The ketogenic diet (or keto diet) has been touted for its many potential health benefits such as weight loss, cognitive enhancement, and prevention of neurodegenerative diseases and cancer. In this post, we cover:
- Different ways to get into ketosis
- Physiology and pathways that are changed when you are in ketosis, which explains how the ketogenic diet may derive its benefits
- Genetic factors that may affect the safety and effectiveness of ketosis
- Health conditions that may be helped by the ketogenic diet
- Negative effects of ketosis and how to mitigate them
What Is the Keto Diet?
Keto diets are defined by a low-carbohydrate (typically under 50 grams/day) and high-fat intake, leading to an elevation of free fatty acids and ketone bodies in the blood .
The first ketogenic diets in the medical literature are noted in publications from the 1920s, although wider popularity and increased research was not observed until the 1960s .
Variations of this diet have remained popular for the past 20-30 years, with proponents claiming that these diets boost weight loss and energy while protecting from certain metabolic diseases .
A ketogenic diet and fasting seem to affect the body similarly. Both deplete the body’s glucose reserves, so the body may start turning fatty acids into ketones .
The Physiology of Ketosis
Beta-hydroxybutyrate is a signaling molecule that can activate HDACs and thereby increase or decrease important genes during ketosis .
|Biochemical Pathway, Hormones, or Benefits||Ketogenic Diet||Calorie Restriction or Fasting||References|
|Nrf2||⬆||⬆||[10, 11, 12]|
|NF-kB||⬇||⬇||[13, 15, 16]|
How to Get Into Ketosis
When the body doesn’t have enough carbohydrates from food, it burns fat to produce energy. This results in the production of ketones or ketone bodies .
In non-diabetics, ketosis can be achieved through 4 ways:
- Fasting or severe caloric restriction 
- Prolonged physical exercise in a fasted state, depending on intensity and duration [19, 20]
- Nutritional ketosis, i.e. by consuming a very low carbohydrate diet
- Supplementation, such as with medium-chain triglycerides or exogenous ketones (ketone esters or ketone ester salts) 
There are 3 different types of ketone bodies, including :
- Beta-hydroxybutyrate, the main ketone body that circulates in the blood
- Acetoacetate, the main ketone body produced by the liver
- Acetone, a very volatile ketone that is generally eliminated through exhalation and is what gives the sweet ketone breath in people in ketosis
In rats, acetoacetate concentration in the blood and brain is very low. A study found that its concentration in the brain was less than 4% of that in the whole blood and 2.6% of that in plasma. However, the brain/blood ratio was highest in starved rats .
In this study, the concentration of beta-hydroxybutyrate in the blood and brain was 5-10 times greater than that of acetoacetate .
Ketone body supplements can provide 8-12 grams of beta-hydroxybutyrate and 1 gram of sodium per serving, which can rapidly increase ketone body availability.
While a ketogenic diet or fasting can take days to raise blood ketone levels, exogenous ketones can reach peak levels in 1-2 hours.
Upon ingestion, ketone esters, such as (R)-3-hydroxybutyl and (R)-3-hydroxybutyrate, have emerged as a more practical and applicable way to increase ketone bodies, especially for athletes.
Ketone esters are cleaved and absorbed in the gut, from where they can either enter circulation or undergo first-pass metabolism in the liver .
Keto-adaptation refers to the process where cells transition from relying on glucose to relying on fat burning for energy production .
After prolonged fasting (over 2 weeks) or diet-induced ketosis, cells adapt to using fatty acids and ketone bodies (keto-adaptation), resulting in a significant reduction in glucose requirement .
Typically, ketone bodies are present in low amounts in the blood. After the first 2-3 days of fasting or being on a very low-carbohydrate diet, the liver starts to produce ketones so ketone levels remain around 2-3 mM .
Keto-adaptation is complete when, after weeks of carbohydrate depletion, cells in the body cut down their uptake of ketone bodies. This results in an increase of ketone body concentration in the blood to ~8 mM .
Keto-adaptation allows the brain to effectively take up and use the ketone bodies because the protein that transports them through the blood-brain barrier is more effective at higher concentrations (Km = 7 mM) .
Nutritional Ketosis vs Diabetic Ketoacidosis
Nutritional ketosis is very different from diabetic ketoacidosis.
In non-diabetics, blood sugar remains normal during ketosis. When the carbohydrate stores are depleted by the end of the first day on a ketogenic diet, the liver starts to produce glucose from other sources, such as pyruvate, glycerol, and amino acids. This helps maintain normal blood sugar levels .
In healthy people eating a ketogenic diet or fasting for long periods of time, ketone levels can reach up to 8 mmol/L, which is a safe level .
Ketone bodies can inhibit their own production, typically preventing these substances from building up to levels that cause ketoacidosis in type 1 diabetics (approximately 20 mmol/L) [29, 18].
Genetic Factors that Determine Whether You Should Adopt a Ketogenic Diet
PPAR-alpha activity is required for ketosis. Mice lacking PPAR-alpha have reduced ability to enter ketosis [9, 8].
People with ApoE3 (CT for RS429358) and ApoE4 genotypes (CC for rs7412) may have very high cholesterol when they consume a diet high in saturated fat. The keto diet is contraindicated in this case, since it increases their risk of heart disease .
Epileptic patients with certain variants at KCNJ11 (rs8175351, rs5219, rs5215) and BAD (rs34882006, rs2286615) genes had lower responses to ketogenic diet treatments after three months in a study on over 500 people .
- Often prescribed to reduce seizures in people with epilepsy
- May help lose weight
- May lower blood fat levels
- May improve blood sugar control
- Early research suggests it may help with neurological conditions such as Alzheimer’s, Parkinson’s, and autism
- Insufficient evidence for some benefits
- Several adverse effects reported, especially if improperly supervised
- Risk of lowering blood sugar levels too much
- May cause digestive problems
- May cause a deficit of essential minerals
- Reported to cause kidney damage in animals
- Not recommended during pregnancy
Health Benefits of the Ketogenic Diet
How the Ketogenic Diet May Derive Its Health Benefits
At the cellular level, the ketogenic diet may derive its health benefits by
- Increasing uncoupling protein, which reduces the number of free radicals that are produced in the mitochondria .
- Increasing the formation of mitochondria and normalizing ATP levels in active tissues such as the brain, heart, and muscles [33, 34].
- Stabilizing blood sugar and reducing cellular dependency on glucose, thus preventing problems that may arise from abnormal blood sugar levels [35, 36].
- Decreasing reactive oxygen species upon exposure to stress, such as glutamate exposure in brain cells .
- Increasing mitochondrial glutathione levels by activating the Nrf2 pathway, which reduces oxidative stress [10, 11].
- Stimulating autophagy (cellular cleanup) .
- Being a fuel source that is more efficient to burn into energy: ketone bodies require only one molecule of NAD+ per molecule of CoA, whereas glucose needs 4 molecules of NAD+ 
- Anti-inflammatory effects, by activating PPAR-gamma while inhibiting NF-kB, TNF-alpha, and COX-2 [16, 40, 13, 16].
In children who don’t respond to conventional anti-seizure medication, the ketogenic diet may be able to reduce seizures. Consult a doctor before implementing this diet and carefully follow their recommendations to avoid malnourishment or effects commonly observed in people following this diet without supervision such as dehydration, constipation, high blood uric acid, and reduced growth.
The ketogenic diet was effective and well-tolerated in 7 clinical trials on over 500 children with difficult-to-treat epilepsy, especially when implemented gradually. In addition to reducing the frequency and severity of seizures, the diet improved alertness, cognitive function, and behavior [41, 42, 43, 44, 45, 46].
A trial on 51 children found the Atkins diet more effective but recommended the ketogenic diet in those younger than 2 years old .
A recent meta-analysis of 70 studies found that the ketogenic diet reduced seizures by at least 50% in 46-62% of cases .
The ketogenic diet may be able to reduce epileptic seizures by :
- Increasing mitochondrial formation
- Increasing mitochondrial glutathione levels
- Reducing oxidative stress
- Decreasing IGF-1, mTOR, sirtuins, and AMPK
- Reducing glucose consumption in the brain by increasing levels of GABA 
- Increasing adenosine levels, although this effect is dependent on the production of the adenosine receptor called A1 receptor 
2) Weight loss
A 24-week ketogenic diet significantly decreased the weight and body mass of obese patients in one study on 83 people. A meta-analysis of 13 studies and over 1,500 people concluded that low-carbohydrate ketogenic diets are more effective than low-fat diets for losing weight [35, 51].
A non-ketosis, low-calorie ketogenic diet, was also able to reduce weight in a pilot study on 25 people, but with a greater loss of both muscle and fat mass .
The ketogenic diet results in less hunger and more muscle maintenance, especially when more protein is included. The appetite-reducing effect of the ketogenic diet was confirmed in a meta-analysis of 26 studies [17, 53].
Compared to other low-calorie diets, participants who underwent the ketogenic diet also reported better mood in a trial on over 100 overweight people, which might make long-term weight management easier .
In the long term, a rebound weight gain, or “yo-yo” dieting, did not occur in the maintenance period after a short-term ketogenic diet. Staying on a ketogenic diet may keep ghrelin (the hunger hormone) and appetite levels low if the subjects stay ketotic, as seen in a study on 50 overweight people [2, 55].
This shows promise for the use of ketogenic diets to promote successful long-term weight loss. However, other diets or lifestyle changes such as doing more exercise may be safer and more effective. Consult it with your doctor and only follow a ketogenic diet under strict medical supervision to avoid its potential adverse effects.
1) Preventing Heart Disease
A long-term (24-56 weeks) ketogenic diet can help lower LDL (“bad”) cholesterol and triglycerides while raising HDL (“good”) cholesterol in obese and overweight people, as seen in 6 trials on almost 500 people. By reducing these risk factors, the diet can protect against heart disease risk [35, 56, 57, 58, 59, 60].
However, the diet has been reported to raise cholesterol (especially LDL) after 1 year in people with normal blood fat levels. This may be due to its high content in fats .
In animal studies, a ketogenic diet was also able to protect the heart and increase recovery after a heart attack .
All in all, the evidence suggests that the ketogenic diet may help prevent heart disease by improving the blood fat profile in people with high blood fat levels. You may discuss with your doctor if this diet may be helpful in your case. Remember to carefully follow your doctor’s recommendations and regularly monitor your blood fat levels.
A ketogenic diet can help lower blood sugar and improve glycemic control in type 2 diabetic patients, as seen in 2 clinical trials on 503 people [36, 63, 64].
The low-carbohydrate diet had a more favorable outcome than a low-fat diet in 2 trials on 25 people with type 2 diabetes and 40 people with metabolic syndrome [65, 66].
In a clinical trial on 146 obese, diabetic patients, a low-carbohydrate ketogenic diet was as effective at improving blood sugar control as a low-fat diet combined with the antidiabetic drug orlistat .
Taken together, the evidence suggests that the ketogenic diet may improve blood sugar control in people with type 2 diabetes and metabolic syndrome. You may use it as a complementary strategy if your doctor recommends it. Importantly, never follow this diet in place of the antidiabetic medication prescribed by your doctor. Diabetic patients on a ketogenic diet should be especially careful in monitoring their blood sugar levels.
The following purported benefits are only supported by limited, low-quality clinical studies and animal research. There is insufficient evidence to support the use of the ketogenic diet for any of the below-listed uses. Remember to speak with a doctor before following this diet and never use it as a replacement for approved medical therapies.
1) Alzheimer’s Disease
Consumption of a ketogenic diet based on medium-chain triglycerides improved cognitive function (especially memory) in 2 small trials on 40 people with Alzheimer’s disease [68, 69].
In another small trial on 16 people with mild to moderate Alzheimer’s, a ketogenic diet based on caprylidene increased blood flow in specific brain regions .
In mice, the ketogenic diet reduced the amount of amyloid beta in the brain without improving cognitive performance .
Brain glucose uptake is impaired in Alzheimer’s disease. A ketogenic diet or supplementation with medium-chain triglycerides can, therefore, provide another source of energy for the brain and, theoretically, reduce symptoms in mild to moderate cases .
The ketogenic diet may also help with Alzheimer’s by reducing glutamate toxicity, thus reducing neuronal cell death  and by increasing BDNF .
Although the results are promising, the evidence is insufficient to support the use of the ketogenic diet in people with Alzheimer’s disease. Larger, more robust clinical trials are needed to validate these preliminary findings.
2) Parkinson’s Disease
In a pilot trial on 7 Parkinson’s patients, the severity of the disease as assessed by the Unified Parkinson’s Disease Rating Scale improved by 43% after 1 month on the ketogenic diet. More recently, a trial on 47 people with this condition found the ketogenic diet as effective as a low-fat diet at improving movement but more effective for other symptoms [75, 76].
In a mouse model of Parkinson’s, beta-hydroxybutyrate can protect against dopaminergic neuron degeneration and mitochondrial damage .
Again, the results are promising but insufficient to conclude for certain that the ketogenic diet helps with Parkinson’s disease. Further clinical research is needed to validate them.
In a study of 30 children, the 60% that could tolerate the ketogenic diet improved their autistic behavior .
In a more recent case-control study on 45 autistic children, the ketogenic diet was more effective than Atkins and gluten-free, casein-free diets at improving cognition and behavior .
As in the two previous cases, the results are promising but insufficient to back this use of the ketogenic diet. More clinical trials on larger populations are needed to confirm its effectiveness in autistic children.
Animal and Cell Research (Lack of Evidence)
No clinical evidence supports the use of the ketogenic diet for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies should not be interpreted as supportive of any health benefit.
Amyotrophic Lateral Sclerosis (ALS)
In inherited ALS cases, a genetic mutation in the gene superoxide dismutase 1 (SOD1) may cause ALS by reducing mitochondrial activity. In addition, ALS patients generally have decreased mitochondrial activity, which could be restored by ketone bodies [80, 81, 82].
In a mouse model of ALS, the ketogenic diet slowed the progression of movement symptoms and loss of the brain cells that control movement in the spinal cord .
Ketone bodies may limit neuron dysfunction resulting from traumatic brain injuries and strokes .
The ketogenic diet can help with traumatic brain juries by:
- Helping with impaired glucose metabolism that is present in traumatic brain injury 
- Reducing oxidative stress 
- Reducing inflammation 
- Increasing omega-3 fatty acid intake 
- Increasing BDNF 
Rett syndrome is a rare X-linked autistic-spectrum disorder that occurs primarily in young girls. The mutation found in Rett syndrome impairs energy metabolism and motor movement as well as increases seizure susceptibility and regresses social behavior. In a mice model of Rett syndrome, the ketogenic diet improved movements and reduced anxiety .
Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is a metabolic disease in women associated with abnormalities in glucose metabolism and androgen (male hormone) metabolism [88, 89].
Women with PCOS are typically infertile and have difficulty losing fat [88, 89].
A ketogenic diet may help manage PCOS by reducing weight and improving insulin sensitivity, but this is a speculation based on its benefits to people with obesity and type 2 diabetes. More studies on women with PCOS are necessary before any conclusions are reached .
The Warburg effect is a phenomenon where most cancer cells rely on glucose to generate the energy needed for cellular processes .
Cancer cells increase glucose uptake and depend heavily on glucose for their metabolism [91, 92].
Tumor cells cannot use fatty acids or ketone bodies as an energy resource and can even be harmed by them. A ketogenic diet can decrease glucose while increasing ketones to supply energy. In a cell study, ketosis reduces tumor growth [93, 94].
Patients adhering to a ketogenic diet can support fatty acid metabolism and inhibit glucose metabolism. So while the body can still get energy from ketone bodies, the tumors do not have a viable energy source .
There are several animal studies demonstrating that the ketogenic diet may help with brain, colon, stomach, and prostate cancers .
In humans, the ketogenic diet may be more effective as an adjunctive treatment to medication and chemotherapy, and additional clinical studies are necessary to confirm their effectiveness .
In mice with astrocytoma, ketone bodies in combination with drugs that inhibit glycolysis provided neuroprotective effects and reduced tumor growth .
Glioblastoma multiforme (GBM) is a highly aggressive tumor of the central nervous system. There has been little progress in treating this disorder. Because it reduces glucose and glutamate levels, the ketogenic diet may reduce the viability of glioblastoma multiforme tumors when used as an add-on to conventional therapy. Several case studies report it helped stabilize the condition with few side effects .
In mice with stomach cancer, a ketogenic diet helped delay the growth of tumors .
In combination with radiation therapy, a ketogenic diet resulted in slower tumor growth in mice with lung cancer compared to radiation alone. It also increased oxidative stress in the tumors .
In comparison to a Western diet, a ketogenic diet prolonged survival and reduced tumor growth in mice with prostate cancer .
The ketogenic diet may help slow the growth of prostate cancer by lowering serum insulin and IGF-1 levels, as well as decreasing caloric intake .
A ketogenic diet does not slow or prevent tumor growth in breast cancer patients, but it can improve some aspects of the quality of life by reducing insomnia and lowering BMI .
Risks and Side Effects
This list does not cover all possible side effects. Contact your doctor or pharmacist if you notice any other side effects.
Call your doctor for medical advice about side effects. In the US, you may report side effects to the FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. In Canada, you may report side effects to Health Canada at 1-866-234-2345.
Common side effects include nausea, vomiting, and lethargy due to reduced energy. The diet also impairs energy homeostasis and the ability to perform high-intensity exercise .
The keto diet can significantly lower blood glucose levels, so diabetic patients should be carefully monitored in case their blood sugar levels become too low. Children participating in a study of ketogenic weight-loss diets were susceptible to hypoglycemia (low blood glucose) and nausea due to low glucose intake [36, 95].
The high-fat content of the diet can also cause stomach and gut problems. After one year of the diet, there can be a progressive increase in cholesterol levels in normal-weight people .
Ketosis can also cause disturbances in the gut microbiota .
Some animal studies show evidence of kidney failure. This is thought to be related to the increased load on the kidneys to clear ketone bodies from the blood, but more research is needed to determine the severity and significance of this risk [105, 104].
Patients are susceptible to deficiencies in minerals like selenium, copper, and zinc in the diet, possibly due to restricting carbohydrate-rich foods which would otherwise provide these nutrients. Researchers have suggested that mineral supplementation should be included in the ketogenic diet to reduce this risk .
Who Should Not Follow the Ketogenic Diet
In mice, a ketogenic diet negatively altered embryonic organ growth and caused organ dysfunction, suggesting that the diet is likely not suitable during pregnancy or gestational diabetes .
How to Mitigate Potential Negative Effects of the Ketogenic Diet
Eating resistant starches while starting a ketogenic diet can help reduce some of the stomach problems that the diet can cause . Good supplementary sources of resistant starch include Jo’s Resistant Starch.
Carbohydrate cycling, or alternating between a low carbohydrate diet and a high carbohydrate diet, can help lower the negative effects of a pure ketogenic diet. This may help a dieter maintain the energy and ability to perform the high-intensity exercise, which can otherwise suffer when sufficient glucose is not available .
Talk to your doctor if you experience any adverse effects after starting a ketogenic diet and what dietary changes you can make to mitigate them.
Taking Ketone Supplements
There are a variety of supplements that contain ketones that you can ingest, which may have many of the potential benefits discussed here.
However, ketone supplements have not been approved by the FDA for medical use due to the lack of solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before taking ketone supplements.