Ketamine and classical psychedelics (psilocybin, LSD, and DMT) work as fast-acting antidepressants by promoting neuroplasticity. Evidence from preclinical and clinical studies shows these compounds trigger synaptic, structural, and functional changes, especially in pyramidal neurons of the prefrontal cortex. They increase glutamate release, activate AMPA receptors, and stimulate BDNF and mTOR signaling, leading to the expression of synaptic proteins and synaptogenesis. This adaptive rewiring of pathological neurocircuitry may explain their robust and sustained therapeutic effects.
A systematic review of preclinical studies found that extracts from 19 mushroom species and 7 other fungus species nearly all produced antidepressant-like effects in animal models of depression. The review identified 50 relevant studies, mostly in male rodents, using oral administration in acute or chronic regimens. The most common animal model was unpredictable chronic mild stress, while the tail suspension test and forced swim test were frequently used as antidepressant screens. The review discusses each experiment in detail and evaluates the strengths and weaknesses of the studies, highlighting that the antidepressant potential of mushroom and fungus extracts extends beyond psilocybin-containing species to include both psychedelic and non-psychedelic varieties.