Search results: We found 4,073 articles on PubMed, 971 articles on Web of Science, and 418 articles on EMBASE, from among these, 906 articles were eliminated because of duplicated findings. After screening of titles and abstracts, 33 out of 4,556 publications were considered as eligible studies and 19 were excluded due to lack of a proper design (n = 9), lack of required data (n = 3), and lack of defined interventions (n = 7) (figure 1). Finally, we found 1 more article through hand searching of references in eligible studies. The general characteristics of the 15 included studies and 669 enrolled patients are presented in table 1. Moreover, the effects of dietary interventions on patients were extracted and are presented in table 2.

Plant-based diet: We detected 3 studies that assessed the effect of plant-based diets on MS patients (Table 1).^13-15 Yadav et al. investigated the effect of a low-fat, plant-based diet for 12 months characterized by consuming a high amount of fruits and vegetables, especially starchy vegetables (beans, potatoes, rice, pasta, and corn), and restricting animal products (eggs, dairy, fish, and meat) and vegetable oils.

This diet meets the mean energy percentage of 10, 14, and 76 from fat, protein, and carbohydrate, respectively. It improved fatigue with medium to large effect size (P = 0.040, ES: -0.6 to -0.7) in MS patients compared to the usual diet in the control group. This dietary pattern could not significantly change disability, QOL, and physical function.¹³

The intervention in the study by Riccio et al. included a calorie-restricted and semi-vegetarian diet for 7 months characterized by a calorie intake of 1700-1800 kcal including 50% carbohydrate, 30% fat (mainly fish, olive, and vegetable oils), and 20% protein per day in comparison to a regular diet in the control group.¹⁴ The diet included a high consumption of vegetables, fruits, nuts, fish, oysters, unrefined bread and pasta, soy, low-fat dairy products, olive oil, tea, and coffee. Alternately, there was low consumption of salt, sugar, animal fat, and red meat (once or twice a week), fried or processed foods (once every 2 weeks), cakes (once a week), alcohol (once a week), and no consumption of processed sweetened drinks and snacks. The diet showed no significant p-value for the variations in fatigue, QOL, and disability, but we calculated a medium to large effect in fatigue (ES: -0.78) and QOL (ES: -3.06) in MS patients.¹⁴ Saresella et al. evaluated a 12-month diet described as high-vegetable and low-protein.¹⁵ This was rich in fruits, vegetables, legumes, nuts, whole grains, and olive oil while it was poor in animal proteins including fish (twice a week), poultry (once a week), eggs (4 times a week), and dairy products (once a week). Patients limited the intake of refined grains, sugar, salt, fried foods, red meat, and saturated fats, while the control group followed a Western diet rich in red meats, refined grains, sweet or salty foods, and omega-6 or saturated fatty acids. The results showed a large effect on disability (P < 0.001, ES: -7.89), and relapse rate ‎(RR) (P = 0.030, ES: 9.23) was reduced (Table 2).¹⁵

Ketogenic and fasting diets: Two articles that evaluated the efficacy of ketogenic and fasting diets in MS patients are available in table 1.^16,17 Choi et al. examined the effects of 2 dietary interventions, including the ketogenic diet (KD) and the fasting-mimic diet (FMD) in comparison with the German diet (GD) as the control group over a 6-month period in MS patients.¹⁶ The KD group had a daily consumption of less than 50 grams of carbohydrates, less than 100 grams of proteins, and more than 160 grams of fats. Another group with the FMD diet followed a Mediterranean diet for 6 months after experiencing a 7-day fasting.¹⁶

The GD is characterized by a lower intake of vegetables, and higher consumption of meats, cereals, fruits, beer, dairy products, and fats.²⁸ Finally, the study showed the beneficial effect of the KD on QOL after 3 and 6 months (P < 0.005, ES: 0.3-0.5). Disability decreased in both KD (P < 0.010) and FMD groups in comparison to the control group with moderate to large effect size (P < 0.050, ES: -0.3 to -0.6).¹⁶

Bock et al. compared the impact of prolonged fasting (PF) or KD in MS patients with the usual diet as the control group.¹⁷ There were several stages of the PF diet, including a 2-day low-calorie vegetarian diet, 7-day intensive fasting (vegetable with 200-350 kcal), a 3-day low-calorie vegetarian diet, and one, every day, week-long, 14-hour per day fast for the remaining study period. The PF and KD meaningfully affected QOL with large ES (ES: 0.7 to 0.8) (Table 2).¹⁷

Modified Paleolithic diet: We found one study that investigated the modified Paleolithic diet (MPD) in MS patients (Tables 1 and 2).¹⁹ The MPD is a diet rich in vegetables and fruits (9 cups per day) and nuts while it is poor in legumes, dairy products, sugar, processed foods, oils, and foods containing gluten such as grains, and includes a moderate intake of meats. Irish et al. compared the effects of MPD with the usual American diet (UAD) as the control group.¹⁸ The UAD consists of low intake of fruits, vegetables, dairy, oils, and high saturated fats, sugar, and sodium. This diet pattern meets or exceeds the recommended intake of grains and protein foods.²⁹ The study revealed that adherence to MPD, compared to UAD, improved fatigue (P = 0.030), mental QOL (P = 0.020), physical QOL (P = 0.030), and upper motor function as a subset of disability test (P for the dominant hand = 0.02 and P for the non-dominant hand = 0.05) (Table 2).¹⁸

Fish oil: We found 4 studies that determined the effects of fish oil (FO) in MS patients (Table 1).^19-22 ‎The study by Ramirez-Ramirez ‎et al. showed that a 12-month intervention with 4 grams of FO per day [containing 1.6 g Docosahexaenoic acid (DHA) and 0.8 g Eicosapentaenoic acid (EPA)] could not significantly change disability (P = 0.600) and RR (P = 0.700) in MS patients, ¹⁹ but it has a medium effect size on disability. ‎Torres-Sanchez et al. compared the effects of 4 grams of FO (containing 1.6 g DHA and 0.8 g EPA) and 4 grams of olive oil (OO) for 12 months in MS patients and reported no significant changes.²⁰

Weinstock-Guttman et al. compared the effects of a 12-month FO intervention with OO in MS patients. One group received FO (1.32 g DHA and 1.98 g EPA) accompanied by a low-fat and low-saturated fatty asids (low-SFAs) dietary pattern (calorie intake from lipids < 15%), and another group received OO (1 g oleic acid) accompanied by a dietary pattern based on guidelines of the American Heart Association (AHA). The AHA guideline recommends a low-cholesterol dietary pattern with less than 10% calorie intake from SFA and about 30% from total fat.²¹ The study showed that physical QOL and mental health had improved in the FO group in comparison to the OO group (P = 0.050 for both) after 6 months, but this trend was close to that in the OO group after 12 months. In addition, RR was reduced in response to both the OO (P = 0.040) and FO (P = 0.020), but FO had a small effect compared to OO. However, fatigue had reduced in the OO group (P = 0.050) compared to the FO group, and disability had insignificantly decreased in the FO group (Table 2).²¹ Zandi-Esfahan et al. reported that 1 gram of fish oil (containing 120 mg DHA and 180 mg EPA) caused no significant improvement in disability (P = 0.080, ES: 0.1) (Table 2).²²

Vegetable oils: Four studies have shown the effects of vegetable oils including OO, evening primrose oil (EPO), and hemp seed oil (HSO) on MS outcomes ^20,21,23,24 2 of which have been described in the previous section (Table 1).^20,21

Rezapour-Firouzi et al. designed a trial including 3 groups of MS patients to investigate the impact of HSO and EPO.²³ The first group received a diet rich in hot-natured foods supplemented with combined HSO and EPO (18-21 g) every day, the second group received OO (18-21 g) every day, and the third group received combined HSO and EPO (18-21 g) every day for 6 months. Disability and RR reduced in the first (P = 0.001 for both) and third groups (P = 0.002 for both) after the intervention compared to before the intervention. In addition, in the OO group, RR and disability significantly reduced (P = 0.005),²³ but HSO and EPO induced a larger effect on RR compared to OO (ES: 0.7-1.5).

Majdinasab et al. showed that 3-month supplementation with EPO (1 gram per day) could improve fatigue and QOL (P < 0.001 for all) compared to the placebo group (Table 2).²⁴ The study showed that HSO and EPO decreased inflammatory cytokines and increased anti-inflammatory cytokines in MS patients.²³ The sterols and tocopherols present in both HSO and EPO may prevent oxidation and help alleviate MS outcomes. Gamma-linolenic acid (GLA) is Omega-6 fatty acid.^30,31 Di-homo-gamma-linolenic acid (DGLA) derives from GLA and is known as a protective factor against inflammation due to its prostaglandin E2 reducing effect.³² Furthermore, monounsaturated fatty acids such as oleic acid and polyphenols existing in OO can prevent lipid peroxidation and ATP-synthesize enzyme oxidation, induce greater fluidity in the membrane, and higher performance of the mitochondria, and thus, may regulate the immune system function, and consequently, reduce RR and fatigue in MS patients.^33-36

Studies have shown the beneficial effects of EPO in the treatment of diseases such as diabetes and rheumatoid arthritis.^37-40 EPO is an excellent source of 3 terpene ester derivatives that scavenge free radicals, and prevent cyclooxygenase and neutrophil elastase activities, and thereby, improve inflammation status.⁴¹

Traditional diet: Traditional therapies classify all foods into cold-natured and hot-natured, and recommend a balanced eating for the maintenance of health.⁴² Moreover, people have a dominant basic temper called Mizaj, which is thought to influence mental and physical functions.⁴³

The hot-natured diet is a dietary pattern characterized by high intake of hot-natured foods and low intake of cold-natured foods. Hot-natured foods include wheat and soy products, eggs, domestic poultry and turkey, garlic, onion, and carrots, cantaloupe, grape, coconut and banana, olive oil, sesame oil, honey, nuts, and spices such as turmeric, mustard, and cinnamon. Furthermore, cold-natured foods include rice, potato, corn, junk foods, beef, fish, solid fats, vegetables such as cucumber and spinach, fruits such as watermelon and citrus, carbonated soft drinks, and beer.²³ Scientists believe that there is a strong association between a hot-natured diet and regulation of the immune system function.⁴⁴

The herbal syrup used in the study by Adalat et al.²⁵ included saffron that is a well-known herb and includes crocin, picrocrocin, and safranal, which have antioxidant, anti-inflammatory, and neuroprotective properties through their inhibiting effects on cyclooxygenase activity and leukocytes filtration.^45-48 St John’s wort has hyperforin, which possesses antioxidant, anti-inflammatory, and anti-depressant properties due to its elevation of serotonin and noradrenaline in the brain.^49-52

Turmeric extract has demonstrated a promoting effect on sodium benzoate formation in the liver. Due to the effect of sodium benzoate on the modulation of the immune system function, maintenance of blood-brain barrier integration, and myelin production, turmeric might prevent the progression of MS.^53-55 Many researches have shown that the components presented in grape contain proanthocyanidins, anthocyanins, and resveratrol, which have anti-inflammatory properties.^56-60

Flavonoids: Flavonoids can diminish oxidative stress, and increase glucose availability and blood flow to the brain, which improve fatigue and physical activity.^61-63 Finally, we recommend fruits and vegetables rich in flavonoids such as onions, kale, grapes, and berries for MS patients.