A New Mechanism Behind Psychedelic Therapy's Lasting Effects
Study shows psychedelics strengthen brain circuits for memory, offering clues to their long-term mental health benefits.
A single psychedelic experience can change the way the brain forms memories, and new research may explain how.
A recent study from the University of Kentucky investigated how the psychedelic compound DOI (2,5-dimethoxy-4-iodoamphetamine) affects brain circuits, finding that the psychedelic enhances communication between the claustrum and the anterior cingulate cortex (ACC).
Psychedelics and mental health
Psychedelic compounds such as psilocybin and LSD are re-emerging as promising tools for treating depression, PTSD and addiction. Scientists are interested in how these substances can produce lasting therapeutic benefits after just one or two doses.
It is understood that psychedelics act on serotonin receptors, particularly a type called 5-HT₂A, but where in the brain and how these molecular effects translate into lasting changes remains unclear.
“The neurobiological mechanisms underlying psychedelic-induced long-term synaptic plasticity have been generally understudied,” said the authors.
Previous studies have focused on well-known cortical areas such as the prefrontal cortex, however, deeper regions that help coordinate activity across the brain have been less explored.
One of those areas is the claustrum – a very thin layer of brain tissue that connects to many other regions and is packed with serotonin receptors. It has been linked to attention, awareness and the way we combine sensory and emotional information. These are the same processes that psychedelics are known to influence strongly. Yet, despite this overlap, very little is known about what role the claustrum actually plays during a psychedelic experience.
In the new study, the team aimed to investigate how psychedelics alter communication between the claustrum and the ACC.
“Because psychedelic therapy can require as little as one treatment session, it has been speculated that psychedelics achieve their long-term remedial effects by inducing neuroplasticity in brain areas responsible for psychiatric disease states, such as the ACC,” said the researchers.
Investigating the claustrum–ACC pathway in psychedelic therapy
The team used male rats to study how the psychedelic DOI affected a specific brain pathway, focusing on neurons in the claustrum that send signals to the ACC. One group of rats received DOI, while a control group did not.
DOI (2,5-dimethoxy-4-iodoamphetamine)
A synthetic psychedelic compound that acts as a serotonin receptor agonist, producing hallucinogenic effects.
The team activated the claustrum neurons that connect to the ACC using optogenetic techniques. They then recorded how strongly these neurons communicated with other neurons.
When the rats had received DOI, stimulating these neurons made their connections stronger. This kind of strengthening, called synaptic potentiation, is how the brain forms memories. In rats that did not get the drug, the same stimulation did not change the connections.
Synaptic potentiation
The process by which the strength of synaptic connections between neurons is increased, often associated with learning and memory formation.
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Neurons only strengthened when the drug was present during activation, suggesting psychedelics may prime the claustrum–ACC pathway for change.
“One idea is that the intensely memorable experience common during psychedelic ‘trips’ is critical for success in psychiatric treatment. Neurons are thought to encode memories by strengthening their connections with other neurons, so this pathway may be the mechanism through which psychedelics intensify memories,” said corresponding author Dr. Pavel Ortinski, an associate professor from the University of Kentucky.
The study shows that this brain circuit could help explain how psychedelic therapy produces lasting effects on thinking and emotion.
Implications of synaptic potentiation in psychedelic-induced memory formation
The findings highlight a possible link between the vivid, lasting nature of psychedelic experiences and their long-term benefits for mental health. By showing how psychedelics strengthen connections between the claustrum and the ACC, the study identifies a potential cellular mechanism behind the improvements seen in conditions such as depression and PTSD. This circuit-level view could guide new treatments that harness the same neural plasticity without producing hallucinations.
The work also helps bridge a long-standing gap between basic neuroscience and clinical psychiatry. It offers a way to connect the subjective, experiential side of psychedelic therapy with measurable changes in brain activity. The quality of the psychedelic experience itself may be key to its therapeutic impact, not only the drug’s chemistry.
There are limitations to the findings, as the experiments were conducted in male rats, and effects may differ in females or humans. The specific psychedelic compound and dose used may not reflect the wide variety of psychedelic substances being studied clinically, and while the results link drug exposure to stronger neural connections, they don’t yet show that this plasticity directly causes therapeutic outcomes.
While the current study provides insights into the claustrum–ACC pathway's role in psychedelic effects, further research is needed to determine if similar changes occur in humans and to explore how long these changes persist.
Reference: Anderson TL, Asadipooya A, Ortinsk PI. Psychedelics reverse the polarity of long-term synaptic plasticity in cortical-projecting claustrum neurons. eNeuro. 2025. doi: 10.1523/ENEURO.0047-25.2025
