How Psilocybin Reduces Symptoms of Depression

Psilocybin may have therapeutic value for many common neuropsychiatric disorders, including depression, obsessive-compulsive disorder, and substance use disorder.

Psilocybin can increase synaptic plasticity in the brain.

Psilocybin may have therapeutic value for many common neuropsychiatric disorders, including depression, obsessive-compulsive disorder, and substance use disorder.

Many recent studies have shown that psilocybin can rapidly relieve the symptoms of depression, and this relief lasted for several months. However, psilocybin has another action in the brain that many patients find unpleasant; it produces hallucinations. Psilocybin is a member of a class of drugs called serotonergic psychedelics because the current best explanation for how these drugs produce their effects is via action at a serotonergic receptor. Almost certainly, this is not the only action that psilocybin has in the brain; it is simply the one that we currently know about.

Third Wave

What specifically does psilocybin do in the brain to reduce the symptoms of depression? Can these benefits be separated from its ability to produce hallucinations? If neuroscientists can uncover how psilocybin and the other psychedelics produce mental health benefits, this knowledge could be used to produce more effective medications with fewer unwanted side effects.

This is what is currently known. After rats were treated with similar serotonergic psychedelics, their brains showed an increased expression of genes that control synaptic plasticity. Studies of neurons in cell culture discovered that these serotonergic psychedelics can induce a transient increase in the size of dendritic spines as well as a proliferation of the number of their branches. These findings are important because changes in synaptic plasticity and the proliferation of their branches are believed to underlie the reduction in depressive symptoms. No one yet knows why; the data are entirely correlational. In addition, only limited evidence links serotonergic psychedelics to actual structural plasticity in vivo. Finally, no one knows whether the time scale in which this synaptic remodeling occurs in the mammalian brain matches what is seen clinically when patients are treated with these drugs.

One recent study investigated whether a single dose of psilocybin would modify the dendritic architecture in the medial frontal cortex of mice. They reported that psilocybin induced a significant increase in spine density after only one day and that spine density continued to increase for at least the next seven days. The increased density was due to an increase in the formation of new spines. Interestingly, the spine formation rate was significantly higher in females, as compared to males, after psilocybin treatment. That finding may have untold clinical relevance! These newly formed spines were also quite long-lasting; the new spines remained stable for at least 34 days.

Third Wave

Can the hallucinogenic effects of psilocybin be separated from its therapeutic effects? The results hinted at one answer: No. This is why. The location of the psilocybin-induced changes in dendritic plasticity is important. In the current study, the plasticity occurred in a brain region that is thought to be responsible for both hallucinogenic potency and the therapeutic benefits. Thus, it might not be possible to separate the two actions of these serotonergic psychedelics.

This new study confirmed that changes in structural plasticity involving dendritic remodeling may underlie its rapid antidepressant effects. Their results also fit nicely with those of another psychedelic. Ketamine also increases spine density in the same cortical regions by elevating spine formation rate. However, ketamine acts with great potency and affinity for glutamate receptors, not serotonin receptors. Future studies will need to investigate how drugs with very different molecular targets can produce comparable dendritic modifications.

© Gary L. Wenk, Ph.D. is the author of Your Brain on Food and a member of the Governor’s Medical Marijuana Advisory Committee for the State of Ohio.


Shao LX et al., (2021) Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. bioRxiv doi:

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