The Therapeutic Ketogenic Diet: Beyond Weight Loss

Ketosis: What It Actually Is

Strip away the Instagram hype and get to the biochemistry. Ketosis is the metabolic state where your body stops running primarily on glucose and switches to burning fatty acids. The liver takes those fatty acids and converts them into ketone bodies — three of them: beta-hydroxybutyrate (BHB), acetoacetate, and acetone. These ketones then fuel the brain, heart, and skeletal muscle in place of glucose.

Nutritional ketosis means blood BHB levels of 0.5 to 3.0 mmol/L. This is a normal, regulated physiological state. It is emphatically not ketoacidosis — the dangerous condition seen in Type 1 diabetes where BHB rockets above 10 mmol/L because there is zero insulin to regulate the process. Confusing these two is like confusing a campfire with a house fire. Same element, entirely different situations.

The Macronutrient Architecture

Standard therapeutic keto macros: 70-80% fat, 15-20% protein, 5-10% carbohydrates (under 20-50g net carbs per day). The protein window matters more than most people realize. Too little protein and you lose muscle. Too much protein and excess amino acids undergo gluconeogenesis — the liver converts them to glucose, which kicks you out of ketosis. Moderate protein. Not low, not high. This is the mistake that derails most keto attempts before they begin.

Therapeutic Applications: The Evidence

Epilepsy — The Original Use

The ketogenic diet was developed at Johns Hopkins in the 1920s specifically for epilepsy, decades before anticonvulsant drugs existed. It remains one of the most powerful tools in neurology. Fifty to sixty percent of patients with drug-resistant epilepsy show significant improvement on a ketogenic diet. For two specific genetic conditions — GLUT1 deficiency syndrome and pyruvate dehydrogenase deficiency — keto is first-line therapy, not an alternative. The Modified Atkins Diet, a less restrictive cousin, also demonstrates meaningful efficacy for seizure reduction in both children and adults.

Alzheimer’s and Neurodegeneration — Type 3 Diabetes

There is growing recognition that Alzheimer’s disease is fundamentally a metabolic disorder of the brain — some researchers call it “Type 3 diabetes.” The mechanism: brain insulin resistance develops, neurons cannot efficiently uptake glucose, and they literally starve despite glucose being present in the blood. Ketones bypass this bottleneck entirely, entering neurons through monocarboxylate transporters independent of insulin signaling.

Fortier’s 2019 study demonstrated that ketone supplementation increased brain energy metabolism in patients with mild cognitive impairment. MCT oil — particularly C8 caprylic acid, the most ketogenic medium-chain triglyceride — serves as a direct ketone precursor even without full dietary ketosis. Dr. Dale Bredesen’s ReCODE protocol for Alzheimer’s reversal includes mild nutritional ketosis as a core component, specifically targeting brain energy rescue.

Cancer — The Warburg Effect

Otto Warburg observed in the 1920s that cancer cells preferentially ferment glucose even in the presence of oxygen — the Warburg effect. Cancer cells have damaged, dysfunctional mitochondria and cannot efficiently metabolize ketones. Thomas Seyfried at Boston College has built the metabolic theory of cancer on this foundation: cancer as a mitochondrial metabolic disease rather than purely a genetic disease.

The ketogenic diet as cancer adjunctive therapy works through multiple mechanisms: reducing circulating insulin and IGF-1 (both potent tumor growth signals), depriving metabolically inflexible cancer cells of their preferred fuel, and reducing systemic inflammation. The Glucose-Ketone Index (GKI) — glucose divided by ketones — is the monitoring tool. Cancer patients aim for a GKI below 2.0.

Critical caveat: some cancers can metabolize ketones and fatty acids. This is not a blanket therapy. Individualized assessment with oncology oversight is mandatory. Keto for cancer is adjunctive, never standalone.

Type 2 Diabetes and Metabolic Syndrome

The Virta Health clinical trial produced remarkable results: 60% of Type 2 diabetes patients reversed their HbA1c to non-diabetic levels at one year on a well-formulated ketogenic diet with medical supervision. The mechanism is straightforward — ketosis dramatically reduces insulin demand, improves insulin sensitivity, drops triglycerides, raises HDL, and reduces hepatic fat (addressing non-alcoholic fatty liver disease directly). For metabolic syndrome, keto addresses every component simultaneously.

PCOS

Polycystic ovarian syndrome is driven by hyperinsulinemia. Excess insulin stimulates ovarian androgen production, disrupting ovulation. Reduce insulin and you reduce androgens. Mavropoulos’s 2005 pilot study: 5 out of 11 women with PCOS became pregnant during a 24-week ketogenic diet trial — women who had been struggling with infertility.

Migraines

Ketones stabilize neuronal excitability, reduce neuroinflammation, and improve mitochondrial function — the three pillars of migraine pathophysiology. Di Lorenzo’s 2015 study found that 90% of participants following a ketogenic diet experienced at least 50% reduction in migraine frequency. This is a response rate that rivals or exceeds most prophylactic medications.

Traumatic Brain Injury

After TBI, cerebral glucose metabolism is severely impaired. Ketones provide an alternative fuel source for injured neurons when they cannot process glucose. Animal models are compelling; human research is emerging. For acute and post-concussive brain injury, ketosis offers a metabolic rescue strategy.

Mental Health — The Frontier

This is the emerging frontier. Pilot studies and case reports document improvements in bipolar disorder and schizophrenia on ketogenic diets. Dr. Iain Campbell and Chris Palmer MD at Harvard/Stanford are leading this research, framing psychiatric conditions as metabolic disorders of the brain — “metabolic psychiatry.” The mechanism parallels the epilepsy rationale: stabilize neuronal membranes, improve mitochondrial energy production, reduce neuroinflammation, normalize neurotransmitter balance.

Foods: What You Actually Eat

Embrace: Avocado, extra-virgin olive oil, coconut oil, MCT oil, butter and ghee from pastured animals, fatty fish (salmon, sardines, mackerel), pastured eggs, nuts (macadamia, pecan, walnut — watch portions), seeds (hemp, flax, chia), non-starchy vegetables (spinach, kale, broccoli, cauliflower, zucchini, asparagus, Brussels sprouts), berries in small amounts (blueberries, raspberries), quality meats and poultry.

Remove: All grains, sugar in all forms, most fruit (except small portions of berries), starchy vegetables (potatoes, corn, peas), legumes, seed oils (canola, soybean, sunflower, corn oil — inflammatory, oxidize at high heat, wrong omega-6:3 ratio).

Common Mistakes That Sabotage Ketosis

Too much protein. Gluconeogenesis is demand-driven but also substrate-driven at high intake levels. More than 1.0-1.5g per kg of lean body mass often pushes people out of ketosis.

Electrolyte neglect. The infamous “keto flu” — headaches, fatigue, muscle cramps, brain fog in the first week — is not an inevitable consequence of carbohydrate withdrawal. It is electrolyte depletion. When insulin drops, the kidneys excrete sodium aggressively, and potassium and magnesium follow. Supplement sodium (5-7g daily — bouillon, salt on food, electrolyte drinks), potassium (1-4g), and magnesium (300-500mg).

Not enough vegetables. Keto is not bacon and butter. Non-starchy vegetables provide fiber, micronutrients, and polyphenols essential for gut health and detoxification. Fill half your plate with low-carb vegetables.

Poor fat quality. Seed oils are inflammatory regardless of macronutrient ratios. Use olive oil, coconut oil, avocado oil, animal fats, and butter.

Rushing adaptation. Fat adaptation — the metabolic machinery to efficiently burn fat and produce ketones — takes 2 to 6 weeks. The first week is the hardest. Patience and electrolytes carry you through.

Monitoring: Track What Matters

Blood BHB via finger-prick meter (Keto-Mojo, Precision Xtra) is the gold standard for confirming ketosis. Urine strips are unreliable after adaptation. Continuous glucose monitors (CGM) provide real-time feedback on how specific foods affect your blood sugar.

Lipid panels require nuanced interpretation on keto. LDL-C often rises transiently — this alone is not cause for alarm. Look at triglyceride-to-HDL ratio (target below 2.0), LDL particle number and size (NMR LipoProfile), ApoB, and inflammatory markers (CRP, homocysteine). A low triglyceride, high HDL pattern with large buoyant LDL particles is metabolically favorable despite elevated LDL-C.

Monitor fasting insulin (target below 5 uIU/mL), HbA1c, and liver enzymes. For cancer patients, track the Glucose-Ketone Index and aim for GKI below 2.0.

Who Should NOT Do Keto

Absolute contraindications: Type 1 diabetes without experienced medical supervision (ketoacidosis risk), pancreatitis, liver failure, gallbladder removal without digestive support (high fat requires adequate bile — supplement ox bile and lipase), carnitine deficiency (cannot transport fatty acids into mitochondria), porphyria, pyruvate carboxylase deficiency, fat oxidation disorders.

Relative caution: Adrenal dysfunction and HPA axis dysregulation (fasting and carb restriction can spike cortisol, worsening the stress response — stabilize adrenals first), pregnancy and breastfeeding (modified keto may be acceptable, strict keto is controversial — ensure adequate calories and nutrients), history of eating disorders (dietary restriction can trigger relapse — assess psychological readiness carefully).

Cycling and Variations

Not everyone needs strict keto indefinitely. Variations allow flexibility:

• Standard ketogenic diet: Consistent daily keto macros
• Targeted keto: Small carbohydrate dose (15-30g) 30 minutes before intense exercise
• Cyclical keto: 5 keto days followed by 2 higher-carb days (150-300g). Useful for athletes, women with hormonal sensitivity, thyroid support
• Modified Atkins: More protein, less strict fat ratios. Used in epilepsy research as an easier alternative
• MCT-based keto: Liberal MCT oil allows slightly more carbohydrates because MCTs are rapidly converted to ketones regardless of carb intake
• Exogenous ketone supplements: BHB salts or ketone esters deliver ketones without dietary restriction. Therapeutic applications include acute cognitive enhancement, TBI, and bridging during dietary transitions. They do not replace the metabolic benefits of endogenous ketosis from diet but can supplement them.

The ketogenic diet is not a fad. It is a century-old medical therapy with expanding evidence across neurology, oncology, metabolic medicine, and psychiatry. Used with precision — correct macros, quality food sources, proper monitoring, and awareness of contraindications — it is one of the most powerful dietary interventions in functional medicine.