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

July 30, 2026 updated by: Murat Açık, Firat University

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
51

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in fatigue severity (Fatigue Severity Scale [FSS]; scale range: 9-63; higher scores indicate greater fatigue)
Time Frame: From baseline to 12 weeks
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in disability status (Expanded Disability Status Scale [EDSS]; scale range: 0-10; higher scores indicate greater disability)
Time Frame: From baseline to 12 weeks
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)
Time Frame: From baseline to 12 weeks
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
Time Frame: From baseline to 12 weeks
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)
Time Frame: From baseline to 12 weeks
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
Time Frame: From baseline to 12 weeks
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
Time Frame: From baseline to 12 weeks
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Firat University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
The Scientific and Technological Research Council of Turkey

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Murat Gönen, Prof. Dr., Firat University Faculty of Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 15, 2024

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 10, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 10, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 22, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 26, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 30, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 31, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 30, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings