BACKGROUND: Migraine, as a widespread neurological condition, substantially impacts quality of life, particularly among women. Therefore, this study aimed to explore the potential effects of alpha-linolenic acid (ALA) and L-carnitine co-supplementation on migraine symptoms, mental health, and life quality in women with migraine. METHODS: In this randomized, triple-blind, placebo-controlled trial, 80 women with migraine were randomly assigned to receive either ALA (1000 mg) plus L-carnitine (500 mg) or matching placebos daily for 12 weeks. Migraine characteristics, mental health parameters, and quality of life measures were assessed at baseline and study end. RESULTS: The intervention group demonstrated a significant reduction in migraine frequency (-2.96
95% CI (-3.48, -2.45) vs -0.07
95% CI (-0.68, 0.53), P <
0.001), severity (-1.6
95% CI (-2.05, -1.15) vs - 0.44
95% CI (-0.91, 0.02), P = 0.001), and duration (-4.9
95% CI (-6.34, -3.45) vs -0.5
95% CI (-1.06, 0.66) hours, P <
0.001) compared to the placebo group. Mental health improvements were observed in depression (-7.4
95% CI (-9.24, -5.55) vs 0.05
95% CI (-1.16, 1.26), P <
0.001), and anxiety scores (-5.7
95% CI (-7.26, -4.14) vs - 0.65
95% CI (-2.33, 1.03), P <
0.001). Quality of life measures showed significant enhancement, with increased migraine-specific quality of life (9.75
95% CI (8.01, 11.49) vs 1.22
95% CI (-0.66, 3.11), P <
0.001) and decreased headache impact test-6 scores (-8.57
95% CI (-11.79, -5.36) vs -1.35
95% CI (-3.41, 0.71), P = 0.005) in the intervention group compared to the controls. CONCLUSION: Co-supplementation with ALA and L-carnitine may offer a promising adjuvant therapy for managing migraine in women, addressing both physical symptoms and psychological burdens. TRIAL REGISTRATION: IRCT20121216011763N57.