Therapeutic Effects of Psychedelics and their Non-Hallucinogenic Analogs on Depressive-Like Behaviour

Major depressive disorder (MDD) is a complex and debilitating condition affecting approximately 280 million people worldwide. Its heterogeneous nature makes it difficult to establish clinical treatment guidelines that address individual differences in treatment response. As a result, many individuals experience treatment-resistant depression (TRD) failing to respond to first-line antidepressants. This increases the burden on healthcare systems and highlights the need for new, fast-acting therapies. Psychedelics have emerged as promising candidates due to their rapid and sustained antidepressant effects, with compounds such as psilocybin demonstrating the ability to enhance neuroplasticity through 5-HT2A receptor activation. However, their hallucinogenic properties limit clinical accessibility, necessitating intensive therapeutic supervision. Non-hallucinogenic analogs, like 2-bromo-lysergic acid diethylamide (2-Br-LSD), offer a potentially safer alternative by promoting neuroplasticity without causing hallucinations. Indeed, it still remains unclear whether hallucinatory activity is required for therapeutic benefit. This thesis examines the antidepressant effects of psilocybin and 2-Br-LSD in rodent models of depression following chronic stress. It is hypothesized that both compounds will reduce depression-like behaviours in mice by modulating neural circuits involved in mood regulation. By investigating whether the therapeutic benefits can occur without hallucinations, this work aims to assess the potential of 2-Br-LSD as a more accessible treatment option for TRD.