Restless Legs Syndrome: The Evidence-Based Supplement Protocol

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Restless legs syndrome (RLS) / Willis-Ekbom disease is primarily a CNS dopaminergic disorder with strong CNS iron involvement. Dopamine agonists, alpha-2-delta ligands (gabapentin enacarbil, pregabalin), and iron repletion remain first-line. Among supplements, iron is the foundational intervention — the supplement evidence is uniquely strong here.

Iron — Replete to Ferritin ≥75 ng/mL (Aim 100+)

The 2018 IRLSSG guidelines specifically recommend ferritin ≥75 ng/mL as the target in adults with RLS, even when systemic iron labs are within normal range. CNS iron deficiency drives RLS regardless of peripheral status. Oral iron (alternate-day ferrous bisglycinate or ferrous sulfate) is first-line; IV iron (ferric carboxymaltose) is considered when oral fails or serum ferritin < 100 ng/mL with severe symptoms. See our iron dosing piece.

Magnesium, 250–400 mg Elemental at Bedtime

Magnesium has small positive RCT signal in RLS, particularly when paired with vitamin B6. The 2019 trial in 100 adults with RLS showed magnesium oxide 250 mg + B6 40 mg at bedtime improved IRLS scores versus placebo. Effect smaller than iron repletion or dopamine agonists. See our magnesium RLS piece.

Vitamin D — Repletion in Deficiency

Vitamin D deficiency is more common in RLS cohorts than controls. Small RCTs show repletion modestly reduces IRLS scores in deficient adults. Test and treat. See vitamin D piece.

Folate — Pregnancy-Related RLS

Pregnancy-related RLS often responds to folate supplementation alongside the recommended prenatal vitamin. Adequate folate is also independently indicated periconceptionally.

What NOT to Take

Avoid caffeine, alcohol, nicotine — all reliably worsen RLS. Avoid most antidepressants except bupropion (SSRIs, SNRIs, and mirtazapine consistently worsen RLS — bupropion is the only relatively RLS-safe option). Avoid antihistamines (diphenhydramine etc) which worsen RLS. Skip "leg cramp" magnesium-only products without RLS-specific evidence. Don't use opioids long-term without RLS specialist input — they work but carry dependence and rebound augmentation risk.

How to Run the Protocol

Test serum ferritin, TSAT, and transferrin. Replete iron to ferritin ≥75 ng/mL (target 100+). Use alternate-day oral iron if ferritin >30; IV iron if <30 or severe symptoms. Test and replete 25-OH-D. Avoid the RLS triggers above. Add magnesium 250 mg + B6 40 mg at bedtime. Re-evaluate IRLS at 12 weeks. If unresolved, neurology referral for dopamine agonist or gabapentin enacarbil. See condition page.