#148 - Psychedelics for Mental Health

0:02Matt Walker: Hi there, it's Matt here and welcome back to the podcast. A quick word before we begin. This podcast is an independent, personal project, entirely separate from my role as a university professor. Everything you hear is my own scientific opinion and my own reading of the evidence, not the position of my university nor of any organization I'm affiliated with, and no endorsement should be inferred. What follows is education, not medical advice. It's no substitute for a qualified physician who knows you and your history. If you have a health concern, speak with your doctor first. With that said, today's podcast is another of our general brain episodes where we learn about how truly remarkable the brain and mind are.

0:52Matt Walker: And in this episode, I want to talk about a class of molecules that has gone in a single generation from the back of a police evidence locker to the front page of the world's most serious medical journals. I want to talk about psychedelics and I want to do it carefully because this is a field where the hype and the evidence are not yet the same size. Let me set the stakes plainly. Depression is now one of the leading causes of disability on the planet. For many people, the medicines we have work and work well, but for a fraction of individuals, one antidepressant fails, then a second, then a third, and they are left in a kind of gray permanent weather told to simply keep trying.

1:37Matt Walker: So when a treatment comes along that claims not to dial the weather down a notch, but to part the clouds entirely in a single afternoon. You can understand why the whole world leaned in. None of this is new, and the history explains why the field runs so hot. In 1943, a Swiss chemist named Albert Hoffman accidentally absorbed a trace of a compound he'd synthesized. A few days later, he took a slightly larger dose and took the most famous bicycle ride in the history of science. Home through a world gone suddenly strange and luminous. That compound was LSD. Through the 1950s and 60s, psychedelics were not fringe at all, but a serious mainstream branch of psychiatric research.

2:27Matt Walker: Then the culture caught fire. The political backlash was ferocious, and by the early 1970s, these drugs were classified as having no accepted medical use and locked away. The research didn't slow. It stopped almost completely for a generation. So what you're watching now in our most cautious journals is not really a discovery. It's a resurrection, a reopening of questions abandoned half a century ago, carrying 50 years of pent-up longing behind it. And longing, as we'll see, is not the same thing as evidence. So let's begin with the molecule. The one doing most of the heavy lifting in the research is psilocybin, the active ingredient in what people casually call magic mushrooms.

3:14Matt Walker: Once it's in the body, it becomes psilocin. And psilocin goes looking for a very specific lock on the surface of your brain cells, a serotonin receptor called the 5-HT2A receptor. It fits that lock and turns it. And from that one small molecular event, the entire cathedral of your conscious experience begins to rearrange itself. Now, what does that rearrangement look like from the inside of the brain? Here is one of the most beautiful counterintuitive findings we have. You'd assume a drug that produces a riot of color and revelation would light the brain up like a stadium. The opposite happens.

3:56Matt Walker: Slide 15 people into a scanner, give them psilocybin through a vein, and activity actually goes down in a set of regions we call the default mode network, the brain's self-referential hub, the seat of that endless inner monologue narrating your life. The very machinery that builds the rigid, egocentric, ruminating sense of me turns its volume down. Hold on to that image, because it's the best metaphor we have for the whole therapy. Think of a hillside covered in snow, with a sledge that has run down the same icy groove 10 ,000 times. That groove is a depressed thought pattern, and the sledge drops into it automatically.

4:40Matt Walker: What the psychedelic seems to do is briefly dump fresh snow across the entire hill. For a few hours, the old groove is gone, and the sledge can travel a path it hasn't taken in years. The clinical bet of this whole field is that with the right guidance during those hours, a person can carve a new groove before the snow settles again. Now go one level deeper down to the single brain cell, because that's where the genuinely new idea lives. Quietening the default mode network is the view from above. Underneath it, in animal work, these compounds set off a burst of structural growth, neurons sprouting new branches and new connection points, the actual physical hardware of learning.

5:28Matt Walker: Some scientists now call this class of molecules psychoplastogens because they throw open a temporary window of heightened plasticity, a span of days in which the brain becomes unusually willing to rewire. If that's true, it changes the whole story. The drug doesn't carry the cure inside it. It pries a window open. And what you do during that window, the therapy, the reflection, the new ways of thinking, is what decides whether anything lasting gets built. The drug is the crowbar, not the renovation.

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8:29Matt Walker: Here is what's new and what I most want you to take from tonight. Psilocybin is not alone. It sits inside a family of classic psychedelics that all pull that same 5-HT2A lever. And in the last decade, the scanners have finally caught each of them in the act, imaging the living brain while a person is actually under the drug. This is the hard science the headlines skip. So let me take you through it properly, because here the detail is the whole point. Start with LSD, the one that began it all. Take 20 healthy volunteers, deliver 75 micrograms into a vein, and watch the brain three different ways at once.

9:12Matt Walker: Its blood flow, its oxygen signal, and the magnetic flicker of its electrical rhythms. Two findings leap out. First, the visual cortex, the patch at the very back of the head that normally answers only to the eyes, floods with extra blood flow and begins pulling in signals from right across the brain. And the size of that effect tracks almost hand in hand with how vivid a person's eyes closed visions are. That is about as close as we have come to watching a hallucination form. Second, the deeper a person's sense of self dissolved, the more one particular link came apart. The connection between two hub regions that normally hold the self together and the decoupling of those hubs predicted the depth of ego dissolution almost point for point, the ego loosening its grip made visible on a scan.

10:06Matt Walker: Then DMT, the molecule inside ayahuasca, and the most spectacular of the lot, a total immersion that arrives in seconds and is gone in minutes. Wire 13 people to an EEG cap, give a modest dose into a vein, and at the very peak the brain's ordinary alpha and beta rhythms, the steady background hum of normal waking, simply collapse, while the raw complexity of the signal, its moment-to-moment unpredictability, climbs past anything we record in ordinary consciousness. The emergence of slower, dreamlike rhythms tracked the eyes-closed visions people reported. Then, a bolder version of the experiment put 20 people through the same journey inside an MRI scanner and an EEG cap at once.

10:54Matt Walker: 20 milligrams straight into a vein, recording from 8 minutes before the injection to 20 minutes after. Now, the whole picture came into view. The cortex became globally hyper-connected. its normal division of labor dissolving, and the usual hierarchy from simple sensory areas up to the regions that do our most abstract thinking flattened almost to nothing. The effect was strongest in exactly those high-level association areas most densely packed with the 5-HT2A receptor, and the richness of a person's inner experience rose and fell with the complexity of their brain signal, a correlation of 0.7.

11:35Matt Walker: Rarely does the inner world line up with the scanner so cleanly. Ayahuasca DMT's slow-brewed Amazonian cousin tells the same story from the other direction. Slide 10 experienced drinkers into a scanner and the brew quiets that same default mode network we met with psilocybin, dropping activity in its two great hubs, the region behind the forehead, and the one deep in the midline of the brain. And this is not merely a laboratory curiosity. In the first randomized placebo-controlled trial of any psychedelic in treatment-resistant depression, 29 patients received a single dose of either ayahuasca or a matched placebo.

12:20Matt Walker: By the seventh day, the gap was stark. 64 % of the ayahuasca group had responded. Their depression scores cut sharply against 27 % on placebo, and the difference widened with every passing day into a very large effect. One brew, one week, in people nothing else had reached. And then the far edge of the map, 5-M-E-O-D-M-T, the compound in the venom of a particular toad, so fast and so total, it is often described as a controlled demolition of the self. Here, I have to be honest that the human evidence is the thinnest of anything I'll mention tonight, essentially a single careful study. But it is a striking one, 29 people, a high vaporized dose, EEG, running throughout.

13:11Matt Walker: And what it revealed was unlike all the others, not merely quieter rhythms, but the brain's great slow waves, which normally sweep front to back across the cortex, like orderly weather systems, breaking apart within seconds into something turbulent and directionless. The most powerful of these molecules, reorganizing the brain's deepest rhythms almost the moment it lands. One study, early days, and I will say so plainly, but a remarkable first look through the door. Now let me set the classics aside for a moment and give you the one that's already crossed the finish line, ketamine. Strictly speaking, it isn't a classic psychedelic at all.

13:53Matt Walker: It works on a completely different lock, the NMDA receptor, and it's an old anesthetic. But at low doses, something remarkable happens. Severe depression can lift in hours rather than weeks. In a placebo-controlled trial in people with treatment-resistant depression, a single low intravenous dose produced a rapid antidepressant response, measurable within a day. And a nasal spray form is now a licensed medicine for treatment-resistant depression in many countries. What does the brain look like while it's happening? Record it with magnetoencephalography, and you see ketamine reshaping the brain's fast rhythms and loosening the front-to-back connections that normally dominate waking thought.

14:39Matt Walker: And separately, in animal and cellular work, ketamine sets off the same surge of neuroplasticity we met a moment ago. Ketamine quietly demolishes the old assumption that antidepressants must take weeks. The brain, under the right molecular conditions, can change fast. And that one approved fact is what makes the rest of this field impossible to wave away as wishful thinking. So what happens when you carry all of this into a room full of suffering people? The results that first shook the field came from a small study of people with severe treatment-resistant depression, the ones for whom nothing else had worked.

15:23Matt Walker: Given psilocybin in a calm room with two therapists present, their depression scores dropped sharply both one week later and three months later. People ill for years described the fog lifting in an afternoon. But here's where I put my other hand on the table. That study had 12 people, 12, and every single one knew they'd received a powerful psychedelic because of course they did. No comparison group, no sugar pill, nobody kept in the dark. It was an open label feasibility study and its job was never to prove the drug works, only to show the experiment was safe enough to run at all. The headlines that followed were rather more confident than the science underneath them.

16:06Matt Walker: The same caution applies to one of the most moving corners of this research, psilocybin for people facing the end of their lives. Imagine being told you have terminal cancer and on top of the physical fear, a suffocating existential dread descends that no conversation seems to touch. In two well-known trials, a single high dose of psilocybin given with therapy produced substantial and sustained reductions in depression and anxiety in exactly these patients. Effects still measurable six months later. Six months from one session. People described making a kind of peace. That may be one of the most important things medicine can offer a frightened human being.

16:54Matt Walker: Then the field did the responsible thing and built bigger, harder, more skeptical trials. Take the one that put psilocybin head to head against a standard, well-respected antidepressant, escitalopram, in moderate to severe depression. This was the big one in the New England Journal of Medicine, a journal that does not traffic in hype. Both groups improved, and on the trial's main pre-specified measure of depression, the difference between psilocybin and the ordinary SSRI was not statistically significant. It's worth repeating, on its primary outcome, psilocybin did not clearly beat a standard antidepressant.

17:35Matt Walker: Several secondary measures did lean psilocybin's way and its side effect profile was gentler. So this is not failure, it's humility. The honest headline was never psychedelic crushes antidepressant, it was the new treatment held its own on some measures and we need to keep looking. There's another rigorous trial worth its due. Give psilocybin assisted therapy to people with major depression and compare them against a group whose treatment is deliberately delayed, and the ones treated right away show large, rapid drops in depression, many reaching response or remission within weeks. One more brick from a different laboratory in the same wall and the same caveats.

18:20Matt Walker: Modest numbers, no possible true blind, skilled therapists in the room throughout. Here's a detail that fascinates and unsettles me in equal measure. Across several of these studies, the patients who improved the most were often those who reported during the session what researchers carefully call a mystical type experience. A sense of unity, of transcendence, of the self-dissolving, and the depth of that inner experience tended to track with the size of the clinical benefit. Sit with how strange that is for medicine. We are not used to a treatment where the quality of a patient's ineffable inner experience predicts whether the drug works.

19:02Matt Walker: It smudges the comfortable line between a pharmacological effect and a psychological one. And it leaves us with a question we cannot yet answer. Is the molecule healing the brain or is it occasioning an experience that heals the mind? The honest answer is that we don't fully know. And I'd rather say that plainly than dress up uncertainty as confidence. There's one more large trial to know about, testing a single dose of psilocybin at different strengths in treatment-resistant depression. The biggest dose produced a significantly greater drop in depression at three weeks than the smallest. A real, measurable, dose-dependent effect, which is exactly the fingerprint of a genuine drug and not pure suggestion.

19:48Matt Walker: But the same study reported something enthusiasts skate past. Adverse events, including in some participants, suicidal thoughts and self-harming behavior. These are not gentle vitamins. They are powerful psychoactive compounds that can, in the wrong setting or the wrong mind, open doors that are very hard to close. And that brings us to the ghost that haunts this entire field. How do you run a fair test of a drug that announces its own presence so unmistakably? Give someone a placebo and they'll know within 20 minutes that the walls are not breathing and that they're in the control group. It's called the breaking of the blind.

20:31Matt Walker: In a normal drug trial, neither patient nor doctor knows who got the real pill. With a psychedelic, almost everyone knows. And the moment you know you've received the miracle treatment, your expectation, your hope, your sheer relief at being chosen, all of it starts working on your mood entirely separately from the molecule. This is not a footnote. It's the single hardest problem in the room and no one has fully solved it. Let me dwell on the risk because it matters more than any efficacy number. The dominant image of a psychedelic session is serene, a blanket, an eye mask, a carefully chosen playlist.

21:12Matt Walker: And for many people, it is exactly that. But the same loosening of the rigid self that lets one person set down a decade of grief can in another become terror, a sense of dissolving with no exit for hours. This is why the phrase the researchers repeat almost like a prayer is set and setting, your mindset going in, the physical and human environment around you. Let me also tell you what one of these sessions actually looks like because drug treatment conjures entirely the wrong picture. There is no quick prescription. A patient first spends hours with therapists before they ever touch the compound, building trust and preparing for the real possibility of fear.

21:59Matt Walker: Then on dosing day, they lie on a couch for six or seven hours, eye mask on, carefully chosen music playing with two trained guides there the whole time, not steering the experience, but holding the space if the journey turns frightening. and afterwards comes integration, further sessions to make sense of what surfaced. The molecule occupies a single day. The treatment around it spans weeks.

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24:10Matt Walker: Now, it's important to be clear about who these treatments are not for. People with a personal or family history of psychosis or schizophrenia are generally excluded and for good reason. A compound that loosens the grip on ordinary reality is precisely the wrong tool for a brain already prone to losing it. There are cardiovascular cautions too, and interactions with other psychiatric medications. The careful screening that filters out the wrong candidates is not red tape. It is part of what makes the treatment safe at all. Which brings me to the compound with the most advanced and most cautionary story of all.

24:53Matt Walker: Not a classic psychedelic, but MDMA, the same chemical sold on the street as ecstasy. MDMA does something different. It doesn't dissolve the self so much as it quiets the brain's threat alarm, the amygdala, while flooding the system with warmth and trust. And we can see that first part on a scan. Give people MDMA and the amygdala's response to angry, threatening faces is measurably blunted while the drug is on board. That particular combination turns out to be uncannily suited to one of the hardest conditions in all of medicine, post-traumatic stress disorder. Think about what trauma therapy requires.

25:35Matt Walker: To get better, a survivor usually has to turn and face the memory to walk back into the burning building in their mind with a guide. For many, the fear is simply too overwhelming. The alarm screams too loudly. The theory behind MDMA assisted therapy is that the drug turns that alarm down just enough and turns trust up just enough that a person can finally approach the memory without being consumed by it. The drug doesn't do the healing. It opens a window so the therapy can walk in. And in a rigorous, randomized, placebo-controlled phase 3 trial, the results were striking. After three sessions of MDMA-assisted therapy, roughly two-thirds of participants with severe chronic PTSD no longer met the diagnostic criteria for the disorder at all, compared with about a third in the placebo-with-therapy group.

26:31Matt Walker: People imprisoned by their trauma for, on average, well over a decade, walking out no longer meeting the definition of the illness. A second confirmatory phase 3 trial in a more diverse group reported the same direction of effect. If it holds, it is one of the most important developments in trauma care in a generation. And yet, you already know what I'm going to say because we've built this muscle together all night. The blinding problem is, if anything, worse with MDMA. And there have been serious questions about the conduct of some of this research, about how adverse effects were reported, and about the fervent belief of some therapists involved, a belief that can subtly shape what a vulnerable patient feels and reports.

27:20Matt Walker: A major regulatory body recently looked at this very evidence and declined to approve the treatment, asking for more, cleaner data. That is not the system failing. That is the system working, doing the careful, frustrating, unglamorous job it's supposed to do before it tells millions of suffering people that something is safe. So let me gather all of this into a single, honest shape, because the truth is more interesting than either cartoon version. The first cartoon is the evangelists, that these are miracle cures, that the establishment is suppressing them, that one journey can rewrite a broken life.

27:59Matt Walker: The evidence does not support that certainty. The most rigorous trials are humbler than the headlines. The blinding is a genuine and unsolved problem, and the risks are real. The second cartoon is the cynics, that this is all placebo and recycled 1960s wishful thinking. And the evidence does not support that either, because the signals in end-of-life anxiety, in treatment-resistant depression, in PTSD, are large, repeated, and appearing in our most demanding journals. Something real is happening here, something worth the most serious science we can bring. The grown-up position lives between those two.

28:45Matt Walker: Here is a genuinely promising set of tools, behaving in ways that suggest they could help people we currently fail. And here is a field that still has to solve hard problems of blinding, of safety, of standardizing the therapy before it earns the right to your full belief. Holding both at once is not fence-sitting. it is what it feels like to think clearly about something that matters. One more thing, because you've certainly heard about it, microdosing. The practice of taking tiny sub-perceptual amounts, far too small to actually feel every few days, hoping to nudge up mood, focus, creativity.

29:27Matt Walker: It's become a genuine cultural phenomenon, especially in high-pressure workplaces. So what does the evidence actually say? Considerably less than the enthusiasm would have you believe. In the largest placebo-controlled study of microdosing to date, where people cleverly blinded themselves, muddling real microdoses and dummy capsules so they couldn't tell which they were taking, the dramatic benefits showed up just as strongly in the placebo group. People who merely thought they were microdosing improved just as much as those who actually were. That doesn't prove the practice does nothing, but it is a bracing reminder that expectation is one of the most powerful drugs any of us will ever take, and that the plural of anecdote is not data.

30:15Matt Walker: Let me leave you with a thought I find quietly hopeful beneath all the caution. For decades, our model of mental illness was essentially a plumbing model. A chemical was low, so you topped it up every day, perhaps forever. What these compounds are forcing us to consider is a completely different idea, that the brain might have, latent within it, a capacity for rapid, profound reorganization, that under the right conditions, in the right hands, a mind frozen into one shape might be able to thaw and reform into another. We are not there yet. The snow has not settled on this science. the grooves are still being cut.

30:57Matt Walker: But the mere fact that we are now asking whether a single guided experience can reopen a closed life, that all by itself has already changed psychiatry. And whatever the trials finally tell us, that question is not going back in the evidence locker. A quick note as we wrap up the episode here, this show is mine and mine alone, and is completely separate from my position as a university professor. Every opinion and interpretation you hear comes from me, not from my university and not from any organization I'm affiliated with. No endorsement is implied. This content was created for education purposes only and should not be taken as medical advice.

31:40Matt Walker: Thanks again for listening to today's episode. Bye for now. And one last thing, this episode discusses depression, trauma, and suicidal thoughts. If you are struggling, please reach out to a doctor or a local crisis line. There are people who want to help.