Therapeutic potential of classic and non-classic psychedelics in neurodevelopmental disorders: Opportunities and challenges

Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions arising from altered brain development and leading to impairments in social, cognitive, emotional, and motor domains. Clinical manifestations are highly variable in severity and symptom profile, reflecting the complex and multifactorial etiology of NDDs. Available treatments are limited to early behavioral interventions, eventually combined with symptomatic pharmacotherapies, but remain largely unsatisfactory. Among possible new therapeutic strategies for NDDs, classic psychedelics, such as LSD or psilocybin, and non-classic psychedelics including ketamine have recently received interest due to their potential in enhancing neuroplasticity and restoring social and cognitive deficits. Classic psychedelics are a group of psychoactive substances sharing agonistic activity on serotonergic 5-HT2A receptors while ketamine is a dissociative anesthetic acting as N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist. Although the literature about the potential of psychedelics in the treatment of NDDs is still scarce and heterogeneous, we revised here available clinical and preclinical data to discuss the opportunities and challenges associated with the use of these drugs in NDDs. We found that most of the evidence comes from small clinical studies on adult subjects mainly evaluating the therapeutic potential of low dose ketamine, while reports with classic psychedelics are scarce and primarily observational. Overall, despite further research being needed before any conclusions can be drawn regarding the efficacy and safety of classic and non-classic psychedelics in the management of NDDs, most findings are promising and report significant behavioral improvements especially in cognitive and social domains.