Never a dull dinner with Gül Dölen 💊🐙🧠 She is the researcher who gave MDMA to octopuses and noted the pro-social effects. Why? She wanted to study an intelligence as alien to ours as we could find on earth. If psychedelics had similar effects as in humans, perhaps some mechanisms of action lay outside the common themes of the Serotonin 2A receptors or activity in certain cortical regions — as the octopus does not have a cerebral cortex or amygdala at all. They have a donut-shaped brain wrapped around the throat with 50 different brain lobes. Our common evolutionary ancestor is a tubule so ancient, neither brains nor eyes yet existed. So, might there be something more primitive still that explains the common effects across species… and across medicines that seem so very different (MDMA, ketamine and the classic psychedelics)? Her recent Nature paper presents a radically different hypothesis: these medicines reopen our critical periods of learning, and they do so by relaxing the extra-cellular matrix (ECM) that embeds the neurons in our brain. Let’s pause to let that sink in. A master switch for critical periods… outside of the neuron. 1) Critical Periods: This is the period of time after birth where the brain boots up a bunch of functionality that is not encoded in our DNA – like the vision system and the ability to discriminate phonemes (and thus learn a new language without an accent). This period shuts down in adulthood, and rarely reopens (with interesting exceptions after extreme events, like a stroke). 2) ECM: Every cell type produces a unique ECM, and they become fibrotic in some diseases of aging. Relaxing the ECM in the brain may be the mechanism for enhanced meta-plasticity underlying critical periods. And it lasts for weeks after each use of psychedelics in mouse models. This explains the importance of a post-treatment integration period to see therapeutic benefits. Notably, psychedelics induce metaplasticity (the plasticity of synaptic plasticity) rather than hyperplasticity (common to the drugs of addiction: cocaine, amphetamines, alcohol, opiates) and are used to cure addiction. So, her work suggests that psychedelics act on a diverse array of binding targets to trigger a change in gene expression that leads to activity-dependent degradation of the ECM, which in turn is the permissive event that enables the metaplasticity seen in critical periods. Her conclusion: “psychedelics could serve as a ‘master key’ for unlocking a broad range of critical periods. Indeed, recent evidence suggests that repeated application of ketamine is able to reopen the critical period for ocular dominance plasticity by targeting the ECM. This framework expands the scope of disorders (including autism, stroke, deafness and blindness) that might benefit from treatment with psychedelics; examining this possibility is an obvious priority for future studies.” And thanks to Jeeshan Chowdhury for organizing the dinner last night. • Dolen’s Nature paper on the ECM: nature.com/articles/s41586-0… • My summary post on octopus intelligence: flic.kr/p/2mZGrT5 • Summary of her octopus + MDMA study: newscientist.com/article/218… • Lab: dolenlab.org