Research has yielded promising results on the efficacy of psychedelic drugs in treating depressive symptoms. However, the hallucinogenic properties and other adverse effects of psychedelics have restricted their use in broader human studies and the treatment of depression. Both the alleviation of depressive symptoms and hallucinations have been thought to be caused by the activation of serotonin receptors in the brain under the effect of psychedelics.
A study conducted at the University of Helsinki uncovered new information on a molecular mechanism through which the psychedelic drugs LSD and psilocin affect the body and alleviate depressive symptoms. Psilocin is a metabolite that mediates the effects of psilocybin, which occurs in hallucinogenic “magic mushrooms”.
The study was carried out in the laboratory in cell cultures as well as in mice.
“These findings can help in the development of novel compounds that could in the future be used to treat depression in humans without causing the hallucinations typical of psychedelics,” says Research Director Eero Castrén from the Neuroscience Center, University of Helsinki.
New information on mechanisms of action
Previously, the research group has demonstrated that conventional antidepressants bind in the brain to a receptor for brain-derived neurotrophic factor (BDNF), known as TrkB, which results in their effects on neuroplasticity. Now, the researchers have found that LSD and psilocin bind in cells to this same TrkB receptor very strongly, as much as a thousand times more effectively than conventional antidepressants. Their binding to TrkB boosted the effect of the BDNF protein, which in turn resulted in an increase in connections between neurons.
“This effect indicates an increase in the plasticity of the brain, which is central to alleviating depressive symptoms,” Castrén explains.
The study furthermore found that a single dose of LSD produced a fairly sustained antidepressant-like effect in mice.
“The behavioural changes in mice that indicate the alleviation of depression were the result of LSD binding specifically to TrkB, and they were not dependent on the binding of psychedelics to serotonin receptors,” Castrén points out.
A head-twitch response, which is considered a sign of hallucinogenic effects of LSD in mice, was specifically associated with the activation of serotonin receptors. This phenomenon was not caused by the activation of TrkB.
According to researchers, the findings indicate that the development of drugs that exclusively bind to TrkB receptors would make it possible to achieve a response that alleviates depression without psychedelic experiences.
The researchers emphasise that the findings are still experimental and that further research is needed on the topic.
The results have been published in the Nature Neuroscience journal.
Article: Moliner, R., Girych, M., Brunello, C.A. et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci 26, 1032–1041 (2023). DOI: doi.org/10.1038/s41593-023-01316-5.