Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

This article (2018) describes psychedelics, ketamine, and a range of other substances as “psychoplastogens,” i.e., substances that help the brain increase its plasticity and thereby enable therapeutic change.

Abstract

“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.”

Author: David E. Olson

Summary

Behavior is controlled by a combination of activity in a variety of neural circuits distributed across the brain. Juvenile brains are remarkably plastic, but adult brains become less plastic after the closure of critical periods.

The prefrontal cortex (PFC) is critical for the top-down control of fear and reward, and its atrophy is a hallmark of depression. Small molecules capable of crossing the blood-brain barrier and activating plasticity mechanisms possess great medicinal value.

Compound-induced neural plasticity, or iPlasticity, occurs after treatment with several classes of small molecules. Traditional antidepressants are some of the most efficacious plasticity-promoting compounds known, but their effects on plasticity are quite slow and require chronic administration.

Ketamine, a dissociative anesthetic, produces fast-acting and relatively long-lasting antidepressant effects. Researchers have identified several compounds that mimic the beneficial effects of ketamine, and have recently introduced the term “psychoplastogen” to distinguish them from other slow-acting molecules that induce plasticity.

Psychoplastogens are small molecules that promote neural plasticity. They produce fast-acting antidepressant effects in humans and include the muscarinic receptor antagonist scopolamine, the NMDA receptor partial agonist GLYX-13 (i.e. rapastinel), and 5-HT2A receptor agonists such as psychedelics.

Recent studies have shown that psychedelic compounds such as DMT, LSD, and 2,5-dimethoxy-4-iodoamphetamine promote dendritic branching and/or increase spine/ synapse number both in cultured cortical neurons and in vivo.

DMT is the minimal pharmacophore for all tryptamine-containing psychedelics, and increases dendritic spine density and spontaneous excitatory postsynaptic currents in the PFC of rats 24 hours after administration. DMT also promotes fear extinction learning and reduces immobility in the forced swim test.

The use of psychoplastogens to promote fear extinction learning is gaining traction, and the same strategy could be used to extinguish drug-cue memories. Psychoplastogens have the potential to treat stroke, brain trauma, and neurodegenerative diseases.

Psychoplastogens, including ketamine, psychedelics, and scopolamine, appear to induce changes in neuronal structure by activating the mammalian target of rapamycin (mTOR). However, many psychoplastogens alter perception or produce other undesired effects.

The most useful psychoplastogens will be those capable of promoting plasticity in a circuit-specific manner. Psychedelics are an attractive starting point for developing circuit-specific psychoplastogens because they activate mTOR by stimulating 5-HT2A receptors, which are highly expressed on layer V pyramidal neurons of the cortex.

Psychoplastogens offer many exciting possibilities for therapeutic interventions, but excessive stimulation of mTOR has been associated with autism spectrum disorder and Alzheimer’s disease.

Modern research on ketamine, psychedelics, and other psychoplastogenic compounds has enabled us to move beyond simplistic therapeutic strategies aimed at controlling monoamine levels toward the selective modulation of neural circuits.