Acute and Chronic Psilocybin in Mouse Models of Psychiatric Disorders

Abstract Background The evident limitations of current treatments for depression, anxiety and obsessive-compulsive disorder (OCD), underscore the need for a paradigm shift in how we understand and treat these disorders. There is enormous public and research enthusiasm for the potential that psychedelic drugs like psilocybin, the psychoactive compound produced by “magic mushrooms” will drive a new paradigm of care for mental ill health. Although promising results are emerging for the treatment of depression, anxiety and OCD, questions remain about the biological mechanisms underlying therapeutic outcomes. Also, the recent approval for the use of psilocybin for treatment-resistant depression in Australia has been criticized as premature considering (i) the difficulty separating therapeutic effects from expectancy (placebo effects), (ii) remaining questions on the biological mechanisms underpinning efficacy and (iii) a lack of well-designed long-term studies assessing potential deleterious effects. Aims & Objectives Dr Renoir will present behavioral and molecular data relevant to both acute and chronic psilocybin in transgenic mouse models relevant to depression, anxiety and obsessive/compulsive-like disorders. Method Using SAPAP3 knockout (KO) mice, a well-validated mouse model of OCD, we assessed the effects of both acute (1 mg/kg, intraperitoneal) and chronic (0.1–1 mg/kg, oral gavage) treatment with psilocybin on (i) immediate behavioural outcomes (i.e. locomotor activity and the head-twitch response) and (ii) possible therapeutic effects on anxiety- and compulsive-like behaviours as well as sociability and gut function. Results Psilocybin administration induced a hyper-locomotor effect in WT but not in SAPAP3 KO animals suggesting differences in in-vivo serotonergic receptor signaling between genotypes. Psilocybin (1 mg/kg) reliability increased the number of head-twitches in mice (regardless of the genotype) indicating its hallucinogenic potential at this dose. Acute psilocybin reduced compulsive grooming behaviours in male KO mice for up to 1 week and significantly reduced grooming in female KO and wild-type (WT) mice. Chronic psilocybin, however, did not improve anxiety-like, depressive-like, or compulsive-like behaviours, nor did it affect the social deficits exhibited by SAPAP3 KO mice. We also have evidence suggesting the potential involvement of the serotonin transporter (5-HTT) in mediating some effects of psilocybin as well as limitations/questions around the psychedelic actions in the context of schizophrenia. Discussion & Conclusions This combined evidence highlights acute psilocybin as a promising candidate for reducing compulsive behaviours, while chronic administration offers limited benefits. This is especially timely as the acceptance and approval of psychedelic-assisted psychotherapy becomes adopted worldwide and there are concerns about the increasing use of repeated low doses of psychedelics (i.e. at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy - often referred to as ‘microdosing’).