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Nutritional supplement series Br J Sports Med 2010;44:609–611. doi:10.1136/bjsm.2010.074625 609 1 Senior Research Associate, University of Oxford, Oxford, UK 2 Head of Sports Nutrition, Australian Institute of Sport, Canberra, Australia 3 Performance Influencers Limited, London, UK 4 English Institute of Sport, London, UK 5 The Ohio State University, Columbus, Ohio, USA 6 Department of Exercise Science, Bloomsburg University, Bloomsburg, Pennsylvania, USA 7 Australian Institute of Sport, Canberra, Australia Correspondence to L M Castell, University of Oxford, Green Templeton College, Oxford OX2 6HG, UK; [email protected] LB, LC and SJ edited this series. Accepted 16 April 2010 A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 9 L M Castell, 1 L M Burke, 2 S J Stear, 3 J Pearce, 4 J R Borchers, 5 C C Kaeding, 5 E S Rawson, 6 G Shaw 7 INTRODUCTORY REMARKS Weight loss and muscle gain are physique goals pursued by many athletes, often with the hope that both will occur simultaneously! Part 9 of our series on dietary supplements includes sum- maries of three products which address these interests among other claimed benefits: choline bitartrate, chromium picolinate and cissus quan- drangularis (CQ). Choline bitartrate is hypoth- esised to increase lipolysis, while CQ is claimed to have anabolic properties. Chromium picolinate is unique among dietary supplements, having been successfully marketed as both a muscle building and a fat loss supplement. While choline and chro- mium are both consumed from a range of dietary sources, CQ is a specific plant. The term adequate intake (AI) is used for the fi rst time in this series, in the article on chromium picolinate. AI refers to the recommendations for dietary intake of a nutrient for which there is insufficient scientific evidence to establish requirements, since deficiency is rare. The observed intake is assumed to be greater than that required, and thus AI meets nutritional require- ments. Chondroitin and glucosamine supplements are covered together because of their shared mar- keting for the support of bone and cartilage. CHOLINE BITARTRATE PLUS ACETYLCHOLINE J Pearce Choline is widely distributed in food fats, espe- cially liver, egg yolk, peanuts, dairy products, human milk and phospholipids. 1 The body syn- thesises choline, and a deficiency due to dietary inadequacy is unlikely. Choline is a precursor for the neurotransmitter, acetylcholine (which gener- ates muscle contractions), and is a donor of methyl groups (lowering homocysteine levels, reducing heart disease risk). Lecithin, a natural source of choline, will be discussed under ‘L.’ Choline is promoted to athletes to improve physical endurance by increasing fat lipolysis and acetylcholine production to increase muscle con- tractions and delay fatigue. Choline supplements are thought to stimulate brain function (improv- ing memory, intelligence and mood state in rats). Cyclists taking 2.34 g of choline showed improved mood state but no improvement in performance. 2 Evidence does not support claims that choline has a role in reducing body adipose tissue, or that high doses elevate fat metabolism in humans. 1 Studies 3–6 reporting decreased plasma choline concentrations (9–40%) during prolonged exercise (>2 h) in elite and well-trained endurance athletes (marathon runners, cyclists, triathletes, military personnel) and possible links to reduced perfor- mance or early fatigue have fuelled interest in supplementation. Decreased choline levels and insufficient acetylcholine availability may con- tribute to fatigue; increasing exogenous choline may enhance acetylcholine availability for neu- romuscular transmission. Two well-designed studies, involving exhaustive exercise protocols in well-trained cyclists and soldiers, provided 2.4–8.4 g of choline citrate and bitratrate in bev- erages consumed prior to exercise. Although sup- plementation increased plasma choline, it failed to delay fatigue or show performance benefits in these studies and one other. 3–5 Free serum choline concentrations vary with die- tary choline intake, peaking within hours of inges- tion. Choline supplements, as capsules or powders, may cause gastrointestinal (GI) side effects includ- ing breakdown to trimethylamine, which leads to fishy body odours. While small supplemental doses are not currently considered harmful, 7 athletes with gout should avoid choline supplementation. 8 There is no clear evidence that decreased plasma choline is associated with acetylcholine depletion and fatigue. Despite studies showing elevated choline concentrations due to choline supplementation, there is no evidence that this translates into benefits in exercise performance or reductions in fatigue. CHONDROITIN/GLUCOSAMINE J R Borchers, C C Kaeding Glucosamine is a primary building block for pro- teoglycans. Glucosamine is available in an oral preparation with approximately 90% GI absorp- tion. 9 10 Oral administration results in absorption by several tissues including bone and articular cartilage. 9 10 Chondroitin is a large molecule that is absorbed from the GI tract but not as readily as glucosamine. 11 Theoretically, it enhances proteo- glycan synthesis and prevents cartilage degrada- tion, whether due to damage or disease. 11 In athletes with degenerative joint disease, non-steroidal anti-inflammatories (NSAIDs) are commonly overused, and this may lead to an increased risk of adverse events. There is there- fore interest in the use of glucosamine and chon- droitin as both treatment and disease-modifying agents for cartilage damage in athletes. Much of the interest for the disease or damage-modifying group.bmj.com on April 9, 2014 - Published by bjsm.bmj.com Downloaded from

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Nutritional supplement series

Br J Sports Med 2010;44:609–611. doi:10.1136/bjsm.2010.074625 609

1Senior Research Associate, University of Oxford, Oxford, UK 2Head of Sports Nutrition, Australian Institute of Sport, Canberra, Australia 3Performance Infl uencers Limited, London, UK

4English Institute of Sport, London, UK 5The Ohio State University, Columbus, Ohio, USA 6Department of Exercise Science, Bloomsburg University, Bloomsburg, Pennsylvania, USA 7Australian Institute of Sport, Canberra, Australia

Correspondence to L M Castell, University of Oxford, Green Templeton College, Oxford OX2 6HG, UK; [email protected]

LB, LC and SJ edited this series.

Accepted 16 April 2010

A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance Part 9L M Castell,1 L M Burke,2 S J Stear,3

J Pearce,4 J R Borchers,5 C C Kaeding,5 E S Rawson,6 G Shaw7

INTRODUCTORY REMARKSWeight loss and muscle gain are physique goals pursued by many athletes, often with the hope that both will occur simultaneously! Part 9 of our series on dietary supplements includes sum-maries of three products which address these interests among other claimed benefi ts: choline bitartrate, chromium picolinate and cissus quan-drangularis (CQ). Choline bitartrate is hypoth-esised to increase lipolysis, while CQ is claimed to have anabolic properties. Chromium picolinate is unique among dietary supplements, having been successfully marketed as both a muscle building and a fat loss supplement. While choline and chro-mium are both consumed from a range of dietary sources, CQ is a specifi c plant. The term adequate intake (AI) is used for the fi rst time in this series, in the article on chromium picolinate. AI refers to the recommendations for dietary intake of a nutrient for which there is insuffi cient scientifi c evidence to establish requirements, since defi ciency is rare. The observed intake is assumed to be greater than that required, and thus AI meets nutritional require-ments. Chondroitin and glucosamine supplements are covered together because of their shared mar-keting for the support of bone and cartilage.

CHOLINE BITARTRATE PLUS ACETYLCHOLINEJ PearceCholine is widely distributed in food fats, espe-cially liver, egg yolk, peanuts, dairy products, human milk and phospholipids.1 The body syn-thesises choline, and a defi ciency due to dietary inadequacy is unlikely. Choline is a precursor for the neurotransmitter, acetylcholine (which gener-ates muscle contractions), and is a donor of methyl groups (lowering homocysteine levels, reducing heart disease risk). Lecithin, a natural source of choline, will be discussed under ‘L.’

Choline is promoted to athletes to improve physical endurance by increasing fat lipolysis and acetylcholine production to increase muscle con-tractions and delay fatigue. Choline supplements are thought to stimulate brain function (improv-ing memory, intelligence and mood state in rats). Cyclists taking 2.34 g of choline showed improved mood state but no improvement in performance.2 Evidence does not support claims that choline has a role in reducing body adipose tissue, or that high doses elevate fat metabolism in humans.1

Studies3–6 reporting decreased plasma choline concentrations (9–40%) during prolonged exercise

(>2 h) in elite and well-trained endurance athletes (marathon runners, cyclists, triathletes, military personnel) and possible links to reduced perfor-mance or early fatigue have fuelled interest in supplementation. Decreased choline levels and insuffi cient acetylcholine availability may con-tribute to fatigue; increasing exogenous choline may enhance acetylcholine availability for neu-romuscular transmission. Two well-designed studies, involving exhaustive exercise protocols in well-trained cyclists and soldiers, provided 2.4–8.4 g of choline citrate and bitratrate in bev-erages consumed prior to exercise. Although sup-plementation increased plasma choline, it failed to delay fatigue or show performance benefi ts in these studies and one other.3–5

Free serum choline concentrations vary with die-tary choline intake, peaking within hours of inges-tion. Choline supplements, as capsules or powders, may cause gastrointestinal (GI) side effects includ-ing breakdown to trimethylamine, which leads to fi shy body odours. While small supplemental doses are not currently considered harmful,7 athletes with gout should avoid choline supplementation.8

There is no clear evidence that decreased plasma choline is associated with acetylcholine depletion and fatigue. Despite studies showing elevated choline concentrations due to choline supplementation, there is no evidence that this translates into benefi ts in exercise performance or reductions in fatigue.

CHONDROITIN/GLUCOSAMINEJ R Borchers, C C KaedingGlucosamine is a primary building block for pro-teoglycans. Glucosamine is available in an oral preparation with approximately 90% GI absorp-tion.9 10 Oral administration results in absorption by several tissues including bone and articular cartilage.9 10 Chondroitin is a large molecule that is absorbed from the GI tract but not as readily as glucosamine.11 Theoretically, it enhances proteo-glycan synthesis and prevents cartilage degrada-tion, whether due to damage or disease.11

In athletes with degenerative joint disease, non-steroidal anti-infl ammatories (NSAIDs) are commonly overused, and this may lead to an increased risk of adverse events. There is there-fore interest in the use of glucosamine and chon-droitin as both treatment and disease-modifying agents for cartilage damage in athletes. Much of the interest for the disease or damage-modifying

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Nutritional supplement series

Br J Sports Med 2010;44:609–611. doi:10.1136/bjsm.2010.074625610

aspects of glucosamine and chondroitin is derived from ani-mal studies. Studies on rabbits suggest that there may be a role for glucosamine use in injury to articular cartilage.12 13 Both glucosamine and chondroitin have been studied to evaluate their effect on response to joint stress in animal chodrocytes.14 Results suggest that cartilage subjected to various stresses (ie, enzyme-induced matrix depletion, heat stress, mechani-cal compression and cytokine stress) have an enhanced pro-tective metabolic response of the chondrocyte when treated with glucosamine and chondroitin. These studies have led to the marketing of glucosamine sulphate and chondroitin to athletes for use in the modifi cation of acute cartilage damage after an acute injury or cartilage damage due to repetitive load in athletics. This is based on the hypothesis that glucosamine sulfate and chondroitin may stimulate chondrocytes to repair damaged cartilage more effi ciently and completely. There are no current studies in athletes of any age for either supplement to suggest that these effects occur.

Pavelká et al looked at the delay of knee osteoarthritis (OA) progression over a 3-year period with 1500 mg/day of oral glucosamine sulphate.15 Many supplements contain lower amounts. Pavelká et al observed no signifi cant joint space nar-rowing after treatment compared with signifi cant narrowing in the placebo group. This supported similar results observed by Reginster et al.16 Using chondroitin sulphate in knee OA, Uebelhart et al found that similar joint space narrowing in the placebo group after 1 year was delayed by chondroitin treat-ment.17 Taken together, these studies demonstrate the poten-tial of both glucosamine and chondroitin to delay radiographic fi ndings of joint space narrowing in sedentary populations. This might be of interest to athletes with degenerative joint disease or damage regardless of age. Systematic studies of the use of these agents by athletic populations are needed before such treatment can be considered fully evidence-based.

There is confl icting evidence for the use of glucosamine and chondroitin as a symptomatic treatment of OA. There are stud-ies that suggest both benefi t and no benefi t for the symptom-atic use of both glucosamine and chondroitin in the treatment of knee OA. The recent large-scale Glucosamine/Chondroitin Arthritis Trial leaves doubt as to the effectiveness of glucosamine and chondroitin in the treatment of knee OA.18 There are data to support a combination of glucosamine and chondroitin as effective in those patients with moderate to severe knee pain. However, no benefi t was observed with individual use of these agents in this population with respect to knee pain. Neither the combination nor individual use showed any benefi t in those patients classifi ed with mild knee pain compared with placebo. A more recent, systematic, clinical review19 determined that there are inconsistent results regarding the effectiveness of glu-cosamine and chondroitin in improving pain and joint function in knee OA. Nevertheless, this more recent review concluded that many studies show evidence of pain relief in knee OA treatment. Both supplements have an excellent safety profi le. Therefore, if an athlete plans to use these products, the authors suggest that clinicians should discuss whether or not there is potential for benefi t in athletes with knee degenerative joint disease, as an alternative to chronic NSAID or analgesic use.

CHROMIUM PICOLINATEE S RawsonChromium (Cr3+) is a required trace mineral that potentiates the effect of insulin. A small number of patients on total par-enteral nutrition have developed severe chromium defi ciencies

and subsequently presented with symptoms of diabetes. However, this was reversed with chromium supplementa-tion.20 Chromium levels in food are quite low, with the high-est levels found in egg yolk, Brewer’s yeast and beef. Although physical activity may increase chromium losses,21 and intes-tinal chromium absorption is low (0.5–2.0%), chromium defi -ciencies are uncommon, and supplementation is generally not warranted. The adequate intake of chromium is 35 and 25 μg/day for adult (19–50 years) men and women, respectively.

Chromium picolinate, a complex of trivalent chromium and picolinic acid, is better absorbed (2–5%) than dietary chro-mium. As a dietary supplement, chromium picolinate has been heavily marketed for muscle building, fat loss and, more recently, to reduce insulin resistance/type 2 diabetes risk.22 23

Based on these claims, sales of chromium picolinate supple-ments have soared, reaching $500 million/year and represent-ing 6% of mineral supplement sales (second behind calcium) in the USA. The overwhelming majority of the data does not support the purported benefi ts of chromium picolinate sup-plementation, and thus, supplementation is not recommended. Adverse events related to chromium picolinate supplementa-tion in humans are rare and based on case studies, but negative effects on iron status were noted in one double-blind placebo-controlled trial.24 Data are not available regarding the safety of high-dose, long-term chromium picolinate ingestion. There is currently little evidence to support the use of chromium pico-linate supplementation by athletes.

CISSUS QUADRANGULARISG ShawCissus quadrangularis (CQ) is an ancient medicinal plant, found in warm regions of India, Sri Lanka, Malaysia, Java and West Africa. It has been used in traditional medicine to treat a num-ber of ailments from healing bones to treating asthma. CQ has been reported to improve the healing time of bone fractures,25 potentially by increasing proliferation and differentiation of mesenchymal stem cells to osteoblasts.26 It has also been suggested to increase collagen synthesis through promoting alkaline phosphatase activity.26 These fi ndings, along with supposed ‘anabolic steroidal substances’ within CQ, have been used to promote its use within the body-building community for enhancing repair of damaged, connective tissue. However, there are no studies in athletic populations to support this. CQ has more recently become a common ingredient in weight-loss supplements. There is preliminary evidence of some effect—subjects who were supplemented with CQ in one study had a signifi cantly greater body-weight loss over a 10-week period than those taking a placebo.27 28

Recommended doses range from 100–500 mg of CQ extract or 3–6 g of the dried plant. There are limited safety data avail-able in humans. Currently, there is no scientifi c support for the use of CQ in the athletic population.

CONCLUDING REMARKSOnce again, the majority of products reviewed in Part 9 of our series have a history of interest within sporting circles, despite little or no evidence of the purported benefi ts that are adver-tised. Although the bulk of the evidence does not support an ergogenic effect, manufacturers continue to include chromium picolinate in muscle-building and weight-loss dietary supple-ments as a ‘cosmetic’ ingredient. The popularity of this prod-uct is demonstrated by the appearance on the popular website http://www.bodybuilding.com of eight products providing

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chromium picolinate as a sole ingredient and a further 39 multinutrient supplements containing chromium. Most of these products have names designed to give the impression that chromium picolinate accelerates fat burning/weight loss. The statement provided in the lay literature that ‘research indicates that the majority of people in the USA are chromium defi cient’ 29 is untrue but testifi es to the longstanding myth that this supplement is needed. Choline and CQ are also mar-keted with testimonials and impressive sounding hypotheses rather than sound evidence. While glucosamine and chondroi-tin supplements appear to have some support for use within a narrow range of clinical conditions, this evidence requires fur-ther investigation, particularly in athletic populations, before any recommendations can be provided.

Competing interests None.

Provenance and peer review Commissioned; not externally peer reviewed.

REFERENCES 1. Zeisel S. Choline and phosphatidylcholine. In: Shils M, Olson J, Shike M, Ross AC,

eds. Modern nutrition in health and disease. 9th edn. Philadelphia, USA: Lippincott

Williams & Wilkins, 1998:513–23.

2. Launders D, He C, Etnier J, et al. The effects of choline on cognitive function and

mood state following exhaustive exercise. Med Sci Sports Exerc 1994;26:S157

(Abstract 879).

3. Warber JP, Patton JF, Tharion WJ, et al. The effects of choline supplementation

on physical performance. Int J Sport Nutr Exerc Metab 2000;10:170–81.

4. Spector SA, Jackman MR, Sabounjian LA, et al. Effect of choline supplementation

on fatigue in trained cyclists. Med Sci Sports Exerc 1995;27:668–73.

5. von Allwörden HN, Horn S, Kahl J, et al. The infl uence of lecithin on plasma

choline concentrations in triathletes and adolescent runners during exercise. Eur J

Appl Physiol Occup Physiol 1993;67:87–91.

6. Conlay LA, Wurtman RJ, Blusztajn K, et al. Decreased plasma choline

concentrations in marathon runners. N Engl J Med 1986;315:892.

7. Williams M, Leutholtz B. Nutritional ergogenic aids. In: Maughan R, ed. Nutrition

in sport. Oxford; Blackwell Science, 2000;362.

8. Mahan L, Escott-Stump S. Krause’s food, nutrition, & diet therapy. 10th edn.

Philadelphia, PA; WB Saunders, 2000:553.

9. Setnikar I, Palumbo R, Canali S, et al. Pharmacokinetics of glucosamine in man.

Arzneimittelforschung 1993;43:1109–13.

10. Setnikar I, Rovati LC. Absorption, distribution, metabolism and excretion of

glucosamine sulfate. A review. Arzneimittelforschung 2001;51:699–725.

11. Gorsline RT, Kaeding CC. The use of NSAIDs and nutritional supplements in

athletes with osteoarthritis: prevalence, benefi ts, and consequences. Clin Sports

Med 2005;24:71–82.

12. Shikhman AR, Amiel D, D’Lima D, et al. Chondroprotective activity of

N-acetylglucosamine in rabbits with experimental osteoarthritis. Ann Rheum Dis

2005;64:89–94.

13. Oegema TR Jr, Deloria LB, Sandy JD, et al. Effect of oral glucosamine on

cartilage and meniscus in normal and chymopapain-injected knees of young

rabbits. Arthritis Rheum 2002;46:2495–503.

14. Lippiello L. Glucosamine and chondroitin sulfate: biological response modifi ers

of chondrocytes under simulated conditions of joint stress. Osteoarthr Cartil

2003;11:335–42.

15. Pavelká K, Gatterová J, Olejarová M, et al. Glucosamine sulfate use and delay

of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled,

double-blind study. Arch Intern Med 2002;162:2113–23.

16. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine

sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical

trial. Lancet 2001;357:251–6.

17. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee

osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind,

multicenter study versus placebo. Osteoarthr Cartil 2004;12:269–76.

18. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate,

and the two in combination for painful knee osteoarthritis. N Engl J Med

2006;354:795–808.

19. Vangsness CT Jr, Spiker W, Erickson J. A review of evidence-based medicine

for glucosamine and chondroitin sulfate use in knee osteoarthritis. Arthroscopy

2009;25:86–94.

20. Jeejeebhoy KN, Chu RC, Marliss EB, et al. Chromium defi ciency, glucose

intolerance, and neuropathy reversed by chromium supplementation, in

a patient receiving long-term total parenteral nutrition. Am J Clin Nutr

1977;30:531–8.

21. Clancy SP, Clarkson PM, DeCheke ME, et al. Effects of chromium picolinate

supplementation on body composition, strength, and urinary chromium loss in

football players. Int J Sport Nutr 1994;4:142–53.

22. Vincent JB. The potential value and toxicity of chromium picolinate as a

nutritional supplement, weight loss agent and muscle development agent. Sports

Med 2003;33:213–30.

23. Trumbo PR, Ellwood KC. Chromium picolinate intake and risk of type 2 diabetes:

an evidence-based review by the United States Food and Drug Administration.

Nutr Rev 2006;64:357–63.

24. Lukaski HC, Bolonchuk WW, Siders WA, et al. Chromium supplementation and

resistance training: effects on body composition, strength, and trace element

status of men. Am J Clin Nutr 1996;63:954–65.

25. Chopra SS, Patel MR, Awadhiya RP. Studies of Cissus quadrangularis in

experimental fracture repair: a histopathological study. Indian J Med Res

1976;64:1365–8.

26. Potu BK, Bhat KM, Rao MS, et al. Petroleum ether extract of Cissus

quadrangularis (Linn.) enhances bone marrow mesenchymal stem cell

proliferation and facilitates osteoblastogenesis. Clinics (Sao Paulo)

2009;64:993–8.

27. Oben JE, Enyegue DM, Fomekong GI, et al. The effect of Cissus quadrangularis

(CQR-300) and a Cissus formulation (CORE) on obesity and obesity-induced

oxidative stress. Lipids Health Dis 2007;6:4.

28. Hasani-Ranjbar S, Nayebi N, Larijani B, et al. A systematic review of the

effi cacy and safety of herbal medicines used in the treatment of obesity. World J

Gastroenterol 2009;15:3073–85.

29. Chromium picolinate info and products: quick fat loss super mineral. http://www.

bodybuilding.com/store/chrompic.html (Accessed February 15 2010).

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 L M Castell, L M Burke, S J Stear, et al. Part 9ergogenic aids for health and performancesupplements, sports nutrition foods and

Z of nutritional supplements: dietary−A

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