Major depressive disorder (MDD) or depression is a serious common mental disorder characterized by persistent sadness, loss of interest and pleasure and a host of associated physical and functional impairments. Over 250 million people are affected by MDD worldwide, which supposes a heavy burden on modern societies beyond the individual, as it significantly undermines overall well-being and productivity globally. Classic antidepressant drugs fall short in meeting the needs of patients: antidepressant medications show an estimated success rate of 50-60%, delayed onset of therapeutic effects, and notable issues of tolerability. The urgent need for novel, improved therapeutics is imperative.

Research on the use of psychedelic-assisted therapy in the treatment of depression has advanced considerably in recent years. As a consequence, psilocybin is gaining increasing scientific and regulatory attention as a potential treatment for depression and other psychiatric disorders. The U.S. FDA has granted Breakthrough Therapy Designation to several psilocybin-based therapies, accelerating their clinical development, though full approval is still pending. In Europe, the EMA is revising its antidepressant guidelines to potentially include psychedelic compounds like psilocybin in formal clinical trial frameworks. Notably, Australia has taken a pioneering step by rescheduling psilocybin and MDMA, allowing authorised psychiatrists to prescribe them for treatment-resistant depression and PTSD, respectively. In order to effectively harness the potential of psilocybin and other psychedelics, it is imperative to understand the neural mechanisms behind their effects, as well as the clinical relevance of them. Evidence suggests that psychedelics may cause structural and functional changes in the brain, which could constitute the basis of their therapeutic benefits. However, the precise nature and underlying mechanism of these changes remain poorly understood.

With the aim to shed light on the complex mechanisms of the therapeutic effects of psilocybin, researchers are making use of animal models of psychiatric disease, particularly rats and mice, which have historically served as pivotal instruments in elucidating the mechanisms of a myriad of active compounds. Rodent models offer us several advantages, including genetic traceability and manipulation, well-understood neuroanatomy and behavioural repertoire, and allowance to control the experimental environment. In spite of the limitations expected from animal models of disease, they function as valuable tools for advancing our understanding of the effects of psilocybin on the brain and on behaviour.

Our most recent publication reports a comprehensive preclinical study on the antidepressant- and anxiolytic-like effects and mechanisms of psilocybin through the use of an array of behavioural and neurochemical evaluations in a translational rodent model of disease. Chronic stress has been identified as a major risk factor for the development of MDD, and the overstimulation and dysregulation of the organism’s stress system (hypothalamic-pituitary-adrenal axis) is implicated in the pathophysiology of the disease. Therefore, the chronic unpredictable mild stress (CUMS) mouse model was implemented, by exposing mice to random, intermittent and unpredictable stressful stimuli over several weeks. The development of the model itself presented a number of experimental challenges, stemming from inconsistencies and the lack of standardized protocols across the literature. The defying task of generating reproducible and reliable animal models could be alleviated by providing detailed methodological information in the publication of manuscripts. Two key findings can be highlighted from testing, evaluating and optimizing CUMS protocols in our facilities. Firstly, social factors play an important role in the development of behavioural and physiological impairments during exposure to stress, and social isolation has been seen to exacerbate such alterations. Secondly, exposure to chronic stressors of varying intensity and duration can lead either to adaptive responses during an initial adjustment phase, or to maladaptive changes that ultimately contribute to the development of the pathology. In spite of the hurdles faced, the implementation of the CUMS protocol described in the work provided a robust, translational animal model with consistent impairments across dimensions associated with depressive and anxiety-like behaviours, accompanied by physiological alterations relevant to chronic stress, in which psilocybin’s therapeutic potential was tested.

Psilocybin was given to mice following an administration scheme similar to that found in several clinical trials, in which patients were given two high (hallucinogenic) doses of psilocybin, separated by a 7-day interval. After de induction of the chronic stress model and the psilocybin treatment, mice were subjected to specific tests for the evaluation of depressive- and anxiety-like footprints, which are also employed to detect and quantify therapeutic response. In this regard, psilocybin was seen to reverse some stress-induced depressive-like alterations, specifically in the dimensions of anhedonia (reduced ability to experience pleasure) and behavioural despair (state of immobility and resignation induced in animals when placed in a stressful situation). Additionally, all psilocybin-treated animals exhibited a mild anxiolytic response. Importantly, the therapeutic behavioural effects where characterized long-term, that is, over a week after the second administration.

In addition to the behavioural findings, our work revealed that psilocybin treatment induced neurochemical and functional effects that could have clinical implications. A hypersensitivity in the head-twitch response (proxy for psychedelic-like effects in rodents) and increased expression of the molecular target responsible for such response (serotonin 2A receptors) in brain cortex was detected upon second administration of psilocybin. Furthermore, psilocybin treatment induced modulation of the stress-response axis (hypothalamic-pituitary-adrenal axis) selectively in chronically stressed mice.

In spite of the progress made, many questions remain unanswered. The optimal posology for the induction and maintenance of antidepressant effects of psilocybin is yet to be defined. Indeed, the duration of the therapeutic effects is still unclear. Of paramount importance, solving the molecular mechanism and unravelling the target(s) responsible for the therapeutic action of psilocybin is pivotal. Particularly, the link between acute psychoactive effects and long-term therapeutic outcomes must be addressed. This matter is critical for promoting clinical scalability by maximizing the potential benefits of psychedelic treatments, while reducing unwanted effects and treatment costs. Finally, there is a need to address sex as a biological variable in the effects of psilocybin, especially regarding a condition with sex-specific prevalence and pathophysiological divergence, as MDD. Further studies are warranted to address the issues mentioned. Ultimately, our work highlights that the use of translational animal models contributes to the understanding of the largely debated therapeutic effects and mechanism of action of psychedelics.