In this episode, we discuss:
- The significance of inflammation in the onset, progression, and severity of chronic and autoimmune diseases
- Chris’s top three nutrients for fighting inflammation and autoimmunity
- The research behind how these three nutrients impact a wide range of inflammation-driven conditions
- What to look for in an inflammation-busting supplement and how to supplement for your diet and lifestyle
- How to use these nutrients to balance and regulate your immune system
- Learn more about the Omega-3 Index test
- Fish Oil profile on Examine.com database
- “The Effect of Omega-3 Fatty Acids on Rheumatoid Arthritis” by Kostoglou-Athanassiou et al.
- “Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus” by Walton et al.
- “A randomized interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus” by Wright et al.
- “Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network” by U. N. Das
- “Omega-3 fatty acids in inflammation and autoimmune diseases” by Artemis P. Simopoulos
- “Effect of omega-3 fatty acids and fish oil supplementation on multiple sclerosis: a systematic review” by AlAmmar et al.
- “Therapeutic Potential of ω-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases” by Li et al.
- “The effects of low dose n-3 fatty acids on serum lipid profiles and insulin resistance of the elderly: a randomized controlled clinical trial” by Fakhrzadeh et al.
- “Effect of n-3 Polyunsaturated Fatty Acid Supplementation on Metabolic and Inflammatory Biomarkers in Type 2 Diabetes Mellitus Patients” by Jacobo-Cejudo et al.
- “Dietary n-3 PUFA, fish consumption and depression: A systematic review and meta-analysis of observational studies” by Grosso et al.
- “Omega-3 fatty acids and cognitive decline: a systematic review” by Amelia Martí Del Moral and Francesca Fortique
- “Omega-3 Fatty Acids and Neurodegenerative Diseases: New Evidence in Clinical Trials” by Avallone et al.
- “Improving the oxidative stability of fish oil nanoemulsions by co-encapsulation with curcumin and resveratrol”by Shehzad, et al.
- “Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells” by Goel et al.
- “Efficacy and Safety of Curcumin and Curcuma longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial” by Zeng et al.
- “Curcumin: A Review of Its Effects on Human Health” by Susan J. Hewlings and Douglas S. Kalman
- “Modulation of Exercise-Induced Muscle Damage, Inflammation, and Oxidative Markers by Curcumin Supplementation in a Physically Active Population: A Systematic Review” by Fernández-Lázaro et al.
- “Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study” by Kuptniratsaikul et al.
- “Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients” by Belcaro et al.
- “Curcumin and rheumatoid arthritis: A systematic review of literature” by Pourhabibi-Zarandi et al.
- “Immunomodulatory Effects of Curcumin in Rheumatoid Arthritis: Evidence from Molecular Mechanisms to Clinical Outcomes” by Haftcheshmeh et al.
- “Curcumin and autoimmune disease” by John J. Bright
- “Curcumin and Curcuma longa Extract in the Treatment of 10 Types of Autoimmune Diseases: A Systematic Review and Meta-Analysis of 31 Randomized Controlled Trials” by Zeng et al.
- “Potential of Curcumin in Skin Disorders” by Vollono et al.
- “Efficacy and safety of curcumin in psoriasis: preclinical and clinical evidence and possible mechanisms” by Zhang et al.
- “Structure-Activity Relationship of Curcumin: Role of the Methoxy Group in Anti-inflammatory and Anticolitis Effects of Curcumin” by Yang et al.
- “Curcumin use in ulcerative colitis: is it ready for prime time? A systematic review and meta-analysis of clinical trials” by Chandan et al.
- “Modulation of Exercise-Induced Muscle Damage, Inflammation, and Oxidative Markers by Curcumin Supplementation in a Physically Active Population: A Systematic Review” by Fernández-Lázaro et al.
- “The effect of curcumin supplementation on delayed-onset muscle soreness, inflammation, muscle strength, and joint flexibility: A systematic review and dose-response meta-analysis of randomized controlled trials” by Beba et al.
- “The Effects of Curcumin on Diabetes Mellitus: A Systematic Review” by Marton et al.
- “Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial” by Small et al.
- “The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes” by Schiborr et al.
- “Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers” by Rohitash Jamwal
- “Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety” by Hannan et al.
- “Review on Clinical Trials of Black Seed (Nigella sativa) and Its Active Constituent, Thymoquinone” by Tavakkoli et al.
- “The effects of Nigella sativa on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review” by Saadat et al.
- “The effect of Nigella sativa (black seed) on biomarkers of inflammation and oxidative stress: an updated systematic review and meta-analysis of randomized controlled trials” by Kavyani et al.
- “The effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) – 1, Nesfatin-1 and anthropometric features in patients with Hashimoto’s thyroiditis: a randomized controlled trial” by Farhangi et al.
- “The effects of powdered black cumin seeds on markers of oxidative stress, intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in patients with Hashimoto’s thyroiditis” by Mahdieh Abbasalizad Farhangi and Siroos Tajmiri
- “The Role of Bioactive Compounds of Nigella sativa in Rheumatoid Arthritis Therapy—Current Reports” by Zielińsk, et al.
- “Comparing Nigella sativa Oil and Fish Oil in Treatment of Vitiligo” by Ghorbanibirgani et al.
- “The Therapeutic Effects of Nigella sativa on Skin Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials” by Nasiri et al.
- “Clinical and experimental effects of Nigella sativa and its constituents on respiratory and allergic disorders” by Gholamnezhad et al.
- “Nigella sativa as an anti-inflammatory agent in asthma” by Ikhsan et al.
- “The effects of Nigella sativa on respiratory, allergic and immunologic disorders, evidence from experimental and clinical studies, a comprehensive and updated review” by Saadat et al.
- “Nutritional Value and Preventive Role of Nigella sativa and Its Main Component Thymoquinone in Cancer: An Evidenced-Based Review of Preclinical and Clinical Studies” by Ansary et al.
- “Nigella sativa and Its Active Compound Thymoquinone in the Clinical Management of Diabetes: A Systematic Review” by Mahomoodally et al.
- “Nigella Sativa (Black Seeds), A Potential Herb for the Pharmacotherapeutic Management of Hypertension: A Review” by Maideen et al.
- “A randomized, double-blind, placebo-controlled, clinical trial to evaluate the benefits of Nigella sativa seeds oil in reducing cardiovascular risks in hypertensive patients” by Shoaei-Hagh et al.
- “Cardiovascular benefits of black cumin (Nigella sativa)” by Adel Shabana, et al
- “A Review on Possible Therapeutic Effect of Nigella sativa and Thymoquinone in Neurodegenerative Diseases” by Samarghandian et al.
- “The effects of Nigella sativa hydro-alcoholic extract and thymoquinone on lipopolysaccharide – Induced depression like behavior in rats” by Hosseini et al.
- “Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice” by Shen et al.
- “A Novel Combination of ω-3 Fatty Acids and Nano-Curcumin Modulates Interleukin-6 Gene Expression and High Sensitivity C-reactive Protein Serum Levels in Patients with Migraine: A Randomized Clinical Trial Study” by Abdolahi et al.
- “Clinical efficacy of the co-administration of Turmeric and Black seeds (Kalongi) in metabolic syndrome – a double blind randomized controlled trial – TAK-MetS trial” by Amin et al.
- “Efficacy of nanomicelle curcumin, Nigella sativa oil, and their combination on bone turnover markers and their safety in postmenopausal women with primary osteoporosis and osteopenia: A triple‐blind randomized controlled trial” by Kheiridoost et al.
- Learn more about the Adapt Naturals Core Plus bundle or take our quiz to see which individual products best suit your needs
- If you’d like to ask a question for Chris to answer in a future episode, submit it here
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- Visit Paleovalley.com/Chris and use the code KRESSER15 to get 15% off your order
Hey, everybody. Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, we are going to talk about my top three nutrients to fight inflammation and autoimmunity. This is a critical topic because inflammation is at the root of all chronic disease. Whether you’re talking about metabolic conditions like diabetes, depression or anxiety, gastrointestinal problems, cardiovascular disease, neurological and cognitive disorders, you name it, inflammation is almost certainly a factor, if not the driving factor. And, of course, every autoimmune disease is also characterized by inflammation. Rheumatoid arthritis involves inflammation of the joints. Hashimoto’s [disease] involves inflammation related to the thyroid. Inflammatory bowel disease (IBD) is characterized by gut inflammation. Psoriasis is skin inflammation, and lupus involves multisystem inflammation. So it’s not an exaggeration to say that modulating inflammation is the key to addressing all kinds of chronic diseases that we face today and improving quality of life in people with autoimmune disease. I’ve written and spoken a lot about dietary and lifestyle strategies for inflammation and autoimmunity in the past.
In this podcast, I want to talk about three specific nutrients I found to be extremely helpful for reducing inflammation and regulating the immune system. These are the long-chain omega-3 fats, [eicosapentaenoic acid] (EPA), and [docosahexaenoic acid] (DHA), found primarily in seafood and fish oil, curcumin, and black seed oil (BSO), which is also known as black cumin seed oil, and it’s from the Nigella sativa plant. Most of you are probably familiar with the first two. They’re well-known at this point. The third, [BSO], has a long history of use in traditional medicine, especially Ayurveda, but it is a relative newcomer in the West. Despite this, there’s already a lot of exciting research supporting its many benefits. And if you’re not already familiar with it, you will be soon. In the show, I’ll also share some research on how these nutrients specifically impact a wide range of conditions driven by inflammation and immune dysregulation, including depression and anxiety, dementia and Alzheimer’s [disease], metabolic syndrome, cardiovascular disease, and several different autoimmune conditions. I’ll also share important things to consider when supplementing with these nutrients because the devil is definitely in the details. You need to consider things like bioavailability, sourcing, standardization, composition, purity, and other factors to get their full benefits. Sadly, as is often the case when a particular nutrient or supplement becomes popular, there’s a proliferation of low-quality or even shady products made by companies that are only out to make a profit and don’t care about your health.
By the end of the show, you’ll know how to use these nutrients to reduce inflammation and balance and regulate the immune system. These powerful nutraceuticals can make a huge difference whether you’re struggling with depression, trying to lower your blood sugar or blood pressure, or seeking relief from pain, soreness, or other symptoms related to autoimmune disease. I think these are particularly important for autoimmune disease because the conventional treatments for autoimmunity leave a lot to be desired. Steroids, for example, just globally suppress the immune system and have a whole range of nasty side effects like weight gain, nutrient deficiencies, and increased susceptibility to infections. And the same is true, to a greater extent, with biologic drugs like Remicade and Imuran. So people with autoimmune conditions, which, unfortunately, is a growing number of Americans and people around the world, are really in desperate need of natural and safe interventions that can move the needle. And I think EPA and DHA, fish oil, [BSO], and curcumin really fit the bill. So, without further delay, let’s dive in.
Let’s start by talking about EPA and DHA. As you probably know, these are the long-chain omega-3 fats, and we get them in two ways. In theory, it’s possible for humans to produce them endogenously in our own bodies. That is from a precursor omega-3 fat called alpha-linolenic acid, which is found in foods like flaxseeds and walnuts. But in practice, that conversion is extremely inefficient. For example, less than one-half of 1% of alpha-linolenic acid gets converted into DHA in most people. This has led some scientists to argue that EPA and DHA should be considered essential nutrients, meaning nutrients that we have to consume in the diet because most people can’t make enough of them on their own. So the second way to get EPA and DHA and, in fact, the most reliable way, or perhaps the only reliable way, is to consume them either in the diet from cod liver, fatty fish, and shellfish or as a supplement like fish oil. It’s difficult to estimate exactly how many people have adequate EPA and DHA levels because this depends on numerous factors, and doctors don’t routinely test EPA and DHA levels in the clinic.
That said, most omega-3 scientists believe that the vast majority of Americans are falling short on EPA and DHA, and I have definitely seen this in my practice. I use a test called the Omega-3 Index, which measures the amount of EPA and DHA in red blood cell membranes. And most patients that I’ve tested are below the recommended EPA and DHA levels. The lack of adequate EPA and DHA is almost certainly contributing to the burden of chronic inflammatory diseases we face in the [United States] and around the world today. And that’s because EPA and DHA are strongly anti-inflammatory. EPA competes for the same enzymes as arachidonic acid, an omega-6 fat that is associated with inflammation and platelet aggregation. When sufficient EPA is present, it will outcompete arachidonic acid and shift the system toward an anti-inflammatory response. EPA and DHA also produce metabolites like resolvins, protectins, and maresins. These metabolites also compete with metabolites of omega-6 fatty acids and like their parent, omega-3 fats, are associated with anti-inflammatory responses. And finally, omega-3 fats also reduce the production of several pro-inflammatory cytokines, like [tumor necrosis factor] (TNF)-alpha, interleukin-6, and interleukin-17.
Let’s look at some studies on the effects of EPA and DHA on autoimmunity and other chronic inflammatory conditions. This will not be an exhaustive review. There are literally thousands of studies like this in the scientific literature, but these are some of the better-studied conditions with the strongest evidence behind them. So the first is rheumatoid arthritis and associated autoimmune joint and muscle conditions. In a 2020 paper called “The Effect of Omega-3 Fatty Acids on Rheumatoid Arthritis,” the authors reviewed decades of research on the impact of EPA and DHA on pain and inflammation in patients with rheumatoid arthritis. And they found that EPA and DHA reduce markers of inflammation, decrease inflammatory cytokine production, relieve pain and swelling, and improve mobility. Lupus is an autoimmune condition where the immune system attacks its own tissues, and this causes, as I mentioned earlier, a multisystem inflammatory process and tissue damage in the affected organs. It’s a really nasty condition, very difficult to treat, and no good treatments [are] available in the conventional medical world.
Several studies have shown that EPA and DHA [have] multiple benefits in patients with lupus, including improved quality of life, prolonged remission, reduce[d] pain and inflammation, and significantly improve[d] endothelial function, which is often compromised in people with lupus and confers a higher risk of cardiovascular disease in those people. So that’s a really important benefit. Fish oil has also shown benefits in other autoimmune diseases, including type 1 diabetes, multiple sclerosis, Crohn’s disease, and psoriasis. And these are just the ones that have been studied. Whenever you see a treatment that’s effective for one autoimmune disease, you have to at least wonder if it could be effective for others because the underlying mechanism of all autoimmune diseases is the same. It’s the body attacking itself due to a dysregulated immune system. So, in my practice, if there was research on a particular nutrient that was beneficial for six or seven autoimmune diseases, I would often use it for a different autoimmune disease, even if there [weren’t] specific studies for that because of that shared mechanism, and often with really good results.
Let’s talk a little bit about fish oil and metabolic health. This is one of the most well-known benefits of EPA and DHA. In particular, it has shown [a] very consistent ability to lower triglycerides and blood pressure in people with metabolic syndrome. Fish oil reduces triglycerides by reducing the amount of triglyceride-rich [very-low-density lipoprotein] (VLDL) in the liver, and it likely reduces blood pressure by increasing nitric oxide production. Nitric oxide is a vasodilator, so it makes the blood vessels wider, [making] it easier for blood to flow through them. That’s why it tends to reduce blood pressure. Other studies have shown that EPA and DHA can improve waist circumference, glucose, hemoglobin A1c, leptin/adiponectin ratio, and lipid profiles in people who are overweight and/or who have prediabetes or diabetes. Given the prevalence of metabolic disease in the [United States] and worldwide today, this is definitely one of the most important benefits of fish oil. As a side note, as we go through this episode, know that you can find all of the scientific references on the podcast episode page on my website, chriskresser.com. That’s always the case, but I want to remind you of that with this show in particular because we’re going to be reviewing a lot of different research.
Next, one of the strongest effects of omega-3 fats and fish oil is in resolving depression. Examine.com, which is a great source of scientific research—they rate the quality of evidence on various topics—rated the quality of evidence for fish oil and depression at the highest level, which is a grade of A. And these studies have suggested several mechanisms for why fish oil impacts depression. One is that it’s anti-inflammatory, as we’ve discussed, and a lot of researchers believe that there is a strong inflammatory component of depression in many people. Two is, omega-3s can easily travel through the brain cell membrane and interact with mood-related molecules inside the brain. Cell membranes are made up partly of omega-3 fats, so it’s possible that increasing the omega-3 levels makes it easier for serotonin to pass through cell membranes. As you might suspect, given that omega-3s reduce inflammation and improve cell signaling in the brain, depression is not the only mental health issue that they help with or brain issue that they help with. EPA and DHA [have] also been shown to improve anxiety, [improve] cognitive health, [boost] memory and focus in older adults, and improve many other neurological and cognitive disorders like Parkinson’s [disease] and dementia.
Let’s talk a little bit about how to get more EPA and DHA. There are two primary ways: consuming it in the diet and food or supplementing with it. In the diet, the primary sources are cold-water fatty fish like salmon, mackerel, herring, anchovies, sardines, and shellfish like oysters. And as I mentioned in the intro, a very small amount of plant-based omega-3s like walnut and flax can be converted into EPA and DHA. But studies have shown that’s not a reliable source for most people, and you’d have to consume enormous amounts of those foods to get meaningful amounts of EPA and DHA. For supplements, the best options are fish oil or cod liver oil, or microalgae for vegans or people [who] can’t or don’t want to consume fish or seafood. But note that algae only contains DHA, not EPA. And EPA is thought to have the primary anti-inflammatory benefit of the long-chain omega-3 fats. Some DHA can be retro-converted into EPA. EPA is like a step before DHA in the conversion cycle, but some can be retro or backward—some DHA can be retro or backward converted into EPA. So that is still the best option for people who can’t eat fish or don’t want to eat fish or seafood.
If [you’ve followed] my work for any length of time, you’ll know that I’ve always advocated getting EPA and DHA in the diet by consuming cold-water fatty fish or shellfish because these foods are loaded with other nutrients like vitamins, minerals, and bioavailable protein, in addition to EPA and DHA. I suggest eating two servings of these types of seafood each week for optimal benefits, and that will provide about 1 gram per day of combined EPA and DHA. That said, I’ve learned, both through my extensive clinical experience and through research, that most people are simply not getting enough EPA and DHA from diet alone. In some cases, this is due to people just not enjoying the taste of seafood. In other cases, it’s a question of not having access, and in still others, it’s because of allergies or environmental concerns. Whatever the reason, the statistics don’t lie. Most people fall short of getting that recommended 1 gram per day. What’s more, some people with autoimmune or other chronic inflammatory conditions like arthritis, depression, skin disorders, migraine, etc., benefit from more EPA and DHA. They experience further reductions in inflammation and pain, along with other improvements. So, for these reasons, supplementing with EPA and DHA in the form of high-quality fish oil can make a lot of sense.
My recommendations for fish oil have evolved over time. I’ll tell you what has remained constant first and then tell you what has changed. I still recommend getting EPA and DHA from the diet whenever possible, either as your exclusive source or as a foundation to build upon. And I still don’t recommend super high doses of fish oil, like 10 grams per day. This isn’t common anymore, but there was a time when many health gurus were suggesting this as a way to reduce inflammation. But it’s not really supported by the research. Most studies don’t show an additional benefit beyond 2 to 3 grams a day, and some studies suggest that 10 to 20 grams of fish oil may actually cause harm. So I think it’s best to stay in the 1- to 3-gram-a-day range.
What has changed is my growing appreciation for the role that fish oil can play in ensuring adequate EPA and DHA intake for many people. For all the reasons I just mentioned, many folks are just not getting enough. And taking a fish oil supplement is probably the only way they’re going to get adequate amounts of these critical fatty acids. And some people benefit from greater amounts of EPA and DHA than they can easily obtain in their diet. My specific recommendations for EPA and DHA supplementation have also evolved. I have recommended cod liver oil for many years, and I still do today. It’s a good option because it contains vitamins A and D in addition to EPA and DHA. However, the amounts of EPA and DHA tend to be lower in cod liver oil than in most fish oil supplements. And if you’re already consuming organ meats like liver or an organ meat supplement like Bio-Avail Organ from Adapt Naturals, you don’t really need or even want the additional [vitamin] A or D from cod liver oil. So this is why I now recommend a high-quality fish oil supplement for people who are either not getting enough EPA and DHA from their diet or who would benefit from additional EPA and DHA because of [a] chronic inflammatory or autoimmune condition.
But finding a high-quality fish oil is easier said than done. The global market for fish oil is now north of $2 billion a year. Whenever there’s that much money to be made, you can be sure all kinds of shenanigans will ensue. You’ve probably heard a lot of concerns about the rancidity and oxidation of fish oil contaminants like [polychlorinated biphenyls] (PCBs) and heavy metals, etc. These are all valid concerns. So I’m going to cover what to watch out for and how to choose a high-quality product. As a general rule, there are five key variables to consider when buying a fish oil: composition, purity, freshness, bioavailability, and sustainability and traceability.
Let’s talk about each of these. By composition, I’m referring to the overall concentration of EPA and DHA and the ratio of EPA and DHA in the fish oil. As noted earlier, I suggest about 1 to 3 grams per day of combined EPA and DHA for most people. Depending on what your background intake is, that could be anywhere from 500 milligrams to 2 grams per day of EPA and DHA in fish oil. The optimal amount will vary based on several factors, including how much fish and seafood you’re already consuming. So if you don’t eat any or you have an inflammatory autoimmune condition, you probably want to aim for the higher end. If you eat fish and seafood regularly and/or you don’t have an inflammatory autoimmune condition, you could aim for the lower end of that range. There’s a lot of controversy over how much EPA and DHA should be in a particular formula, and, to a certain extent, it depends on what you’re using it for. But for general anti-inflammatory benefits, studies suggest the most effective preparations appear to have at least 60% EPA relative to DHA, and I would suggest a three to two ratio. So that’s 65% EPA and 35% DHA for optimal results.
Let’s talk about purity. Many species of fish are known to concentrate toxic chemicals like heavy metals, PCBs, and dioxins, which can cause serious disease, especially in children and developing babies. These chemicals are somewhat less of a concern when eating whole fish because fish also contains selenium, which binds to metals like mercury and other toxins and makes them unavailable to tissues, thus protecting, at least to some extent, against the damage that they may cause. To address this, fish oil manufacturers tend to use a process called molecular distillation to remove the toxins from the oil. And when it’s done well, molecular distillation is capable of reducing toxins to levels considered to be safe by the EPA and other international agencies. But although almost any fish oil manufacturer will tell you their product is free of these toxins, independent lab analyses tell a different story. In fact, there have been several lawsuits in California and a few other states against the manufacturers of 10 popular fish oils because they contain undisclosed and possibly unsafe levels of contaminants.
The best manufacturers and products will start with very high-quality fish oil from reputable suppliers that regularly have their oils tested for contaminants. So this would include heavy metals like mercury, arsenic, lead, and cadmium, PCBs, dioxins, pesticides, and benzopyrenes. The fish oil should meet or exceed standards like IFOS, which is International Fish Oil Standards; Five Star; GOED, which is Global Organization for EPA and DHA; and EU legislation, which tends to be much stricter than legislation in the [United States]. And this can be verified by a Certificate of Analysis or COA. A COA is an analysis that’s performed by an independent lab to measure the ingredients of a product and confirm whether it lives up to claims made by the manufacturers. Good manufacturers and brands will be able to provide a COA that attests to the quality of their product.
[Let’s talk about] freshness [next]. While I’ve written and spoken extensively about the dangers of oxidized rancid oils of any kind, whether you’re talking about omega-6 or omega-3, they promote oxidative damage and increase inflammation, both of which are risk factors for nearly every modern disease. This is why it’s crucial to ensure that the fish oil you select is fresh and not rancid. Once it has gone rancid, it will have the opposite effect on your body than you want it to. The oxidation parameters to check for are peroxides, p-anisidine, and [total oxidation] (TOTOX). The peroxide value measures the rancidity reactions in the oil that have occurred during storage. IFOS and GOED standards suggest the value should be less than five, but the best products will be significantly lower than that. The p-anisidine value measures secondary oxidation products, so the IFOS and GOED standard is less than 20 units. However, it’s important to note that the p-anisidine value is not appropriate for measuring secondary oxidation in omega-3 oils that have a strong color or contain added flavoring. For example, salmon oil contains carotenoids naturally, which have a yellow-orange coloring. And other fish oil products may contain curcumin or other antioxidants that have natural orange colorings, and that throws off the [P-]anisidine value and makes it an irrelevant test.
TOTOX is the last way to measure oxidation. It’s simply a combination of the peroxide value and p-anisidine values. So, for that reason, it’s also not appropriate for products that have strong natural coloring. Lastly, simply smelling or trying the product is actually a pretty reliable way to determine whether it’s rancid. Our noses have evolved over a very long period of time to detect rancidity because [of] its potential threat to our health. We have a pretty sensitive sense of smell to be able to determine this. If the product smells rancid to you, then that can definitely be a sign that it has oxidized. [The] last thing I want to mention is that some manufacturers are adding antioxidants to fish oil to improve stability. And this can be a good approach, according to research. Some studies suggest, for example, that adding curcumin or resveratrol can be a particularly good option.
Let’s move on to bioavailability, which is, of course, the ability to absorb the ingredients in a particular food or supplement. This is important for fish oil, just like it’s important for anything else, and the ability to absorb the EPA and DHA in fish oils is based on the molecular shape of the fatty acids. The short version is that the more natural the structure of those fatty acids is, not surprisingly, the better. When it comes to fish oil, there are three forms currently available on the market. There are natural triglyceride oils. This is what you get when you essentially squeeze the whole fish and extract the natural oil from it. It’s the closest to eating fish in its natural form—fish oil in its natural form, and it is, again, not surprisingly, the most bioavailable.
The second is ethyl ester oil. This is what you get when natural triglyceride oil is concentrated and molecularly distilled to remove impurities. The ester form is still in a semi-natural state because it’s the result of a process that naturally occurs in the body. So it’s second in bioavailability to the natural triglyceride form. [The] third form is synthetic triglyceride oil. This is what’s made when natural triglycerides are converted to ethyl esters for concentration but then reconverted into synthetic triglycerides. The original position of the triglyceride’s carbon bonds change, and the molecule’s overall structure is altered, which means the body can’t recognize it as well, and that lowers its bioavailability.
Lastly, I want to talk a little bit about sustainability and traceability. Our global fisheries are in dire straits, and fish oil is a big business, so it’s crucial to choose a product that’s manufactured with sustainability in mind and that has [a] fully transparent and traceable supply chain. The easiest way to do this is to choose a product that’s certified by organizations like Friend of the Sea or MarinTrust, which are two of the leading organizations for sustainable and responsible fishery management. I would also choose a supplier [and] manufacturer with practices that minimize waste and its environmental impact. There [are] some good options out there.
I think GC Rieber is probably the best fish oil supplier that I’m aware of. They’ve been involved in the fish oil industry for 140 years and have a really strong commitment to sustainability. For example, rather than catching fish that’s only used to produce fish oil, they instead use fish meal to make the oil. Fish meal is a byproduct of fish processing, so they are not removing fish from the ocean just for the purpose of making fish oil. That eliminates one of the main concerns about the sustainability of fish oil, which is that it will further deplete fisheries. What’s more, GC Rieber uses the biofuel created from their fish oil production for local aquaculture and food production industries, which further reduces the need for external energy sources. GC Rieber [is] not a product that you buy; it’s a supplier. And some of the best fish oil manufacturers will use raw material from GC Rieber. I think it’s a great option. I’m just highlighting it here to give you a sense of what the quality differences can be from one supplier to another and why it’s really important to choose brands that [use] raw material from really good suppliers.
Let’s move on to the second nutrient, which is curcumin. It’s the principal curcuminoid that’s found in turmeric, which is the Curcuma longa plant, and that’s a rhizome or root in the ginger family. It’s been used for over 4,000 years in Asian countries as a culinary spice, a component in religious ceremonies, and a therapeutic agent in both traditional Chinese medicine [and] Ayurveda. Curcumin has been the subject of intensive research over the past couple of decades, and we’re still learning about its mechanisms of action. But several have already been well established, including balancing and regulating the immune system, reducing oxidative stress, inhibiting inflammation, acting as an anticoagulant, scavenging free radicals, improving neurotransmitters signaling in the brain, supporting detoxification, and altering the activities of enzymes, receptors, and related transcription factors. When you look at the research on curcumin, it’s almost hard to believe how many effects it has. And as I said, we’re still learning more and more every day.
Because of these multiple modes of action, curcumin is used clinically to treat a wide variety of conditions and diseases, including arthritis, diabetes, depression, cognitive decline, and autoimmunity, to name just a few. First, as with fish oil, we’ll talk about how curcumin reduces inflammation, and then I’ll review some of the research on curcumin in various conditions. Curcumin reduces inflammation via multiple mechanisms. It inhibits signaling pathways associated with inflammation, and the most notable is the cyclooxygenase-2 or COX-2 enzyme pathway, which is responsible for the conversion of arachidonic acid to prostaglandins. And this is, incidentally, exactly how NSAIDs like ibuprofen reduce inflammation, by acting on this COX-2 pathway. However, unlike other selective COX-2 inhibitors like NSAIDs, curcumin does it without producing significant side effects and risks, even at pretty high doses. This is one of the reasons clinicians and scientists are so excited about it and why it is so intensively studied.
Second, curcumin decreases the production of several inflammatory mediators like cytokines and chemokines. And these include TNF-alpha, interleukin-6, interleukin-1 [beta], C-reactive protein [(CRP)], and [monocyte chemoattractant protein-1] (MCP-1). It also inhibits nuclear factor kappa, which protects and regenerates muscle and plays an important role in controlling [the] physiological mechanisms of inflammation. These cytokines and chemokines are often elevated in chronic inflammatory conditions like arthritis, psoriasis, and autoimmunity, and they’re the targets of medications that are commonly prescribed for these conditions. Again, curcumin is sort of mimicking the form of some of [the] drugs that are used for these conditions but doing it with fewer side effects and risks. Third, curcumin supports the immune system by modifying the balance between Th1 and Th2 and Th17 and T regulatory cells and by regulating adaptive immunity and affecting macrophages, neutrophils, and dendritic cells. Numerous studies have shown that patients with autoimmune inflammatory conditions have a decreased T reg/Th17 ratio and that improving this ratio leads to both objective and subjective measures of improvement.
As with fish oil, because curcumin has potent anti-inflammatory and antioxidant effects and because virtually all chronic diseases are characterized by these factors, curcumin has been used by clinicians for a wide variety of conditions. We can’t possibly cover all of them in this podcast. So I’m going to focus on a few categories that I’ve used curcumin the most often with in my practice and the ones that I think the research is strongest for. The first is arthritis and pain. I think when most people consider curcumin, this is likely the indication they think of, and for good reason. Numerous studies have shown that curcumin is effective for reducing inflammation, swelling, and pain and inflammatory joint conditions like osteoarthritis and rheumatoid arthritis. For example, a randomized controlled trial in 2014 involving about 370 patients with osteoarthritis in the knee found that curcumin was just as effective as ibuprofen for reducing inflammation, swelling, and pain but with far fewer gastrointestinal side effects.
A 2010 study found that taking curcumin for eight months improved osteoarthritis symptoms in 50 patients. People in the treatment group experienced improvements in several inflammatory markers, including interleukin-1 beta, interleukin-6, soluble CD40, soluble vascular cell adhesion molecule—that one’s a tongue twister—and erythrocyte sedimentation rate (ESR). These folks also saw really significant subjective improvements in pain, mobility, and quality of life. Most importantly, curcumin was well tolerated with no significant adverse effects, which suggested it’s safe to take over longer time periods. Curcumin is also effective for rheumatoid arthritis, which is an autoimmune inflammatory joint condition. In a systematic review of 51 studies published in 2021, researchers found that curcumin improved clinical and inflammatory markers as well as morning stiffness, walking time, and joint swelling. Another 2021 study found that curcumin relieves symptoms in rheumatoid arthritis patients by reducing the expression or function of pro-inflammatory mediators like nuclear factor kappa beta, activator protein 1, and mitogen-activated protein kinases.
Let’s talk a little bit about curcumin and other autoimmune diseases. As I mentioned before, because autoimmune diseases share a common underlying mechanism, it’s not surprising to see that curcumin would be effective in many different autoimmune diseases. So it’s been studied in inflammatory bowel diseases like Crohn’s disease and ulcerative colitis, ankylosing spondylitis, multiple sclerosis, lupus, psoriasis, lichen planus, type 1 diabetes, and Hashimoto’s [disease], fibrositis. Curcumin’s positive impact on these diseases is largely due to its ability to inhibit inflammatory cytokines and associated signaling pathways in immune cells. But it also has a potent balancing and regulating effect. So it’s not just suppressing inflammation like steroids do. It’s also balancing and regulating the immune system. And I think that’s also why it’s so much better tolerated.
Let’s look at two autoimmune diseases as example[s]: psoriasis and IBD. Psoriasis is a chronic inflammatory skin disease affecting about 3% of the world population, so that’s almost a quarter of a billion people. It results in thick, silvery plaques caused by uncontrolled proliferation of keratinocytes. Curcumin has been shown to suppress the excessive production of keratinocytes by inhibiting TNF-alpha and impairing lipopolysaccharide signaling. It also reduces the expression of several other inflammatory cytokines, which tend to be elevated in psoriasis patients. Subjectively, curcumin consistently reduces the psoriasis area and severity index, or PASI, which is the gold standard indicator of psoriasis severity. A meta-analysis of four studies that evaluated the PASI score in patients with psoriasis found that curcumin significantly improved the score compared to placebo when used alone, and it amplified the effect of conventional treatments.
IBD is a general term for autoimmune inflammatory diseases of the intestine, including Crohn’s disease and ulcerative colitis. It affects about 1 in 200 people in North America and Europe, which is quite a lot of people, with lower but increasing prevalence in Asia, Africa, and other countries. Multiple animal and human studies have found that curcumin is an effective treatment with and without conventional therapies in patients with IBD. Again, it inhibits pro-inflammatory cytokines that tend to be elevated in IBD patients. It also regulates Th1, Th2, and Th17 and T reg cell production, which is that balancing effect that I mentioned before. This is so important because most conventional treatments for IBD, including steroids and biologic drugs, suppress inflammation rather than [regulate] the immune system. That can help reduce symptoms, and it is sometimes necessary when severe flares [occur], but it does come with significant side effects and risk[s]. For example, many biologic drugs like Remicade and Imuran that are used to treat IBD come with black box warnings because they significantly increase the risk of infection and even death.
Remember, inflammation is not always harmful. It’s part of our normal immune defense against pathogens and other threats. And if we globally suppress it with powerful drugs, we’re less able to fight these pathogens and threats. Curcumin seems to be able to modulate the immune response in autoimmune diseases like IBD without globally suppressing the immune system, which is one of the many reasons scientists and clinicians are excited about it. Curcumin isn’t just effective for treating inflammatory disease. It also has been shown to improve athletic performance and recovery in healthy, physically active people, whether they’re serious competitive athletes or weekend warriors. One thing most people forget is that physical activity, particularly high-intensity eccentric muscle contraction, produces exercise-induced muscle damage. This is often not a bad thing. It’s just part of the hormetic response we get from exercise, which is what leads to the many benefits it’s responsible for. But as we age or if we over-train, it can be harder to recover from that muscle damage induced by exercise. And this can lead to decreased performance and recovery and a higher risk of injuries.
A systematic review in 2020 found that curcumin reduces the subjective perception of the intensity of muscle pain, reduces muscle damage through the decrease of creatine kinase, increases muscle performance, and has an anti-inflammatory effect by modulating pro-inflammatory cytokines. Similarly, a 2022 review found that curcumin led to improvements in muscle damage, muscle soreness, inflammation, muscle strength, and joint flexibility. This is fantastic news for those of us [who] aren’t necessarily struggling with a chronic disease but want to improve our physical performance, reduce recovery time, and reduce the risk of injury.
Let’s talk about curcumin’s metabolic benefits. Several epidemiologic studies have shown an association between markers of inflammation and oxidative stress and type 2 diabetes and other metabolic conditions. As you now know, curcumin has potent anti-inflammatory and antioxidant effects. So it shouldn’t come as a surprise that it can be helpful for people with type 2 diabetes and other metabolic disorders. A systematic review in 2021 of 16 trials involving roughly 1,300 patients with diabetes showed improvements in fasting blood glucose levels, hemoglobin A1c, triglycerides, total cholesterol, [low-density lipoprotein] (LDL), [high-density lipoprotein] (HDL), and [CRP] as well as systolic and diastolic blood pressure. Many other large reviews and randomized controlled trials have found similar results, and I have definitely seen huge metabolic benefits with curcumin in my practice. It’s one of the clinical situations that I consider curcumin in most [often].
Inflammation is at the root of all autoimmune and chronic diseases, from which approximately 80 million Americans suffer. But, inflammation can be treated, and the symptoms of chronic disease can be lessened, or even eradicated, with the right blend of synergistic nutrients. Chris shares the science behind his top 3 inflammation-fighting nutrients in the latest episode of Revolution Health Radio. #chriskresser #inflammation #autoimmunity #blackseedoil #curcumin #fishoil
Lastly, I want to at least briefly cover one more benefit of curcumin. Honestly, it’s hard not to just keep going because it’s such a remarkable nutritional compound. But given that two of three Americans will struggle with cognitive decline by age 70 and Alzheimer’s [disease] is now the sixth leading cause of death, I want to mention that curcumin has shown great promise in reducing cognitive decline and improving memory and focus. The best evidence of this is an 18-month, double-blind, placebo-controlled trial out of UCLA that was published in 2018. It included 40 participants between the ages of 51 and 84 with mild cognitive impairment or just the normal age-associated cognitive decline, and it lasted for 18 months. So that’s a really long, randomized controlled trial and strengthens the quality of the evidence.
Curcumin led to improvements in memory and attention in adults as measured by the gold standard assessments, and even more impressively, brain scans that were performed pre- and post-treatment showed an objective decrease in plaque and tangle accumulation in brain regions that modulate mood and memory. This study suggested that curcumin has anti-amyloid and anti-inflammatory effects and may protect the brain from neurodegeneration. It’s one of the longest studies that’s been done on curcumin or any other nutritional component for that matter, and the findings were quite remarkable. It also suggests, along with some of the other studies we’ve talked about that lasted for several months, that curcumin is safe when taken long-term at appropriate doses.
As with fish oil, supplementing with curcumin has several important considerations. The most important with curcumin is bioavailability. Standard preparations of curcumin have extremely low bioavailability due to its fast metabolic turnover in the liver and the intestinal wall. Numerous papers have shown low blood and tissue concentrations of standard curcumin after taking it orally. In humans, even extremely high doses of 10 to 12 grams per day result in serum levels in the low nanomolar range. Many methods have been used to increase the bioavailability of curcumin, including combining it with piperine and encapsulation into nanoparticles, liposomes, phytosomes, polymeric micelles, and cyclodextrins. Each of these methods has merit and leads to greater absorption and serum levels of curcuminoids in their metabolites over the standard preparations. And as you might imagine, there’s a lot of controversy about which of these methods are best. It’s beyond the scope of this podcast to do a full analysis that would take two hours or more, but I have used nearly all of these in my practice, and I’ve read most of the research, so I’ll just cut to the chase and give you my recommendations. Adding piperine, black pepper, to curcumin or applying crystalline curcumin in a micronized form like Theracurmin leads to a roughly 20- to 30-fold increase in bioavailability, as indicated by [the] area under the plasma concentration-time curve or AUC. As a side note, AUC is the best way to measure bioavailability because it takes into account the entire response over time, whereas Cmax, which is used by some researchers, measures only one point in time and is, therefore, less reliable.
But a company in Germany, Aquanova, recently developed a liquid micellized form of curcumin called NovaSOL that performs even better. It’s a proprietary process of converting curcumin into a fully water-soluble and pH-stable form. NovaSOL has a biomimetic or nature-like micelle structure, which leads to optimal oral bioavailability. As I mentioned with [the] triglyceride form of fish oil, humans are accustomed to getting nutrients in a nature-like structure, through food, typically. So the closer you can make a supplement to the food-based form of a particular nutrient, the more bioavailable it will tend to be. It’s not always the case, but it is very often the case. Studies have shown that NovaSOL increases bioavailability by 185 fold, as measured by AUC, compared to piperine and Theracurmin, which is 20 to 30 fold. NovaSOL is much more bioavailable. It’s also absorbed seven times faster, as measured by Tmax. That can be helpful if you’re using it and want faster relief from inflammation and pain. There are a few other water-soluble forms of curcumin and other lipid curcumin particles that have increased bioavailability, like CurcuWIN and Longvida. Those are solid options, but none are approaching the 185-fold increase that NovaSOL has. As with GC Rieber with fish oil, NovaSOL is not a product. It’s an ingredient that manufacturers can put in their products. And there are some products out there that have it. I’m just, again, showing you the importance of bioavailability and the raw material that goes into these products in determining their clinical efficacy.
In terms of safety, curcumin has been the subject of more than 150 clinical trials, including 20 double-blind, placebo-controlled trials and 30 other trials, which have found that curcumin is safe and well tolerated when taken at recommended doses. This is true in both short-term trials and in studies lasting up to 18 months and for doses as high as 8,000 to 12,000 milligrams or 8 to 12 grams. Of course, those are the standard preparations. You would never want or need to take that much of something like NovaSOL because it’s so much more bioavailable. There have been a few rare cases of liver toxicity or autoimmune hepatitis in people taking curcumin preparations with piperine or black pepper for long periods. But in all of these cases, patients were taking multiple medications and either had other autoimmune diseases or a strong family history of autoimmune disease. So it’s hard to know what role curcumin played there.
Nevertheless, I would suggest avoiding preparations with piperine if taken long-term because there’s some concern that the interaction of piperine and curcumin may lead to some potentially negative effects if it’s taken long-term. I think there are just better ways of increasing the bioavailability of curcumin at this point. The only other cases of toxicity I’m aware of involved adulteration with synthetic curcumin or other toxic food contaminants. As always, it’s critical to choose a reputable brand and not just buy a random curcumin supplement at Costco or Amazon. There are a few important precautions and contraindications to be aware of with curcumin, [like] pregnancy and breastfeeding. While turmeric is commonly used in small amounts of spice and food, concentrated doses of curcumin haven’t been tested. It’s possible that they’re safe, but it’s possible that they’re not, and we just don’t know because they haven’t been tested, and they won’t be because no one in their right mind is going to volunteer for that study when they’re pregnant. So I think it’s best to stay on the safe side and avoid taking it during pregnancy and lactation.
[Another one is] gallbladder problems. Curcumin, in some studies, can make gallbladder problems worse, but in others, it actually improves them. So that one’s a bit murky. I would suggest speaking with your healthcare provider, especially if you have gallstones or a bile duct obstruction. [Another is] bleeding or coagulation issues. Curcumin can act as a blood thinner or an anticoagulant, so it’s best to avoid it or discuss it with your doctor if you have a bleeding disorder or you’re already taking another blood thinner. And then [also] other medications. Curcumin may be contraindicated with some medication. So, if you’re taking meds, it’s best to check with your prescribing clinician before you start curcumin.
Moving on to [BSO]. It’s also known as black cumin or black cumin seed, and it comes from the Nigella sativa plant, which is native to the Eastern Mediterranean, Northern Africa, the Indian subcontinent, and Southwest Asia. It’s been used, like curcumin, as a culinary spice and a traditional medicine for thousands of years. Hippocrates even wrote about its medicinal uses, and it was also used in Ayurvedic and Arabian systems of medicine. Like curcumin, it has an almost unbelievable range of therapeutic properties. It’s antioxidant; anti-inflammatory; immunomodulatory; anticancer; neuroprotective; antimicrobial; antihypertensive; cardioprotective; antidiabetic; gastroprotective, protects the gut; nephroprotective, protects the kidneys; and hepatoprotective, protects the liver. It’s also a potent antimicrobial with activity against bacteria, viruses, parasites, worms, and fungal pathogens. Aren’t plants amazing? I mean, you know that most medicines, most prescription medicines are isolated from plant compounds, right? This is why. They’re just remarkable. The more you learn about botanical medicine, the more you realize that nature has provided these incredible plants and substances that have so many different healing properties.
Because of all of these mechanisms, it explains why it’s been used in traditional and modern medicine for so many different diseases and conditions, from asthma and upper respiratory infections to autoimmune disease to cognitive and mood disorders to metabolic and cardiovascular disease to cancer. These days, and even in most traditional systems, the essential oil of Nigella sativa, which, again, is usually called [BSO] or black cumin seed oil, is the most frequent way to take it or to benefit from it, rather than eating the seeds or drinking a tea or anything like that. The active compounds include thymoquinone, or TQ for short, thymol, carvacrol, p-Cymene, nigellidine, nigellicine, and alpha-hederin, along with fatty acids. [BSO] has been awarded Natural Ingredient of the Year by a few different trade organizations over the last few years because of its therapeutic potential in such a wide range of conditions, its tolerability and safety, and the huge amount of research being published about its benefits. This is why I said in the introduction, if you’re not familiar with it yet, you will be soon because there’s a huge amount of attention on it at the moment. As a trained herbalist myself, I’ve been using it for many years in my practice with great success, and it’s one of the natural compounds that I am most excited about.
Let’s talk about its impact on inflammation. It reduces the production of anti-inflammatory cytokines like [TNF], CRP, and interleukin-6 and inhibits pro-inflammatory factors like nitric oxide, nitric oxide synthase, and COX-2, which we talked about in the curcumin section. Nigella sativa or [BSO] also inhibits the release of histamine. This is a really important function that it has, and it partly explains why it’s effective for so many different conditions like allergies, asthma, and other conditions that involve excessive histamine release or inadequate breakdown of histamine. [BSO] is also a powerful antioxidant, which goes hand in hand with its anti-inflammatory properties. It reduces reactive oxygen species while upregulating antioxidant enzymes like superoxide dismutase, catalase, and glutathione. Finally, it has potent immunomodulatory effects. Like curcumin, it regulates Th1, Th2, and Th17 and T reg cell balance, CD4+, CD8+ differentiation, and T lymphocyte profiles. And that explains why it’s so useful for reducing inflammation and balancing the immune system in autoimmune disorders.
Let’s start our review of conditions there because it’s probably the category, I think, of most autoimmunity, that is, for [BSO]. It has shown significant benefits in multiple autoimmune conditions. I’ll share three here to give you an idea: Hashimoto’s [disease], rheumatoid arthritis, and vitiligo, which is an autoimmune skin condition. A 2016 randomized controlled trial with 40 patients with Hashimoto’s [disease] found that [BSO] reduced [thyroid-stimulating hormone] (TSH) and anti-TPO [(thyroid peroxidase)] antibodies, and it increased [triiodothyronine] (T3) levels after just eight weeks. There was also a significant decrease in vascular endothelial growth factor, or VEGF, which is a marker of inflammation that’s often elevated in [patients with] Hashimoto’s [disease]. In another study on [patients with] Hashimoto’s [disease], treatment with [BSO] increased total antioxidant capacity, [malondialdehyde] (MDA), superoxide dismutase, all of which tend to be depressed in [patients with] Hashimoto’s [disease]. And the researchers also noted significant decreases in body mass index and improvements in endothelial function and lipid profiles.
In a 2021 review of studies of BSO and rheumatoid arthritis, there were multiple benefits, including a lower disease activity score, improved bone resorption, reductions in markers of oxidative stress and inflammation, and significant immunomodulatory activity. It improves the immune response, especially T lymphocytes, and increases the ratio of T helper lymphocytes to suppress T lymphocytes, which in turn increases the activity of natural killer cells. And finally, a 2014 study looked at fish oil and [BSO] together, two of my top three nutrients for autoimmunity, in the treatment of vitiligo. Both led to a reduction in the Vitiligo Area Scoring Index, or VASI, but the benefits of [BSO] were more significant. This study didn’t look at combining them. I wish it had. We’re going to talk about some studies that do look at combining these three nutrients a little bit later. So it’s possible, or even probable, that combining [BSO] and fish oil would have produced a synergistic effect and led to even greater improvements than using either alone. But this study didn’t look at that. We’ll talk about some that did in a little bit.
The researchers on this paper speculated that thymoquinone, or TQ, the primary active constituent of [BSO], may have been primarily responsible for the effect because TQ protects cells against oxidative damage induced by a variety of free radical-generating pathologies, and it also stimulates the production of acetylcholine, which causes the release of melanin and darkening of the skin through stimulation of cholinergic receptors. It’s worth mentioning that vitiligo is not the only skin condition that [BSO] improves. A 2022 systematic review and meta-analysis of [randomized controlled trials] (RCTs) found that BSO was effective in the treatment of a wide range of skin disorders, including atopic dermatitis, eczema, warts, keratosis, psoriasis, vitiligo, infant skin infections, and acne. And again, the reason for that is that virtually all skin conditions are inflammatory, and many of them are autoimmune in nature, as well, including dermatitis, psoriasis, and vitiligo. So it’s no surprise that it works with so many different skin conditions. Given that, it’s also not a surprise that it would be effective for allergic and atopic conditions because of its ability to inhibit histamine production. Like autoimmune diseases, these conditions are characterized by oxidative stress and inflammation and inappropriate release of histamine in many cases. And [BSO] is a potent antioxidant, anti-inflammatory agent, and antihistamine.
A 2019 review of [BSO] for allergies and asthma found several positive effects, including reduced histamine production, stabilization of mast cells, which produce histamine, fewer allergy symptoms, and better bronchial function. As with autoimmunity, BSO’s ability to balance and regulate the immune system is one of the main reasons it’s so effective for these allergic atopic conditions. It’s also shown benefits in upper respiratory infections. Remember I mentioned that it’s antimicrobial? It’s antibacterial and antiviral, as well, [and is effective in] obstructive pulmonary diseases like [chronic obstructive pulmonary disease] (COPD), where it has a bronchodilatory effect [and] makes it easier to breathe.
Let’s talk a little bit about BSO and cancer. Cancer is, of course, an expression of a dysregulated immune system. So again, given BSO’s multiple effects on balancing and regulating immunity, it’s not surprising that studies show that it can be helpful as an adjunctive therapy for cancer. A 2021 review showed that BSO and its primary active constituents, like TQ and alpha-hederin, have potent anticancer and chemosensitizing effects against a whole bunch of different types of cancer, like liver, colon, breast, cervical, lung, ovarian, pancreatic, prostate, and skin tumors. It’s also been shown to reduce cell proliferation, promote cancer cell destruction, inhibit angiogenesis, and reduce metastasis or the spread of cancer. And it has a synergistic effect, it appears, with chemotherapeutic drugs and radiation therapy. It seems to enhance the effects of those treatments.
[Next, let’s talk about its] metabolic and cardiovascular benefits. Again, if we consider conditions that are characterized by inflammation and oxidative stress, metabolic syndrome and cardiovascular disease would be at the top of the list. BSO has a long history of traditional use in these contexts, and modern research has shown huge promise, as well. For example, a systematic review of 17 studies examining BSO as a treatment for patients with diabetes and other metabolic conditions found significant improvements in fasting glucose, postmeal glucose, fasting insulin, hemoglobin A1c, and [Homeostatic Model Assessment for Insulin Resistance] (HOMA-IR). BSO has also been shown to reduce both systolic and diastolic blood pressure in patients with hypertension. A 2021 review of RCTs and other trials found, “significant reduction of blood pressure in almost every patient who participated in those RCTs.” That’s pretty rare. The studies often found that patients were able to reduce their medication doses or, in some cases, stop their medication entirely by adding BSO to their overall treatment regimen. They also found other significant benefits like reductions in body weight, [body mass index], waist-to-hip ratio, liver enzymes, triglycerides, and LDL and total cholesterol.
A 2021 RCT found that BSO led to improvements in several cardiovascular risk markers, including an increase in HDL and glutathione levels and a decrease in blood pressure, LDL, and total cholesterol markers of oxidative stress. Animal studies have shown that BSO significantly inhibits plaque formation in the arteries and reduces the expression of monocyte-derived macrophage growth, which is really important because those macrophages have been shown to take up oxidized LDL, then they become foam cells in the blood vessel wall and accelerate local inflammatory response that eventually leads to plaque formation.
Lastly, I want to talk about [BSO’s] benefits in cognitive and neurodegenerative disease. As with curcumin, it’s really hard to know where to stop with [BSO’s] benefits. There [are] so many conditions that it helps with, but cognitive and neurodegenerative disorders are so common now, so debilitating, and their prevalence is increasing so much that I think it’s important to at least touch on this. Most brain conditions, as you now know, if you didn’t already, including mood disorders like depression and cognitive disorders like dementia and Alzheimer’s [disease], are driven by inflammation and oxidative stress.
BSO has shown protective effects against a wide range of these conditions, including Alzheimer’s [disease], depression, epilepsy, Parkinson’s [disease], and traumatic brain injury. While a lot of this research has been done in animals, more research in humans is underway, and the results have been very promising so far. BSO or TQ primary active ingredients have been shown to reduce neurotoxicity, inhibit oxidative stress, decrease beta-amyloid, induce cell damage, and improve mitochondrial function in the brain. They also have a wide range of benefits in neurodegenerative conditions, including improving memory and cognition, promoting better communication between neurons, and reducing inflammation in the brain. BSO has also been shown to increase [gamma aminobutyric acid] (GABA) and reduce plasma nitrite levels in the brain, which, in turn, reduces anxiety symptoms. In animal models, where depression was induced by lipopolysaccharide, which is an inflammatory compound, BSO reduces that lipopolysaccharide-induced inflammation and alleviates depressive behaviors. Taken together, studies on the neuroprotective effects of BSO show its great promise for both mood and cognitive and neurological disorders.
As with both curcumin and fish oil, there are many important considerations when it comes to taking [BSO] as a supplement. Given how much interest there is in it right now, it’s not surprising that there’s been a flood of low-quality products hitting the market with inferior ingredients and preparations. These factors I’m about to discuss are especially important with BSO. The first is extraction. Traditional herbalists have always preferred using either the whole herb or botanical or a full-spectrum extract. This provides the complete range of therapeutic compounds in the plant and leverages the synergistic relationships between these compounds. Even a single plant can have hundreds or thousands of these compounds, and we’re just beginning to understand all the relationships between them. In contrast, the allopathic model is to try to identify the most active ingredient, isolate it, and then amplify it. This does have some merit in that it can increase the concentration of the most active ingredients and ensure a consistent and standardized dose, which is hard to achieve with the whole plant. But there are considerable downsides. You miss out on the synergies between the constituents found in the whole plant or the full-spectrum extract, many of which we don’t fully understand yet. And you may not get some important compounds that were not included in the isolated product.
BSO has many key phytochemical compounds, including TQ, p-Cymene, carvacrol, nigellidine, nigellicine, and alpha-hederin. There are also numerous other compounds found in a full-spectrum [BSO], including sterols and saponins, novel lipid constituents, and volatile oils of varying compositions. So what appears to work best in achieving a balanced and full-spectrum [BSO] is using freshly harvested black cumin seeds and a cold-depressed extraction method. This is what TriNutra has done with their patented form of [BSO] called ThymoQuin. Again, like with GC Rieber and NovaSOL, ThymoQuin is not a product. It’s a patented ingredient that supplement brands and formulators who are making [BSO] products can use. TriNutra uses fresh seeds with cold-pressed extraction to produce a standardized full-spectrum oil with optimal ratios of all the bioactives found in black seeds. These precise ratios contribute to the synergistic effects available in [BSO]. On the other hand, extractions that force really high ThymoQuin concentrations will often leave other beneficial compounds out or in low proportions, resulting in a pretty narrow composition and, therefore, a reduced therapeutic benefit.
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The next factor is standardization. When you’re trying to use a botanical like BSO therapeutically—this is really important—it ensures that you’re getting enough of the active compounds to achieve the therapeutic goals. Black cumin seed naturally contains about 0.3 to 0.7 percent TQ and 25 to 40 percent oil. But a lot of manufacturers will use extraction by solvent or carbon dioxide to remove the lipid fraction of the [BSO], and that results in less-than-optimal ratios of free fatty acids and [TQ] with a decrease in the health benefits. ThymoQuin from TriNutra is standardized to contain 3% TQ with very low levels, less than 2%, of free fatty acids. I can’t stress how important this is because high levels of free fatty acids interfere with [BSO’s] ability to reduce inflammation and oxidative stress. Free fatty acids are a significant contributor to free radical production, which destabilizes the TQ and triggers an inflammatory response in the body. And the higher the content of free fatty acids, the more potential there is for inflammation. So it’s really important to choose a [BSO] that has low levels of free fatty acids, and ThymoQuin is the lowest that I’ve found.
[The] next factor is composition. Along with standardization, the specific composition of active compounds of [BSO] is important. p-Cymene is a naturally occurring, aromatic organic compound in [BSO], and studies show that it creates a synergistic effect with TQ to reduce inflammation. The best ratio between p-Cymene to TQ is equal to or below one to three. Carvacrol is another aromatic compound that’s found in [BSO] and other plants and herbs. Research has shown that carvacrol levels of no more than 0.1% in a formulation stabilize and enhance the anti-inflammatory activity of TQ. And again, the ThymoQuin ingredient from TriNutra has the optimal ratios of p-Cymene to TQ and carvacrol to TQ, which is one of the reasons I think it’s one of the best BSO ingredients out there.
As for dosage, the dose range will vary significantly, as you can imagine, depending on whether it’s taken as a full-spectrum extract or as isolated TQ. For most applications, I would suggest a dose of 500 milligrams per day, which gives you 15 milligrams of TQ if it’s standardized to 3% TQ content. In terms of safety, several studies have been done to evaluate [the] safety and toxicity of BSO, and in short, it seems to be remarkably safe when taken at appropriate doses. Studies of participants that took between 1 and 5 grams or 1,000 to 5,000 milligrams per day showed no adverse effects. In animal studies, no toxicity symptoms were evident at TQ doses as high as 40 milligrams per kilogram. In humans, this would be equivalent to a TQ dose of roughly 250 milligrams or a full-spectrum [BSO] dose of 8,333 milligrams. This is almost 17 times higher than the daily dose of 500 milligrams of [BSO] with 15 milligrams of TQ, [which] studies suggest is optimal for most people.
So far, we’ve been talking about the benefits of each of these compounds when they’re taken on their own, but this ignores the power of nutrient synergy. We talked about this briefly in the context of using the whole plant or a full-spectrum extract versus an isolated single constituent like TQ. I mentioned that using the whole plant or a full-spectrum extract is preferred because of the synergies between all of the active ingredients, enzymes, and other cofactors within a given botanical or food. Those could be considered internal synergies, or synergies that occur between constituents within the same botanical or food. But there are also external synergies, which occur between different botanicals, nutrients, and foods when they’re combined together. Vitamin K2 and calcium are a great example of this in the world of essential nutrients. [Vitamin] K2 regulates calcium metabolism and directs it to the bones and teeth where it’s needed and keeps it out of the soft tissues where it can cause harm. So that’s an example of external synergy between two different nutrients.
With this in mind, let’s talk about some of the synergies that we can leverage between fish oil, curcumin, and [BSO], starting with fish oil and [BSO]. A 2020 study found that ThymoQuin, that patented BSO ingredient that I was just talking about, has significant synergies with fish oil. The researchers studied the effects of both fish oil and ThymoQuin BSO on obesity-induced oxidative stress, inflammation, and insulin resistance, and both fish oil and BSO were effective in inhibiting or reducing these markers. However, a combination of fish oil and BSO was significantly more effective at reducing inflammation, reducing fat droplet number and size, increasing mitochondrial energy production and function, and improving cellular sensitivity to insulin. In the case of fish oil and curcumin, studies have shown that fish oil improves curcumin absorption and vice versa. Adding curcumin to fish oil preparations has also been shown to improve freshness and reduce oxidation, [which is] not surprising because curcumin is a powerful antioxidant. And a 2018 randomized [clinical] trial found that combining fish oil with curcumin reduced inflammatory markers like interleukin-6 and [CRP] in patients with migraine headaches more significantly than either fish oil or curcumin alone.
With [BSO] and curcumin, a few studies have examined synergies. A 2015 RCT found that coadministration of BSO and curcumin led to greater improvements in metabolic markers like body weight, lipid profiles, blood pressure, and blood glucose than either botanical did alone. A 2022 triple-blind [RCT] found that BSO and curcumin significantly improved markers of bone health in a group of postmenopausal women. Collectively, these studies suggest that taking curcumin, BSO, and fish oil together almost certainly confers benefits above and beyond what you’d get from taking each of them individually. This makes perfect sense when you understand the principle of nutrient synergy.
If you’re still listening, congratulations. This has been quite a marathon. But before we finish up, I want to briefly cover a few case studies from my practice where I use these nutrients either alone or in combination with great success. This will give you an idea of the situations where I use these nutrients clinically and an idea of whether they’d be a good fit for you. The first case is a 36-year-old female with Hashimoto’s [disease], psoriasis, and celiac disease. This patient had three different autoimmune conditions, which, unfortunately, is not uncommon because, again, autoimmune disease[s] all share that common underlying process of autoimmunity. She’d had some success with [the autoimmune protocol] (AIP), which is an anti-inflammatory autoimmune diet, and other dietary interventions, but she still wasn’t where she wanted to be. Her thyroid antibodies were still elevated, and [her] psoriasis was itchy and painful and quite conspicuous. She was ultra-sensitive to gluten. Even the smallest amount of cross-contamination sent her into a tailspin. So I gave her fish oil, [BSO], and curcumin, and her skin improved almost immediately. She had less itching. Her plaque[s] started to resolve, and they were less painful.
After about two months, we retested her thyroid numbers. Her antibodies were down, her TSH was down, and her free T3 was increased. In fact, she had to reduce her thyroid medication dosage along with her doctor because her immune system was not attacking her thyroid as much as it was before. Her thyroid was actually able to produce more of its own thyroid hormone. That can sometimes happen, [and it’s] something to keep in mind if you’re listening to this and you’re considering using these nutrients. The biggest surprise was how much less sensitive to gluten she became. She still had celiac disease, of course, so she couldn’t eat gluten, or at least not in significant amounts, but she wasn’t as bothered by cross-contamination or small exposures. If any of you have celiac [disease] or severe gluten intolerance, you know how life changing that can be. Just the ability to go out to restaurants and eat with other people and not be as vigilant about it can make an enormous difference in quality of life. So she was really, really happy about that.
The next case is a 52-year-old male athlete with joint muscle pain and declining performance and recovery. I mentioned before that these nutrients aren’t just helpful for people who are trying to deal with complex chronic diseases. They can also significantly improve quality of life because of their anti-inflammatory, antioxidant, and so many other benefits. This guy was a former competitive tennis player, and he still competed in masters in recreational leagues. Over the past three to four years before he came to see me, he’d been experiencing a lot more injuries and declining performance and recovery, a lot of stiffness and pain, and he was getting a lot worse, to the point where he couldn’t really play tennis anymore, or he paid the price if he did, and even started to have trouble with basic activities like walking [and] household chores without pain. He got to the point where he was taking ibuprofen every day. He was having a lot of GI side effects, and he developed an ulcer, so his doctor appropriately told him he had to stop taking ibuprofen, or he was going to risk serious harm. That’s what finally motivated him to come see me. [I] put him on an anti-inflammatory diet and gave him fish oil and curcumin. This was before I had started to use [BSO] regularly, so we just did fish oil and curcumin in that case, and the results were almost immediate. He had way less pain in his joints and muscles after just a week. After a month, he was playing tennis again, he was performing at a higher level than he had in years, and his recovery time was shortened significantly. And after three months, he was still improving. That’s an important thing to keep in mind with these nutrients, specifically, and nutritional interventions, in general, is they can have a cumulative effect, and the benefits will compound over time. So it can sometimes take three to six months of consistent use to get the full impact.
[The] next case is a 42-year-old female with brain fog, depression, and anxiety. She had three young kids, I think under the age of seven, if I recall. She was working outside the home [and was] struggling with depression, anxiety, and inability to concentrate. And some days, it was so bad. She felt incapacitated and barely able to function at work or as a mom. She tried a lot of different supplements and antidepressant medications without much benefit. When she came to see me, we made some dietary modifications, and then I put her on the full stack of fish oil, curcumin, and [BSO]. After three weeks, she noticed significant changes. She was engaging in more of her typical activities, spending more time with her friends, exercising more often, and feeling more connected with her kids and her husband, which brought tears to her eyes when she came back and reported on this because she really felt isolated and alone, and that was so hard on her and her family.
Her mind was also sharper. She could focus better at work, and she didn’t feel so exhausted and kind of foggy and out of it all the time. The fish oil, curcumin, and [BSO] put her on an upward spiral where it improved her symptoms enough that she was able to do other things like eat better, exercise more, and sleep better that further improved her symptoms. And again, this was life changing. She was able to function so much better and enjoy her life so much more.
[The] last case was a 34-year-old female with pre-diabetes and several different allergies and asthma. She was overweight with high fasting glucose and insulin and dyslipidemia. She also had pretty severe allergies, both food and environmental, and asthma and mast cell activation disorder, which is a condition where the mast cells that produce histamine become hyperactive. And that can lead to what we call a polysystemic hyperreactive response where the body is just in this high, alert hyperreactive state and is negatively reacting to multiple different things. These are people who, often, can only eat a small handful of foods. They’re sensitive to supplements. They can be some of the most difficult patients to work with because they’re sensitive to every kind of treatment that we offer. We started her on fish oil, [BSO], and curcumin, but had to go slowly because she was intolerant of most supplements. So it did take a bit longer with her, but it was really worth it. After three months, she was able to stop her allergy shots, the range of food she could eat had expanded hugely, and her asthma inhaler use dropped by about 75%. She also had huge improvements in her metabolic markers. Glucose and insulin went from the pre-diabetic to normal range, and her lipids normalized. So across the board, we saw some really big improvements with her.
Okay. We made it. I hope this has been helpful. Autoimmune inflammatory conditions are so common now, and rates continue to increase every year. I think the latest statistics I’ve seen is, of 80 million Americans that have an autoimmune disease, 6 in 10 have chronic disease, 4 in 10 have multiple chronic diseases, and, as we discussed, almost all of those have a component of inflammation or mostly driven by inflammation and oxidative stress. As you know, the conventional treatments for these conditions leave a lot to be desired. They can sometimes be helpful in reducing the symptoms, but they have many side effects and some very serious risks, all the way up to death, in some cases. So there’s a pressing need for natural, safe, and effective interventions that can be used in these situations, and fish oil, [BSO], and curcumin are the three most effective nutrients that I’ve used in my practice and according to the research. So, with all of that in mind, stay tuned for an exciting announcement next week related to what we’ve covered in this podcast. Thank you for listening, and keep sending your questions to chriskresser.com/podcastquestion. I will talk to you next time.
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