March 23, 2017

Truth in Science

The beauty of science is that is self-correcting. When a study is published, others get to scrutinize the data and methods. When issues arise, the scientific community gets to discuss and debate the findings, and when appropriate, challenge their veracity.

Recently, I collaborated with some of the world’s top sports scientists on a letter to the editor about a study published in the Journal of Strength and Conditioning Research, that showed an extremely large anabolic effect to consuming a supplement containing HMB+ATP. We wrote an extensive letter that covered our issues with the paper in hopes of seeking truth in science. However, we had to substantially cut down our response to conform to the journal’s policy of allowed only 400 words in such letters. This watered down our points so that the true impact was markedly diminished.

Thus, I wanted to present the unedited version of our letter here so that further discussion can be had on the topic. Only through discourse can we maintain confidence in the research process and facilitate true evidence-based practice.

Extraordinary changes in body composition and performance with supplemental HMB-FA+ATP

Stuart M. Phillips, Ph.D., McMaster University
Alan Aragon, M.S., California State University, Northridge
Shawn M. Arent, Ph.D., Rutgers University
Graeme L. Close, Ph.D., Liverpool John Moores University
D. Lee Hamilton, Ph.D., University of Stirling
Eric R. Helms, M.S., M.Phil, Sports Performance Research Institute New Zealand
Jeremy P. Loenneke, Ph.D., The University of Mississippi
Layne Norton, Ph.D., Owner BioLayne LLC
Michael J. Ormsbee, Ph.D., Florida State University
Craig Sale, Ph.D., Nottingham-Trent University
Brad J. Schoenfeld, Ph.D., Lehman College
Abbie Smith-Ryan Ph.D., University of North Carolina
Kevin D. Tipton, Ph.D., University of Stirling
Matthew D. Vukovich, Ph.D., South Dakota State University
Colin Wilborn, Ph.D., University of Mary Hardin-Baylor
Darryn Willoughby, Ph.D. Baylor University

The authors of this letter read with skepticism the recent report from Lowery et al. (10), employing a supplement that provided 3g of beta-hydroxy-beta-methyl butyrate as a free acid (HMB-FA; three doses of 1g each) plus 400mg of oral adenosine triphosphate (ATP) in young men who resistance-trained for 12wk. Lowery et al. (10) report gains in lean mass and performance that are greater than those reported in a similarly surprising earlier study from Wilson et al. (18). Our skepticism of the results reported by Lowery et al. (10) exists on several levels. However, our collective disbelief of these data rests on the collective experience of the authors of this letter, who have conducted more than 60 resistance training studies, and who have never observed gains in lean body mass that are of a similar incredibly uniform magnitude as those reported by Lowery et al. (10). As opposed to the often-observed heterogeneity in resistance training-induced hypertrophy, Lowery et al. (10) must have observed remarkably consistent between-group changes in muscle mass to find statistical significance between the supplemented and placebo groups. What makes this more remarkable in that this was seen in a total of 17 subjects (n=9 placebo, n=8 HMB-FA+ATP). We are particularly nonplussed on this point since the sharp ‘divergence’ between the HMB-FA+ATP versus placebo groups occurred in the face of what the authors refer to as an optimal training paradigm, with optimal nutritional support, and the advice of an experienced dietitian. And thus the difference is due, ostensibly, to two compounds (HMB-FA and/or ATP), which have been studied previously and resulted in a trivial training-induced adaptive advantage (13). Would the authors be willing to share subjects’ individual data? We ask since the mean gain in lean body mass in the supplemented group was ~8.5kg (10), meaning there had to be some subjects who gained more and uniformly so for the treatments (in only 17 subjects) to be so robustly different! This is also an astounding gain of lean body mass when one considers that the subjects were previously resistance-trained and so would have had less propensity to gain lean body mass (11). We could not ascertain the absolute values for the beginning and final values for body composition and so readers would have to make assumptions (since the reported data were incomplete and given as percentages) as to how much body composition changed. Would the authors be willing to present these data?

We are aware of a previous letter from Hyde et al. (7) asking for clarification from Lowery et al. (10) on their methods. Thus, our concern is clearly shared by others and, given the number and research experience of the authors on this letter, quite widespread. In their reply to this letter (7) Lowery et al. (10) went to great lengths to compare their rates of hypertrophy with those previous reported by other studies. Importantly, however, a number of studies discussed by Lowery et al. (10) as having comparable ‘rates’ of hypertrophy were markedly (5wk) shorter than their 12wk intervention (14). Thus, while ‘rates of hypertrophy’ (assessed with different methods and in different labs (3, 9, 14, 16), in different study populations, being overfed and not exercising (3), with different dietary backgrounds (3, 9, 14, 16), and/or consuming different supplements (i.e., creatine) (9, 14, 16), may have been similar (or greater) to those seen by Lowery et al. (10) the total accrued (over 12wk) lean body mass cannot be assumed to be linear and extrapolated to that seen in their study. Further, what is revealing is the astonishing performance differences reported by Lowery et al. (10), which implies not only greater total lean mass gains but an extraordinary functionality to the accrued lean mass or by some other unexplained mechanism. That is, why did HMB-FA+ATP impart an astonishing ‘functional overreaching’ response with the optimal training paradigm, with great dietary support, and in highly trained and motivated subjects and not in the placebo group?

It is important to understand the limitations of dual-energy x-ray absorptiometry (DXA), which derives by difference fat- and bone-free mass, which is a variable that is not equivalent to muscle (6, 12). The limitations of DXA and ultrasound, the two muscle-based outcome measures have been clearly outlined in a recent review (6). As stated, DXA “Cannot specifically discern skeletal muscle mass [bold added] and quality as can CT [computerized tomography] and MRI [magnetic resonance imaging]” and is subject to changes in hydration status (6). For ultrasound, “Technical skill required. Excess transducer pressure and orientation can influence muscle size measurements. Identification of reproducible measurement sites critical. Care needed to make sure muscle is in relaxed state. Conditions such as proximity to exercise bout, hydration, are important to control” (6). Lowery et al. (10) report nothing with respect to the ultrasound machine used, the hydration or feeding status of their subjects, or proximity to an exercise. It would be useful for readers if Lowery et al. (10) would detail for the readers the training level of the researcher(s) who conducted the ultrasound tests (inter-rater reliability of more than one researcher was used), noted whether more than one researcher carried out testing, whether these testers were blinded to the group assignment while completing/analyzing the thickness measures, and clarify the temporal aspects of testing to determine if there may be any associated confounding issues.

In the response to Hyde et al (7) Lowery et al. (10) purport to have selected “…a responsive population who possess a quantity of lean mass indicative of previous responses to resistance training…” Notwithstanding the scientific inaccuracy of this statement, the authors must have gone through a screening process of sorts to recruit 17 subjects with lean mass “…an order of magnitude [we note that an order of magnitude is defined as 10-times greater so this cannot be the case] higher than average lean mass typically seen in recreationally trained subjects…” Could the authors please state what the exact criteria for inclusion as a subject in this study were? Can the authors please detail the screening process describing how many subjects were recruited and screened, final entered the study, and dropouts, to reach this number of subjects meeting these criteria and who completed the protocol? Please also clarify if the subjects were randomised to treatment and placebo groups or pair matched based on body mass, lean body mass, strength or other variable.

The only form of HMB for which there is plausible data showing a mechanistic underpinning for its potential role aiding in muscle protein turnover is for calcium-HMB (15). We are unaware of any similar proof-of-principle mechanistic data for the free acid form of HMB despite apparently greater bioavailability and uptake (into what tissue is unclear) (4). Do the authors know of any data showing that HMB-FA has a similar credible effect as calcium-HMB on human muscle protein turnover (15)? We note that leucine had the same anabolic effects as calcium-HMB (15). We also note that dietary protein can exert a positive effect on gains in muscle mass with resistance training (1) and yet the placebo group did not appear to respond at all to the overreaching phase. As another ingredient of the supplement used by Lowery et al (10), ATP would appear to be, given an extraordinarily low bioavailability (2), to be unusable. However, we note that Wilson et al. (17), using the same study protocol as that employed by Lowery et al. (10), reported that ATP (400mg/d) resulted in a positive effect on muscle mass, strength, and power gains. This seems to us highly improbable given that oral ATP even up to doses of 5000mg/d [more than an order of magnitude greater than the dose used by Wilson et al. (17) and Lowery et al. (10)] for 4wk leads only to increases in circulating uric acid with no detectable changes in ATP in the blood (2) let alone muscle. Thus, as opposed to an inconsequential increase in post-exercise blood flow induced by the ATP (8) in the HMB-FA+ATP supplemented group, we find it biologically implausible that 400mg/d of oral ATP would exert any effect on processes leading to enhanced performance let alone hypertrophy. What is remarkable is that given the expert dietary advice and total protein intake of the subjects studied, the optimal training program, and ‘responsive’ subjects that the differences in lean mass (and performance) between the HMB-FA+ATP and placebo groups are as impressive as they are (10). Moreover, that these differences are statistically significant in such a small sample of subjects and ascribed to an, as yet, mechanistically untested form of HMB and a biologically unavailable quantity of ATP.

We ask, in accordance with all reasonable guidelines regarding full disclosure of potential conflicts of interest now in place at many journals (including the Journal of Strength and Conditioning Research – http://journals.lww.com/nsca-jscr/Pages/InstructionsforAuthors.aspx – accessed Oct 1, 2016) that Dr. Wilson and Mr. Lowery disclose here whether they have ever received travel expenses, stipends, or honoraria, or shares associated with their work and the companies involved with ATP and/or HMB and/or whether they or their spouses have any public or private interests with Metabolic Technologies, Inc. and/or companies selling or dealing in oral ATP supplements or their affiliates? This is not an accusation and we fully accept that neither Dr. Wilson nor Mr. Lowery may have ever received such support, but believe this is an honest and reasonable question to ask on both scientific and ethical grounds (5) and it is standard practice to make such disclosures.

Reference List
1. Cermak NM, Res PT, de Groot LC, Saris WH and van Loon LJ. Protein supplementation augments the adaptive response of skeletal muscle to resistance-type exercise training: a meta-analysis. Am J Clin Nutr 96: 1454-1464, 2012.
2. Coolen EJ, Arts IC, Bekers O, Vervaet C, Bast A and Dagnelie PC. Oral bioavailability of ATP after prolonged administration. Br J Nutr 105: 357-366, 2011.
3. Forbes GB, Brown MR, Welle SL and Lipinski BA. Deliberate overfeeding in women and men: energy cost and composition of the weight gain. Br J Nutr 56: 1-9, 1986.
4. Fuller JC, Jr., Sharp RL, Angus HF, Baier SM and Rathmacher JA. Free acid gel form of beta-hydroxy-beta-methylbutyrate (HMB) improves HMB clearance from plasma in human subjects compared with the calcium HMB salt. Br J Nutr 105: 367-372, 2011.
5. Gorman DM. Can We Trust Positive Findings of Intervention Research? The Role of Conflict of Interest. Prev Sci 2016.
6. Heymsfield SB, Gonzalez MC, Lu J, Jia G and Zheng J. Skeletal muscle mass and quality: evolution of modern measurement concepts in the context of sarcopenia. Proc Nutr Soc 74: 355-366, 2015.
7. Hyde PN, Kendall KL and LaFountain RA. Interaction of beta-hydroxy-betmethylbutyrate free acid and adenosine triphosphate on muscle mass, strength, and power, in resistance trianed invidividuals. J Strength Cond Res 30: e10-e14, 2016.
8. Jager R, Roberts MD, Lowery RP, Joy JM, Cruthirds CL, Lockwood CM, Rathmacher JA, Purpura M and Wilson JM. Oral adenosine-5′-triphosphate (ATP) administration increases blood flow following exercise in animals and humans. J Int Soc Sports Nutr 11: 28, 2014.
9. Jowko E, Ostaszewski P, Jank M, Sacharuk J, Zieniewicz A, Wilczak J and Nissen S. Creatine and beta-hydroxy-beta-methylbutyrate (HMB) additively increase lean body mass and muscle strength during a weight-training program. Nutrition 17: 558-566, 2001.
10. Lowery RP, Joy JM, Rathmacher JA, Baier SM, Fuller JC, Jr., Shelley MC, Jager R, Purpura M, Wilson SM and Wilson JM. Interaction of Beta-Hydroxy-Beta-Methylbutyrate Free Acid and Adenosine Triphosphate on Muscle Mass, Strength, and Power in Resistance Trained Individuals. J Strength Cond Res 30: 1843-1854, 2016.
11. Morton RW, Oikawa SY, Wavell CG, Mazara N, McGlory C, Quadrilatero J, Baechler BL, Baker SK and Phillips SM. Neither load nor systemic hormones determine resistance training-mediated hypertrophy or strength gains in resistance-trained young men. J Appl Physiol (1985) 121: 129-138, 2016.
12. Prado CM and Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and intervention. JPEN J Parenter Enteral Nutr 38: 940-953, 2014.
13. Rowlands DS and Thomson JS. Effects of beta-hydroxy-beta-methylbutyrate supplementation during resistance training on strength, body composition, and muscle damage in trained and untrained young men: a meta-analysis. J Strength Cond Res 23: 836-846, 2009.
14. Stone MH, Sanborn K, Smith LL, O’Bryant HS, Hoke T, Utter AC, Johnson RL, Boros R, Hruby J, Pierce KC, Stone ME and Garner B. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int J Sport Nutr 9: 146-165, 1999.
15. Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ and Atherton PJ. Effects of leucine and its metabolite beta-hydroxy-beta-methylbutyrate on human skeletal muscle protein metabolism. J Physiol 591: 2911-2923, 2013.
16. Willoughby DS, Stout JR and Wilborn CD. Effects of resistance training and protein plus amino acid supplementation on muscle anabolism, mass, and strength. Amino Acids 32: 467-477, 2007.
17. Wilson JM, Joy JM, Lowery RP, Roberts MD, Lockwood CM, Manninen AH, Fuller JC, De Souza EO, Baier SM, Wilson SM and Rathmacher JA. Effects of oral adenosine-5′-triphosphate supplementation on athletic performance, skeletal muscle hypertrophy and recovery in resistance-trained men. Nutr Metab (Lond) 10: 57, 2013.
18. Wilson JM, Lowery RP, Joy JM, Andersen JC, Wilson SM, Stout JR, Duncan N, Fuller JC, Baier SM, Naimo MA and Rathmacher J. The effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid supplementation on muscle mass, strength, and power in resistance-trained individuals: a randomized, double-blind, placebo-controlled study. Eur J Appl Physiol 114: 1217-1227, 2014.


  1. The compact version I’ve also read, on the JSCR website. What do you think of publishing this bigger (and prettier) version on RG? Jacob Wilson-Fans will love it.

    Comment by JOÃO PEDRO ALVES NUNES — March 28, 2017 @ 5:27 pm

  2. […] não muito prometedores, havendo apenas 2 estudos com excelentes resultados, cuja validade foi contestada recentemente pela comunidade científica. Como tal, o preço ainda não justifica o seu uso, mesmo numa preparação para […]

    Pingback by Recomendações para Culturismo Natural – MySupertrainingPlan — March 31, 2017 @ 9:55 am

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