Iron

The leading theory is the iron–dopamine connection: many people with RLS have reduced iron availability in certain brain regions. Brain iron is required for normal dopamine production and function; low brain iron appears to dysregulate subcortical dopamine pathways that are implicated in RLS symptoms. Improving systemic iron (when deficient or low-normal) can increase brain iron availability and reduce symptoms in some patients. SpringerLink

Consensus statements and recent editorials emphasize that regional brain iron deficiency is a central pathophysiologic element of RLS and provide the biological rationale for iron therapy. Oxford Academic

a. Test first (always):

• Measure serum ferritin and transferrin saturation (TSAT) before treating. The modern RLS guidelines recommend treating when ferritin ≤ 75 ng/mL or TSAT < 20%; if ferritin is between 75–100 ng/mL some guidelines favor IV iron only rather than oral. These thresholds are higher than many general-population iron thresholds because RLS symptom relief is tied to restoring brain iron, not just treating anemia. JCSM

b. If ferritin ≤ 75 ng/mL or TSAT < 20% — consider iron replacement:

• First-line (typical): Oral iron (ferrous salts) is often used first—particularly if ferritin is clearly low (e.g., <50 ng/mL) and there are no contraindications or intolerance. Modern practice favors lower daily elemental iron doses or alternate-day dosing to improve absorption and reduce GI side effects (examples: ~50–100 mg elemental iron once daily or every-other-day). Ferrous sulfate 200 mg (≈65 mg elemental iron) once daily is a commonly used regimen; alternate-day dosing (same or slightly larger single dose) may increase fractional absorption. NICE
• When to use IV iron: IV iron (most evidence uses ferric carboxymaltose / FCM) is recommended for:
• Patients who fail or cannot tolerate oral iron, or
• Patients with ferritin between ~75 and 100 ng/mL where guideline panels recommend IV rather than oral, or
• Those who need faster repletion or have malabsorption/ongoing blood loss. JCSM

c. Example IV dosing used in clinical trials

• A recent randomized, placebo-controlled trial used ferric carboxymaltose 750 mg IV on Day 0 and again on Day 5 (two doses) and showed benefit for RLS symptoms as a group. This is one of the stronger recent RLS-specific IV iron trials. Actual dosing in clinical practice may vary by product, body iron deficit, and local protocols—so follow product labeling and local IV-iron guidance. Oxford Academic

d. Children

• Thresholds differ for children; guidelines commonly use ferritin < 50 ng/mL for considering iron therapy in pediatric RLS. JCSM

Practical checklist for clinicians / patients

1. Confirm diagnosis of clinically significant RLS and look for reversible causes/exacerbating medications (e.g., some antihistamines, dopamine blockers, etc.). E-Journal of Science and Medicine
2. Order ferritin and TSAT (and full blood count if indicated). AASM
3. If ferritin ≤75 ng/mL or TSAT <20% → start iron therapy (oral unless IV indicated). If ferritin 75–100 ng/mL consider IV iron directly per guideline wording. JCSM
4. Reassess symptoms and iron indices after appropriate interval (and monitor for adverse effects). JCSM

Major randomized trial (IV iron):

• Earley et al., SLEEP (multicenter RCT, 2024) — randomized, double-blind trial of ferric carboxymaltose (750 mg ×2) vs placebo in adults with moderate-to-severe RLS; reported improvements in RLS severity measures in the FCM group. This is a high-quality recent RLS-specific IV iron RCT. Oxford Academic

Earlier IV iron clinical studies / phase 2 trials:

• Multiple earlier trials and phase-2 studies of IV iron (ferric carboxymaltose and other IV irons) have been conducted and are listed on ClinicalTrials.gov and in trial reports. Example registry: VIT-45 phase 2a IV iron study. Clinical Trials.gov+1

Systematic reviews / meta-analyses:

• Systematic reviews and meta-analyses pooling trials of iron therapy (oral and IV) for RLS conclude that iron can improve symptoms in iron-deficient or low-ferritin patients; IV ferric carboxymaltose shows some consistent benefit in trials and meta-analyses. (See EJINME systematic review and more recent meta-analyses on IV FCM in RLS). Ejinme

Guidelines (evidence synthesis + recommendations):

• American Academy of Sleep Medicine (AASM) clinical practice guideline (2024/2025) — recommends measurement of iron indices for all clinically significant RLS and provides thresholds and guidance about oral vs IV iron (ferritin ≤75 ng/mL or TSAT <20% → consider iron; ferritin 75–100 ng/mL → IV iron may be preferred). This guideline synthesizes available trial evidence and expert consensus. JCSM

Pathophysiology and mechanistic reviews:

• Reviews describing brain-iron deficiency and its relation to dopamine abnormalities in RLS provide biological plausibility and summarize human neuropathology/imaging and animal data. SpringerLink