4 Little-Known Causes of Restless Legs Syndrome

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Few things are more frustrating than lying in bed at night exhausted, but not being able to fall asleep because of an uncontrollable urge to move your legs. This phenomenon, known as restless legs syndrome (RLS), affects between 4% and 29% of adults in Western populations, and is a major contributor to sleep loss. (1, 2)

Pinpointing the cause of RLS has been an active research topic for years, but the condition is still not fully understood. The symptoms have been convincingly linked to impaired dopamine function in the brain, but the cause of this dysfunction is still being explored.

In this article, I’ll review four factors that could contribute to RLS, as well as steps you can take for improving your symptoms.

1. Systemic Inflammation and Immune Dysregulation

Restless legs syndrome has been associated with numerous conditions involving systemic inflammation and immune dysregulation. (3) One review paper published in 2012 investigated health conditions that were reported to cause or exacerbate RLS symptoms, and found that 95% of the 38 different health conditions that were strongly associated with RLS have an inflammation or immune component. (4) These conditions include Parkinson’s disease, multiple sclerosis, ADHD, Alzheimer’s disease, Celiac disease, Crohn’s disease, rheumatoid arthritis, sleep apnea, diabetes, and depression.

As further evidence, an elevated blood level of C-reactive protein (a marker of systemic inflammation) has been associated with increased RLS severity. (5) A small crossover trial found that a hydrocortisone infusion, which reduces systemic inflammation, reduced RLS symptoms. (6)

Researchers have proposed three potential mechanisms to explain the association between RLS and inflammatory or autoimmune states: direct autoimmune attack on the nervous system; genetic factors that could predispose an individual to RLS and be triggered by inflammation or autoimmunity; and iron deficiency caused by inflammation, which I’ll talk more about below.

What to do: If your RLS is a symptom of underlying systemic inflammation or immune dysregulation, the goal should be to find and treat the root cause. As I’ve mentioned many times in the past, gut infections are often the culprit—even if you don’t have noticeable digestive symptoms—so get your gut tested.

If you already have a diagnosed inflammatory or immune condition such as those I mentioned above, the best first step you can take is to adopt a “low-inflammatory” diet and lifestyle. This means eating a nutrient-rich, low-toxin diet based on whole foods; getting enough sleep every night; prioritizing stress management; and incorporating regular movement into your day.

You can also check out the bonus chapter about autoimmune disease from my book, as well as explore other information on my site about reversing autoimmune disease, the autoimmune protocol, the role of the microbiome, and alternative therapies such as LDN.

Do you have restless legs syndrome? Find out what might be causing it, and what to do.

2. Small Intestinal Bacterial Overgrowth (SIBO) and IBS

Some of the more recent research on restless legs syndrome has focused on a connection with small intestinal bacterial overgrowth (SIBO) and IBS, which is often caused by SIBO. One study found that 69% of RLS patients also had SIBO, compared with only 28% of controls. (7) They also found that 28% of RLS patients had IBS, compared to only 4% of controls. And according to the 2012 review I mentioned in the previous section, 32% of the 38 conditions associated with RLS are also associated with SIBO. (8)

A strong association between SIBO and RLS doesn’t mean that SIBO is causing RLS in these patients. But a few trials have found that in patients with both SIBO and RLS, their RLS symptoms improve after being treated for SIBO. (9) For example, one double-blind, placebo-controlled study reported that treatment with the antibiotic rifaximin—the standard treatment for SIBO—significantly improved RLS symptoms in patients with both conditions. (10) This, of course, does suggest a causal link between SIBO and RLS.

What to do: If you have both RLS and SIBO, the best option would be to find a functional medicine practitioner who has experience dealing with SIBO and get treated. That said, two steps you can try on your own are a low-FODMAP diet and probiotics. Low-FODMAP diets reduce the amount of fermentable carbohydrates that “feed” bacteria in the small intestine, and a couple studies have shown that probiotics can be as effective as antibiotics for treating SIBO. (11, 12) I’ve found the probiotics Prescript Assist, S. boulardii (a beneficial yeast), and MegaSporeBiotic to be helpful.

One important note about low-FODMAP diets, however, is that it’s generally not a good idea to stay on one indefinitely. Low-FODMAP diets eliminate sources of prebiotics, which can improve symptoms by starving pathogenic bacteria, but can also starve your beneficial bacteria. The best approach is to follow a low-FODMAP diet until symptoms subside (and your SIBO breath test is normal), and then gradually re-introduce prebiotic foods (or supplements) to support your gut microbiome.

3. Vitamin D Deficiency

As I mentioned in the introduction, one of the most-researched theories about the cause of restless legs syndrome is impaired dopamine signaling, which has led to the conventional treatment of RLS by dopamine agonists (i.e. chemicals that can bind to and activate dopamine receptors). Unfortunately, these treatments can become less effective over time, and can even result in a worsening of symptoms.

And while replacing neurotransmitters might be an effective way to manage symptoms in the short term, the goal should be to figure out why dopamine signaling is impaired in the first place.

This is where vitamin D comes into play. The role of vitamin D in dopamine signaling is only beginning to be investigated, but some evidence indicates that vitamin D could play an important role by increasing levels of dopamine and its metabolites in the brain, as well as protecting dopamine-associated neurons from toxins. (13)

RLS has been associated with vitamin D deficiency in several studies, and disease severity has been inversely correlated with vitamin D levels. (14, 15, 16) One study has also found that vitamin D supplementation improved the severity of RLS symptoms. (17)

What to do: If you have RLS, one of the easiest first steps you can take is to get your vitamin D levels tested. A good range to shoot for is typically between 25-50 ng/mL, but if you have an autoimmune disease or another chronic health condition, I prefer to bring vitamin D levels up to 35-60 ng/mL. One way to supplement vitamin D is cod liver oil; I recommend extra-virgin cod liver oil. You can also take a D3 supplement, such as this one that contains both vitamin D and vitamin K2. And of course, you should get regular sun exposure to bring your vitamin D levels up naturally.

4. Iron Deficiency

Iron deficiency isn’t exactly a “little-known” cause of restless legs syndrome; in fact, it’s probably one of the most well-researched areas relating to RLS. Iron is required for proper dopamine signaling, but its role is much better established than that of vitamin D, and it’s pretty clear that iron deficiency in the CNS can cause RLS symptoms by impairing dopamine function. (18)

Several studies have found that low iron levels in the cerebrospinal fluid and in the brain occur more frequently in patients with RLS compared with matched controls. (19, 20) And this difference isn’t always reflected in serum ferritin levels.

Other abnormalities in iron metabolism have also been observed in RLS patients, and many conditions that increase the risk of RLS (including pregnancy and end-stage kidney disease) are known to cause iron insufficiency. (21, 22)

Further, iron supplementation significantly improves or even eliminates the symptoms of RLS in many patients. For example, RLS patients with low-normal serum ferritin experienced significant improvements in their RLS symptoms after 12 weeks of iron supplementation. (23) And oral iron was as effective for treating RLS as pramiprexole, a dopamine agonist, although the response rate for both treatments was relatively low (46.7%). (24)

The tricky thing about iron deficiency is that the solution is often not as simple as taking an iron supplement. Iron deficiency is frequently secondary to SIBO, gut infections, or other inflammatory states, which explains at least in part the association between RLS and these conditions. Iron deficiency caused by infection or inflammation is mediated primarily by the hormone hepcidin, which at high levels can decrease serum iron and reduce iron absorption from the GI tract. (25)

One cause of increased hepcidin levels is the production of IL-6, an inflammatory cytokine present in most inflammatory diseases. Another cause of increased hepcidin levels is the presence of lipopolysaccharides (LPS), which are components of gram-negative bacteria that can enter circulation as a result of SIBO or other gut infections. Thus, increased levels of circulating IL-6 or LPS can result in iron deficiency, and subsequently, RLS.

What to do: If you have RLS and iron deficiency, the first step is to identify why you’re iron deficient. If the cause is blood loss (such as from heavy menstruation in women) or dietary insufficiency (such as in vegetarian or vegan diets), increase your consumption of iron-rich foods such as liver and red meat. You can also consider an iron supplement; I recommend Proferrin ES and bovine ferritin, because they are better absorbed and better tolerated than plant-based iron supplements. 

However, if the cause is SIBO or a gut infection, increasing iron intake can often make matters worse by creating an environment that promotes pathogen growth and inflammation. (26, 27, 28) For this reason, it’s best to address the gut before (or at least concurrently with) adding iron supplements.

As you can see, restless legs syndrome is complex, and several factors could come into play when trying to figure out the cause. As with many other health conditions, RLS is best seen as a symptom which signals that something else is amiss, and it’s necessary to dig deeper to find out the root cause, and how to treat it.

Do you suffer from restless legs syndrome? If so, has this article helped clarify what might be causing it? Share your experience in the comments.

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