Magnesium stearate, hypothesis, nocebo and harmful "halo effect" - a critical review

A small number of clinicians, manufacturers and health lobbyists argue that magnesium stearate, which has been safely used by the dietary supplement and pharmaceutical industries for over 50 years, is a harmful and unnecessary ingredient. In addition, critics claim negative effects on the immune system and that magnesium stearate could adversely alter gastrointestinal flora, impairing digestive function and nutrient absorption.

 

The controversial topic of magnesium stearate

Sensational articles that unfairly pillory additives or otherwise blur the line between truth and falsehood are not in the public interest.

And, of course, a hypothesis that is put forward must be substantiated. After all, a hypothesis is nothing more than an explanation for a phenomenon that can be tested. Ideally, the test result supports or refutes the hypothesis. It is assumed to be true for the test period. The aim of the scientists is now to precisely test the limits of the hypothesis.

The assumption that magnesium stearate could pose a risk to human health must be based on substantial, reproducible and verifiable explanations. At the very least, it should be relational - i.e. based on observations and explanations that are scientifically plausible. A hypothesis is therefore a plausible, possible explanation for a process, an event or an entity. Of course, not all hypotheses are valid or correct.

However, opinion leaders can receive unqualified support for their hypothesis due to the so-called "halo effect". This describes the phenomenon whereby we assume that people who do thing A well will also do B, C and D well (or vice versa - because they did thing A badly, they will also do B, C and D badly).

Negative reports about alleged problems in connection with magnesium stearate in food and medicines are so widespread on the internet that they are now responsible for a "nocebo" effect. A nocebo effect occurs when adverse side effects occur due to negative expectations, a negative placebo effect so to speak. Placebo and nocebo effects impressively demonstrate the extent to which the therapeutic context and different areas of the brain are connected.

There is no doubt that nocebo effects exist and negatively influence the course of standard treatments, even when no placebos have been administered. Nocebo and placebo effects, which directly influence a person's ability to function, are the result of the psychosocial context or therapeutic environment for the patient's mind, brain and body. Both phenomena can be triggered and reinforced by various factors: written statements, verbal recommendations, previous experiences, etc. Such effects not only play a role in treatment, but also complicate the validity of studies when they are related to unfounded hypotheses.

In this respect, there must be a balance between communicating relevant nutritional information and ensuring that unfounded negative claims are minimized and negative therapeutic associations are reduced. This balance must take into account the autonomy of the patient or consumer to make a decision for themselves based on the relevant information, while communicating information in a non-deceptive yet reassuring manner. I hope that the following information is taken in this light.

 

First, a brief insight into chemistry

Magnesium stearate, also known as octadecanoic acid and magnesium salt, has been used for more than 40 years in the manufacture of foods, pharmaceutical tablets and capsules. The chemical formula is: Mg (_C18H35O2⁾².

It is a salt with two equivalents of stearate (the negatively charged anions of stearic acid) and a positively charged magnesium cation (^Mg2+). Magnesium stearate is therefore a new compound that is formed when the positive ions of stearic acid combine with magnesium.

In many food supplements, especially those from well-known manufacturers, it is only present in very small quantities. In most cases, magnesium stearate makes up less than one percent of the end product. Manufacturers use it together with other carriers to enable accurate mixing of different ingredients and to avoid sticking and other complications. Pharmaceutical magnesium stearate should always comply with cGMP (Good Manufacturing Practice) guidelines for both the food and pharmaceutical industries.

Octadecanoic acid

Stearic acid (also known as octadecanoic acid) is one of the most common long-chain fatty acids found in both vegetable and animal fats. It is also known as a fatty acid with 18 carbon atoms (C18:0) due to its structure; the formula is _C36H70MgO4. It is used as a lubricant in the manufacture of food and pharmaceutical products.

Although stearic acid is classified as a saturated fatty acid (SFA) both biochemically and for purposes of nutrition labeling and dietary recommendations, data from the past 50 years show that stearic acid is unique among SFAs in the food supply. Stearic acid is found in many foods that are consumed daily, such as meat, coconut oil and chocolate. Evidence suggests that it is converted to oleic acid (_CH3(_CH2)7CH=CH(_CH2)7COOH) by enzymes during digestion, neutralizing negative risks associated with cholesterol levels.

Stearic acid is well absorbed in the intestine and broken down into chylomicrons and other particles before being metabolized in the liver. In the liver, excess stearic acid is converted into monounsaturated 18-carbon oleic acid by a desaturating enzyme. As oleic acid, it then circulates in lipoprotein complexes; the cholesterol level remains unchanged. As described above, this conversion to oleic acid could explain why stearic acid does not increase blood plasma cholesterol levels.

Magnesium

Magnesium (Mg) is an extremely important mineral for humans. It is combined with stearic acid to produce safe magnesium stearate. The manufacturing processes used can provide stearic acid without any hydrogenation processes that can create by-products of trans fats.

The British Pharmacopoeia of 2011 describes magnesium stearate as a compound of magnesium with a mixture of solid organic acids (stearic acid and palmitic acid), consisting mainly of variable proportions of magnesium stearate and magnesium palmitate. The fatty acids come from edible source materials (in food supplements mostly of plant origin). It contains a minimum of four percent and a maximum of five percent magnesium (calculated by dry weight).

How does magnesium stearate work?

Magnesium stearate is either present as tabular crystals (or lamellae) that lie on top of each other like a stack of cards. When different ingredients or medicines are mixed, these tablets continuously shear off and coat surrounding particles. The higher the concentration of magnesium stearate or the longer the mixing lasts, the more complex the coating of the surrounding particles. To ensure excellent flow properties, manufacturers do not need or want to coat all the particles, as this changes the speed at which the tablet or capsule is bioavailable. Magnesium stearate is contained in a tablet or capsule at a level of approximately one percent. This amount is not only safe, but also ensures that the supplement is effective and bioavailable. And as with all good food supplements, the concentration, level and mixing parameters must be closely monitored. The relevant manufacturers apply their own quality criteria for this and also comply with the standards of good manufacturing practice.

Problems with bioavailability

Studies have shown that magnesium stearate affects the release time of active ingredients in tablets etc.. However, it does not reduce the bioavailability of these ingredients. Millions and millions of food supplements and medicines containing magnesium stearate are taken every day. Some are thought to contain more than one percent magnesium stearate to intentionally delay the release of the ingredients.

Magnesium stearate is not table chalk

One of the unfounded claims made by some critics is that magnesium stearate is ordinary table chalk. This is chemically impossible. In the past, blackboard chalk was mainly made from natural lime (calcite) and referred to as calcium carbonate (CaCO3); today, gypsum or calcium sulphate (_CaSO4-2H2O) is often used. Both forms are very different from magnesium stearate.

What about the safety of magnesium stearate? 

In the USA, the Food and Drug Administration (FDA) is responsible and issues regulations for ingredients that are "generally recognized as safe" (approval designation GRAS, which indicates the safety of food additives). The FDA has recognized magnesium stearate as generally recognized as safe as long as consumption does not exceed 2,500 mg/kg daily.

The FDA report cited above further states: "... concludes that none of the available evidence indicates a potential hazard when magnesium-based compounds with GRAS labeling are used as food ingredients." In light of the above, the Select Committee concludes as follows:

"The available information on magnesium carbonate, magnesium chloride, magnesium sulphate, magnesium hydroxide, magnesium oxide, magnesium stearate, dibasic magnesium phosphate and tribasic magnesium phosphate does not indicate that these compounds pose or suggest a hazard to the general public as long as they are used in quantities and in a manner consistent with current guidelines. Such hazards are not expected in the future."

In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) regulates ingredients for food and medicines. It is supported by the FSA (Food Standards Agency). The British Pharmacopoeia is the leading collection of standards for British medical devices and pharmaceutical substances. All confirm that magnesium stearate is suitable, safe and approved for human consumption. Within the EU, the European Food Authority is responsible. It supervises food additives and ingredients and confirms that magnesium stearate can be used in food supplements and medicines.

Does magnesium stearate affect immune function?

Our immune system is essential for our survival and the maintenance of healthy bodily functions. It is the most advanced area of human biology. Its complexity has been cited by some critics to suggest or infer a dubious influence of magnesium stearate on immune function. They often refer to an article published in the journal Immunology in 1990, from which they were keen to infer an immunological risk from ingestion.

Natural killer cells are then often mentioned in connection with this denigration. The conclusion is drawn that these are suppressed by magnesium stearate and that taking food supplements or medicines containing this excipient leads to immunosuppression. Natural killer cells (NK) play an important role in direct immune defense. They are considered prototypical innate immune cells that function immediately and are similar to adaptive T cells. However, the latter must first be activated by stimuli. This means that NK and T cells are not the same thing. Natural killer cells are the third type of lymphocyte. The other two are T and B cells.

The link to this article and the accusations made against magnesium stearate are at best specious, at worst they reveal a lack of knowledge of how to understand and interpret scientific research. The article in the journal Immunology refers to the use of isolated stearic acid - which is not the same as magnesium stearate - added to T and B cells from mice in a test tube. The cells were stimulated using an exogenous mediator and then spiked with stearic acid. Due to an inherent enzyme deficiency in T cells, the stearic acid was taken up into the cell membrane, whereas B cells rejected it. As a final result - after six to eight hours of saturation - the cell walls of the T cells collapsed.

The authors write: "This is not evidence of an effective relationship between changes in membrane lipids and impairment of membrane potential."

They suggest that further trials should investigate whether this mechanism could be used to prevent rejection of transplanted organs or to suppress autoimmune activity, as this would have a similar effect to ciclosporin but without the usual side effects. However, no further research results have been published in this regard and it is highly unlikely that this will happen in the near future.

The key aspects are as follows:

• The test was carried out "in vitro" - a notoriously unreliable indicator for drawing conclusions about human health.
• Pure stearic acid was used and not magnesium stearate.
• The cells came from mice.
• The result was considered positive (from the scientists' point of view).
• Adaptive T cells were used and not innate NK cells. The membranes of both cell forms are similar, but not identical.

Magnesium stearate is not the same as stearic acid, but a compound derived from it. Stearic acid is a saturated fatty acid found in all plants, seeds, nuts and animal fats. Stearic acid can be obtained from many sources, including beef. However, most dietary supplements use vegetable stearic acid from coconuts or palm oil. Studies conducted on humans have shown positive effects of stearic acid.

Does magnesium stearate cause biofilms?

Some commentators are of the opinion that magnesium stearate forms a biofilm in the human intestine. The formation of such a biofilm is inferred from deposits of vegetable stearin in the bath or sink. This so-called "foam ring" in the bathtub, sink or in some toilets consists of minerals contained in water, dirt, body fat, skin flakes and bacteria.

The link to magnesium stearate is once again only achieved by leaving the field of scientific plausibility; there is no research whatsoever that suggests, let alone proves, the formation of a biofilm due to magnesium stearate in the human digestive tract. In fact, there are no human studies that imply or confirm a risk associated with the ingestion of magnesium stearate.

Biofilms are the tightly meshed colonies that some bacteria form on surfaces to protect themselves from antimicrobial attack. Biofilms contribute to the ability of bacteria to communicate and behave as a group for social interactions like a multicellular organism. This helps them colonize host organisms, defend against competitors and gives them significant advantages in adapting to changing environments. In the general hysteria that all biofilms are bad, it is often overlooked that they can actually be beneficial and are vital for the human microbial flora.

The large intestine is the organ most colonized by microorganisms. The microbial flora in the large intestine is usually regarded as a homogeneous unit. However, this is a gross oversimplification. The bacteria exist in a variety of different microhabitats and metabolic niches in the mucus layer lining the gut, in the mucosa and on the surfaces of digestive residues on the gut wall. These microcosms are constantly changing, depending on whether and which nutrients are being digested or whether new food sources are available. Environmental factors, nutrient composition, the chemical composition of the culture medium and defense mechanisms related to the adaptive and innate immune system all play a role in the formation and breakdown of biofilms. The surface of the intestinal wall can be modified by the choice of food. Diet, prebiotics, probiotics and antibiotics are probably the most important external modifiers of bacterial communities. The assumption that only the ingestion of magnesium stearate could form a harmful biofilm reveals a lack of understanding of the complex dynamics of bacteria and yeasts in the gut wall.

Contamination of magnesium stearate?

The raw material for vegetable stearate usually comes from palm trees. It is repeatedly assumed that contamination with pesticides is not only possible, but also poses a health risk, as some plantations use pesticides. Others suspect that a single case of contaminated magnesium stearate (which incidentally had no adverse health effects) will render useless all food supplements that use this ingredient to improve quality and consistency. The "risk" is simply too high.

However, this assumption is unfounded and also highly questionable. Most plants used for the production of food supplements draw their minerals and pollutants from the soil or the air. We all consume such plants almost every day, even if we only consume organic products. The potential risk must always be seen in context. Toxic chemicals enter the body not only through external sources (air, water, food, drugs and radiation), but also through processes that take place inside our bodies. These include inflammation, lipid peroxidation, oxidative stress, existing diseases, infections and the intestinal flora. We have a highly adaptable homeostatic management system to deal with this.

Magnesium stearate in dietary supplements consists of a non-hydrogenated plant-based fatty acid and magnesium. It is taken every day by millions and millions of people around the world - with no known or scientifically confirmed side effects. However, nocebo effects may have been caused by inappropriate and unfounded emphasis on risk by opinion leaders.

In fact, there are many harmful substances of concern in our food and the environment that not only have an independent effect on our health, but also act collectively. A new model, called the exposome, maps the totality of exposure beginning with pregnancy and is gaining increasing importance in environmental and health sciences. This model helps us to develop better clinical care. Proponents of the exposome concept distinguish this approach as a broad assessment of all exposures as opposed to the traditionally parochial approach of environmental scientists and activists who look at one toxin or group of exposures at a time.

Concluding remarks on magnesium stearate

Magnesium stearate has no known risk to humans as long as it is taken in small amounts via dietary supplements or medicines as recommended. Not a single website run by any of the various critics offers even one piece of hard evidence that this statement is incorrect. The same applies to online medical libraries such as PubMed or Medline.

One's own opinion can still lead one to avoid supplements or medicines containing this carrier. Ultimately, this is an emotional decision and not one based on actual evidence.

 

Sources (in English):

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Uzunović, A. & Vranić, E. (2007, August). Effect of magnesium stearate concentration on dissolution properties of ranitidine hydrochloride coated tablets. Bosnian Journal of Basic Medical Sciences, 7(3):279-83

Kris-Etherton, P. M., Griel, A. E., Psota, T. L., Gebauer, S. K., Zhang, J. & Etherton, T. D. (2005, December). Dietary stearic acid and risk of cardiovascular disease: intake, sources, digestion, and absorption. Lipids, 40(12):1193-200

Lin, D. S., Connor, W. E. & Spenler, C. W. (1993, August). Are dietary saturated, monounsaturated, and polyunsaturated fatty acids deposited to the same extent in adipose tissue of rabbits? The American Journal of Clinical Nutrition, 58(2):174-9.

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Tebbey, P. W., Buttke, T. M. (1990, July). Molecular basis for the immunosuppressive action of stearic acid on T cells. Immunology, 70(3):379-84

Tammaro, A., Abruzzese, C., Narcisi, A., Cortesi, G., Persechino, F., Parisiella, F. R. (2012). Magnesium stearate: an underestimated allergen. Journal of Biological Regulators and Homeostatic Agents, 26(4):783-4 

Hunter, J. W., Zhang, J. & Kris-Etherton, P. M. (2010, January). Cardiovascular disease risk of dietary stearic acid compared with trans, other saturated, and unsaturated fatty acids: a systematic review. The American Journal of Clinical Nutrition, 91(1):46-63, doi: 10.3945/ajcn.2009.27661 

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