What is the evidence for using thiamine, B12 (Vitamin B12), and magnesium in treating patients with Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD)?

Evidence for Thiamine, B12, and Magnesium in RLS and PLMD

Direct Answer

Current evidence-based guidelines do not support the use of thiamine, vitamin B12, or magnesium as standard treatments for RLS or PLMD, with the American Academy of Sleep Medicine 2025 guidelines making no recommendations for any of these supplements. 1, 2

Thiamine (Vitamin B1)

• No evidence exists in current guidelines or research literature supporting thiamine supplementation for RLS or PLMD treatment. 1, 2
• Thiamine is not mentioned in the comprehensive 2025 American Academy of Sleep Medicine clinical practice guideline for RLS and PLMD treatment. 1

Vitamin B12 (Cobalamin)

• Vitamin B12 supplementation is not recommended in current RLS/PLMD treatment guidelines. 1, 2
• The American Academy of Sleep Medicine 2025 guideline does not include B12 as a treatment option for RLS or PLMD. 1
• One observational study in inflammatory bowel disease patients found that 38.7% of RLS patients had iron deficiency, folate deficiency, and/or vitamin B12 deficiency, but this represents a comorbid condition rather than evidence for B12 as primary treatment. 3
• The key distinction: B12 deficiency may coexist with RLS in certain populations (particularly those with malabsorption), but correcting B12 deficiency has not been proven to improve RLS symptoms in controlled trials. 3

Magnesium

• Magnesium supplementation lacks sufficient evidence for routine use in RLS or PLMD, though limited data suggest possible benefit in select patients. 4
• A 2019 systematic review found only one randomized placebo-controlled trial of magnesium for RLS/PLMD, which did not demonstrate significant treatment effect and may have been underpowered. 4
• The systematic review concluded: "We were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD." 4

Limited Supporting Evidence for Magnesium

• One small open-label pilot study (n=10) from 1998 showed magnesium 12.4 mmol nightly reduced periodic limb movements with arousals (17±7 vs 7±7 events/hour, p<0.05) and improved sleep efficiency (75±12% to 85±8%, p<0.01). 5
• A 2022 randomized controlled trial (n=75) found that 250 mg magnesium oxide daily for 2 months significantly reduced RLS symptom severity and improved sleep quality compared to placebo (p=0.001). 6
• However, these studies are not incorporated into current evidence-based guidelines, and the American Academy of Sleep Medicine does not recommend magnesium as standard therapy. 1, 2

Guideline Position on Magnesium

• The American Academy of Sleep Medicine suggests magnesium citrate 200 mg daily or magnesium oxide 250 mg daily may be considered only as adjunctive therapy after addressing iron deficiency and implementing first-line treatments. 2
• Critical caveat: Magnesium should never be used as monotherapy for clinically significant RLS without first addressing iron status and considering guideline-recommended treatments. 2

Evidence-Based Treatment Algorithm Instead

Rather than pursuing thiamine, B12, or magnesium, the American Academy of Sleep Medicine 2025 guidelines recommend the following approach: 1, 2

Step 1: Iron Assessment and Repletion

• Check morning fasting serum ferritin and transferrin saturation (avoiding iron supplements/foods for 24 hours prior). 1, 2
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% (conditional recommendation, moderate certainty). 1, 2
• Use IV ferric carboxymaltose if ferritin ≤75 ng/mL or transferrin saturation <20% and oral therapy fails (strong recommendation, moderate certainty). 1, 2

Step 2: Address Exacerbating Factors

• Eliminate or reduce alcohol and caffeine, particularly in the evening. 2, 7
• Discontinue antihistaminergic medications, serotonergic medications (SSRIs), and antidopaminergic medications if possible. 1, 2
• Screen for and treat untreated obstructive sleep apnea. 1, 2

Step 3: First-Line Pharmacological Treatment

• The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy (strong recommendation, moderate certainty of evidence). 1, 2, 7
• Start gabapentin 300 mg three times daily, titrating by 300 mg/day every 3-7 days to maintenance dose of 1800-2400 mg/day. 2, 7
• Pregabalin allows twice-daily dosing with potentially superior bioavailability. 2, 7

Step 4: Second-Line Options for Refractory Cases

• Extended-release oxycodone or other low-dose opioids (conditional recommendation, moderate certainty). 2
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty). 2

Critical Pitfalls to Avoid

• Do not delay evidence-based treatment by trialing unproven supplements like thiamine, B12, or magnesium as monotherapy. 1, 2
• Do not assume "normal" B12 or magnesium levels exclude deficiency as a contributor—but also recognize that supplementation without deficiency has no proven benefit. 4, 3
• Avoid dopamine agonists (pramipexole, ropinirole, rotigotine) as first-line therapy due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread. 1, 2
• Insomnia is present in approximately 90% of RLS patients and represents the primary morbidity, making effective treatment urgent. 1

Special Population: End-Stage Renal Disease

• In patients with end-stage renal disease and RLS, the American Academy of Sleep Medicine conditionally recommends vitamin C (low certainty of evidence), but not thiamine, B12, or magnesium as standard therapy. 2
• IV iron sucrose is conditionally recommended if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty). 2