Dr. Matthew Johnson: Psychedelics for Treating Mental Disorders

High-Level Overview

In this conversation, Andrew Huberman talks with Dr. Matthew Johnson, a psychologist who at the time of recording was a professor of psychiatry at Johns Hopkins School of Medicine, where he helped lead one of the world's leading centers for psychedelic research. They define what a psychedelic actually is, sort the main drug classes by how they act on the brain, and walk step by step through what a psilocybin clinical trial looks like, from screening and preparation to the dosing day and follow-up integration. They explore why a single guided experience can produce lasting change, with Johnson's leading hypothesis being a shift in how people represent themselves. The discussion then covers MDMA, bad trips, flashbacks and HPPD, the real dangers for people prone to psychosis or mania, the weak evidence for microdosing, legal status and regulation, research on head injuries, and how philanthropy kept the field alive.

The tone is curious, candid and careful: Huberman brings a neuroscientist's questions about receptors and plasticity, while Johnson answers as a behavioral pharmacologist who is excited about big therapeutic effects but quick to flag what isn't yet known. The conversation moves from definitions and mechanisms into clinical practice, then widens to risks, policy and the future of the field.

The Discussion Explores:

• What makes a substance a psychedelic, and the main classes: classic serotonergic psychedelics, NMDA antagonists, salvinorin A and MDMA
• How psychedelics may dissolve the brain's predictive models of reality
• What happens in a Hopkins psilocybin trial, from screening to integration
• Letting go, and why changes in self-representation may drive lasting benefit
• MDMA's unique profile, bad trips, and why flashbacks and HPPD are misunderstood
• The real dangers: psychotic and bipolar predisposition, and behavior during bad trips
• Microdosing claims, the evidence so far, and heart valve concerns
• Legal status, regulation, head injury research and the role of philanthropy

Deep Dive into Main Ideas

What Counts as a Psychedelic

Johnson begins by admitting that nomenclature is a real challenge. To a pharmacologist, "psychedelic is unsatisfying because it spans several distinct drug classes; it's more of a cultural term. What unites them, in his words, is that they all had the ability to profoundly alter one sense of reality," including, acutely, the sense of self. The classic psychedelics (or classic hallucinogens) include LSD, psilocybin (found in over 200 known mushroom species), DMT (in dozens of plants) and mescaline (in peyote and San Pedro cacti). Chemically they fall into tryptamines (psilocybin, DMT) and phenethylamines (mescaline), but what matters most is that all of them act as agonists or partial agonists at the serotonin 2A receptor.

Beyond the classics, Johnson describes NMDA antagonists such as ketamine, PCP and dextromethorphan, which produce overlapping but more dissociative effects; salvinorin A from Salvia divinorum, a kappa opioid agonist on which his group did the first blinded, controlled human research, producing reality-altering experiences on par with smoked DMT; and MDMA, which stands in a class by itself. MDMA is often called an entactogen ("touching within") or empathogen. Unlike the classic psychedelics, which mimic serotonin at the receptor, MDMA works on the presynaptic side by releasing more of the brain's own serotonin, along with dopamine. Johnson uses these examples to show that chemical structure doesn't dictate effects: small molecular tweaks can profoundly change how a drug interacts with receptors. He also mentions anticholinergics like atropine and scopolamine, which produce true hallucinations, such as conversations with people who aren't there, something the classic psychedelics rarely do.

Dissolving the Brain's Models

Huberman asks whether psychedelics disrupt the brain's analysis of space and time. Johnson finds that interesting but notes alcohol and benzodiazepines also scramble space-time orientation. He prefers to describe psychedelics as profoundly altering models: we are prediction machines, and much of perception is top-down. A child learns that a thrown ball falls down; seeing it fly upward would be mind-blowing, and psychedelics can loosen those learned predictions so that the violation isn't filtered out. He mentions rare but credible cases of people who believed they could fly, and a research volunteer who appeared to try to dive through a painting on the wall.

On mechanism, Johnson is frank that answers are limited. Serotonin itself obviously isn't psychedelic, or eating a bagel would make everyone trip. Classic psychedelics activate the 2A receptor, which increases glutamate transmission downstream, possibly a commonality with ketamine. He discusses esketamine (Spravato), approved for treatment-resistant depression, noting it is given at low doses without psychedelic therapy and its antidepressant effects last about a week. By contrast, older Russian work by Krupitsky, using high-dose ketamine treated as a psychedelic therapy with preparation and discussion, found high success rates for heroin and alcohol addiction. Johnson wonders whether ketamine would produce longer-lasting results, like the year-plus effects seen with psilocybin, if it were delivered in a psychedelic therapy model.

Inside a Psilocybin Trial

Johnson walks through the process. First comes screening over a couple of days: structured psychiatric interviews to exclude psychotic disorders like schizophrenia and bipolar disorder, plus cardiovascular screening. Then come about four to eight hours of preparation, building therapeutic rapport with the guides and explaining the range of possible effects. He describes drugs as "uppers, downers, and all arounders," with psychedelics being all-arounders: you could have the most beautiful or the most terrifying experience of your life, so the team lays out everything that might happen.

Participants receive pure psilocybin in a small capsule rather than mushrooms (which in the U.S. are most likely Psilocybe cubensis). Early studies in healthy volunteers compared placebo with 5, 10, 20 and 30 milligrams per 70 kilograms of body weight; newer trials drop body-weight adjustment, and therapeutic doses are typically in the 20 to 30 milligram range. Effects begin in about 15 minutes to an hour. The session involves few tasks, since fMRI scans and cognitive testing make the experience less meaningful. Participants wear eyeshades and lie on a couch, and every emotional response is welcome, even crying hysterically. Johnson notes that people with recreational experience sometimes have to unlearn the social rule of holding it together. Blood pressure and pulse are checked about every half hour; on the rare occasions it rises too high, a physician gives nitroglycerin under the tongue, which doesn't affect the experience. He recalls one participant asking, "tell me again, I can't die," because her heartbeat felt overwhelming.

Dosing happens around 9 a.m., and by late afternoon there's an initial conversation. That night participants write about the experience, anywhere from a few bullet points to 20 pages, and return the next day for a one to two-hour integration session using supportive, non-directive therapy. Johnson encourages people to take the experience seriously, unlike friends who might dismiss it the next day. He also advises against big decisions right away, like ending a relationship or quitting a job: "sit on that two weeks."

Letting Go and the Changing Self

Huberman frames the therapeutic core as letting go: expanding a narrow perceptual "bubble", whether a sensation, an emotion, a memory or even a pen, without fear of where it leads. Johnson agrees that people who try to hang on are more likely to have a bad trip, and that eyeshades help turn attention inward. Normally, habituation lets us ignore the miracle of everyday things so we can function; under psilocybin, someone might find their own hand breathtaking, which is one reason people shouldn't navigate city streets in that state. Huberman compares this to Aldous Huxley's description in The Doors of Perception of a chair exuding its chair-ness after a large dose of mescaline.

Why would falling in love with a pen and reprocessing childhood trauma both lead to feeling better? Johnson's best speculation is that "the common denominator are persisting changes in self-representation." He adds that "the self is the biggest model," including labels like smoker or failure. He credits philosopher Chris Letheby's book for arguing that changes in self-representation can explain therapeutic effects from a naturalistic point of view, with or without spiritual interpretations. A smoker in one of his studies said it felt like he could simply decide not to smoke, like flicking a switch. Johnson calls these "duh experiences: people realize, with real force, something they'd told themselves a million times, as in, my God, I could just decide. Huberman adds that neural networks don't change in response to language or affirmations, which he considers an unkind idea for depressed people; They change in response to experience," given the right neuromodulators. He also stresses that plasticity is a process, not an event, and may unfold over long periods after the trigger.

MDMA, Bad Trips and Flashbacks

MDMA raises both dopamine and serotonin, an unusual combination. Johnson speculates that reduced amygdala reactivity may help people reprocess traumatic memories without a fight-or-flight response, which could explain its focus on PTSD. It may also be better suited to trauma for a broader range of people because truly challenging bad trips are much less likely than with classic psychedelics, where people can feel all of reality shattering.

On flashbacks, Johnson says the popular idea that drug gets stored in body fat has no evidence. The term covers several things. Hallucinogen persisting perceptual disorder (HPPD), in the DSM, involves distressing, persistent halos, trails or color distortions. It has never been seen in thousands of participants in either the early era of research or modern trials, and some people with HPPD have never taken a psychedelic, with episodes sometimes prompted by alcohol, benzodiazepines, cannabis or tobacco. He suspects a rare neurological susceptibility and says psychedelics get the blame through a kind of xenophobia toward the unfamiliar, pointing to the widely reported "bath salts" face-eating case in which the only drug found was cannabis. More commonly, flashbacks are state-dependent learning, where a similar context brings back the thoughts and feelings of the experience, or mild perceptual anomalies for a day or two afterward.

The Real Dangers

Johnson names two big risks. The first is people with psychotic disorders like schizophrenia or the mania of bipolar disorder, or a strong predisposition to them. Psychedelics can destabilize them, as with Syd Barrett of Pink Floyd, though cause and effect are hard to untangle because first psychotic breaks and first drug use both tend to occur in adolescence and early adulthood. Trials exclude these people, and even those with a close relative who has these disorders, out of an abundance of caution, and a careful psychiatric interview can reliably identify them.

The far more likely danger is a bad trip, which anyone can have. Even in Hopkins' carefully prepared setting at around 30 milligrams of psilocybin, "about a third of people will say, essentially at some point they have a bad trip," though they may have one of the most beautiful experiences of their life minutes later. Usually people get through it, but Johnson keeps a growing file of cases where people panicked and were hurt or killed, running into traffic or falling from heights, including an 18-year-old in Oregon who took a large dose, ended up disoriented in a neighbor's house, and was killed by police. Context, a sober companion and a safe setting matter enormously.

Microdosing: Claims Versus Evidence

Huberman notes that "micro" can mislead, since LSD is active in micrograms. Johnson explains that psychedelic effects from LSD typically start around 100 micrograms, which is a full dose, not a microdose, and a common mistake is ending up with a full-blown experience. Microdosing aims for about a tenth of an entry-level dose, roughly a milligram of psilocybin or half a gram of mushrooms, though street methods like cutting blotter paper are imprecise. Claims fall into two groups: a better alternative to ADHD stimulants and a better antidepressant.

The handful of double-blind studies, four or five at the time, have found anything from no effect to slight impairment, such as worse time estimation, along with people feeling a little high. None have shown improved creativity, cognition or sustained mood, though no study has yet modeled the intermittent dosing schedules promoted by advocates like Paul Stamets. Huberman brings up his Stanford colleague Alia Crum's research on belief effects to note that placebo is part of all medicine. Johnson's bet, based on anecdotes, is that any real effect is most likely antidepressant, like a better SSRI. But he adds a caution: most common psychedelics, including MDMA, also stimulate the serotonin 2B receptor, which has been linked to heart valve problems and was why fen-phen was pulled from the market. That's not a concern for a few therapeutic sessions, but taking something twice a week for years is a different question. Ultimately, he says, "I'm interested in big effects," meaning durable improvements from one to three high-dose sessions.

Young People, Legal Status and Regulation

No formal research has tested psychedelic therapy in people under 18, but Johnson expects it, since the FDA has signaled interest in studies in young people and depression is a serious problem in adolescents. Huberman shares that his own high school has been known for a high suicide rate, which makes careful clinical exploration seem worth pursuing.

Legally, these compounds remain Schedule I federally, so local decriminalization, which can mean anything from near-legalization to a lowest-enforcement-priority policy, doesn't eliminate risk. Johnson describes Oregon's state-level psilocybin therapy initiative and its challenge of integrating with federal law. Long term, he doubts today's criminalization model is sustainable and says, "I like the word regulation better than legalization," imagining something like a driver's license with training and guided first experiences for personal use. He predicted MDMA would be approved for PTSD within about three years, with psilocybin for depression a year or two later, delivered in clinics rather than as a take-home prescription. Both psilocybin and MDMA had received FDA breakthrough therapy designations, and he argues medical research would be needed even if these drugs had never been criminalized.

Head Injury Research and Funding the Field

Huberman points out that much traumatic brain injury comes not from sports but from construction work, the military, and bike accidents and falls. Johnson calls psychedelic treatment for brain injury exploratory, resting on human anecdotes plus rodent research from labs like David Olson's and Bryan Roth's showing growth of dendrites and new connections in the days after psychedelics. He hoped to study retired athletes with head impact histories, such as UFC fighters, treating their depression while also measuring cognition and gray matter on MRI.

Finally, Johnson explains that most psychedelic research was funded by philanthropy, not the NIH. The Heffter Research Institute, co-founded by ethnobotanist Dennis McKenna, the Beckley Foundation led by Amanda Feilding, which funded early smoking-cessation work, Bob Jesse's work on mystical experience, and MAPS kept the field alive. A $17 million gift, split between the Cohen foundation and a collaborative led by Tim Ferriss, created the Hopkins center. Johnson says this work lets him feel he is making a real difference. He directs people interested in trials to the Hopkins psychedelic research website and to clinicaltrials.gov, and notes upcoming studies on opioid addiction, PTSD and LSD for chronic pain, plus surveys on therapeutic psychedelic use and holotropic-style breathwork.

Conclusion

This conversation makes the case that psychedelics are powerful but double-edged tools whose value depends heavily on context. In Dr. Johnson's clinical model, careful screening, hours of preparation, a safe setting, a willingness to let go and structured integration afterward help one to three high-dose sessions produce durable relief from depression, addiction and existential distress, possibly by reshaping the way people see themselves. The risks are real: destabilization in those prone to psychosis or mania, and bad trips that can turn dangerous outside a protected setting. Microdosing claims remain unproven. Johnson's measured optimism, grounded in rigorous trials and a preference for smart regulation over either prohibition or a free-for-all, offers listeners a clear picture of where the science stands and where it is heading.

This is a summary of "Dr. Matthew Johnson: Psychedelics for Treating Mental Disorders" from Huberman Lab, giving you the GIST so you can decide if you want the REST. Listen to the full episode.