Discovering the Potential Mechanisms of Medicinal Mushrooms Antidepressant Activity: A Review

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TL;DR

This review explores the potential antidepressant mechanisms of medicinal and edible mushrooms, including their role as a source of serotonin precursors like L-tryptophan and 5-hydroxy-L-tryptophan, anti-inflammatory and neurotrophic effects, and modulation of the gut-brain axis. Psilocybin from psychedelic mushrooms is discussed as a rapid-acting antidepressant candidate, with a large trial showing a single 25 mg dose significantly reduced depression scores over 3 weeks. The authors conclude that incorporating mushrooms into the diet may lower depression risk through multiple biological pathways, supporting their consideration as functional foods in nutritional psychiatry.

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**Background:** Depression affects over 322 million people worldwide and is a leading cause of disability. Current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are based on the monoamine theory but require weeks to take effect and are ineffective for many patients, with nearly 30% of Major Depressive Disorder (MDD) patients suffering from treatment-resistant depression (TRD). Medicinal and edible mushrooms have gained attention for their potential antidepressant properties, supported by a population-based study showing mushroom consumers are less likely to suffer from depression. This review aims to elucidate the potential mechanisms underlying this antidepressant activity.

**Methods:** This is a narrative review synthesizing evidence from in vitro, in vivo, and clinical studies on the antidepressant mechanisms of medicinal/edible mushrooms. The review covers four main areas: (1) content of indole compounds (L-tryptophan, 5-hydroxy-L-tryptophan, tryptamine) in mushroom fruiting bodies and mycelia; (2) psilocybin as a rapid-acting antidepressant; (3) anti-inflammatory and neurotrophic effects; and (4) modulation of the gut-brain axis. Data are drawn from published studies including randomized clinical trials, animal models, and cell-based assays.

**Key Results:** - **Indole compounds:** The highest L-tryptophan content was found in *Suillus bovinus* (25.90 mg/100 g dw) and *Pleurotus djamor* (24.84 mg/100 g dw). The highest 5-hydroxy-L-tryptophan (5-OH-L-Trp) was in *P. djamor* fruiting bodies (193.95 mg/100 g dw). Mycelia from in vitro cultures showed even higher 5-OH-L-Trp content, with *P. djamor* mycelia reaching 703.56 mg/100 g dw. Thermal processing reduced indole compound content by approximately 2-fold, but mushrooms remained a good source. - **Psilocybin:** The largest clinical trial (Goodwin et al., n=233) found that a single 25 mg dose of psilocybin significantly reduced Montgomery-Åsberg Depression Rating Scale scores compared to 1 mg over 3 weeks, though adverse effects included headache, nausea, and dizziness. Psilocybin acts as a 5-HT2A receptor agonist, induces down-regulation of these receptors, and increases BDNF synthesis in the medial prefrontal cortex. Microdosing (0.5 g) showed no evidence of enhanced cognitive function in a double-blind placebo-controlled study (n=35). - **Anti-inflammatory activity:** Multiple mushroom species demonstrated anti-neuroinflammatory effects in LPS-induced microglia models. *Lentinula edodes* β-glucan reduced TNF-α, IL-6, and IL-1β in the hippocampus and prefrontal cortex of high-fat diet-fed mice. *Hericium erinaceus* erinacine A reduced TNF-α, IL-1β, and iNOS gene expression in LPS-injected rats. *Ganoderma lucidum* deacetyl ganoderic acid F attenuated LPS-induced neuroinflammation via NF-κB pathway inhibition. - **Neurotrophic effects:** *H. erinaceus* extract upregulated BDNF, doublecortin, nestin, synaptophysin, and TrkB mRNA/protein expression in chronically stressed mice and enhanced hippocampal neurogenesis. A clinical trial (n=80) showed *H. erinaceus* mycelium promoted BDNF and NGF concentrations in elderly patients. *Ganoderma lucidum* polysaccharide-peptide reversed depression behaviors in mice and upregulated BDNF/TrkB expression in the prefrontal cortex. - **Gut-brain axis:** Mushroom polysaccharides acted as prebiotics, altering gut microbiota composition. *G. lucidum* ethanolic extract increased *Turicibacter*, *Bifidobacterium*, and *Parabacteroides* while decreasing *Escherichia/Shigella* in colitis mice. *Armillaria mellea* fermentation liquor increased 5-HT1A and 5-HT2A proteins in the hippocampus and reduced peripheral inflammation (IL-6, TNF-α, IL-1β) in an insomnia rat model. *H. erinaceus* supplementation in a pilot study (n=13) increased alpha and beta diversity and promoted butyrate-producing bacteria.

**Clinical Implications:** The review suggests that medicinal/edible mushrooms may exert antidepressant effects through multiple complementary mechanisms: providing serotonin precursors, reducing neuroinflammation, promoting neurotrophin expression and neurogenesis, and modulating the gut microbiota to reduce peripheral inflammation and improve intestinal barrier function. The authors note that psilocybin shows promise for TRD but requires more clinical trials, especially evaluating long-term effects. Dietary incorporation of mushrooms or mushroom-based supplements is proposed as a potentially valuable adjunctive strategy in depression management, consistent with nutritional psychiatry recommendations.