Dr. Matthew Johnson on Psychedelics for Treating Depression, Addiction and Trauma

High-Level Overview

In this episode of the Huberman Lab podcast, Andrew Huberman talks with Dr. Matthew Johnson, professor of psychiatry at Johns Hopkins School of Medicine and director of its Center for Psychedelic and Consciousness Research. They cover what makes a compound "psychedelic," how the classic psychedelics, MDMA, ketamine and others differ, and what actually happens in a Hopkins psilocybin session from screening to follow-up. Johnson offers his best guess at why such different experiences lead to lasting improvements: a change in how people represent themselves.

The tone is curious, careful and collegial. Huberman brings a neuroscientist's questions about receptors, neuroplasticity and perception, and Johnson, who calls himself primarily a behavioral pharmacologist, answers with clinical observations while repeatedly flagging what is still unknown. The conversation moves from definitions and biology into the therapeutic model, then to risks (bad trips, psychosis, flashbacks, heart valves), microdosing, legal status, brain injury research and how the field is funded.

The Discussion Explores:

• What counts as a psychedelic: classic serotonin 2A agonists, NMDA antagonists like ketamine, salvinorin A, and MDMA as an entactogen
• Why ketamine (Spravato) is prescribed without psychedelic therapy, and what that may cost in lasting benefit
• A Hopkins psilocybin session step by step: screening, preparation, dosing, eye shades, monitoring and integration
• Letting go, and why changes in self-representation may explain lasting therapeutic effects
• Flashbacks, HPPD and why the fat-storage myth is false
• The real dangers: psychotic and bipolar vulnerability, and bad trips in unsafe settings
• Microdosing claims versus the evidence, including a possible heart valve concern with frequent use
• Legal status, regulation versus legalization, research on brain injury, and philanthropy's role

Deep Dive into Main Ideas

What Makes Something a Psychedelic

Johnson says "psychedelic" is more of a cultural term than a pharmacological one, because it spans several drug classes. What they share is the ability to profoundly alter one's sense of reality, including the sense of self. The classic psychedelics, LSD, psilocybin (found in over 200 mushroom species), DMT and mescaline, act as agonists or partial agonists at the serotonin 2A receptor. Other classes that can be called psychedelic include NMDA antagonists such as ketamine, PCP and dextromethorphan, and salvinorin A, a kappa opioid agonist from Salvia divinorum that his group studied in the first blinded controlled human research. MDMA stands in a class by itself: an entactogen that works mainly by releasing serotonin rather than mimicking it at the receptor.

Huberman asks whether psychedelics alter the brain's analysis of space and time. Johnson notes alcohol and benzodiazepines disrupt that too, and prefers a different framing: we are prediction machines, and psychedelics loosely dissolve the models we build, from how a ball falls to who we think we are. Chemistry does not neatly predict effects, he adds; mescaline looks more like dopamine than serotonin yet acts on the same receptor as psilocybin.

Ketamine Without the Therapy

Ketamine is psychedelic in a more dissociative way, and a nasal form, Spravato (esketamine), is FDA approved for treatment-resistant depression. Johnson points out it is not given as psychedelic therapy: patients are essentially told to ignore the altered experience as a side effect. Its antidepressant effect kicks in immediately but lasts about a week, while his group sees effects from psilocybin a year or more later. Older work in Russia by Krupitsky used higher ketamine doses framed as psychedelic therapy, with preparation and discussion, and reported very high success rates for heroin and alcohol addiction. Johnson wonders whether ketamine clinics would get more out of it if they treated it the same way.

Inside a Hopkins Psilocybin Session

Participants first undergo a couple of days of screening: structured psychiatric interviews to exclude psychotic disorders and bipolar disorder, plus cardiovascular checks. Then come roughly four to eight hours of preparation, building rapport with the guides and learning what could happen. Johnson calls psychedelics "all arounders," in contrast to uppers and downers: you could have the most beautiful or the most terrifying experience of your life, so the aim is that nothing comes as a surprise. On the day, people take pure psilocybin in a small capsule, usually 20 to 30 milligrams (his group has stopped adjusting for body weight), and it kicks in after about 15 minutes to an hour.

The session is not filled with tasks. People wear eye shades and are told that any emotional response is welcome, even crying hysterically. Johnson says people with recreational experience can be harder to train because in social settings the rule is to "hold your shit. Blood pressure and pulse are checked regularly; on the rare occasions it has gone too high, a physician has given nitroglycerin. He recalls one woman who said, Matt, tell me again, I can't die," because she felt her heart would burst through her chest. That evening participants write about the experience, and they return the next day for an integration session. He advises against big life decisions for a couple of weeks afterward.

Letting Go and Changing the Self

Huberman frames the experience as expanding a narrow "perceptual bubble, whether that is falling in love with a pen or reliving a painful family conflict, and asks why such different experiences lead to similar benefits. Johnson's best guess, crediting philosopher Chris Letheby, is lasting change in self-representation. I think that the self is the biggest model," he says: I am a smoker who can't quit, I am a depressed person who is a failure.

He describes what he calls "duh experiences. A smoker in one session realized, I can decide not to smoke, and held on to it. People with cancer have said, I'm causing most of my own suffering. These sound obvious, but in the experience they carry a supercharged sense of agency. Huberman adds that affirmations alone rarely rewire people; neural networks change in response to experience," especially with neuromodulators like serotonin and dopamine present. Johnson also says fear and resistance shape bad trips: surrendering to the experience tends to go better than trying to hang on.

Flashbacks and HPPD

The street idea that psychedelics are stored in body fat and released later has no evidence behind it, Johnson says. "Flashbacks" covers several things. Hallucinogen persisting perceptual disorder (HPPD), involving lasting halos, trails and color distortions that cause distress for months, is real but rare, and has never been seen in thousands of research participants in either era of study. It has even been reported in people who never took a psychedelic, after alcohol, cannabis, benzodiazepines or tobacco, which suggests a rare neurological susceptibility. More common is state-dependent recall, where a similar context brings back the feelings of a trip, and brief perceptual oddities in the day or two after, which people often joke about as a "free trip."

The Real Dangers

Johnson names two big risks. The first is people with or predisposed to psychotic disorders or mania, who can be destabilized. He cites Syd Barrett of Pink Floyd as a likely example, while noting that first breaks and early drug use happen at the same ages, which makes cause hard to untangle. Screening can reliably identify these people, and his trials also exclude those with close relatives who have these conditions.

The second, more common risk is the bad trip, which can happen to anyone. Even in his lab's ideal setting at around 30 milligrams, about a third of people report a period of strong anxiety or fear at some point, though they may have a beautiful experience minutes later. Outside such settings, he keeps a growing file of cases where people ran into traffic, fell from heights or were killed, including an 18-year-old in Oregon who took a large dose, wandered disoriented into a neighbor's house and was killed by police. He also notes MDMA tends to produce fewer terrifying experiences, which may make it better suited to trauma work.

Microdosing: Claims and Evidence

Microdosing means taking roughly a tenth of an entry-level psychedelic dose, about 10 to 20 micrograms of LSD (where 100 micrograms is a full dose) or around half a gram of mushrooms. Claims fall into two camps: a better Adderall for focus, or a better antidepressant. The handful of placebo-controlled studies so far have found no benefit, or slight impairment, such as worse time estimation, and people feel a little high. However, no study has yet tested the specific intermittent schedules advocates like Paul Stamets recommend. Johnson's bet is that if anything is real, it is an antidepressant effect.

He raises a caution rarely discussed: most common psychedelics, including MDMA, also activate the serotonin 2B receptor, which has been linked to heart valve problems and was why the diet drug fen-phen was pulled. That is unlikely to matter for a few therapeutic doses in a lifetime, he says, but taking something twice a week for years is a different matter. Huberman adds that he dislikes the goal to "increase plasticity" in general, saying "plasticity is never the goal"; goal-directed plasticity is.

Law, Regulation and Young People

All these compounds remain Schedule I federally, so local "decriminalization, which can mean anything from near-legalization to a low police priority, still leaves people exposed. Johnson points to Oregon's state-level psilocybin therapy program, which is still working out how it fits with federal law. Long term he favors smart rules over criminalization: I like the word regulation better than legalization." He imagines something like a driver's license for psychedelic use, with training and guided first experiences. He predicted that MDMA would be approved for PTSD within about three years of the recording, with psilocybin for depression a year or two after, delivered in clinics rather than pharmacies. Both have FDA breakthrough therapy designations. There is no formal research in people under 18 yet, but he expects the FDA will want it, given adolescent depression; Huberman mentions the high suicide rate at the high school he attended.

Brain Injury and the Future of the Field

Johnson hopes to study retired UFC athletes with depression and a history of repeated head impacts, aiming to treat the depression and, more tentatively, look for improvements in cognition and changes in gray matter. The idea draws on rodent studies from labs such as David Olson's and Bryan Roth's showing new dendrite growth and connections after psychedelics, plus anecdotes from athletes. He stresses this is exploratory.

On funding, he explains that federal money has mostly supported studying these drugs as drugs of abuse, while most of his group's work was funded by philanthropy: the Heffter Research Institute, the Beckley Foundation and the Council on Spiritual Practices. A $17 million gift, split between the Cohen Foundation and a Tim Ferriss-led group, allowed Hopkins to create its center. People interested in trials should check hopkinspsychedelic.org or search clinicaltrials.gov rather than emailing him directly, because treatment only happens within specific approved studies.

Conclusion

Dr. Matthew Johnson presents psychedelics as powerful but double-edged tools whose benefits depend heavily on context. In a carefully screened, prepared and supported setting, a few high-dose sessions of psilocybin or MDMA appear to produce lasting relief from depression, addiction and trauma, possibly by loosening the rigid stories people tell about themselves. Outside that setting, bad trips and vulnerable minds make real harm possible, and popular practices like microdosing remain largely unproven. His measured approach, careful about what is known and open about what is not, makes this a useful listen for anyone trying to separate the promise of psychedelic medicine from the hype.

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