of oceanic boundlessness
- Feeling of massive connectedness with one’s environment, guides, oneself, past, present, people outside the room, the entire world, and maybe even the universe
Correlation between Experience and Therapeutic Outcomes
- Positive therapeutic outcomes (relief from major depression) correlated with:
- Strong experience of unity
- Spiritual experience
- Blissful state
- Insightfulness
- Non-responders (no relief from depression) reported:
- Less experience of unity
- Less spiritual experience
- Less blissful state
- Less insightfulness
Potential Real-Time Tools to Adjust Anxiety
- Dr. Matthew Johnson at Johns Hopkins is exploring the use of real-time respiration tools (breathing tools) to help adjust anxiety levels during psychedelic sessions
- Based on work in Dr. Andrew Huberman’s laboratoryDr. David Spiegel’s Laboratory and Physiological Psy
- Reduces anxiety quickly in real time
- Demonstrated in previous podcasts and a recent paper in Cell Reports Medicine
- Collaborative work with Dr. David Spiegel’s laboratory at Stanford School of Medicine
- One of the fastest and most effective ways to reduce autonomic arousal (anxiety or stress)
- Used in Dr. Matthew Johnson’s laboratory during psychedelic sessions to help participants self-direct their own calm
Therapeutic Use of Psilocybin: Practical Considerations for Dosing and Administration
- Paper goes through pharmacology of psilocybin, dosage, and administration
- Discusses contraindications, such as pregnancy, breastfeeding, and predisposition to psychosis
- Evidence for positive therapeutic outcomes:
- Strongest for cancer-related depression, cancer-related anxiety, and treatment-resistant depression
- Moderate for alcohol use disorder, tobacco addiction
- Least for obsessive-compulsive disorder, cluster headaches, migraines, and demoralization due to AIDS diagnosis
Psilocybin Dosages in Animal Studies
- Mouse studies often use high doses of psilocybin (1 mg/kg body weight)
- Equivalent to double or triple the human therapeutic dose
- Animal metabolism and difficulty in observing effects may contribute to higher doses
Therapeutic Use of Psilocybin
- Strongest evidence for treating major depression and intractable depression
- Clinical trials exploring psilocybin’s impact on mood disorders and addictive disorders
- Researchers pioneering legal, funding, and research efforts
- Robin Carhart-Harris, Matthew Johnson, Roland Griffiths, Nolan Williams, and others
Psilocybin Clinical Trials
- Around a dozen clinical trials exploring single or two-session psilocybin treatment (25–30mg range)
- Comparisons of psilocybin vs SSRIs or other antidepressants
- Comparisons of psilocybin plus psychoanalysis or cognitive behavioral therapy vs therapy alone
- 60–75% of people with major depressive disorder report positive relief from depression with psilocybin
- Combined with proper therapeutic support, psilocybin produces large, rapid, and sustained antidepressant effects
- Effect sizes 2.5 times greater than psychotherapy and 4 times greater than psychopharmacologic depression treatment studies
- Combining drug therapy with talk therapy is more effective than either treatment alone
Understanding Psilocybin’s Effects
- Serotonin and activation of serotonin 2A receptor play a significant role in psilocybin’s effects
- Associated with the expansion of the neocortex across evolution
- Psilocybin journey can lead to enhanced ways of thinking, changed ways of thinking, and actual learning within the session
- Potential for psychedelics like psilocybin to provide relief for mental health issues that have been difficult to access
- Fundamental interest in understanding the brain, how it works, and how it can change through neuroplasticity
Neuroplasticity and Psilocybin
- Neuroplasticity: the Holy Grail of the human nervous system
- Humans have long-lasting neuroplasticity throughout their lifespan
- Psilocybin: potential to achieve maximal plasticity in a short amount of time
- Must be used safely and with caution
- Not recommended for those with predisposition to psychosis or bipolar disorder, or with a family history of these conditions
- Not recommended for individuals 25 years of age or younger
- Should only be used under the guidance of a dedicated and highly trained physician
- Psilocybin is an exciting and promising compound, but still in a preliminary stage
- Future episodes will revisit psilocybin and other psychedelics, including LSD, DMT, 5‑MeO-DMT, ketamine, MDMA, and mescaline
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