Clinical research in chronic inflammatory conditions presents a range of clinical results, with most trials showing significant benefits
We’re all familiar with the kind of inflammation that causes the area around a minor wound or sprain to swell and redden, but then subsides within hours or days.
Inflammation now ranks among the hottest topics in medicine, thanks to a wealth of recent research documenting its links to heart disease, Alzheimer’s disease, cancer, and more.
This debilitating, occasionally life-threatening kind of runaway inflammation has prompted extensive research into dietary factors with therapeutic potential. And the results indicate that omega-3 fatty acids from fish offer more promise than most.
We can thank some major publishing events for the public’s increased awareness of inflammation:
The silent, symptom-free inflammation that these authors and others decry is a cause for concern over the long term, and the evidence indicates that diet plays a major role in fueling it (see “Omega-3s and the omega-6 overload” below).
Before we review the evidence from clinical trials in the major inflammatory diseases (see “Omega-3s in inflammatory disease”, below), it helps to understand why so many researchers expect results from these unique, fish-derived fatty acids.
Inflammation is a series of multifaceted interactions between the largely gene-governed networks that constitute the human immune system, and food factors such as fatty acids, vitamins, minerals, and antioxidants.
While chronic inflammation is deeply destructive, acute (short-lived) inflammation plays a key role in the body’s immune response to injury and to perceived foreign agents like viruses and microbes:
- Inflammation increases blood flow to deliver needed nutrients, oxygen, and immune cells to injured or infected tissues and hasten removal of dead bacteria and toxic bacterial secretions.
- Inflammation gives the affected area time to heal by making it stiff and painful to move.
This confusion of bodily components for foreign invaders is the common thread connecting rheumatism, irritable bowel disease, Crohn’s disease, psoriasis, eczema, and all other so-called “autoimmune” (immune-to-self) diseases. Childhood-onset (Type I) diabetes is another autoimmune condition, but the damage it does to pancreatic cells occurs too silently and quickly for subsequent anti-inflammatory therapy to help.
Hypotheses explaining the onset of these immune-system aberrations abound, but none can account for all of these conditions. Instead, it appears that each of the various auto-immune diseases has unique genetic roots and environmental or dietary triggers.
Asthma is not an autoimmune disease, but we’ve included it in this review because it shares many of the inflammatory characteristics of those disorders and may also be affected positively by dietary omega-3s.
Essential fatty acids (EFAs) and inflammation
To survive and thrive, humans need to consume omega-3 and omega-6 EFAs. Both kinds are considered essential, as they constitute fundamental structural and functional components of our cells, regulate many critical aspects of metabolism and immunity, and must be obtained from foods.
When it comes to omega-3 EFAs, our bodies depend primarily on the long-chain forms (EPA and DHA) found only in seafood. Unfortunately, almost all of the omega-3s in the average American’s diet consist of a short-chain, plant-derived form called ALA, which the body converts to EPA and DHA at rates ranging from five to 18 percent, depending on a person’s gender, genetics, and hormonal status. (The remaining 82 to 95 percent of dietary ALA gets burned for energy.)
Omega-3 EFAs reduce inflammation via their ability to promote anti-inflammatory components of our immune systems, and suppress pro-inflammatory actors. (While both of the major long-chain omega-3s—EPA and DHA—exert anti-inflammatory effects, EPA is the stronger of the two.)
And, in general, omega-6 EFAs tend to promote inflammation because they are the substrates (raw materials) for inflammatory chemicals. The picture isn't black and white, since generally pro-inflammatory omega-6 EFAs sometimes act to reduce inflammation (see “The omega-3/omega-6 face off”, below).
Leading researcher summarizes anti-inflammatory effects of omega-3s
Professor Philip Calder, Ph.D. of the University of Southampton, England is one of the most widely cited researchers in the field of essential fatty acids (EFAs), and his areas of interest include the effects of omega-3s on inflammation.
Dr. Calder penned an informal evidence review earlier this year, whose main points bear repeating:
- Therapeutic potential of marine omega-3s
- Marine omega-3s may be therapeutic in a variety of acute and chronic inflammatory conditions.
- Evidence of their efficacy is reasonably strong in rheumatoid arthritis but weaker for inflammatory bowel diseases and asthma.
- We need larger, better-designed clinical trials to determine the therapeutic value of marine omega-3s in autoimmune and other inflammatory diseases.
- Plant-derived, short-chain omega-3s display no anti-inflammatory effects at intake levels that are practical to achieve.
- Consumed in sufficient amounts, the long-chain marine omega-3s found in fish and fish oils decrease the production of inflammatory internal agents (eicosanoids, cytokines, free radicals) and the "expression" of adhesion molecules.
- Marine omega-3s reduce inflammation directly, by replacing omega-6 arachidonic acid in cell membranes, which reduces the pool of appropriate raw material available to produce pro-inflammatory eicosanoids.
- Marine omega-3s also reduce inflammation indirectly, by inhibiting activation of pro-inflammatory nuclear transcription factors (e.g., NF-kB).
- Marine omega-3s give rise to anti-inflammatory lipid mediators that help resolve (shut off) runaway inflammation.
Before they can be incorporated into our cells, dietary EFAs must undergo conversion into usable forms via a metabolic process enabled in part by the delta-6 desaturase enzyme.
But, if your diet is weighted heavily in favor of omega-6 EFAs, they will overwhelm your body’s limited delta-6 desaturase capacity, and your cells will not get enough long-chain omega-3 EFAs.
This dietary imbalance matters because over-consumption of omega-6 EFAs tends to promote chronic, low-grade inflammation and an inflammatory overreaction by the immune system to otherwise-innocuous stimuli.
The pro-inflammatory bodily environment created by over-consumption of omega-6 EFAs may lay the groundwork for the onset of conditions physicians consider inflammatory in nature, such as the diseases reviewed below, as well as the persistent inflammation found in Alzheimer’s disease, cardiovascular disease, and certain cancers.
Omega-3s are generally anti-inflammatory and omega-6s are generally pro-inflammatory, but it isn't a black-and-white picture.
Italian investigators examined markers of immune function in a cross-section of adults of all ages and found that body levels of some substances that promote inflammatory responses were higher when concentrations of both omega-6 and omega-3 EFAs were low (Ferrucci L et al 2006).
This finding may stem from the fact that, like omega-3s EPA and DHA, omega-6 arachidonic acid is needed to stimulate production of certain anti-inflammatory lipid mediators (e.g., lipoxin).
It also supports the idea that we need both types of EFAs in roughly equal amounts, rather than the extreme overabundance of omega-6 EFAs and scarcity of omega-3 EFAs that characterize diets in modern industrial societies.
While research results leave no doubt that long-term consumption of even modest amounts of fish or fish oil results in reduced levels of inflammation in the body, relatively low intake levels have no measurable effect in the short term.
Other research results suggest that significant replacement of pro-inflammatory omega-6 arachidonic acid with omega-3s in cell membranes occurs only after routine ingestion of about 1.6 grams of omega-3 EPA per day (Adams O et al 2003), and that this effect is more pronounced when the amount of omega-6 EFAs in the diet is lower than normal for developed countries (Hibbeln JR et al 2006, Adam O et al 2003, Volker D et al 2000).
In terms of alleviating major inflammatory symptoms, studies in rheumatoid arthritis and psoriasis indicate that people with serious inflammatory disease may need to consume three to six grams of omega-3s per day to enjoy significant relief.
It is worth noting that, due to cost, availability, standardization and dosage control factors, omega-3 research studies typically utilize cheap, highly processed fish oils.
Comparable or even superior results may be achieved with lower doses of whole, unrefined food sources of omega-3 EFAs, which contain synergistic compounds (e.g., oleic acid and phospholipids). For more on this topic, see “Natural Omega-3s Seen Superior to Standard Supplements”).
Omega-3s in inflammatory disease: the clinical record
We searched the medical literature, and the available evidence indicates that supplemental omega-3s can make a real difference in diseases characterized by chronic inflammation.
When reading these summaries, we urge you to consider a medical concept called “bio-individuality”. Simply put, no two people with a disease will respond identically to a synthetic drug or natural therapy. A potential remedy that has little or no effect in most may confer substantial relief in a few, and vice versa.
Patients with chronic inflammatory conditions should keep bio-individuality in mind when considering a proposed therapy whose safety and anti-inflammatory effects are well established. This is certainly true of supplemental omega-3s, which offer varying prospects for relief, bring bountiful ancillary health benefits, and have virtually no downside.
Whenever omega-3s have shown positive clinical results, it has usually taken weeks or months for them to manifest fully (unless taken intravenously). And, as with synthetic drugs, omega-3s will not always offer full relief.
But, given the wide variations in people's responses to drugs and nutrients, there are likely to be many cases where sufficient omega-3s could bring benefits comparable to those delivered by pharmaceutical drugs. And at the very least, omega-3s can offer a very healthful way to reduce reliance on synthetic drugs that often elicit adverse side effects.
The successful trials employed doses ranging from 3,000 to 6,000 mg (three to six grams) of omega-3s per day.
The evidence from laboratory (test tube and animal) studies indicates that omega-3s reduce the inflammation characteristic of RA, which causes pain and damage in joint tissues, and that EPA may be more important than DHA in reducing body levels of the inflammatory markers associated with the disease.
But the therapeutic promise of omega-3s depends in part on the overall dietary context. The results of a small clinical trial from Australia suggest that people who consume fewer omega-6 EFAs than is common in developed industrial countries get maximum benefit from omega-3s (Volker D et al 2000). This is the regimen that showed particularly good results:
- Intake of omega-6 EFAs among study participants averaged less than 10 grams (about one-third ounce) per day. In contrast, the average American ingests about 22 grams (more than 3/4 of an ounce) of omega-6 EFAs per day.
- Study participants took 40 mg of omega-3s per kilogram (2.2 pounds) of body weight. In a 130-pound person, this would be about 2.4 grams (2,400 mg) of omega-3s per day, or more than double the one gram per day the American Heart Association recommends for people with diagnosed cardiovascular disease. (People on blood thinning drugs or with implanted cardiac defibrillators should seek their doctor’s guidance.)
Olive oil may boost the benefits of omega-3s. The findings of a Brazilian research group (Berbert AA 2005) confirmed those of an earlier study by American researchers, who reported greater decreases in inflammatory cytokines and RA symptoms in patients who received both fish oil and olive oil (Kremer JM et al 1990).
The 43 RA patients in the controlled Brazilian trial were divided into three groups, one of which took three grams of omega-3s and 9.6 ml of olive oil per day. Compared with the other two groups (whose members received either fish oil plus soy oil or fish oil alone), the fish oil/olive oil group showed greater improvements in grip strength, pain intensity, ability to move, and fatigue after three months, with the benefits becoming more pronounced after six months.
The greater benefit seen in patients who take both olive oil and fish oil, versus fish oil alone, is not surprising because oleic acid, the monounsaturated fat found in olive oil (and in our salmon oil), enhances uptake of omega-3s.
Osteoarthritis results from gradual wear and tear on cartilage, and a decreasing ability of the body to maintain cartilage integrity as we age. As cartilage degrades, bone begins to impinge directly on bone, and inflammation will occur to some extent.
Our search of the literature found no clinical research that tested the effects of omega-3s in this painful, common, but much less serious condition, which is not inherently inflammatory in nature.
But in recent years, a team of researchers at Cardiff University in Wales published encouraging findings, which indicate that omega-3 EFAs decrease the cartilage-degrading and inflammatory aspects of cell metabolism characteristic of osteoarthritis. Accordingly, the authors speculated that dietary supplementation with omega-3s might slow the progression of osteoarthritis (Curtis CL et al 2000 and 2002).
Inflammatory Bowel Disease (IBD)
IBD is an umbrella term that covers two similar autoimmune conditions: Crohn’s disease (CD) and ulcerative colitis UC. (Note: IBD is distinct from irritable bowel syndrome; a condition unrelated to inflammation in which intestinal muscles contract uncontrollably.)
Crohn’s disease is usually characterized by inflammation in the ileum (small intestine), colon (large intestine), or both. Common symptoms include abdominal pain, diarrhea, fever, weight loss, and poor appetite. And the chronic inflammation seen in CD reduces the colon’s ability to absorb water and food-borne nutrients.
Some clinical trials of omega-3s have produced significant alleviation of symptoms, and the symptoms of some Crohn’s disease patients taking fish oil supplements remain in remission longer, compared with those taking placebo pills.
For example, the authors of a small, eight-month pilot trial at a Veterans’ Administration hospital in California reported distinctly positive results (Aslan A et al 1992): “We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis.”
The term “asthma” refers to either of two distinct diseases—allergic and non-allergic asthma—with clear genetic components and similar symptoms: coughing, wheezing, shortness of breath or rapid breathing, and chest tightness.
Both types are characterized by inflammation that causes airways (bronchi) to narrow and produce excess mucus, which makes breathing difficult. And both types of asthma are controlled with inhaled synthetic corticosteroids that mimic the anti-inflammatory hormone cortisone.
The available evidence suggests that omega-3s can do three things:
- Decrease production of inflammatory chemicals in asthmatic patients.
- Alleviate symptoms modestly in some people.
- Reduce the risk of asthma in children with comparatively high tissue levels and in the children of mothers who consume comparatively high levels of omega-3s.
Eczema and Psoriasis
Scientists speculate that both of these related conditions may stem from deficiencies in the metabolism of dietary EFAs, but the causes remain a mystery.
The results of clinical studies testing the effects of omega-3s in patients with psoriasis or eczema preclude unambiguously positive conclusions. As the authors of a recent review put it, “…the results of studies evaluating the therapeutic benefit of dietary fish oil have been conflicting and not clearly dose-dependent” (Mayser P et al 2002).
Trials in which people took fish oil capsules produced mixed, generally minor benefits. But the results were far better in trials that involved intravenous omega-3s. While these highly positive results exhibit the strong anti-inflammatory effects of high doses of omega-3s, it is not very practical or cost-effective for patients to get them this way on an ongoing basis.
Interestingly, the results of a crossover clinical trial in which patients alternated eating oily fish or white fish showed that the oily fish produced modest improvements (Collier PM et al 1993).
As the authors said, “dietary advice to increase the daily intake of oily fish is a useful adjunct in the treatment of psoriasis. The fish that should be recommended include mackerel, sardine, salmon, pilchard, kipper and herring.”
These results suggest that substances in oily fish or undistilled fish oils (probably phospholipids) may enhance the efficacy of omega-3s, compared with the isolated omega-3s used in virtually all trials.
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