Psilocybin acts on 5-HT2A receptors in brain regions tied to mood and pain, including the prefrontal cortex and anterior cingulate cortex, increasing glutamate signaling and network flexibility. It reduces inflammatory markers like IL-6, a signaling protein your immune system releases when something is wrong, and TNF-α, a key inflammatory signal linked to chronic inflammation, pain, and depression, while boosting BDNF-linked neuroplasticity and disrupting rigid default mode network patterns. Because ~66% of depression patients report pain and over 50% of pain patients meet depression criteria, this shared pathway targeting allows symptoms in both conditions to improve together.