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Here’s a very quick summary of some randomized controlled trials (RCTs) and meta-analyses of RCTs that were published toward the end of 2019 and didn’t find evidence of an effect. This is known as a null effect.

Keep this 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.

Allergies and immunity

Omega-3 supplementation’s ability to reduce the risk of developing childhood allergies is unclear[1]
  • What was studied? RCTs examining the development of allergic diseases (such as asthma, eczema, food allergy, or allergic rhinitis) in children who supplemented with omega-3s were meta-analyzed.

  • Why study it? Observational studies have found that children breast-fed with milk lower in DHA and EPA have a higher risk developing of allergic diseases, and clinical trial evidence is mixed.

  • What was(n’t) found? There was no statistically significant reduction in the risk of developing any allergy at all, or any particular allergy.

  • How null was it? Not very, since most of the evidence quality was rated as low or very low, with the exception of the evidence for eczema, which was rated as moderate. Furthermore, low sample sizes mean there’s a lot of uncertainty in the risk reduction estimate, and the data are sometimes consistent with fairly large, clinically significant risk reductions. More high quality research is needed.

Autoimmune diseases

Fish oil didn’t impact psoriasis[2]
  • What was studied? RCTs examining fish oil supplementation’s impact on psoriasis. The meta-analysis ultimately involved three studies of 337 people. Daily doses were around 1.5–4.2 grams of EPA and 1.5–4.2 grams of DHA.

  • Why study it? Fish oil has anti-inflammatory effects which may impact psoriasis, but clinical trial evidence has been mixed.

  • What was(n’t) found? There was no clear benefit on psoriasis, as measured by the Psoriasis Area and Severity Index (PASI).

  • How null was it? While the data are consistent with a reduction in the main outcome of almost two points, the PASI score ranges from 0 to 72, with higher being more severe. This suggests that the data isn’t consistent with clinically meaningful changes in PASI.

Vitamin D supplementation has little impact on disability rating in people with multiple sclerosis[3]
  • What was studied? RCTs involving people with multiple sclerosis (MS) supplementing with vitamin D were meta-analyzed. Six trials were included, involving 331 people with an average starting score of around 3 out of 10 on the Expanded Disability Status Scale[4] (EDSS).

  • Why study it? Observational studies have found that people with lower vitamin D levels have more active relapsing-remitting MS, but the effect of supplementation is unclear.

  • What was(n’t) found? Vitamin D supplementation, with or without calcium, had no statistically significant impact on EDSS score compared to placebo.

  • How null was it? The results are a mixed bag… literally. The included studies were very different from each other in important ways, such as doses and dosing schedules. While the available evidence wasn’t consistent with a large effect, more evidence would be useful given how different the studies were from each other and how small each of them was.


An aqueous kava extract didn’t outperform placebo in people with generalized anxiety disorder[5]
  • What was studied? The effect of an aqueous extract of dried kava, standardized to 120 milligrams of kavalactones, taken twice a day for 16 weeks in 171 people diagnosed with generalized anxiety disorder.

  • Why study it? Ethanolic and acetonic extracts of kava can reduce anxiety, but may also have serious adverse effects, especially on the liver. Aqueous kava extracts have been less well studied.

  • What was(n’t) found? Aqueous kava extract didn’t improve the primary outcome of Hamilton Anxiety Rating Scale score compared to placebo.

  • How null was it? Fairly null for the aqueous extract, since the study was powered to detect a pretty small difference (≈2.5 points; the scale ranges from 0 to 30, and the participants’ baseline scores were around 22, indicating mild to moderate anxiety). Also the study was preregistered and the primary outcome wasn’t switched over the course of the study.

  • Anything else? The kava group experienced significantly more adverse effects than the placebo group, including worse memory, tremor, and elevated liver damage markers. However, there were no cases of severe adverse effects in the kava group.

Fat loss

The effects of prebiotics on body weight are unclear[6]
  • What was studied? RCTs involving prebiotic supplementation in people with overweight and obesity were meta-analyzed. A total of 12 trials involving 535 people were included.

  • Why study it? Animal data has suggested that prebiotics can impact the gut microbiome and in turn affect weight. However, human studies have been small and equivocal.

  • What was(n’t) found? There were no statistically significant improvements in BMI, body weight, or fat mass compared to placebo.

  • How null was it? The confidence intervals for body weight and BMI suggest that the data is consistent with reductions up to 1.2 kilograms and 0.58, respectively. While this study provides some evidence against large effects on weight, it doesn’t rule out a more modest impact.

  • Anything else? Some statistically significant improvements in inflammatory markers were seen with prebiotic supplementation.

Foods and diet patterns

Dietary interventions showed little benefit for people who survived cancer[7]
  • What was studied? RCTs of people who survived cancer were meta-analyzed. The population was mostly female, with breast cancer being the most represented form of cancer. However, trials involving people with mixed-site, colorectal, and gynecological cancer were also included.

  • Why study it? Cancer risk is known to be influenced by diet, and dietary guidelines for cancer prevention exist. However, the effects of dietary changes in people who have survived a bout of cancer are less clear.

  • What was(n’t) found? Dietary interventions had no clear effect on risk of dying or rate of the cancer spreading. Energy intake also didn’t seem to be affected.

  • How null was it? Not very, since most of the evidence was rated as low or very low in quality, which implies that more evidence of higher quality could change the conclusions.

Memory and focus

B vitamin supplementation didn’t outperform placebo in people with mild cognitive impairment[8]
  • What was studied? The influence of 500 micrograms of methylcobalamin (vitamin B12) and 400 micrograms of folic acid daily for two years on 279 people with mild cognitive impairment. The people in the study were at least 65 years old and tended to have diseases that can impact blood vessels, such as high blood pressure and diabetes.

  • Why study it? Vitamin B12 and folic acid can lower plasma homocysteine levels, which is associated with cognitive decline.

  • What was(n’t) found? Supplementation had no clear effect on the primary outcome of cognitive decline, as measured by the clinical dementia rating scale sum of boxes.

  • How null was it? The trial’s placebo group didn’t experience a big change in the primary outcome over time, which surprised the authors and raises the strong possibility that this study wasn’t big enough to detect clinically meaningful changes in cognition, assuming any exist.

Muscle gain and exercise

Vitamin D supplementation didn’t clearly improve athletes’ muscle strength[9]
  • What was studied? RCTs studying the effect of vitamin D supplementation on athletes’ muscle strength was meta-analyzed. The athletes tended to be vitamin D insufficient at baseline.

  • Why study it? Vitamin D levels are associated with muscle health, but the results from trials testing supplementation’s effects have yielded mixed results.

  • What was(n’t) found? Although athletes became vitamin D sufficient over the course of the trials included in this meta-analysis, no clear effect was seen on overall muscle strength or specific measures like bench-press one-repetition maximum.

  • How null was it? The confidence intervals were wide on all metrics, and only 163 athletes were included in the meta-analysis. This means that more trials are needed to shrink uncertainty and reveal an effect, if there is one.

Vitamins and minerals

Vitamin D didn’t improve muscle strength in people with vitamin D insufficiency[10]
  • What was studied? 417 people between 40 and 80 years old with baseline vitamin D levels around 34 nmol/L (14 ng/mL) were given either placebo or a loading dose of 100,000 IU vitamin D3 followed by 20,000 IU per week for four months.

  • Why study it? Low vitamin D levels can cause several musculoskeletal problems through several plausible mechanisms. Clinical studies to date have used different dosing regimens and involved different types of people, making meta-analysis hard and justifying further clinical research.

  • What was(n’t) found? No statistically significant effect on any measure of muscle strength (such as hand grip, hip flexion, and biceps flexion) was found.

  • How null was it? This should be taken as preliminary evidence, since this was a substudy of a larger study not designed to test the hypothesis of vitamin D’s impact on strength. Also, multiple measurements were taken, no primary outcome was specified, and a specific, non-daily dosing regimen was used.

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See other articles with similar topics: Omega 3, Allergies, Psoriasis, Fish Oil, Multiple Sclerosis, Vitamin D, Anxiety, Kava, Prebiotics, Weight Loss, Cancer, Diet, Vitamin B, Cognitive Decline, Cognition, Muscle Mass, Nulls.

See other articles in Issue #64 (February 2020) of Study Deep Dives.

Other Articles in Issue #64 (February 2020)


  1. ^ Zhang Y, et al. Effect of omega-3 fatty acids supplementation during childhood in preventing allergic disease: a systematic review and Meta-Analysis. J Asthma. (2020)
  2. ^ Yang SJ, Chi CC. Effects of fish oil supplement on psoriasis: a meta-analysis of randomized controlled trials. BMC Complement Altern Med. (2019)
  3. ^ Doosti-Irani A, et al. The effects of vitamin D supplementation on expanded disability status scale in people with multiple sclerosis: A critical, systematic review and metaanalysis of randomized controlled trials. Clin Neurol Neurosurg. (2019)
  4. ^ Çinar BP, Yorgun YG. What We Learned from The History of Multiple Sclerosis Measurement: Expanded Disability Status Scale. Noro Psikiyatr Ars. (2018)
  5. ^ Sarris J, et al. Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study. Aust N Z J Psychiatry. (2019)
  6. ^ Qu H, et al. The lacking effects of prebiotic products on decreasing adiposity parameters in overweight and obese individuals: a systematic review and meta-analysis. Curr Med Chem. (2019)
  7. ^ Burden S, et al. Dietary interventions for adult cancer survivors. Cochrane Database Syst Rev. (2019)
  8. ^ Kwok T, et al. A randomized placebo-controlled trial of using B vitamins to prevent cognitive decline in older mild cognitive impairment patients. Clin Nutr. (2019)
  9. ^ Han Q, et al. Effects of vitamin D3 supplementation on serum 25(OH)D concentration and strength in athletes: a systematic review and meta-analysis of randomized controlled trials. J Int Soc Sports Nutr. (2019)
  10. ^ Grimnes G, Kubiak J, Jorde R. Four months vitamin D supplementation to vitamin D insufficient individuals does not improve muscular strength: A randomized controlled trial. PLoS One. (2019)