This randomized controlled trial will evaluate the effects of a low histamine-based modified Mediterranean diet in adults with relapsing-remitting multiple sclerosis (RRMS). The study will compare three groups: a low-histamine modified Mediterranean diet, a traditional Mediterranean diet, and a control group without dietary intervention. The main outcomes include clinical measures such as disability status, fatigue, migraine, gastrointestinal symptoms, and quality of life, as well as blood markers including plasma histamine, diamine oxidase activity, total antioxidant capacity, and oxidative stress indicators. The goal is to determine whether reducing dietary histamine within a Mediterranean diet pattern provides additional benefits beyond a traditional Mediterranean diet in improving symptoms and biological markers related to inflammation and oxidative stress in RRMS.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Current immunomodulatory treatments have important side effects and do not fully address symptoms or quality of life, highlighting the need for complementary strategies such as targeted dietary interventions. The Mediterranean diet is one of the most promising patterns because of its anti-inflammatory and antioxidant properties and has been associated with reduced fatigue, improved quality of life, and potential benefits on disability in people with MS. However, some components of the traditional Mediterranean diet, such as certain fish, aged cheeses, fermented products, tomatoes, and citrus fruits, are relatively high in histamine. Histamine is a biogenic amine that may influence neuroinflammation and blood-brain barrier permeability, and diets that lower histamine intake have shown benefits in conditions like migraine and gastrointestinal dysfunction, which are common in MS. This study was designed to explore whether a low histamine-based modified Mediterranean diet can optimize the benefits of the Mediterranean pattern in relapsing-remitting MS (RRMS).

The trial is a three-arm, parallel-group, randomized controlled clinical study in adults with RRMS. Participants are randomly assigned to one of three groups: (1) a low histamine-based modified Mediterranean diet, which maintains the core principles of the Mediterranean pattern while restricting foods known to be high in histamine or to promote histamine release; (2) a traditional Mediterranean diet without specific histamine-related restrictions; or (3) a control group that does not receive a structured dietary intervention. The intervention focuses on high intake of fresh vegetables and fruits, legumes, whole grains, olive oil, and appropriate fish options, while the modified diet group additionally limits aged cheeses, processed meats, fermented foods, vinegar, certain fish, and selected vegetables and fruits that are high in histamine. This design allows direct comparison of no diet intervention, a well-established Mediterranean pattern, and a targeted low-histamine modification of that pattern.

Clinical outcomes include disability status assessed by the Expanded Disability Status Scale (EDSS), fatigue measured with the Fatigue Severity Scale (FSS), and health-related quality of life evaluated by standardized questionnaires such as the SF-36. To investigate potential mechanisms, blood biomarkers are measured, including serum total antioxidant capacity, oxidative stress markers (for example malondialdehyde), plasma histamine levels, and activity of diamine oxidase (DAO), an enzyme that metabolizes histamine. The primary hypotheses are that both Mediterranean diet interventions will improve fatigue, quality of life, and oxidative stress parameters compared with the control group, and that the low histamine-based modified Mediterranean diet will provide the greatest benefits, particularly in reducing plasma histamine, improving DAO activity, and alleviating fatigue, migraine, gastrointestinal symptoms, and disability scores in RRMS. If confirmed, the findings could support a more targeted dietary approach as a complementary medical nutrition therapy for MS and provide a basis for future interventional studies on histamine metabolism, oxidative stress, and diet in this population.

Inclusion Criteria:

• Age 19 to 64 years.
• Diagnosis of relapsing-remitting multiple sclerosis (RRMS) according to 2017 McDonald criteria.
• EDSS score < 4.5.
• On stable immunomodulatory treatment for at least 6 months.
• Body mass index (BMI) 18.5-24.9 kg/m².

Exclusion Criteria:

• Relapse and/or corticosteroid treatment within the last 1 month.
• Clinically significant metabolic, progressive, or malignant disease.
• Use of at least 1 g/day fish oil supplementation.
• Insulin-dependent diabetes mellitus.
• Participation in another interventional study.
• Weight loss or gain ≥ 5% in the last 6 months.
• Following a weight-loss diet in the last 2 months.
• Use of oral anticoagulant therapy.
• Presence of eating disorders, alcohol or substance dependence.
• Pregnancy or breastfeeding.
• Inability to comply with dietary intervention according to weekly follow-up assessments.

At this time, there is no finalized plan for sharing individual participant data (IPD). Decisions about IPD sharing will depend on ethical approval, participant consent language, and institutional policies that may be updated in the future.