Can Psilocybin Stimulate Neurogenesis in the Hippocampus?

A staggering 280 million people suffer with depression worldwide, reports the World Health Organization, and many experience debilitating symptoms that are not effectively treated by currently approved therapies. Depression is a complex condition that presents variably in different people, although persistent low mood, sleep disturbance, and cognitive dysfunction are common symptoms and can severely impact many areas of life. Innovative therapies that target the underlying biological processes associated with depression are desperately needed.

In some people, postmortem studies indicate, depression may be related to disrupted adult hippocampal neurogenesis (AHN)—the birth and growth of new neurons in the hippocampus. This mechanism is important for regulating mood and maintaining spatial learning and memory throughout life, and it is critical for brain plasticity.

Psilocybin is a psychedelic compound found in psilocybe species of mushrooms, and a synthetic, investigational formulation of psilocybin is currently in Phase 3 clinical trials for treatment-resistant depression. However, psilocybin’s antidepressant mechanism of action remains elusive. Increasing evidence suggests psilocybin may promote neuroplasticity, contributing to its antidepressant effects.

Adult hippocampal neurogenesis is affected in depression

Before the 1960s, scientists didn’t think it was possible for new neurons to be generated in the adult brain. It wasn’t until 1998 that Eriksson and colleagues detected newly born neurons in the postmortem brains of cancer patients who were given bromodeoxyuridine (BrdU), a molecule that incorporates into the DNA of dividing cells.

Since then, it has been established that in a small region within the hippocampus, known as the dentate gyrus, a pool of stem cells gives rise to progenitor cells that, as they mature, travel and integrate into the neural circuitry of the hippocampus as functional neurons.

Growing in vivo animal research suggests that adult hippocampal neurogenesis (AHN) plays a critical role in emotion regulation, stress resilience, and cognitive flexibility—where reduced AHN is associated with anxiety and depressive-like behaviours. The reduction in AHN may alter interactions between the hippocampus and amygdala, also involved in mood regulation, and could potentially impact the stress response mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis. The findings implicate abnormal AHN in the pathology of depression.

AHN is influenced by multiple intrinsic and environmental factors, including diet, exercise, sleep, and drugs. Its dynamic nature involves it in multiple processes that can occur over several weeks. It has, therefore, been difficult to capture real-time AHN changes in living humans using available brain imaging techniques; and this has led to controversy in the past, with some researchers questioning whether adult neurogenesis even occurs.

The Thuret Lab at King’s College London developed a proxy biomarker for AHN using a blood test. It measures changes in markers of proliferation and differentiation of hippocampal progenitor cells in a dish exposed to serum from people. The dentate gyrus has a rich blood supply, allowing blood components to directly impact the stem cells in that region.

Using this assay, Du Preez et al. (2022) found that serum from patients with depressive symptoms, compared to those without, was associated with impaired neuron shape and structure as well as changes in neurogenesis markers. The findings suggest that alterations in AHN are associated with depression, which raises the question whether psilocybin alleviates depression by modifying AHN. If so, it may reveal a new mechanism of action explaining how psychedelic compounds produce antidepressant effects.

Psilocybin promotes neuroplasticity

When ingested, psilocybin is quickly transformed into psilocin, which has a similar chemical structure to serotonin. Psilocin then binds to different types of serotonin (5-HT) receptors; activation of (mostly) 5-HT2a receptors is what researchers think produces the characteristic effects of psychedelics, such as hallucinations and altered perception.

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At a cellular level, studies have found that intracellular 5HT2a receptor activation by psilocin increases branching of cortical neurons, multiplying the number of synapses and creating a greater quantity of spines on dendrites, which tend to be reduced in depressed individuals.

More recent evidence suggests that another receptor could be responsible for the neuroplastic effects, independent of 5HT2a receptors. Ppsilocin increases levels of a nerve growth factor, brain-derived neurotrophic factor (BDNF), and it may also be an allosteric modulator. Moliner et al (2023) showed that psilocin binds to a specific subunit of tropomyosin-related kinase B (TrkB) receptor, the binding site of BDNF, and changes the receptor shape, facilitating BDNF binding and enhancing activation of the receptor. This mechanism is both relevant for neurogenesis and associated with reducing depressive-like behaviours in mice.

Essentially, psilocybin appears to boost BDNF and increase the number of neural connections, abetting the potential for communication between neurons. This activity could be really important for regulating hippocampal neurogenesis.

Psilocybin stimulates adult hippocampal neurogenesis … in mice!

Recently, to assess the potential therapeutic benefit of psilocybin for PTSD, which commonly co-occurs with depression, Du et al. (2023) studied mice that had been fear-conditioned. The extinction of fear is a process that relies on hippocampal-associated learning and memory.

After a single dose of a synthetic formulation of psilocybin, developed by Beijing Institute of Pharmacology and Toxicology, the fear response of mice improved, and the effect was associated with several indicators of increased hippocampal neurogenesis. Psilocybin increased the number and density of dendritic branches and synaptic connections in the hippocampus; likely related to increased levels of BDNF, which supports proliferation and differentiation of hippocampal progenitor cells. One week after the fear-conditioned mice received psilocybin, the researchers found a higher number of cells labelled with BrdU and doublecortin (DCX), a marker of proliferating cells and immature neurons, respectively, in the dentate gyrus.

Even though this study didn’t look at depressive-like behaviors in mice, the findings are promising and suggest that psilocybin may play a role in enhancing hippocampal-dependent neuroplasticity by increasing AHN, which could benefit functions that are impaired in depression, such as cognitive flexibility. Previous trials have shown that psilocybin can improve cognitive flexibility in people with depression, but this has not been studied in the context of AHN.

Further research is needed to understand whether psilocybin, along with psychological support, stimulates AHN in humans, too, and whether such activity correlates with its antidepressant effects. Understanding how psychedelic compounds such as psilocybin work mechanistically can be valuable for developing new medicines having fewer side effects and optimising care.

Zarah Haniff

Used with permission

Zarah Haniff is a pharmacist and Ph.D. fellow in mental health research funded by the Wellcome Trust at the Institute of Psychiatry, Psychology, and Neuroscience, King’s College London. She previously completed an M.Sc. in dementia research at the Queen Square Institute of Neurology, University College London, and has clinical, industrial, and academic experience. Her Ph.D. project explores the effects of psilocybin on mood and cognitive function mediated by adult hippocampal neurogenesis and microglial activity in patients with major depressive disorder. This project is supervised by Professor Sandrine Thuret, Dr Anthony Vernon, and Professor Allan Young and is supported by clinical collaborator, Dr James Rucker.