Therapeutic modulation of the kynurenine pathway in severe mental illness and comorbidities: A potential role for serotonergic psychedelics.

The kynurenine pathway (KP) plays a crucial role in the altered gut-brain axis balance in severe mental illness (SMI), including depression, bipolar disorder, and schizophrenia, as well as in cardiometabolic comorbidities. Serotonergic psychedelics may hold therapeutic potential by modulating the KP, either directly through influencing rate-limiting enzymes and tryptophan levels, or indirectly via effects on the gut microbiome, metabolism, and immune system. Preliminary evidence suggests psychedelics improve outcomes in preclinical models of obesity, metabolic syndrome, and vascular inflammation. However, the mechanisms and outcomes remain largely unknown, and concerns about side effects in specific SMI cohorts require further investigation.

Study at a glance

Abstract

Mounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI. Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the rate-limiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system. Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities.