The Huberman Lab podcast episode featuring Andrew Huberman provides an in-depth discussion on psilocybin, a psychedelic that modifies the psyche and alters consciousness. The episode covers its nature, how it works at the molecular and cellular levels, its effects on brain circuitry, clinical applications, dosages, and risks.
Definition and Effects of Psilocybin:
- Psilocybin is a psychedelic that changes one's perception of the external and internal world, including memories, thoughts, and feelings.
- These changes can persist long after the immediate influence of the drug, leading to growing excitement for its application in treating various mental health issues.
- It is considered a tryptamine, a chemical class that closely resembles serotonin.
Mechanism of Action - Mimicking Serotonin:
- Psilocybin's primary effect is to mimic serotonin, specifically by activating a subset of serotonin receptors in a strong fashion.
- Psilocin, not psilocybin, is the active compound that enters the brain to create changes in consciousness and rewiring effects. Psilocybin is converted to psilocin, which affects the duration of the "journey" and the window for neuroplasticity.
- Psilocin predominantly binds to and activates the serotonin 2A receptor (5-HT2A), which is expressed in specific brain areas and neurons, leading to precise changes in neural circuitry. This selectivity explains its distinct effects compared to the more general action of serotonin or SSRIs.
- Serotonin, a neuromodulator, impacts mood, satiety, pleasure, and motivation, and has many receptors, explaining why drugs affecting serotonin have diverse side effects.
Brain Circuitry and Neuroplasticity:
- Psilocybin leads to neuroplasticity, which is the rewiring of brain areas and their connections involved in memory and perception.
- It causes a shift from modular to integrated brain activity, increasing communication across disparate brain regions and reducing the hierarchical organization of information flow, particularly through the thalamus.
- The serotonin 2A receptors are highly expressed in the neocortex, including the prefrontal cortex (involved in context and behavior) and the visual cortex (explaining visual hallucinations).
- Psilocybin induces neuroplasticity primarily through the growth of dendrites and dendritic spines on pyramidal neurons, especially in the frontal cortex. This is significant because a reduction in dendritic spines is observed in depressed patients, and treatments that relieve depression often correlate with increased spine growth.
- It's crucial that neuroplasticity is adaptive, meaning it allows someone to function better, rather than simply rewiring the brain (which can also occur with brain injury or maladaptive drug use).
The Psilocybin Journey: Set and Setting:
- The "set" (mindset) and "setting" (environment) are critical for a therapeutically beneficial and safe journey.
- Safety: The setting must be secure, preventing harm to oneself or others, ideally with one or more sober individuals present as guides.
- Eyes Closed/Masked: For therapeutic benefit, keeping eyes closed or masked for most of the session is recommended to encourage introspection and focus on internal experiences rather than external visual distortions.
- Music: Music plays a crucial role in shaping the cognitive and emotional experience, often curated to match the journey's contour (e.g., soft, instrumental music at the start, intense percussion during the peak, then softer, melodic, and nature sounds).
- Food: It's advised not to eat for at least four hours prior to the session to optimize absorption and reduce variability in gut acidity.
- Anxiety/Ego Dissolution: The peak of the journey often involves intense emotion, anxiety, and "ego dissolution" (a temporary loss and restoration of self-sense). Guides help individuals navigate this peak, encouraging them to "let go". While some anxiety is part of the process, extreme anxiety is inversely correlated with positive outcomes.
- Physiological Sigh: Breathing techniques, like the physiological sigh, can be used in real-time to reduce anxiety during the session, promoting self-calm and enabling a more beneficial experience.
Subjective Experiences and Therapeutic Outcomes:
- Common experiences include perceptual blending (synesthesia), where senses merge (e.g., music affecting visual hallucinations, breathing linked to sounds).
- Oceanic boundlessness and mystical experiences (feelings of massive connectedness, unity, spiritual significance) during the journey are positively correlated with positive therapeutic outcomes, particularly relief from major depression.
- Positive outcomes are also linked to experiences of unity, bliss, and insightfulness.
- Psilocybin can lead to long-standing improvements in mood, tremendous insight into oneself and others, and changes in creativity and the ability to experience joy (e.g., from music). Studies show it can increase positive responses to liked music and reduce the sad impact of depressing music.
Dosage and Administration:
- Clinical studies typically use synthetic psilocybin to ensure precise dosing.
- Microdosing generally refers to 1-3 milligrams per day over time.
- Therapeutic doses in clinical studies range from 10 milligrams to 25-30 milligrams, often given once or twice in separate sessions.
- Conversion from mushrooms: 1 gram of "magic mushrooms" typically contains about 10 milligrams of psilocybin (assuming 1% concentration), but concentration can vary from 0.5% to 2%.
- "Heroic doses", a popular term, often refer to about 5 grams of mushrooms, equating to roughly 50 milligrams of psilocybin.
Therapeutic Applications and Clinical Evidence:
- Psilocybin has received "breakthrough status" at the FDA, leading to more clinical trials.
- Strongest evidence for positive therapeutic outcomes is for cancer-related depression and anxiety, and treatment-resistant depression.
- Moderate evidence supports its use for alcohol use disorder, dependence, and tobacco addiction.
- Minimal evidence exists for obsessive-compulsive disorder (OCD), cluster headaches, migraines, and demoralization due to AIDS diagnosis.
- Clinical trials show that 25-30mg doses, often in one or two sessions spaced a week or two apart, provide significant and sustained antidepressant effects, sometimes outperforming standard therapy and SSRIs by a factor of 2.5 to 4 times.
- These effects are often seen when psilocybin is combined with psychotherapy.
Safety and Contraindications:
- As of May 2023, psilocybin is a Schedule I drug and illegal in the United States, with rare exceptions for specific therapeutic settings in Oregon and decriminalized areas like Oakland, California.
- Contraindications:
- Individuals with existing psychosis, bipolar disorder, or a predisposition to such episodes (including close family members with these conditions) should avoid psilocybin.
- Young people (25 years or younger) should avoid it, as their brains are still undergoing significant developmental neuroplasticity.
- Pregnant or breastfeeding women should not use it.
- Individuals taking antidepressants should abstain for weeks prior to a psilocybin journey in clinical trials; stopping antidepressants without medical supervision can be very dangerous.
- Adverse events (e.g., headaches, anxiety, suicidal ideation) can occur, and are more frequent with higher dosages.
In conclusion, psilocybin is an exciting and potent compound with significant potential for adaptive neuroplasticity and therapeutic benefits in mental health, particularly depression, when used within carefully controlled settings with proper guidance and safety precautions. However, it is not without risks and legal implications.