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Here’s a very quick summary of some randomized controlled trials (RCTs) and meta-analyses of RCTs that were published in March through April of 2020 and didn’t find evidence of an effect. This is known as a null effect.

Keep the following in mind when interpreting a null effect:

  • While one study can provide evidence that something doesn’t work, it doesn’t prove the lack of an effect. Similar, repeatable results from multiple studies make for stronger evidence, whether the finding is positive or negative.

  • Not all null effects are the same. A meta-analysis of low quality studies or a small clinical trial usually won’t provide strong evidence, whether the finding is positive or negative.

  • The population matters. For example, the lack of an effect in healthy young people doesn’t necessarily mean that an intervention wouldn’t work in people who are older and have a specific health condition.

Cardiovascular disease

Pycnogenol does not affect blood pressure[1]
  • What was studied? Researchers conducted a meta-analysis on placebo-controlled clinical trials examining the effects of pycnogenol supplementation on blood pressure.

  • Why study it? Pycnogenol has several effects that could help lower blood pressure, in theory, including inhibiting angiotensin-converting enzyme and increasing nitric oxide.

  • What was(n’t) found? Pycnogenol supplemented up to 200 milligrams per day for three months had no statistically significant effect on systolic or diastolic blood pressure.

  • How null was it? Fairly null. The quality of the included studies tended to be high, and the included studies weren’t very different from each other, suggesting that they were able to be meta-analyzed properly. However, the included trials were all fairly short term and small, with some involving people without high blood pressure. This leaves a little room for larger, longer, studies to examine pycnogenol’s effects in people with hypertension.

Neither potassium nitrate supplementation nor green, leafy vegetables reduced blood pressure[2]
  • What was studied? Researchers randomized 231 people 50-70 years old to one of three conditions for five weeks: a low nitrate veggies plus placebo pill, a low nitrate veggies plus potassium nitrate containing 300 milligrams of nitrate, or high nitrate leafy veggies plus a placebo pill. The primary endpoint was 24-hour ambulatory systolic pressure. The participants’ starting systolic pressure was between 130-150 mmHg.

  • Why study it? The DASH diet is known to lower blood pressure, and is high in green, leafy veggies. The diet is thought to lower blood pressure in part through the veggies’ high nitrate content. Studies exploring this issue have mostly been small, or have focused on other nitrate-rich foods like beetroot juice.

  • What was(n’t) found? No group experienced a reduction in ambulatory blood pressure. Clinical systolic or diastolic blood pressure also did not change over the course of the study.

  • How null was it? This was a fairly surprising result, even though the study was powered to detect a rather small 3 mmHg decrease and adherence was high as measured by both self-report and plasma and urinary nitrate levels. The authors go through several reasons why they may not have seen an effect, ranging from dose (which the authors deem an unlikely explanation) to interference with vascular nitric oxide synthesis in the blood vessel linings, an effect which has been seen in animal studies. However, the reason for the lack of effect seen here is not clear.

Diets & foods

Whole-grain consumption does not seem to strongly impact bodyweight and fat[3]
  • What was studied? A total of 21 clinical trials involving 1,798 participants were meta-analyzed to explore the impact of whole grain intake on anthropomorphic measures like bodyweight, fat mass, and waist circumference.

  • Why study it? Whole grains may be more satiating because they slow gastric emptying, increase intestinal transit time, and are fermented by the intestinal microbiome to produce short-chain fatty acids. However, the results of clinical trials have been mixed and the last meta-analysis exploring this topic was performed seven years ago.

  • What was(n’t) found? There was no significant effect of whole grain consumption on any anthropometric measure, including bodyweight, BMI, fat mass, or waist circumference.

  • How null was it? Pretty null, given the current evidence. However, the authors note that there’s room for better quality clinical trials that explicitly take into account physical activity differences, and intake of other nutrients, which many of the included studies didn’t do.

A high-sugar breakfast did not affect hunger or energy balance[4]
  • What was studied? Twenty-nine healthy people (mostly women) were enrolled in a crossover study to determine whether the sugar content of breakfast influenced hunger, energy intake, or metabolic markers in a free-living environment. The study involved eating a porridge-based breakfast that either had sugar added (total of 32 grams of sugar) or unsweetened porridge (8 grams of sugar) for three weeks before crossing over. The two breakfasts were isocaloric.

  • Why study it? Some public health guidelines recommend low sugar breakfast in order to reduce caloric intake and for metabolic health. However, the direct impact of sugary breakfasts on these parameters hasn’t been well studied.

  • What was(n’t) found? There was no statistically significant effect on appetite ratings, daily caloric intake, or metabolic measurements like total cholesterol or fasting glucose.

  • How null was it? The study was powered to detect a 225 kcal per day difference between the conditions. However, the researchers just missed the mark for recruiting enough people, opening the door for slightly higher differences in intake to be missed. Also, there may have been some error in estimating the caloric intake due to inaccurate food logging. Finally, the population was made up of healthy, younger people without metabolic diseases, so these results may not generalize to other populations.

  • Anything else? The authors did find that the sugar intake of the high sugar group was indeed higher, which was attributed to the sugar content of the breakfast. They note that cutting sugar from breakfast would still be a viable way to reduce daily sugar intake for people looking to do so.

Memory, focus, & cognition

Supplementation with two B vitamins in early childhood didn’t impact cognition later on[5]
  • What was studied? The impact of six months of supplementing 1.8 micrograms of vitamin B12 and 150 milligrams of folate daily in children aged 6 to 30 months on cognition later on in life (ages 6 to 9 years).

  • Why study it? Both B vitamins are essential for brain development, and deficiencies in early childhood have been associated with poorer cognitive development outcomes.

  • What was(n’t) found? Once adjusted for socioeconomic and educational confounders, there was no significant effect of supplementation early in life on cognitive development.

  • How null was it? This is essentially an observational follow-up to a trial that was originally designed to test the effects of these B vitamins on infection rate, not cognition. The observational nature of this study weakens the confidence that can be placed in its conclusions. Also, the fact that the length of treatment may have been suboptimal, and many of the children were not vitamin deficient, leaves open the possibility that longer treatment duration in a vitamin-deficient population may be useful.

Men's health & testosterone

Antioxidant supplementation didn’t improve male fertility[6]
  • What was studied? This study was designed to examine the effect of supplementing a blend of antioxidants daily for three to six months on two semen parameters for men with abnormal semen who were trying to conceive a child. The two primary outcomes were sperm motility and sperm DNA fragmentation. The blend contained 500 milligrams of vitamin C, 400 milligrams of vitamin E, 200 micrograms of selenium, 1,000 milligrams of L-carnitine, 20 milligrams of zinc, 1,000 micrograms of folic acid, and 10 milligrams of lycopene. If the primary outcome was confirmed, there were plans to move forward with a larger study examining live births as a primary outcome.

  • Why study it? Oxidation can damage semen, and semen quality is thought to play a large role in some forms of male infertility. Single antioxidants have been shown to improve semen quality in some trials, but those trials have been small and quite different from each other.

  • What was(n’t) found? No significant difference on semen quality was observed, either, although supplementation did boost sperm count. While the study wasn’t designed to test live births outcomes at this stage, there was no statistically significant difference in birth rate.

  • How null was it? Moderately. This was a well-designed, two-stage study consisting of a pilot to test the effects of antioxidants on semen quality. If the pilot came out as expected, the researchers believed they would be justified in beginning a larger trial looking at live births as the primary outcome, since their hypotheses about antioxidants’ mechanisms would have been supported. However, their hypotheses about semen quality didn’t pan out, so they didn’t go ahead with the larger trial.

  • Anything else? The population wasn’t selected for high oxidative stress or low vitamin levels, leaving open the possibility that some subpopulations may still benefit from antioxidants.

Muscle gain & exercise

Time-restricted feeding doesn’t offer clear benefits over continuous calorie restriction when combined with resistance training[7]
  • What was studied? Twenty-six healthy, young, recreationally active males with an average BMI of around 26 were assigned to either a 25% caloric deficit via continuous energy restriction or restricting feeding to an eight-hour window starting in the early afternoon for four weeks. Both groups undertook a thrice-weekly full body split resistance training regimen while on their assigned diet. They also consumed 1.8 grams of protein per kilogram of bodyweight. The goal was to see if the type of diet impacted body composition or performance metrics.

  • Why study it? There’s a relative lack of evidence for the effects of time-restricted feeding on weight and body composition in actively exercising populations.

  • What was(n’t) found? Both groups had similar performance improvements, similar loss of fat mass, and similar maintenance of fat-free mass. This suggests that time-restricted feeding is neither better nor worse for performance and body composition while resistance training under caloric deficit.

  • How null was it? This was a fairly small study with lots of outcomes measured. While a generic power calculation was performed, a primary outcome was not declared. Thus, it’s quite possible that a larger study with a focused primary outcome may find differences between these feeding schedules later on.

Women's health

Vitamin D supplementation didn’t impact gestational diabetes[8]
  • What was studied? Pregnant women at six weeks gestation with overweight or obesity and no pre-existing diabetes were randomized to receive placebo or 1,600 IU of vitamin D3 on top of a multivitamin to determine how supplementation affected glycemic control.

  • Why study it? Overweight and obesity are associated with lower vitamin D status, which in turn is associated with poorer glucose control and also an increased rate of gestational diabetes.

  • What was(n’t) found? No effect on gestational diabetes rate or insulin sensitivity was seen. There was a small beneficial effect of borderline statistical significance on fasting plasma glucose at weeks 35 to 37.

  • How null was it? Somewhat. The odds of gestational diabetes was not a primary outcome, but fasting plasma glucose was. However, not much weight should be placed on the small decrease seen at weeks 35 to 37 due to multiple comparisons. Furthermore, while the sample size was too small to rule out small effects on glycemic control, such effects may not have much clinical relevance.

Weight loss through lifestyle interventions didn’t have a statistically significant effect on live birth outcomes in women with fertility issues and obesity[9]
  • What was studied? Eight studies involving over 1,000 women with obesity who were undergoing treatment for fertility issues were meta-analyzed. The goal was to examine the impact of lifestyle interventions for weight loss like diet and exercise on birth outcomes.

  • Why study it? Women with overweight and obesity who undergo fertility treatment are sometimes advised to lose weight to improve pregnancy outcomes. There have been only a few studies that have directly explored the evidence for this suggestion, however, and those that have done so have produced inconsistent results.

  • What was(n’t) found? There was no statistically significant impact on live birth rate. However, there was a significant improvement in pregnancy rates.

  • How null was it? Not very, since the quality of evidence was rated as low to moderate and the studies were fairly different from each other. Also the 95% confidence intervals were mostly consistent with an improvement in live birth rates. Finally, removing one study from the analysis that differed from the others and had a high attrition rate resulted in a statistically significant improvement in live birth rates. There’s room for higher quality evidence exploring this issue.

  • Anything else? Women who partook in lifestyle interventions to lose weight also had a borderline significant increase in miscarriage rates. However, this became less statistically significant when the study mentioned above was removed.

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See other articles with similar topics: Blood Pressure, Pycnogenol, DASH Diet, Diet, Hypertension, Nitrate, Whole Grains, Weight Loss, Sugar, Breakfast, Appetite, Vitamin B, Children, Supplementation, Cognition, Antioxidants, Male Fertility, Fertility, Caloric Restriction, Resistance Training, Fat Loss, Exercise, Vitamin D, Diabetes, Glycemic Index, Obesity, Fasting Glucose, Pregnancy, Miscarriage, Dieting, Nulls.

See other articles in Issue #68 (June 2020) of Study Deep Dives.

Other Articles in Issue #68 (June 2020)


  1. ^ Federica Fogacci, et al. Effect of Pycnogenol on Blood Pressure: Findings From a PRISMA Compliant Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled, Clinical Studies. Angiology. (2020)
  2. ^ Michaela L Sundqvist, et al. A Randomized Clinical Trial of the Effects of Leafy Green Vegetables and Inorganic Nitrate on Blood Pressure. Am J Clin Nutr. (2020)
  3. ^ Omid Sadeghi, et al. Whole-Grain Consumption Does Not Affect Obesity Measures: An Updated Systematic Review and Meta-analysis of Randomized Clinical Trials. Adv Nutr. (2020)
  4. ^ Harriet A Carroll, et al. Effect of Plain Versus Sugar-Sweetened Breakfast on Energy Balance and Metabolic Health: A Randomized Crossover Trial. Obesity (Silver Spring). (2020)
  5. ^ Ingrid Kvestad, et al. Vitamin B 12, Folate, and Cognition in 6- To 9-Year-Olds: A Randomized Controlled Trial. Pediatrics. (2020)
  6. ^ Anne Z Steiner, et al. The Effect of Antioxidants on Male Factor Infertility: The Males, Antioxidants, and Infertility (MOXI) Randomized Clinical Trial. Fertil Steril. (2020)
  7. ^ Matthew T Stratton, et al. Four Weeks of Time-Restricted Feeding Combined With Resistance Training Does Not Differentially Influence Measures of Body Composition, Muscle Performance, Resting Energy Expenditure, and Blood Biomarkers. Nutrients. (2020)
  8. ^ Rosa Corcoy, et al. The DALI Vitamin D Randomized Controlled Trial for Gestational Diabetes Mellitus Prevention: No Major Benefit Shown Besides Vitamin D Sufficiency. Clin Nutr. (2020)
  9. ^ Juan J Espinós, et al. The Effect of Lifestyle Intervention on Pregnancy and Birth Outcomes on Obese Infertile Women: A Systematic Review and Meta-Analysis. Int J Fertil Steril. (2020)