Copper Bisglycinate

Copper has a nuanced relationship with mast cells. Copper is also a cofactor for DAO (diamine oxidase), the gut enzyme that breaks down histamine - the DiSilvestro 2010 RCT showed copper supplementation increased DAO activity by 75% in healthy women. That's clearly beneficial for histamine clearance. The nuance: excess copper can promote mast cell maturation, and copper interacts with tryptase activity in complex ways. At nutritional doses (2 mg), copper supports DAO without crossing into the territory where excess effects matter. Net effect is favorable for MCAS at this dose; we wouldn't dose higher.

Copper is foundational for hEDS - possibly the single most mechanistically essential trace mineral. Lysyl oxidase (LOX) is the enzyme that cross-links collagen and elastin fibers, and copper is the only cofactor LOX requires. Without adequate copper, cross-links can't form properly, and the collagen your body produces won't have the tensile strength it needs. The DiSilvestro 2010 RCT showed 2 mg/day of copper for 8 weeks increased the urinary collagen crosslink ratio by 62%. The genetic copper-deficiency disorders (Menkes, occipital horn syndrome) produce an EDS-like phenotype - demonstrating how essential copper is for proper connective tissue architecture.

For POTS, copper's role is mostly indirect through DAO support (histamine clearance), oxidative stress reduction (ceruloplasmin is a major plasma antioxidant), and the LOX cross-linking work in vascular wall connective tissue. Vascular wall integrity matters for POTS because compromised vessel wall structure contributes to the blood pooling pattern that drives orthostatic tachycardia. The DiSilvestro 2010 RCT showed 39% reduction in F2-isoprostanes (a marker of systemic oxidative stress) with 2 mg/day copper. No direct POTS clinical evidence, but the mechanism layers (vascular wall, oxidative stress, DAO) all support broader autonomic stability.