The discovery challenges decades of assumptions and points to new hope for patients with depression, Alzheimer's, and beyond
Study: Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors (DOI: 10.1038/s41380-025-03257-w)
The most basic assumption about how psychedelic medicine works is at least partially flawed: Psychedelics are altering not just a few specific brain cells, but the vast majority of them, according to a new University of Michigan study.
The research shows that even neurons without serotonin 2A receptors-which are important for physiological processes, including mood regulation, perception and cognitive functions-can dramatically benefit from psychedelic compounds. This means that the therapeutic use of psychedelic medicine is far broader than currently appreciated, with important implications for Alzheimer's disease and PTSD.
"We identified brain regions where most neurons are completely lacking serotonin 2A receptors. Surprisingly, psychedelic treatment was still able to strongly boost connectivity onto these neurons," said the study's senior author Omar Ahmed, U-M professor of psychology whose lab studies behavioral neural circuits and attempts to repair them when they go awry in specific disorders.
Psychedelic medicine is being successfully used in clinical trials to treat major depression. For decades it has been presumed that psychedelics work therapeutically by targeting the serotonin 2A receptor found on neurons in the frontal cortex and boosting connections onto those neurons. It has been assumed that frontal neurons with this serotonin 2A receptor were the only neurons benefiting from psychedelic therapy. This is why psychedelic medicine has focused on treating conditions relating to frontal dysfunction, such as major depression, Ahmed said.
When the research team studied the genes expressed in neurons of the entire cortex of the brain, they identified brain regions that did not express the serotonin 2A receptor that is supposed to be needed for psychedelic therapy to work. Ahmed's lab, including co-first authors Tyler Ekins and Chloe Rybicki-Kler, showed that the retrosplenial cortex-a brain region important for memory, orientation and even imagining oneself in the future-was remarkably devoid of these receptors. The retrosplenial cortex is one of the first brain regions to be impaired in Alzheimer's disease.
The team then recorded from these neurons lacking serotonin 2A receptors and found that they also show robust neuroplasticity (more synapses) after psychedelic treatment.
"This was a very unexpected finding given the current assumptions about how psychedelic medicine works," Ahmed said.
The next step used a genetic engineering technique called CRISPR-Cas to reveal the rules that govern this surprising boost in brain connectivity, leading to a revised theory of how psychedelics control the brain's ability to adapt and change. These new rules do not require neurons to have serotonin 2A receptors themselves to receive a synaptic boost from psychedelics, dramatically increasing the number of brain connections that can be potentially repaired by psychedelic medicine.
"The most successful medicines are those where we fully understand how they work. That is why it is so important to understand the fundamentals of how psychedelic medicine actually works," Ahmed said.
The new findings are cause for both caution and optimism, he said. Caution, because they show that we need to be wary of psychedelics acting on unintended neurons. Optimism, because they open up the possibility of using psychedelic-like compounds to restore brain connections in Alzheimer's disease and other disorders involving the retrosplenial cortex, such as PTSD.
"We are actively working on essential preclinical research to test this hypothesis related to Alzheimer's disease," Ahmed said.
The study appears in the latest issue of Molecular Psychiatry. Other authors included Tao Deng, Isla Brooks, Izabela Jedrasiak-Cape and Ethan Donoho, all members of Ahmed's lab.
The work was funded by: NIH R01MH129282; NIH R34NS127101; NIH P50NS123067; Alzheimer's Association Grant AARG-NTF-21-846572; NIH T32-DC000011; NIH T32-DA007268; NIH T32-NS076401; and the University of Michigan Eisenberg Family Depression Center Eisenberg Scholar Award to Ahmed.
