In an era where weight management is synonymous with well-being, dietary trends ebb and flow into popularity. Many individuals have praised and adopted the ketogenic diet, attributing many positive outcomes to it. However, beneath its current spotlight as a weight loss method lies an interesting historical narrative interwoven with medical origins and therapeutic uses.

To understand the intricacies of the ketogenic diet, we first have to understand how the body normally breaks down and utilises its preferred energy source. The three macronutrients, fats, carbohydrates, and protein, can all be converted into energy via varying metabolic pathways. However, carbohydrates are being digested into multiple glucose molecules which

are the preferred energy source as the brain primarily relies on glucose for energy, which is the sugar molecule taken up into the bloodstream after the digestion of carbohydrates. An increased concentration of glucose in the blood causes the release of the body’s endogenous hormone – insulin. With the help of insulin, cells throughout the body, including muscle cells, can take up glucose from the blood and convert it to the energy currency of the cells, called ATP. Excess glucose is being stored as fat. When glucose availability declines, due to the absence of carbohydrate intake for three to four days, the body has to resort to an alternative energy source [1]. The body initiates lipolysis, breaking down fats (triglycerides) into fatty acids that cells utilise for energy production, primarily through ATP conversion. While fatty acids cannot directly fuel the brain [2], the liver’s ketogenesis process transforms them into ketone bodies, offering an alternative energy source for the brain once fat stores are depleted [3].

Controlling the input of nutrients through fasting or specialised diets has been employed to manipulate these cycles. In fact, fasting has been used to treat various diseases for centuries. If you look back to 500 BC, the Greek physician Hippocrates already described fasting as a way to treat neurological disorders such as epilepsy [4]. In more modern years (early 20th century), low carbohydrate diets were used combined with restricting fats and proteins, ultimately starving the patients, which occasionally led to deadly side effects [5]. Nevertheless, reports published cognitive improvement with fasting regimens in epileptic patients [6-8]. Simultaneously, it was understood that diabetic patients had an increase in fatty acid metabolism and showed increased concentration of ketone bodies in their blood (ketonemia) and urine (ketonuria) due to their inability to metabolise glucose [2]. In 1918, further research suggested that, in order to mimic the metabolism of fasting, one could increase fat consumption. This later proved to be a more manageable and very successful therapy for diabetic and epileptic patients alike [6,9]. And so the ketogenic diet – consisting of low-carbohydrate (<50g/day) and high-fat consumption – was born. 

A century after the introduction of the ketogenic diet, its anticonvulsant mechanisms are still not completely understood. The current hypotheses are basing the success of the ketogenic treatment on the influence ketone bodies have on gut microbiome regulation [10], neurotransmitter control, brain energy metabolism, and oxidative stress [11]. It is believed that a long-term ketogenic diet improves the neuronal function in epileptic patients by becoming more resistant to metabolic stress. The presence of ketone bodies reduces the electrical excitability of neurons, which increases their activation threshold, and ultimately prevents excessive firing of neurons, and thereby seizures [12].

The ketogenic diet proved widely successful during the 1920s and 1930s. Several reports showed gratifying results for complete or improved control of seizures and even textbooks started including ketogenic treatment strategies [13-15]. Nevertheless, the discovery of antiepileptic drugs in 1938 began driving away attention from the research and usage of the non-pharmacological treatment option which was the keto diet [6]. Even though studies have shown that the ketogenic diet is not less effective than anti seizure medication, patients often discontinued their diet due to its restrictiveness and  side effects [16]. Regardless of the diet’s efficacy, pharmacological interventions allowed patients to lead a less restrictive life as most patients characterised the ketogenic diet as being unpleasant and challenging to sustain [17]. The ketogenic diet has a handful of short-term side effects referred to as the “keto-flu”, that typically subside within a week. Its symptoms include dehydration, fatigue, nausea, vomiting, dizziness, and constipation. Long-term effects are less well understood, due to limited evidence, but could manifest in nutrient deficiencies, kidney stones, or cardiomyopathy [18].

In early 2000, the popularity for using ketogenic diet as a treatment for epilepsy rose again. The story of a young epileptic boy received national publicity when after repetitive failure of antiepileptic drugs his seizures finally reduced due to the ketogenic diet received at the Johns Hopkins Hospital in New York [19]. In thanks, his father started a foundation to help epileptic children and directed the documentary film “First Do No Harm”, which depicts the boy’s true story and supports the implementation of the ketogenic diet as antiepileptic treatment [20]. Nowadays, the ketogenic diet is only used as ‘an option’ for treating epilepsy but is often only used when drug-resistant against pharmacological drugs occur [6,17].