Ann Arbor Times

A new study from the University of Michigan challenges a longstanding assumption about how psychedelic medicines affect the brain. The research, published in Molecular Psychiatry, finds that psychedelics can alter connectivity in a wide range of neurons, not just those with serotonin 2A receptors.

Traditionally, it has been believed that psychedelic compounds exert their therapeutic effects by targeting serotonin 2A receptors found on certain neurons in the frontal cortex. These receptors are known to play roles in mood regulation, perception, and cognitive functions. However, the University of Michigan team discovered that even neurons lacking these receptors can experience significant neuroplastic changes after exposure to psychedelics.

“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 Omar Ahmed, senior author of the study and professor of psychology at the University of Michigan.

The researchers examined gene expression across all cortical neurons and pinpointed areas such as the retrosplenial cortex—a region important for memory and orientation—that do not express serotonin 2A receptors. This area is among the first affected in Alzheimer’s disease. Using advanced recording techniques, Ahmed’s lab found that neurons here also showed increased synaptic connections following psychedelic treatment.

“This was a very unexpected finding given the current assumptions about how psychedelic medicine works,” Ahmed stated.

To further investigate, the team used CRISPR-Cas genetic engineering to explore how psychedelics could enhance brain connectivity without requiring serotonin 2A receptors on target neurons. Their findings suggest a broader mechanism for how these drugs may help repair neural circuits implicated in disorders like Alzheimer’s disease and PTSD.

“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 explained.

Ahmed noted that while these results offer optimism for expanding therapeutic uses—such as potentially restoring connections lost in Alzheimer’s disease—they also warrant caution regarding unintended effects on other neuron types. “We are actively working on essential preclinical research to test this hypothesis related to Alzheimer’s disease,” he added.

The study was funded by several NIH grants, an Alzheimer’s Association grant, and support from the University of Michigan Eisenberg Family Depression Center Eisenberg Scholar Award.

Other contributors included Tyler Ekins and Chloe Rybicki-Kler (co-first authors), Tao Deng, Isla Brooks, Izabela Jedrasiak-Cape, and Ethan Donoho—all members of Ahmed’s laboratory.