The Trouble with Turmeric
Liver Injury Lotto
Turmeric is the common name for Curcuma longa. Most people are familiar with using the underground stem (rhizome) in cooking, and many have also probably heard about it as part of some traditional medicine. Like many plants, turmeric contains bioactive compounds, most notably a class called curcuminoids, which includes curcumin. It is curcumin that gives turmeric its distinctive yellow color. Both turmeric and curcumin are promoted as natural medications or supplements, and the benefit of turmeric is believed to be due to curcuminoids, primarily curcumin. The global turmeric/curcumin supplement market was $70 million/year in 2020, estimated to be $112 million/year in 2025. Yes, for one supplement. It is aptly referred to as the golden spice.
To see how much an individual could make from turmeric, I set up my own supplement and distribution system (read about that here). If I charge $35 a bottle, I net $15 a bottle. If I can sell just 8,333 bottles, I can cover my start-up costs and net $195,760. It’s easy to see how someone with a million followers on Instagram or a popular podcast could leverage that large presence to make hundreds of thousands of dollars a year just selling turmeric or curcumin.
“He who controls the spice controls the universe” is a quote from Dune (1994) that seems to apply to turmeric today.
Recently, turmeric has received more attention courtesy of Dr. Marie Claire Haver, an OB/GYN and menopause specialist with a supplement business. Given her promotion of turmeric for menopause and the money to be made, I felt it was worth a closer look.
Are menopausal women wasting their money with turmeric products, like those sold by Dr. Haver, or is there something to turmeric?
The Biology of Turmeric and Curcumin
For a substance like turmeric to provide medicinal value beyond the gut, it must be absorbed into the blood. When ingested, about 99% of turmeric remains in the gut and heads out of the body with stool. This means that almost none of it gets into the blood, which also means that turmeric in reasonable doses is nontoxic, although adulteration with lead can be a concern with turmeric spice and turmeric supplements (which are much higher amounts than used in cooking). Contamination with lead can come from the soil where the turmeric is grown, or turmeric/curcumin can be purposely adulterated with lead chromate to enhance the yellow color.
Curcumin is a highly problematic molecule. In addition to being poorly absorbed, it’s challenging to study in a lab. Curcumin is classified as one of the pan-assay interference compounds, or PAINS, which means it can interfere with lab tests in various ways (and means the acronym PAINS is very accurate). I asked Kevin Klatt, PhD, RD, a research scientist and instructor in Nutrition Sciences and Toxicology at Berkeley, who told me, “PAINS are a problem because, in science, we can rarely observe what is happening biologically, but rather we develop assays with specific readouts that tell us what is happening biologically (e.g., a color change, increased fluorescent signal) and curcumin interferes with these readouts.” This kind of interference can lead researchers to believe that curcumin might be doing something when, in reality, it’s just messing with the test results, so the results may be spurious. There is also concern about curcumin being unstable.
Compounds that are absorbed poorly, that may be unstable, and that create unreliable results are generally not good candidates for medications. This means studying curcumin requires the utmost scientific rigor; otherwise, the results will be meaningless. Science needs reproducibility and reliability, not crap shoots. The problems inherent in studying curcumin are laid out in detail in a 2017 review of the biology of curcumin in the Journal of Medicinal Chemistry that calls the substance “an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead.” The way curcumin can respond in the lab can make weak research leads look more robust than they are, leading to research that is destined to fail because it was built on a false premise. This sucks up precious research funding.
There are also issues with many papers evaluating curcumin. Bharat B. Aggarwal, PhD, was a biochemist from MD Anderson Cancer Center who co-authored over 120 papers on curcumin. In 2012, the U.S. Department of Health and Human Services' Office of Research Integrity notified MD Anderson about concerns regarding image manipulation in 65 of his papers. By 2022, at least 30 of his papers had been retracted due to concerns about scientific misconduct; apparently, more are problematic. Dr. Aggarawal is currently at #27 on the Retraction Watch Leader Board for most retracted papers, yet people continue to cite his work in articles about turmeric or curcumin! In addition, many studies about curcumin from other authors have been flagged as potentially originating from paper mills.
Does Turmeric/Curcumin do Anything Medical?
From 1995 to 2017, the NIH funded curcumin with over $150 million, yet we have no quality data to make a solid recommendation for any indication.
There are many studies of varying quality, but very few are high-quality, randomized, double-blind placebo control trials. There is no orderly progression from basic science or lab research to Phase 1, then Phase 2, and then Phase 3 clinical trials, as we demand with pharmaceuticals. In addition, many studies use different formulations, so comparing the results meaningfully isn’t possible. We need quality Phase 3 studies to recommend a pharmaceutical, so why should we hold turmeric/curcumin to a lower standard? There have been over $150 million in NIH funding, and it’s a $70 million-dollar-a-year and growing business, so the absence of quality studies can’t be for want of money.
There is a recent scoping review of curcumin (2023). A scoping review is a lay-of-the-land kind of review; it is not the kind of rigorous scientific review we see with a systemic review, which is a deep dive into the data to attempt to answer a specific question. Scoping reviews are generally done when the data isn’t strong enough yet to support a systemic review. While many of the studies included were randomized double-blinded placebo-controlled trials, the quality of these studies wasn’t interrogated. Some studies included in the review were small (as few as 3 or 4 participants), most were short-term, and there was no evaluation of study methods, statistical analysis, or potential bias (this is typical of a scoping review). In addition, formulations of curcumin were not consistent between studies. Conclusions about benefits aren’t possible with scoping reviews, and these publications should not be used to guide therapy. The result of the scoping review suggests that maybe curcumin might have benefits for arthritis and for people with metabolic syndrome, but additional research is needed with high-quality clinical trials.
However, another review (2022) looking at the data had a much harsher conclusion:
Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.
And:
However, compared with a large number of exciting preclinical studies on curcumin, the clinical studies on curcumin are rather dull.
And therein lies one of the issues with low quality studies that are typical of so-called alternative medicine. If you consider low-quality studies, the results look more promising, but when stricter criteria are applied, the results become underwhelming.
Dr. Klatt agreed with me about the state of the literature. He told me that robust clinical trials with curcumin are:
“often lacking, with a few small, high risk of bias trials in diseases like inflammatory bowel disease and osteoarthritis suggesting small clinical benefit. To date, no societies are recommending curcumin, partly due to the lack of RCTs, and partly due to the challenges in having standardized formulations (i.e. giving a similar amount of curcuminoids across batches) that are shelf-stable. One of the problems in the curcumin research space is that few trials have measured outcomes that are clinically relevant - for example, you can find trials that show a certain curcumin formulation slightly lowers an inflammatory marker like hsCRP or an oxidative stress marker, but these have limited prognostic capacity in many disease states. Whether the curcumin is actually improving validated disease metrics (e.g. histology, pain scores, remission rates/duration, disease events) is often unknown. Unfortunately, claims around inflammation, metabolism, and oxidative stress are recognizable by the public and imply a clinical benefit where one rarely has been demonstrated.”
In simpler terms, we just don’t have the kind of quality clinical trials we need to make recommendations. This is shocking, considering the funding.
A common reason to recommend turmeric or curcumin is arthritis. The 2019 guidelines on osteoarthritis from the American College of Rheumatology (ACR) don’t mention turmeric or curcumin. Interestingly, Dr. Haver recommends turmeric for bone mineral density, but neither of her two provided references for turmeric supports that claim. The Menopause Society 2021 Position Statement on Osteoporosis doesn’t mention turmeric or curcumin. There are a few small, low-quality, short-term studies suggesting turmeric/curcumin might benefit bone density, but we shouldn’t make clinical recommendations based on that kind of data. In one of the studies I found, two authors worked for the company that made the curcumin, and one was a consultant for the company. Many women in menopause are concerned about their bone health, and in my opinion, it is predatory to suggest turmeric as a viable therapy and then conveniently sell it.
Dr. Haver also recommends turmeric to treat exercise-induced muscular pain to improve recovery, but a 2017 Cochrane review of antioxidant supplements for muscle soreness after exercise, which included curcumin supplements, concluded, “There is moderate to low‐quality evidence that high dose antioxidant supplementation does not result in a clinically relevant reduction of muscle soreness after exercise at up to 6 hours or at 24, 48, 72 and 96 hours after exercise.” I added the bold for emphasis.
Also, no supplement is recommended in the Menopause Society’s latest guidelines for treating hot flashes.
Liver Injury
As curcumin isn’t absorbed well, there has been an explosion of different formulations to improve absorption and bioavailability, such as combining turmeric or curcumin with piperine (from black pepper) or formulating the curcumin in nanoparticles or encasing it in lipids. Some claim that these methods might increase absorption by 2000%. But here’s the catch. Turmeric and curcumin have been considered relatively benign because absorption was so bad, so what might happen when it’s actually absorbed?
Curcumin can negatively affect iron metabolism, and there are reports of iron deficiency. This may be an issue for those who already have low iron levels, which is a common issue for women. There is a concern that if absorbed curcumin might be toxic to more than cancer cells as there is also data showing it can be toxic to human kidney cells and macrophages (a type of white blood cell). A recent animal study evaluating curcumin nanoparticles shows that while low and medium doses of curcumin nanoparticles were safe for rodents, high doses damaged the liver, spleen, kidneys, lungs, and pancreas. This means these new curcumin products with enhanced absorption/bioavailability need rigorous safety data (and, of course, data showing they actually work) before they are used. Like we demand of any new drug.
The biggest safety concern with turmeric/curcumin appears to be liver injury, and there are multiple reports from many countries:
The Italian Ministry of Health banned health claims regarding turmeric and curcumin supplements, spurred on by more than 20 cases of turmeric/curcumin-related hepatitis.
The French Agency for Food, Environmental and Occupational Health & Safety reports over 100 cases of adverse effects (15 cases of hepatitis) related to turmeric and/or curcumin.
In Australia, there have been at least 18 cases of liver injury related to turmeric/curcumin, including one fatality.
At least 10 cases of liver injury related to turmeric/curcumin have been reported in the United States, with one death. The most common scenario was a woman “using turmeric for arthritis, pain relief, and/or general health.”
Contamination with lead or dyes as a cause of the liver injury has been ruled out, so it seems to be the curcumin. In addition, the rising numbers of liver injuries seem to parallel the flood of new products designed to enhance curcumin absorption.
Currently, only 0.5% of drug-related liver injuries are due to turmeric/curcumin, but there has been an alarming bump that parallels the recent introduction of newer products. As they have not been studied meaningfully, from a safety standpoint, this is all buyer beware.
Unknowns
Could a formulation of turmeric/curcumin with enhanced absorption be safe and effective for some medical conditions? Sure. We must always be open to quality data; that is the amazing meandering path of science. However, an equally plausible hypothesis is that no meaningful benefit will be found. This is why we do research. It’s concerning that over $150 million in American taxpayer dollars later, we still don’t have good data for curcumin. In 2022, endometriosis received $27 million in NIH funding, but it has traditionally been much lower than that. It’s hard to play research favorites, but it’s also hard to see money go to support funding for a molecule that has resulted in less than spectacular results, and yet we still don’t understand the basic biology of a disease that affects 10% of women.
Some have wondered if curcumin's beneficial effects might be via an effect on the gut microbiome, and that avenue is largely unexplored. So yes, it’s possible. Again, we need data.
Products with enhanced absorption need quality studies to show they work and rigorous safety testing, but those are not the kind of studies we have come to expect from the supplement industry. And because the supplement industry doesn’t have to do those studies, it’s up to the taxpayers to fund them, which diverts funding from other diseases and therapies.
Women Deserve Data
I am so tired of inadequately tested products being foisted on women. If you think your product is effective and safe, prove it. Not doing that work means you think women don’t deserve quality data. Also, there’s the issue of spending $420 ($35/bottle x 12 bottles per year) or so dollars a year on a product with dismal data.
The fact that turmeric is a plant doesn’t mean it’s effective or safe (the dose in supplements is far more than people ingest with cooking), and the fact that it has been used traditionally doesn’t mean it’s effective or safe. Those who sell curcumin supplements don’t fund rigorous studies because they don’t have to. Look, they are already making a small fortune selling them, so why risk a negative result?
If you are taking a turmeric/curcumin supplement that doesn’t have something to enhance absorption, you are likely just paying for expensive feces. If you are taking a product designed to enhance absorption, you should be mindful of your iron status and know that you are paying to play the liver injury lotto with no quality data to prove that the product can help you meaningfully. I think you deserve better than that.
Those who sell curcumin supplements don’t fund rigorous studies because they don’t have to. Look, they are already making a small fortune selling them, so why risk a negative result?
References
Lowe, D. Science.org Curcumin will Waste Your Time https://www.science.org/content/blog-post/curcumin-will-waste-your-time (of note the author has his PhD in organic chemistry)
Kathryn M. Nelson, Jayme L. Dahlin, Jonathan Bisson, James Graham, Guido F. Pauli, and Michael A. Walters. The Essential Medicinal Chemistry of Curcumin Miniperspective. Journal of Medicinal Chemistry 2017 60 (5), 1620-1637
DOI: 10.1021/acs.jmedchem.6b00975 https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b00975
Newman, D. J. (2021). Problems that Can Occur when Assaying Extracts to Pure Compounds in Biological Systems. Current Therapeutic Research, 95, 100645. https://doi.org/10.1016/j.curtheres.2021.100645
Dahlin, J. L., Auld, D. S., Rothenaigner, I., Haney, S., Sexton, J. Z., Nissink, J. W. M., Walsh, J., Lee, J. A., Strelow, J. M., Willard, F. S., Ferrins, L., Baell, J. B., Walters, M. A., Hua, B. K., Hadian, K., & Wagner, B. K. (2021). Nuisance compounds in cellular assays. Cell Chemical Biology, 28(3), P356-370. https://doi.org/10.1016/j.chembiol.2021.01.021
Retraction Watch https://retractionwatch.com/2013/04/10/md-andersons-bharat-aggarwal-threatens-to-sue-retraction-watch/
Nowak KL, Farmer-Bailey H, Wang W, You Z, Steele C, Cadnapaphornchai MA, Klawitter J, Patel N, George D, Jovanovich A, Soranno DE, Gitomer B, Chonchol M. Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial. Clin J Am Soc Nephrol. 2022 Feb;17(2):240-250. doi: 10.2215/CJN.08950621. Epub 2021 Dec 14. Erratum in: Clin J Am Soc Nephrol. 2022 Jun;17(6):877-878. PMID: 34907021; PMCID: PMC8823928.
Yan Jiao, John Wilkinson, IV, Xiumin Di, Wei Wang, Heather Hatcher, Nancy D. Kock, Ralph D'Agostino, Jr, Mary Ann Knovich, Frank M. Torti, Suzy V. Torti. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 2009;113:462–469.
2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee Arthritis & RheumatologyVol. 72, No. 2, February 2020, pp 220–233
Panknin TM, Howe CL, Hauer M, Bucchireddigari B, Rossi AM, Funk JL. Curcumin Supplementation and Human Disease: A Scoping Review of Clinical Trials. Int J Mol Sci. 2023 Feb 24;24(5):4476. doi: 10.3390/ijms24054476. PMID: 36901908; PMCID: PMC10003109.
Liu S, Liu J, He L, Liu L, Cheng B, Zhou F, Cao D, He Y. A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health. Molecules. 2022 Jul 8;27(14):4400. doi: 10.3390/molecules27144400. PMID: 35889273; PMCID: PMC9319031.
Munn, Z., Peters, M.D.J., Stern, C. et al. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol 18, 143 (2018). https://doi.org/10.1186/s12874-018-0611-x
Lombardi N, Crescioli G, Maggini V, et al. Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports. Br J Clin Pharmacol. 2021; 87: 741–753. https://doi.org/10.1111/bcp.14460
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