Supplement safety: dangers of hitting the bottle

NB: 0.4 ng/ml (red line) represents the upper limit of the reference range in males. Female subjects are indicated with red circles. The x axis represents the subject identification number and the y axis represents the values of plasma progesterone. The plant-derived supplements consumed by these users included beta-Sitosterol, Pygeum extract, Guarana extract, Cordyceps extract, Rhaponticum Carthamoides, Muira Puama, Gotu Kola extracts and high doses of soy derived proteins.

Figure 2: Specific values of plasma estrogens in 15 users of plant-derived supplements

NB: 35 pg/ml represents the upper limit of the reference range in males (green lines), 650 pg/ml represents the upper limit of the reference range in females (red line). The x axis represents the subject identification number and the y axis represents the values of plasma estrogens. In the users (left) there were 13 males and 2 females (red circles).

The researchers concluded that the habitual consumption of plant-derived nutritional supplements is frequently associated with significant hormonal alterations both in males and females. More worryingly, they also concluded that while these biochemical alterations were not associated with signs or symptoms of organ toxicity at the time of the study, it couldn’t be ruled out that in the mid-long term, these subjects wouldn’t suffer health problems arising as a consequence of chronic exposure to heavily altered hormonal levels.

Does familiarity breed contempt?

While it’s true that much of the recent concern over sports supplement safety has focused on plant-derived (herbal) supplements that have been poorly researched for safety and efficacy, this doesn’t mean that other more commonly used and familiar supplements can always be used with impunity. A quick scan of the medical literature reveals that there are a number of cases of toxicity associated with health and sports supplements that might not be described as exotic.

MHA: A case study

MHA (full name methylhexaneamine) is a stimulant originally derived from the geranium plant but is now mostly synthetically produced. It was first developed as a nasal decongestant in the 1940s but has been found in dietary or nutritional supplements under many different names other than MHA. These include: Methylhexaneamine; Methylhexaneamine; DMAA (dimethylamylamine); Geranamine; Forthane; Forthan; Floradrene; 2-hexanamine, 4-methyl-; 2-hexanamine, 4-methyl- (9CI); 4-methyl-2-hexanamine; 1,3-dimethylamylamine; 4-Methylhexan-2-amine; 1,3-dimethylpentylamine; 2-amino-4-methylhexane; Pentylamine, 1, 3-dimethyl-; pelargonium graveolens; pelargonium extract; geranium, geranium oil or geranium root extract [Drug Test Anal. 2023 Aug;15(8):803-839].

MHA has been marketed as a pre work-out supplement with thermogenic or stimulant properties and may have mild stimulant effects but there is no publicly available data on its specific mechanism of action, absorption, pharmokinectics, metabolism or excretion. Anecdotal evidence suggests the effects of MHA last between 1-3 hours, and that it increases focus, heart rate and productivity whilst other users have reported increased anxiety, nervousness, breathlessness and sweating.

Placed on the World Anti-Doping Agency (WADA) ‘Prohibited List’ back in 2010, MHA is classed as a ‘specified stimulant’ prohibited in-competition only. In short, this means that actively competing sportsmen and women taking MHA (either deliberately or inadvertently) risk failing a doping test, and all the consequences flowing from that. MHA has caused a number of positive cases in rugby (and other sports) recently for both amateur and professional players. Alarmingly, MHA is also added as an ingredient to a number of other sports supplement products, some of which do not declare this on the labeling. Some products which have openly contained, or have been identified in certain countries to contain, MHA or its variants include: Hemo Rage, Jack3d, OxyElite Pro, 1.M.R., Mesomorph, Rocked, Crack, USN Anabolic Nitro, Ergolean Amp 2, DynaPep, Core Zap and C4 Extreme, Nutrimax Burner, NitroX, IBE XForce, Fusion Geranamine, ClearShot and Musclespeed.

For example, a 2007 paper looked at the association between consumption of Herbalife nutritional supplements (not normally regarded as exotic) and acute liver toxicity⁽⁷⁾. Following the identification of four cases of acute hepatitis associated with Herbalife intake in 2004, the Israeli Ministry of Health began an investigation in all Israeli hospitals. As a result, twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. Eleven of the patients were females (average age 49) and the average duration of Herbalife product consumption recorded in these patients was just under a year. The researchers noted that the hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. However, three patients resumed their consumption of Herbalife products following normalization of liver enzymes, which then resulted in a second bout of hepatitis!

Another case in point is vitamin D. Vitamin D toxicity as a result of supplementation has only been rarely reported in the past. However, in recent years, it has been reported much more frequently⁽⁸⁾. This rise may be attributable to an increase in vitamin D supplement use among athletes and the general population alike, because of a growing realisation of the importance of optimum vitamin D intake for long-term health.

Although the normal concentrations of blood vitamin D blood span a wide range, excessive and prolonged intake of vitamin D supplements can result on overload, leading to symptoms such as vomiting, loss of appetite, weight loss, thirst, excessive water intake and constipation. Current guidelines suggest that administration of vitamin D is safe at 1000 IU/day for ages 0-1, 2500 IU/day for ages 1-3, 3000 IU/day for ages 3-8, and 4000 IU/day for age 9 and above, adults and pregnant women⁽⁹⁾. However, vitamin D supplements providing in excess of 5000IU per capsule are now fairly commonplace and it’s easy to understand how prolonged over-enthusiastic supplementation could lead to toxicity, especially as some individuals seem to be more vulnerable to vitamin D toxicity⁽¹⁰⁾. In addition, the scientific literature reports at least one instance where a subject presented with life-threatening complications due to the intake of vitamin D-concentrated supplements, which turned out to contain 100-1,000 times the dose stated on the label of the dietary supplements^(11,12).

Another nutrient that has caused problems in the past is selenium. Selenium is an essential trace element, but can be toxic in excess. In May 2008, US FDA reported 201 individuals with adverse reactions to liquid nutritional supplements containing excess selenium resulting in the largest epidemic of selenium toxicity in the history of the United States⁽¹³⁾. A retrospective observational case series was performed on nine patients between March 2008 and May 2008 with symptoms of selenium toxicity after consuming a nutritional supplement; testing on this supplement subsequently revealed almost 200 times the declared amount of selenium! However, even without errors in the formulation of supplements, optimum selenium supplementation can be tricky. Current recommendations are that adults should consume at least 55mcgs of selenium per day⁽¹⁴⁾. However, many academics believe that optimum intakes may be in the range of 100-200mcg/day yet the upper tolerable limit is set at 400mcg per day – ie there exists a relatively small margin for error.

Yohimbe: A classic case of herbal hazard

Yohimbine is the principal alkaloid of the bark of the West African evergreen Pausinystalia yohimbe. There are 31 other yohimbane alkaloids found in Yohimbe. In Africa, Yohimbe has traditionally been used as an aphrodisiac, while in the West, Yohimbe has been used as both an over-the-counter dietary supplement in herbal extract form and prescription medicine in pure form for the treatment of sexual dysfunction. However, Yohimbe has also been very popular as an ingredient in ‘performance’ and ‘fat loss’ supplements.

The problem with Yohimbe is that its consumption at higher doses can produce a number of side effects. These commonly include rapid heart rate, high blood pressure, overstimulation, insomnia and/or sleeplessness. Rarer side effects include panic attacks, hallucinations, headaches, dizziness, and skin flushing and more seriously, seizures and renal failure. Yohimbe in combination with drugs that inhibit the reuptake of norepinephrine, such as dextromethorphan, tramadol, some antidepressants, and central nervous system stimulants used to treat ADHD, can cause a ‘hypertensive crisis’. This is because such a combination leads to too much norepinephrine in the brain, which causes blood pressure to spike to dangerous levels; for this reason, Yohimbe should not be consumed by anyone with liver, kidney, heart disease, or a psychological disorder.

In a 2010 study, Californian researchers carried out a retrospective study into adverse drug events reported to the California Poisons Control Center (CPCS) associated with Yohimbe-containing products within a 7-year period (2000-2006)(15). A total of 238 cases were identified and the prevalence (per 10,000 total adult exposures) increased from 1.8 cases in 2000 to 8.0 cases in 2006. The majority (98.7%) of cases involved herbal Yohimbie products and the most common adverse reactions included: gastrointestinal distress (46%), tachycardia (43%), anxiety/agitation (33%), and hypertension (25%). The researchers concluded that there was a substantial increase in the prevalence of adverse reaction to Yohimbe herbal products and that these reactions were associated with significantly more serious outcomes than the average exposures reported to the CPCS.

Summary and advice

Sports supplementation is now a routine and accepted practice among many sportsmen and women at all levels of sport. The good news is that the most commonly used sports supplements such as carbohydrate energy drinks, hydration drinks, caffeine and carbohydrate-protein recovery drinks are both scientifically proven and safe. However, many athletes use a range of other supplement products, specifically those containing numerous biologically active substances derived from plant products. Far fewer of these are scientifically validated and many may have unexpected and/or undesirable side effects.

In particular, the evidence suggests that the use of herbal products may be particularly problematical for athletes’ health and well-being (not to mention the legality of some products). There’s even evidence that fairly routine supplements may pose problems if administered haphazardly, excessively or are dubiously sourced. Athletes should therefore be aware of these issues and approach the issue of supplementation cautiously and scientifically, not forgetting that top sports performance starts with optimum training and a top quality day-to-day diet!

In terms of practical recommendations therefore, here are some tips:

• Try to focus on the importance of diet for performance rather than sports supplements. Without the foundations of a nutritious diet, no amount of supplementation is going to improve your long-term performance.
• If you are a coach or personal trainer, consider running educational programmes for athletes under your wing so that they can understand which kinds of nutritional products are likely to be safe and effective and which are not.
• Keep a record of any products you use (and doses), and check the listed ingredients for potentially harmful ingredients;
• Familiarize yourself with the current WADA guidelines on prohibited substances to make sure that you or your athletes don’t inadvertently fall foul of doping regulations.
• As a rule of thumb, products supplied by larger, well-established companies with manufacturing procedures accredited to recognized standards are less likely to suffer problems such as cross contamination or incorrect formulations. Check ‘Informed Sport’ for more information on this topic: www.informedsport.com)
• Beware of using herbal products of any description, especially if you are a competitive athlete needing to comply with anti-doping regulations. These are far more likely to be problematical. If you do use them, only purchase from a highly accredited company such as Solgar.

References

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4. J Int Soc Sports Nutr 2012, 9:28

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6. Ann Intern Med 2002; 136: 590-595

7. J Hepatol. 2007 Oct;47(4):514-20

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10. J Steroid Biochem Mol Biol 2010; 121: 71-77

11. Clin Toxicol (Phila). 2010 Jun;48(5):460-2

12. Pediatrics 2008; 122: 398-417

13. Clin Toxicol (Phila). 2012 Jan;50(1):57-64. Epub 2011 Dec 14.

14. US Office for Dietary Supplements2012; ods.od.nih.gov/factsheets/Selenium-HealthProfessional

15. Ann Pharmacother. 2010 Jun;44(6):1022-9. Epub 2010 May 4.