• Islon Woolf MD

B vitamin supplements don’t work and may cause cancer.

Updated: Oct 22


In this email, I will review the history and evidence for B vitamin supplementation. Weak evidence initially made B vitamin supplementation look promising. Then, large clinical trials showed that it doesn't do much, and when it does, there are trade-offs. This story represents a common scenario in medicine. We are initially misled by weak evidence until newer better evidence comes along. Learning from these mistakes is invaluable. Relying on wishful thinking and unreliable kinds of evidence wastes money, wastes time, and wastes lives.



What are vitamins


Vitamins are defined as molecules that can't be synthesized by the body, and must come from food. They were given the name "vitamins" because they are "vital", and some are "amines", molecules containing nitrogen. "Vital amines" was shortened to "vitamins". They are considered "micronutrients" because only small amounts are required. In contrast, the "macronutrients" (carbs, proteins, and fats) must be consumed in much larger quantities. By the turn of the last century, we had isolated and identified all of the major vitamins. A crucial step in the diagnosis and treatment of the severe deficiency states, such as scurvy, a deficiency of vitamin C.



Why do we take vitamins?


Fortunately, in present-day, first world nations the severe deficiency states are exceedingly rare. We have access to a great variety of foods to cover all our micronutrient needs, and prossessed foods are further supplemented. Hence, none of us have ever seen a case of scurvy. Yet, the practice of taking extra vitamins in pill form is very common and growing. As of 2018, about 30% of the US population consumes at least a daily multivitamin. Paradoxically, those who consume vitamins the most, tend to have the best nutrition, and need them the least.


Those who consume vitamins the most, tend to have the best nutrition, and need them the least.

So, why do we take extra vitamins? The vast majority of vitamin users are invested in the idea that, above and beyond the classic deficiency states, there exists an “optimal” range that will lead to “optimal” health. The key to improving functioning, and the key to preventing and treating a plethora of diseases, including aging itself.


Vitamin users are invested in the idea that vitamins have an "optimal" range that will lead to "optimal" health.

This idea of an "optimal range" for vitamins is not unfounded. It started in the 1950's and was promoted by giants in science, like Linus Pauling. It was based on the best kind of evidence for its day: reductionist models and observational studies.



Reductionist models of B vitamins


Reductionism, simply put, is a method of explaining a complex system by looking at its parts. We take a system apart, tinker with the parts, and make a simplified model. It’s not a bad thing. In fact, it's one of the best ways to begin comprehending the most complex system we know, the human body (see my prior email explaining complex systems). Reductionism is what distinguishes modern medicine from ancient medicine. In modern medicine we began to take the human body apart and tinker. We biopsied, autopsied, and sampled the parts, we looked at them under microscopes, analyzed the chemicals, and then played with the parts in test tubes. Things the ancient Greeks, Chinese, and Indians never did.


Reductionism is a method of explaining a complex system by looking at its parts.

Around the 1950's, we began to tinker with the "vital" elements in our food. Folate (B9), for instance, is found in green leafy vegetables. If we starve the body of folate and examine the effects in a test tube, we can figure out what folate does on a microscopic and chemical level. Then, we can extrapolate what effects this may have on the entire system.


It turns out that folate is part of a critical pathway, known as the “methylation cycle". A set of chemical reactions that allows the body to generate a methyl group - a carbon surrounded by three hydrogens. The methyl group is the basic building block of all organic life, and allows us to build and repair essential molecules like DNA, amino acids, and neurotransmitters. Several other B vitamins including B2 (riboflavin), B6, and B12, are also involved in the methylation cycle. Below is a diagram of this pathway.



Methylation cycle


A deficiency at any point in the cycle leads to: low blood counts from slow cell division, poor development of a fetus from slow cell division, cancer from poor DNA repair, and neurological impairment from lack of neurotransmitters (memory loss, fatigue and depression). A deficiency also leads to the accumulation of homocysteine. A metabolite that causes inflammation in blood vessels and oxidation of cholesterol - both triggers for heart disease and strokes.


It is, therefore, reasonable to infer from this reductionist model that more B vitamins will lead to: “optimal” neurological functioning, healthy babies, and prevention of heart disease, strokes, and cancer.



Observational studies of B vitamins


Like the reductionist models, observational studies also led us to believe that more B vitamins are better. In theory, the observational study is quite simple. We take a population of people, measure an exposure, and measure a disease. If those with more exposure have more disease, the exposure may be causative. If those with more exposure have less disease, the exposure may be preventive. These kinds of studies began to become popular from the 1950's and proved to be invaluable. The link between cigarette smoking and cancer, for instance, could never have been so strongly established without them.


With respect to B vitamins, high levels always seem to be associated with better health outcomes. For instance, in the Nurses Health study, we took 100,000 nurses and measured folate intake and the number of colon cancers. After 15 years of follow up, those with high folate intake had 75% less colon cancers than those with lower intake. Hence, it appears that folate prevents colon cancer. The results of observational studies in cardiovascular disease were equally striking. The higher the folate (and the lower the homocysteine), the less likely you are to have heart disease or strokes.



Clinical trials


Up to this point, the reductionist models and observational studies were sending a strong and coherent message about B vitamins. They are good. More is better. However, by the 1990's and the birth of evidence-based medicine, we realized that the best kind of evidence comes from randomized placebo controlled trials. Expensive trials where a large group of people are randomly split into two similar groups, one group given the treatment, and the other, a placebo. They are followed for years to see if there is a difference in outcomes between the two groups.


Unfortunately, private industry (supplement companies) are not incentivized to fund clinical trials. This is because vitamins were deregulated in 1994, and since then, require no proof of effectiveness or safety to be sold. Furthermore, vitamins are not patentable. If a company spends money to prove they work, another company will just sell at a lower cost. Instead, supplement companies are far better off investing into marketing and lowering production costs. This strategy has paid off. No supplement company has ever been prosecuted, despite the fact that up to 50% of its products are substandard or contain tainted ingredients,


Instead, public institutions (like the NIH) using taxpayer money began to take on the financial burden of funding trials. Dozens were completed. What did they show? Vitamin B supplementation was a disappointment. It does not appear to improve neurological function, such as: depression, memory loss, or fatigue. It may modestly lower stroke risk, but only in those with low baseline B levels, and may increase the risk of heart attacks as a trade-off. Finally, and most disturbing, instead of preventing cancer, it seems to cause cancer.


Some of the more dramatic trials showing increased cancer include the B-proof trial. A trial of 3000 patients randomized to B12/folate supplementation or placebo for 2 years. At follow-up, the vitamin B group had a 56% increased incidence of cancers. Another series of randomized trials from Norway studied 7000 participants for 7 years. The vitamin B group had a 38% increased risk of cancer death, and an 18% increased risk of all-cause mortality. This is very disturbing. There are very few trials in the field of medicine that show an increase in all-cause mortality. It suggests an all-around bad effect on health.


One glimmer of hope came from the trials in pregnancy. Folate supplementation significantly reduced the chance of having a child born with neural tube defects. However, even this seems to be accompanied with a chilling trade-off. Mothers and their children may have an increased risk of cancer (adding further evidence that B vitamins may induce cancer).



Conclusion


From the clinical trials, B vitamin supplementation does not "prevent and treat a plethora of disease, including aging itself". There doesn't seem to be an "optimal range" for B vitamins. Just trade-offs.


In my next email, I will discuss where we went wrong. I will explain why the reductionist models and the observational studies mislead us, and why they are weak forms of evidence. Understanding this is crucial so that we don't make the same mistakes again.