The medical-grade diet

This post is based on a talk we gave at BSidesLV on August 1st, 2013. You can also watch the video (20 minutes long).

In the face of a severe medical condition, typical dietary therapies have little or no power. The ketogenic diet, however, has proven potency. Here's how it's different.

In brief

• Ketogenic diets are uniquely powerful among dietary therapies. They have been shown to have profound medical effects on serious conditions, especially in the brain.
• These effects may be beneficial even if you aren't currently sick.
• This power is accessible to practically anyone.

Diets are weak medicine

If someone tells you they know of a diet that treats a serious medical condition, you ought to be skeptical.

We don't mean a diet that restricts something you are allergic to or intolerant of — yes, we can prevent retardation in phenylketonurics by avoiding phenylalanine, and if you have gluten intolerance, avoiding gluten is a no-brainer.

However, if someone tells you that you can follow their diet and stop taking medication for a formidable disease like bipolar disorder, or that it would cure a progressive terminal disease like Alzheimer's or cancer, you would probably think that person was a quack. That's because dietary therapies for major diseases don't typically withstand scientific scrutiny. When tested in clinical trials, they show no significant results, or weak results at best.

Diets might help you feel better or might slightly improve your chances, but they are unlikely to cause the sort of profound changes in your body that can completely reverse the course of a major disease.

The ketogenic diet is an exception.

Ketogenic diets are strong medicine

The ketogenic diet is currently used by doctors to treat a major illness, not as an “alternative therapy” — but as a standard, proven medical practice. It is now recognized by neurologists that ketogenic diets are at least as effective as the best anti-epileptic drugs. Around 15% of epilepsy patients who are put on a keto diet by their neurologist become completely seizure free. About a third have a 90% reduction in seizures, and a third have better than a 50% reduction in seizures ¹. That's state-of-the-art treatment for that disease.

A keto diet induces a distinct, favourable metabolic state

As we described in our article on keto-adaptation, a ketogenic diet shifts your metabolism from relying mostly on glucose for fuel, to relying mostly on fuels derived from fat (including ketone bodies — a fuel used by all human bodies, but used in greater quantities when on a keto diet). This change has extensive effects at both the cellular level, and the whole-body level.

It causes profound effects in the brain. Although the mechanisms aren't fully understood, it is well-established that ketogenic diets are neuroprotective against a variety of insults. That is, they protect against different kinds of brain damage. For example, in animal experiments, those animals on a ketogenic diet sustain significantly less brain damage after artificially induced stroke ² or trauma ³. It even protects against damage from nerve gas ⁴.

Ketogenic diets also improve conditions associated with heart disease and diabetes, such as high triglycerides and low HDL (“good cholesterol”) ⁵, insulin resistance ⁶, and obesity. ⁷

Moreover, there is preliminary evidence that ketogenic diets are effective against other serious conditions, including bipolar disorder ⁸, Alzheimer's disease ⁹, and cancer ¹⁰.

Finally, on a keto diet your energy supply is managed more directly by your body. So it makes sense that energy, focus, and mood would become more stable. This has been reported anecdotally and we've previously given a possible explanation for it.

Try this at home!

Ketogenic diets are safe. Like starting an exercise program, starting a keto diet doesn't require a prescription or the supervision of a doctor, except in special cases ^{footnote †}. It's not difficult to do (though there are some common pitfalls). The potential benefits are high and the evidence for those benefits is strong. As we argue in How to Judge a Health Practice, this is a rare and valuable combination of qualities.

Summary

• Ketogenic diets are recognized as being at least as powerful as drugs in at least one major clinical condition, and there is reason to believe they are useful against others.
• The effects may be beneficial even if you currently consider yourself to be healthy. Perhaps you could be even more healthy!
• It's easy and practical to try a ketogenic diet yourself.

^{footnote †}

Like starting an exercise program, starting a keto diet is safe for healthy people. However, if you have a dangerous or unstable medical condition—for example you are in danger of having a heart attack or you have bipolar disorder—you should of course consult your doctor before doing something like starting an exercise program or a keto diet.

Also, of course, you should always consult a doctor before discontinuing a medication or changing your dosage. This is particularly relevant to keto diet, because for some conditions the diet could cause you to need less of your medication, such as for blood pressure, diabetes, epilepsy, or bipolar. Therefore, if you go on a keto diet and keep taking the same dosage of your medication, then you may end up taking too much medication for your needs, which itself could be dangerous. On the other hand, reducing or discontinuing your medication could be dangerous. Therefore, if you are currently taking a medication, you should consult your doctor before starting a keto diet.

This is not because keto diet is unsafe! At least, no more so than exercising. It's just that if you have a dangerous or unstable medical condition or you are taking prescription medications, then you have to be extra careful about making changes.

References

¹ Evidence type: review of clinical reports
Neal EG, Cross JH. Efficacy of dietary treatments for epilepsy. J Hum Nutr Diet. 2010 Apr;23(2):113-9. doi: 10.1111/j.1365-277X.2010.01043.x.

There have been two systematic reviews on the efficacy of the KD. The first included 11 studies published since 1970 (Lefevre & Aronson, 2000). Using a combined analysis of outcome data, the authors reported 15.8% of children to be seizure free and 55.8% to have a greater than 50% reduction in seizures, and it was concluded that there was sufficient evidence to determine that the diet is efficacious in children with intractable epilepsy. A more recent review of 14 studies arrived at the same conclusion (Keene, 2006), reporting an average of 15.6% of a total collective population of 972 patients to be seizure free after 6 months, with 33% having a greater than 50% seizure reduction. A statistical meta-analysis of 19 studies and a total of 1084 patients (Henderson et al., 2006) found the diet reduced seizures by >90% in one-third of the patients, regardless of age or seizure type; the pooled odds ratio of treatment success among patients staying on the diet relative to those discontinuing was 2.25.

² Evidence type: review of controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

To date, no clinical trials of the KD have been performed in patients with stroke, but several animal studies of hypoxia-ischemia support the potential beneficial effect of the diet. Most of these models entail pre-treatment with the KD (or with BHB), resulting in decreased structural and functional damage from the stroke.

³ Evidence type: review of controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Several recent animal studies support this idea [that dietary therapy might ameliorate brain injury and possibly, long-term consequences such as epilepsy], and investigators have principally focused on ketone bodies (Prins, 2008a). Using a controlled cortical impact (CCI) injury model, Prins et al. (2005) showed that pre-treatment with a KD significantly reduced cortical contusion volume in an age-related manner that correlated with maturation-dependent differences in cerebral metabolism and ketone utilization. Later, they showed that cognitive and motor functioning was also improved with KD treatment (Appelberg et al., 2009). Further, using a weight drop model, Hu et al. (2009) showed that the KD pre-treatment reduced Bcl-2 (also known as Bax) mRNA and protein levels 72 h after trauma, indicating that apoptotic neurodegeneration could be prevented with this diet. Consistent with these observations, it was found that fasting – which shares the key feature of ketosis with the KD – led to significant tissue sparing in brain following CCI injury, and that again ketosis (with improved mitochondrial functioning) rather than the relative hypoglycemia seen with fasting was the important determinant of neuroprotection (Davis et al., 2008).

⁴ Evidence type: controlled animal experiments
Jeffrey L. Langston, Todd M. Myers Diet composition modifies the toxicity of repeated soman exposure in rats. Neurotoxicology. 2011 Jun;32(3):342-9. doi: 10.1016/j.neuro.2011.03.001. Epub 2011 Mar 17.

Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group.

⁵ Evidence type: controlled clinical trial and review of past trials
Westman EC, Yancy WS Jr, Olsen MK, Dudley T, Guyton JR. Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. Int J Cardiol. 2006 Jun 16;110(2):212-6. Epub 2005 Nov 16.

Recent research implicates dietary carbohydrates, especially refined carbohydrates, as a risk factor for cardiovascular disease [1]. In recent studies, a low-carbohydrate, ketogenic diet (LCKD) led to weight loss and improvements in high-density lipoprotein cholesterol (HDL-C) and serum triglyceride over a 6- to 12-month period [2], [3], [4] and [5]. Because obesity, low HDL-C, and elevated triglyceride are recognized as cardiovascular risk factors, and can be made worse by a low-fat/high-carbohydrate diet [6], [7] and [8], an LCKD might be a candidate treatment for these conditions.

...

Triglyceride is increasingly thought to be important in the pathogenesis of atherosclerosis, and treatments that lower triglyceride and raise HDL-cholesterol have been shown to reduce major coronary events [38] and [39]. High triglyceride levels promote the formation of small LDL by a process of cholesterol ester/triglyceride exchange and subsequent lipase action on triglyceride-enriched LDL [40]. Small HDL appear to be formed by a similar process and are then cleared from the circulation more rapidly than large HDL [41]. Based on the findings of this study, the reduction of dietary carbohydrate should be evaluated as a treatment for hypertriglyceridemia, low HDL-C, and ultimately atherosclerosis.

⁶ Evidence type: small clinical trial
Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med. 2005 Mar 15;142(6):403-11.

(Emphasis ours)

On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, -35% and -10%, respectively).

⁷ Evidence type: meta-study of controlled trials
Hession M, Rolland C, Kulkarni U, Wise A, Broom J. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obes Rev. 2009 Jan;10(1):36-50. doi: 10.1111/j.1467-789X.2008.00518.x. Epub 2008 Aug 11.

(Emphasis ours)

Note that these studies were on low carb diets that were not even necessarily so low as to be ketogenic.

Abstract

There are few studies comparing the effects of low-carbohydrate/high-protein diets with low-fat/high-carbohydrate diets for obesity and cardiovascular disease risk. This systematic review focuses on randomized controlled trials of low-carbohydrate diets compared with low-fat/low-calorie diets. Studies conducted in adult populations with mean or median body mass index of > or =28 kg m(-2) were included. Thirteen electronic databases were searched and randomized controlled trials from January 2000 to March 2007 were evaluated. Trials were included if they lasted at least 6 months and assessed the weight-loss effects of low-carbohydrate diets against low-fat/low-calorie diets. For each study, data were abstracted and checked by two researchers prior to electronic data entry. The computer program Review Manager 4.2.2 was used for the data analysis. Thirteen articles met the inclusion criteria. There were significant differences between the groups for weight, high-density lipoprotein cholesterol, triacylglycerols and systolic blood pressure, favouring the low-carbohydrate diet. There was a higher attrition rate in the low-fat compared with the low-carbohydrate groups suggesting a patient preference for a low-carbohydrate/high-protein approach as opposed to the Public Health preference of a low-fat/high-carbohydrate diet. Evidence from this systematic review demonstrates that low-carbohydrate/high-protein diets are more effective at 6 months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to 1 year. More evidence and longer-term studies are needed to assess the long-term cardiovascular benefits from the weight loss achieved using these diets.

⁸ Evidence type: case studies
James R. Phelps, Susan V. Siemers & Rif S. El-Mallakh The ketogenic diet for type II bipolar disorder. Neurocase: The Neural Basis of Cognition DOI: 10.1080/13554794.2012.690421

Successful mood stabilizing treatments reduce intracellular sodium in an activity-dependent manner. This can also be achieved with acidification of the blood, as is the case with the ketogenic diet. Two women with type II bipolar disorder were able to maintain ketosis for prolonged periods of time (2 and 3 years, respectively). Both experienced mood stabilization that exceeded that achieved with medication; experienced a significant subjective improvement that was distinctly related to ketosis; and tolerated the diet well. There were no significant adverse effects in either case. These cases demonstrate that the ketogenic diet is a potentially sustainable option for mood stabilization in type II bipolar illness. They also support the hypothesis that acidic plasma may stabilize mood, perhaps by reducing intracellular sodium and calcium.

Evidence type: review of hypotheses and controlled animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Mood stabilizing properties of the KD have been hypothesized (El-Mallakh and Paskitti, 2001), but no clinical studies have been conducted as of this writing. The potential role of the KD in depression has been studied in the forced choice model of depression in rats, which led to a beneficial effect similar to that afforded by conventional antidepressants (Murphy et al., 2004; Murphy and Burnham, 2006).

⁹ Evidence type: review of human and animal experiments
Carl E. Stafstrom and Jong M. Rho. The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders Front Pharmacol. 2012; 3: 59. Published online 2012 April 9. Prepublished online 2012 January 25. doi: 10.3389/fphar.2012.00059

Clinical studies to date have been equivocal but promising. A randomized double-blind, placebo-controlled trial of a MCT KD resulted in significantly improved cognitive functioning in APOε4-negative patients with AD but not in patients with a APOε4 mutation (Henderson et al., 2009). In this study, the primary cognitive end-points measured were the mean change from baseline in the AD Assessment Scale-Cognitive subscale, and global scores in the AD Cooperative Study – Clinical Global Impression of Change (Henderson et al., 2009). This significant clinical improvement was considered to be secondary to improved mitochondrial function, since ketone bodies (specifically, beta-hydroxybutyrate or BHB) have been shown to protect against the toxic effects of β-amyloid on neurons in culture (Kashiwaya et al., 2000). Alternatively, the KD may actually decrease amounts of β-amyloid deposition (VanderAuwera et al., 2005).

...

[T]here is growing evidence that the KD may be an effective treatment for AD through a variety of metabolism-induced mechanisms that reduce oxidative stress and neuroinflammation, and enhance bioenergetic profiles – largely through enhanced mitochondrial functioning.

¹⁰ Evidence type: plausible mechanism and case studies
Seyfried TN, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res. 2012 Jul;100(3):310-26. doi: 10.1016/j.eplepsyres.2011.06.017. Epub 2011 Aug 31.

Abstract

Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress. The current standard of care provides brain tumors with access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) will target glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. The restricted KD (RKD) targets major signaling pathways associated with glucose and glutamine metabolism including the IGF-1/PI3K/Akt/Hif pathway. The RKD is anti-angiogenic, anti-invasive, anti-inflammatory, and pro-apoptotic when evaluated in mice with malignant brain cancer. The therapeutic efficacy of the restricted KD can be enhanced when combined with drugs that also target glucose and glutamine. Therapeutic efficacy of the RKD was also seen against malignant gliomas in human case reports. Hence, the RKD can be an effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer.