How One Dose of Psilocybin Treats Depression

Medscape

16-06-2025

This transcript has been edited for clarity.
Welcome to Impact Factor , your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson from the Yale School of Medicine.
The story of our lives is etched into the pathways of our brains. Some of those pathways are positive, giving us a sense of self-worth, a resilience to adversity. Some are maladaptive, promoting anxiety, fear, and depression. The pathways lead to actions, and those actions tend to reinforce the pathways. Anxiety breeds anxiety, depression breeds depression.
I think this is part of the reason why problems with mental health are so difficult to treat; our brains are molded into these problematic self-reinforcing configurations and we keep falling into the same ruts. And yes, talk therapy and SSRIs can help to nudge us out of those ruts; work to create new, more productive ruts; and improve our health. But those gains can be difficult to maintain over time.
But what if there were a reset button in our brains? What if we could step outside of those ruts, even for a few hours, and see the pathways for what they are? What if we could start over?
It seems too good to be true, and, to be clear, it may be, but data continue to emerge that the chemical psilocybin — the psychoactive component of so-called 'magic mushrooms' — may do just that. And it may do it after just a single dose.
Magic mushrooms are on my mind — no, not literally — this week thanks to this article, appearing in the journal Cancer . Note the famous final author, Ezekiel Emanuel. It's a small, phase 2 trial of psilocybin, a single 25 mg dose, among individuals with cancer and major depressive disorder.
What's interesting about this study is the duration of follow-up: 2 years. Most psilocybin studies end after a few months, making the long-term implications of treatment unclear.
Here's the setup: Thirty patients (average age, 58 years; 70% women; 80% White) were enrolled, and everyone got the same intervention here. There is no control group.
The intervention occurred over 8 weeks. They first had four visits with a psychotherapist for screening and psychological work, preparatory to receiving the drug. Then they received 25 mg of psilocybin, in a monitored setting, where they remained for about 6 or 7 hours. After that, there were four more psychotherapy visits to integrate the psychedelic experience. Eight weeks, one visit a week, basically.
At multiple timepoints, a participant's mental health was evaluated using some standardized surveys: the Montgomery-Åsberg Depression Rating Scale and the Hamilton Anxiety Rating Scale.
Let's talk about these scales for a moment before I show you the results of this study. The depression scale used here gives scores ranging from 0 to 60, with higher scores being consistent with worse depression. Patients have reported that a reduction by 5 points would be clinically meaningful. A meta-analysis of SSRI therapies showed that these common antidepressant drugs lead to an average reduction of around 3 points vs placebo. Of course, some people do better and some do worse; I just wanted to do some level setting.
Let's look at the psilocybin study. At baseline, participant depression scores ranged from about 10 to 45 or so — pretty significant pathology. By the end of the 8-week intervention period, the average reduction in depression score was 20 points. That is a huge effect.
True, there is no placebo group here, so that 20-point reduction includes the placebo effect, which can be significant in depression trials, but I find it hard to believe that this is all placebo.
We can triangulate the placebo question a bit from this study, 'Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression,' which appeared in The New England Journal of Medicine in 2022.
This was a placebo-controlled trial among people with severe, treatment-resistant depression and used the same depression scale as the study we're talking about today. The psilocybin group had a 12-point improvement and the placebo group a 5.5-point improvement — a net difference that is still around twice as effective as SSRIs.
Of course, the concern about placebo effect is somewhat academic. Especially for conditions like depression, there's a reasonable argument to be made that we shouldn't care whether the effect is mediated biologically or via placebo or both; if it works, it works.
Improvements on the anxiety scale were also impressive. At 8 weeks, there was a 17-point improvement from baseline.
But the most interesting part of this study is the long-term follow-up, which was available for 28 out of the original 30 participants. At 2 years of follow-up, more than half of participants had scores on the depression scale that were less than 50% of their baseline scores — an average reduction of 15 points. Similar effects were seen on anxiety scores.
How might all this work? How can a drug, a molecule like this, lead to sustained changes in serious psychological conditions?
There are a lot of theories. But let's look at the mechanism of action of psilocybin itself. Psilocybin binds to a particular receptor in the brain called the serotonin 2A receptor — in my opinion, the most interesting receptor in the entire brain.
Other substances that bind to this receptor? Mescaline and LSD. Certain mutations in this receptor predispose to schizophrenia as well. And it's hard not to see the parallels between some symptoms of schizophrenia: the sense of unreality, the paranoia, the hallucinations — and the experiences of taking some of these psychedelic drugs. Of course, the drugs are self-limited. Well, at least the acute effects are.
But how are they therapeutic? Some researchers are using a new term to describe drugs like psilocybin: psychoplastogens. The science suggests that one-time use of these agents can allow for a sudden increase in neural plasticity, allowing new neuronal connections to form where they wouldn't in other conditions, and for older connections to break down and restructure. If our brains are etched with the stories of our lives, if our behaviors deepen and reinforce those psychological ruts, psychoplastogens like psilocybin may loosen the soil, so to speak.
This may suggest that those concomitant psychotherapy sessions are actually a critical component of this type of therapy. Perhaps the psilocybin shakes loose some maladaptive pathways, but putting them together in a healthy way still takes work. It wouldn't surprise me if that is the case, and it's a good reminder to those of you reading this that these drugs are not a panacea for mental health. In fact, we're really just beginning to explore the possibilities and the risks in this space. The promise is there, for sure. How many of us wouldn't want to hit 'reset' on some of the maladaptive thinking patterns we have? But for now, the use of these agents for therapeutic purposes really needs to be done under the supervision of a medical professional with experience.