Effect of Low Histamine-Based Modified Mediterranean Diet in Multiple Sclerosis (HistaMed-MS)

A Randomized Controlled Trial of a Low Histamine-Based Modified Mediterranean Diet in Multiple Sclerosis: The Effect of Dietary Interventions on Clinical Findings, Plasma Histamine, and Oxidative Stress

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.

Study Overview

• Status: Completed
• Conditions: Mediterranean Diet; Multiple Sclerosis (MS) - Relapsing-remitting
• Intervention / Treatment: Behavioral: Low Histamine-Based Modified Mediterranean Diet; Behavioral: Traditional Mediterranean Diet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Turkey (Türkiye)
  • Elâzığ
    • Elâzığ, Elâzığ, Turkey (Türkiye), 23119
      • Firat University Hospital, Neurology Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Histamine-Based Modified Mediterranean Diet; Participants receive a low histamine-based modified Mediterranean diet with restriction of high-histamine and histamine-releasing foods while preserving core Mediterranean diet principles.	Behavioral: Low Histamine-Based Modified Mediterranean Diet; Structured dietary program based on the Mediterranean diet with restriction of high-histamine and histamine-releasing foods (e.g., aged cheeses, processed meats, certain fish, fermented products, vinegar, some fruits and vegetables.
Active Comparator: Traditional Mediterranean Diet" Arm Description; Participants receive a traditional Mediterranean diet without specific histamine-related restrictions.	Behavioral: Traditional Mediterranean Diet; Structured dietary program following a traditional Mediterranean diet rich in vegetables, fruits, whole grains, legumes, olive oil, and fish, without specific histamine-related restrictions.
No Intervention: Control (Usual Diet); Participants continue their usual diet and do not receive a structured dietary intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fatigue severity (Fatigue Severity Scale [FSS]; scale range: 9-63; higher scores indicate greater fatigue)	Fatigue will be assessed using the Fatigue Severity Scale (FSS). Higher scores indicate greater fatigue. The primary outcome is the change in FSS score from baseline to the end of the intervention across the three study groups.	From baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disability status (Expanded Disability Status Scale [EDSS]; scale range: 0-10; higher scores indicate greater disability)	Disability will be assessed using the Expanded Disability Status Scale (EDSS). The outcome is the change in EDSS score from baseline to the end of the intervention.	From baseline to 12 weeks
Change in health-related quality of life (36-Item Short Form Survey [SF-36]; scale range: 0-100 per domain; higher scores indicate better health-related quality of life)	Health-related quality of life will be assessed using the SF-36 questionnaire. The outcome is the change in SF-36 scores from baseline to the end of the intervention.	From baseline to 12 weeks
Change in serum total antioxidant capacity	Serum total antioxidant capacity will be measured to evaluate antioxidant status. The outcome is the change in serum total antioxidant capacity between baseline and the end of the intervention.	From baseline to 12 weeks
Change in oxidative stress markers (e.g., malondialdehyde)	Oxidative stress will be assessed using markers such as malondialdehyde (MDA). The outcome is the change in oxidative stress markers between baseline and the end of the intervention.	From baseline to 12 weeks
Change in plasma histamine levels	Plasma histamine levels will be measured to evaluate changes in histamine metabolism. The outcome is the change in plasma histamine concentration (ng/mL) between baseline and the end of the intervention.	From baseline to 12 weeks
Change in diamine oxidase (DAO) activity	Diamine oxidase (DAO) activity will be measured as a key enzyme of histamine metabolism. The outcome is the change in DAO activity (U/mL) between baseline and the end of the intervention.	From baseline to 12 weeks

Collaborators and Investigators

• Sponsor: Firat University
• Collaborators: The Scientific and Technological Research Council of Turkey
• Investigators: Principal Investigator: Murat Gönen, Prof. Dr., Firat University Faculty of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2024
• Primary Completion (Actual): February 10, 2025
• Study Completion (Actual): June 20, 2025

Study Registration Dates

• First Submitted: January 22, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Quality of Life; Relapsing-Remitting Multiple Sclerosis; Fatigue; Oxidative Stress; Mediterranean Diet; Diamine Oxidase; Low Histamine Diet
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Multiple Sclerosis; Fatigue; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: 2023/03-26; 223S505 (Other Identifier: The Scientific and Technological Research Council of Turkey (TÜBİTAK))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No