Chapter 3: If It Ain’t Broke

If you believe that you’re sick because your body isn’t working right, then drugs and drug-like supplements will seem like the proper solution, because the only way to fix it is to change the way your body works. If you think your health problems are the result of genetics, or of something inherently broken about your state, you will seek corrective interventions and assume that you will need them as long as you live.

This is sometimes true, of course. Once you have developed type 1 diabetes, for example, it’s unlikely, at least with our current state of knowledge, that you will ever live free of the need to take insulin. [1] That’s why it’s sometimes called “insulin-dependent” diabetes. Similarly, even though type 2 diabetes can often be put into remission with a low carb diet [2], this still isn’t a “cure”. Even in people who have reversed all diabetes-related symptoms and associated conditions, there is no evidence that they can maintain that result if they go back to eating carbohydrates.

I know some people don’t like this argument, that low carb is not a cure for diabetes. They insist that of course if you reintroduce the factor that caused the disease in the first place, it will return. But carbohydrates by themselves are unlikely to cause diabetes. There are too many examples across the world and throughout history of people living free of diabetes on high carbohydrate diets for that to make sense. Even if it could be shown that diabetes develops over a long period or pattern of exposure to certain types of carbohydrates, for example table sugar, or refined grains, then to be a cure, an intervention would have to put you back to the state before diabetes developed. Whatever it is that brought a person from carb tolerance to carb intolerance is what diabetes is caused by.

Although there are definitely cases where body function seems compromised, it normally makes sense to assume your body is working correctly. Sickness is usually a temporary result of an insult from the outside: an injury, infection, or an unmet need. We are good at recognising these insults as causal when they are acute, but they can also cause chronic illnesses. Illness becomes chronic if an injury, infection, or unmet need is continuous, even at a low level. As if continuous insult weren’t enough, sometimes the body’s own healing responses can create a vicious cycle.

The body heals itself through a set of processes collectively called inflammation. Inflammation is named for the heat and redness associated with it. But it’s a mistake — an all-too-common one — to consider inflammation damaging like fire. The heat of inflammation isn’t normally a cause of the damage, it’s part of the response. Heat, redness, and swelling come from increased blood flow to the injured area, which brings nutrients and other materials for repair, as well as immune cells to facilitate that repair. Immune cells also fight off foreign intruders and remove damaged tissue. There is some evidence that elevated temperature may enhance immune cell function [3]. On the other hand, if this increased blood flow is prevented, inhibiting immune cell movement to the area, for example by putting ice on it, healing can actually be impaired [4]. At a certain point, swelling can itself start causing more damage. For example, swelling in the brain can be a dangerous situation. Likewise, it’s conceivable that unrelenting inflammatory processes of other kinds can begin to actually contribute to illness. Nonetheless, these are secondary effects.

You’ll often see people blaming inflammation itself for disease, saying they are sick because of inflammation. Inflammation is often uncomfortable, so it’s an easy mistake to make. In cases where the chronic nature of the problem has perpetuated inflammation to the point where it’s contributing to damage, or it’s causing chronic discomfort, reducing it can be helpful, but it doesn’t address the root cause. In other words, it doesn’t stop the source of the need for inflammation in the first place.

When we use these kinds of symptomatic treatments in cases where there is still an ongoing insult, it can give the illusion that you’ve treated the problem even though the source of the problem is actually still there. This reinforces the perception that there is just something inherently wrong with you. After all, you’ve treated it and yet you’re not getting better. It comes back, or, like a game of whack-a-mole, new symptoms pop up in other places.

Many sellers of supplements capitalise on this by claiming to address root causes that are focused on supposed individual differences. In its extreme form, we get the much lauded “Personalised Medicine”: the idea that we can use genomics, the collection of gene variations that make each of us individual, to guide treatment.

Again, just like type one diabetes really requires permanent intervention, there really are genetic disorders that do as well. For example, inborn errors of metabolism that used to cause early death can now sometimes be managed with careful dietary strategies. However, many sellers would have you believe that having certain very common genetic variants renders you incapable of getting along in good health without their products.

An instructive example is the currently popular MTHFR gene. This gene is involved in the “folate cycle” [5] — affecting the ability to generate and regenerate an active form of folate called methylfolate that’s necessary for many important reactions. Symptoms of low folate can be quite severe; it’s implicated in brain dysfunction and depression [6], and ultimately causes a kind of anemia (megaloblastic) which results in fatigue, muscle weakness and other debilitating symptoms.

If you are having these kinds of symptoms you can order lab tests that purport to tell you whether your problems are a consequence of genetics. If so, then to deal with this unlucky handicap, the typical recommendation is to take pre-methylated forms of folate and B12, and other methylation boosters like choline or glycine. Because of their interdependencies, both B12 and choline deficiencies can lead directly to folate deficiency. If your problem comes from inadequate levels of any of these then the supplements will likely make you feel better, and you’ll be glad you found the helpful genetic guidance.

But there is some weaselly logic in the above story. As researchers Wood and Owens explain in a recent paper [7], most people have the variants that result in lower methylation capacity. So at the very start, to frame these normal, typical variants as pathologically low functioning is disingenuous. It is less common not to have them. They are the norm. In other words, you can spend money on this test, and it will probably show you qualify for the treatment, because most people do!

But doesn’t having the gene variant mean that your symptoms are caused by it? Not necessarily. In the same paper, the authors show that homocysteine levels, an important marker of methylation function, vary only a tiny amount due to this genetic component. This is probably because methylation is incredibly important. So it’s likely that there are multiple redundancies built in to the system to cope with bottlenecks at any point in the cycle. It suggests that in real life you are about as likely to benefit from supplementation whether you have the unlucky genes or not — which is not to say you are unlikely to benefit if you have the variation, only that other people are, too. Since the treatment may help regardless of your genes, having or not having the variant isn’t the important factor.

There are many reasons a person might be low in these vitamins. As you might expect, depletion usually results mostly from a combination of inadequate dietary supply and excess demand. Folate is depleted by some toxic exposures, including alcohol [8], some common drugs used for epilepsy [9] and arthritis [10], some antibiotics [11], aspirin [12] and high doses of non-steroidal anti-inflammatory drugs (NSAIDs) [13]. Smoking [14] and birth control pill use [15] are also associated with lower folate status, but causality is yet to be determined. B12 absorption can be impaired by proton pump inhibitors (PPIs) that are often prescribed for heartburn [16] and possibly by Metformin, a widely prescribed diabetes drug [17]. And ironically, folic acid, the form of folate that is often used in fortification and vitamin supplements because of its high bioavailability, can actually inhibit MTHFR, creating what some researchers have described as a “pseudo-MTHFR deficiency [18]. The effect is worse if you have the common variant, because you have less MTHFR function to spare.

Stepping back, this sales pitch also has strange evolutionary implications. If most of the population has some degree of this supposed malfunction, how did that ever arise? Why wouldn’t these variations become rare if they have such a profound detriment on health and we didn’t have the knowledge or resources to treat it until now? The levels of nutrients in corrective supplements are beyond plausible dietary intake in the evolutionary context. If a lot of people are susceptible to suffering from inadequate methylation factors, that seems unlikely to be the fault of the human genome. It seems to me that individual differences calling for “Personalised Medicine” have less to do with DNA and more to do with medical history and lifestyle. While this example illustrates a case for which supplements really can be an effective solution, it also suggests that improvements could be made in some cases by reducing environmental toxins and using fewer interventions, not more. In other words, maybe if you have a folate deficiency it’s a consequence of a medical condition and the resulting chronic use of drugs, not the wrong genes.

The onslaught of ever-increasing intervention is almost comical. Browsing through the pharmacy aisles at the grocery store, there are walls of aids for everything a body is supposed to do: digestion, sleep, staying awake… and always endless rows of remedies for killing pain and inflammation. How did we get to the point where such physical dysfunction is the norm? We may find ourselves in the proverbial situation of side-effect pile on, where we start with a problem with an obvious beginning, say inadequate sleep. So we take caffeine to stay awake, an anti-anxiety pill for the resulting jitters, a tonic for the consequent tank in libido which in turn causes muscle aches, and on and on. It’s possible that some of what’s being sold in the other grocery store aisles are adding one more level to this tangled web of symptoms.

But this is where the confusion becomes even more acute. The lack of clear scientific understanding of the basic effects of food on health would be difficult enough, if it weren’t portrayed as alternately known with consensus, or so complex as to be unknowable. When nutritional education favours a view of our physiological needs as hopelessly complex, both pharmaceutical and supplement industries benefit, because it would appear fruitless to try to solve health issues on your own, and because every minor discovery, no matter how weak, sounds like a breakthrough.

Some areas of medicine have clear victories to claim. The discovery of germs and therefore antibiotics and vaccines are good examples of real progress and benefit to humans, as are the discovery of vitamins leading to curing and prevention of deficiency diseases, at least in places where we’ve put these technologies into practice. This is not the case with understanding the development and cure of chronic disease, which is poorly understood and mostly based on extravagant statistical guesswork. The confident pretending of knowledge in this area has unfortunately led to generalised distrust of medicine in some social groups, leading people to call into question all medical ideas even those that do deserve our confidence.

Clever marketers recognise that most people haven’t been taught how to tell good evidence from poor. These marketers are often good scientists themselves, though, but the efficacy they are concerned with is evidence of a likely sale, not a likely good outcome for the buyer. Likewise, pop articles and even scientific press releases have incentive to make it sound like we’re making more scientific progress than we actually are.

Don’t Fix It?

The confusion is not about the fact that something is broken, but where the breakage is. The fact that there is a huge audience for articles claiming to explain why you feel tired, depressed, and sick all the time, suggests that ill health is a terribly common problem. But identifying that you have a biomarker that’s associated with illness is not the same as finding the cause.

If you have low thyroid, or high homocysteine, or low cortisol, or high cholesterol, or low serotonin, or high C-reactive protein — it doesn’t necessarily mean that those things are causing your illness, or that anything you might do to change the levels of them will heal you. In many cases these markers are actually a completely appropriate response to something else that’s going on. Trying to correct a biomarker when it is a response to a problem and not a cause can ultimately make things worse, as your body now not only has to continue to deal with the original problem, but also has to get around the interference.

Living systems strive for homeostasis, that is, to keep certain parameters within a narrow range. For example, warm blooded animals need to keep their internal temperatures within a narrow range to function properly. If you think depression is caused by low serotonin levels, and try to fix it by interfering with the ability for neural synapses to clear away serotonin, don’t be surprised if the neurons respond by downregulating receptors. Neural adaptations to this kind of drug, SSRIs, can create a long term dependence that makes depression worse for a long time after stopping the drug [19].

Even nutrient interactions can be extremely complex. Adding more of a nutrient you think you need, either by pill or by targeted food consumption, can sometimes create further problems.

For example, trying to correct oxidative stress by taking antioxidants like vitamin E and beta carotene may sound like a good idea, but in clinical trials giving these to smokers has led to poor outcomes; not only did they not decrease lung cancer or deaths but they may have even slightly increased them [20]. This could be because oxidation is a necessary process that the body uses to direct many things, including tissue repair. In other studies, interfering with this by taking high doses of vitamin C has been shown to prevent muscle recovery and growth after exercise [21].

Even food sources of nutrients can be problematic. A few years ago I met a woman who told me about her terrifying experience with mysterious, serious neurological symptoms. She had been suffering from numbness, difficulty walking, forgetfulness, and tremors. Her neurologists were baffled, and her symptoms were increasing rapidly. They were considering invasive treatments when she figured out the problem. As it happened, she had been eating Brazil nuts daily as a source of selenium, which she had decided her diet was otherwise low in. It came to light in a conversation with her brother that selenium toxicity was the likely culprit. When she stopped eating them, her symptoms resolved and she made a full recovery.

Trying to manually assemble a complex set of interacting ingredients can sometimes be a recipe for disaster. Fortunately, it’s unlikely we need to target our nutritional needs with laser precision. If we had to use the prefrontal cortex to get our bodies to function, we probably wouldn’t have made it this far. Medicine is sometimes needed. Nutritional supplements, too! But in the absence of injury, infection, or unusual nutrient depletion, your body can probably handle some fluctuations in the environment. Looking at it from the other side, if you’ve got a health problem that doesn’t resolve eventually on its own, you may actually be suffering from a chronic injury, infection, or other nutrient depleting situation. If that’s the case, figuring out what that is will be more fruitful than assuming you’re broken.

[1] Type one diabetes is an interesting case, because the low carb intervention can drastically reduce dependence on insulin.

[2] McKenzie, Amy L., Sarah J. Hallberg, Brent C. Creighton, Brittanie M. Volk, Theresa M. Link, Marcy K. Abner, Roberta M. Glon, James P. McCarter, Jeff S. Volek, and Stephen D. Phinney. “A Novel Intervention Including Individualized Nutritional Recommendations Reduces Hemoglobin A1c Level, Medication Use, and Weight in Type 2 Diabetes.” JMIR Diabetes 2, no. 1 (2017): e5.

[3] Mace, Thomas A., Lingwen Zhong, Casey Kilpatrick, Evan Zynda, Chen-Ting Lee, Maegan Capitano, Hans Minderman, and Elizabeth A. Repasky. “Differentiation of CD8+ T Cells into Effector Cells Is Enhanced by Physiological Range Hyperthermia.” Journal of Leukocyte Biology 90, no. 5 (2011): 951–62.

[4] In this blog post, Dr. Gabe Mirkin, the doctor who coined the phrase RICE — rest, ice, elevation, compression— explains why he no longer supports this advice for injuries. In short, the evidence is against it.
Mirkin, Dr Gabe. “Why Ice Delays Recovery | Dr. Gabe Mirkin on Health.” Accessed December 2, 2019.

[5] Fowler, Brian. “The Folate Cycle and Disease in Humans.” Kidney International, Proceedings of the Fourth International Congress of Uremic Toxicity, 59 (February 1, 2001): S221–29.

[6] Young, Simon N. “Folate and Depression—a Neglected Problem.” Journal of Psychiatry & Neuroscience 32, no. 2 (March 2007): 80–82.

[7] Wood, Thomas R., and Nathan Owens. “Using Synthetic Datasets to Better Understand and Explain Health Outcomes Associated with Common Single Nucleotide Polymorphisms.” BioRxiv, September 11, 2019, 765586.

[8] Halsted, Charles H., Jesus A. Villanueva, Angela M. Devlin, and Carol J. Chandler. “Metabolic Interactions of Alcohol and Folate.” The Journal of Nutrition 132, no. 8 (August 1, 2002): 2367S-2372S.

[9] Morrell, Martha J. “Folic Acid and Epilepsy.” Epilepsy Currents 2, no. 2 (March 2002): 31–34.

[10] Whittle, S. L., and R. A. Hughes. “Folate Supplementation and Methotrexate Treatment in Rheumatoid Arthritis: A Review.” Rheumatology 43, no. 3 (March 1, 2004): 267–71.

[11] Ho, Joanne M.-W., and David N. Juurlink. “Considerations When Prescribing Trimethoprim–Sulfamethoxazole.” CMAJ : Canadian Medical Association Journal 183, no. 16 (November 8, 2011): 1851–58.

[12] Lawrence, V. A., J. E. Loewenstein, and E. R. Eichner. “Aspirin and Folate Binding: In Vivo and in Vitro Studies of Serum Binding and Urinary Excretion of Endogenous Folate.” The Journal of Laboratory and Clinical Medicine 103, no. 6 (June 1984): 944–48.

[13] Baggott, J E, S L Morgan, T Ha, W H Vaughn, and R J Hine. “Inhibition of Folate-Dependent Enzymes by Non-Steroidal Anti-Inflammatory Drugs.” Biochemical Journal 282, no. 1 (February 15, 1992): 197–202.

[14] Okumura, Kenji, and Hideto Tsukamoto. “Folate in Smokers.” Clinica Chimica Acta 412, no. 7–8 (March 2011): 521–26.

[15] Okumura, Kenji, and Hideto Tsukamoto. “Folate in Smokers.” Clinica Chimica Acta 412, no. 7–8 (March 2011): 521–26.

[16] Marcuard, S. P., L. Albernaz, and P. G. Khazanie. “Omeprazole Therapy Causes Malabsorption of Cyanocobalamin (Vitamin B12).” Annals of Internal Medicine 120, no. 3 (February 1, 1994): 211–15.

[17] Kim, Jiwoon, Chul Woo Ahn, Sungsoon Fang, Hye Sun Lee, and Jong Suk Park. “Association between Metformin Dose and Vitamin B12 Deficiency in Patients with Type 2 Diabetes.” Medicine 98, no. 46 (November 2019): e17918.

[18] Christensen, Karen E, Leonie G Mikael, Kit-Yi Leung, Nancy Lévesque, Liyuan Deng, Qing Wu, Olga V Malysheva, et al. “High Folic Acid Consumption Leads to Pseudo-MTHFR Deficiency, Altered Lipid Metabolism, and Liver Injury in Mice12345.” The American Journal of Clinical Nutrition 101, no. 3 (March 2015): 646–58.

[19] Andrews, Paul William, J. Anderson Jr Thomson, Ananda Amstadter, and Michael C. Neale. “Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good.” Frontiers in Psychology 3 (2012).

[20] The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. “The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers.” Research-article., January 15, 2010.

[21] Ristow, Michael, Kim Zarse, Andreas Oberbach, Nora Klöting, Marc Birringer, Michael Kiehntopf, Michael Stumvoll, C. Ronald Kahn, and Matthias Blüher. “Antioxidants Prevent Health-Promoting Effects of Physical Exercise in Humans.” Proceedings of the National Academy of Sciences of the United States of America 106, no. 21 (May 26, 2009): 8665–70.

Chapter 4: Carbohydrate Restriction: too much or not enough?