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

High-Level Overview

In this solo deep dive recorded in May 2023, Andrew Huberman explains what psilocybin is, how it acts on the brain, and why clinical trials are generating so much excitement about it for treatment-resistant depression, addiction and other conditions. He starts with the chemistry: psilocybin is converted in the gut into its active form, psilocin, which closely resembles serotonin but strongly and selectively activates the serotonin 2A receptor. From there he explains why that selectivity produces visual hallucinations, blended senses and a more interconnected, less hierarchical brain, and how those changes can set lasting neuroplasticity in motion.

He then turns to the practical and clinical side: how to translate mushroom grams into milligrams of psilocybin, what "set and setting" mean in research studies, the roles of eye masks, music and trained guides, the typical arc of a four- to six-hour journey, what subjective experiences predict good outcomes, how to handle anxiety, and what the major trials in the New England Journal of Medicine and JAMA Psychiatry have found. Throughout, he stresses that psilocybin remained a Schedule I drug at the time of recording, that it is dangerous for some people, and that plasticity only helps when it is adaptive. The tone is enthusiastic but cautious, moving from molecules to brain networks to therapy rooms and clinical data.

The Discussion Explores:

• Psilocybin's legal status and the groups who should not take it
• How psilocybin becomes psilocin and why its selectivity for the serotonin 2A receptor matters
• Why psilocybin differs from SSRIs, and why eyes-closed sessions work better therapeutically
• Converting mushroom grams to psilocybin doses, microdosing and "heroic" doses
• Set, setting, guides and the carefully structured music of clinical sessions
• How psilocybin makes brain communication broader and less hierarchical
• Oceanic boundlessness, ego dissolution, anxiety, and the physiological sigh
• Dendritic spine growth, clinical trial results and the "wedge" model of neuroplasticity

Deep Dive into Main Ideas

Legal status and who should avoid it

Huberman opens by underscoring that, as of May 2023, psilocybin was still a Schedule I drug and illegal in the United States, with exceptions such as Oregon, where it was approved in particular therapeutic settings, and decriminalized areas such as Oakland, California. Possessing and especially selling it remained against the law outside clinical studies and those areas, and he says the warning is to protect listeners, not just himself.

He also sets out clear safety limits that he repeats throughout. People with psychosis or a predisposition to it, including those with a first-degree relative with schizophrenia or bipolar disorder, are typically excluded from studies because psilocybin can trigger psychotic episodes, potentially lasting ones. Most studies include only adults aged 25 to about 70, since younger brains are still in a period of developmental plasticity. Pregnant or breastfeeding women should avoid it. Studies generally require participants to be off serotonin-affecting antidepressants, but he is emphatic that no one should stop antidepressants on their own, which could be very dangerous, and that any change should go through a physician and psychiatrist.

Psilocybin is basically serotonin, with a twist

Psilocybin is a tryptamine, like DMT and 5-MeO-DMT, and it is converted by the gut's acidity into psilocin, the compound that crosses into the brain. Chemically, both look strikingly similar to serotonin, a neuromodulator involved in satiety, mood, pleasure, motivation and much more. (He notes that although about 90% of the body's serotonin is made in the gut, brain serotonin comes from separate neurons in the brain.) Serotonin does so many things because it acts on many receptor types, which is also why antidepressants that broadly raise serotonin cause side effects involving mood, libido, appetite and sleep.

The key to psilocybin is that psilocin mainly and strongly activates one receptor: serotonin 2A. Huberman contrasts the two approaches with an image: SSRIs spray extra serotonin non-specifically across many receptors, while psilocin hits serotonin 2A selectively. Those receptors are dense in the neocortex, including the prefrontal cortex, which manages context and appropriate behavior, and especially in the visual cortex. That is why psilocybin produces visual hallucinations even with the eyes closed, and why clinical trials, as he will describe, are outperforming standard therapy and SSRIs in ways he calls staggering to the psychiatric community.

Why eyes-closed sessions matter

Because hallucinations occur either way, Huberman explains that researchers he has spoken to consider an eye mask, or keeping the eyes closed for most of the session, a very if not the critical feature of a therapeutic journey. With eyes open, people tend to fixate on the altered outside world, faces melting or morphing, geometric fracturing. With eyes closed, they can go inward and combine internal imagery with thoughts, memories and emotions, which appears to be what drives lasting benefit. That is the difference, he says, between a clinical journey and taking mushrooms and heading to the woods or the beach.

Dosing: from mushrooms to milligrams

Clinical studies typically use synthetic psilocybin given orally or intravenously so doses can be controlled. Microdosing generally means about 1 to 3 milligrams repeatedly over days. Therapeutic sessions usually use 10 milligrams or, most often, 25 to 30 milligrams, given once or twice. Magic mushrooms contain roughly 1% psilocybin, so one gram of mushrooms (1,000 milligrams) contains about 10 milligrams of psilocybin. The so-called heroic dose discussed by longtime psychonauts corresponds, according to researchers he consulted, to about 5 grams of mushrooms, or roughly 50 milligrams of psilocybin.

The problem is variability: potency can range from half a percent to 2% depending on strain, age and storage, so a gram could contain 5 or 20 milligrams. Sourcing matters, and synthetic psilocybin will be far more consistent. Higher doses tend to produce greater therapeutic effects but also more adverse events.

Set, setting and music

Set refers to mindset and setting to the environment and people present. Setting must be physically safe: no windows to jump from, no streets or bodies of water nearby, no way to get lost, and one or two sober people present to keep the person safe. Huberman recalls that isolated incidents in the late 1960s and early 1970s, like people staring at the sun on LSD, fed into the Controlled Substances Act, and says getting safety right is critical at this moment in psychedelic history. Clinical sessions usually take place in one closed room with the person lying down in an eye mask and guides who can talk them through anxious moments. Participants typically fast for about four hours beforehand because food changes gut acidity and thus conversion to psilocin.

Robin Carhart-Harris of UCSF impressed on Huberman that music is not incidental but one of the major drivers of the experience. The journey lasts four to six hours, begins about 30 to 45 minutes after dosing, builds to a peak of emotional intensity and often anxiety, and gradually tapers, sometimes called parachuting back in. Music is matched to that arc: low-volume, mostly wordless music such as classical at first, then intense, percussive, louder music for 45 to 90 minutes around the peak, then softer choral or melodic music, often female voices, and finally nature sounds.

Blended senses and a less hierarchical brain

People on psilocybin often report synesthesia, a blending of senses: music changing the imagery they see in the mask, a long exhale seeming to stretch out a musical note, or rubbing a fingertip on the couch appearing to raise or lower a sound, all linked to emotion. Huberman explains the biology. Pyramidal neurons in the cortex have apical dendrites that reach up and fan out to communicate laterally, and many serotonin 2A receptors sit on those branches. Activating them increases lateral communication, so the brain becomes less modular (areas talking mostly to their own kind) and more integrated.

It also becomes less hierarchical. Normally, sensory input flows from the eyes, ears and skin through the thalamus, a switchboard that routes each sense to its center. Under psilocybin, thalamic gating broadens, allowing more sensory and interoceptive information to flow and blend. Patterns of activity are not random, he says, but they are far less channeled. There are four prominent, largely compatible models of which networks change most, including the default mode network involved in daydreaming, and he recommends a review from Bryan Roth's lab at Duke titled The neural basis of psychedelic action. A study from Carhart-Harris's lab on psilocybin and MDMA in healthy volunteers found increased connectivity between resting-state networks even after the drugs wore off. Importantly, people rarely report long-term memory problems, suggesting the rewiring tends to be adaptive when set and setting are right.

Music, emotion and creativity

Many listeners asked whether psilocybin boosts creativity or enjoyment of life. Direct creativity studies are few, but a paper titled Increased low-frequency brain responses to music after psilocybin therapy for depression offers a template. People with depression often feel music no longer lifts them. After psilocybin therapy, brain imaging showed rewired connections between emotion centers, including the ventral tegmental area and reward pathways, and auditory networks. Participants could enjoy music they liked again, while sad music lost some of its power to crush them, and those changes lasted well beyond the session.

Huberman ties this to depression's habitual thinking patterns, the sense that if A, then B, then C, and every relationship or job will go wrong. Psilocybin seems to open new relationships between sensory and emotional states and new considerations of what is possible. His central analogy: psychedelics are "a wedge" under the boulder of neuroplasticity. They initiate plasticity but are not the plasticity itself, and whether the rolling boulder clears a path through old destructive patterns or just bulldozes depends on how people use their conscious minds afterward. Rewiring alone is not the goal, since brain injury and methamphetamine also rewire the brain, maladaptively.

What makes a journey therapeutic, and handling anxiety

A study titled Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression gave participants 10 milligrams and then 25 milligrams, measuring experiences with an altered states of consciousness questionnaire. The strongest predictor of benefit was "oceanic boundlessness," a mystical sense of vast connectedness to one's surroundings, guides, past, present, other people and even the universe. Responders reported more unity, spirituality, bliss and insight. Non-responders reported less of those, and there was little difference between groups in hallucinations or synesthesia; everyone saw complex imagery, but imagery alone did not bring relief. The paper concludes that "it seems vital that appropriate consideration is paid to the importance of promoting a certain kind of experience."

The peak, typically around two hours in, often brings fear, elevated heart rate and blood pressure, and ego dissolution, the temporary loss of one's sense of self. Researchers including Carhart-Harris and Matthew Johnson of Johns Hopkins emphasize "letting go" and moving through that anxiety. Yet very high anxiety was negatively correlated with benefit, which makes well-trained guides essential. Johnson's lab has begun teaching participants the physiological sigh, a breathing pattern that Huberman's lab and David Spiegel's lab found in a Cell Reports Medicine study to be one of the fastest ways to reduce stress, so they can calm themselves in real time and keep moving through the experience.

He also recommends a paper titled Therapeutic use of psilocybin: practical considerations for dosing and administration, which covers pharmacology, the arc of a session, dosing, contraindications and adverse events. It rates the evidence as strongest for cancer-related depression and anxiety and treatment-resistant depression, moderate for alcohol use disorder and tobacco addiction, and weakest, though present, for OCD, cluster headaches and migraines, and demoralization after an AIDS diagnosis.

How the brain physically changes

Asked whether psilocybin grows new neurons, Huberman says neurogenesis in the adult human brain is limited mostly to the hippocampus's dentate gyrus and accounts for perhaps 1 to 2% of meaningful rewiring at most; it is not how psilocybin works. The main mechanism is the growth of dendrites and dendritic spines, small protrusions that happen to look like tiny mushrooms (he pre-empts any comment claiming mushrooms grow from neurons) and serve as sites for new excitatory connections. A study in Neuron titled Psilocybin induces rapid and persistent growth of dendritic spines in the frontal cortex in vivo found such spines grew and persisted in mice. Depressed patients show fewer spines in frontal cortex neurons in postmortem tissue, and effective treatments correlate with spine growth. He notes, however, that the mouse studies used about 1 milligram per kilogram, roughly double or even triple human therapeutic doses, and that multiple mechanisms likely act in parallel, including pruning of unhelpful connections. For more depth he points to a review titled Psychedelics and neuroplasticity: a systematic review unraveling the biological underpinnings of psychedelics.

What the clinical trials show

Research resumed in a few labs around 2006 and accelerated after psilocybin received FDA breakthrough status about five years before this recording. Huberman credits researchers including Robin Carhart-Harris, Matthew Johnson, Roland Griffiths and Nolan Williams. A 2022 New England Journal of Medicine study, Single-dose psilocybin for a treatment-resistant episode of major depression, randomized roughly 75 to 79 participants per group to 25, 10 or 1 milligram with psychological support. At three weeks, 25 milligrams produced significantly greater relief than 1 milligram, while 10 milligrams did not differ from 1 milligram, and meaningful relief persisted to 12 weeks. Adverse events such as headache, anxiety and, in some cases, suicidal ideation or self-harm occurred in all groups and were most frequent at 25 milligrams.

Across about a dozen strong trials, typically two 25-milligram sessions about a week apart with supportive therapy, roughly 60 to 75% of people with major depressive disorder experience substantial relief. A trial titled Effects of psilocybin-assisted therapy on major depressive disorder reported, as Huberman paraphrases, effect sizes about 2.5 times greater than those in psychotherapy studies and more than four times greater than those in antidepressant drug studies, with about 11 hours of psychotherapy alongside the sessions, consistent with evidence that combining drug and talk therapy beats either alone.

Conclusion

Huberman presents psilocybin as a remarkable tool with real limits. By selectively activating serotonin 2A receptors, psilocin makes the brain temporarily more interconnected and less hierarchical, producing hallucinations and blended senses, and it appears to launch lasting structural changes like dendritic spine growth. When given at 25 to 30 milligrams in a safe, eyes-closed setting with carefully arced music, trained guides and supportive therapy, one or two sessions can relieve treatment-resistant depression in a majority of people, especially when they experience unity and insight rather than overwhelming anxiety. But psilocybin is only the wedge under the boulder: plasticity must be adaptive to help. With its legal status, risks for people prone to psychosis or under 25, antidepressant interactions and adverse events, he calls these compounds sharp blades that can do incredible things but can also cut you badly, and urges careful, clinically guided use.

This is a summary of "How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks" from Huberman Lab, giving you the GIST so you can decide if you want the REST. Listen to the full episode.