An international research effort led by Cornell University has revealed new insights into how psilocybin, the active ingredient in magic mushrooms, alters brain function to potentially treat depression. The study, published on December 5, 2023, in the journal Cell, combines psilocybin with a modified version of the rabies virus to map the drug’s effects on brain connectivity.
The research team demonstrated that psilocybin weakens cortico-cortical feedback loops, which are responsible for negative thought cycles often experienced by individuals with depression. At the same time, the drug enhances connections to subcortical regions that facilitate sensory perception and action, effectively improving sensory-motor responses. Lead author Quan Jiang, a postdoctoral researcher, highlighted that this dual effect of psilocybin could offer new therapeutic avenues for mental health treatment.
Mapping Brain Connectivity
The study is part of a broader investigation led by Alex Kwan, a professor of biomedical engineering at Cornell. Kwan’s lab has focused on understanding how psychiatric drugs like psilocybin, ketamine, and 5-MeO-DMT can rewire brain circuits to alleviate symptoms of depression. Previous research from Kwan’s group indicated that a single dose of psilocybin could induce structural changes in the brain by promoting the growth of dendritic spines, which play a crucial role in synaptic connections.
Kwan noted, “A lot of people were excited about the earlier study because psychedelics are promising therapeutics, but we don’t know why they work. Our study showed that the rewiring in the brain lasts a long time.” This latest research aimed to identify specific brain regions involved in the rewiring process triggered by psilocybin.
To achieve this, the researchers employed a novel technique by pairing psilocybin with a variant of the rabies virus, developed in collaboration with the Allen Institute for Brain Science in Seattle. Kwan likened the approach to mapping city streets, stating, “With psilocybin, it’s like we’re adding all these roads to the brain, but we don’t know where the roads go.”
After administering a dose of psilocybin to the frontal cortical pyramidal neurons of mice, the team followed up with the rabies virus to label neurons connected to those affected by the drug. Imaging conducted a week later uncovered significant changes in brain connectivity compared to control subjects who had only received the virus.
Implications for Depression Treatment
The findings revealed that psilocybin effectively weakens recurrent connections in the cortex, which are believed to contribute to the unhealthy rumination often associated with depression. Kwan explained, “Rumination is one of the main points for depression, where people have this unhealthy focus and they keep dwelling on the same negative thoughts. By reducing some of these feedback loops, our findings are consistent with the interpretation that psilocybin may rewire the brain to break, or at least weaken, that cycle.”
Additionally, researchers observed that psilocybin strengthens the link between sensory regions of the brain and subcortical areas, which may enhance the translation of sensory experiences into actions. Kwan expressed surprise at the extent of the rewiring, noting, “This is really looking at brain-wide changes. That’s a scale that we have not worked at before.”
The study also suggested that the level of neural activity in specific brain regions could influence the rewiring process induced by psilocybin. This insight opens up potential therapeutic strategies, enabling researchers to enhance positive plasticity while minimizing negative effects.
Co-authors of the study include postdoctoral researcher Ling-Xiao Shao, doctoral student Amelia D. Gilbert, and others from Yale University, the University of California, Irvine, and the Chinese University of Hong Kong. The research received support from One Mind and the National Institutes of Health, further underscoring its significance in the field of mental health research.
