The Science of Psychedelics for Mental Health

Dr. Robin Carhart-Harris, a psychiatry and neurology researcher who had recently moved from Imperial College London to UCSF, joins Andrew Huberman for a long conversation on the origin of the word "psychedelic," what happens in the brain during a dosing session, Carhart-Harris's trials on psilocybin for depression, anorexia, and fibromyalgia, comparisons with LSD, DMT, and MDMA, and the path toward FDA approval.

Etymology, pharmacology, and the unconscious

"Psychedelic" was coined around 1956 by psychiatrist Humphry Osmond, corresponding with Aldous Huxley, because "psychotomimetic" (mimicking psychosis) felt inaccurate. From Greek roots for mind and for making visible, it means roughly mind-revealing, chosen to be valence-neutral: revealed material could be heavenly or hellish. A recent consensus statement defines "classic" psychedelics (psilocybin, LSD, DMT) as serotonin 2A receptor agonists, though Carhart-Harris says pharmacology alone can't explain them without the subjective experience. He links that experience to Freud's personal unconscious and Jung's collective unconscious: previously inaccessible material tends to surface in a session, and awareness of it, paired with emotional release, appears to catalyze change, an action he argues sets classic psychedelics apart from psychedelic-like compounds such as ketamine or MDMA.

Dosing, microdosing, and a session itself

Depression trials typically use two high 25mg psilocybin doses, sometimes against 10mg or a near-placebo 1mg dose, weeks apart; dried mushrooms run roughly 1 percent psilocybin by mass, though Carhart-Harris says this shouldn't guide personal dosing. On microdosing (sub-perceptual, below roughly 10 to 12 micrograms of LSD), he calls the evidence "pretty thin": a self-blinded citizen-science study found that once expectancy was accounted for, people who believed they'd microdosed but got placebo did as well as those who really had (more in Psylopedia's microdosing roundup). A clinical session follows a template: eye mask, two facilitators, and instrumental music building toward strings to "coax emotion," a standard he admits is rarely tested directly. "Trust, let go, be open" maps to measurable predictors, rapport, surrender, and openness, that each statistically predict experience quality and outcome; fear is common early, and the tone often shifts later.

The brain in the scanner, plasticity, and a shortcut

Imaging shows psilocybin, LSD, and (unpublished) DMT each increase communication across normally separate brain networks, reproduced by models built purely from cortical serotonin 2A receptor density. This can outlast the trip: measured a day and three weeks later in depression cohorts, its size predicting symptom improvement. A 2022 trial compared psilocybin against escitalopram, with remission cited around 67 to 70 percent. In a separate first-time-use study, psychedelic-naive volunteers given 1mg then later 25mg showed a rise in brain-activity complexity on EEG (the "entropic brain effect") and, on MRI, white-matter changes resembling brain maturation rather than aging, alongside improved well-being. Some groups now engineer 2A-targeting molecules stripped of hallucinogenic effects; Carhart-Harris is skeptical, suspecting the "psyche-revealing" part is the therapeutic part.

Anorexia, fibromyalgia, integration, and the placebo test

Trials underway then tested psilocybin for anorexia (three sessions, two weeks apart), the psychiatric illness with the highest mortality rate, with early signals including improved weight at follow-up, plus a fibromyalgia trial that doesn't direct patients to focus on their pain. Carhart-Harris frames "integration" as open-ended, more a practice than a finite treatment (Psylopedia's integration guide). And on whether all this is just placebo: expectancy predicted escitalopram response but not psilocybin response.

LSD, DMT, ego dissolution, and combining compounds

LSD is rare in trials mainly for practical reasons, sessions running 8 to 15 hours with roughly 8 hours of required monitoring, not an efficacy gap. DMT is a "rocket ship," less potent per molecule than psilocybin but intensely powerful and brief; related 5-MeO-DMT reportedly produces full ego dissolution more reliably. Underground therapists reportedly combine psilocybin with MDMA (a "hippie flip"), pairing psilocybin's depth with MDMA's more reliably positive tone. Ego dissolution is framed as expansion rather than loss, the self/world boundary loosening into felt interconnection, tied to dense serotonin 2A receptor expression in newer cortex; a separate study found cocaine reliably inflates a sense of self with no effect on dissolution, the opposite pattern. The insight rarely persists alone: relapse past roughly three months is more rule than exception in treatment-resistant depression, and since psilocybin stays controlled outside trials, relapsed participants cannot legally redose.

The legal landscape

Oakland's decriminalization is a patchwork, mushrooms sold semi-openly and a church invoking a religious-exemption model like peyote's, none of it federal legality. FDA phase III trials are the real threshold. MDMA therapy for PTSD, led by MAPS, had completed two, the first reporting around 67 percent remission, with rollout anticipated within a year or two. Psilocybin trials, led by Compass Pathways, were earlier, with estimates then pointing toward 2026. Open questions include who gets licensed to provide these therapies, and the risk that street-sourced material is laced with fentanyl. More at Psylopedia's psychedelic laws by country.

Key takeaways

• ●"Psychedelic," coined by Humphry Osmond around 1956, means roughly mind-revealing; classic psychedelics act on the serotonin 2A receptor.
• ●Depression trials commonly use two high (25mg) psilocybin sessions with eye masks and music, guided by "trust, let go, be open."
• ●Microdosing evidence is thin; a self-blinded citizen-science LSD study found much of the effect tracked expectancy, not the drug.
• ●Cross-network brain connectivity, and white-matter changes after a single 25mg dose, can persist for weeks and correlate with symptom improvement.
• ●Pre-session expectancy predicted escitalopram response but not psilocybin response, evidence against a mainly-placebo explanation.
• ●Ego dissolution ties to serotonin 2A receptor density in newer cortex, but insights often fade without integration, and relapse is common.
• ●MDMA therapy for PTSD was further along the FDA pathway than psilocybin therapy at the time, both facing open questions on providers and sourcing.