What is the evidence for using L-carnitine (L-carnitine) in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Mitochondrial Myopathies (MM)?

Evidence for L-Carnitine in ME/CFS and Mitochondrial Myopathies

L-carnitine shows promising benefit for mitochondrial myopathies with documented carnitine insufficiency but lacks sufficient evidence for routine use in ME/CFS, though a trial may be reasonable in selected patients who have failed standard therapies.

Mitochondrial Myopathies

Strong Evidence for Benefit

• Plasma carnitine insufficiency (esterified to free carnitine ratio >0.25) occurs in 44% of mitochondrial myopathy patients and provides both a diagnostic clue and treatment indication 1

• Clinical improvements with L-carnitine (50-200 mg/kg/day in four divided doses) are substantial in mitochondrial myopathy patients with documented insufficiency: 1

  • Muscle weakness improved in 95% of patients (19/20)
  • Cardiomyopathy improved in 100% of patients (8/8)
  • Failure to thrive improved in 50% of patients (4/8)

• Treatment should be targeted to patients with biochemically proven carnitine deficiency or insufficiency, not given empirically 1

Dosing for Mitochondrial Myopathy

• Use 50-200 mg/kg/day divided into four daily doses for patients with documented plasma carnitine insufficiency or deficiency 1

ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)

Limited but Suggestive Evidence

• One crossover trial of 30 ME/CFS patients found L-carnitine was well-tolerated and produced statistically significant improvement in 12 of 18 clinical parameters after 8 weeks, with greatest improvement occurring between weeks 4-8 2

• Only 1 patient discontinued L-carnitine due to side effects (diarrhea), compared to amantadine which was poorly tolerated with only 15/30 patients completing treatment 2

Current Guideline Position

• The 2022 VA/DoD guidelines for chronic multisymptom illness make no recommendation in favor of any pharmacologic agent for ME/CFS management 3

• A 2017 systematic review concluded that nutritional supplements may be of value only in ME/CFS patients with biochemically proven deficiencies, and larger RCTs are urgently needed 4

• A 2021 systematic review of mitochondrial-targeting nutraceuticals in ME/CFS found insufficient evidence, with only 6 of 9 studies showing fatigue improvements 5

Theoretical Rationale

• Acetylcarnitine has been proposed for neuropsychiatric long COVID and ME/CFS based on its role as a regulator of mitochondrial function, neuroinflammation, and energy production pathways 6

• L-carnitine is essential for mitochondrial energy production, and disturbances in mitochondrial function may contribute to ME/CFS fatigue 2

Safety Profile

Common Side Effects

• Gastrointestinal effects (nausea, vomiting, abdominal cramps, diarrhea) occur at approximately 3 g/day 7, 8

• High doses may cause fishy body odor 7

• L-carnitine has a favorable safety profile compared to other interventions, with rare serious adverse effects 3

Contraindications and Precautions

• Rare effects include muscle weakness in uremic patients and seizures in those with seizure disorders 9

• L-carnitine supplementation may elevate fasting plasma TMAO levels, which could be pro-atherogenic, though evidence is not strong 8

Clinical Approach Algorithm

For Mitochondrial Myopathy:

1. Measure plasma carnitine levels (free, esterified, and total) and calculate the esterified to free carnitine ratio 1
2. If ratio >0.25 or total/free carnitine deficiency present, initiate L-carnitine 50-200 mg/kg/day in four divided doses 1
3. Monitor for clinical improvement in muscle weakness, cardiomyopathy, and other symptoms over 8 weeks 1

For ME/CFS:

1. Ensure standard therapies have been attempted first (pacing strategies, management of sleep disturbances, treatment of comorbid conditions) 3
2. Consider measuring carnitine levels, though routine determination is not recommended in healthy adults 9
3. If standard therapies fail and patient has documented carnitine deficiency, consider trial of L-carnitine for 8 weeks, starting at lower doses and titrating up to 3 g/day maximum 2, 7
4. Assess response at 4 and 8 weeks, as greatest improvement may occur between weeks 4-8 2
5. Discontinue if no benefit after 8 weeks or if gastrointestinal side effects are intolerable 2

Critical Caveats

• Do not use L-carnitine routinely without documented deficiency or insufficiency—there is no evidence supporting empiric supplementation in healthy individuals or unselected ME/CFS patients 7, 9

• The evidence base for ME/CFS is extremely limited, with only one small crossover trial showing benefit 2

• Mitochondrial myopathy patients require biochemical confirmation of carnitine abnormalities before treatment 1

• Avoid confusing L-carnitine with acetyl-L-carnitine, which is NOT recommended for chemotherapy-induced peripheral neuropathy prevention 9