🫠 Psychonaut POV

Welcome to Tricycle Day. We're the psychedelics newsletter our mom thought was a crazy idea. She's since updated her priors. 🌹

Gül Dölen has a correction for anyone who’s ever gone off about “neuroplasticity” in a podcast, press release, or pitch deck. (Guilty.) Her lab at UC Berkeley demonstrated that psychedelics actually induce something called metaplasticity, and the difference isn’t just semantics.

We asked Gül why the length of your trip matters, what an octopus on MDMA reveals that a brain scan never could, and where the science extends beyond mental health.

Fun fact: the ayahuasca served at retreats usually isn't fresh.

It's dehydrated paste, reconstituted and heated up. (Appetizing, we know.)

There's also a cold-brew form called crudo that tastes nothing like traditional ayahuasca. Hardly anyone outside the jungle has heard of it.

If details like these are news to you and you’re even thinking about sitting with ayahuasca, this free 9-video course is worth your time.

It covers what's in the cup, what the science says, what ceremony feels like, and the safety red flags most people miss.

As an undergraduate at Duke, I designed my own major, Comparative Perspectives on the Mind. It covered a variety of disciplines that were trying to understand consciousness, from philosophy and neuroscience to linguistics, religion, and art. As part of that, I took a class called Drugs, Brain, and Behavior.

I remember the day we looked at a picture of the molecular structures of serotonin and LSD side by side. They’re remarkably similar. Then we read about those early studies in the ‘60s and ‘70s by Solomon Snyder showing that LSD binds to the serotonin receptor. I thought, this is it. Two molecules interacting with each other can produce a massive altered state of consciousness. That convinced me I wanted to pursue a physicalist framework for understanding consciousness, and that psychedelics might be the tool to do it.

At the time, psychedelics weren't considered serious science, so I backburnered the lab work. But that moment was a turning point, and it pushed me toward neuroscience.

The word “plasticity” was coined by William James in the late 1800s to describe some change in neuronal tissue that likely enables the brain to learn from its environment. By the 1950s, neuroscientists had narrowed it to synaptic plasticity, meaning changes in the weights of synaptic inputs. “Neurons that fire together wire together” is the version most people know. What most people don't realize is that there are several distinct types of plasticity, and even scientists who claim to be experts on the subject often can't name them.

What my lab has discovered is that psychedelics don't induce plasticity itself. What they induce is a change in the brain's ability to induce plasticity. That's called metaplasticity, and the distinction matters enormously. Think of it this way. A drug like cocaine is like taking a pill and waking up speaking Japanese. It locks in one specific learned response: I love this drug, and I want more of it. You've learned one thing, and it's very sticky. What psychedelics seem to do instead is give you the ability to learn any of 7,000 possible languages, depending on the set and setting you're in when you take them, and in the weeks that follow.

That distinction is also why I'm skeptical of the term “psychoplastogen,” which some companies and government grant programs have embraced. Cocaine is a psychoplastogen. Using that word to describe psychedelics conflates their mechanism with something implicated in drug abuse. That's scientifically sloppy, and it's politically dangerous for a field that's still fighting the DEA's Schedule I designation.

Critical periods are windows of time when the brain is especially able to learn from its environment. They were first described in 1935 by Konrad Lorenz, who noticed that goslings would form a lifetime attachment to whoever was moving around them in the 48 hours after hatching, including Lorenz himself. After that window closed, the attachment didn't form. He called that window a critical period.

We now think there are dozens of critical periods. They exist because there aren't enough genes in the genome to encode every possible behavior. What's encoded instead is the ability to learn flexibly from our environment during constrained windows of time. That's efficient evolutionarily, but it creates a clinical problem. By the time we get around to treating most brain diseases, the relevant critical period has already closed, and there's no reliable way to reopen it.

What my lab discovered, starting with a 2019 MDMA study, is that psychedelic drugs reopen critical periods. We've since tested ketamine, ibogaine, psilocybin, and LSD. Every psychedelic we tested reopened the critical period, and this has now been independently reproduced by five or six other labs.

We've also found that the duration of a psychedelic trip is proportional to the duration of the open state. Ketamine's two-hour trip keeps the critical period open for about 48 hours. Psilocybin and MDMA keep it open for two to three weeks. LSD, about three weeks. Ibogaine, whose trip lasts 36 to 72 hours, keeps it open for at least four weeks. That's probably why people fly to Mexico to take ibogaine despite its cardiotoxicity. The longest trip gives the longest window to reconfigure learned behaviors around addiction, suicidality, or PTSD.

It also means drug companies trying to make psychedelics with shorter trips are probably interfering with their therapeutic function.

The octopus experiment is actually separate from the critical period work. It's really about the acute subjective effects, which none of the critical period studies address directly. At the time, people like David Nutt and Robin Carhart-Harris were arguing that psychedelics could never be studied in mice, because how would you know what a mouse seeing God looks like anyway? Their solution was to give people psychedelics and put them in an fMRI machine.

My problem with that runs deeper than methodology. fMRI doesn't have the spatial or temporal sensitivity to detect the molecular changes we think are actually driving the effects. Anatomy-based explanations like the default mode network are just one version of how these molecules can work, shaped by a particular evolutionary history, and I wanted a way to test that.

Octopuses are nearly ideal. Our last common ancestor with them was over 650 million years ago. They don't have any of the brain regions that fMRI researchers focus on. And yet, when we gave octopuses MDMA, they behaved almost identically to mice. Octopuses are normally asocial; on MDMA, they spend significantly more time in the social chamber. When we looked at the MDMA binding site in an octopus versus a human, they're virtually identical at the molecular level. The brain anatomy lights up differently across species, but the molecule finds the same lock.

But the fact that the mechanism is molecular doesn't mean everyone reads the molecular data the same way, and this is also where the chemist and the neurobiologist part ways. Chemists see psychedelics binding to serotonin receptors and try to engineer cleaner, more targeted molecules along that axis, which is just an extension of the biochemical imbalance model. The idea that depression is simply a serotonin deficit, anxiety is a GABA deficit, and so on. It's a clean story that has driven psychiatric drug development for 70 years. The neurobiologist looks at the same data and sees a window for learning. Psychedelics are not the therapy itself; they're what makes the therapy work.

Mental health gets most of the attention, but the critical period hypothesis opens the door for anything that has a critical period. My lab is currently collaborating with Steve Zeiler on the motor learning critical period after stroke, pairing psychedelics with physical and occupational therapy. Stroke often closes a window for motor relearning. If psychedelics can reopen it, the therapy has somewhere to land.

We're also testing whether the immune system has critical periods. There are anecdotal reports, including one from Andrew Weil, who said he took LSD, petted his cat, and resolved his cat allergy, suggesting immune responses might be context-dependent and reopenable. My mom is an immunologist. When I first told her the idea, she thought I'd lost the plot. She's coming around.

That said, I want to be clear about how much work is still left to do. We're getting close to regulatory approval for some of these compounds, and my biggest concern is that we'll treat them just as casually as we treat SSRIs today. The open critical period means people are in a hyper-suggestible state not just during the trip, but for weeks afterward. That window is an opportunity and a vulnerability. We need to protect people during that time and train clinicians to treat these as the powerful medicines they are. If we don't, we'll do real harm, and we'll set the field back in a way that will be very hard to recover from.

Her clinical trial pairing psychedelics with physical therapy for stroke recovery is actively enrolling.

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

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.