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Considering the Possible Side Effects of Antioxidants: A Case-by-Case Approach

side effects of antioxidants

As people become more health-conscious and increasingly seek natural alternatives to pharmaceutical drugs, patients with wide variety of medical conditions are expressing interest in the benefits of antioxidant supplementation. There is good reason for this; in the body, antioxidant molecules scavenge the free radicals that are produced by oxidative processes, which otherwise have the potential to cause significant cell and tissue damage. Indeed, a growing body of research indicates that in food and in nutritional supplements, antioxidant-containing compounds may aid in the prevention and treatment of a broad range of physical and mental health conditions, from cardiovascular disease to autism spectrum disorder (ASD). For many patients looking to manage conditions like these, antioxidants pose an appealing alternative to traditional pharmacotherapy, given that they are often derived from all-natural sources.

The appeal of antioxidants also hinges on the notion that they are less likely to have side effects than standard pharmaceutical treatments. However, this idea has been called into question over the years and many patients have concerns about the safety of antioxidant use. Upon consideration of the reported side effects of dietary supplementation, there is no clear connection between a compound’s antioxidants and its potential side effects. In fact, most side effects are relatively mild, and they have been reported in only a minority of patients. Therefore, it’s best to approach the use of antioxidant-containing compounds for health purposes on a case-by-case basis. By examining the evidence more closely, you can determine whether antioxidant supplementation is right for you.

Possible Side Effects of Beta-Carotene: Early Concerns About Antioxidant Side Effects

One of the first cases in which the safety of antioxidants was called into question was that of beta-carotene, a carotenoid found in many fruits and vegetables. In the late 1990’s and early 2000’s, there were several clinical studies in which higher mortality rates were observed in patients who were taking beta-carotene supplements. While these studies naturally raised concerns in the research community, follow-up studies were unable to confirm a direct connection between beta-carotene and disease or mortality risk. As early as 1999, scientists pointed out that the concerns about the side effects of antioxidants like carotenoids were limited to highly specific clinical circumstances. Indeed, according to a review in the Journal of the American College of Nutrition, the antioxidant activities of carotenoids “promote health when taken at dietary levels,” and adverse health effects are only observed when the compounds are “taken in a high dose by subjects who have smoked or who have been exposed to asbestos.”

In recent years, more comprehensive studies on beta-carotene have also failed to demonstrate an association between the antioxidant-containing compound and potential long-term side effects. In 2013, the data from a meta-analysis of six randomized controlled trials (which included over 40,500 patients) indicated that the link between beta-carotene and cancer risk was tenuous at best, even in high-risk populations; the authors of the study found that the incidence of cancer was not significantly higher among healthy patients who took beta-carotene supplements, and their risk was only “marginally increased” among cancer patients.

This lack of long-term side effects of beta-carotene was verified in a broader 2016 meta-analysis. In their review, the researchers probed seven studies for evidence of a link between beta-carotene and all-cause mortality—not just death from cancer. Not only was beta-carotene not associated with a higher risk of mortality, but their data indicated that supplementation with beta-carotene actually led to a significantly lower risk of all-cause mortality, directly contradicting what had been found in the studies in earlier decades. As more evidence has accumulated, it now appears that the potential long-term side effects of beta-carotene are outweighed by its beneficial antioxidant activities and other possible health benefits.

Possible Side Effects of Other Phytochemicals with Antioxidant Activity

Beta-carotene is, of course, far from the only compound with significant antioxidant activity. In recent years, researchers have been exploring a wide range of all-natural, plant-based phytochemicals with antioxidant effects. Most of the human and animal studies on the efficacy of these compounds for various health issues have included evaluations of potential side effects. On the whole, the side effects of antioxidants tend to be minimal or nonexistent. Consider the findings for a few of the antioxidant-containing compounds that have recently shown particular promise for various physical and mental health conditions:

Curcumin

Within the clinical and research communities, curcumin has a well-established safety record. Both the Joint United Nations and World Health Organization Expert Committee on Food Additives (JECFA) and the European Food Safety Authority (EFSA) have established an allowable daily intake of curcumin at 0-3 mg/kg of body weight for patients. While the patients in some studies have reported minor side effects—including nausea, diarrhea, headache, and rash—these were most often observed when patients were taking an unusually high dosage of 500 to 12,000mg per day. Considering that curcumin supplements are now provided in highly bioavailable forms, patients usually do not need to take such high doses to see clinical results.

Resveratrol

Like curcumin, resveratrol is generally considered to be safe and well-tolerated by almost all patients. In a 2017 review in the journal Oxidative Medicine and Cellular Longevity, researchers examined clinical studies in which resveratrol supplements were taken in doses ranging from 20mg per day to 2g per day, and they found that almost all patients reported no side effects. Only when healthy patients were taking 2mg to 5mg per day did side effects become more frequent, and they were still limited to mild gastrointestinal complaints: flatulence, nausea, stomach pain, and/or diarrhea. Similarly, studies in animal models have reported no adverse short-term or long-term side effects of resveratrol supplementation.

Quercetin

A 2018 review in the journal Molecular Nutrition and Food Research examined the safety profile of quercetin, another phytochemical with beneficial antioxidant activity. According to the researchers, in human research studies, negative side effects “have rarely been reported, and any such effects were mild in nature.” Indeed, since the late 1990’s and early 2000’s, studies have consistently shown that quercetin has “very small side effects,” even at dosages as high as 4g per day. Although the authors did report on animal studies suggesting possible interactions between quercetin and common pharmaceutical drugs, this issue must be considered when trying any nutritional supplement, not just an antioxidant.

Exploring the Safety of Glutathione

Another antioxidant-containing compound that has recently risen to prominence as a possible alternative to pharmaceutical treatments for various health conditions is glutathione (GSH). As the most abundant endogenous antioxidant in the body, its activity is considered essential to a wide range of cellular processes. In a recent randomized controlled trial, research showed, for the first time, that daily supplementation with glutathione can significantly increase the stores of GSH within the body, which otherwise decline with age. Moreover, no serious side effects were reported by participants in the study, which further adds to its promise as a nutritional supplement.

This result mirrors earlier findings. In a 2011 clinical study involving GSH supplementation, only 8 of the 40 participants reported adverse effects: 5 noted increased flatulence and loose stools, 2 said they experienced flushing, and 1 said they had gained weight. Therefore, in regards to safety, the researchers concluded that “it is not an apparent barrier to continued clinical trials” on GSH supplementation. This notion was further verified in a 2015 study comparing oral and sublingual glutathione supplementation. Although the study was relatively small in scale—only 20 participants-—no adverse events were reported by any participant, regardless of the GSH supplementation method. Considered in the context of the other research on the topic, these findings suggest that it is unlikely for patients to experience adverse symptoms from taking GSH. Even when they do, the side effects of this antioxidant-containing compound are likely to be far more mild than those often reported for the most common pharmaceutical drugs on the market.

Bringing Together the Evidence on the Side Effects of Antioxidants

Ultimately, when considering the existing body of scholarly literature, it appears unwise to draw a broad conclusion about the side effects of antioxidants, because they vary so widely. Based on the results of studies on beta-carotene, common phytochemicals, and glutathione, there are a few major factors that affect the potential for an antioxidant-containing compound to produce side effects: the dosage, the patient’s unique physiology, and the nature of the compound itself.  Because there are no clear connections between the side effects observed for different antioxidants, it does not seem like the antioxidant activity of these compounds is directly responsible for any adverse effects.

That’s good news for patients and practitioners, as it leaves lots of room for experimentation. For instance, if a patient experiences mild gastrointestinal discomfort when they increase their intake of a particular antioxidant (either through nutritional supplementation or dietary changes), they may still be able to reap the health benefits of antioxidant intake by trying a different dosage or a different antioxidant compound that has been shown to play a similar physiological role. Further research into the efficacy of these compounds may also shed more light on the reasons some patients experience adverse effects and others do not, and it may even be possible for researchers to develop new delivery methods for nutritional supplements that reduce side effects in the future. For now, patients and practitioners can take relative comfort in the knowledge that most antioxidants are generally considered safe and pose a low risk of side effects, especially compared to the pharmaceutical drugs that might otherwise be used to prevent and treat important health concerns.

Foundational Medicine Review offers analysis and insight for patients, clinicians, and researchers on all-natural prevention and treatment options like antioxidant supplementation. To stay up-to-date with the latest and most innovative health research, join our mailing list today.

Works Cited

Allen J, Bradley RD. 2011. Effects of glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. Journal of Alternative and Complementary Medicine. 17(9):827-33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162377/

Andres S, Pevny S, Ziegenhagen R, Bakhiya N, Schaifer B, et al. 2018. Safety aspects of the use of quercetin as a dietary supplement. Molecular Nutrition & Food Research. 62(1). https://www.ncbi.nlm.nih.gov/pubmed/29127724

Espinoza JL, Trung LQ, Inaoka PT, Yamada K, An DT, Mizuno S, et al. 2017. The repeated administration of resveratrol has measurable effects on circulating T-cell subsets in humans. Oxidative Medicine and Cellular Longevity. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435979/

Hewlings SJ, Kalman DS. 2017. Curcumin: A review of its effects on human health. Foods. 6(10):92. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664031/

Jeon YJ, Myung SK, Lee EH, Kim Y, Chang YJ, et al. 2011. Effects of beta-carotene supplements on cancer prevention: Meta-analysis of randomized controlled trials. Nutrition and Cancer. 63(8):1196-1207. https://www.ncbi.nlm.nih.gov/pubmed/21981610

Ji JJ, Huang SS, Zhang HL, Diao YP, Li K. 2013. Quercetin: A potential natural drug for adjuvant treatment of rheumatoid arthritis. African Journal of Traditional, Complementary and Alternative Medicines. 10(3):418-21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777580/

Markus MA, Morris BJ. 2008. Resveratrol in prevention and treatment of common clinical conditions of aging. Clinical Interventions in Aging. 3(2):331-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546476/

Novo R, Azevedo PS, Minicucci MF, Zornoff LAM, Paiva SAR. 2013. Effect of beta-carotene on oxidative stress and expression of cardiac connexin 43. Arquivos Brasileiros de Cardiologia. 101(3): 233-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032303/

Paiva SA, Russell RM. 1999. Beta-carotene and other carotenoids as antioxidants. Journal of the American College of Nutrition. 18(5):426-33. https://www.ncbi.nlm.nih.gov/pubmed/10511324

Pham-Huy LA, He H, Pham-Huy C. 2008. Free radicals, antioxidants in disease and health. International Journal of Biomedical Science. 4(2):89-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614697/

Richie JP, Nichenametla S, Neidwig W, Calcagnotto A, Haley JS, Schell TD, et al. Randomized control trial of oral glutathione supplementation on body stores of glutathione. European Journal of Nutrition. 54(2):251-63. https://www.ncbi.nlm.nih.gov/pubmed/24791752

Schmitt B, Vicenzi M, Garrel C, Denis FM. 2015. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study. Redox Biology, 6:198-205. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536296/

Zhao LG, Zhang QL, Zheng JL, Li HL, Zhang W, et al. 2016. Dietary, circulating beta-carotene and risk of all-cause mortality: A meta-analysis from prospective studies. Scientific Reports, 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886629/

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