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Psychedelics promote growth of neural connections that have been lost due to depression

The researchers observed an increase in the number and size of dendritic spines after 24 hours of psilocybin administration. The alterations were still visible a month later. Furthermore, after being agitated, mice given psilocybin showed behavioral improvements and increased neurotransmitter activity. (Photo credit: Getty Images)

For years, researchers have been looking at the hallucinogenic substance psilocybin, a naturally occurring chemical found in certain mushrooms, as a possible therapy for depression. But it’s still unclear how exactly it works in the brain and how long the positive effects will persist.

In a new study, Yale researchers show that a single dose of psilocybin given to mice prompted an immediate and long-lasting increase in connections between neurons. The findings were published in the journal Neuron.

“We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well,” said Yale’s Alex Kwan, associate professor of psychiatry and of neuroscience and senior author of the paper.

Previous research had suggested that psilocybin, as well as the anesthetic ketamine, might help people feel less depressed. These chemicals have been found to enhance the density of dendritic spines, tiny protrusions seen on nerve cells that help in the transfer of information between neurons, according to the new Yale study.

The number of these neural connections is known to be reduced by chronic stress and depression.

Figure 2 from the research paper displaying the data that shows Psilocybin elevating the formation rate of dendritic spines.

Kwan and lead author Ling-Xiao Shao, a postdoctoral associate at Yale School of Medicine, photographed dendritic spines in high resolution and tracked them over many days in living mice using a laser scanning microscope. Within 24 hours of psilocybin treatment, they discovered an increase in the number and size of dendritic spines.

A month later, the changes were still noticeable. In addition, mice administered psilocybin demonstrated behavioral gains and enhanced neurotransmitter activity after being stressed.

Psilocybin, an active chemical found in “magic mushrooms,” can induce a deep spiritual experience in certain people. The psychedelic was formerly a common part of indigenous New World religious rites and is now a popular recreational drug.

According to Kwan, the new psychological effects of psilocybin itself may be what’s stimulating the development of neural connections.

“It was a real surprise to see such enduring changes from just one dose of psilocybin,” he said. “These new connections may be the structural changes the brain uses to store new experiences.”


The study was published in the journal Neuron, on July 5th, 2021.

Abstract. Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. Here we chronically imaged apical dendritic spines of layer 5 pyramidal neurons in mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine density and spine head width. Synaptic remodeling occurred quickly within 24 hours and was persistent 1 month later. The results demonstrate structural plasticity that may underpin psilocybin’s long-lasting beneficial actions.

Results. Our results indicate that a single dose of psilocybin induces a significant elevation in spine density (+7±2% on Day 1, +12±3% on Day 7; main effect of treatment, P=0.011, mixed-effects model to account for variations across dendrites and mice; Fig. 1g–i) and increase in the width of spine heads (+11±2% on Day 1, and +5±1% on Day 7; main effect of treatment, P=0.013; Fig. 1j–l, Supplementary Fig. 1). Details for all statistical tests including sample sizes are provided in Supplementary Table 1. Increased spine density could be due to higher formation rate, lower elimination rate, or both. To distinguish between the possibilities, we leveraged the longitudinal data set to determine the turnover rates of dendritic spines. In females, the spine formation increased by 8±2% after psilocybin (7±1% on Day -1, 15±2% on Day 1; Fig. 2a, b). Likewise, the spine formation rate was higher by 4±2% in males after psilocybin (6±1% on Day -1, 10±2% on Day 1). By contrast, there was no change in the elimination rate of spines (Fig. 2c). A key question was whether the new spines formed after psilocybin administration would persist, because nascent dendritic spines can take 4 days to mature into functional synapses14. For this reason, we imaged 34 days after psilocybin administration and observed that a fraction of the psilocybin-induced new spines remained stable (Fig. 2d). Altogether, these results demonstrate that a single dose of psilocybin induces rapid and long-lasting dendritic remodeling in layer 5 pyramidal neurons in the mouse medial frontal cortex.

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