Psilocin, the active compound in magic mushrooms, promotes the rapid growth of neural connections in laboratory settings at a level comparable to established psychiatric drugs like ketamine and lithium. These structural changes to brain cells offer a biological explanation for the rapid antidepressant effects observed in recent clinical trials of psychedelics. The findings were published in the Journal of Psychopharmacology.
Neuroplasticity refers to the brain’s ability to modify its physical structure and rewire its connections in response to new experiences. This biological process plays a fundamental role in learning and memory, as well as in the development of neuropsychiatric conditions. Disorders such as severe depression, anxiety, and post-traumatic stress disorder are often accompanied by a loss of neuroplasticity. Over time, neurons in specific regions of the brain begin to shrivel, losing the tiny branches and synaptic connections they use to communicate with one another.
Standard psychiatric treatments generally aim to restore these lost connections, but they often operate on a delayed timeline. Selective serotonin reuptake inhibitors, commonly known as SSRIs, are the most widely prescribed class of antidepressants. Drugs like fluoxetine work by blocking the reabsorption of serotonin in the brain, which slowly helps reopen a window of plasticity. However, these structural effects take weeks to materialize, and many patients do not experience a reduction in symptoms.
Lithium, a medication primarily used as a mood stabilizer for bipolar disorder, also promotes neuroplasticity and protects neurons from damage. Despite its efficacy, lithium carries a narrow safety margin and a risk of severe side effects involving the kidneys and thyroid. Because of these limitations, psychiatric research has shifted toward finding interventions that can trigger neuroplasticity safely and rapidly.
In contrast to traditional daily medications, compounds like ketamine and classical psychedelics produce rapid and long-lasting antidepressant effects after a single dose. These drugs are often grouped as psychoplastogens because of their capacity to rapidly induce structural growth in neurons. Yana Vella and Kateřina Syrová, researchers at the National Institute of Mental Health in Czechia, led a team to compare these new and old compounds directly. The researchers sought to document exactly how these distinct classes of drugs influence brain cells at a molecular level.
To observe this growth in a highly controlled environment, the research team extracted brain cells from the cerebral cortex of rat embryos. They isolated the cells and seeded them onto specially coated laboratory plates. Over several weeks in a nutrient-rich medium, the isolated neurons grew and formed spontaneous communication networks.
Once the cell networks matured, the researchers treated different batches with a single dose of psilocin, LSD, DMT, ketamine, fluoxetine, or lithium. After 24 hours of exposure, the scientists used fluorescent antibodies to visually tag specific structural proteins within the neurons. They targeted synapsin, a protein located in the vesicles at the transmitting end of a nerve cell, and PSD-95, a protein that anchors receptors at the receiving end of a nerve cell.
Using a confocal laser scanning microscope and specialized image analysis software, they mapped the physical architecture of the neurons. They counted the microscopic spots where the presynaptic synapsin and postsynaptic PSD-95 proteins spatially overlapped. This overlapping visual signal indicates a fully established synaptic connection between two cells.
Psilocin increased the overall number of formed synapses across the cultured neurons. This rapid synapse-building capacity matched the growth produced by ketamine and lithium. Ketamine also selectively increased the density of PSD-95 proteins, indicating a specific enhancement on the receiving ends of the synapses.
Conversely, LSD, DMT, and fluoxetine produced no measurable changes in the number of synaptic connections during this 24-hour testing window. The lack of structural growth from fluoxetine aligns with the drug’s typical pharmacological timeline. Fluoxetine generally requires chronic administration over several weeks to alter brain architecture in living animals, making a single laboratory dose an ineffective trigger for rapid structural change.
In a separate phase of the study, the researchers measured the activation of immediate early genes within the cultured neurons. These genes act as a rapid response system in biological environments. They switch on within minutes of a stimulus without requiring the cell to synthesize new proteins first. Once activated, these genes initiate a chain reaction, providing the instructions for other proteins that build, stabilize, and maintain new synaptic connections.
The researchers extracted genetic material from the cells one hour and 24 hours after drug exposure. They used a technique called quantitative polymerase chain reaction to measure the expression levels of three specific genes known to support neuroplasticity. By analyzing the genetic material, they could measure which drugs triggered the molecular machinery necessary for long-term neural adaptation.
One hour after treatment, psilocin caused a rapid spike in the expression of the Arc gene. The Arc gene produces a protein that helps shape the physical structure of the synapse and manages the flow of chemical signals across the cell membrane. The rapid activation of Arc provides a potential molecular mechanism for how psilocin initiates neural growth so quickly.
At the 24-hour mark, fluoxetine increased the activity of the Egr1 and Npas4 genes. Egr1 acts as a transcription factor that binds to DNA and regulates the overall organization of synapses. Npas4 operates as a homeostatic regulator, helping to maintain a healthy balance between excitatory and inhibitory electrical signals in the brain. The other tested drugs did not reliably activate these specific genes at the tested time points, suggesting different compounds might rely on distinct molecular pathways to produce their effects.
The study took place in isolated cells in a laboratory rather than in a living animal or human. Living brains contain diverse networks of interacting cell types, including specialized support cells, that a simple laboratory culture cannot fully replicate. The researchers also used a mixture of cells from both male and female rat embryos, which might mask sex-specific differences in how neurons respond to psychedelics or antidepressants.
The lack of structural effects from LSD and DMT might stem from how the specific chemical preparations interacted with the cells. The researchers used a fumarate salt form of these compounds to ensure stability in the growth medium. However, they did not add a chemical solvent, such as dimethyl sulfoxide, to help the drugs cross the cell membrane.
Recent biological research suggests that serotonergic psychedelics must enter the interior of the neuron to activate intracellular receptors and trigger growth. Without a permeation enhancer, the salt forms of LSD and DMT may simply have been unable to penetrate the lipid barrier of the cells in this specific experimental setup. Future studies using different drug formulations will be necessary to determine if LSD and DMT possess the same rapid synapse-building properties as psilocin.
The study, “Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression – comparison with ketamine, fluoxetine and lithium,” was authored by Yana Vella, Kateřina Syrová, Aneta Petrušková, Isis Koutrouli, Viera Kútna, Jan Pala, Klára Šíchová, Marek Nikolič, Vladimír Mazoch, Radek Jurok, Martin Kuchař, Zdeňka Bendová, and Tomáš Páleníček.