Psilocybin appears to produce long-term antidepressant effects by inducing persistent changes in how neurons fire, a form of functional plasticity, rather than by maintaining permanent increases in structural connections. In rats, a single psilocybin dose led to months-long antidepressant-like behavior and durable shifts in the electrical properties of prefrontal cortical neurons, even after measurable structural changes had faded (Neuropsychopharmacology, 2026).
What did the new rat study show?
Researchers administered a single dose of psilocybin or a highly selective 5-HT2A receptor agonist, 25CN-NBOH, to rats and tracked behavior and brain physiology for three months. Both compounds reduced immobility in the forced swim test, a standard measure of antidepressant-like effects in rodents, with no decline in effect size across the testing period. The team then performed brain-slice electrophysiology in the medial prefrontal cortex (mPFC) and found lasting changes in Layer 5 pyramidal neurons, including a depolarized resting membrane potential, increased firing rates, and enhanced synaptic excitation.
Months after a single dose, rats showed persistent antidepressant-like behavior and prefrontal neurons remained more excitable, yet synaptic density and dendritic spine classifications were not different from controls (Nature journal report).
Microscopy did not detect differences in synaptic density or spine type distributions, and gene expression panels for several pre- and postsynaptic markers in the mPFC were unchanged. Together, the data point to enduring functional tuning of neuronal activity, rather than lasting structural remodeling, as a driver of the long-term behavioral effects.
How might psilocybin create long-lasting changes in brain function?
Psilocybin’s active metabolite, psilocin, stimulates 5-HT2A receptors that are abundant on cortical pyramidal neurons. Activation of this receptor engages intracellular signaling pathways that acutely increase excitability and can promote plasticity. In this study, a selective 5-HT2A agonist reproduced psilocybin’s sustained behavioral and electrophysiological effects, suggesting that 5-HT2A activation is sufficient to initiate long-lived functional changes in prefrontal circuits. Prior work has shown that psychedelics can enhance both structural and functional plasticity shortly after dosing (Cell Reports, 2018), but the new findings indicate that persistent benefits may reflect long-term adjustments in excitability and synaptic drive rather than permanent structural growth.
Functional plasticity refers to durable changes in neuronal excitability and synaptic strength, while structural plasticity refers to changes in physical architecture such as dendritic spine number and shape.
How does this compare to structural plasticity findings?
Several studies have reported rapid increases in dendritic spine density and size in frontal cortex after psilocybin, with some effects detectable for weeks (Neuron, 2021). In pigs, a single psilocybin dose increased a synaptic density marker and decreased 5-HT2A receptor density shortly after administration (Int J Mol Sci, 2021). The new rat data refine this picture: structural changes may be transient or subtle at later time points, while functional adjustments in firing properties persist and align more closely with the time course of antidepressant-like behavior.
In the rat prefrontal cortex, long-lasting behavioral effects were linked to persistent shifts in neuronal excitability, not to enduring differences in spine density or synaptic marker expression (Neuropsychopharmacology, 2026).
What does this mean for depression treatment in humans?
Clinical studies have found that psilocybin-assisted therapy can reduce depression and anxiety symptoms for weeks to months in some patients. For example, randomized trials in people with life-threatening cancer reported rapid and sustained symptom reductions (J Psychopharmacol, 2016), (J Psychopharmacol, 2016), with follow-up work suggesting durability of benefit in some individuals (J Psychopharmacol, 2020). A randomized trial in major depressive disorder found that psilocybin produced substantial improvements, although it did not outperform escitalopram on the primary endpoint (NEJM, 2021).
The new animal data offer a mechanistic clue that could help explain why benefits can outlast the acute psychedelic experience: psilocybin may leave prefrontal networks in a persistently retuned functional state. Translating this to patients will require careful study, since human outcomes also depend on psychological support, individual differences, diagnosis, and dosing paradigms.
What are the limitations and open questions?
- Animal model constraints: The forced swim test is widely used to detect antidepressant-like activity but is also interpreted as a measure of stress-coping strategy rather than depression per se (Nat Protoc, 2012), (ACS Chem Neurosci, 2017). Results may not fully generalize to human depression.
- Sampling of brain circuits: Electrophysiology focused on Layer 5 pyramidal neurons in the mPFC. Other cell types and networks may show different or additional changes.
- Time course and structure-function link: Structural changes reported in other studies may be transient or below detection at later time points. Determining how transient structural events seed long-lived functional tuning remains an open question.
- Receptor mechanisms: This work supports 5-HT2A sufficiency for long-lasting effects, but other studies have reported antidepressant-like actions that are not strictly dependent on 5-HT2A in certain mouse paradigms (PNAS, 2021). Reconciling these findings will require standardized models and cross-species comparisons.
- Clinical translation, safety, and access: While research is advancing, psilocybin remains a controlled substance in many jurisdictions and can carry risks, particularly for people with psychosis risk or certain cardiovascular conditions. Clinical use should follow regulated, supervised protocols within trials or approved programs.
Bottom line
A single psilocybin dose can produce months-long antidepressant-like effects in rats and persistent increases in prefrontal neuron excitability without lasting structural changes. This points to enduring functional plasticity, initiated by 5-HT2A receptor activation, as a plausible mechanism for psilocybin’s durability. Human trials show promising, though variable, symptom relief, and ongoing research is clarifying how transient molecular and structural events translate into long-term functional recalibration of mood-related circuits.