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Nulls: November–December 2020

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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 November and December 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 it. 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 instance, 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.

Depression, anxiety & stress

A year of omega-3s on top of standard treatment doesn’t budge bipolar disorder[1]
  • What was studied? Researchers investigated whether 1 gram of EPA plus 1 gram of DHA daily for a year in combination with standard treatment could help prevent relapse in adults with bipolar I or II disorder, based on the older DSM-IV criteria.

  • Why study it? Emerging evidence suggests that omega-3 supplementation could affect depressive symptoms. Studies looking at its effects on bipolar disorder have been mixed, though, possibly due to suboptimal dosing of DHA (which seems to have a bigger effect on depression) or short study lengths. This randomized controlled trial was designed to use higher DHA and longer time frames to overcome these past problems.

  • What was(n’t) found? Supplementation on top of standard treatment did not improve time to relapse to depressive, manic, hypomanic, or mixed mood episodes compared to standard treatment alone.

  • How null was it? While relatively small, consisting of 80 participants, this is one of the largest and longest trials examining the effects of omega-3 fatty acids on bipolar disorder to date. While it can’t rule out small effects, it is moderate evidence against omega-3 supplementation producing clinically relevant benefits above and beyond what standard medication provides on its own.


High-dose vitamin D doesn’t affect body composition in people with advanced colorectal cancer[2]
  • What was studied? Researchers evaluated how 4,000 IU of vitamin D3 daily affected body composition in people with advanced colorectal cancer, compared to 400 IU daily, for 16 weeks during chemotherapy.

  • Why study it? Vitamin D can stimulate activity in both muscle and fat tissues, both of which are indicators of colorectal cancer prognosis. It’s possible that vitamin D’s ability to delay cancer deaths could be, in part, due to its effects on lean and fatty tissues.

  • What was(n’t) found? There was no difference between the 4,000 and 400 IU groups in any anthropometric measurement, including bodyweight, muscle, or fatty tissue area.

  • How null was it? This was an exploratory substudy of the SUNSHINE trial, which wasn’t specifically designed to test these outcomes. That said, both the 400 and 4,000 IU groups both lost weight and muscle mass, and the data are pretty consistent with there being no clinically significant differences between groups.

Lycopene doesn’t seem to lower prostate-specific antigen levels in men with prostate cancer[3]
  • What was studied? This meta-analysis included randomized clinical trials examining whether lycopene supplementation can lower prostate-specific antigen levels (a marker for prostate cancer progression) in men with prostate cancer.

  • Why study it? Observational evidence suggests an inverse correlation between lycopene intake and prostate cancer risk, and petri dish evidence suggests that lycopene could affect prostate cancer cells. However, evidence in humans has provided mixed results, suggesting that a meta-analysis could provide more clarity.

  • What was(n’t) found? There was no clear effect of lycopene supplementation on prostate-specific antigen levels.

  • How null was it? There’s room for more evidence, given that only six trials were found and there was a substantial amount of difference between them. Subgroup analysis suggested that men with higher starting prostate-specific antigen levels may have benefited, but this requires higher-quality evidence to confirm.

Cognition & memory

Souvenaid probably doesn’t improve Alzheimer’s very much[4]
  • What was studied? Researchers meta-analyzed randomized controlled trials that were at least 16 weeks in duration and examined the effects of Souvenaid on Alzheimer’s outcomes.

  • Why study it? Souvenaid is a drink consisting of a patented blend of compounds (Fortasyn Connect™), including omega-3 fatty acids and various trace elements, that is claimed to promote synaptic growth.

  • What was(n’t) found? There was no clear effect on mild-to-moderate Alzheimer’s disease after 24 weeks, but there may be a mild effect on mild cognitive impairment after 24 months that is likely to be of little clinical significance.

  • How null was it? Moderately null. Only three trials explored this issue, but combined, they included over 1,000 participants. The quality of evidence was graded as moderate by the authors. The data was consistent with possibly relevant risk reduction, leaving open the possibility of mild benefit.

Healthy aging & longevity

Study suggests that creatine may not add much to older men’s strength training regimen[5]
  • What was studied? Researchers investigated how adding 0.1 grams of creatine monohydrate per kilogram of bodyweight per day to a thrice-weekly whole-body split resistance training program using 3x10 reps with load progressed over the course of a year affected bone, muscle, and strength outcomes in men over 50.

  • Why study it? While shorter-term use of creatine has found to be useful for older men, longer term studies have been relatively sparse.

  • What was(n’t) found? No significant differences in bone, strength, or muscle measurements was found between the supplemented and placebo groups after 12 months.

  • How null was it? Not very. This was a small study (n = 46) with almost a quarter of men dropping out and multiple outcomes measured. While this study probably rules out large differences, no power calculation was performed so it can’t be said for sure. However, it’s unlikely that a study this small would have been able to discern many medium or small differences between the groups. Also, there were discrepancies in recruitment details between the published paper and the preregistration.

Infants, children & teenagers

D3 didn’t help with childhood asthma[6]
  • What was studied? This study was designed to investigate whether 1,000 IU of vitamin D3 per day could reduce asthma in children ages 4–12 who had vitamin D deficiency (less than 20 ng/mL) for nine months.

  • Why study it? Vitamin D is known to influence key immune and inflammatory markers that contribute to asthma. However, clinical trial data has been inconsistent.

  • What was(n’t) found? No difference between the supplement and placebo groups was found for the primary outcome: the proportion of children having a Childhood Asthma Control Test of at least 20 (which is considered well-controlled asthma).

  • How null was it? This was a well-designed study that had a clear primary outcome and was powered to detect a 15% difference in the primary outcome. However, the dose of vitamin D or compliance may have been too low, since only about 35% of the children in the supplemented group had vitamin D levels over 20 ng/mL by the end of the study. This issue, coupled with the fact that most childrens’ asthma (almost 80%) was already well controlled at the study’s start, may have contributed to the null result seen here.

Muscle gain & exercise

Betaine doesn’t have a huge impact on aerobic capacity and oxidative stress[7]
  • What was studied? Researchers looked at how 1.25 grams of betaine daily for two weeks affected aerobic capacity, oxidative stress, and other programmed cell death after exhaustive endurance exercise in healthy men.

  • Why study it? Exhaustive exercise can generate oxidative stress and lead to white blood cells to undergo apoptosis (programmed cell death) which may lower immune function. Betaine has been found to dampen oxidation and also affect apoptotic pathways in cell cultures.

  • What was(n’t) found? Betaine had no effect on aerobic capacity or oxidative stress.

  • How null was it? So-so. This was a small trial, but it used a cross-over design that increased its ability to find positive results. However, there was no power calculation done, which makes it difficult to interpret these null results.

  • Anything else? Lymphocyte apoptosis was lower in the betaine group, which suggests a possible benefit for immune function for people undertaking exhaustive exercise. This finding justifies further study to determine if these changes persist over the long term and what practical consequences there are, if any.

Beetroot juice may not help with low-oxygen performance[8]
  • What was studied? In this study, researchers examined how daily consumption of beetroot juice containing 12.4 mmol of nitrate affected the endurance performance of male athletes undergoing high-intensity intermittent exercise at different oxygen levels meant to simulate different altitudes.

  • Why study it? Dietary nitrate’s transformation to nitric oxide is dependent on how much oxygen there is: lower oxygen leads to more conversion to nitric oxide. Since nitric oxide is ergogenic, it’s possible that dietary nitrate may be especially potent in lower oxygen environments, and thus could be especially helpful for athletic performance at higher altitudes.

  • What was(n’t) found? There was no effect of nitrate supplementation on time to exhaustion in normal oxygen conditions, or in conditions simulating oxygen levels at an altitude of 2,400 meters.

  • How null was it? This was a small study that, while well designed, didn’t have a power calculation, making it hard to interpret the null result. This study probably rules out large or medium effects, but may not rule out small effects that could matter to professional athletes.

Bovine colostrum didn’t affect immune markers in elite basketball players[9]
  • What was studied? Researchers investigated whether 24 weeks of supplementing 3.2 grams of bovine colostrum twice daily would affect the blood immune markers of elite female basketball players after a stress test.

  • Why study it? One of the functions of “first milk,” or colostrum, is to help boost the immune systems of newborns, and it has been shown to have several effects on immune cells. Since extreme exercise is known to suppress immune function, it’s possible that bovine colostrum could help fend off sickness in athletes. However, this hasn’t been very well studied.

  • What was(n’t) found? No difference in any immune marker was found between the placebo and colostrum groups after stress tests.

  • How null was it? Not very. The study was small, and although a power calculation was done, the details are somewhat unclear, making the null results hard to interpret. Also, the stress tests didn’t affect any of the immune markers measured except for IL-10 at one time point, suggesting that the exercise performed during the stress test may not have been sufficient to suppress immunity, or that the markers were not measured at an appropriate time relative to the stress tests in order to observe differences in immune markers.

Quinine doesn’t help with longer cycling races[10]
  • What was studied? This study was designed to evaluate whether trained male cyclists consuming a drink containing about 16 mg of quinine just over halfway through a 3-kilometer cycling time trial could boost power output at the end of the race.

  • Why study it? Quinine has been found to improve short-term sprint performance, but its effects on longer-term performance remain unclear.

  • What was(n’t) found? There was no difference in power output in the last kilometer of the time trial between quinine and two control conditions: plain water and a placebo made to taste similar to quinine.

  • How null was it? Pretty null. While this study was small, it had a crossover design that boosted its power. The study may not rule out tiny improvements that could matter to elite cyclists, though.

Acute capsiate ingestion didn’t boost 10 km running time[11]
  • What was studied? Researchers investigated whether taking 12 mg of capsiate (a less harsh analog of capsaicin) 45 minutes before and again immediately before a 10-km time trial could boost times in amateur male athletes.

  • Why study it? There’s some evidence that capsiate can boost shorter and medium-distance aerobic performance in humans, but longer-distance human data is lacking.

  • What was(n’t) found? There was no advantage in time trial performance for the capsiate group over placebo.

  • How null was it? This study was well-powered to detect a medium effect size, but can’t rule out small effects.

Outside the box

Vitamin D supplementation doesn’t provide clear benefit for people with cystic fibrosis[12]
  • What was studied? This meta-analysis included clinical trials that explored how vitamin D supplementation affects clinical outcomes in people with cystic fibrosis.

  • Why study it? People with cystic fibrosis have low vitamin D levels, and the Cystic Fibrosis Foundation recommends that vitamin D levels be maintained above 30 ng/dL. Given vitamin D’s wide-ranging effects on body tissues, it’s possible that vitamin D supplementation could influence cystic fibrosis outcomes. However, clinical trials exploring the effects of supplementation have been equivocal due in large part to their small sample sizes. Meta-analysis may be able to pool these trials together to increase the chances of finding effects.

  • What was(n’t) found? No immunological, respiratory, or bone-related outcomes were clearly influenced by vitamin D supplementation.

  • How null was it? Not very null. Why high doses were used in some cases, the quality of evidence was assessed to be very low in general. Higher quality evidence could shed more light on this issue.

Vitamins & minerals

Not much need for vitamin C on top of iron for iron deficiency anemia[13]
  • What was studied? This study was designed to evaluate whether adding 200 mg of vitamin C on top of 100 mg of ferrous succinate taken every eight hours for eight weeks would help with iron deficiency anemia more than just the ferrous succinate alone.

  • Why study it? Vitamin C can improve iron absorption by creating a more acidic environment and prevent iron oxidation. But, whether this translates to improved outcomes for people with iron deficiency anemia remains unclear.

  • What was(n’t) found? Adding vitamin C didn’t boost hemoglobin (the primary outcome), nor did it strongly affect iron absorption.

  • How null was it? Pretty null for the main outcome, but see below for some notes on the secondary outcomes. The study was well designed, had a large sample size of over 400 people, and the researchers predeclared the primary outcome and tested for a clinically important change in hemoglobin of 1 g/dL. There are two caveats, though: the study was short and these results may not extend to the long term, and the population was mostly women so whether the same effect carries over to men remains less clear.

  • Anything else? There were some mild benefits found in mean corpuscular volume (the average size of red blood cells) and mean corpuscular hemoglobin (how much hemoglobin is packed inside red blood cells on average) in the vitamin C group.

Vitamin supplementation provides little relief for rheumatoid arthritis[14]
  • What was studied? Researchers reviewed and meta-analyzed trials examining the effects of vitamin supplementation on rheumatic inflammatory diseases.

  • Why study it? Vitamins play many roles in inflammatory processes, so supplementation could help relieve inflammation. The aim of this study was to systematically review and meta-analyze the literature on how several vitamins could affect inflammatory rheumatic diseases to give a broad view of the state of the literature.

  • What was(n’t) found? Although all inflammatory rheumatic disorders were included in the search, only studies on rheumatoid arthritis were found. Overall, supplementation with vitamins D, E, K, or folic acid were not found to have any clear effect on rheumatoid arthritis outcomes.

  • How null was it? Not very. First, there weren’t many studies uncovered and some were of low quality, leaving room for more evidence in many cases. Also, vitamin D had a borderline significant effect on one measure of rheumatoid arthritis activity, which may bear fruit with more study.

  • Anything else? The authors still recommend folic acid supplementation to help prevent side effects when people with rheumatoid arthritis are treated with methotrexate, and suggest that vitamin D supplementation may also be useful due to the high rate of vitamin D deficiency in people with rheumatoid arthritis.

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See other articles with similar topics: Nulls.

See other articles in Issue #77 (March 2021) of Study Deep Dives.

Other Articles in Issue #77 (March 2021)


  1. ^ Genevieve McPhilemy, et al. A 52-week prophylactic randomised control trial of omega-3 polyunsaturated fatty acids in bipolar disorder. Bipolar Disord. (2020)
  2. ^ Justin C Brown, et al. Effect of High-Dose vs Standard-Dose Vitamin D 3 Supplementation on Body Composition among Patients with Advanced or Metastatic Colorectal Cancer: A Randomized Trial. Cancers (Basel). (2020)
  3. ^ Mehdi Sadeghian, et al. Lycopene Does Not Affect Prostate-Specific Antigen in Men with Non-Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutr Cancer. (2020)
  4. ^ Marion Burckhardt, et al. Souvenaid for Alzheimer's disease. Cochrane Database Syst Rev. (2020)
  5. ^ Darren G Candow, et al. Effect of 12 months of creatine supplementation and whole-body resistance training on measures of bone, muscle and strength in older males. Nutr Health. (2020)
  6. ^ Kana Ram Jat, et al. Efficacy of vitamin D supplementation in asthmatic children with vitamin D deficiency: A randomized controlled trial (ESDAC trial). Pediatr Allergy Immunol. (2020)
  7. ^ Ming-Ta Yang, et al. Effects of Two-Week Betaine Supplementation on Apoptosis, Oxidative Stress, and Aerobic Capacity after Exhaustive Endurance Exercise. Antioxidants (Basel). (2020)
  8. ^ George P Robinson, et al. Influence of Dietary Nitrate Supplementation on High-Intensity Intermittent Running Performance at Different Doses of Normobaric Hypoxia in Endurance-Trained Males. Int J Sport Nutr Exerc Metab. (2020)
  9. ^ Anna Skarpańska-Stejnborn, et al. Effects of Long-Term Supplementation of Bovine Colostrum on the Immune System in Young Female Basketball Players. Randomized Trial. Nutrients. (2020)
  10. ^ Naroa Etxebarria, et al. Quinine Ingestion During the Latter Stages of a 3,000-m Time Trial Fails to Improve Cycling Performance. Int J Sport Nutr Exerc Metab. (2020)
  11. ^ Ana Elisa von Ah Morano, et al. Capsaicin Analogue Supplementation Does Not Improve 10 km Running Time-Trial Performance in Male Amateur Athletes: A Randomized, Crossover, Double-Blind and Placebo-Controlled Study. Nutrients. (2020)
  12. ^ Márk Félix Juhász, et al. Vitamin D supplementation in patients with cystic fibrosis: A systematic review and meta-analysis. J Cyst Fibros. (2020)
  13. ^ Nianyi Li, et al. The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial. JAMA Netw Open. (2020)
  14. ^ Yann Nguyen, et al. Efficacy of Oral Vitamin Supplementation in Inflammatory Rheumatic Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. (2020)