Psychedelics and Neural Plasticity: Therapeutic Implications

Abstract

Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as well as other unanswered basic neuroscience questions addressable with future studies.

Keywords: 5-HT2AR; circuits; plasticity; psychedelics; psychoplastogens.

Figure 1.

Psychedelics. A, Psychedelics are mind-altering drugs that produce their hallucinogenic effects through activation of 5-HT_2ARs. Psychedelic-like drugs include dissociative anesthetics (e.g., ketamine), entactogens (e.g., MDMA or “ecstasy”), deliriants (scopolamine), and oneirogens (ibogaine). B, Psychedelics are much less harmful to users than other recreational drugs (see Nutt et al., 2010).

Figure 2.

Psychedelics and neuroplasticity. A, Many traditional antidepressants (SSRIs) promote iPlasticity: they induce juvenile-like plasticity in the adult brain (see Castrén, 2005; Umemori et al., 2018). A property of many psychedelics is that they are psychoplastogens: they are exogenously administered therapeutic drugs that promote long-lasting neuroplasticity after a single dose (see Olson, 2018). B, To date, evidence of promoting structural or functional plasticity has been shown for several psychedelics or psychedelic-like drugs (see Olson, 2020; de Vos et al., 2021; Lukasiewicz et al., 2021; Jaster et al., 2021).

Figure 3.

Models of neuroplasticity. A, While various terms have been used to describe neuroplasticity in the brain (i.e., Hebbian plasticity, homeostatic plasticity, hyperplasticity, and others), there is an ongoing deficiency in the field for clearly communicating aspects of these processes meaningfully. Here we propose the use of four actions of neuroplasticity (α, Ω, Δ, and μ) within a particular frame of action (brain-wide, brain region, network, neurons, etc.) to communicate outcomes (maximize, minimize, contrast, normalize) for paths of activity in the brain. Experience modifies the nature of the outcomes. B, Examples of the use of a systematic nomenclature for describing neuroplasticity in the brain. Other examples (not shown) are “Drug induced plasticity^Δ in active networks” and “Time-delayed plasticity^μ in inhibitory neurons.”