Background: Serotonergic psychedelics administered with psychological support have therapeutic potential. Psilocybin, dimethyltryptamine (DMT), 2,5-Dimethoxy-4-iodoamphetamine (DOI) via 5-HT1, 5-HT2, and sigma-1 receptors have immune-modulatory properties. Little is known about the immuno-modulatory mechanisms of psychedelics in Major Depressive Disorder (MDD), known to be associated with dysregulated immune function.
Aim: (1). Investigate the anti-inflammatory action of DOI, DMT, and psilocybin/psilocin on Peripheral blood mononuclear cells (PBMCs) in MDD and healthy controls (HCs) and explore the relationship with mood, stress, cognition, and resilience (2). Investigate the expression of pro and anti-inflammatory markers in the blood and brain in rats after systemically administered psychedelics (3). Investigate the effects of psychedelics on inflammatory signalling and behaviour in an immune challenge rodent model of depression.
Methods: 40 adults with at least moderate MDD (HAM-D≥17) and matched HCs will be recruited. Mood, stress, resilience, and cognitive performance (model-based planning, trail making and memory binding) will be captured by a combination of clinical scales and the Neureka smart phone app. PBMCs will be stimulated with T-cell mitogen anti-CD3 or LPS or unstimulated, in the presence and absence of psychedelic compounds and dexamethasone to determine glucocorticoid and psychedelic mediated responsivity. ELISA and HPLC/LC-MS will quantify protein and metabolic biomarkers (kynurenine pathway metabolites) respectively in the media. Pro and anti-inflammatory markers in the blood and brain will be measured in response to systemic administration of psychedelics in rats, together with BDNF, tryptophan/kynurenine metabolites and microglial/astrocytic responses. The effects of psychedelics on sustained depression and anxiety-like behaviours and immune signalling will be further investigated using a Bacillus Calmette-Guerin (BCG) rat model.
Conclusion: We hypothesize that psychedelics will exhibit anti-inflammatory and antidepressant like effects. This will advance the mechanistic understanding of the immuno-modulatory mechanisms of psychedelics and pave the way for more precise therapeutic applications, all the more important in a post-COVID era.
