The Dark Side of Antioxidants
Not all vitamins are good for all people, all the time. In fact, some can kill you. And guess what? We know where the bodies are buried.
The story of the dark side of antioxidant research isn't well known outside of medical circles. It's an unseemly story, profoundly unsettling; a story that refuses to be made pretty or happy or uplifting no matter how hard you try to duct-tape a silver lining around it. It doesn't fit the "antioxidants are good for you" mantra that sells billions of dollars per year of blueberry- and pomegranate-fortified granola bars and tocopherol-enrichened cereals, acai-berry Jell-O mixes, juices and yogurts with added vitamins, organic baby foods, and so forth, not to mention the billions of dollars of nutritional supplements sold each year (to say nothing of the sub-industry of books and magazines devoted to nutrition).
Still, it's a story that needs to be told. And some of us know where the bodies are buried.
For decades, mainstream medicine pooh-poohed the possibility that vitamins or supplements could "move the needle" on major diseases. Two-time Nobel laureate Linus Pauling was harshly criticized in the 1970s and 80s for suggesting a role for Vitamin C in prevention and treatment of cancer. Even so, laboratory workers had known for years that changes to diet could influence the rate of tumor appearance in lab animals. By the early 1980s, case-control studies and epidemiological evidence from a variety of sources had begun to accumulate, showing that persons who routinely ate large quantities of fresh fruits and vegetables consistently did better with regard to cardiovascular disease (and other diseases) than most people.
In 1981, Sir Richard Peto and colleagues published a paper in Nature that dared asked the simple question: "Can dietary beta-carotene materially reduce human cancer rates?" (Nature, 290:201-208) Shortly thereafter, the National Cancer Institute (whose Chemoprevention branch was headed by Dr. Michael B. Sporn, one of the coauthors of the Nature article) decided to green-light two large intervention-based studies of the cancer-preventing effects of nutritional supplements: a study in Finland involving beta-carotene and alpha-tocopherol (Vitamin E), and a U.S.-based study involving retinol (a form of Vitamin A) and beta-carotene.
The Finland study (conducted by Finland's National Institute for Health and Welfare) was initially designed to encompass 18,000 male smokers between the ages of 50 and 69. Why just smokers? And why male, and 50+ years old? Lung cancer is ten times more likely to affect smokers; hence a cancer study limited to smokers would need only a tenth as many participants as a study involving the general population. Based on what was known about the age-specific rates of lung cancer among Finnish men, study designers calculated that the desired effect size (a hoped-for 25% decrease in cancer incidence over a period of 6 years) would be measurable with the required level of statistical relevance if 18,000 older male smokers made up the study group. As it turned out, the age distribution of actual volunteers didn't match the demographics of the eligibility group (volunteers tended to be toward the young end of the eligibility range), and as a result the study's enrollment target had to be reset to 27,000 in order to get good statistical relevance.
Full-scale recruitment of subjects into the ATBC (Alpha-Tocopherol Beta-Carotene) Lung Cancer Prevention Study began in April 1985 and continued until a final enrollment of 29,246 men occurred in June 1988. Enrollees were randomized into one of four equal-sized groups, receiving either 50 mg/day (about 6 times the RDA) of alpha-tocopherol, or 20 mg/day of beta-carotene (equivalent to around 3 times the RDA of Vitamin A), or AT and BC together, or placebo only.
At the same time, which is to say starting in 1985 (after some very small, very brief pilot studies to validate recruitment mechanics), the Carotene and Retinol Efficacy Trial (CARET) started enrolling volunteers in the U.S. Unlike Finland's ATBC study, volunteers for CARET were both male and female and were heavy smokers or came from asbestos-exposed workplace environments. They ranged in age from 45 to 69 and were divided initially into four groups (30 mg/day beta carotene only, 25,000 IU retinol-only, carotene plus retinol, or placebo), but in 1988 the treatment groups were consolidated into one group taking both beta-carotene and retinol. The study design called for continuing the vitamin regimen through 1997, with reporting of results to occur in 1998.
Alas, things went horribly awry, and CARET never got that far.
When the Finns reported results from the ATBC study in April 1994, it sent shock waves through the medical world. Not only had alpha-tocopherol and beta-carotene not provided the expected protective effect against lung cancer; the supplement-treated groups actually experienced more cancer than the placebo group—18% more, in fact.
This was an astonishing result, utterly bewildering, as it contradicted numerous prior animal studies that had shown Vitamin E and beta-carotene to be promising cancer preventatives. Surely an error had occurred. Something had to have gone wrong. One thing it couldn't be was chance variation: with almost 30,000 participants (three quarters of them in treatment groups), this was not a small study. The results couldn't be a statistical fluke.
As it turns out, the Finnish investigators had actually done a meticulous job from start to finish. In analyzing their data, they had looked for possible confounding factors. The only thing they found of interest was that heavy drinkers in the treatment group got cancer more often than light drinkers.
Two weeks before the Finnish study hit, the National Cancer Institute was awash in conference calls. Accounts vary as to who knew what, when, but CARET's lead investigator, who had seen the Finnish group's data prior to publication, knew that NCI now had a serious problem on its hands. CARET was doing essentially the same experiment the Finns had done, except it was giving even bigger doses of supplements to its U.S. participants, and the study was due to run for another three and a half years. What if CARET's treatment group was also experiencing elevated cancer rates? Participants might be dying needlessly.
When statisticians presented interim results to CARET's Safety Endpoint Monitoring Committee in August 1994, four months after the Finnish study appeared in print, it became clear that CARET participants were, if anything, faring worse than the patients in the ATBC study. Even so, the safety committee found itself deadlocked on whether to call a premature halt to CARET. The study's formal stopping criteria (as given by something called the O’Brien–Fleming early-stopping boundary) had not been met. Ultimately a decision was made to continue to accumulate more data.
A second interim statistical analysis was presented to CARET's safety committee in September 1995, one year after the first analysis. According to the committee:
At that time it was clear that the excess of lung cancer had continued to accumulate in the intervention regimen at about the same rate during the time since the first interim analysis. Further, the cardiovascular disease excess persisted. The conditional power calculations showed that it was extremely unlikely that the trial could show a beneficial effect of the intervention, even if the adverse effect ceased to occur and a delayed protective effect began to appear.Therefore the SEMC voted unanimously to recommend to NCI that the trial regimen should be stopped but the follow-up should continue.
The study was halted—but not until January 1996, nearly two years after final publication of the Finnish results. (Even then, CARET participants were contacted by snail mail to let them know of the study's early termination and the reasons for it. See this writeup for details.)
CARET's results were published in The New England Journal of Medicine in May 1996. Once again, shock waves reverberated throughout the medical world. Participants who took beta-carotene and Vitamin A supplements had shown a 28% higher rate of lung cancer. They also fared 26% worse for cardiovascular-related mortality, and 17% worse for all-cause mortality.
There was great reluctance in the medical community to believe the results. Perhaps the even-worse results of the CARET study (relative to the Finnish experiment) had to do with the decision to include 2,044 asbestos-exposed individuals in the treatment group of 9,241 persons? Not so, it turns out. Segment analysis of the asbestos group's data relative to the heavy-smoker group showed that "There was no statistical evidence of heterogeneity of the relative risk among these subgroups."
What the CARET study had, in fact, done was not just replicate the ATBC results but provide the beginnings of a dose-response curve. The Finns had used 20 mg/day of beta-carotene; CARET employed a 50% higher dose. The result had been 50% more cancer.
It was hard to understand the results of the ATBC and CARET studies in light of the fact that another large trial involving beta-carotene, the Physicians' Health Study, had reported neither harm nor benefit from 50 mg of beta carotene taken every other day for 12 years. However, the Physicians' Health Study population was younger and healthier than ATBC or CARET study groups and was predominantly (89%) made up of non-smokers. This turned out to be quite important. (Read on.)
It's been almost 20 years since the ATBC and CARET results were reported. What have we learned in that time?
In 2007, Bjelakovic et al. undertook a systematic review of existing literature on antioxidant studies covering the time frame 1977 to 2006. The systematic review procedure was conducted using the well-regarded methodology of the Cochrane Collaboration, a group that specializes in (and is known for) high-quality meta-analyses. In analyzing the 47 most rigorously designed studies of supplement effectiveness, Bjelakovic et al. found that 15,366 study subjects (out of a total treatment population of 99,095 persons) died while taking antioxidants, whereas 9,131 placebo-takers, in control groups totalling 81,843 persons, died in those same studies. (This is not including ATBC or CARET results.) The studies in question used beta-carotene, Vitamin E, Vitamin A, Vitamin C, and/or selenium.
In a separate meta-analysis, Miller et al. found a dose-dependent relationship of Vitamin E with all-cause mortality for 135,967 participants in 19 clinical trials. At daily doses below about 150 International Units, Vitamin E appears to be helpful; above that, harmful. Miller et al. concluded:
In view of the increased mortality associated with high dosages of beta-carotene and now vitamin E, use of any high-dosage vitamin supplements should be discouraged until evidence of efﬁcacy is documented from appropriately designed clinical trials.
How are we to make sense of these results? Why have so many studies shown a harmful effect for antioxidants when so many other studies (particularly those carried out in animals, but also those carried out in predominantly healthy human populations) have shown a clear benefit?
The answer may have to do with something called apoptosis, otherwise known as programmed cell death. The body has ways of determining when cells have become dysfunctional to the point of needing to be told to shut down. Most cancer therapies exert their effect by inducing apoptosis, and it's fairly well accepted that in normal, healthy individuals, precancerous cells are constantly being formed, then destroyed through apoptosis. Antioxidants are known to interfere with apoptosis. In essence, they promote the survival of normal cells as well as cells that shouldn't be allowed to live.
If you're a young non-smoker in good health, the level of cell turnover (from apoptosis) in your body is nowhere near as high as the level of turnover in an older person, or someone at high risk of cancer. Therefore, antioxidants are apt to do more good than harm in a young, healthy person. But if your body is harboring cancer cells, you don't want antioxidants to encourage their growth by interfering with their apoptosis. That's the real lesson of antioxidant research.
The food industry and the people who make nutritional supplements have no interest in telling you any of the things you've read here. But now that you know the story of the dark side of antioxidants (a story made possible by thousands of ordinary people who died in the name of science), you owe it to yourself to take the story to heart. If you're a smoker or at high risk for heart disease or cancer, consider scaling back your use of antioxidant supplements (Vitamins A and E in particular); it could save your life. And please, if you found any of this information helpful, share it with family, friends, Facebook and Twitter followers, and others. The story needs to get out.
Join Radiolab's Latif Nasser at 1pm ET today as he chats with Malcolm Gladwell live on Big Think.
Can voters really predict who will be a good leader? Malcolm Gladwell joins Big Think Live to discuss this how lotteries could, in theory, distribute leadership more effectively, from government elections, college admissions, and grant applications.
It's the first time scientists have discovered an animal that doesn't perform aerobic respiration.
- The animal is a tiny parasite called Henneguya salminicola.
- The parasite infects salmon and lives within the fish muscle, though scientists aren't quite sure how it breaks down nutrients for survival.
- The findings are published in the journal PNAS.
H. salminicola inside of a salmon
An evolutionary advantage<p>Losing that mitochondrial genome appears to have been a less-is-more type of advantage for the parasite.</p><p style="margin-left: 20px;">"Myxozoans have gone through outstanding morphological and genomic simplifications during their adaptation to parasitism from a free-living cnidarian ancestor," the authors wrote. "As a highly diverse group with >2,400 species, which inhabit marine, freshwater, and even terrestrial environments, evolutionary loss and simplification has clearly been a successful strategy for Myxozoa, which shows that less is more."</p><p>The researchers aren't quite sure how <em>H.</em> <em>salminicola </em>breaks down nutrients without oxygen. One possibility is that it absorbs molecules from its host. It's hard to tell, however, because the researchers analyzed dead parasites — they'd need to look at parasites living within the fish to get a better understanding of how the creatures operate.</p><p>The discovery highlights how much scientists still have to learn about the diversity of life on Earth. Atkinson told <a href="https://www.cnn.com/2020/02/26/world/first-animal-doesnt-breathe-oxygen-scn-trnd/index.html" target="_blank"><em>CNN</em></a> that he expects <em>H.</em> <em>salminicola </em>isn't the only animal that can survive without oxygen, or in even "weirder modes of existence." </p>
The search for alien life<p>One interesting implication of the discovery is what it means for the search for alien life. It's long been thought that, if aliens exist, they'd likely breathe oxygen. After all, it's the best element that we know of for producing large amounts of energy for metabolism, allowing us to "grow large, run and jump and think," as David Catling, a planetary scientist at the University of Washington, told <a href="https://www.forbes.com/sites/brucedorminey/2012/11/20/why-e-t-would-also-breathe-oxygen/#48fdfed63c55" target="_blank"><em>Forbes</em></a>. <br></p><p style="margin-left: 20px;">"Because of oxygen's chemical advantages and the history of complex life on earth is so intertwined with oxygen levels," he said. "I think E.T. would also breathe oxygen."</p><p>This is one reason why many think Earth-like exoplanets with atmospheres that likely contain oxygen would be good candidates for harboring alien life. But, in a small way, the newly discovered parasite gives reason to think that the search for alien life — and their life-supporting planets — might be far more complicated.</p>
UNC School of Medicine researchers identified the amino acid responsible for the trip.
- Researchers at UNC's School of Medicine have discovered the protein responsible for LSD's psychedelic effects.
- A single amino acid—part of the protein, Gαq—activates the mind-bending experience.
- The researchers hope this identification helps shape depression treatment.
What is Bicycle Day?<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="d346092205da3c9ed10bad283222c9f1"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/L32mAiLXnLs?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>Back in the world of clinical science, LSD has always showed promise. That trend continues as restrictions are finally easing up. Understanding LSD's effects on our brain's complex system of networks is an important step toward discovering therapeutic actions. As Roth <a href="https://www.inverse.com/mind-body/how-lsd-binds-to-the-brain-study" target="_blank">says</a> of his research,</p><p style="margin-left: 20px;">"Now we know how psychedelic drugs work – finally! Now we can use this information to, hopefully, discover better medications for many psychiatric diseases."</p><p>Using X-ray crystallography, Roth's team discovered a single amino acid—a building block of the protein, Gαq—responsible for binding to serotonin receptors. As LSD is only a partial agonist, they also experimented with a full-agonist designer psychedelic in order to observe complete receptor activation. This amino acid appears to be the master switch for the psychedelic experience. </p><p>While psilocybin has been in the news, the psychedelic renaissance is expanding in all directions. Phase 1 clinical trials on the <a href="https://newatlas.com/science/landmark-clinical-trial-lsd-mdma-mindmed/" target="_blank">combination</a> of LSD, MDMA, and psychotherapy will soon commence. LSD's effects on <a href="https://clinicaltrials.gov/ct2/show/NCT03866252" target="_blank" rel="noopener noreferrer">Major Depressive Disorder</a> and <a href="https://www.sciencealert.com/first-clinical-trial-shows-micro-doses-of-lsd-can-increase-a-person-s-pain-tolerance" target="_blank">pain management</a> are ongoing. With the <a href="https://www.bloomberg.com/news/articles/2020-09-18/-magic-mushroom-company-moves-toward-mainstream-in-nasdaq-ipo" target="_blank" rel="noopener noreferrer">first psychedelics company</a> to IPO on the American stock market, along with hundreds of millions of dollars of investment flowing into similar companies and organizations, the push for legalized psychedelics intensifies. </p>
Credit: ynsga / Shutterstock<p>Researchers are actively attempting to remove the hallucinogenic component of psychedelics for widespread therapeutic usage—<a href="https://www.healtheuropa.eu/could-ibogaine-offer-a-revolutionary-long-term-solution-to-addiction/100635/" target="_blank">trials</a> using ibogaine for addiction treatment, for example. Identifying the chemical effects of psychedelics on our brains is an essential step in that process.</p><p>Of course, believing psychedelics <em>only</em> matters to brain chemistry is problematic as well. The rituals associated with their use are just as relevant. The "<a href="https://en.wikipedia.org/wiki/Set_and_setting" target="_blank">set and setting</a>" model espoused by Timothy Leary reminds us that biology isn't everything; environmental factors play just as important a role in mental health. </p><p>Isolating specific chemicals without understanding the impact of the drug <em>and</em> the environment overlooks the holistic nature of the psychedelic experience. For example, ketamine trials <a href="https://bigthink.com/surprising-science/ketamine-depression" target="_self">were rushed</a> and could potentially backfire; we can't afford to make that mistake again. </p><p>Still, understanding the pathways LSD utilizes is an important step forward. As Roth says, "Our ultimate goal is to see if we can discover medications which are effective, like psilocybin, for depression but do not have the intense psychedelic actions." In a world where more people are growing anxious and depressed by the day, every intervention should be explored.</p><p> --</p><p><em>Stay in touch with Derek on <a href="http://www.twitter.com/derekberes" target="_blank">Twitter</a>, <a href="https://www.facebook.com/DerekBeresdotcom" target="_blank" rel="noopener noreferrer">Facebook</a> and <a href="https://derekberes.substack.com/" target="_blank" rel="noopener noreferrer">Substack</a>. His next book is</em> "<em>Hero's Dose: The Case For Psychedelics in Ritual and Therapy."</em></p>
A team of researchers have discovered the brain rhythmic activity that can split us from reality.
- Researchers have identified the key rhythmic brain activity that triggers a bizarre experience called dissociation in which people can feel detached from their identity and environment.
- This phenomena is experienced by about 2 percent to 10 percent of the population. Nearly 3 out of 4 individuals who have experienced a traumatic event will slip into a dissociative state either during the event or sometime after.
- The findings implicate a specific protein in a certain set of cells as key to the feeling of dissociation, and it could lead to better-targeted therapies for conditions in which dissociation can occur.
What is dissociation?<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="bd2f1f29418bd4805bf1282001dca814"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/XF2zeOdE5GY?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>Dissociation is an experience commonly described as a feeling of sudden detachment from the individual's identity and environment, almost like an out-of-body experience. This mysterious phenomena is experienced by about 2 percent to 10 percent of the population.</p><p>"This state often manifests as the perception of being on the outside looking in at the cockpit of the plane that's your body or mind — and what you're seeing you just don't consider to be yourself," explained senior author Karl Deisseroth, MD, PhD, <a href="https://med.stanford.edu/news/all-news/2020/09/researchers-pinpoint-brain-circuitry-underlying-dissociation.html" target="_blank" rel="noopener noreferrer">in a Stanford Medicine news release</a>. Deisseroth is a professor of bioengineering and of psychiatry and behavioral sciences, as well as a Howard Hughes Medical Institute investigator.</p><p>Nearly three-quarters of individuals who have experienced a traumatic event will slip into a dissociative state either during the event or in the hours or even weeks that follow, according to Deisseroth. Most of the time, the dissociative experiences end on their own within a few weeks of the trauma. But the eerie experience can become chronic, such as in cases of post-traumatic stress disorder, and extremely disruptive in daily life. The state of dissociation can also occur in epilepsy and be invoked by certain drugs. </p><p>Until now, no one has known what exactly is going on inside the brain triggering and sustaining the feeling of dissociation — and so it has been a challenge to figure out how to stop it and develop effective treatments. </p>
New Research: The Molecular Underpinnings of Dissociation<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNDQyNjk3My9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYwNTQ3MTI1NX0._nJoxm1eDcTsHsy1Y27JxNl2uR5hlbEYDWYoQlO0EAU/img.jpg?width=1245&coordinates=0%2C121%2C0%2C121&height=700" id="26e86" class="rm-shortcode" data-rm-shortcode-id="1094af23e35a498a8a6b691f1d0cbfaf" data-rm-shortcode-name="rebelmouse-image" alt="neurons" />
Neurons from a mouse spinal cord
Credit: NICHD on Flickr<p>Last week, in a study published in <a href="https://www.nature.com/articles/s41586-020-2731-9" target="_blank">Nature</a><a href="https://www.nature.com/articles/s41586-020-2731-9">,</a> Deisseroth and his colleagues at Stanford University uncovered a localized brain rhythm and molecule that underlies this state.</p><p>"This study has identified brain circuitry that plays a role in a well-defined subjective experience," said Deisseroth. "Beyond its potential medical implications, it gets at the question, 'What is the self?' That's a big one in law and literature, and important even for our own introspections."</p><p>The authors' findings implicate a specific protein existing in a particular set of cells as key to the feeling of dissociation. </p><p>The research team first used a technique called widefield calcium imaging to record brain-wide neuronal activity in lab mice. They observed and analyzed changes in those brain rhythms after the animals had been administered a range of drugs that are known to cause dissociative states: ketamine, phencyclidine (PCP), and dizocilpine (MK801). At a certain dosage of ketamine, the mice behaved in a way that suggested that they were likely experiencing dissociation. For example, when the animals were placed on an uncomfortably warm surface, they reacted to it by flicking their paws. However, they signaled that they didn't care enough about the unpleasantness to do what they would typically do in such a situation, which is to lick their paws to cool them off. This suggested a dissociation from the surrounding environment.</p><p>The drug produced oscillations in neuronal activity in a region of the mices' brain called the retrosplenial cortex, an area essential for various cognitive functions such as navigation and episodic memory (a unique memory of a specific event). The oscillations occurred at about 1-3 hertz (three cycles per second). The authors then examined the active cells in more detail by using two-photon imaging for higher resolution. This revealed that the oscillations were occurring only in layer 5 of the retrosplenial cortex. Next, the researchers recorded neuronal activity across other regions of the brain. </p><p>"Normally, other parts of the cortex and subcortex are functionally connected to neuronal activity in the retrosplenial cortex," Ken Solt and Oluwaseun Akeju wrote in <a href="https://www.nature.com/articles/d41586-020-02505-z#ref-CR1" target="_blank">Nature</a>. "However, ketamine caused a disconnect, such that many of these brain regions no longer communicated with the retrosplenial cortex."</p><p>The scientists then used optogenetics, a method of manipulating living tissue with light to control neural function, to stimulate neurons in the mice's retrosplenial cortex. When the scientists did this at a 2-hertz rhythm, they were able to cause dissociative behavior in the animals analogous to the behavior caused by ketamine without using drugs. The experiments conducted by the team displayed how a particular type of protein, an ion channel, was essential to the generation of the hertz signal that caused the dissociative behavior in mice. Scientists are hopeful that this protein could be a potential treatment target in the future. </p>