Did You Hear About the Octopus on MDMA?

*This is an excerpt from Joe Dolce’s new book Modern Psychedelics: A Handbook for Modern Exploration

What are psychedelics doing in our brains? And what can we do to ensure better trips?

Anyone who has ever taken a psychedelic has likely grappled with these questions. Until recently, philosophers and psychoanalysts tried to provide answers, but they lacked the tools for deep investigation. Today, it’s neuroscientists (or psychologists with fMRI or MEG^* scanning machines) who are leading the inquiries, so that’s who I turned to first.

Brain scans are the tools most commonly used to investigate the brain’s landscape and activity. Subjects are given a shot of psilocybin and slid into fMRI machines with electrodes attached to their skulls. Scientists measure increases or decreases in blood flow to infer the neural activity and mental states caused by the psychedelic. It’s common to hear scientists say things like, “MDMA decreases activity in the amygdala, the brain area responsible for the fear response. This allows people to process their experiences with less fear.”

fMRI is also used to track activity in neural networks, which are groups of interconnected brain regions that are theorized to produce different types of cognition. If you’ve read How to Change Your Mind, you may recall that psychedelics reduce activity in the default mode network (DMN), which is thought to control ruminative thinking and contribute to our conception of “self.” Originally, scientists supposed that psychedelics would amp up activity in this part of the brain, but fMRI showed the opposite—that psychedelics quiet down this network. This led to the theory that the DMN becomes overly active in people who are depressed or suffering from mental illnesses. More negative thinking leads to more rumination, which leads to a biological entrenchment of neural patterns in the brain.

Other studies by Franz Vollenweider’s lab in Switzerland, using a different technology, support the idea that the visual and other perceptual changes are caused by dysregulation in the thalamus (or, more correctly, thalamic circuits).

The thalamus is a brain region that filters the barrage of sensory information coming at us in all waking moments; it “decides” what to transfer to conscious awareness. A more exact version of Huxley’s reducing valve, the thalamus literally takes all the information from our senses and reduces it to a manageable fraction of the total. This is hugely important because, without this “gating,” as it’s called, the overload would incapacitate us, making us unable to focus our attention or function. Psychedelics, thus, send the thalamus, the gatekeeper of our senses, on vacation.

Octopuses on Ecstasy

Brain scans give us a peek inside our brains, the most dauntingly complex thing in the universe. But there’s not much that we explorers (or therapists, for that matter) can do with a thalamus or a default mode network. While brain scans may be revealing, it’s unlikely that they’re giving us the full picture of what’s going on under the hood. At least that’s what studies with octopuses on MDMA suggest.

Gül (pronounced Gool) Dölen is a Turkish American neuroscientist who, in 2023, became the Bob and Renee Parsons^* Endowed Chair in psychedelics, psychology, and neuroscience at the University of California, Berkeley. She is considered one of the leading researchers in the field of psychedelics. Based on her past work investigating the pathophysiology of diseases such as autism and schizophrenia, she suspected that something else was happening on a more molecular level in the brain that her colleagues’ scans weren’t picking up. It is one of the main reasons she gave octopuses molly.

Most MDMA studies are performed on mammals whose brains structurally resemble those of humans. But octopus brains are nothing like human brains—they’re more akin to slugs. Our last common ancestor was 650 million years ago—that predates the dinosaurs—so when Dölen bathed her octopuses in water laced with ecstasy, “there was a good chance nothing was going to happen.”

If anything, Dölen presumed that once dosed, the octopuses would speed around the tank in a frenzy or stand at attention, since MDMA is structurally similar to methamphetamine. And at high doses, that’s exactly what occurred. But as doses were lowered to correspond to what humans take, the octopuses relaxed, doing backflips and engaging in a floaty eight-arm water ballet. They became docile and remarkably social. In contrast with what My Octopus Teacher might lead you to believe, octopuses are aggressively antisocial creatures. Except for brief mating periods, they’re more prone to attacking fellow octopods than cuddling with them. That’s why everyone in Dölen’s lab was surprised when the octopuses on ecstasy broke through a barrier to nuzzle up to one another. This “socializing” was a 180-degree change in behavior.

What the findings indicate is that the conclusions based on scans of human brains on psychedelics may have led researchers in the wrong direction. MDMA may appear to be dampening activity in the amygdala or activating the thalamus in mammalian brains, but the octopus brain differs from the human brain in that these regions do not exist. For MDMA to have the same effect on humans as it does on octopuses, it must be acting on a common biological structure or function shared by the two. And what octopus brains share with human brains is a nearly identical serotonin transporter, a protein that recycles serotonin (a neurotransmitter that’s key to regulating mood) by moving it back into the cell from the synapse.

Dölen’s findings suggest that psychedelics aren’t simply altering the connections within and between certain brain areas. Instead, they are working on a molecular level to open “critical periods” of learning.

OLD MICE, NEW TRICKS

In 1935, Konrad Lorenz observed that baby snow geese learn to recognize and respond to their mother forty-eight hours after hatching in a process known as imprinting. They follow mom around, studying her every move, learning how to feed, how to vocalize, and other basic survival skills. Lorenz called this the critical period in which the brain is chemically sensitized to absorbing massive amounts of information for a finite period of time. He won the Nobel Prize for the discovery.

It turns out that, just like young goslings, young humans also have critical periods for learning the skills they need to survive, and once a particular critical period closes, learning that skill becomes more difficult. It’s easier to learn a language or ride a bike earlier in life. Babies who are deprived of touch have a hard time establishing intimate relations as adults because their critical period closed before those emotional ties were established.

Dölen and other neuroscientists suspect there are as many critical periods as there are brain functions, and they theorize that there is a critical period for every skill we develop that isn’t genetically encoded. But critical periods close for good reason. “Living in a world where you’re highly sensitized and paying attention to everything around you is emotionally and energetically costly,” says Dölen. “At some point, you want a stable representation of the world that is not changing as much; that’s why critical periods close.” It’s also one reason adults develop habits that allow us to perform many tasks efficiently or on autopilot. It would be highly inefficient to constantly be learning and relearning the same thing repeatedly. The downside is that habits can make the magic of the world seem a little less magical as we age.

In another experiment, Dölen dosed adult mice with MDMA. She wanted to see if she could open a critical period for social behavior and how long it would stay open once the cuddly effects of MDMA wore off. Older mice are far less social than juveniles. Just like people, they enjoy being surrounded by a hundred other “friends” when young, but value their alone time as adults. Surprisingly, for two weeks following MDMA, the adult mice continued to snuggle with other mice just like teenagers. In further tests with LSD, ibogaine, ketamine, and psilocybin—psychedelics that are all far less social than MDMA—the old mice continued cuddle puddling, sometimes for weeks after the drug effects ended.

“This study suggests that all psychedelics reopen a critical period and they do it whether they are prosocial drugs like MDMA, or hallucinogenics like psilocybin or LSD, or dissociatives like ketamine, or dream-inducing oneirogens like ibogaine. All psychedelics do it. And that tells us that the prosocial character of MDMA is a red herring; instead, all psychedelics are putting the brain in an altered state^** which we think is the same as an open critical period. It’s what all psychedelics share in common. The ability to open critical periods coheres the category.”

Dölen isn’t yet sure how this works, but she has an inkling. By using an advanced whole cell patch technology, her lab has been able to measure the activity inside the neurons of cells extracted from mouse brains. These intraneural investigations showed that psychedelics are actually resetting the molecular structure inside cells. “When psychedelics hit the brain, they sit in a variety of receptors for an unusually long time. This may be sending a signal to the brain that something is abnormal here, and that sets off a biochemical reaction that tells it to reestablish new connections.” A psychedelic trip is like a biochemical “resetting of the router in our brains,” is how she puts it. And it parallels the opening of a critical period. “It doesn’t have to do with my default mode network or my amygdala,” she adds, contradicting the countervailing wisdom. “By reopening critical periods, psychedelics enable the brain to get back to that state where it’s receptive to the world, like a child, and open to learning new things.”

Interestingly, it appears the critical period remains open far longer than the duration of the trip. Further studies on mice have correlated the length of each psychedelic journey with the length of time each critical period remains open. It’s not the strength of the dose driving this correlation. It’s the length of the journey. A ketamine trip lasts thirty to forty-five minutes; the critical period closes two to four days later. MDMA and psilocybin journeys last about six hours; the critical period closes at two weeks. LSD is eight hours–the critical period is three weeks. Ibogaine lasts thirty-six to seventy-two hours, and the upper limit of that critical period is yet to be determined.

THE CONTEXT DRIVES THE OUTCOME

In Dölen’s model, the psychedelic is the catalyst that opens the brain to new learning, but what you learn depends on the context in which the drug is administered. Taking MDMA at a rave won’t have any effect on your PTSD, “but in the company of a supportive therapist over time, the same drug permits people to undertake the cognitive reappraisal needed to heal,” she says. This is why the psychedelic aspects of a trip, and what bookends it, may be more important than most people think. The intention you set prior to a trip primes the neurons in the brain that hold memories or feelings to become malleable again. The psychedelic biochemically opens the critical period, which allows people to wander down the rabbit holes of their minds, stumbling across old memories or trauma and appraising them anew. In follow-up sessions, people talk about their insights, if there were any, and therapeutic support helps them figure out how to integrate the insights into their lives.

The model is not dissimilar to what happens to Neo in The Matrix, the 1999 film that psyochonauts have been obsessively dissecting for decades. Neo takes the red pill, which brings him into the Matrix. Once there, a video is downloaded into his system, but he doesn’t instantly become a jujitsu master. He first must train and practice before he can take down his enemies. The red pill = the psychedelic. The download = the trip. The training = support and integration.

“If you conceptualize depression as a lasting habit of thinking about the world or yourself in a negative way, then the real utility of the psychedelic is to break that habit and allow you to create new thinking that enables you to see the world with a new, updated sense of what’s possible,” is how Dölen explains it. PTSD is similar. “The traumatizing event [such as surviving rape] causes people to close down. That’s an adaptive response that may have saved someone’s life in that moment, but over time it interferes with their ability to trust, form bonds, and engage in the world. If the psychedelic can open a critical period so you can revisit those maladaptive responses without the threat, you may be able to learn to stand up to your rapist and confront your fear from the stronger version of yourself today.”

MASTER KEYS

Scientists have long been interested in reopening critical periods in adults, but they have feared that doing so might disrupt the neural and chemical connections that hold our memories, habits, and histories—the accumulated knowledge that distinguishes you from me—in place. But Dölen suspects that under controlled conditions, psychedelics might be used to encourage such reopenings, not only for mental disturbances but for physical disabilities, too. Her next experiments will test her theories by seeing if psychedelics can be used to restore motor function in people who have lost limb movement following a stroke.

Typically, stroke victims regain some function in the first three months of recovery; after that, improvement flatlines because that critical period has closed. Dölen’s lab will pair psychedelics with a new type of 3D physical therapy to investigate if they can return people to that early post-stroke period of improvement even if their stroke occurred years prior.

It’s commonly said that psychedelic therapy “rewires” the brain, but until Dölen’s research, no one could offer a satisfying explanation for how this entire class of compounds that have such a short duration of effects can produce transformations that extend for months or, in some cases, years.

Ancient sages, curanderos, and ayahuasqueros have a saying: “Once the trip has ended, the real work begins.” Neuroscience may finally be catching up to them.

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Joe is the author of Modern Psychedelics, The Handbook of Mindful Exploration.

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