• Contents
  • Key Takeaways
  • Protocols
  • Source
  • Full Notes
  • Support the Podcast
Last Updated: 16.05.23

How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks

Dr. Huberman delves into psilocybin’s chemistry, cellular effects, and neuroplasticity, creating lasting shifts in emotions, cognition, and behavior. Clinical trials for depression, addiction, and psychiatric challenges, along with dosage categories, set, setting, and support importance, are discussed. High-​​risk and beneficial groups and evolving legal and medical landscapes are highlighted.

Key Takeaways

High level takeaways from the episode.

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

Psilocybin mimics serotonin by activating a subset of serotonin receptors strongly, leading to neuroplasticity in neural circuits related to memory and perception.

As of May 2023, psilocybin is still a Schedule 1 drug and considered illegal in the United States

  • Exceptions: Oregon (approved for depression and addiction treatment) and some decriminalized areas like Oakland, California

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
  • Psilocybin’s effects on mood, pleasure, and creativity are linked to its activation of the serotonin 2A receptor.

For therapeutic benefits, it’s recommended to have eyes closed during the majority of the psilocybin session

  • Allows the person to go inward and focus on thoughts, memories, and emotions
  • Experts running clinical studies emphasize the importance of this aspect

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

In clinical studies, dosages range from:

  • 1–3 mg per day (microdosing) given repeatedly over time
  • 10 mg given once or twice in separate sessions
  • 25–30 mg given once or twice

Conversion of grams of mushrooms to psilocybin:

  • 1 gram of mushrooms (1000 mg) contains approximately 1% psilocybin, or 10 mg of psilocybin
  • 25–30 mg dosage has shown the most pronounced therapeutic outcomes, but with increased side effects

Individuals under 25 years old should avoid psilocybin because of their brain’s neuroplasticity.

Music is 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 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), sound linked to visual phenomena

Psilocybin expands the functional connectivity of the brain

  • This expanded connectivity persists after the effects of psilocybin have worn off

Psilocybin does not seem to cause long-​​term issues with memory.

Psilocybin may enhance the brain’s response to music, potentially increasing creativity and the experience of life outside of psychedelic journeys.

  • 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

Psilocybin allows for new learning and new relationships between sensory and emotional states

  • These new relationships persist long after the psychedelic journey has been finished
  • Psilocybin initiates the neuroplasticity process, but the journey itself is not where all the neuroplasticity occurs
  • Think of psilocybin as a wedge that gets underneath the boulder of neuroplasticity

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.

  • Letting go and ego dissolution during the peak is important for positive therapeutic outcomes
  • Extreme levels of anxiety seem negatively correlated with positive therapeutic outcomes
  • Importance of getting dosage right and having well-​​trained guides who understand the psychedelic journey and can help with anxiety in real time
  • Can use breathing tools to calm anxiety in real-time

Psilocybin-​​induced neuroplasticity occurs largely through the addition or strengthening of new neural connections, or through the elimination or weakening of other neural connections

  • Predominant theory: psilocybin induces neuroplasticity through the addition of novel connections in pyramidal neurons of the frontal cortex, visual cortex, and possibly subcortically in areas like the thalamus and brain stem

Clinical studies have demonstrated promising results in using psilocybin to treat major depression and intractable depression, with ongoing research exploring its potential for other mood and addictive disorders.

  • 25–30mg dose most effective for treatment-​​resistant depression
  • Higher dosages provide greater relief but also greater chance for adverse event
  • Significant depression relief still observed 12 weeks after single 25mg dose

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


Science-​​based tools and supplements that push the needle.


Components of an Effective Therapeutic Psilocybin Journey



We recommend using this distillation as a supplemental resource to the source material.

  • How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks

    Huberman Lab #129

    Dr. Huberman explores psilocybin’s chemical and neural impact on neuroplasticity, discusses clinical trials, dosage categories, and emphasizes set, setting, and support, while highlighting high-​​risk and beneficial user groups and legal changes.

Full Notes

Support the Podcast