If It’s Not Proven to Work in Humans, It’s Not Proven to Work

In 1996, when I was 19, I landed my first research job as a summer student intern doing lung cancer epidemiology. In 1997, I got another internship doing research on micronutrients in a nutrition lab. At the time, I was a strong believer in the power of nutrition, vitamins, and all things natural to change the world. As it turned out, this was a very interesting time for research at the intersection of nutrition and lung cancer.

The 1970s, 1980s, and early 1990s had seen a series of very promising studies on the potential for beta-carotene (the provitamin our body converts to vitamin A) to prevent cancer–particularly lung cancer, the leading cause of cancer death.¹

Notably, the research included:

1. Molecular and cellular studies showing beta-carotene to be a powerful anti-oxidant with potent anti-inflammatory and anti-cancer properties.
2. Animal studies showing the potential of beta-carotene to prevent cancer.
3. Large observational studies of people showing that high levels of beta-carotene and high intake of beta-carotene in diet were correlated with lower cancer risk.

At the time, there were also news headlines along the lines of “studies show beta-carotene prevents cancer,” books pushing beta-carotene’s benefits, and plenty of supplements to boost your intake of beta-carotene. 

Question: So, why aren’t we all supplementing our diets with extra beta-carotene?

Answer: Despite all of the evidence and hype presented above, beta-carotene does not prevent lung cancer.

While the rest of the world may have been ready to take beta-carotene, several scientists saw the need to pursue large (thousands of people) double-blinded placebo-controlled randomized controlled trials to determine whether or not beta-carotene actually prevented cancer in people at high risk for lung cancer. I can still remember talking about these studies with my mentors. The results were truly shocking. 

The first two studies found beta-carotene supplementation significantly increased the risk of lung cancer among smokers.^{2, 3} Subsequent studies either confirmed these results or at best found to effect on cancer.⁴ 

How could we have gotten things so wrong? What lessons can we learn here?

Key takeaways from this example:

1. Unless we know that something is safe and effective in humans as a result of adequately-designed clinical trials, we don’t know that it is safe and effective. We will talk in later blogs about what makes a clinical trial adequate. Whenever possible, it should be large, randomized, blinded (meaning neither the researchers nor participants know what they are getting until the end of the trial), and with a placebo or other control group.
   
   
2. Basic science (molecular, cellular and animal studies) and observational (correlational) studies should NOT be assumed to predict how a treatment will work in people. We will also go into these points in more depth in later blogs, but in a nutshell: a) People are not simply large mice or collections of cells. Basic science results need to be confirmed; and b) Correlation does not prove causation. In this example, it is possible that other factors (e.g. people who eat a lot of vegetables are also richer and see their doctors more) could explain the link between beta-carotene and cancer.
   
   
3. Don’t get lost in hype. I italicized several words in this blog—anti-inflammatory, anti-oxidant, anti-cancer, prevents cancer—that should look familiar as they continue to show up in a lot of news stories, books and supplement packages. 
   
   
4. Natural is not always safe. This is a point you can expect I’ll make in the future. Even before these studies were done, it was known that too much vitamin A (several times what you would get in your diet or a typical multi-vitamin) is toxic and could cause serious health effects including rash, abdominal pain, and even coma. Ironically, one of the most common cause of vitamin A toxicity is people taking megadoses of supplements for their health.

As a postscript: In doing research for this blog, I was surprised that there were still books by pseudo-experts pushing the benefits of beta-carotene. A quote from one of these books suggests that it protects “against HIV/AIDS, measles, malaria, cancer, diarrhea, blindness, and other life-threatening illness,” and that people were still selling and taking high doses of beta-carotene (mostly as a “natural tanning” supplement) and thus putting themselves at risk for vitamin A toxicity.

References:

1. Peto R, Doll R, Buckley JD, Sporn MB. Can dietary beta-carotene materially reduce human cancer rates? Nature 1981;290:201-208.

2. Alpha-Tocopherol BCCPSG. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035.

3. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:1550-1559.

4. Goralczyk R. Beta-carotene and lung cancer in smokers: review of hypotheses and status of research. Nutr Cancer 2009;61:767-774.