A foundational assumption about how psychedelic compounds affect the brain has been overturned by new research, revealing their influence is far more extensive than previously believed. A study from the University of Michigan demonstrates that these substances promote neuroplasticity—the growth of new connections between brain cells—in vast regions of the brain, including areas largely devoid of the specific receptor thought to be essential for their action. This discovery fundamentally alters the scientific understanding of how these potential therapies work and opens the door to new treatment possibilities for a wider range of neurological disorders.
For decades, the therapeutic benefits of psychedelics, particularly for conditions like major depression, were thought to stem exclusively from their interaction with the serotonin 2A receptor (5-HT2A) on the surface of neurons, primarily in the brain’s frontal cortex. The new findings, published in Molecular Psychiatry, show that psychedelics can robustly enhance synaptic connections onto neurons that completely lack these receptors. This suggests a more complex and indirect mechanism of action, expanding the potential clinical applications to disorders involving brain regions previously considered unresponsive to these compounds, such as Alzheimer’s disease and post-traumatic stress disorder (PTSD).
Challenging a Core Tenet of Psychedelic Science
The prevailing theory of psychedelic action centered on direct stimulation of 5-HT2A receptors located on the main body and dendrites of a neuron—known as postsynaptic receptors. This interaction was believed to be the trigger for the downstream effects that lead to increased neuroplasticity, which is hypothesized to underlie the rapid and sustained antidepressant effects observed in clinical trials. Because of this focus, research and drug development have largely targeted disorders associated with dysfunction in the prefrontal cortex, a region rich in these receptors.
This model assumed that only neurons expressing the 5-HT2A receptor could benefit from psychedelic-induced growth. The University of Michigan research team, led by senior author Omar Ahmed, directly tested this assumption by mapping the expression of the gene responsible for producing the receptor across the entire neocortex of mice. Their analysis confirmed that while areas like the frontal cortex were rich in these receptors, other regions were surprisingly sparse, creating a natural experiment to see if psychedelic compounds had any effect there.
Surprising Effects in the Retrosplenial Cortex
The investigation zeroed in on a region called the granular retrosplenial cortex (RSG), a critical hub for cognitive functions that are distinctly human. This area is integral to spatial memory, orientation, the ability to recall past events, and even the capacity to imagine oneself in the future. Crucially, the RSG is also one of the first brain regions to show signs of impairment in the early stages of Alzheimer’s disease and is implicated in the fear extinction process that is often dysfunctional in PTSD.
An Unexpected Hub of Plasticity
The team’s genetic mapping confirmed that pyramidal cells, the principal neurons in the RSG, have virtually no 5-HT2A receptors. According to the conventional model, these neurons should have been unaffected by the administration of psychedelics. However, when researchers directly recorded from these cells in mice after treatment, they discovered a powerful and lasting increase in synaptic enhancement. The neurons, despite lacking the target receptor, were undergoing significant structural changes indicative of neuroplasticity. This unexpected finding demonstrated that the long-held theory was, at best, incomplete.
A New Mechanism of Action Revealed
To understand how neurons could be remodeled without directly receiving the psychedelic signal, the researchers employed advanced genetic engineering. Using a CRISPR-Cas-based tool, they developed a conditional knockout mouse line that allowed them to selectively delete the 5-HT2A receptor from different parts of the neural circuit. This powerful technique enabled them to pinpoint precisely where in the communication chain the receptor was necessary for the observed effects.
The Presynaptic Connection
The experiments revealed a novel, indirect mechanism. The neuroplasticity observed in the receptor-deficient RSG neurons was dependent on 5-HT2A receptors located on the presynaptic terminals of neurons originating in a different brain structure: the anterior thalamus. These thalamic neurons form connections, or synapses, with the RSG cells. The psychedelics appear to act on the axon terminals—the sending end—of these thalamic inputs, which in turn strengthens the connection onto the receiving RSG neuron. This finding revises the rules of psychedelic-induced plasticity, showing that a neuron does not need to express the receptor itself to benefit, but can be modified through its connections from other neurons that do.
Broader Implications for Brain Disorders
This discovery dramatically expands the number of brain circuits and connections that could potentially be repaired by psychedelic medicine. By showing that the sphere of influence extends well beyond the cells that express the 5-HT2A receptor, the research opens up new therapeutic avenues for diseases characterized by a loss of synaptic connections in brain regions like the RSG.
New Hope for Alzheimer’s and PTSD
The finding that psychedelics can augment circuit function in the retrosplenial cortex is particularly significant for Alzheimer’s disease and PTSD. In early Alzheimer’s, the degradation of the RSG is linked to the profound disorientation and memory loss that patients experience. Therapies that can promote plasticity in this specific region could potentially restore or protect these functions. Similarly, since the RSG is involved in processing fear-related memories, enhancing its plasticity could aid in the treatment of PTSD. The research team is now actively pursuing preclinical research to test these hypotheses.
Optimism Tempered with Caution
Senior author Omar Ahmed noted that the findings are cause for both optimism and caution. The optimism lies in the potential to develop psychedelic-like compounds to treat a wider array of devastating neurological and psychiatric conditions. The caution, however, is equally important. Understanding that these drugs act on a much broader set of neurons than previously known means researchers and clinicians must be more vigilant about potential unintended or off-target effects. This deeper and more accurate understanding of how these powerful compounds work is a critical step toward developing safer and more effective medicines.
