Exploring the Ketogenic Diet as Adjunctive Therapy in Multiple Sclerosis: A Review

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system, leading to inflammation, demyelination, and neurodegeneration. Although disease-modifying therapies (DMTs) have shown efficacy in reducing relapse rates, they offer limited benefit in addressing cognitive symptoms and overall disease burden. The ketogenic diet (KD), a high-fat, low-carbohydrate dietary approach, has emerged as a promising adjunctive strategy. Recent research suggests that KD may modulate key inflammatory pathways, enhance mitochondrial function, and reduce oxidative stress through mechanisms involving ketone bodies such as β-hydroxybutyrate. These effects have been linked to improvements in fatigue, cognition, quality of life, and markers of neuronal injury in individuals with MS. Furthermore, KD may positively influence the gut microbiome, insulin sensitivity, and myelin repair processes. Despite encouraging results, challenges such as dietary adherence, nutrient deficiencies, gastrointestinal side effects, and cardiovascular risks limit widespread adoption. Current evidence is largely based on short-term studies with limited diversity and variable dietary protocols. Future research should focus on long-term safety, standardized guidelines, and personalized strategies to better integrate KD into comprehensive MS care.

Keywords

ketogenic diet multiple sclerosis neuroinflammation cognitive function disease-modifying therapy

Introduction

Multiple Sclerosis (MS) is a chronic auto-immune condition affecting the Central Nervous System (CNS) causing inflammation, demyelination and neuronal death with myelinated axons in the CNS being the primary targets of MS attacks (Haki et al., 2024). It mostly affects young adults, predominantly females. MS is categorized into 4 types including Relapsing/Remitting MS (RRMS), Progressive Relapsing MS (PRMS), Primary (PPMS) and Secondary Progressive MS (SPMS). Recently, MS is managed by a variety of strategies including neuroprotective measures, Disease Modifying Therapies (DMTs) and stem cell therapy. A meta-analysis and systematic review on controlled trials comparing the efficacy of DMTs with placebo in RRMS patients found that all DMTs especially Alemtuzumab, Ocrelizumab, Natalizumab and Fingolimod effectively reduced relapse rate of MS during the 2 year follow up with a reduced incidence of treatment discontinuation due to serious adverse effects (Li et al., 2020). On the other hand, lack of data and pharmacological trials that include in-depth cognition assessment has created a lack of evidence about effectiveness of DMTs for enhancing cognition of RRMS patients (Landmeyer et al., 2020). Overall, further research is needed to bridge the gaps in establishing the effectiveness of current treatment options available.

A single arm pilot study on 15 MS patients with a diagnosis of less than 2 years, enrolled from the Pacific Neuroscience Institute aimed to assess the effectiveness of lifestyle modifications in MS. The patients were guided to follow a Mediterranean diet along-with some basic exercises including stretching, strength training and moderately rigorous aerobic workout with their individual goals taken into consideration for a period of 12 weeks. The results showed remarkable improvement in Quality of Life (QOL) (p = 0.02), fatigue (p = 0.005), fitness (p = 0.04) and cognition (Symbol Digital Modalities Test, SDMT) (p = 0.006) followed with a high participant satisfaction score (Giesser et al., 2024). KD is a distinctive diet which is abundant in fat, very low in carbohydrates with the quantity of proteins customized to one's necessities. It is classified into Classic KD, Medium Chain Triglyceride (MCT) KD and Modified Atkins Diet (MAD). Through reducing carbohydrate accessibility, KD promotes the synthesis of ketone bodies that can be used as a source of energy instead of glucose. It offers

improvement in diabetes, obesity and certain neurological diseases (Malinowska and Żendzian-Piotrowska, 2024). Adenosine, Rapamycin pathways, Peroxisome Proliferator Activated Receptor-gamma (PPAR-γ), ketone bodies and NLR Family Pyrin Domain containing 3 (NLPR3) inflammasome are the potential inflammatory pathways targeted by KD. Beta Hydroxy Butyrate (BHB), one of the anti-inflammatory mediators generated following KD, suppresses NLRP3 mediated Interleukin-1β (IL-1β) activation. Emerging research has shown NLRP3 to promote movement of myelin specific autoreactive CD4+ T cells, macrophages and dendritic cells into the central nervous system (CNS) producing neuro-inflammation in early MS (Gharagozloo et al., 2017).

This review aims to explore KD as an emerging treatment option for MS. This review concisely focuses on the underlying mechanisms with which KD potentially alleviates MS symptoms backed with recent research and clinical evidence while also shedding light on the challenges and future directions regarding implementation of KD in treating MS. The review intends to educate healthcare professionals, patients and researchers about the potential benefits and limitations of implementing KD in treatment of MS.

2. Mechanisms of Ketogenic Diet in MS

Multiple sclerosis (MS) is an enduring autoimmune disorder characterized by inflammation, loss of myelin, and degeneration of nerve cells within the central nervous system. The ketogenic diet (KD), which is characterized by a high fat content and minimal carbohydrates, triggers a state of ketosis that transitions energy generation from glucose to ketone bodies, where the body uses ketones for energy. Seminal studies have revealed that ketone bodies, especially β-hydroxybutyrate (BHB), are not only alternative energy substrates but also neuroprotective signaling molecules. BHB promotes oligodendrocyte precursor cell survival and maturation into myelinating oligodendrocytes, enhances myelin basic protein (MBP) expression, and safeguards axons by stabilizing mitochondrial membranes (Liu et al., 2020; Stumpf et al., 2019). These findings define the biochemical and cellular foundation of KD-driven myelin regeneration. This change in metabolism appears to hold potential for treating neurological conditions, like multiple sclerosis (MS), a long-term autoimmune disease that leads to demyelination and neurodegeneration. This article explores how the ketogenic diet may impact multiple sclerosis, referencing findings from recent research.

Multiple sclerosis results in neuronal injury due to energy scarcities and oxidative stress. The ketogenic diet provides ketone bodies, which enhance mitochondrial performance and neuronal energy levels. A phase II clinical trial revealed that MS patients following the ketogenic diet experienced an improved quality of life, suggesting neuroprotective effects (Brenton et al., 2022). Inflammation accelerates the progression of multiple sclerosis. The ketogenic diet decreases pro-inflammatory cytokines and stimulates anti-inflammatory pathways. A Ketosis-inducing diet showed reduced autoimmunity and symptoms resembling to those of MS (Keto diet alters immune cell function - MS-UK [Internet], 2025).A key mediator of neuroinflammation in multiple sclerosis, the NLRP3 inflammasome, is inhibited by ketones, especially β-hydroxybutyrate (BHB), which function as signalling metabolites. This inhibition decreases peripheral immune cell infiltration into the central nervous system and microglial activation by reducing the release of pro-inflammatory cytokines such IL-1β and IL-18 (Youm et al., 2015). Additionally, ketosis suppresses NF-κB signalling, which further reduces the synthesis of inflammatory mediators (Rahman et al., 2014). BHB encourages an anti-inflammatory environment through these actions, which could aid in stabilising the course of the disease..Excitotoxicity is associated with neuronal death in MS and may potentially be lessened by the ketogenic diet through the modulation of glutamate and GABA (Ortí et al., 2023). Although there is a lack of research specifically linked to MS, the neuroprotective properties of the ketogenic diet imply possible advantages. The gut microbiome significantly influences immune responses in multiple sclerosis. The ketogenic diet promotes the growth of beneficial gut bacteria, which can decrease autoimmune responses. MS patients adhering to a ketogenic diet showed enhanced diversity in their microbiome and lower levels of inflammation (Swidsinski et al., 2017). Together, these anti-inflammatory and mitochondrial-stabilizing effects of BHB preserve axonal integrity and create a biochemical environment conducive to remyelination. Further, metabolomic and imaging studies have shown that KD enhances the synthesis of long-chain fatty acids and cholesterol precursors essential for myelin membrane assembly (Collongues et al., 2022; Jana et al., 2024). These landmark findings connect ketone metabolism directly to the structural and functional recovery of white matter in demyelinating disease models. Autophagy plays a crucial role in maintaining myelin health. The ketogenic diet enhances this mechanism, which could assist in repair processes. In a study regarding a demyelinating condition, the ketogenic diet facilitates myelination and reduced axonal injury (Stumpf et al., 2019). Both myelin protein synthesis and oligodendrocyte precursor cell (OPC) differentiation are necessary for remyelination. Ketone bodies help OPCs mature into myelinating oligodendrocytes by acting as alternate energy sources (Kim et al., 2015). Additionally, BHB increases insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF), both of which promote myelin repair (Keto et al., 2025). The ketogenic diet enhances insulin sensitivity and improves metabolic indicators, which is related in the context of multiple sclerosis where metabolic dysregulation is common (Bahr et al., 2020). There is a need for more studies focused specifically on hormones relating to MS. Fatigue significantly impacts multiple sclerotic patients. In a clinical trial, the ketogenic diet led to lower fatigue assessments, potentially through enhanced energy metabolism (Brenton et al., 2022). Axonal degeneration and neuronal death in multiple sclerosis are largely caused by mitochondrial malfunction. By increasing oxidative phosphorylation efficiency, decreasing the generation of reactive oxygen species (ROS), and promoting mitochondrial biogenesis through the activation of PGC-1α and SIRT3 pathways, the ketogenic diet enhances mitochondrial bioenergetics. (Bough et al., 2006) Neurones are more resilient to oxidative and metabolic stress when mitochondrial integrity is restored. Increased ATP synthesis facilitates synaptic transmission and axonal transport, two processes that are impaired in demyelinated axons. (Bhat et al., 2015) The Potential mechanisms of the ketogenic diet effect in Multiple Sclerosis and in other neurological diseases is shown in Figure 1 (Dyńka et al., 2022).

Figure 1.

Proposed mechanisms of the ketogenic diet in multiple sclerosis, including metabolic, anti-inflammatory, neuroprotective, and remyelinating effects.

The effectiveness and tolerance of ketogenic diet (KD) regimens in people with multiple sclerosis can be greatly impacted by variation. Strong ketosis is produced by the traditional KD, which follows a rigid 4:1 or 3:1 fat-to-carbohydrate-plus-protein ratio. However, because of gastrointestinal distress and a restricted food selection, it may be difficult to maintain (Kossoff et al., 2009)On the other hand, modified strategies including the low-glycemic-index treatment (LGIT), modified Atkins diet (MAD), and medium-chain triglyceride (MCT) diet seek to preserve therapeutic ketosis while enhancing taste and compliance. The MCT diet makes use of lipids that produce more ketones per calorie, allowing for higher intakes of protein and carbohydrates. While the LGIT concentrates on carbs with a glycaemic index below 50 to achieve mild, long-lasting ketosis, the MAD offers moderate restriction with better adherence. These modifications show similar clinical and metabolic advantages with improved tolerability, indicating that customised food choices may maximise MS treatment results. (Idzikowska et al., 2025) Additionally, BHB upregulates brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), which further promote oligodendrocyte survival and axonal regeneration, consolidating the mechanistic basis of KD-induced neurorepair (Sleiman et al., 2016).

3. Clinical Evidence & Current Research

The ketogenic diet (KD) is being explored as a potential treatment for multiple sclerosis (MS). Researchers are investigating its ability to slow disease progression, manage symptoms, and impact specific bodily processes (Rubio et al., 2025). This discussion highlights current findings, compares KD to other diets, and identifies areas needing further research.

Animal studies using experimental autoimmune encephalomyelitis (EAE) mouse models indicate that KD can protect the brain and nerves. For example, a fasting-like diet reduced nerve damage and aided in nerve cell repair in EAE mice (Choi et al., 2016; Lin et al., 2022). A study by Liu in 2020 showed that KD enhances brain nerve cell protection by improving mitochondrial function and lowering oxidative stress (Liu et al., 2020). The diet reduces harmful inflammation and promotes beneficial anti-inflammatory substances, aiding brain and nerve recovery. KD affects certain genes and increases substances like β-hydroxybutyrate (BHB), which fight inflammation (Bock et al., 2018). This process may reduce inflammation in the nervous system and support the repair of damaged nerve coverings.

Research on KD's effects on MS patients shows mostly positive outcomes. In a 2022 study by Brenton and colleagues, individuals with relapsing MS followed a ketogenic diet for six months. Results showed significant reductions in fatigue and improvements in disability levels, as measured by the Expanded Disability Status Scale (EDSS), a tool for assessing MS disability (Brenton et al., 2022). Participants also experienced clearer thinking. Another 2022 study by Bock and colleagues found that MS patients had lower levels of serum neurofilament light chain (NfL)—a marker linked to nerve cell damage—after adopting KD. Reducing this marker is associated with less nerve damage. NfL is a marker that indicates nerve damage, so a reduction in NfL levels suggests the diet might help protect nerve health (Bock et al., 2022). Not all studies agree with these positive outcomes. For example, research by Lee and colleagues in 2021 showed that although a modified medium-chain triglyceride (MCT)-based ketogenic diet (KD) increased the levels of β-hydroxybutyrate (BHB) in the blood, it didn't have much effect on fatigue compared to a modified paleolithic diet (Lee et al., 2021). Smaller research, such as a case report by Nathan in 2019, shared stories of benefits, like improved movement and less muscle stiffness in a patient with secondary progressive multiple sclerosis (SPMS) who followed a KD (Nathan et al., 2019). Aside from managing symptoms, KD has shown potential in changing gut bacteria. In 2017, Swidsinski and his team found that after six months on the diet, MS patients experienced more diverse gut bacteria and less colon inflammation (Swidsinski et al., 2017). This suggests the gut-brain connection could be a treatment target. These findings indicate that KD may have multiple roles in managing MS, but because studies differ in how they're done and in their results, more detailed research is needed. Summary of Clinical Studies on the Ketogenic Diet in MS is given in table 1.

Table 1.
Clinical Studies of the Ketogenic Diet in Multiple Sclerosis, Summarizing Study Design, Population, Duration, and Main Outcomes.

Study Design Population Duration Key Outcomes

Brenton et al. (2022) [7] Phase II trial 77 Patients were screened and 65 relapsing MS were enrolled 6 months ↓ Fatigue, ↓ Depression, ↑ QoL (physical & mental), ↓ EDSS, ↑ 6-min walk distance, ↓ Nine-Hole Peg Test time, ↓ Fat mass, ↓ Serum leptin, ↑ Adiponectin, KD safe/tolerable, ↑ Adherence (83%).

Bock et al. (2022) [5] Retrospective analysis of prospective RCT 60 MS patients (common diet vs. ketogenic diet vs. fasting); sNfL levels assessed in 40 participants (baseline vs. 6-month endpoint) via SIMOA assay. 6 months ↓ Serum NfL, ↓ Neuroaxonal damage

Lee et al. (2021) [6] Randomized pilot 24 patients were screened and 15 MS patients were randomized 3 months Achieved sustained ketosis and improved metabolic markers (↓ glucose/insulin) but no clinical improvements in MS symptoms. No change in fatigue vs. paleo diet

Swidsinski et al. (2017) [9] Cohort study 25 MS patients and 14 healthy control 6 months ketogenic diet normalized concentrations of the colonic microbiome

Bock et al. (2018) [10] RCT 60 MS patients 6 months ↓ COX/LOX gene expression, ketogenic diets suppress pro-inflammatory eicosanoid enzymes

Nathan et al. (2019) [11] Case report 1 Patient with secondary progressive multiple sclerosis (SPMS) 18 months Ketogenic diet (KD) monotherapy reversibly improved mobility, balance, and bladder control in secondary progressive MS, with symptom relapse upon discontinuation

Benlloch et al. (2019) [12] Pilot study 27 MS patients 4 months ↑ Muscle strength, ↓ oxidative stress

Study	Design	Population	Duration	Key Outcomes
Brenton et al. (2022) [7]	Phase II trial	77 Patients were screened and 65 relapsing MS were enrolled	6 months	↓ Fatigue, ↓ Depression, ↑ QoL (physical & mental), ↓ EDSS, ↑ 6-min walk distance, ↓ Nine-Hole Peg Test time, ↓ Fat mass, ↓ Serum leptin, ↑ Adiponectin, KD safe/tolerable, ↑ Adherence (83%).
Bock et al. (2022) [5]	Retrospective analysis of prospective RCT	60 MS patients (common diet vs. ketogenic diet vs. fasting); sNfL levels assessed in 40 participants (baseline vs. 6-month endpoint) via SIMOA assay.	6 months	↓ Serum NfL, ↓ Neuroaxonal damage
Lee et al. (2021) [6]	Randomized pilot	24 patients were screened and 15 MS patients were randomized	3 months	Achieved sustained ketosis and improved metabolic markers (↓ glucose/insulin) but no clinical improvements in MS symptoms. No change in fatigue vs. paleo diet
Swidsinski et al. (2017) [9]	Cohort study	25 MS patients and 14 healthy control	6 months	ketogenic diet normalized concentrations of the colonic microbiome
Bock et al. (2018) [10]	RCT	60 MS patients	6 months	↓ COX/LOX gene expression, ketogenic diets suppress pro-inflammatory eicosanoid enzymes
Nathan et al. (2019) [11]	Case report	1 Patient with secondary progressive multiple sclerosis (SPMS)	18 months	Ketogenic diet (KD) monotherapy reversibly improved mobility, balance, and bladder control in secondary progressive MS, with symptom relapse upon discontinuation
Benlloch et al. (2019) [12]	Pilot study	27 MS patients	4 months	↑ Muscle strength, ↓ oxidative stress

The Keto Diet (KD) is all about achieving ketosis, which makes it different from diets like the Swank diet and the Mediterranean diet. The Swank diet focuses on reducing the intake of saturated fats. On the other hand, the Mediterranean diet helps reduce inflammation in the body by using foods packed with polyphenols (Lin et al., 2022). The ketogenic diet (KD) helps boost energy by using ketones. Similarly, intermittent fasting supports ketosis and offers similar benefits according to early research (Choi et al., 2016). However, since direct comparisons of these diets are rare, it's unclear which diet offers the most advantages. In the context of multiple sclerosis (MS), research on the ketogenic diet highlights significant points .Even if a number of studies back up KD's promise as a treatment for MS, the body of data is still in its infancy. It is challenging to prove causation in the majority of existing trials since they are small, have short durations, and lack control groups or strict randomised design. Most studies, such as the 2019 study by Benlloch et al., are short, typically lasting 12 months or less, making it hard to evaluate the long-term safety and effectiveness of KD for MS (Benlloch et al., 2019). Many studies lack diversity, excluding those with progressive MS types or people from varied backgrounds, so findings might not be applicable to everyone (Ortí et al., 2023). There's also no standard way to conduct the KD; the fats-to-carbs ratio can vary, like 3:1 or 4:1, complicating study reproduction and guideline creation (Lee et al., 2021).Additionally, we don't fully understand how gut bacteria or genetics affect KD response, and this knowledge is crucial for improving treatments (Swidsinski et al., 2017). To fully leverage KD in managing MS, longer, standardized, and more inclusive research is necessary. Generalisability to people with progressive forms of MS is limited since participant selection frequently favours those with recurrent forms of MS.Variability in results is increased by variations in diet formulation, including fat content, the usage of medium-chain triglycerides, and macronutrient proportions. It is also more difficult to compare and understand results when endpoints (such as fatigue, impairment, and biochemical indicators) are inconsistent. Consequently, even while KD shows encouraging effects on neuroinflammation, mitochondrial function, and symptom management, more extensive, carefully monitored, and standardised research is needed to confirm its clinical usefulness.

The underlying mechanisms of KD's neuroprotective actions, its comparison with other dietary approaches, and limitations in existing evidence are summarized in Table 2.

Table 2.

Summary of the Mechanisms Behind the Neuroprotective Effects of Ketogenic Diet Along-with its Comparison with Other Types of Diets and Limitations in Current Available Studies Regarding Efficacy and Safety Profile of KD.

Aspect	Key Findings / Mechanisms	Representative Studies	Limitations
Neuroprotection & Mitochondrial Function	KD helps prevent neuronal degeneration, optimizes mitochondrial performance and combats oxidative stress.	Liu et al., 2020 (17); Animal EAE models (Choi et al., 2016; Liu et al., 2020)	Mostly preclinical studies since there is limited human research demonstrating the mitochondrial benefits.
Anti-inflammatory Effects	β-hydroxybutyrate (BHB) promotes remyelination, limits proinflammatory cytokines and minimizes neuroinflammation whilst elevating anti-inflammatory mediators.	Liu et al., 2020 (17); Brenton et al., 2022 (7)	Limited human data available; use of variable biomarkers employed in different studies.
Symptom Management (Fatigue, Disability, Cognition)	KD for six months improved disability scores (EDSS) and cognitive efficiency while reducing fatigue.	Brenton et al., 2022 (7); Nathan et al., 2019 (21)	Current available data offers small sample sizes; short intervention duration; no long-term follow-up.
Neurodegeneration Markers	KD is associated with lower levels of serum neurofilament light chain (NfL), resulting in reduced axonal injury.	Bock et al., 2022 (19)	Limited evidence; undetermined long-term neuroprotective effects.
Gut–Brain Axis Modulation	KD improved the variety of microbes found in the gut and mitigated intestinal inflammation.	Swidsinski et al., 2017 (10)	Few studies; it's uncertain how gut changes correlate with MS outcomes.
Comparison with Other Diets	KD promotes ketosis and might boost the energy metabolism; Swank and Mediterranean diets focus on low-fat or anti-inflammatory remedies.	Lee et al., 2021 (20); Benlloch et al., 2019 (22)	Low number of trials directly comparing the diets; variation in diet composition and adherence assessment.
General Limitations Across Studies	Small-scale and similar study populations (mostly RRMS). Diverse KD formulations (e.g., 3:1 or 4:1 ratios). Brief gaps between follow-ups (less than 12 months). Inadequate standardization of measuring outcomes. Ambiguity regarding long-term safety and compliance.

We need larger studies spanning over two years to understand how KD affects the progression of disabilities and MRI results, such as lesion counts. Studying multiple biological layers, called multi-omics, might uncover indicators of who responds well to the diet. It's crucial to explore KD in combination with treatments that change disease progression (Rubio et al., 2025).

4. Challenges and Considerations

Ketogenic diet can be a possible therapeutic option in patients with multiple sclerosis but there are some challenges faced while following it, including adherence and sustainability issues, gastrointestinal disturbances, nutritional deficiencies, cardiovascular concerns and lack of availability of long term data. It can be further justified by the fact that because of the Ketogenic diet's stringent carbohydrate restrictions, which might not suit patients’ dietary choices or social dining circumstances, maintaining adherence to it can be challenging. As evidenced by the study, in which 95% of patients adhered for three months and approximately seventy- for six, adherence problems can have a substantial impact on the success of the ketogenic diet in patients with multiple sclerosis. Consistent adherence is therefore essential for possible benefits (Brenton et al., 2019). Nutrient deficiency is also one of its aspects. According to a study the patients following Keto diet were found to be deficient in several micro as well as macronutrients including vitamin A, b12 . Thiamin, calcium, magnesium which were responsible for exacerbation of some of the disease symptoms (Titcomb et al., 2021). Gastrointestinal disturbances caused by this diet is also a challenge. This can be proved by a study according to which, MS patients’ colonic microbiomes had less mass and variety, and this decreased even more in the short term after starting a KD. But after six months, the variety of the microbiome had recovered and returned to normal. This decrease in colonic microbiome can give rise to gastrointestinal disturbances (Swidsinski et al., 2017). LDL cholesterol or “bad” cholesterol, is an established risk factor for heart disease, and those following a ketogenic diet had greater levels of LDL than people who report eating a more balanced diet. A randomized control trial in 2022 evaluated the effect of a well formulated ketogenic diet (WFKD) and Mediterranean plus (Med-plus) diet on 40 pre-daibetic and type-2 diabetic patients aged ≥18, for 12 weeks each. The patients following WFKD had improved levels of High Density Lipid or “good” cholesterol (from 49.1 mg/dL to 54.1 mg/dL) and lower triglyceride levels (from 118.8 mg/dL to 99.5 mg/dL) as compared to Med-plus diet group. However, WFKD also lead to an increase in LDL levels (from 97.8 mg/dL to 111.3 mg/dL) in the same patients, as compared to the Med-plus diet group (from 111.5 mg/dL to 95.3 mg/dL) (Gardner et al., 2022). Besides, an issue in evaluating the long-term effects of ketogenic diets in patients with multiple sclerosis is highlighted by the study's findings that, although safe and tolerated for a 6-month period, it does not offer long-term data beyond this time frame (Keto-Like’ Diet May be Linked to Increased Risk of Heart Disease – Centre for Heart Lung Innovation [Internet], 2025). Hence, KD therapy should be modified to cater the requirements of the patient while considering their underlying health issues, autonomy, preferences, feeding methods and accessibility. Certain comorbidities have been established as an absolute contraindication to KD and may require a specialist referral including familial hyperlipidemia, cardiac disease, osteopenia/osteoporosis, nephrolithiasis, pregnancy and porphyrias. Therefore, with appropriate assessment and guidance of a nutritionist, patients can follow KD but also successfully minimize its mild side effects like constipation via dietary modifications such as lowering processed fat, exercise and increased uptake of plant fiber and fluids ensuring improved adherence to the diet (Cervenka et al., 2020).

5. Conclusion & Future Directions

Multiple sclerosis (MS) is a long term autoimmune disease with significant impacts on quality of life, with current disease-modifying therapies often falling short, especially in addressing cognitive symptoms. As interest grows in lifestyle-based strategies, the ketogenic diet (KD) has emerged as a potential complementary approach to DMTs as it exerts neuroprotective effect by reinforcing endothelial tight junctions that reduces the permeability of blood brain barrier and restricts further immune cell infiltration. Furthermore, ketone bodies like beta-hydroxybutyrate downregulate pro-inflammatory cytokines and key inflammatory pathways such as NLRP3 inflammasome. By improving mitochondrial synthesis and energy efficiency, KD potentially empowers neurons by minimizing axonal damage that still exists despite DMT use. In addition to these metabolic and cardiovascular considerations, the long-term neuro-metabolic consequences of chronic ketosis warrant careful evaluation. Prolonged elevation of ketone bodies may influence neurotransmitter homeostasis by altering glutamate-GABA cycling and synaptic vesicle release dynamics. Sustained ketosis has also been shown in preclinical models to modify astrocytic and microglial mitochondrial oxidative capacity, potentially impacting redox signaling and calcium buffering. Although these adaptations may initially confer neuroprotection through reduced oxidative stress and enhanced mitochondrial efficiency, prolonged metabolic strain could lead to altered neuromodulator balance or impaired glial support under chronic exposure. Furthermore, limited longitudinal data exist regarding how chronic ketosis affects cerebral energy metabolism, neuronal plasticity, and cognitive performance in MS populations. Therefore, future trials should not only assess cardiovascular and nutritional safety but also incorporate advanced neuroimaging and metabolomic endpoints such as cerebral ATP flux, neurotransmitter ratios, and glial mitochondrial function to comprehensively evaluate the neuro-metabolic trade-offs of extended ketogenic therapy. Early studies indicate that KD may alleviate fatigue, enhance cognitive performance, and boost overall well-being in individuals with MS. Nonetheless, due to the existing research being in early stages, large scale randomized controlled trials incorporating various types of patient populations, disease biomarkers like serum inflammatory cytokine and neurofilament light chain (sNfL) levels, MRI imaging and standardized ketogenic dietary formulations are essential to confirm the therapeutic value and safety profile of KD. With MS care increasingly moving towards personalised and integrative strategies, it may serve as a useful adjunct. Future studies should focus on refining dietary protocols, improving adherence, and evaluating how best to incorporate KD into holistic, multidisciplinary treatment plans.

Footnotes

Acknowledgement

The authors would like to thank the faculty members of Jinnah Sindh Medical University and Kabul University of Medical Sciences for their support and guidance during this work.

ORCID iDs

Ahmed Asad R

Abedin Samadi

Ethical Approval

Not applicable, as this is a narrative review based on previously published literature.

Author Contributions

All authors made a significant contribution to the work reported, whether in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author, A.S., upon reasonable request.

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