**Background:** Migraine is a common neurovascular disorder affecting over one billion people worldwide, with substantial socioeconomic impact. Current treatments have limitations including adverse effects, vasoconstrictive properties, high costs, and regulatory restrictions. The authors propose an alternative hypothesis: stress-induced heightened sympathetic tone leads to chronic microvascular constriction, reducing cerebral blood flow and activating nociceptors. They hypothesize that vasodilatory nutraceuticals—L-arginine (a nitric oxide precursor) and aged garlic extract (AGE, which increases vasodilatory prostaglandins and has antioxidant/anti-inflammatory properties)—may prevent or attenuate this microvascular constriction, thereby reducing migraine frequency and severity. Neither agent has been previously investigated for migraine prophylaxis.
**Methods:** This is a single-site, phase-II, randomised, double-blind, placebo-controlled, parallel-group trial conducted in Perth, Australia. The target sample is 240 participants (with up to 300 recruited to account for 20% dropout), aged 18–80 years, with chronic frequent episodic migraines (2–6 migraine episodes per month, diagnosed ≥1 year ago, onset before age 50). Exclusion criteria include use of vasoactive medications, other headache disorders, pregnancy, bleeding risks, and significant comorbidities. Participants undergo a 2-week placebo run-in, then are randomised 1:1:1:1 to one of four groups for 12 weeks: placebo, L-arginine 1.5 g/day, AGE 1 g/day, or combination. All capsules are identical and garlic-scented to maintain blinding. The primary outcome is change in migraine frequency (mean number of migraine episodes per month) and intensity from baseline to 12 weeks, assessed via daily migraine diaries. Secondary outcomes include photosensitivity threshold (via an acute light challenge), retinal vessel density and foveal avascular zone area (via OCTA), blood biomarkers of vascular tone (ADMA, SDMA, nitrates/nitrites, endothelin-1), and quality of life (MSQ, SF-MPQ, L-VISS, VLSQ-8). Statistical analysis uses a factorial design with ANCOVA and mixed models, with 87% power to detect an effect size of 0.2 at α=0.05.
**Clinical Implications:** If positive, this trial could provide evidence for two safe, affordable, and well-tolerated nutraceuticals as prophylactic treatments for migraine, offering an alternative to current medications that are often vasoconstrictive, expensive, or have adverse effects. The use of both subjective and objective measures (retinal imaging, biomarkers) strengthens the mechanistic understanding. Limitations include fixed-dose design, lack of direct cerebral imaging (e.g., MRI), and potential interaction with other medications. The study includes a wide age range (18–80 years) and both sexes, enhancing generalizability.