How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks
Andrew Huberman explores psilocybin's chemistry, neural mechanisms, and neuroplasticity. He discusses its clinical use for depression and addiction, emphasizing set, setting, dosage, and critical safety precautions.
Deep Dive Analysis
17 Topic Outline
Introduction to Psilocybin and its Therapeutic Potential
Psilocybin's Chemical Structure and Serotonin Mimicry
The Serotonin 2A Receptor: Psilocybin's Primary Target
Serotonin 2A Receptor Location and Visual Hallucinations
Safety Considerations and Contraindications for Psilocybin Use
Psilocybin Dosing: Mushrooms to Milligrams and Microdosing
The Importance of Set, Setting, and Support in Psychedelic Journeys
Music's Critical Role in Shaping the Psilocybin Experience
Subjective Experiences: Perceptual Blending and Synesthesia
Neural Circuit Changes: Reduced Modularity and Increased Connectivity
Psilocybin's Impact on Creativity and Emotional Response to Music
Psilocybin as a Neuroplasticity 'Wedge' for Adaptive Change
Key Subjective Experiences: Oceanic Boundlessness and Ego Dissolution
Managing Anxiety During a Psilocybin Journey
Structural Brain Changes: Dendritic Spine Growth and Neuroplasticity
Clinical Trial Evidence for Psilocybin in Depression Treatment
Comparing Psilocybin Therapy to SSRIs and Psychotherapy
8 Key Concepts
Tryptamine Psychedelics
Psilocybin and related psychedelics like DMT are tryptamines, meaning they share a similar chemical composition. They closely resemble serotonin, a natural neuromodulator in the brain and body.
Serotonin 2A Receptor (5-HT2A)
This is the primary receptor that psilocybin (specifically its active form, psilocin) binds to and activates very strongly. Its selective activation is responsible for the specific changes in neural circuitry and therapeutic effects associated with psilocybin, unlike the more diffuse action of natural serotonin or SSRIs.
Neuroplasticity
The brain's ability to rewire itself by forming, strengthening, or weakening neural connections. Psilocybin is a powerful inducer of neuroplasticity, but for it to be therapeutic, this rewiring must be adaptive, leading to improved function in life.
Set and Setting
These are critical variables influencing a psychedelic journey's outcome. 'Set' refers to the individual's mindset, expectations, and intentions, while 'setting' encompasses the physical environment, the presence of guides, and other external factors like music.
Perceptual Blending (Synesthesia)
A common subjective experience during psilocybin journeys where different senses merge, such as seeing geometric shapes influenced by music or feeling control over sounds through breathing. This occurs due to increased lateral communication across brain areas.
Oceanic Boundlessness
A subjective experience during a psilocybin journey characterized by a sense of unity, mystical experience, and massive connectedness with one's environment, past, present, and even the universe. The intensity of this experience correlates positively with therapeutic outcomes for depression.
Ego Dissolution
A temporary loss of one's sense of self, often accompanied by anxiety, that can occur during the peak of a psilocybin journey. Moving through this experience and 'letting go' is considered an important feature for an effective therapeutic session.
Dendritic Spines
Small, mushroom-shaped protrusions on the branches of neurons (dendrites) that are sites of new excitatory connections. Psilocybin has been shown to induce the rapid and persistent growth of these spines, particularly in the frontal cortex, which may underlie its antidepressant effects.
9 Questions Answered
Psilocybin is a tryptamine psychedelic that chemically resembles serotonin. Its active form, psilocin, primarily binds to and activates the serotonin 2A receptor in the brain.
Psilocybin increases lateral communication across brain areas, reducing the brain's modularity and hierarchical organization. It broadens the flow of sensory information, leading to more extensive communication between normally disparate brain regions.
Clinical studies typically use dosages of 10mg or 25-30mg of synthetic psilocybin. A 'heroic dose' often refers to about 5 grams of mushrooms, which translates to approximately 50mg of psilocybin, though mushroom potency varies.
A safe and effective journey requires a controlled 'setting' (safe environment, trained guides, eye mask, specific music) and a prepared 'set' (mindset of the individual), with the individual being 25 years or older and not predisposed to psychosis.
Music is a major driver of the cognitive and emotional experience, with specific contours of music (e.g., low volume classical, then intense percussion, then soft melodic, then nature sounds) used to match and guide the journey's emotional arc.
Yes, studies show psilocybin can increase positive emotional responses to music, allowing people to 'feel' music again and reducing the sadness associated with certain music, even after the session. This suggests a rewiring of emotion and auditory perception centers.
Psilocybin is contraindicated for pregnant or breastfeeding women, individuals with a predisposition to psychotic episodes (e.g., schizophrenia, bipolar disorder) or a first-degree relative with such conditions, and generally not recommended for individuals under 25 years old.
Psilocybin primarily induces neuroplasticity through the growth of dendrites and the addition of new dendritic spines on pyramidal neurons, particularly in the frontal cortex, rather than through neurogenesis (the production of new neurons).
Clinical trials show that one or two sessions of 25-30mg psilocybin, combined with psychotherapy, can provide rapid, substantial, and sustained relief from treatment-resistant depression, with effect sizes significantly greater than traditional psychotherapy or SSRIs alone.
24 Actionable Insights
1. Avoid Psilocybin with Psychosis Risk
Do not use psilocybin if you have an existing predisposition to psychotic or bipolar episodes, or if a first-degree relative has bipolar, schizophrenic, or schizotypal issues, as it can trigger such episodes.
2. Avoid Psilocybin Under 25
Individuals 25 years old or younger should avoid psilocybin because their brains are still undergoing significant developmental neuroplasticity, and most clinical studies focus on adults 25 and older.
3. Understand Psilocybin’s Legal Status
Be aware that psilocybin is a Schedule I drug and generally illegal in the United States, with rare exceptions in clinical studies or decriminalized areas, making possession or sale unlawful. This is critical for personal safety and legal protection.
4. Consult Doctor on Antidepressants
If currently taking antidepressants, do not cease them to use psilocybin without consulting your physician or psychiatrist, as stopping medication abruptly can be very dangerous. Clinical studies typically require abstinence from antidepressants prior to psilocybin use.
5. Ensure Safe Physical Environment
The physical setting for a psilocybin journey must be absolutely safe, free from hazards like open windows, moving traffic, or bodies of water, to prevent harm to the individual.
6. Have Sober Guides Present
Always have at least one, and ideally two or more, sober individuals present during a psilocybin journey to ensure the safety of the person under the influence and prevent self-harm or harm to others.
7. Prioritize Set and Setting
For a therapeutically beneficial psilocybin journey and to avoid a ‘bad trip,’ it is crucial to prioritize ‘set’ (mindset) and ‘setting’ (environment and people present), as these bias the probability of a positive outcome.
8. Combine Psilocybin with Psychotherapy
For major depressive disorder, combining psilocybin therapy with supportive psychotherapy (talk therapy) is significantly more efficacious than either intervention alone, producing large, rapid, and sustained antidepressant effects.
9. Consider Therapeutic Psilocybin Dosage
For pronounced therapeutic outcomes in clinical studies, a dosage of 25 to 30 milligrams of psilocybin, taken once or twice, has been shown most effective, compared to microdosing (1-3mg daily) or lower single doses (10mg).
10. Optimize Psilocybin Journey Conditions
To ensure a psilocybin journey is therapeutically adaptive and leads to long-term positive changes, pay close attention to conditions such as eyes closed vs. open, the presence and type of music, dosage, and who is present or not.
11. Utilize Eye Mask for Inward Focus
Wear an eye mask or keep eyes covered for most, if not all, of the psilocybin session to limit focus on external visual hallucinations and encourage an inward journey of thoughts, memories, and emotions for therapeutic benefit.
12. Incorporate Music Strategically
Music is a critical driver of the cognitive and emotional experience during a psilocybin journey, profoundly influencing whether it is perceived as beneficial and one of life’s most important positive experiences.
13. Tailor Music to Journey Phases
Select music that matches the journey’s contour: start with low-volume, non-vocal classical music, transition to intense, percussive music during the peak (45-90 minutes), and conclude with softer, melodic music or nature sounds.
14. Fast Before Psilocybin Journey
Do not eat for at least four hours prior to a psilocybin journey, especially if consuming mushrooms, as food in the gut can impact the conversion of psilocybin to psilocin and affect the journey’s duration and intensity.
15. Allow Ego Dissolution and Anxiety
During the peak of a psilocybin journey, embrace the anxiety and ’ego dissolution’ by letting go and moving through the experience, understanding that this intense phase is temporary and crucial for therapeutic benefit, with guides providing support.
16. Use Physiological Sigh for Anxiety
If anxiety becomes too high during a psilocybin session, use the physiological sigh (two inhales through the nose, followed by a long exhale through the mouth) as a real-time tool to rapidly and significantly reduce stress and regain calm.
17. Engage in Post-Journey Integration
Understand that much of the therapeutic benefit and neuroplasticity from psilocybin occurs after the session; actively use your conscious brain to guide this plasticity in adaptive ways, clearing paths through old, ineffective thought patterns.
18. Consider Psilocybin for Depression/Anxiety
Psilocybin shows the strongest evidence for positive therapeutic outcomes in treating cancer-related depression, cancer-related anxiety, and treatment-resistant depression when administered with appropriate dosage, set, and setting.
19. Consider Psilocybin for Addiction
There is some evidence supporting the use of psilocybin journeys for improving outcomes in alcohol use disorder and tobacco addiction, typically involving one or two sessions with proper support.
20. Consider Psilocybin for OCD/Headaches
Minimal clinical trial support exists for psilocybin providing relief or partial relief for obsessive-compulsive disorder, cluster headaches, migraines, and demoralization due to an AIDS diagnosis.
21. Convert Mushroom Weight to Psilocybin
To estimate psilocybin content from mushrooms, remember that one gram of mushrooms (1000mg) typically contains approximately 10 milligrams of psilocybin, based on an average 1% psilocybin concentration.
22. Be Aware of Psilocybin Variability
The actual concentration of psilocybin in mushrooms can vary significantly (0.5% to 2%) depending on strain, age, and storage, meaning a gram of mushrooms might contain anywhere from 5 to 20 milligrams of psilocybin.
23. Ensure Daily Electrolyte Hydration
To maintain optimal brain and body function and prevent diminished cognitive/physical performance, ensure adequate hydration and electrolyte intake (sodium, magnesium, potassium) by drinking an electrolyte mix like Element, especially upon waking and during exercise.
24. Practice Meditation or Yoga Nidra
Engage in meditation, mindfulness training, or yoga nidra/non-sleep deep rest (NSDR) sessions, even for just 10 minutes, to restore cognitive and physical energy and explore different states of consciousness.
3 Key Quotes
Just because something invokes neuroplasticity, changes in brain circuitry, does not mean that it's therapeutic, or I should say, does not necessarily mean that it's therapeutic. For neuroplasticity to be therapeutic, it has to be adaptive.
Andrew Huberman
It seems vital that appropriate consideration is paid to the importance of promoting a certain kind of experience as the quality of that experience may be the critical determinant of therapeutic success.
Andrew Huberman (quoting a paper)
The present trial showed that psilocybin administered in the context of supportive psychotherapy consisting of approximately 11 hours of psychotherapy produced large, rapid, and sustained antidepressant effects. The effect sizes reported in the study were approximately 2.5 times greater than the effects sizes found in psychotherapy and more than four times greater than the effect sizes found in psychopharmacologic depression treatment studies.
Andrew Huberman (paraphrasing a paper's discussion)
1 Protocols
Therapeutic Psilocybin Journey Structure
Andrew Huberman (describing clinical trial protocols)- Ensure a safe and controlled environment, typically a single room, with no external hazards.
- Have at least one, and ideally two or more, responsible individuals present who are not under the influence of psychedelics to act as guides and ensure safety.
- The individual taking psilocybin should be seated or lying down, wearing an eye mask or having their eyes covered for the majority, if not the entire, session.
- Abstain from food for at least four hours prior to ingesting psilocybin.
- Play specific music throughout the journey, starting with low-volume classical, transitioning to intense percussion during the peak, then softer melodic music (often with female voices), and finally nature sounds.
- Guides should encourage the individual to 'let go' and move through any anxiety or ego dissolution experienced during the peak, potentially using tools like physiological sighs to self-regulate anxiety.
- Engage in supportive psychotherapy, typically around 11 hours, before and after the psilocybin sessions to integrate insights and facilitate adaptive changes.