Multiple sclerosis (MS) is a chronic neurodegenerative disorder affecting millions worldwide. Characterized by damage to the central nervous system (CNS), MS leads to a variety of debilitating symptoms, including functional disability, fatigue, obesity, depression, and anxiety. The pathogenesis of MS involves axonal demyelination, mitochondrial dysfunction, increased inflammation, and disruptions in glutamate neurotransmitter activity. In recent years, the ketogenic diet (KD) has emerged as a promising non-pharmacological therapeutic alternative for managing MS, showing potential in reducing peripheral obesity and central inflammation.
Understanding Multiple Sclerosis
MS is marked by multifocal and temporally dispersed damage to the CNS, impacting approximately 2.3 million people globally, with an increasing incidence. Key pathogenic mechanisms at the central level include:
- Excessive buildup of intra-axonal Ca2+.
- Axonal demyelination, leading to degeneration due to the lack of trophic support provided by myelin.
- An inflammatory process triggered by immune system alterations mediated by reactive T and B lymphocytes.
These mechanisms disrupt mitochondrial activity, resulting in decreased ATP production and increased oxidative stress. Functional disability, a prominent clinical factor directly associated with gray matter atrophy, is quantified using the Expanded Disability Status Scale (EDSS), which is a reliable tool for assessing life expectancy. Functional impairment, as assessed by the EDSS, directly influences emotional well-being, particularly in relation to depression and anxiety.
Obesity and MS
Most MS individuals are obese, with greater levels of obesity correlating with increased disability. Excessive adiposity is linked to insulin resistance and an altered profile of various lipoproteins in the bloodstream.
Inflammation in MS
Inflammation is a prevalent feature in MS, with elevated levels of proinflammatory interleukins, such as IL-17, IL-6, and IL-1β, playing a significant role. The rise in IL-17 levels in both the serum and cerebrospinal fluid (CSF) correlates with disease activity. IL-6 is involved in the induction of IL-17-producing T cells, even during the remission phase, leading to increased levels of IL-17, which positively correlate with disease severity according to the EDSS. Elevated levels of IL-6 interfere with synaptic plasticity mechanisms, affecting the ability to compensate for the clinical manifestation of new brain lesions in individuals with relapsing-remitting multiple sclerosis (RRMS). IL-6 has also been identified as an important mediator in the association between body mass index (BMI), adiposity, and risk of MS.
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The Link Between Inflammation, Mental Disorders, and MS
A direct association between elevated levels of inflammatory cytokines in the bloodstream and the presence of depressive and anxiety symptoms has been established. IL-6 is associated with depression as a predictive factor and is positively correlated with its increase, as well as the presence of anxiety symptoms. Oxidative stress triggered by elevated levels of IL-6 directly influences the normal functioning of the brain through hyperstimulation of the hypothalamic-pituitary-adrenal (HPA) axis. This oxidative stress and increased depression lead to demyelination and cerebral atrophy, accompanied by elevated concentrations of inflammatory mediators such as tumor necrosis factor (TNFα) and specifically interleukin IL-6, along with IL-1α and IL-1β, in the serum and CSF. IL-1β appears to be more relevant, particularly in relation to anxiety and depression. Improvement of these symptoms following pharmacological treatment has been directly associated with a significant decrease in this interleukin, identifying it as a therapeutic target for the treatment of depression in individuals with MS. Elevated levels of IL-17 have recently been associated, along with IL-6, with subjects with first-episode depressive disorder (FDD), and it also stands out among the various interleukins as being most strongly associated with the presence of anxiety, being considered as a severity indicator.
Inflammation-Independent Neurodegenerative Mechanisms
Recent research has shown the importance of some inflammation-independent neurodegenerative mechanisms associated with mitochondrial dysfunction, iron deposition, and oxidative stress. An excess of glutamate is related to MS symptomatology, and modulation of glutamate release and transport, as well as blocking its receptors, may be relevant targets for future therapeutic interventions. Glutamate excitotoxicity, where excess glutamate leads to neuronal dysfunction and degeneration, has been associated with various chronic neurodegenerative disorders. In various psychiatric disorders, glutamate has been associated with the perception of anxiety and depression. Common mechanisms have been seen between depression and MS, including alteration of brain-derived neurotrophic factor, dysregulation of the hypothalamic-pituitary-thalamic axis, and inflammation or dysregulation of serotonin, norepinephrine, and glutamate. Proinflammatory cytokines contribute to excitotoxicity in gray and white matter by impairing glutamate reuptake through astrocytes and oligodendrocytes, as well as monoaminergic neurotransmission in MS. IL-17A may promote glutamate excitotoxicity by reducing the uptake capacity of astrocytes and converting glutamate into non-toxic glutamine, but also by stimulating Ca2 + −dependent glutamate release.
The Ketogenic Diet: A Potential Therapeutic Approach
The ketogenic diet (KD) is a high-fat, adequate-protein, and very low-carbohydrate diet that forces the body to use fat as its primary energy source, producing ketone bodies in the blood, mainly β-hydroxybutyrate (βHB). The KD has shown promising results in peripheral obesity reduction and central inflammation reduction. The main findings suggest that the KD, as a source of ketone bodies in the blood, improves glutamate activity by reducing obesity, which is associated with insulin resistance and dyslipidemia, promoting central inflammation (particularly through an increase in interleukins IL-1β, IL-6, and IL-17).
How the Ketogenic Diet Works
The KD mimics the biochemical effects of intermittent fasting on the body. The reduction in blood glucose and consequent decrease in glycolysis result in improved mitochondrial function by reducing the production of reactive oxygen species. KD not only helps modulate mitochondrial function by reducing oxidative stress but also reduces neuroinflammation and promotes autophagy, regulates central and peripheral metabolism, and affects the intestinal microbiome in these diseases. All these mechanisms appear to have a particular relevance in MS, as KD has been shown to promote axonal remyelination.
Clinical Evidence of the Benefits of KD in MS
- A randomized parallel-group three-arm pilot trial (NCT01538355) was conducted in RRMS subjects, where a slight reduction in EDSS scores was observed.
- In a population sample of 65 individuals with relapsing MS, significant reductions in fat mass were observed after 6 months of treatment with a KD, leading to improvements in fatigue, depression, neurological disability, and inflammation.
- Positive changes in the development of the disease have also been seen following the intake of coconut oil (as a source of ketone bodies) combined with the administration of epigallocatechin gallate (EGCG), resulting in anthropometric improvements, characterized by a decrease in waist-to-hip ratio and body fat percentage, and an increase in muscle mass percentage. Additionally, the increase in paraoxonase 1, a marker associated with low levels of oxidative stress and inflammation, as well as serum albumin, also contributed to the reduction of cardiac risk in individuals with MS.
Given the previously established relationship between functional disability and obesity, and the association of obesity with insulin resistance and dyslipidemia, functional improvement may be attributed to the regulation of these variables by ketone bodies. From an anthropometric perspective, KD acts by reducing visceral fat mass. On a serological level, they decrease fasting insulin levels by increasing insulin sensitivity, and regulate triglyceride levels, total cholesterol, glucose, and glycosylated hemoglobin. In animal models, it has been seen that a 3-day intervention with a KD leads to a decrease in fasting insulin levels, resulting in glucose intolerance, which may be associated with increased lipid oxidation.
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The Role of Ketone Bodies in Inflammation
Regarding the activity of ketone bodies in relation to inflammation, there is abundant scientific evidence supporting their role both peripherally and centrally. β-hydroxybutyrate (βHB) has a particularly active role, with its anti-inflammatory action including IL-1β activity modulation. βHB may suppress NLRP3 inflammasome activation and improve various inflammatory diseases.
Recent Studies and Findings
A late-breaking study presented at the 2025 ACTRIMS Forum reported that a modified Atkins diet reduced inflammation and altered immune cell metabolism in multiple sclerosis. The study analyzed cryopreserved peripheral blood mononuclear cells and plasma from 39 patients with relapsing MS, who completed a previously-conducted phase 2 study of MAD for 6 months. Key findings included a reduction in proinflammatory myeloid cell phenotypes, a shift from memory to naïve CD8 T cells, and an increase in regulatory T (Treg) cells with enhanced suppressive function. Additionally, B-cell activation was reduced, which may suggest a broader dampening of inflammatory immune activity. Plasma analysis revealed decreased levels of inflammatory cytokines and chemokines, including IL-6 and CCL2. The study confirmed that 6 months on MAD promoted a shift from glycolysis to fatty acid oxidation across immune subsets.
A preliminary study released on March 1, 2022, found that a ketogenic diet may be safe for people with multiple sclerosis (MS). The study also found people with MS may experience less fatigue and depression and report an improved quality of life while on the diet. The study enrolled 65 people diagnosed with relapsing-remitting MS. Participants consumed a ketogenic diet for six months and were instructed to consume two to three ketogenic meals per day consisting of one to two servings of low-carbohydrate proteins such as eggs, fish or meat alongside two to four tablespoons of fat, such as butter, oil, avocado, ghee or heavy cream, and one to two cups of non-starchy vegetables such as cucumbers, leafy greens or cauliflower. A total of 83% of participants adhered to the diet for the full study period. Researchers found that not only did participants have less body fat after six months, they also had a decline in fatigue and depression scores. Participants had an average physical health score of 67 at the start of the study compared to an average score of 79 at the end. Scores also improved on a common MS disease progression test.
Nutritional Approaches in MS (NAMS) Study
The Nutritional Approaches in MS (NAMS) study was a single-center, randomized, controlled, parallel-group study (ClinicalTrials.gov, NCT03508414). Participants were randomized to either a standard healthy diet (SD), a fasting diet (FD), or a ketogenic diet (KD). The primary outcome was the number of new T2-hyperintense lesions found in cranial MRI after 18 months on FD or KD compared to SD. Secondary outcomes included MRI outcomes and neurodegeneration markers, neurological-functional disability, clinical relapses, and participant-reported outcomes.
The results suggest beneficial effects of dietary interventions, underscoring their potential as a complementary strategy in the treatment of RRMS. In the FD group, Neurofilament light chain (NfL)-concentrations were lower at 9 months, and depressive symptoms improved slightly at 18 months. In the KD group, cognition improved at 18 months. Cardiometabolic risk markers (body mass index, abdominal fat, blood lipids, adipokines, blood pressure) improved in all three groups at 9 months differently and were partially associated with clinical outcomes in the FD and KD group. To further clarify the impact of such interventions on the disease course and patient-centered outcomes, future studies with larger, more homogeneous study populations are warranted.
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Potential Mechanisms of Action of KD in Improving Anxiety and Depression in MS
The production of ketone bodies resulting from KD intake reduces obesity and improves insulin resistance, thereby enhancing functional capacity. This activity, along with the ability of ketone bodies to cross the BBB, may explain central glutamate activity, particularly at the extrasynaptic level, and through the reduction of IL-1β, IL-6, and IL-17A levels.