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A New Mechanism of Psychedelic Action in the Brain Has Been Discovered

A microscopic image of a cortical neuron (white) expressing 5-HT2A receptors (multicolored).
A cortical neuron (white) expressing 5-HT2A receptors (multicolored). Credit: David Olson/UC Davis
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A new paper has turned science’s understanding of how psychedelics affect the brain upside down by solving a longstanding molecular mystery in the field. Psychedelics are thought to produce their effects by activating the serotonin (5-HT)2A receptor class. These receptors are present on the surface of neurons throughout the brain. But if these compounds cause such strong hallucinations, why aren’t we always tripping on our brain’s natural serotonin supply?

The answer may have been found by looking inside neurons, where researchers at the University of California, Davis (UC Davis) identified that it is through the activation of an intracellular population of serotonin receptors that psychedelics exert their effects. The team concludes that another molecule – potentially N,N-dimethyltryptamine (DMT), which is found in short-lived but widespread levels in the brain – is the natural activator of these intracellular receptors rather than serotonin.

The findings could explain why the effects of psychedelics, such as neuroplasticity and even antidepressant action, vary between different drugs. Could we one day exploit our brain’s own psychedelic molecules to fight mood disorders?

The paper was published in Science.

Serotonin and psychedelics: A complex relationship

The research began with a series of in vitro experiments conducted by UC Davis PhD student Max Vargas. Vargas’s supervisor, Professor David Olson, focuses on the neuroplastic function of psychedelics. These molecules have been shown repeatedly to engender the growth of neuronal connections called axons in the brain after administration, which Olson and team believe is crucial to psychedelics’ effects on mood disorders. Vargas wanted to explore whether stronger binding to extracellular 5-HT2A receptors produced more extreme neuroplasticity. To the team’s surprise, there was no such relationship.

Instead, the team noted a positive relationship between compounds’ abilities to cross cell membranes and their neuroplastic effects. This led the team to hypothesize that intracellular receptor activation was driving psychedelic-stimulated neuronal growth.

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To test this hypothesis, the team reached into a deep chemical toolkit. They modified the structure of two common psychedelics – DMT and psilocin, the active chemical component of psychedelic mushrooms. They also tweaked the structure of a chemical, ketanserin, often used to block psychedelic activity because it can bind to and seal off 5-HT2A receptors. All three molecules can permeate the cell membrane, but after modification, the new versions – N,N,N-trimethyltryptamine (TMT), psilocybin and methylated ketanserin – could not.

These newly modified psychedelics were unable to promote neurogenesis. Methylated ketanserin was unable to block neuronal growth, despite being able to bind to surface-level 5HT2A receptors. What the molecules needed was quite literally a shock to the system.

High-voltage psychedelic science

A technique called electroporation applies a high-voltage electric current to a cellular membrane. This creates tiny holes in the membrane that permit molecules entry into the cell’s interior. When added to electroporated cells, the modified psychedelics were suddenly capable of producing plasticity in the same way as their unmodified congeners. The modified ketanserin also recovered its blocking potential once it was able to worm its way into the cell’s interior.

Working now in kidney cells modified to overexpress 5HT2A receptors, the team showed that without electroporation, methylated ketanserin was fully able to stop serotonin from activating 5HT2A receptors, while it was only partially able to stop DMT from doing so – because DMT was still able to bind to intracellular receptors. This suggests that serotonin is not the natural activator of a considerable proportion of 5HT2A receptors, despite literally being the molecule that defines them.

The researchers confirmed their findings with a variety of other tests, first working with a protein called the serotonin transporter (SERT) that carries serotonin into the interior of neurons. SERT is not normally found in rat cortical neurons, but its presence turned serotonin into a plasticity-inducing molecule, an effect that disappeared when the SERT-blocking drug citalopram was added.

Looking inside neurons for an antidepressant effect

Next, the team devised experiments to explore whether other effects of psychedelics, such as rapid-acting antidepressant responses, were also dependent on intracellular 5HT2A activation. Mice were given a molecule called para-chloroamphetamine (PCA) that releases serotonin without activating 5HT2A receptors itself. A subgroup of these mice was genetically modified to express SERT, which would enable the serotonin produced by PCA to enter neurons. In unmodified animals subjected to behavioral tests that approximate measures of depression, SERT did nothing to improve their performance, but the modified animals, whose neurons were flooded by serotonin due to the presence of both PCA and SERT, showed improvements in their test performance.

Mice, of course, can’t fill out mood questionnaires, so there is no way of testing how these animals’ mood was affected. These assays nevertheless are the field standard for assessing depressive behavior. The researchers also noted that their modified mice showed a head-twitch response once serotonin was permitted access to their neurons’ interiors, suggesting that this classic measure of “hallucinatory” activity might be dependent on intracellular receptor activation.

The study could shift how we understand psychedelics’ activity in the brain. In a perspectives article, University of Maryland researchers Dr. Evan M. Hess and Professor Todd D. Gould, who were not involved in the research, called Vargas’s paper a “key achievement in the understanding of the mechanism of action of psychedelics.” Bryan Roth, Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the University of North Carolina School of Medicine, told Technology Networks that the paper was a “very important and potentially disruptive study.”

Hess and Gould hint at the further work that will have to be conducted to validate the findings fully. Are these effects also seen in humans? What are the signaling cascades involved? Do psychedelics like mescaline, which have a fundamentally different chemical structure, also activate intracellular 5HT2A receptors? All these questions remain unanswered. For now, the paper has made what Hess and Gould call “an important step forward for a rapidly expanding and much-needed field of study.”

Reference: Vargas M, Dunlap L, Dong C et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science. 2023;379(6633):700–706. doi: 10.1126/science.adf0435