Randomized Controlled Trials in Nutrition

This is a collection of high quality research studies in nutrition, about some of the topics we cover on this website.

All of these studies are published in respected, peer-reviewed journals.

A Randomized Controlled Trial is a type of experiment that is considered to be the gold standard for a clinical trial.

Participants in such a study are randomized into two or more groups, where each group gets a different type of treatment.

All of the studies on this page are randomized controlled trials in humans, unless otherwise noted!

Low-Carbohydrate vs. Low-Fat Diets

A low carb diet is based on foods that contain a low amount of carbohydrate. Foods that are high in sugars and starches are replaced with foods that are high in protein and fat.

A low fat diet, is based on foods that contain a low amount of fat, typically under 30% of total calories. Foods like fruits, vegetables and whole grains are emphasized.

The studies below are controlled trials where people are randomized to either a low-carb or a low-fat diet. The outcomes measured are usually body weight and risk factors for disease.

  1. Krebs NF, et al. Efficacy and safety of a high protein, low carbohydrate diet for weight loss in severely obese adolescents. J Pediatr. 2010 Aug;157(2):252-8.
  2. Hernandez, et al. Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet. Am J Clin Nutr March 2010 vol. 91 no. 3 578-585.
  3. Brinkworth GD, et al. Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo. Am J Clin Nutr. 2009 Jul;90(1):23-32.
  4. Volek JS, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009 Apr;44(4):297-309.
  5. Tay J, et al. Metabolic effects of weight loss on a very-low-carbohydrate diet compared with an isocaloric high-carbohydrate diet in abdominally obese subjects. J Am Coll Cardiol. 2008 Jan 1;51(1):59-67.
  6. Keogh JB, et al. Effects of weight loss from a very-low-carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity. Am J Clin Nutr. 2008 Mar;87(3):567-76.
  7. Shai I, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008 Jul 17;359(3):229-41.
  8. Dyson PA, et al. A low-carbohydrate diet is more effective in reducing body weight than healthy eating in both diabetic and non-diabetic subjects. Diabet Med. 2007 Dec;24(12):1430-5.
  9. Halyburton AK, et al. Low- and high-carbohydrate weight-loss diets have similar effects on mood but not cognitive performance. Am J Clin Nutr. 2007 Sep;86(3):580-7.
  10. Gardner CD, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007 Mar 7;297(9):969-77.
  11. McClernon FJ, et al. The effects of a low-carbohydrate ketogenic diet and a low-fat diet on mood, hunger, and other self-reported symptoms. Obesity (Silver Spring). 2007 Jan;15(1):182-7.
  12. Nickols-Richardson SM, et al. Perceived hunger is lower and weight loss is greater in overweight premenopausal women consuming a low-carbohydrate/high-protein vs high-carbohydrate/low-fat diet. J Am Diet Assoc. 2005 Sep;105(9):1433-7.
  13. Meckling KA, et al. Comparison of a low-fat diet to a low-carbohydrate diet on weight loss, body composition, and risk factors for diabetes and cardiovascular disease in free-living, overweight men and women. J Clin Endocrinol Metab. 2004 Jun;89(6):2717-23.
  14. JS Volek, et al. Comparison of energy-restricted very low-carbohydrate and low-fat diets on weight loss and body composition in overweight men and women. Nutr Metab (Lond). 2004; 1: 13.
  15. Yancy WS Jr, et al. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med. 2004 May 18;140(10):769-77.
  16. Aude YW, et al. The national cholesterol education program diet vs a diet lower in carbohydrates and higher in protein and monounsaturated fat: a randomized trial. Arch Intern Med. 2004 Oct 25;164(19):2141-6.
  17. Brehm BJ, et al. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003 Apr;88(4):1617-23.
  18. Sondike SB, et al. Effects of a low-carbohydrate diet on weight loss and cardiovascular risk factor in overweight adolescents. J Pediatr. 2003 Mar;142(3):253-8.
  19. Samaha FF, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003 May 22;348(21):2074-81.
  20. Foster GD, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003 May 22;348(21):2082-90.
  21. Low-Carb and Type II Diabetes:

  22. Guldbrand, et al. In type 2 diabetes, randomization to advice to follow a low-carbohydrate diet transiently improves glycaemic control compared with advice to follow a low-fat diet producing a similar weight loss. Diabetologia. 2012 Aug;55(8):2118-27.
  23. Westman EC, et al. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008 Dec 19;5:36.
  24. Daly ME, et al. Short-term effects of severe dietary carbohydrate-restriction advice in Type 2 diabetes – a randomized controlled trial. Diabet Med. 2006 Jan;23(1):15-20.

Main Results: Low-carb diets usually lead to more weight loss than low-fat diets, even when the low-fat groups are calorie restricted while the low-carb groups are not.

Low-carbohydrate diets also significantly improve major risk factors for diseases like cardiovascular disease and type II diabetes.

Meta-Analyses of Low-Carb Diet Studies

These studies are meta-analyses of randomized controlled trials of low-carbohydrate diets.

  1. Santos F, et al. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obesity Reviews, 13: 1048–1066.
  2. Hession M, et al. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obesity Reviews, 10: 36–50.
  3. Westman EC, et al. Low-carbohydrate nutrition and metabolism. Am J Clin Nutr August 2007 86: 2 276-284
Main Results: Same as above. Low-carb diets lead to more weight loss and further improvements in metabolic health compared to the low-fat diet that is usually recommended by nutritionists and governments around the world.

The Paleolithic Diet

Randomized controlled trials of the paleolithic diet (commonly known as the paleo diet or caveman diet).

  1. Jönsson T, et al. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovascular Diabetology 2009, 8:35.
  2. Lindeberg S, et al. A Palaeolithic diet improves glucose tolerance more than a Mediterranean-like diet in individuals with ischaemic heart disease. Diabetologia. 2007 Sep;50(9):1795-807.
Main Results: The paleo diet has favorable effects on body weight and major risk factors. However, the studies available are very small so the results must be taken with a grain of salt.

Vitamin D3 Supplementation

A deficiency in Vitamin D is very common today, especially in countries where there is little sun throughout most of the year.

Vitamin D3 and cancer:

  1. Lappe JM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.
  2. Vitamin D, fractures and falls:

  3. Meta-analysis: Bischoff-Ferrari HA, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005 May 11;293(18):2257-64.
  4. Trivedi DP, et al. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469.
  5. Broe KE, et al. A higher dose of vitamin d reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J Am Geriatr Soc. 2007 Feb;55(2):234-9.
  6. Vitamin D3 and Influenza A Infections:

  7. Urashima M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr May 2010.
Main Results: Vitamin D supplementation reduces risk of falls and fractures in the elderly at higher doses. May reduce risk of cancer and respiratory infections.

Is This List Missing Something?

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There is no cherry picking here. All relevant studies are included. If you find something that should be included in this list, post it in the comments below.

28 Comments

  1. Hello and thank you for this article. I’m wondering have you looked into research on vitamin D3 shortage and supplementation and it’s effects on depression symptoms/clinical depression?

    • I haven’t seen much research on it but it wouldn’t surprise me if there was some effect. A Vitamin D deficiency can affect the body in many ways.

    • I recently started supplementing with Vitamin D3 50,000 IU capsules; I had a month or two where I just felt like garbage all the time and had a viral sinus infection that just wouldn’t go away. I performed what is referred to as a Stoss Dose (look it up for more info) and took a capsule every a.m. for three days, though it is sometimes recommended to take two or three depending upon weight. It’s made a huge difference – I feel much better, don’t need as much sleep, and don’t feel low-energy all the time. It is an immune/mood booster, and now I take a capsule every couple weeks to maintain my levels. Highly recommend it, even if only to perform the Stoss Dose.

  2. Do all the studies listed that compare low carb to low fat include body composition in the conclusions? I’ve read several studies that showed that low fat diets will get you more WEIGHT loss, however low carb diets get you more FAT loss. I think it’s an important distinction and you can usually tell if the study didn’t go as the researchers wanted if they did body composition at the beginning but not at the end.

  3. Just thought you might want to know that Dr. Lindeberg did another study comparing a Paleo diet to a Mediterranean diet:
    http://www.ncbi.nlm.nih.gov/pubmed/21118562
    As expected, the Paleo diet won.

  4. Hi Kris,

    What is your take on this article against saturated fat?

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572653/

    • I’ll have to give it a closer read when I have the time.

      Excess carbs get turned into saturated fats in the liver. On a low-carb diet, the body preferably burns saturated fat for energy, which actually leads to a reduction in the blood.

      A quick glance seems to tell me that the studies are referring to blood levels of saturated fat, not dietary intake per se. It is known that low-carb diets actually reduce blood levels, even though dietary intake may be high.

      • Thanks A lot Kris!

        It’s nice to know that there are evidence based people with the right critical thinking skills to turn to when you have questions.

        I love the site and have got so much useful stuff and external links from it. I especially like how easy to follow and straight forward the articles are.

        Keep up the great work and I will keep sharing the site to friends and family.

        Luke

  5. Aaron Richoux says:

    I would like to see evidence supporting avoiding artificial sweeteners.

  6. David F says:

    Re Anna’s query (above), Emily Deans at evolutionary psychiatry (http://evolutionarypsychiatry.blogspot.com/) wrote about supplementation of vitamin D albeit with very Vit D deficient females. The study she quoted: http://aje.oxfordjournals.org/content/176/1/1.full.pdf was not supportive of the notion (patients tended to report more depressive symptoms).

    Dr Deans has some comments re the underlying mechanism, and notes (anecdotal) that psychiatric interventions seemed more effective after the ‘D’ levels were brought up.

  7. You missed the CSIRO and IDI Baker Institute studies, which are publicly funded, double blind tests in Australian diabetic populations. Results should be applicable to the US as a) we’re all human b) we have very similar rates of obesity and type 2 diabetes and c) we eat a very similar crappy diet (many of your brands are here).

    Definitely worth your time to find and read the papers by these authors.

    http://www.ncbi.nlm.nih.gov/pubmed/23448804
    “Consumption of a HP diet was more effective for improving body composition compared with an HC diet.”

    http://www.ncbi.nlm.nih.gov/pubmed/15007396?dopt=AbstractPlus
    “No real change in groups after 68 weeks” <– shows the need to make it a permanent change

    http://www.ncbi.nlm.nih.gov/pubmed?term=Noakes%20M%5BAuthor%5D&cauthor=true&cauthor_uid=15007396

    http://www.csiro.au/en/Outcomes/Health-and-Wellbeing/Prevention/CSIRO-nutrition-trials.aspx

    Thanks,
    Andrew

  8. Hi Kris,
    Greetings from UK.

    Just started on LCHF eating. Reasons both for myself but most of all to support my 18 year old son with ASD.

    I am hoping for a good result. Did read about the mice study (fancy making mice autistic!!) and am not totally convinced, but I am very positive that this will have a good effect on my son in many ways.

    Just needed contact and some support :0)

    • I think that’s wonderful that you are supporting your son by jointly following a LCHF diet! Best wishes for you both.

  9. Guido Vogel says:

    Hi Kris,

    What do you think about this article that states that there is not much difference between the differtent types of diets?

    http://jama.jamanetwork.com/article.aspx?articleid=1730520

    • Hey Guido.

      If it’s just about weight loss, then I agree that the macronutrient composition is less important than simply being able to stick to the diet.

      But low-carb has benefits beyond weight loss, especially for people with metabolic syndrome, type 2 diabetes and obesity.

  10. Hi Kris.

    I’m glad I found your site. I have been advocating high fat, low carb diet for diabetes in my blog mainly aimed at the diabetic community prevalent in my country. Local medical practitioners and dietitians still recommend low fat and low calorie diets for diabetes.

    I am not medically trained so my words are opposed by them. My writings are based on what I gained from pro low carb medical specialists and online and offline readings. Your site provides the research facts that I can use to substantiate my articles. Thank you so much.

  11. Hi Kris,

    Here are a couple of meta-analysis papers you missed. This one deals with fat vs. carbohydrates for insulin resistance:

    http://www.ncbi.nlm.nih.gov/pubmed/12589186

    And this one talks about diet in general for PCOS, but the conclusion is that moderate carb restriction works better than fat restriction in normalizing hormonal issues in PCOS:

    http://www.ncbi.nlm.nih.gov/pubmed/23420000

  12. John Ediger says:

    Have you read “The China Study”? I’m curious about your thoughts on this evidence based study about animal products and disease.

    • Haven’t read the book, no. But the actual study that the book is based on was an observational study. Plenty of other even more rigorous observational studies, as well as controlled trials, have come to the opposite conclusion. Animal protein is good and so is animal fat, as long as it is not coming from processed meat.

      From what I’ve read about the book, a lot of it is pseudoscience designed to promote the vegan cause.

      • Appreciate your delving into the data in nutrition. I am Director of Cancer Nutrition at Yale and was Curriculum Director of Nutrition at the Yale School of Medicine and more recently interested in busting the many myths as you are. Unfortunately too few MD’s are educated, interested or engaged in this.

        As for the China Study, as noted, Campbell went from large observations regarding animal, specifically dairy intake, particularly protein (casein) and increased cancer risk and went on to study in his lab the effect of dietary casein on hepatocellular carcinogenesis, a significant leap. Most adherents recommend avoiding all dairy and recommend an only plant based diet as their mantra.

        The VERY large cohort studies show no relationship between the level of dietary F/V and cancer risk OR survival though it is linked to lower CV risk. (EPIC/NHS/HPFS/etc) What dairy is linked to, in very early childhood, is robust growth and adult height, which ironically is clearly linked to increased adult cancer risk at most sites.

        Mechanism? Increased tissue stem cell number raising probability of adult cancer risk. Despite this, populaion health is universally better (except cancer) with increasing height. That may be the link between dairy and cancer, not any direct influence in later life on cancer risk. But you can’t convince true believers!

        My best, DBB MD, MS.

  13. Nancy Scott says:

    I would be interested in your review of Nina Planck’s book, Real Food. Thank you for all of this helpful information.

  14. Pamela Hutchens says:

    I have tried the low carb diet and lost a bunch of weight but one thing I found you have to pretty much stay on this type of eating plan to keep the weight from coming back so no sugar (splenda is not good for me, I have very bad migraines when I consume it) and stay low on the starches.

    I have now found loads of low carb recipes to maintain that weight loss, so I am going to start again. The person who ask about eating vegetarian on the diet, could they eat Choiboini (not sure that is spelled right) – it has a lot of protein?

    My question for me is which of the acceptable foods can I add to this diet to get the vitamin D?

  15. Pamela Hutchens says:

    Forgot to add that I read an article that said lack of vitamin D could actually cause… well, here is a bit from the article. I was actually looking on lack of sleep may be causing the need to eat, here is the blurb.

    “Studies are beginning to show a link between vitamin D level and quality of sleep; optimizing your vitamin D level may improve sleep quality, although more studies are needed to establish the exact mechanism.”

    I would love to get you take on this.

  16. @Pamela: most foods contain little vitamin D, with the exception of fatty fish, like mackerel, herring, sardines and salmon. In a number of countries, some foods are fortified with vitamin D.

    But it is questionable whether or not vitamin D is a nutrient at all. Depending on where you live, approximately three quarters of your vitamin D input throughout the year comes from the sun, or more precisely, the UV-B-rays of the sun shining on your skin (the close you live to the equator, the larger this fraction).

    In winter, people living in northern areas tend to get vitamin D deficient unless they take a supplement or eat a whole lot of fatty fish.

  17. Fred and Alice Ottoboni says:

    We are new subscribers (from Northern Nevada) who have recently found your excellent site. We are long-retired PH scientist (9th decade) who have devoted the thirty years of our retirement to studying nutritional biochemistry.

    We are taking the liberty of writing to you in this Evidence section because we do not know where else to put it. We want you to know what we have observed because, with all you have on your plate, it could have very well escaped your notice.

    We have been very disturbed by what we see as a recent trend in reporting of epidemiological data in top quality journals by eminent nutritional scientists. We call it the new epidemiology. This new method for reporting statistical associations no longer expresses the findings as probability of the existence of an association but rather as the risk of the potential event happening. This requires elaborate statistical manipulation of probability figures and converting them into statements of risk.

    This new method is valid only when used for associations in which a causal relationship has already been established. But we see it now being used to create the impression that a causal relationship exists in the absence of any scientific proof that it does by simply converting probability of association to degree of risk. For example:

    “… 9.3% of deaths in men and 7.6% in women in these cohorts could be prevented at the end of follow-up if all the individuals consumed fewer than 0.5 servings per day (approx. 42 g/d) of red meat (1).”

    We consider that the reporting of risk of mortality and CVD from consuming red meat when there is no scientific proof of a cause/effect relationship is irresponsible and immoral.

    1.) Pan A, et al. Red Meat Consumption and Mortality. Archives of Internal Medicine. 2012; 172(7): 555-563.

    Kris, we feel very strongly that the public should be informed of this matter. Ketopia posted a more complete discussion of this (http://ketopia.com/ I told them I was writing to you). When you have time, we sure would appreciate your take on this.

    Many, many thanks.

    • Hey Fred and Alice, thanks for the comments.

      This is something I’ve definitely noticed before, even respected scientists seem to be jumping to conclusions based on epidemiological evidence alone.

      Unfortunately, epidemiological evidence has often turned out to be completely wrong in the past. Sometimes the controlled trials report the exact opposite effect. For example, the reduction in CVD from hormone replacement therapy, then the controlled trials showed that HRT actually increased CVD.

      • Alice and Fred Ottoboni says:

        Kris, you honor us. We appreciate very much your taking the time to respond.

        You are right. Epidemiological evidence is often wrong because it is bastard epidemiology designed to promote a favorite thesis rather than true science.

        Epidemiology is not science but actually an invaluable tool for guiding direction for scientific research. When done properly it can identify factors that have a potential for a cause-effect relationship. The second part of epidemiology, the proof of cause-effect, is the difficult part that is ignored by researchers who promote pseudoscience.

        We discuss epidemiology at length in our book because of the great damage its misuse has done to public health. We are taking the liberty of enclosing two pages on the corruption of epidemiology for one of those rare moments when you have time for some side issues.

        Sorry, we have to paste because we do not know how to attach a file.

        Many thanks for your graciousness in listening to us.
        ____________________________________________
        THE CORRUPTION OF EPIDEMIOLOGY
        Probably one of the most significant impediments to the solution of today’s fiscal crisis in health care is the misuse, either inadvertent or deliberate, of the major tool for investigation of chronic disease causation. That tool is epidemiology.

        DR. SNOW FORGOTTEN? The lessons of Dr. Snow, mentioned above, illustrate the basic approach to disease investigation and prevention. Today, Snow’s approach is called epidemiology. Its essence is: First, use available science to see if there is an association between two situations; Second, if there is a statistical association, prove the association is causal using sound scientific methodology.

        In Snow’s case the available science was data tabulated from interviews of both the sick and the healthy, plus common sense to identify the possible source. He saw that his tabulated data showed a clear association between the ill people and the Broad Street Well. But he also had the good sense to know that associations do not prove cause and effect. He proved the association by removing the pump handle. When new cases of cholera failed to appear, he knew that the well was the true cause of his cholera cases. Modern epidemiologists frequently assume that association proves cause and effect and neglect to “remove the pump handle.” Curiously, they tend to forget that associations do not prove cause and effect. They seem to have forgotten Snow’s second lesson.

        IGNORANCE OF KOCH’S POSTULATES? Modern epidemiology, literally the science of epidemics, refers to the study of the incidence, prevalence, and movement of diseases that attack many people in a population at the same time. It is based on an old statistical methodology that was designed decades earlier to record and analyze disease incidence. After discovery that microorganisms were the cause of infections, the methods of epidemiology were adapted for use in the investigation of epidemics of infectious diseases.

        The model for a sound epidemiological study was established in 1876 by German physician Robert Koch. In essence, Koch’s postulates set the criteria for determining whether there was an association between an organism and a disease and, if there was association, what specific steps were required to establish whether the association was causal. Thus, Koch’s postulates had the two essential parts of epidemiology: one, association (might the organism have caused the disease?) and two, causation (did the organism actually trigger the disease?). Part two is proof that is analogous to Dr. Snow’s removal of the pump handle. Koch’s postulates became a requirement in the study of epidemics of infectious diseases. Had Koch’s postulates not been ignored during the pellagra epidemic, the fact that the disease was not of infectious origin would have been accepted much sooner.

        EPIDEMIOLOGIC INCOMPETENCE: The epidemics at issue in this book are, to a great extent, the result of the failure of almost all of the epidemiologists who studied diet versus disease to learn from Snow’s work. A reading of a variety of papers that were representative of the huge number that sprung forth from early inquiries into the relationship between diet and heart disease makes it obvious that most looked only for associations, and incompletely at that.

        Influenced by the popularity at the time of Ancel Keys’ lipid hypothesis, only the fat component of the diet was considered in most of the studies. The carbohydrate component was largely ignored. In no case was there any attempt to “remove the pump handle” to prove the association was causal. Chapter Three provides a detailed description of the flaws in the epidemiology on which the early research that led to the so-called heart-healthy diet was based.

        The failure of the official nutrition policy to slow the epidemics of chronic disease has fostered another false proposition, namely that regular exercise is required for good health. Rather than concede that the low-fat diet plan itself may be the problem, some other reason had to be found for its ineffectiveness. A very convenient excuse for the lack of effect of the official nutrition policy was an alleged laziness of the general public. It was obvious that people got fat because they did not exercise enough!

        The faulty epidemiology showing that exercise is required to make people healthy provided the justification needed to create the MyPyramid icon with exercise as a third dimension. The defect in the many studies on which this decision was made is that no study is capable of distinguishing between people who are healthy because they exercise and people who exercise because they are healthy. The new icon will have no impact on preventing diseases but will delay exposure of the heart-healthy diet as being not heart healthy.

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