Long-term antidepressant effects of psilocybin linked to functional brain changes

A new study suggests that the long-term antidepressant effects of psychedelics may be driven by persistent changes in how neurons fire rather than by the permanent growth of new brain cell connections. Researchers found that a single dose of psilocybin altered the electrical properties of brain cells in rats for months, even after physical changes to the neurons had disappeared. These findings were published in the journal Neuropsychopharmacology.

Depression is a debilitating condition that is often treated with daily medications. These standard treatments can take weeks to work and do not help every patient. Psilocybin, a compound found in certain mushrooms, has emerged as a potential alternative therapy. Clinical trials indicate that one or two doses of psilocybin can alleviate symptoms of depression for months or even years. However, scientists do not fully understand the biological mechanisms that allow a single treatment to produce such enduring results.

Researchers have previously focused on the concept of neuroplasticity to explain these effects. This term generally refers to the brain’s ability to reorganize itself. One specific type is structural plasticity, which involves the physical growth of new connection points between neurons, known as dendritic spines. Short-term studies conducted days or weeks after drug administration often show an increase in these spines. The question remained whether these physical structures persist long enough to account for relief lasting several months.

To investigate this, a team of researchers led by Hannah M. Kramer, Meghan Hibicke, and Charles D. Nichols at LSU Health Sciences Center designed an experiment using rats. They chose Wistar Kyoto rats for the study. This specific breed is often used in research because the animals naturally exhibit behaviors analogous to stress and depression in humans.

The investigators sought to compare the effects of psilocybin against another compound called 25CN-NBOH. Psilocybin interacts with various serotonin receptors in the brain. In contrast, 25CN-NBOH is a synthetic drug designed to target only one specific receptor known as the 5-HT2A receptor. This is the receptor believed to be primarily responsible for the psychedelic experience. By using both drugs, the team hoped to isolate the role of this specific receptor in creating long-term behavioral changes.

The study began with the administration of a single dose of either psilocybin, 25CN-NBOH, or a saline placebo to the male rats. The researchers then waited for a substantial period before testing the animals. They assessed the rats’ behavior at five weeks and again at twelve weeks after the injection. This timeline allowed the team to evaluate effects that persist well beyond the immediate aftermath of the drug experience.

The primary method for assessing behavior was the forced swim test. In this standard procedure, rats are placed in a tank of water from which they cannot escape. Researchers measure how much time the animals spend swimming versus floating motionless. In this context, high levels of immobility are interpreted as a passive coping strategy, which is considered a marker for depressive-like behavior. Antidepressant drugs typically cause rats to spend more time swimming and struggling.

The behavioral results indicated a lasting change. Rats treated with either psilocybin or 25CN-NBOH showed reduced immobility compared to the control group. This antidepressant-like effect was evident at the five-week mark. It remained equally strong at the twelve-week mark. The persistence of the effect suggests that the single dose induced a stable, long-term shift in behavior.

After the twelve-week behavioral tests, the researchers examined the brains of the animals. They focused on the medial prefrontal cortex. This brain region is involved in mood regulation and decision-making. The team utilized high-resolution microscopy to count the density of dendritic spines on the neurons. They specifically looked for the physical evidence of new connections that previous short-term studies had identified.

The microscopic analysis revealed that the number of dendritic spines in the treated rats was no different from that of the control group. The structural growth seen in other studies shortly after treatment appeared to be transient. The physical architecture of the neurons had returned to its baseline state after three months. The researchers also analyzed the expression of genes related to synaptic structure. They found no difference in gene activity between the groups.

Since structural changes could not explain the lasting behavioral shift, the team investigated functional plasticity. This refers to changes in how neurons process and transmit electrical signals. They prepared thin slices of the rats’ brain tissue. Using a technique called electrophysiology, they inserted microscopic glass pipettes into individual neurons to record their electrical activity.

The researchers classified the neurons into two types based on their firing patterns: adapting neurons and bursting neurons. Adapting neurons typically slow down their firing rate after an initial spike. Bursting neurons fire in rapid clusters of signals. The recordings showed that the drugs had altered the intrinsic electrical properties of these cells.

In the group treated with psilocybin, adapting neurons sat at a resting voltage that was closer to the threshold for firing. This state is known as depolarization. It means the cells are primed to activate more easily. The bursting neurons in psilocybin-treated rats also showed increased excitability. They required less input to trigger a signal and fired at faster rates than neurons in untreated rats.

The rats treated with 25CN-NBOH also exhibited functional changes, though the specific electrical alterations differed slightly from the psilocybin group. For instance, the bursting neurons in this group were not as easily triggered as those in the psilocybin group. However, the overall pattern confirmed that the drug had induced a lasting shift in neuronal function.

These electrophysiological findings provide a potential explanation for the behavioral results. While the physical branches of the neurons may have pruned back to normal levels, the cells “remembered” the treatment through altered electrical tuning. This functional shift allows the neural circuits to operate differently long after the drug has left the body.

The study implies that the 5-HT2A receptor is sufficient to trigger these long-term changes. The synthetic drug 25CN-NBOH produced lasting behavioral effects similar to psilocybin. This suggests that activating this single receptor type can initiate the cascade of events leading to persistent antidepressant-like effects.

There are limitations to this study that provide context for the results. The researchers used only male rats. Female rats may exhibit different biological responses to psychedelics or stress. Future research would need to include both sexes to ensure the findings are universally applicable.

Additionally, the forced swim test is a proxy for human depression but does not capture the full complexity of the human disorder. While it is a standard tool for screening antidepressant drugs, it measures a specific type of coping behavior. The translation of these specific neural changes to human psychology remains a subject for further investigation.

The researchers also noted that while spine density returned to baseline, this does not mean structural plasticity plays no role. It is possible that a rapid, temporary growth of connections acts as a trigger. This early phase might set the stage for the permanent electrical changes that follow. The exact molecular switch that locks in these functional changes remains to be identified.

Future studies will likely focus on the period between the initial dose and the three-month mark. Scientists need to map the transition from structural growth to functional endurance. Understanding this timeline could help optimize how these therapies are delivered.

The study, “Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity,” was authored by Hannah M. Kramer, Meghan Hibicke, Jason Middleton, Alaina M. Jaster, Jesper L. Kristensen and Charles D. Nichols.