🫠 Psychonaut POV

Welcome to Tricycle Day. We’re the psychedelics newsletter that thought biomarkers were just what happened when a Crayola box made the rounds at daycare. 🖍️

Three decades into studying PTSD, Rachel Yehuda thought she'd seen every overhyped treatment come and go. Now she runs Mount Sinai's Center for Psychedelic Psychotherapy and Trauma Research, where she's learning that healing is more nuanced than anyone imagined.

We asked Rachel what changed her mind about MDMA, why she focuses on post-traumatic growth over pathology, and how genetic biomarkers might predict who benefits most from psychedelic therapy.

FROM OUR SPONSORS

Entrepreneurs are hopelessly addicted to “systems.”

Problem is, most are using someone else’s instead of their own. And they wonder why they don’t work. Go figure.

Alexander Ford's free 90-minute masterclass reveals how understanding behavioral science can help you stop outsourcing your power, reconnect to your original vision, and find your own path to success in business.

That goes for psychedelic coaches, transformational leaders, or any entrepreneur drowning in borrowed blueprints.

It’s time to stop copying and start creating.

Save your seat for "The Moment" masterclass.

You weren't always a believer in psychedelic therapy. What changed your mind?

I'm a fairly mainstream academic. Let’s put it this way: I had very limited personal experience with Schedule I compounds, and none with MDMA or classic psychedelics.  As a scientist, I'm naturally skeptical, and in my area of interest, trauma and PTSD, there have been a lot of people promising that very brief treatment approaches can offer miraculous outcomes. Having worked in the field for several decades, I knew that it's more complicated than that.

When word started talking about the Phase 2 trials with MDMA and PTSD, I thought, "Oh, not another one of these promises." Because MDMA had been linked with neurotoxicity—or so I read—and because many people with PTSD struggle with addictions, that combination of "it's too good to be true" and "people love it too much" made me question whether this was a good idea.

Then I met Rick Doblin. One of his donors asked me if I could explain why MDMA works for PTSD from a neuroscience perspective, and I said no, because I couldn’t. Rick told me I needed to update my information—that I was wrong about the neurotoxicity and that their clinical results really were good.

He invited me to the therapist training in Israel, where I met Michael and Annie Mithoefer. Their focus on the psychotherapeutic process that went along with MDMA really resonated with me. They emphasized that it's not a drug-alone phenomenon; it wasn't presented as a quick fix. I had already become disenchanted with reductionist views that a drug will change a brain circuit and then everything will be fine in trauma survivors. That's not how you heal from trauma. But this was different. That wasn't the claim.

Why did you start the Center for Psychedelic Psychotherapy and Trauma Research at Mount Sinai? What gaps were you seeing that needed to be filled?

The practical answer is that it seemed like such a heavy lift to get one study off the ground that you might as well think big. To run even a single psychedelic study would require a lot of effort, reframing, and training. So why create a whole infrastructure and just do one little study?

The deeper answer is that there’s still so much room for improvement in how we treat trauma. I've been doing clinical trials for a long time, and mostly the results we got trying to replicate other people's findings just weren't as great as what others were reporting. Part of the discrepancy had to do with the fact that veterans with PTSD seem to do less well than civilians.

For example, with prolonged exposure, which some consider the treatment with the best evidence, we had a lower rate of positive outcomes and a 30% dropped out. Even in the best case scenarios, our current treatments may give you a very good boost, but don't really graduate you from extremely symptomatic to non-symptomatic.

I wondered if psychedelic-assisted therapy could be a much better way to help veterans with PTSD than what we have. Since I already head a division for the study of trauma and PTSD, creating this psychedelic center was a nice way to contextualize all that knowledge and advance it to the next stage.

Your work focuses on post-traumatic growth rather than only on pathology. What does that actually mean when it comes to treating trauma?

The idea is that you can process trauma in a way that really promotes growth, purpose, and resilience. Some of the most impactful people in society have been trauma survivors, and they're impactful not despite their trauma, but because of it. There's a process of meaning making that can allow people to cross over to a place where, because of what happened to them, they want to either make things better for someone else or use their experience for personal growth.

You can go through a very meaningful existential process where you feel that you've made room for the trauma as part of you—not as a blemish, but as something you can exist with. Maybe you’re even proud of what you’d made of that experience. That’s a big counterweight to feeling like you don't belong on earth because of what happened to you, which is where many people start. It's like what Viktor Frankl wrote about his own search for meaning: I didn't have control over what happened then, but I do have control over what I do now.

Those are conversations that happen in good psychotherapy, but can’t happen in quick or targeted approaches. What psychedelics seem to do is encourage this deeper work. It's not "let's stop your nightmares"; it's "let's talk about what happened, what you’re experiencing, what you’re feeling." To me, it harkens back to earlier days of psychiatry where clinicians focused on the individual and developed very customized plans for them, even if they couldn't be standardized.

Your research is looking for biomarkers that could predict who's likely to respond to MDMA therapy. What have you discovered so far?

That work is early for us, so I won't draw conclusions yet. But there's been a paper published looking at epigenetic markers, where we found that some of the genes we previously reported to change with positive cognitive behavioral therapy outcomes were also found to associate with MDMA. We've completed a trial and collected biomarker samples, and now we want to explore these questions.

This idea of looking at responders and non-responders has been a research interest of mine for 15 years, long before I even thought about psychedelics. We have a lot of data about these biomarkers in connection with other kinds of therapies. So we'll be in a position to ask: what does recovery look like however it's achieved, and is it different depending on what treatments were used to achieve it?

A hypothesis I have (with no hard data to support it) is that people who come to MDMA-assisted therapy to “do the work” will have better outcomes than people who believe that the power lies in the drug's ability to rewire the brain while they just lie there passively.

One thing we're getting a handle on in the field is the durability of effects. So far people's experiences seem durable, but they may be particularly durable if they use the experience to continue healing and take actionable steps after their psychedelic sessions. A simple analogy is losing weight. I could lose 10 pounds on a diet, but I'm more likely to keep them off if I stop eating the foods that made me gain weight to begin with.

You're studying both MDMA and psilocybin for PTSD. How do you decide which medicine might work better for different patients, and what differences are you seeing between them?

When we started our initial Phase 2 study with psilocybin, I wasn't expecting much, but 80% of the people we treated had great outcomes. It helped me understand that the psychotherapy during the psychedelic session may not be as important as I thought, because in the psilocybin model, unlike with MDMA, you're not doing a lot of talking. The patient is having their own internal experience.

I became more excited about psilocybin for trauma than I expected to. There are obviously many kinds of approaches that will help, and maybe comprehensive psychotherapy isn't always necessary as long as they have a powerful internal experience that they can process later. A few years ago, if someone said they’d had a transformative experience without any psychotherapy during a session, I would have raised an eyebrow. I think we still need to learn more about how healing happens in these contexts. At some point, traumatic experiences need to be processed, but maybe there is more than one way to do it.

Still, I think there's a lot more to what happens in a psilocybin session than you can easily quantify. As a therapist or facilitator, you could be doing nonverbal things that are very reassuring and make people feel safe while encouraging an internal process. Even if there is no strict psychotherapy happening, it's still a lot more complicated than just looking at the pharmacology.

For scientists, it's an inconvenient truth that what's going on here is more than a drug effect. We need to understand how the drug facilitates processes outside of its own properties. The whole point of our biomarker research is to see if there are commonalities or different features between MDMA, psilocybin, and other forms of therapy that don't require a psychedelic. These studies may take awhile, so we're settling in for a marathon, not a sprint.

Want more from Rachel?

Find her at Mount Sinai in New York City, or browse her published research papers.

UNTIL NEXT TIME

That’s all for today, Cyclists! Whenever you’re ready, here’s how we can help.

ONE CYCLIST’S REVIEW

Forwarded this email? Subscribe here.

DISCLAIMER: This newsletter is for educational and informational purposes only and is not intended as a substitute for professional medical advice. The use, possession, and distribution of psychedelic drugs are illegal in most countries and may result in criminal prosecution.