Psychoplastogens represent a new category of compounds with the ability to rapidly restructure brain circuits implicated in various mental health conditions. These small molecules promote neural plasticity, which is the brain’s capacity to change and adapt by forming new connections.
This class of therapeutics offers a different approach compared to conventional treatments. While many neuropsychiatric conditions involve impaired neural plasticity, psychoplastogens aim to directly facilitate the reorganization of neural circuits. This focus on brain restructuring positions them as an area of significant research interest for addressing various brain disorders.
How Psychoplastogens Work
Psychoplastogens exert their effects by promoting rapid and sustained neural plasticity. This involves cellular changes such as increased dendrite length, spine density, and the number of synapses. These changes typically occur within 24 to 72 hours of a single administration, a timeline much faster than traditional pharmacotherapies.
The compounds activate key signaling pathways, including the mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), which are involved in neuronal growth, survival, and function. For instance, ketamine, a psychoplastogen, increases dendritic branching and synapse formation in cultured cortical neurons. This enhanced connectivity and communication between neurons can lead to improvements in cognitive and emotional functioning.
Many psychoplastogens increase the secretion of glutamate, a neurotransmitter, which then stimulates mTOR by activating AMPA receptors. This initial burst of glutamate can lead to BDNF secretion, which further activates mTOR, creating a feedback loop that supports cell growth and the production of proteins necessary for synapse formation. The ability to rapidly promote these neuronal changes is considered a common therapeutic activity and mechanism of action for psychoplastogens.
Conditions Targeted by Psychoplastogens
Psychoplastogens are being investigated for their potential to treat a range of mental health disorders and neurological conditions. These include major depressive disorder (MDD), where they aim to restore synaptic connectivity in the prefrontal cortex, a brain region involved in mood regulation.
Post-traumatic stress disorder (PTSD) is another condition where psychoplastogens show promise, as they may help “rewire” maladaptive thought patterns and facilitate fear extinction learning. This involves addressing dysfunction in areas like the amygdala and its communication with the medial prefrontal cortex. Psychoplastogens are also being explored for substance use disorders and alcohol use disorder, aiming to break cycles of addiction by reorganizing neural circuits.
The broad therapeutic potential of psychoplastogens likely stems from their ability to impact the structure and function of layer V pyramidal neurons in the prefrontal cortex. These compounds are also being studied for anxiety disorders and obsessive-compulsive disorder (OCD), with research indicating robust structural and functional deficits in the prefrontal cortex across these conditions. Their fast-acting and sustained effects after a single administration offer hope for individuals who have not found relief from conventional treatments.
Key Psychoplastogen Compounds and Their Development
Several compounds are categorized or being explored as psychoplastogens, including existing drugs and novel experimental therapeutics. Ketamine, a dissociative anesthetic, is considered a prototypical psychoplastogen due to its rapid and relatively long-lasting antidepressant effects and its ability to promote the growth of dendritic spines and the formation of synapses in the prefrontal cortex within 24 hours.
Modified psychedelics are also a significant area of development, with researchers exploring non-hallucinogenic analogs of compounds like psilocybin and LSD. The goal is to retain the neuroplasticity-promoting benefits while reducing or eliminating the psychoactive experiences. For example, lisuride, a non-hallucinogenic structural analog of LSD, has shown antidepressant properties in clinical settings.
Other compounds, such as the muscarinic receptor antagonist scopolamine and the NMDA receptor partial agonist GLYX-13 (rapastinel), have also been identified as psychoplastogens. The development of these compounds is often in preclinical or early clinical trial stages, with the overarching aim of creating safe and effective treatments that can be more widely accessible.
Distinguishing Psychoplastogens from Traditional Psychedelics
While some psychoplastogens are derived from or inspired by psychedelics, a key distinction lies in their intended psychoactive effects. The primary goal of psychoplastogens is to induce therapeutic neuroplasticity with significantly reduced or absent hallucinogenic properties.
This difference has considerable implications for patient accessibility and administration. Psychoplastogens that lack hallucinogenic effects could potentially be administered in a broader range of clinical settings and might not require the intensive supervision currently associated with psychedelic-assisted therapies.
The development of non-hallucinogenic psychoplastogens aims to separate the beneficial neuroplastic effects from the mind-altering experiences. Research involves identifying the specific mechanisms by which these compounds promote neural growth, such as the activation of BDNF and mTOR pathways, and engineering molecules that selectively engage these pathways without triggering the hallucinogenic responses mediated by receptors like 5-HT2A. This targeted approach seeks to provide the “rewiring” benefits without the “trip,” potentially transforming how these therapies are delivered.