Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

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.

Twenty percent better with 20 micrograms? A qualitative study of psychedelic microdosing self-rapports and discussions on YouTube

“…On the other hand, evidence from full-dose psychedelic research shows a comparable width of beneficial results. For instance, research has provided evidence for the effectiveness of psychedelic substances in treating addiction, depression, and PTSD [e.g., [6, 35, 36]]. Also, our findings parallel with positive psychology research of full-dose psychedelic use where acute and lasting effects on mood, well-being, prosocial behaviors, cognitive flexibility, creativity, value alignments, nature-connection, personality factor openness, and mindfulness-associated capabilities have been shown [37].…”

Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

“…At the molecular level, activation of the 5-HT 2A receptor increases glutamatergic tone and activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) glutamate receptors, BDNF’s high-affinity receptor (tyrosine kinase B receptor, TrkB), and the mammalian target of rapamycin (mTOR). These effects converge into increases in BDNF expression, neuritogenesis, spinogenesis, and synaptogenesis in the PFC (dos Santos et al, 2016; Ly et al, 2018; Marek, 2018; Nichols, 2004, 2016; Nutt et al, 2020; Olson, 2018). Such enhanced neuroplasticity is also produced by ketamine and is currently thought to be one of the main mechanisms involved in its antidepressant effects (Ly et al, 2018; Olson, 2018).…”

“…These effects converge into increases in BDNF expression, neuritogenesis, spinogenesis, and synaptogenesis in the PFC (dos Santos et al, 2016; Ly et al, 2018; Marek, 2018; Nichols, 2004, 2016; Nutt et al, 2020; Olson, 2018). Such enhanced neuroplasticity is also produced by ketamine and is currently thought to be one of the main mechanisms involved in its antidepressant effects (Ly et al, 2018; Olson, 2018). Compounds like ketamine and serotoninergic psychedelics that produce such effects on neural plasticity have been labeled ‘psychoplastogens’ (Olson, 2018).…”

Psychedelics as a treatment for disorders of consciousness

“…In addition, presynaptic 5-HT 2A receptors located at thalamo-cortical synapses have been shown to play an important role in the control of thalamo-frontal connectivity, also known to be important for consciousness (Giacino et al 2014; Barre et al 2016). 5-HT 2A receptor agonism in animals is associated with enhanced cognitive flexibility as well as cortical neural plasticity (Frankel and Cunningham 2002; Boulougouris et al 2008; Furr et al 2012; Zhang and Stackman 2015; Ly et al 2018; Olson 2018) whereas 5-HT 2A receptor antagonism is associated with reduced cognitive flexibility and increased slow-wave sleep (Carhart-Harris and Nutt 2017). We recognize that one should be cautious when extrapolating from findings in animals to humans.…”