I am going to play a Devil’s advocate and make a case against supplementation.
What I gathered from reading the posts here that a majority of forum member focus on potential benefit of a given supplement. I am more concerned of potential harm that a given supplement can cause. You certainly don’t want to take something for years just to find out later that it caused more harm that good. This certainly seems to be the case with Niacin which unfortunately was used by medical doctors in high doses to lower LDL !!!
Every single supplement has risks, every single one. Even our beloved fish oil can cause unacceptable levels of hypocoagulability, I have seen many patients with easy bruising that at risk for major bleeds with trauma as a result of fish oil supplementation.
Here are other examples potential harm associated with supplements:
Vitamin D, Hypercalciuria and Kidney Stones
Emmanuel Letavernier 1 2 3, Michel Daudon 4 5 6
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Free PMC article
Abstract
The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption-as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements.
Safety Aspects of the Use of Quercetin as a Dietary Supplement
Susanne Andres 1, Sophie Pevny 1, Rainer Ziegenhagen 2, Nadiya Bakhiya 2, Bernd Schäfer 2, Karen Ildico Hirsch-Ernst 2, Alfonso Lampen 2
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Abstract
The flavonoid quercetin is frequently found in low amounts as a secondary plant metabolite in fruits and vegetables. Isolated quercetin is also marketed as a dietary supplement, mostly as the free quercetin aglycone, and frequently in daily doses of up to 1000 mg d-1 exceeding usual dietary intake levels. The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements. Among the numerous published human intervention studies, adverse effects following supplemental quercetin intake have been rarely reported and any such effects were mild in nature. Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (≥1000 mg) are currently not available. Based on animal studies involving oral quercetin application some possible critical safety aspects could be identified such as the potential of quercetin to enhance nephrotoxic effects in the predamaged kidney or to promote tumor development especially in estrogen-dependent cancer. Furthermore, animal and human studies with single time or short-term supplemental quercetin application revealed interactions between quercetin and certain drugs leading to altered drug bioavailability. Based on these results, some potential risk groups are discussed in the present review.
Keywords: adverse effects; drug interaction; nephrotoxicity; quercetin; tumor promotion.
4. Negative Effects of Resveratrol
Resveratrol is widely known for its renowned beneficial biological effects, namely involving its chemopreventive and antioxidant properties. However, some studies have documented that it may behave as a pro-oxidizing agent [112]; thus, paradoxically, it may also have implication in pathology of several diseases.
Resveratrol antioxidant potential has been attributed to its ROS-scavenging capacity [112,113] and to an up regulation capacity on cells antioxidant defense [114]. Studies have reported that resveratrol could act as a signaling molecule within tissues and cells in modulating genes and proteins expression through redox-sensitive intracellular pathways activation. Thus, cell tolerance against oxidative environment could be attributed to gene expression changes and to a raise in antioxidant defense systems action and synthesis, which eventually results in cell survival and adaptation [115,116,117]. Moreover, depending on enzymatic reactions conditions, resveratrol can be (auto-)oxidized to generate semiquinones and relatively stable 4′-phenoxyl radical, finally leading to ROS production [118,119]. Such polyphenols’ oxidative reactions are influenced by pH and presence of hydroxyl anions or organic bases [120,121].
A study carried out by Martins et al. revealed that resveratrol can modulate different pathways at a time, which can result in distinct and even opposite biological effects, depending on its concentration or treatment time defined. The authors documented that, although a dose-dependent resveratrol pro-oxidative effect leads to cells oxidative stress over lesser time exposure, at same dose but with an increase in exposure time, less expressive cytotoxicity was found. This suggest that surviving cells seemed to be more resistant to resveratrol-induced damages, being its effects attenuated over treatment time [114]. Additionally, low resveratrol doses (0.1–1.0 μg/mL) has been documented to enhance cell proliferation, whereas higher doses (10.0–100.0 μg/mL) induces apoptosis (Figure 2) and decreases mitotic activity on human tumors and endothelial cells [122]. Recently, dual resveratrol pattern effects on HT-29 colon cancer cells death and proliferation were observed, where at low concentrations (1 and 10 μmol/L), resveratrol increased cells number, while at higher doses (50 or 100 μmol/L) resveratrol reduced cells number and increased apoptotic or necrotic cells percentage [123].
4. Adverse Effects of Antioxidants
The most popular “antioxidants” forms include vitamins, such as vitamin A (retinol, retinoic acid), vitamin C (L-ascorbic acid, ascorbic acid, ascorbate), vitamin E (α-tocopherol), β-carotene, minerals, like Se, and naturally-occurring polyphenols, each one has a different effect on body cells. Vitamins and β-carotene have conjugated double bonds and key functional groups responsible for their antioxidant role and quality as pigments in several foods, like fruits and vegetables. Below, we briefly summarize the adverse effects of these popular antioxidants, often consumed as supplements at much higher doses than those found in foodstuffs. While their adverse effects are known in the medical community, they are not well-known among the population, who believe that natural products cannot be toxic. Czernichow investigated the effect of antioxidant supplementation for 7.5 years on metabolic syndrome (MetS) incidence and even the epidemiologic association between baseline serum antioxidant concentrations and MetS prospective risk [16]. No beneficial effects of antioxidant supplementation were observed in a generally well-nourished population. Baseline serum antioxidant concentrations of β-carotene and vitamin C, however, were negatively associated with MetS risk. Baseline serum zinc concentrations were positively associated with the risk of developing MetS [16]. Park [17] found that there was no association between dietary intakes of vitamins A, C, and E and colon cancer risk in this pooled analysis of thirteen prospective cohort studies. However, total vitamins A, C, and E intakes were each one inversely associated with colon cancer risk. Multivitamin use, particularly in combination with a single vitamin A, C and/or E supplements use, was inversely associated with colon cancer risk. A low dietary intake of antioxidant vitamins and minerals raises the incidence of cardiovascular diseases and cancer [17]. After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. In fact, supplementation may be effective in men only because of their low basal status of certain antioxidants, especially of β-carotene [18].
Researchers reported the existence of increased teratogenicity risk or birth defects among babies born from women who took more than 10,000 IU vitamin A per day in the form of supplements [19]. Indeed, excessive dietary vitamin A intake has been associated with birth defects in humans in several studies reported in past years [20,21,22]. A controlled clinical trial found that people who took 25,000 IU of vitamin A per day for a median of 3.8 years had 11% increase in triglycerides, 3% increase in total cholesterol and 1% decrease in high-density lipoprotein (HDL) cholesterol, unlike those who did not take vitamin A [23]. In a recent case report, a 4-year-old boy presented several bone pains due to vitamin A toxicity (600,000 IU every day for more than 3 months) [2]. In fact, it has been reported that excessive vitamin A intake can accelerate bone loss and risk of hip fracture, possibly due to vitamin A-induced osteoclasts stimulation, besides it inhibits new bone formation, increasing osteoporosis risk [24].
On the other hand, vitamin C can be metabolized to oxalate and might increase kidney oxalate excretion. Several studies suggest that vitamin C supplements may increase urinary oxalate concentrations, doubling the risk of calcium oxalate kidney stones [25,26,27]. A study defined that high vitamin C intake from supplements is associated with a rise in cardiovascular disease mortality in postmenopausal women with diabetes but this has never been confirmed [28]. Theoretically, vitamin C may cause too much iron absorption but this is likely to be significant only in persons who have high iron stores or in patients with iron overload, such as hereditary hemochromatosis, where an increasing iron toxicity risk may exist [29]. Pavlotou [30] evaluated free oxygen radicals (FORT) and free oxygen radicals defense (FORD) levels in patients with newly diagnosed type 2 DM patients. The authors found that FORT levels were increased in diabetic patients compared to controls; however, FORD levels were lower in diabetic patients compared to controls.
A study reported that dietary vitamin E supplementation significantly increases prostate cancer risk among healthy men [31]. A meta-analysis renders more evidence of vitamin E adverse effects on stroke subtypes. Indeed, the study defined a 22% increased hemorrhagic stroke risk and a 10% decreased ischemic stroke risk with vitamin E supplementation, although the absolute effects are minor [32]. Still, a study underlined that 22–30 mg/day of vitamin E in human pregnancy may be associated with birth weight decrease [33].
Scientists have reported that β-carotene supplementation (and not the intake of vegetables rich in β-carotene) has actually increased the risk of death from lung cancer or heart disease in smokers, rather than reducing cancer incidence [34,35,36,37]. In fact, we believe that other antioxidant side effects may not be reported and other ones will be discovered in the future. Nonetheless, the studies performed so far have severely impaired the reputation of antioxidants in general. However, in an ideal world, we could go back to this study, through examining tissues pre- and post-treatment, and determine whether interventions had a signaling effect in the tumors. Based on previous studies of ebselen, an organoselenium compound with broad antioxidant properties [38], it is likely that ROS reduction in tumors, for instance in Burkitts lymphoma, results in MAP kinase signaling activation and an increased tumor growth rate [15]. In addition, more rapidly growing tumors may be more susceptible to subsequent chemotherapy and radiation. Thus, the current state of affairs suggests that the most common antioxidants are, at best, ineffective and potentially harmful.
Personally I am with Dr. Attia on that instead wasting time and money on supplements, we should rather focus exercise in forms strength, cardio and stability as best healthspan boosting behavior. Second attention should be to carefully cultivated diet which can provide many of the supplements in lower dose, more complete isoforms, more bioavailable. Micronutrients in contained in real foods are probably much safer given that we co-evolved with them over the past 100,000 years and did quite well as a species. Finally sleep, stress reduction, social interactions and cognitive stimulation (playing a musical instrument, learning a language) are the final piece of the puzzle.
Personally I did experiment with a number of supplements and saw no notable difference by any measure, except for Creatinine and Transparent Labs Stim Free Pre-Workout helping get through cardio interval and weightlifting sessions… very subjective though.
To enhance the benefit to risk ratio I am reducing my supplementation to intermittent and/or as needed use.
For example -
Vit D with URI’s and when my sun exposure is low
Curcumin, Magnesium and Fish Oil for musculoskeletal injuries
Creatinine and pre-work out formula containing TMG, Taurine among other things prior to exercise routines…
and so on.
OK, daily hyaluronic acid supposedly for joints, wound healing (mountain biking and trail running), my GERD and of course keep the skin from sagging - all of those seemed to improved so why not.
