Psychedelic-induced neuroplasticity as a potential and alternative therapy for mental disorders

Classic psychedelic compounds, such as DMT, psilocybin, and LSD show promising results in treating different mental disorders, such as depression, PTSD, addiction, mood and anxiety disorders. By interacting with serotonergic receptors, psychedelics seem able to increase many neuroplasticity-related changes such as neuritogenesis, spinogenesis, and synaptogenesis in the prefrontal cortex. PFC regulates many key cognitive functions, behavior, social interactions, executive functions like planning, reasoning decision-making, and many more. Alterations in this region of the brain can lead to many cognitive dysfunctions and impairments largely associated with depressive symptoms. Currently, the most prescribed antidepressants are selective serotonin reuptake inhibitors SSRI, however, because of their limitations and several side effects, research has been directed towards alternative fast-acting antidepressants, such as ketamine and psychedelics. Comparisons are drawn between the two, underlying similar plasticity-promoting mechanisms. Although ketamine remains limited by its abuse potential and dissociative proprieties, psychedelics seem to highlight their therapeutic effects by overcoming addiction with a safe pharmacological profile. In this thesis, I reported the results obtained by different in vitro and in vivo experiments adopting innovative approaches and techniques to explore psychedelic plasticity-promoting effects and mechanisms of action. The analysis was carried out starting from a broader focus, analyzing different classes of psychedelic substances, and then narrowing the field to psilocybin, the most studied psychedelic drug, and LSD, with particular attention to its impact on DNA methylation. The most important disadvantages related to the therapeutic use of these substances include hallucinations, characterized by unpredictability and high subjectiveness such as perception distortion and mind-altering states, as well as the need for assisted psychotherapy during treatment. Since negative effects are correlated with higher doses, further studies need to be conducted to define psychedelics’ dosage. This report provides a general analysis of psychedelic drugs' therapeutic potential as an alternative and fast-acting treatment for depression and related disorders.