🫠 Psychonaut POV

PRESENTED BY SCHOOL OF PSYCHEDELICS 🤝

Welcome to Tricycle Day. We’re the psychedelics newsletter that has one big irrational fear. That you’ll never realize there is a real-life human being behind the 🫠 emoji that you can reach by replying to any of our emails.

Greg Fonzo started out as a spiritual seeker reading Ram Dass and exploring Eastern religions. (A man after our own hearts.) But somewhere along the way he picked up a PhD in clinical psychology (as one does) and ended up co-directing the psychedelic research center at UT Austin.

We asked Greg how spider phobia could unlock the secrets of psychedelic therapy, why he's combining psilocybin and magnetic brain stimulation, and where he’d take psychedelic science with unlimited funding.

FROM OUR SPONSORS

Just when you thought you’d seen everything, they go and put mushrooms in a can.

BREZ combines microdosed cannabis and functional mushrooms in fizzy, flavor-forward drinks that deliver euphoria without the edible anxiety.

Thanks to their nano-emulsification process, effects hit in 5 minutes (not 2 hours) and fade gently after 90 minutes.

They’ve got a flavor for every occasion. We’re partial to the OG lemon elderflower, but honestly, you can’t go wrong with any of 'em.

No hangovers, no regret, no problem.

Try BREZ and see what the fuss is about.

How did you end up co-directing the psychedelic research center at UT Austin?

My interest in psychedelics began back in college at The University of Georgia. Even though my work today is focused on clinical research, I actually came to learn about psychedelics through a personal interest in spirituality. I was raised Roman Catholic, but I felt disillusioned with that belief system and moved away from it after high school.

In college, I began learning about eastern religions like Hinduism and Buddhism. I became very interested in their ideas about a unifying, underlying reality and consciousness. That curiosity led me to Ram Dass's book, Be Here Now, which was really eye-opening. Reading that book, I learned about his experiences with psilocybin when he was working at the Harvard Psilocybin Project with Timothy Leary back in the sixties.

I was fascinated by his description of his psychedelic experience. The idea that a plant or chemical could provoke such a drastic change in consciousness really intrigued me. So I began doing more research on psychedelics, learning more about Timothy Leary’s work, and reading books by other pioneers like Stanislav Grof and Robert Anton Wilson. That sparked a lifelong interest with the consciousness-altering potential of psychedelics.

I eventually moved to UT Austin to start my first faculty position at the end of 2018. That was really the first time I had the academic freedom to potentially pursue this line of research. I spoke with my chair, Dr. Charlie Nemeroff, who's now the other co-director of the center, and expressed my interest. He was a little skeptical at first, but seeing how the field was rapidly evolving and evidence accumulating, he got on board. That led to efforts to fundraise and officially launch the Charmaine & Gordon McGill Center for Psychedelic Research & Therapy. It was really a combination of lifelong interest mixed with the right place, right time, luck, and hard work.

There's a lot of excitement around psychedelics right now, but you've said we're in a phase of “more hype than evidence.” What's the reality check people need to hear?

I think that's still accurate, though it's beginning to self-correct. The main message is that psychedelics are not a cure-all. They're not a cure for mental illness. They can help, but it's not a magic bullet. You will not be enlightened afterwards. You will not permanently stop struggling with emotional issues, depression, or anxiety. But it does give people an opportunity to self-correct, work on themselves, facilitate new insights, and behavioral change.

For a while there was a narrative that if you're a little blue, take some psilocybin, and that would cure your problems. That's beginning to self-correct because we're seeing in larger studies that not everybody benefits. There are folks who go through trials and even get the active dose, but do not show sustained therapeutic benefit or sometimes receive no benefit at all.

That's an important consideration because psychedelics are not necessarily going to be effective for everyone. That's the case with every treatment we have in psychiatry. There's no one size fits all. Everybody's brain and psychology are different, and we have to account for that variance. It becomes a process of trying to match the person to the right treatment.

Your lab is combining psilocybin with transcranial magnetic stimulation (TMS). What's the thinking behind pairing psychedelics with other brain stimulation techniques?

We know psychedelics, at least in animal models, promote a window of enhanced synaptic plasticity after administration. It's never been confirmed in humans, but it's probably the case for us, too.

I think about psychedelics as a two-step process. First, you have a profound disruption in your typical state of consciousness. Everything looks new and different; people aren't stuck in normal thinking modes. But the second part is this synaptic plasticity window that occurs afterwards for weeks to months. People think about this part as the "integration" phase, where you're supposed to be doing work on yourself, meditate, or go to therapy.

I realized that if we're only using psychotherapy and behavioral approaches in that window, there may be suboptimal utilization of that plasticity. So the idea was, why not use brain stimulation as a tool to sculpt the brain in its more plastic state? We know transcranial magnetic stimulation is FDA cleared for treatment-resistant depression when delivered to a specific target and frequency.

The hypothesis is that combining psilocybin with brain stimulation directly afterward will reconfigure the brain into a more durable state of mental health. We're using a newer form of TMS called SAINT that came out of Stanford. Normally, TMS takes six weeks, but Stanford condensed the protocol to ten sessions daily over five days. The target is individualized based on brain connectivity patterns. We have that study running now and are early in recruitment.

You’ve also proposed a study using MDMA to treat spider phobia. How does tackling something so specific help us understand broader applications?

That idea arose from supervising a master's student interested in combining exposure therapy with psychedelics. We homed in on spider phobia because it's a very uncomplicated mental health condition clearly related to conditioning and Pavlovian associative learning. You see a spider, maybe have a negative experience when younger, and it conditions you to be afraid.

Essentially, spider phobia is a simple model of fear conditioning. It’s also well-treated by exposure therapy, which is based on fear extinction principles. You expose the person to what they're afraid of in a way that disconfirms the belief that it's dangerous.

Specific phobias are straightforward because they're so circumscribed. Those people don't tend to be suicidal or have co-morbid depression or substance use disorders. It's a very clean population. So as an experimental model where we can make clear inferences, this was simple and straightforward.

We know MDMA promotes pro-social interpersonal relating and fear extinction—the ability to learn that something you thought was dangerous isn't actually dangerous anymore. The hypothesis is that MDMA plus exposure therapy, combined with a dyadic interaction model, would benefit people with spider phobia.

If that worked, we'd move to testing in larger populations. But the fascinating element is looking at mechanisms. What changes in the brain? What are the indicators of this process? Then, we can better understand MDMA's underlying mechanism and apply it to more complex disorders like PTSD or other anxiety disorders.

If you had unlimited funding and total freedom, where would you take psychedelic research next?

One question I'm particularly interested in is around the integration portion of treatment. What should be done during that period to most benefit a particular condition? We're considering a study where drug dosage is one factor, but we’d also manipulate the type of behavioral treatment given during integration to understand the relative impact.

For depression, you might look at behavioral activation, where you get people engaged with the environment doing things they enjoy. You could compare that to regular supportive therapy or cognitive therapy, for example. Are they equally useful? Is one better?

The other thing we really need is large-scale studies looking at predictors and moderators of response. We have smaller studies showing efficacy of various psychedelics, but still no information about what predicts response on the individual level.

If I had $10 million for a multi-site study, I’d compare two active psychedelics with different mechanisms, head to head. It could be MDMA versus psilocybin, or 5-MeO-DMT versus regular DMT. On a large scale, you might detect subtle differences with certain psychedelics being better for certain conditions. But the most interesting part would be looking at differential predictors of response—what makes somebody better suited to one treatment versus another.

What we’re talking about is personalized medicine. The unfortunate truth is this is a bigger problem in medicine generally. We don't have good clinical predictor knowledge even for basic things like SSRI antidepressants. So for psychedelics, it's even more unclear. There's much more work needed to get us to that point.

Want more from Greg?

Check out the psychedelic studies that are currently recruiting at his lab.

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.