Psychedelics and Other Psychoplastogens for Treating Mental Illness

Abstract

Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do they produce sustained therapeutic effects following a single administration, they also appear to have broad therapeutic potential, demonstrating efficacy for treating depression, post-traumatic stress disorder (PTSD), anxiety disorders, substance abuse disorder, and alcohol use disorder, among others. Psychedelics belong to a more general class of compounds known as psychoplastogens, which robustly promote structural and functional neural plasticity in key circuits relevant to brain health. Here we discuss the importance of structural plasticity in the treatment of neuropsychiatric diseases, as well as the evidence demonstrating that psychedelics are among the most effective chemical modulators of neural plasticity studied to date. Furthermore, we provide a theoretical framework with the potential to explain why psychedelic compounds produce long-lasting therapeutic effects across a wide range of brain disorders. Despite their promise as broadly efficacious neurotherapeutics, there are several issues associated with psychedelic-based medicines that drastically limit their clinical scalability. We discuss these challenges and how they might be overcome through the development of non-hallucinogenic psychoplastogens. The clinical use of psychedelics and other psychoplastogenic compounds marks a paradigm shift in neuropsychiatry toward therapeutic approaches relying on the selective modulation of neural circuits with small molecule drugs. Psychoplastogen research brings us one step closer to actually curing mental illness by rectifying the underlying pathophysiology of disorders like depression, moving beyond simply treating disease symptoms. However, determining how to most effectively deploy psychoplastogenic medicines at scale will be an important consideration as the field moves forward.

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

“…In terms of RDoC, structural and functional neuroplasticity broadly falls under molecular and cellular units of analysis and probably applies, at least some degree, to all domains. The ability of psychedelics to rapidly rewire neural circuitry by engaging plasticity mechanisms has given rise to the term-"psychoplastogens" (168)(169)(170)(171)(172)(173). While, it is generally accepted that the quality of the subjective experience, dependent on the optimization of set and setting (context) is a critical component of the therapeutic mechanism of action of psychedelic therapy (87,174), some propose that the subjective effects may not be necessary to produce long-lasting changes in mood and behavior (171).…”

The Hallucinogenic Serotonin2A Receptor Agonist, 2,5-Dimethoxy-4-Iodoamphetamine, Promotes cAMP Response Element Binding Protein-Dependent Gene Expression of Specific Plasticity-Associated Genes in the Rodent Neocortex

“…Diverse serotonergic psychedelics, as well as the hallucinogenic 5-HT 2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), can elicit both unique and distinctive molecular, behavioral and electrophysiological effects (Aghajanian and Marek, 1999;González-Maeso et al, 2003, 2007Marek, 2017;Banerjee and Vaidya, 2020;Savino and Nichols, 2021). Common to all of these 5-HT 2A receptor agonists is a regulation of neuronal structural plasticity in the neocortex; from increased dendritic complexity to enhanced synaptogenesis (Ly et al, 2018(Ly et al, , 2020Savalia et al, 2021;Shao et al, 2021;Vargas et al, 2021). The rapid transcriptional effects evoked via agonistic action at the 5-HT 2A receptor, in particular the enhanced expression of neuronal plasticity-associated gene expression, are implicated in contributing to these psychoplastogenic effects (Nichols et al, 2003;Olson, 2018;Berthoux et al, 2019;Artin et al, 2021;de Vos et al, 2021;Jefsen et al, 2021).…”

Mycotherapy: Potential of Fungal Bioactives for the Treatment of Mental Health Disorders and Morbidities of Chronic Pain

“…Serotonin syndrome for example which is a potentially life-threatening condition can be caused by using serotonergic drugs and overactivation of 5-HT 1A and 5-HT 2A receptors [ 52 ]. Additionally, antidepressants such as TCAs and SSRIs are known to increase the concentration of neurotransmitters at synapses within minutes, yet it takes weeks to months for mental illness symptoms to regress in patients [ 53 ]. Additional theories of depression include the neurogenic hypothesis of depression and inflammatory hypothesis based on an increase in proinflammatory cytokines in the nervous system [ 7 ].…”

“…Psychedelic compounds produce hallucinogenic experiences via activity in brain regions regulating cognition, emotions, self-awareness and perception of pain [ 73 ]. Psychedelics are included in the psychoplastogens class of compounds which have effect on neural plasticity in key circuits involved in brain health [ 53 ]. By definition psychoplastogens produce a quantifiable change in plasticity within a short time frame (>72 h) post administration [ 74 ].…”