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.

Keywords: depression; hallucinogenic; ketamine; neuroplasticity; prefrontal cortex; psilocybin; psychedelic; psychoplastogen.

Figure 1

The antidepressant effects of psychoplastogens (e.g., ketamine and psilocybin) are more rapid and sustained than those of traditional antidepressants (e.g., fluoxetine). Data adapted from three clinical trials evaluating the effects of fluoxetine (6), ketamine (7), and psilocybin (8) for treating depression. Dashed lines represent the efficacy of either 1 or 8 weeks of fluoxetine treatment.

Figure 2

Genetic and environmental factors lead to the cortical atrophy observed in depression, which includes retraction of dendritic branches and loss of dendritic spines. These structural changes are reversed by psychoplastogens (12).

Figure 3

Opto- and chemogenetic experiments have revealed a number of circuits originating in the PFC that are relevant to the treatment of neuropsychiatric disorders. Arrows indicated excitatory projections.

Figure 4

Percentage of patients excluded from recent large MDD trials of the hallucinogenic drug psilocybin and the non-hallucinogenic drug vortioxetine. A comprehensive analysis of all psychedelic trials is beyond the scope of this review. For additional information on the broad range of smaller trials with psychedelics, please see (262, 263).

Figure 5

Percentage of MDD with various comorbidities. Data for bipolar disorder, psychosis, substance use disorder, personality disorders, and suicidality were obtained from references (–271), respectively.

Figure 6

Estimated quarterly (3 months) costs (L = low, M = medium, H = high) for daily administration of non-hallucinogenic take-home traditional antidepressants (blue) and intermittent dosing of clinically administered, dissociative psychoplastogen (ketamine) treatments (red). Note: generic ketamine costs include drug, administration (IV), and required monitoring, while Prozac^®, Zoloft^®, Celexa^®, and Spravato^® costs are for the drug only. Retail costs for SSRIs reflect the low and high branded price published on goodrx.com with the medium price being calculated as an average of the two. To estimate the total cost, we used medium doses for each drug (Prozac^® 20 mg, Zoloft^® 50 mg, and Celexa^® 20 mg,) and assumed daily dosing for 90 days. Ketamine infusion cost was sourced from ketamineclinicsdirectory.com/ketamine-infusion-cost/. This site estimates the low and high cost of a complete set of 4–6 generic ketamine infusions to be $1,600–$4,800, respectively. The medium cost was calculated as an average of the two ($3,200). Our estimate for the 3-month cost of generic ketamine assumes that no additional doses are needed beyond the initial 4–6 doses. Retail Spravato^® costs were estimated based on the price of a 56 mg dose ($900) published on goodrx.com and dosing was based on the package insert (Revised 7/2020). The label indicates Spravato^® should be dosed twice a week during the induction phase (weeks 1–4; $900 × 2 × 4 = $7,200), once a week during the maintenance phase (weeks 5–8; $900 × 1 × 4 = $3,600), and once a week thereafter (weeks 9–12; $900 × 1 × 4 = $3,600). The estimated low cost of Spravato^® includes the induction phase only. The estimated medium cost of Spravato^® includes the induction phase and the maintenance phase. The estimated high cost of Spravato^® includes the induction phase, maintenance phase, and 4 weeks of additional treatment. Note: the cost of administration and monitoring for Spravato are not publicly available, and thus not included, but these costs are anticipated to be significant.

Figure 7

Comparison of traditional antidepressant treatments with hallucinogenic and non-hallucinogenic psychoplastogen treatments. *Currently, no clinical trials have been conducted with non-hallucinogenic psychoplastogens, and thus, their fast-acting and long-lasting effects refer to preclinical testing only. **The scalability and cost-effectiveness of non-hallucinogenic psychoplastogens are based on the assumption that they will produce clinical efficacy greater than the standard of care (i.e., traditional antidepressants).