Today, I review, link to, and excerpt from The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Ann Med. 2026 Dec;58(1):2603016. doi: 10.1080/07853890.2025.2603016. Epub 2026 Jan 4.
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All that follows is from the above article.
- Abstract
- Graphical abstract
- 1. Introduction
- 2. Methodology
- 3. The ketogenic diet and the state of ketosis
- 4. Absolute contraindications to the ketogenic diet (all very rare but important)
- 5. Relative contraindications to the ketogenic diet
- 6. Situations in which special care should be taken when following the ketogenic diet
- 7. KD and drug interactions
- 8. Possible side effects of KD
- 9. Potential problems with the KD in clinical practice
- 10. Strengths and limitations
- 11. Conclusions
- Acknowledgments
- Funding Statement
- Disclosure statement
- Data availability statement
- References
- Associated Data
Abstract
Background: The ketogenic diet (KD), initially developed for the treatment of neurological disorders, has gained increasing attention for its potential role in the management of various metabolic diseases. Alongside its expanding clinical use, concerns have emerged regarding its safety, tolerability, and suitability in specific patient populations. This review summarises key contraindications, clinical situations requiring caution, relevant drug interactions, and commonly reported adverse effects associated with KD.
Discussion: Rare absolute contraindications include selected inborn errors of metabolism affecting pyruvate carboxylase activity, carnitine transport or utilisation, fatty acid oxidation pathways, as well as porphyria. Relative contraindications encompass acute pancreatitis, advanced hepatic or renal disease, familial hypercholesterolaemia, and other conditions that may be aggravated by KD-induced metabolic changes, including concomitant use of propofol. Particular caution is warranted in patients with type 1 or type 2 diabetes receiving specific glucose-lowering therapies, pharmacologically treated hypertension, gallbladder disease or prior cholecystectomy, electrolyte disturbances, cardiac arrhythmias, pregnancy or lactation, underweight status, intense physical activity, significant psychosocial stress, or postoperative recovery.Clinically relevant interactions with medications are reviewed, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, insulin and sulphonylurea derivatives, antiepileptic drugs, diuretics, lipophilic drugs, and corticosteroids. The most frequently reported adverse effects range from transient “keto flu” symptoms (fatigue, headache, nausea) to gastrointestinal disturbances, polyuria, and hypoglycaemia.
Conclusions: KD demonstrates therapeutic potential in the management of a broad range of metabolic and neurological diseases; however, it is not an intervention suitable for all clinical situations. Awareness of existing contraindications, conditions requiring particular caution, and potential drug interactions enables a more responsible, individualised, and safe approach to patient selection and clinical management. In this context, the present paper provides a concise yet comprehensive synthesis to support clinicians and researchers in the rational and effective application of the ketogenic diet in both clinical practice and scientific research.
Keywords: Ketogenic diet (KD); absolute contraindications; diseases; drug interactions; relative contraindications; side effects.
Keywords: Ketogenic diet (KD), absolute contraindications, relative contraindications, drug interactions, side effects, diseases
Graphical abstract
1. Introduction
The ketogenic diet (KD) has been in clinical use for over a century since 1921, when it was first used in the treatment of epilepsy [1,2]. However, recent years have seen a rapidly growing interest in this dietary model. A manifestation of this trend is the sharp increase in the number of scientific publications on KD, reflecting the intense search for new potential clinical applications. The beneficial antiepileptic effects of KD raise legitimate questions about the effect of this diet in other brain disorders and diseases, such as Alzheimer’s disease (AD) [3], Parkinson’s disease (PD) [4], multiple sclerosis (MS) [5], migraine [6], and brain tumour [7,8]. There is also a growing number of promising findings on the action of KD in mental illnesses including schizophrenia and bipolar affective disorder [9,10], depression [11], and others [12–16]. For many years, research has also been moving beyond neurology, demonstrating the benefits of KD in other conditions such as type 2 diabetes, where it can often lead to a reduction or complete discontinuation of medication, accompanied by a remission [17–20]. Other areas of research include obesity [21–23], metabolic dysfunction-associated fatty liver disease (MAFLD) [24], cardiovascular diseases [25,26], cancer [27,28], and polycystic ovary syndrome (PCOS) [29,30]. Findings in inflammatory bowel disease (IBD) are also promising, albeit still preliminary [31]. The ketogenic diet is also gaining popularity in the context of sports and physical activity. Although its effectiveness compared to traditional dietary models remains a subject of debate, an increasing number of studies are investigating its impact on physical performance, metabolic adaptation, and recovery [32–34].
The multifaceted (and often successful) clinical application of the ketogenic diet and the growing popularity of this nutritional model calls for a discussion of potential contraindications, side effects and situations in which this particular diet should be used with particular care. Like all other dietary models, the ketogenic diet is not right for everyone. By discussing these concerns, specialists can develop a more responsible and reliable approach to the ketogenic diet.
2. Methodology
This manuscript is a narrative review, intentionally chosen due to the heterogeneity of the included evidence (clinical guidelines, mechanistic studies, narrative reviews, case reports, observational studies and expert recommendations), which cannot be synthesised using systematic methods. Searches were primarily conducted in PubMed and Google Scholar. The initial search strategy employed broad combinations of keywords related to the ketogenic diet (e.g. ‘ketogenic diet’, ‘ketosis’), safety considerations (‘absolute contraindications’, ‘relative contraindications ‘, ‘drug interactions’, ‘side effects’, ‘adverse effects’), and clinical conditions potentially affecting ketogenic therapy. To develop a comprehensive review, when individual articles identified a specific contraindication, comorbidity, or safety concern (e.g. acute pancreatitis, primary carnitine deficiency, gallbladder disease, use of SGLT-2 inhibitors), additional targeted searches were performed using the name of the condition or drug together with terms such as ‘ketogenic diet’ or ‘ketosis’. This approach allowed the inclusion of evidence that might not have been captured through broader search strategies.
Selection was based on article titles, abstracts, and full texts.
3. The ketogenic diet and the state of ketosis
Due to its complex and often context-dependent nature, the ketogenic diet has been defined in many different ways. The definition describing KD as a dietary regimen leading to increased endogenous production of ketone bodies, resulting in a metabolic state of ketosis is considered the most accurate [35], as it addresses all relevant contexts and nuances. There are a few ways to induce ketosis, one of which is fasting. In a certain way, KD mimics fasting but without the negative effects of starvation. Thus, unlike fasting, it is feasible for long-term use [36–38]. It is important to note that nutritional ketosis typically occurs in the context of low insulin levels, which lead to increased circulating free fatty acids (FFAs), enhanced mitochondrial uptake of FFAs, and elevated ketone body production. This explains why a ketogenic diet must be very low in carbohydrates [39]. Ketosis involves increased oxidation of fatty acids and the resulting ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) are used as the main energy substrate [37]. This makes the KD different from other diets, in which the body derives energy mainly from glucose. The state of ketosis achieved by the diet can be referred to as nutritional ketosis, which in itself shows a therapeutic potential. Some of its benefits are described in Chapter 1.
Nutritional ketosis is a state achieved by following a low-carbohydrate, high-fat and moderate-protein diet. The macronutrient distribution varies depending on the type of KD and the purpose of the diet. A low-carbohydrate, high-fat and normal-protein diet is the most common type. Depending on the patient’s needs and the intended purpose, the share of energy coming from fat and protein ranges from 60% to 90% and from 6% to 30%, respectively [40]. Conversely, according to the 2024 expert consensus [41], the share of energy from carbohydrates is less than 10%, which in practice corresponds to 20–50 g of carbohydrates per day – this is because higher carbohydrate intake requires higher insulin production, which inhibits ketogenesis, as previously mentioned. Protein sources typically used in the ketogenic diet include meat, fish, eggs, offal and seafood. Fat sources include olive oil, avocado, fatty fish, fatty meats, nuts, seeds, MCT oil (typically used as a supplement), butter, lard, or egg yolks, while carbohydrate sources include mainly vegetables and nuts [42]. However, nutritional ketosis is possible in a variety of dietary models, as long as the right proportions of macronutrients are ensured. Those models include a plant-free ketogenic diet, as well as a plant-based ketogenic diet, although it is helpful to include animal products. Another commonly used diet is the Mediterranean version of KD [43]. The term ‘ketogenic diet’ does not refer to a single standardized dietary pattern; rather, its health effects depend heavily on proper formulation. While certain ultra-processed foods such as diet soda and pepperoni may technically comply with ketogenic macronutrient ratios, they are not necessarily conducive to long-term health.
It is essential to clearly distinguish between nutritional ketosis and ketoacidosis, as the two states may be mistakenly conflated. Nutritional ketosis is a physiological and desirable metabolic condition, whereas ketoacidosis represents a pathological state. The most well-known form is diabetic ketoacidosis (DKA), characterized by markedly elevated blood glucose levels (typically >250 mg/dL) and a high concentration of ketone bodies (15–25 mmol/L), levels that are virtually unattainable in nutritional ketosis. In contrast, nutritional ketosis is defined by ketone levels >0.5 mmol/L—typically within a range of a few mmol/L depending on the depth of ketosis—while blood glucose levels generally remain within the normal laboratory range [19,44–46].
4. Absolute contraindications to the ketogenic diet (all very rare but important)
Absolute contraindications to the use of the ketogenic diet are rare, however, they carry significant clinical importance, as their presence renders the implementation of this dietary intervention unsafe and, in some cases, potentially life-threatening. Most of these conditions are associated with disorders of fat metabolism and are typically diagnosed early in life, most often during infancy.
4.1. Pyruvate carboxylase (PC) deficiency
Pyruvate carboxylase (PC) deficiency is a very rare metabolic disorder, occurring at a frequency of 1 in 250,000 cases [47]. Pyruvate carboxylase deficiency is caused by a mutation in the PC gene (11q13.4-q13.5). The gene plays a role in the conversion of pyruvate to oxaloacetate (an intermediate product in the citric acid cycle and gluconeogenesis). Three types of PC deficiency have been distinguished: type A (infantile PC deficiency), type B (referred to as severe neonatal PC deficiency) and the less common type C (referred to as intermittent or mild PC deficiency). All of these types involve metabolic acidosis [48]. Symptoms of type A include intellectual disability, developmental delay, abdominal pain, vomiting, fatigue, and acid-base imbalance with increased concentrations of lactic acid (lactic acidosis) and increased concentrations of ketone bodies (ketoacidosis). Unfortunately, only some children with type A PC deficiency survive to adulthood. Type B symptoms also include intellectual disability, lactic acidosis and ketoacidosis, as well as hyperammonemia. These are often accompanied by hypotonia, liver failure, seizures, and coma. In these cases, children usually do not survive beyond three months. In contrast, the mildest form, type C, involves mild and intermittent lactic acidosis with normal (or slightly delayed) development and standard life expectancy [49–53].
There have been a series of findings suggesting that the ketogenic diet is contraindicated in each type of PC deficiency as it may aggravate symptoms, for instance by exacerbating metabolic acidosis and further increasing ketone bodies [54–58]. Among other things, this is due to the fact that patients with pyruvate dehydrogenase deficiency are in a way dependent on food-derived glucose, as gluconeogenesis itself is impaired in these individuals [59]. Therefore, in these patients fasting is also contraindicated and their diet should be rich in carbohydrates and protein. Meals should be frequent to prevent the body from becoming dependent on gluconeogenesis [55].
4.2. Disorders of fatty acid β-oxidation
Beta-oxidation is a key process for obtaining energy from fatty acids [60], involving gradual degradation of acyl-CoA to acetyl-CoA in the mitochondria. Long-chain fatty acids (LCFA) must be transported into the mitochondria by carnitine and the enzymes CPT1, CACT, and CPT2, while short and medium chains permeate directly [61]. The resulting acetyl-CoA fuels the Krebs cycle, and the generated NADH and FADH2 enable ATP production in the respiratory chain. Beta-oxidation becomes critical during starvation, intense exercise and low-carbohydrate diets [60,62]. In individuals with disorders of this pathway, turning to fatty acids as the main energy source is challenging or impossible; restricting carbohydrate supply could lead to serious metabolic complications, therefore, the ketogenic diet is contraindicated in these individuals.
