Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelin's paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis.Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis.In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions:1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression?2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids?
Keywords: gut microbes; serotonergic hallucinogens; severe psychiatric illness.