Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

KEYPOINTS

• 01

  Classic psychedelics act mainly on serotonin receptors, but chemistry doesn't predict the experience

  Johnson groups LSD, psilocybin (found in more than 200 mushroom species), DMT and mescaline as classic psychedelics. Psilocybin resembles serotonin, yet mescaline structurally resembles dopamine and still produces a similar receptor-level effect. Huberman stresses that a molecule can trigger different parts of the same receptor's signaling pathway at different rates. That's why similar-looking compounds feel so different, and why people shouldn't try to 'cowboy their own chemistry.'

• 02

  Hopkins-style sessions: screening, rapport, then a single high dose

  Participants first undergo days of structured psychiatric interviews to exclude psychotic disorders and bipolar mania, plus cardiovascular screening. They then spend 4–8 hours of preparation building rapport with their guides. Early dose studies used placebo or 5, 10, 20 or 30 mg of psilocybin per 70 kg. Therapeutic work targets 20–30 mg (some people received 40–45 mg under weight adjustment), and the team has since dropped weight adjustment. The capsule takes effect in 15–60 minutes, and pulse and blood pressure are checked roughly every half hour.

• 03

  Surrender, not control, seems to drive the benefit

  Johnson tells participants that any emotion is welcome, even crying hysterically. That can be harder for experienced recreational users, whose party rule is to 'hold your shit.' He speculates that the reality-shattering phase, which can include losing one's sense of self, can be met by surrender, which tends toward transcendent experiences, or by clinging, which tends toward a bad trip.

• 04

  Lasting change often looks like a shift in identity and agency

  In his work with cancer patients who had cancer-related depression and anxiety, and with smokers who had repeatedly failed to quit, Johnson sees people step out of identities like 'I'm a smoker, I can't do it.' They report a supercharged sense of agency ('I'm just going to make a decision') and often say, 'I know this sounds like bullshit.' He contrasts this with ordinary advice to depressed people, which rarely sticks.

• 05

  Ketamine works differently, and how it's delivered may matter

  Spravato (esketamine nasal spray) is FDA-approved for treatment-resistant depression at fairly low, mildly psychedelic doses. Patients are told to ignore the altered state. Its antidepressant effect starts immediately but lasts about a week, whereas psilocybin effects have been seen a year or more later. Johnson points to Russian studies by Krupitsky in the 1990s–2000s that gave high-dose ketamine as psychedelic therapy and reported high success rates for heroin and alcohol addiction, and asks whether framing explains part of the gap.

• 06

  The two big dangers: psychotic vulnerability and bad trips

  People with schizophrenia, bipolar mania or a strong predisposition can be identified fairly reliably through a few hours of history-taking, and Johnson says psilocybin research in schizophrenia should be low on the list. The more common danger is a bad trip, which can happen to anyone at a high enough dose. Even in his lab, after the best preparation, about a third of people at roughly 30 mg report a stretch of intense fear, feeling trapped or 'losing their mind,' sometimes minutes before a beautiful experience.

• 07

  Lasting perceptual effects exist but are rare and often confounded

  Hallucinogen-persisting perceptual disorder is in the DSM: a very small percentage of users keep seeing halos or trails. Johnson notes that cases are clouded by unknown doses, purity and mixed drugs, and suspects a rare neurological susceptibility. He also argues the field historically blamed 'the weird other thing,' psychedelics, rather than alcohol or tobacco.

• 08

  Microdosing is unproven and may carry its own risk

  A microdose is roughly a tenth of an entry-level dose. For psilocybin that's about 1 mg. For LSD, whose psychedelic effects start around 100 micrograms, a common mistake is calling a 100-microgram dose a microdose. So far, studies haven't shown improved creativity, cognition or sustained mood, and none have tested the every-few-days schedules promoted by people like Paul Stamets. Johnson suspects there may be some real antidepressant effect, based only on anecdotes. He also flags that serotonin 2B activation (the mechanism behind fen-phen's heart-valve damage) is more worrying with repeated dosing over years than with a few therapeutic sessions.

• 09

  Legal reform is moving, but approval isn't guaranteed

  Johnson calls the assumption that everything will be legal in a few years premature. He distinguishes decriminalization from legalization and from regulated medical use, citing Oregon's state-level psilocybin therapy program, which must still work out how to coexist with federal law. If Phase 3 trials hold up, even at half the current effect sizes, he expected MDMA for PTSD and then psilocybin for depression to be approved within a few years.