Why Do Weight Loss Trials See Success in the Placebo Group?
In late 2024, the US FDA proposed removing phenylephrine, the active ingredient in Sudafed PE (PE stands for phenylephrine), from over-the-counter drug shelves.[1] The FDA found no evidence that the medication was dangerous, but instead reviewed data showing it was no better than a placebo at treating colds, allergies, or nasal congestion.[1] This may sound like the drug isn’t effective, but that view overlooks another truth: those in the placebo group of these research studies experienced significant relief from their symptoms. This is a “problem” for many investigational medications, but is good news for research participants. The placebo effect doesn’t just affect participants in cold and flu studies. In fact, research participants in the placebo groups of weight loss studies make significant improvements as well, even when they struggle with being overweight or having obesity.
Obesity is a growing problem in the United States and around the world.[2] It has reached pandemic status and negatively affects multiple organs, leading to a reduced quality of life, heart problems, breathing issues, metabolic changes, diabetes, vitamin deficiency, bone damage, intestinal complications, and mental health disorders.[3] Weight loss is the primary goal of most obesity treatments. The challenges of weight loss are heavy, however. Weight loss is often difficult to achieve even with medication, which is why the improvements from the placebo effect are so impressive.
Several meta-analyses have been done to evaluate the effect of placebo on weight loss. A meta-analysis is a study that combines data from many other studies to examine broader trends. The results of these studies are clear: people who join clinical weight loss trials lose weight - even when they receive a placebo.[2,4,5] One analysis of 69 studies, which enrolled a total of over 20,000 participants, found that 1 in 5 of them lost at least 5% of their bodyweight, equal to 8 pounds for a 160 lb adult, and that 1 in 16 lost 15%, around 24 pounds for the same 160 lb adult.[4] This is a significant amount of weight loss, with one study finding that participants who lost 5% of body weight had improved metabolic function in the liver and muscles, and improved white blood cell function.[6] A much larger analysis of 182 trials found that 95% of enrolled patients who were in the placebo group lost weight, and those without diabetes lost an average of more than 4 ½ pounds.[2] In addition, they found that those who had a higher BMI at the start of the study had greater success over the course of the study. This effect has also been observed with fake injected drugs, sham bariatric surgery, and even situations when patients are fully aware they are receiving a placebo![2,5,7]
But… how can this be? These are patients taking medications with no active ingredients but achieving significant weight loss. Of course, there is the clear benefit of being in a clinical trial in the first place. For many participants, being in a clinical trial is the first time they experience the healthcare system as it should be: full of compassionate, inquisitive medical professionals who are required to know everything happening to you medically. Furthermore, lifestyle education, along with diet and exercise information and accountability, is the primary treatment for obesity and is required for robust weight loss.[2,8] Simply being in a clinical trial is a good start, but not the whole story. Research shows that being on a placebo leads to about 50% more weight loss than receiving lifestyle advice alone.[7]
So placebos can produce surprising results without any active ingredients, but is that all? Of course not. Clinical trials use a placebo, along with diet and exercise training, to ensure that investigational medications are even better. Placebo testing is a critical part of the clinical trial process, which lets scientists determine whether the weight loss people experience in a trial is due to the active ingredients or the placebo effect. Everyone enrolled in weight loss studies is critical to the scientific process. And the fact that those on placebo are likely to lose weight as well is effectively awesome!
Creative Director Benton Lowey-Ball, MWC, BS, BFA
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References:
[1] FDA Proposes Ending Use of Oral Phenylephrine as OTC Monograph Nasal Decongestant Active Ingredient After Extensive Review. U.S. Food and Drug Administration. November 7, 2024. Available from:
[2] Guo Y, Yang W, Lin C, Wu H, Li Z, Jiao R, Bai S, Liu G, Yang X, Cai X, Ji L. Placebo response on the weight change and its influencing factors in overweight or obesity with or without diabetes: a meta-analysis of 182 anti-obesity medications trials. Communications Medicine. 2026 Jun 5. https://doi.org/10.1038/s43856-026-01659-7
[3] Lim Y, Haq N, Boster J. Obesity and comorbid conditions. InStatPearls [Internet] 2024 Jun 27. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK574535/
[4] Chin YH, Ng CH, Chew NW, Kong G, Lim WH, Tan DJ, Chan KE, Tang A, Huang DQ, Chan MY, Figtree G. The placebo response rate and nocebo events in obesity pharmacological trials. A systematic review and meta-analysis. EClinicalMedicine. 2022 Dec 1;54. https://doi.org/10.1016/j.eclinm.2022.101685
[5] Jonas WB, Crawford C, Colloca L, Kaptchuk TJ, Moseley B, Miller FG, Kriston L, Linde K, Meissner K. To what extent are surgery and invasive procedures effective beyond a placebo response? A systematic review with meta-analysis of randomised, sham controlled trials. BMJ open. 2015 Dec 1;5(12):e009655. https://doi.org/10.1136/bmjopen-2015-009655
[6] Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, de Las Fuentes L, He S, Okunade AL, Patterson BW, Klein S. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell metabolism. 2016 Apr 12;23(4):591-601. https://doi.org/10.1016/j.cmet.2016.02.005
[7] Schaefer M, Kühnel A, Enge S. Open-label placebos reduce weight in obesity: a randomized controlled trial. Scientific Reports. 2024 Sep 12;14(1):21311. https://doi.org/10.1038/s41598-024-69866-7
[6] Hassan Y, Head V, Jacob D, Bachmann MO, Diu S, Ford J. Lifestyle interventions for weight loss in adults with severe obesity: a systematic review. Clinical obesity. 2016 Dec;6(6):395-403. https://doi.org/10.1111/cob.12161
