Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity
This review (2022) explores our current understanding of the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules. The ability of psychedelics to promote structural and functional plasticity in the prefrontal cortex (PFC) and the implications this has for many stress-related neuropsychiatric disorders like PTSD are some of the topics discussed.
Abstract
In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioural changes relevant to the treatment of neuropsychiatric disorders that last long after the compounds have been cleared from the body. One hypothesis with the potential to explain the remarkable enduring effects of psychedelics is related to their abilities to promote structural and functional neuroplasticity in the prefrontal cortex (PFC). A hallmark of many stress-related neuropsychiatric diseases, including depression, post-traumatic stress disorder (PTSD), and addiction, is the atrophy of neurons in the PFC. Psychedelics appear to be particularly effective catalysts for the growth of these key neurons, ultimately leading to the restoration of synaptic connectivity in this critical brain region. Furthermore, evidence suggests that the hallucinogenic effects of psychedelics are not directly linked to their ability to promote structural and functional neuroplasticity. If we are to develop improved alternatives to psychedelics for treating neuropsychiatric diseases, we must fully characterize the molecular mechanisms that give rise to psychedelic-induced neuroplasticity. Here, I review our current understanding of the biochemical signalling pathways activated by psychedelics and related neuroplasticity-promoting molecules, with an emphasis on key unanswered questions.
Research Summary of 'Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity'
Introduction
Stress-related neuropsychiatric disorders such as depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD) are associated with atrophy and dysfunction of neurons in the prefrontal cortex (PFC). Olson outlines that classic serotonergic psychedelics and a broader class of compounds he terms psychoplastogens can produce rapid and sustained behavioural improvements after only one or a few doses, in contrast to traditional daily-administered neurotherapeutics. One mechanistic hypothesis proposed to explain these durable effects is that psychedelics catalyse structural and functional neuroplasticity in the PFC, restoring synaptic connectivity and thereby repairing pathological circuits that control mood, fear and reward. This perspective sets out to review current biochemical knowledge of how psychedelics and related psychoplastogens promote neuronal growth. Olson summarises preclinical and some clinical evidence that various psychoplastogens (including LSD, psilocin, DMT, DOI, MDMA, ibogaine, ketamine and nonhallucinogenic analogues such as tabernanthalog) induce neuritogenesis, spinogenesis and synaptogenesis, and then focuses on the signalling pathways and unresolved questions linking receptor activation to long-lasting changes in cortical structure and function. The aim is to identify molecular targets and experimental gaps that must be addressed to design improved, potentially nonhallucinogenic, neuroplasticity-promoting therapeutics.
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Olson, D. E. (2022). Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity. Biochemistry, 61(3), 127-136. https://doi.org/10.1021/acs.biochem.1c00812
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