This is an early, lightly edited draft of a section from an upcoming scientific review.
Early days: carbohydrate restriction for diabetes and weight loss
Historically, culturally, and clinically, what is called the ketogenic diet is in fact a conglomeration of a number of dietary applications. What today might seem like an obvious, singular concept in retrospect in fact represents multiple independent interventions that have, by their family resemblance, been placed under essentially two major semantic umbrellas: low-carbohydrate and ketogenic diet. Diets called low-carbohydrate or ketogenic vary widely in their composition and have a range of different physiological effects. In this section, a brief history of these various ketogenic diets will be elucidated.
The first case of the successful use of a therapeutic carbohydrate-restricted diet, although probably not a ketogenic one, was reported in 1797 by English physician John Rollo for the treatment of what we now call type 2 diabetes mellitus. Rollo reported that after confinement to one room without exercise was ordered, food should consist of the following: “Breakfast, 1½ pints of milk and 1 pint of lime-water, mixed together; and bread and butter. For noon, plain blood puddings, made of blood and suet only. Dinner, game, or old meats, which have been long kept; and as far as the stomach may bear, fat and rancid old meats, as pork. To eat in moderation. Supper, the same as breakfast.” Rollo’s patient would steadily improve, lose substantial weight, and being a captain in the Navy, resume military duty. Echoes of John Rollo’s methods would be heard in the case report literature throughout the 19th century , including the perhaps most famous account by William Banting as retold by Gary Taubes . An indication of the depth of the influence of Rollo’s method, William Osler would write in The Principles and Practice of Medicine in 1892 that in order to treat diabetes mellitus “the carbohydrates in the food should be reduced to a minimum” . In the 1910s, this treatment would indeed be embraced even for type 1 diabetes and the outcomes reported, despite the frequently cited (if not fully understood) concern of ketoacidosis, are impressive . Recently, carbohydrate-restriction has been once again rediscovered as an adjunct to insulin for type 1 diabetes  and as a means of remission for type 2 diabetes .
A few of decades after Rollo, in 1825, a similar diet would be recommended for the treatment of obesity by a Frenchman Jean Anthelme Brillat-Savarin in his classic The Physiology of Taste. He writes: “a more or less rigid abstinence from everything that is starchy or floury will lead to the lessening of weight” . Later, in 1905, President Taft was treated using carbohydrate by an English physician who advocated such a diet in bestselling popular works [8,9]. From there, the low-carb diet for weight loss would cycle in and out of fashion for the next two centuries, with the names of popularizers William Banting, Robert Atkins, and Gary Taubes among the most familiar in the United States today.
Even earlier days: fasting for epilepsy
But perhaps the most ancient and fundamental strand of the ketogenic diet story is thought to relate to its use in the treatment of epilepsy, starting with Hippocrates. However, just as the oft-cited “Let food by thy medicine and medicine thy food” is a fabrication , it is remarkably difficult to find in the Hippocratic corpus advocacy for fasting for the treatment of epilepsy, despite claims of such having become a mythical, permanent fixture in the literature [11–16], with several recent articles providing false citations [14,16], others falsely claiming that fasting was the only treatment for epilepsy advocated by Hippocrates [11,15], and few properly referencing the actual source document . What was actually written by Hippocrates in the relevant passage bears strikingly little resemblance to the claims typically made about it:
On the fifth day, tongue severely affected; the convulsion came on and he was beside himself. When these things ceased, his tongue with difficulty returned to its own condition. On the sixth day, as he abstained from everything, both gruel and drink, there were no further seizures  (pg. 353).
On Epidemics, the book in which this account is to be found, was a case report series, not a series of recommendations, and this is an account with scant detail indeed (fasting is not mentioned in On the Sacred Disease, as is often claimed). What is clear moreover is that the primary intervention for epilepsy among the Hippocratics was not fasting. As epilepsy and ketogenic diet expert William Lennox wrote, directly quoting Hippocrates in his 1960 classic textbook: “Epilepsy in young persons is most frequently removed by changes of air, of country and of modes of life” . Later physicians would later lament the vagueness of Hippocrates’s therapeutic prescriptions for epilepsy .
The relationship of fasting to epilepsy in antiquity becomes just as unclear when interpreting the commonly cited line in the King James Bible (e.g. Wheless, 2008): “This kind can come forth by nothing, but by prayer and fasting.” (Mark 9:29) This apparent quote is in fact is subject to interpretation: many modern translations do not include “and fasting”, leaving things at “by prayer.” This calls into question the supposed New Testament pedigree of the fasting for epilepsy concept. Some articles take this mistake further, claiming that Jesus actively instructed a boy suffering from convulsions to fast . No translation of the verse is compatible with this claim.
Still, while fasting may have a peripheral role in the Hippocratic therapeutic armamentarium, it quickly comes to play a central role in Greek medicine two centuries later, as Alexandrian physician Erasistratus makes clear:
One inclining to epilepsy should be made to fast without mercy and be put on short rations, but should beware of too much bathing and things causing a powerful change .
Thereafter, fasting would figure in the medical texts from the Hellenistic period, transmitted to the Romans, playing an important role in Galen’s writing on epilepsy, and through physicians in the Middle Ages (who cited the Byzantine Bible rather than Greco-Roman medical knowledge) [17,20].
Thus, while neither Jesus nor Hippocrates endorsed fasting for the treatment of epilepsy (sorry), making the ketogenic-diet-for-epilepsy story less mythical and clear-cut than almost always misreported, still, it is clear that the concept of fasting for epilepsy is quite old if it could find its way, even as a fabrication, into the Byzantine manuscript or the works of Alexandrian physicians at all. And its persistence suggests that perceptive clinical acumen was enough to keep it alive as a therapeutic modality. However, that same experience was noisy enough as a whole that fasting was only one therapeutic modality among others, with most medical writers preferring other approaches [17,20]. Proper recognition of fasting’s place as an epilepsy treatment, much less the ketogenic diet, would have to wait for modern science. To imply that it was somehow always present and central to the wisdom traditions of the past, as many writers have, is an anachronistic distortion of the historical record.
Modern science: the rise and fall of the ketogenic diet for epilepsy
The first modern case report of fasting for epilepsy was published by Parisian physicians Guelpa and Marie in 1911 . Word soon spread of an osteopathic physician Hugh W. Conklin using fasting for epilepsy . In 1921, Geyelin would present the case reports of Hugh W. Conklin at that year’s American Medical Association conference. Conklin would follow in 1922 by publishing data showing cure rates of 90% in his juvenile patients and 50% in adults . A wealthy New York corporate lawyer enlisted Conklin’s help to treat his son (H.T.H.), who had intractable epilepsy. After following Conklin’s starvation regimen, the boy’s seizures left him, permanently , which we now know occurs in a substantial minority of pediatric epilepsy patients treated with the KD for several years .
H.T.H.’s parents asked Stanley Cobb, a Harvard professor, to explain the success of starvation and would fund some of the first research into fasting for epilepsy. In a series of experiments, it was demonstrated that the fast was broken with carbohydrate or protein but not with 40% cream . Wilder at Mayo Clinic in a concurrent article wrote: “If this is the mechanism responsible for the beneficial effect of fasting, it may be possible to substitute for that rather brutal procedure a dietary therapy which the patient can follow with little inconvenience and continue at home as long as seems necessary.” It was in this paper that the term “ketogenic diet” was born .
The ketogenic diet was a breakthrough for the long-term management of epilepsy and the first truly efficacious and sustainable treatment for the disease. For the majority of patients, fasting does not cure epilepsy and seizures recur upon cessation of fasting, making the treatment impractical, especially for growing children. But once it was recognized that ketogenesis drove the therapeutic effect, and that ketogenesis could be maintained in the fasted state with the addition of fat but not carbohydrate or protein, it became possible to conceive of a diet that maintained the ketogenic benefits of fasting while avoiding many of the downsides, namely excessive calorie restriction, growth retardation, and wasting.
The publication by Peterman of the precise macronutrient formulation of the diet for children—1 gram of protein per kilogram of bodyweight, 10-15 grams of carbohydrate, and the remainder fat—followed Wilder’s publication in 1924 . Talbot and colleagues at Harvard then published the classic 3:1 and 4:1 fat-to-carbohydrate-and-protein gram ratios in 1926 . These formulations are used in refractory cases to the present day .
With the discovery of diphenylhydantoin in 1938 and with attention focused on the growing number of antiepileptic medications (which were easier to administer), the ketogenic diet soon fell by the wayside. Only modest developments in the use of the diet occurred during the subsequent decades. Perhaps most notable, in 1971, Huttenlocher et al published on the use of medium-chain triglycerides (MCTs), which enables ketogenesis with less carbohydrate restriction but still shows clinically significant antiepileptic effects .
Re-emergence of the ketogenic diet for epilepsy
Use of ketogenic diets for epilepsy almost vanished until 1994 when NBC-TV’s Dateline aired the story of Charlie Abrahams, son of director Jim Abrahams, whose intractable epilepsy was successfully treated with the ketogenic diet at the Johns Hopkins Epilepsy Center, which was at that time one of the few treatment centers still using the diet. Charlie was among the minority of children for whom the ketogenic diet could achieve complete and permanent remission, even after discontinuing the treatment , after only a few years using the diet . When Charlie became seizure-free, Jim Abrahams started the Charlie Foundation, distributing educational videotapes about the ketogenic diet to tens of thousands of doctors and directing a television drama called …First Do No Harm about a mother (Meryl Streep) who defies doctors’ orders and uses the ketogenic diet to treat her son with intractable epilepsy. Research interest in the ketogenic diet for epilepsy has since exploded . A recent systematic review on modern clinical trials published by the Cochrane Collaboration concluded that the ketogenic diet resulted in clinically significant reduction in seizure activity in drug-resistant epilepsy and maintained that the diet was a valid treatment in such cases . A recent review by an international consensus group noted that four randomized controlled trials have shown that KD is efficacious compared to placebo and has a response rate of 70% or better consistently reported in the literature for twelve epilepsy syndromes. The mechanisms of KD for epilepsy are thought to be “parallel, multiple, and potentially synergistic,” due to proposed changes in neurotransmitter synthesis, ion channel modulation, glucose utilization, mitochondrial bioenergetics, and more, depending on the pathobiology of the syndrome 
Since the resurgence of the ketogenic diet for epilepsy, several new permutations of the diet have been formulated for this purpose, perhaps most notably the modified Atkins diet (MAD), so named because while the original Atkins diet prescribes an increase in carbohydrate intake after the initial “induction period”, the modified Atkins diet does not. In contrast to the classic 4:1 ketogenic diet (90% fat), MAD maintains a much more liberal ratio of 1:1 fat-to-carbohydrate-and-protein, or 65% of calories from fat, 25% from protein, and 10% from carbohydrate. This makes it more palatable and less restrictive than the stricter, classic ketogenic diet . Despite this liberalization, in clinical trials MAD showed similar efficacy to the classical ketogenic diet [30–32]. Another alternative to the classic ketogenic diet, the low glycemic index treatment (LGIT), was developed at Harvard at around the same time as MAD . Each of these diets shows similar efficacy to the classical ketogenic diet and are used at discretion of the clinician and families , though a minority of patients may experience better seizure control on more highly restricted forms of the ketogenic diet, such as the classical 3:1 or 4:1 ketogenic diet .
Parallel developments in carbohydrate restriction
While all this was happening with the ketogenic diet for epilepsy, carbohydrate restriction and ketogenic dietary therapies were developing elsewhere.
- Mackarness’s , Atkins’s , and Taubes’s  popular works and David Ludwig’s research  on the use of carbohydrate restriction for obesity;
- Reaven’s  and Krauss’s  scientific work establishing carbohydrate restriction as a viable treatment for metabolic syndrome and atherogenic dyslipidemia;
- Mary and Steve Newport’s experiences with medium-chain triglycerides and ketone esters for Alzheimer’s disease ;
- Stephen Phinney and Jeff Volek’s work on the ketogenic diet for exercise performance ;
- Clinical data and single-arm trials demonstrating the efficacy of the ketogenic diet for type 2 diabetes [6,42];
- Reports of a very-low-carbohydrate/ketogenic diet for maintaining glycemic control in the normal range with fewer complications and insulin use in type 1 diabetes ;
- Development of a number of exogenous ketones for inducing ketosis without carbohydrate restriction.
Ketogenic diet timeline
~400 BC – Hippocrates mentions fasting as curative of epilepsy in a case study 
~260 BC – Erasistratus suggests that fasting should be an important part of the treatment of epilepsy 
1797 – John Rollo publishes case studies using a low-carbohydrate diet for treatment of patients with diabetes mellitus 
1825 – Brillat-Savarin publishes The Physiology of Taste, part of which advocates a carbohydrate-restricted diet for the treatment of obesity 
1863 – Banting publishes Letter on Corpulence, Addressed to the Public, which advocates a diet of meat and vegetables and dietary restriction of starches and beer for the treatment of obesity 
1909 – Moreschi shows that tumors implanted into rats did not grow as quickly when calories are restricted 
1900-1930 – Explorers document the high-fat, low-carbohydrate diet of the Inuit in Alaska and Canada
1911 – Guelpa & Marie report that pediatric epilepsy can be treated by fasting 
1921 – Geyelin presents Conklin’s work at the 1921 American Medical Association conference, which makes fasting for epilepsy widely known to the medical community 
1921 – Wilder coins the term “ketogenic diet” for epilepsy and explains its efficacy 
1924 – Peterman defines the macronutrient requirement ketogenic diet as 1 grams protein daily/kilogram bodyweight, 10-15 grams carbohydrate daily, and the remainder of the diet as fat 
1927 – Talbott publishes the classic 4:1 and 3:1 ketogenic diet formulations 
1930 – Steffanson and Andersen consume an all-meat diet for a full year under the supervision of physicians at Bellevue Hospital in New York [46,47]
1938 – Merritt and Putnam discover diphenylhydantoin, ushering in the era of epilepsy pharmacotherapy, causing KD for epilepsy to wane 
1972 – Atkins publishes Dr. Atkins Diet Revolution, starting the modern low-carb/ketogenic diet for weight loss era 
1994 – Jim Abrahams tells Charlie’s story on NBC-TV’s Dateline, causing a resurgence in interest in KD for epilepsy 
2003 – Seyfried publishes mouse xenograft study showing that ketogenic diet impairs growth of glioblastoma multiforme
2005 – 73 academic centers in 41 countries have a ketogenic diet center for the treatment of epilepsy 
2007 – Taubes publishes Good Calories, Bad Calories, a sweeping historical and scientific popular work that provides a critical reference point for his followers, who have been highly successful in popularizing the ketogenic diet 
2011 – Phinney and Volek publish The Art and Science of Low Carbohydrate Living, a book summarizing the research on the ketogenic diet for practical application by laypeople to treat obesity and metabolic syndrome disease 
2012 – Seyfried publishes Cancer as a Metabolic Disease, a controversial book that defends Warburg’s hypothesis that the etiology of cancer was metabolic and mitochondrial; advocates for the ketogenic diet 
2012-2019 – Several investigators publish studies showing that a ketogenic diet produces superior outcomes for type 2 diabetes compared to standard of care [6,42,51–54]
Ketogenic and carbohydrate-restricted diets used today
|Diet name||F:C&P*||Fat kcal %||Carb + protein kcal %||References|
|MCT oil diet||1.9:1||50%/21%**||29%|
|Low glycemic index treatment||1:1||60%||30%|
|Modified Atkins ciet||0.8:1||65%||35%|
|Low-carbohydrate diet||N/A||N/A||50-150 g/d carbs|
|Very-low-carbohydrate ketogenic diet||N/A||N/A||<20-50 g/d carbs|
|* F:C&P is the ratio of fat to protein and carbohydrate. This is calculated in grams, not kilocalories.|
|** Percent of calories from medium chain triglycerides / long chain triglycerides (MCT/LCT)|
|Ketogenic diets used in clinical practice may deviate substantially from the above.|
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