Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics
Neural plasticity—the ability to change and adapt in response to stimuli—is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens—a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.
overview of "psychoplastogens"
By definition, psychoplastogens are small molecules and thus plasticity-promoting proteins like BDNF do not fall into this category. To be classified as a psychoplastogen, a compound should produce a measurable change in plasticity (eg, changes in neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration. Because their impact on neural plasticity enables subsequent stimuli to reshape neural circuits, they should produce relatively long-lasting changes in behavior that extend beyond the acute effects of the drug. In addition to ketamine, several other psychoplastogens have been identified, all of which produce fast-acting antidepressant effects in humans.4 These include the muscarinic receptor antagonist scopolamine,5 the NMDA receptor partial agonist GLYX-13 (ie, rapastinel),6 and 5-HT2A receptor agonists such as psychedelics
The advent of psychoplastogenic compounds has enabled us to move beyond simplistic therapeutic strategies aimed at controlling monoamine levels toward the selective modulation of neural circuits—a fundamental shift in our approach to treating CNS disorders. Significant progress has been made in recent years and provides hope that modern research on ketamine, psychedelics, and other psychoplastogens will lead to safe and effective strategies for harnessing neuralplasticity to treat mood and anxiety disorders such as depression and PTSD. It is clear that psychoplastogens can serve as powerful tools for understanding the basic biology of neural plasticity.
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