Antioxidant Megavitamins for Brain Health: Puffery vs. Fact

Reynold Spector

Billions of dollars are spent on worthless and even harmful megavitamin therapy, especially with vitamins C and E.  How did the craze for megavitamins and multivitamins come about, and why does it continue?  

Credit: Carol Donner

Many worthless medical products and procedures are widely marketed and sold, some falling under the alternative medicine label. Two examples I am intimately familiar with are the irrational use of megavitamins C and E. In humans, the two are the principal exogenous antioxidants, and they are essential for body and brain health. Antioxidant vitamins C and E are particularly important in the brain because neurons that are damaged and die by uncontrolled oxidation cannot be replaced in the adult human brain, i.e., there is no neurogenesis after about age seven (Arellano et al. 2018). Other exogenous antioxidants in foods or supplements generally do not enter the human brain and cannot substitute for vitamins C and E. After careful analysis of the data, public health authorities have published recommended daily allowances (RDAs) for vitamins. For vitamin C, the RDA is 60 mg daily (up to 140 mg for smokers); for vitamin E, 30 international units of α-tocopherol (vitamin E) daily. However, in the 1970s, the double Nobel laureate Linus Pauling recommended megavitamin C therapy (greater than ten times the RDA) for those who suffer from some brain diseases, including schizophrenia; he also suggested that megavitamin C could make one “think better.” We now know that these recommendations are incorrect. In 1977, I explained to Professor Pauling in person and published correspondence (Pauling and Spector 1977) why his theories were incorrect. Even more distressing, decades later, professorial recommendations from some prestigious university faculties (e.g., Willet 2003) recommended daily doses of vitamin C of 200 to 300 mg; Willet also suggested that daily megavitamin E was safe and might prevent cardiovascular disease, including stroke (Willet 2003). Even in 2002, we knew that was bad advice (Spector and Vesell 2002). Yet to this day, billions of dollars have been spent on worthless or even harmful megavitamin therapy. Moreover, it is also clear that daily RDA multivitamins in most Americans are unnecessary for body and brain health (Haslam and Prasad 2018). Yet again, billions have been spent on multivitamins. How did the persistent “craze” for megavitamins and multivitamins come about and why does it continue? Is this fixation just a waste of money or does it have harmful effects? These are issues I will explore focusing on brain health. There is a grain of truth in multivitamin and megavitamin therapy in rare clinical situations, as discussed below.

To understand the issues relevant to brain health, let’s review briefly brain development and then the physiology, biochemistry, and molecular biology of these two vitamins. For vitamin C (also known as ascorbic acid), approximately three centuries ago the British Navy found lemons and limes would prevent scurvy (Brown 2003). Interestingly, in severe scurvy, even as the patient (typically a sailor) was dying, his brain function was still intact. In 1933, Szent-Gyorgyi isolated vitamin C, for which he won a Nobel Prize (Brown 2003). We now know vitamin C is deficient in scurvy. Since then, multiple investigators have studied vitamin C in animal and human brains. One problem solved was how vitamin C enters the brain from blood because water-soluble compounds such as vitamin C cannot penetrate through the blood-brain or blood-cerebrospinal fluid (CSF) barriers by simple diffusion (Spector and Johanson 2006). These anatomical barriers protect the brain from many toxic substances in the blood, including certain drugs. It turns out that vitamin C enters the brain by a back door route; specifically, it is “pumped” by a small brain organ, the choroid plexus (CP), from blood into CSF. The choroid plexus is a component of the blood-CSF barrier (Spector and Johanson 2006). The specific vitamin C transporter is termed the sodium-dependent vitamin C transporter 2 (Svitamin CT2) (Spector and Johanson 2006). This transporter vigorously pumps vitamin C into the cerebrospinal fluid to replace the vitamin C lost in the constant turnover of the CSF. From the CSF, vitamin C then diffuses into the brain on the other side of the barriers; vitamin C is then pumped into neurons by Svitamin CT2 in neurons. These systems are configured in such a way as to keep the high concentration of vitamin C in neurons relatively constant (homeostasis). These processes begin early in the development of the brain and are crucial for brain development (Silva-Alvarez et al. 2017; He et al. 2015). In fact, in animals, manipulation of vitamin C fetal brain concentrations during brain development (either too high or too low) leads to abnormal brain development (He et al. 2015). Moreover, lack of Svitamin CT2 is incompatible with life (Spector and Johanson 2006). For pictures of these processes see Spector and Johnson (1989).

Vitamin C has three functions in the brain. It is necessary:

  1. as a cofactor for several enzymes, e.g., those that make dopamine and norepinephrine;
  2. as a crucial antioxidant (as is vitamin E). In the brain, vitamin C in its protective role is oxidized, but in a complex process it is then generally reduced back to vitamin C so it can be reutilized (Nualart et al. 2014). 
  3. as a molecule critical for the development of certain neuronal subpopulations, e.g., dopamine neurons in a part of the brain called the substantia nigra; when too many nigra neurons die off, patients develop Parkinson’s disease (He et al. 2015). This recently described (epigenetic) process is astounding in its complexity.

As with vitamin C, it is very difficult to deplete the brain of vitamin E. Moreover, in humans, in a study in which the daily dose of vitamin E was raised more than 100 times the RDA, there was no significant increase in the CSF concentration of vitamin E (again, profoundly effective homeostasis) (Spector and Johanson 2007). However, there is a syndrome called ataxia associated with vitamin E deficiency (Avitamin ED) due to a genetic lack of α-tocopherol transport protein (αTTP). The Avitamin ED syndrome attests to the importance of both the αTTP and vitamin E in brain function. In humans, megavitamin E is helpful in this very rare syndrome (Spector and Johanson 2007).

After Pauling’s incorrect recommendations for megavitamin C for brain health, there was continued interest in vitamin therapy, in part because of the great successes in understanding and overcoming deficiency states. An excellent example is pellagra, which affected millions of people in the southern United States around the turn of the twentieth century. These patients who consumed a niacin-deficient diet suffered from dementia, dermatitis, and diarrhea. Like magic, when sufficient niacin (or the amino acid tryptophan, which can be converted in the body to niacin) was included in the diet, pellagra disappeared—a triumph of nutrition research and chemistry.

Over time, gradually other vitamin dietary deficiency syndromes were uncovered, understood, and effectively combated, including thiamine, folate, B-12, and many others. These were also great triumphs of nutrition research and chemistry. However, after a series of epidemiology/observation (big data) studies were published by investigators from prestigious universities in the best journals (e.g., the New England Journal of Medicine), claims were made that vitamin E prevented cardiovascular disease, including stroke (Spector and Vesell 2002; Willet 2003; Patel et al. 2015). After their publication, these claims provoked an explosion of interest in megavitamin  E. In retrospect, these studies suffered from bias and/or confounding, misuse of statistics, poor validation of the measurement instruments, cherry picking, and other nonscientific problems (see Table 1; Spector and Vesell 2002; Patel et al. 2015). Years later in the early 2000s, multiple randomized, placebo-controlled, double-blind trials were published that showed that megavitamin E was not superior to placebo and even suggested megavitamin E might increase deaths (Spector and Vesell 2002). Despite these results, Walter Willet suggested megavitamin E was safe and might be helpful (Willet 2003); he would not accept that the causal conclusions from his epidemiology-observation studies were incorrect.    


Table 1

Reasons for Erroneous Conclusions (Patel et al. 2015; Hill 1965)

  1. Bias
  2. Confounding (false assignment of a cause)                     
  3. Cherry picking
  4. Misuse of statistics
  5. Context
  6. Improper generalization of results
  7. Multiple comparisons not taken into account
  8. Post-hoc analyses
  9. Association does not prove causation

Indeed, epidemiology/observation (big data) studies have a checkered history, including corrupt practices as described in a well-documented recent report (Kearns et al. 2016). The fact that such epidemiology/observation studies were and still are published in premier journals was and remains a scientific scandal (Hill 1965; Patel et al. 2015). To be able to conclude that an association found in such studies implies causation requires satisfaction of the Hill criteria (Spector and Vesell 2002; Hill 1965), which are almost never met in published epidemiology/observation studies.

Recently Chirag Patel and colleagues (2015) quantitatively discussed the epidemiology/observation trials of vitamin E and showed that, depending on how one analyzed the data, you could obtain any answer, from higher to lower risk of mortality. These analyses show the danger of conclusions from “big data,” unlike those from randomized, blinded controlled trials with an up-front hypothesis and a data-analysis plan outlined in advance.

Thus, there are multiple reasons to eschew antioxidant megavitamin use. First, the rationale for their use is not sound; oral megavitamins C and E do not increase brain vitamin C or E much if at all. Second, and more important, the gold standard of controlled randomized, blinded trials disconfirmed their general utility. Billions of dollars are wasted by consumers, but worse, megavitamin therapy is not without side effects (Willet 2003) and may delay patients from receiving effective medical care. Of course, the sellers (from the manufacturers to the retail outlets) benefit.


Table 2

Reasons for Popularity of Worthless Therapies, including Megavitamins/Multivitamins

  1. Placebo effect
  2. Erroneous studies (see text)
  3. Incorrect authoritarian advice (see text)
  4. Dissatisfaction with conventional therapy
  5. Habit (once started, it is hard to stop)
  6. “More the merrier”
  7. Prevention of deficiency
  8. Demand to “do something”
  9. Advertising, often misleading or false
  10. Corruption

Why, then, does the use of antioxidant megavitamins persist and in some places actually increase? Table 2 notes several reasons, as suggested in the extant literature. Some of these “causes” are surprisingly very powerful motivators (including the placebo effect and habit).

However, there are a few noteworthy exceptions where specific megavitamins and/or multivitamins are clearly useful and sometimes crucial (Table 3). First and obviously, patients with abnormal GI tracts and those who take certain drugs may not absorb vitamins properly and often require higher doses to prevent vitamin deficiency states. Some elderly otherwise healthy persons may also require higher doses of certain vitamins (e.g., B-12 and vitamin D) because of poor GI absorption. Pregnant women, especially those with hyperemesis gravidarum, often require vitamin B-6, folate, and multivitamins. There are also a small number of patients with defective transporters of specific vitamins into blood or the brain who benefit from one specific vitamin. Over the past forty-odd years, specific defects in separate brain transporters of thiamine, riboflavin, and folates have been discovered (Spector 2014). Without the specific vitamin given as megavitamin therapy, these patients develop severe neurological disorders or die. The unraveling of the molecular cause and treatment of these rare disorders is a triumph of pediatric neurology (Spector 2014). There are also infants and children who present with seizures who respond to large doses of vitamin B-6. There are at least six different brain enzyme disorders and one body disorder, all defined at a molecular level, as well as other ill-defined syndromes that respond with cessation of seizures to vitamin B-6 (Spector and Johanson 2007). Finally, there is the use of vitamin “therapy” by sophisticated physicians for the placebo effect. This is often done in patients with vague complaints in which no cause can be found. The ethics and utility of this practice (e.g., unnecessary B-12 injections) are discussed at length in my textbook (Spector 1985).


Table 3

Examples of Conditions for Which Megavitamin Therapy May Be Indicated

  1. Malabsorption syndromes
  2. Use of proton pump inhibitors and other drugs
  3. Genetic defects in transporters/enzymes
  4. Elderly
  5. Pregnant women (multivitamin)
  6. Rare utilization of the “placebo effect”

Credit: Carol Donner

In summary, there is no scientific basis for megavitamins (or for that matter, multivitamin use) in general in the U.S. population (Haslam and Prasad 2018). Vitamins are omnipresent in the diet, and many foods are fortified with vitamins. Even patients in whom vitamin deficiency might be expected (e.g., dementia patients with Alzheimer’s disease) when studied carefully are not generally deficient (Spector and Johanson 2013). There are, as noted in Table 3, exceptions that generally must be handled on a case by case basis; when an abnormality is found, the appropriate vitamin or vitamins must be given. Giving massive doses of vitamin C or E will not help those who need riboflavin or thiamine or B-6 or nothing!

In a free country it is not clear how to stop unwise and wasteful practices. There are many such practices in the health field (e.g., acupuncture, homeopathy, and megavitamins), practices that in many American localities continue to expand. It is true there are not “big” or in some cases any health risks in the use of multivitamin and megavitamin therapy, homeopathy, and acupuncture. Consequently, it is very hard to stop their use (Table 2). Thus, the big question (paraphrasing Lenin) is: What is to be done now?  


Acknowledgement

I thank Michiko Spector for her many valuable points and her aid in preparing the manuscript.


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Reynold Spector

Reynold Spector, MD has served as a professor of medicine (and pharmacology and/or biochemistry) at Iowa, Stanford, and Harvard-MIT. He is currently clinical professor of medicine at the Robert Wood Johnson Medical School (New Jersey) and is the author of almost 200 peer-reviewed scientific papers and one textbook. His award-winning work has concerned itself principally with vitamin function, transport, and homeostasis in the central nervous system, the effect of food on the function of the kidneys, and the treatment of the poisoned patient. Dr. Spector also served as executive vice president in charge of drug development at Merck from 1987 to 1999, where he oversaw the introduction of fifteen new drugs and vaccines