TOKYO - What does it feel like to have Restless Legs Syndrome? From my own experience, it is like being buried in sand, with a deep, heavy ache that can only be relieved by moving the legs or through constant massage. Resisting the urge to move can trigger a sense of panic, similar to claustrophobia—just when all you want to do is sleep. It’s exhausting, often lasting through the night and into the early morning hours, sometimes even longer.
This debilitating condition can take a serious toll on mental well-being—and in its most severe form, even diminish the will to carry on—yet it remains rarely discussed, likely due to the uncertainty surrounding its cause and the lack of safe, effective treatments.
Traditional theories have pointed to iron deficiency (Allen et al., 2018), nerve dysfunction (Garcia-Borreguero et al., 2016), diet (Patton et al., 2023), or genetics (Winkelmann et al., 2007; Schormair et al., 2017) as potential contributors to RLS.
Still, none of these theories alone provide a complete explanation. Over the last few years, I’ve been gathering profoundly interesting information that seems to unlock the mysteries surrounded this inexplicable condition, specifically regarding the role of nitric oxide. To the best of my knowledge, no published research has explored whether a deficiency in nitric oxide could be a potential cause of RLS, and how sinus function, facial muscle tension, and brain activity may work together to trigger the overwhelming urge to move the legs.
It is well established that nitric oxide (NO) production declines significantly with age—by as much as 75% by the time individuals reach their 60s or 70s (Münzel et al., 2013). Coincidentally, RLS becomes more prevalent and severe with age. In the United States alone, it’s estimated that around 10% of adults suffer from RLS (Phillips et al., 2000), with as many as 20% of those over 60 experiencing moderate to severe symptoms (Berger et al., 2004).
One of the mysteries of RLS is why it characteristically happens at night. This matches the phenomena that nitric oxide production in the body follows a circadian rhythm, with levels peaking in the morning and reaching their lowest in the evening (Schaad et al., 2009). NO plays a major role in facilitating oxygen delivery to the limbs through vasodilation, helping blood vessels open to supply oxygen and nutrients (Mortensen et al., 2012). Individuals with RLS often describe sensations as "crawling," "creeping," or "pulling" that typically occur within the legs rather than on the skin (Mayo Clinic, n.d.). These sensations could equate to the feeling of muscle repair during a period of peripheral hypoxia. When the body reaches a deep level of relaxation, it signals muscles to begin repair, as they are best restored while inactive (Zhu et al., 2025). Satellite cells that are usually inactive on the surface of muscle fibers spread across injured areas to support repair and regeneration, adding sticky layers to rebuild the affected tissue (Forcina et al., 2020). A key ingredient in muscle repair is oxygen. However, if NO is insufficient, oxygen is unable to jump off red blood cells (Ghosh et al., 2018), creating a state of peripheral hypoxia (Doctor & Stamler, 2011). Tidball (2005) explains that insufficient oxygen impairs the inflammatory and regenerative processes required for effective muscle repair. Without sufficient oxygen, muscle repair is slower, less efficient, and potentially incomplete. A 2014 study found that individuals with RLS have lower oxygen levels in their legs compared to their chest, suggesting that impaired peripheral oxygen delivery may play a role in the development of RLS (Ghosh et al., 2014).
Peripheral hypoxia (a deficiency of oxygen in the body's extremities, such as the arms or legs) can potentially contribute to feelings of panic or anxiety (Ley, R., 2001). In order to relieve the peripheral hypoxia, a signal may be sent to the brain to move the muscles in an attempt to increase oxygen flow and decrease the build-up of bicarbonate that can result from oxygen deprivation. Animal studies have shown that hypoxia can induce panic-like escape behaviours, suggesting a direct link between low oxygen levels and panic responses (Garcia, S., et al., 2021).
Most cells in the body can produce nitric oxide in response to inflammation, changes in blood flow, oxygen levels, or physiological stress (Förstermann & Sessa, 2012). NO can also be present in the saliva, as dietary nitrates (from vegetables like spinach and beets) are converted into nitrite by nitrate-reducing bacteria in the mouth, which is why some physicians now caution against excessive mouthwash use, as it can inhibit this pathway (Kapil et al., 2013).
While these pathways are important, the paranasal sinuses may provide a critical source for the purposes of supplying sufficient NO to the extremities during periods of muscle repair. These sinuses occupy some of the most important real estate in the human body, just behind the eyes and forehead—an indication of their biological importance. Abdel-Razek and Khattab (2020) directly challenge the common belief that paranasal sinuses are evolutionary remnants or serve minor functions such as voice resonance or skull lightening, arguing instead that their primary role is the production of nitric oxide. Researchers now believe that NO synthesis is the primary role of the paranasal sinuses (El-Anwar & Nofal, 2020).
Epithelial cells in the paranasal sinuses release nitric oxide into the nasal cavity through small openings called ostia. NO then follows the airflow into the lungs and onwards into the bloodstream (Lundberg et al., 1995). Nitric oxide, as a free radical, has a short biological half-life of up to approximately two seconds, depending on oxygen concentration and tissue environment (Lancaster & Buettner, 1999). Nitric oxide released from the paranasal sinuses reaches the legs via the bloodstream in approximately one second, indicating that a continuous supply from the airways may be essential for effective NO delivery to the extremities (Ghosh et al., 2018).
Another possible influence in the distribution of nitric oxide is its role in brain thermoregulation. Some studies suggest NO helps cool the brain during heightened mental activity through cerebral vasodilation (Lin et al., 2000; Blessing, 1999). While direct evidence is lacking, it seems plausible that if the brain is overstimulated—by stress, anxiety, or racing thoughts— the body prioritizes nitric oxide delivery to the brain. Under stress, the demand for cerebral blood flow increases, potentially redirecting NO distribution to this organ that uses around 20% of the body’s energy (Tarantini et al., 2021).
Since nasal breathing enhances nitric oxide delivery to the lungs (Lundberg et al., 1995), facial muscle tension may also play a role in the supply of NO from the paranasal sinuses. If muscles around the cheeks and nose are tight, they could subtly compress the ostia, which are only about 1mm to 3mm wide (Souza et al., 2016), restricting the delivery of NO. Relaxing the face may improve sinus airflow and boost nitric oxide release into the lungs and bloodstream. Studies have shown that certain techniques—like humming—can increase nasal NO levels by temporarily improving sinus ventilation (Weitzberg & Lundberg, 2002).
Interestingly, dopamine boosts nitric oxide production (Melis et al., 1996), which may explain the effectiveness of dopamine agonists in treating RLS. However, these medications are no longer recommended long-term due to a phenomenon called augmentation, where symptoms worsen over time and dopamine receptors become less responsive (Allen et al., 2016).
Taken together, the true origins of Restless Legs Syndrome may lie in the natural decline of nitric oxide production during the evening and with age, compounded by impaired paranasal sinus function. This combination can lead to peripheral hypoxia, disrupting muscle repair during rest and triggering a sensation of anxiety. In response, the brain may signal the legs to move in an attempt to restore oxygen delivery. This perspective opens new avenues for understanding the underlying causes of RLS, leading to new methods in relieving its symptoms, and potentially helping millions of people who suffer from this condition.
References
Abdel-Razek, H., & Khattab, M. A. (2020). Nitric oxide unravels the enigmatic function of the paranasal sinuses. The Egyptian Journal of Otolaryngology, 36, 7. https://doi.org/10.1186/s43163-020-00011-7
Allen, R. P., Picchietti, D. L., Auerbach, M., Cho, Y. W., Connor, J. R., Earley, C. J., ... & Winkelman, J. W. (2018). Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: An IRLSSG task force report. Sleep Medicine, 41, 27–44. https://doi.org/10.1016/j.sleep.2017.11.1126
Allen, R. P., Picchietti, D. L., Garcia-Borreguero, D., Ondo, W. G., Walters, A. S., Winkelman, J. W., ... & Lee, H. B. (2016). Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. Sleep Medicine, 17, 7–19. https://doi.org/10.1016/j.sleep.2015.10.009
Berger, K., Luedemann, J., Trenkwalder, C., John, U., & Kessler, C. (2004). Sex and the risk of restless legs syndrome in the general population. Archives of Internal Medicine, 164(2), 196–202. https://doi.org/10.1001/archinte.164.2.196
Blessing, W. W. (1999). Nitric oxide and body temperature control. Physiology, 14(1), 30–36. https://doi.org/10.1152/physiologyonline.1999.14.1.30
Bramble, D. M., & Lieberman, D. E. (2004). Endurance running and the evolution of Homo. Nature, 432(7015), 345–352. https://doi.org/10.1038/nature03052
Doctor, A., & Stamler, J. S. (2011). Nitric oxide transport in blood: a third gas in the respiratory cycle. Comprehensive Physiology, 1(3), 541–568. https://doi.org/10.1002/cphy.c100009
Earley, C. J., Connor, J., Garcia-Borreguero, D., Jenner, P., Winkelman, J., Zee, P. C., & Allen, R. (2014). Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Medicine, 15(11), 1288–1301. https://doi.org/10.1016/j.sleep.2014.05.009
El-Anwar, M. W., & Nofal, A. A. (2020). Nitric oxide unravels the enigmatic function of the paranasal sinuses. The Egyptian Journal of Otolaryngology, 36(1), 11. https://doi.org/10.1186/s43163-020-00011-7
Forcina, L., Cosentino, M., & Musarò, A. (2020). Mechanisms regulating muscle regeneration: Insights into the interrelated and time-dependent phases of tissue healing. Cells, 9(5), 1297. https://doi.org/10.3390/cells9051297
Förstermann, U., & Sessa, W. C. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829–837. https://doi.org/10.1093/eurheartj/ehr304
Garcia-Borreguero, D., Williams, A. M., & Winkelmann, J. (2016). Restless legs syndrome: Diagnostic criteria, differential diagnosis, and pathophysiology. Sleep Medicine Clinics, 11(3), 313–325. https://doi.org/10.1016/j.jsmc.2016.05.002
Garcia, S., et al. (2021). Enhanced responsiveness to hypoxic panicogenic challenge in female rats. Journal of Psychopharmacology, 35(1), 83–92. https://doi.org/10.1177/02698811211058986
Ghosh, S. M., Kapil, V., Fu, D., & Ahluwalia, A. (2018). Erythrocytes and vascular function: Oxygen and nitric oxide. Frontiers in Physiology, 9, 125. https://doi.org/10.3389/fphys.2018.00125
Kapil, V., Haydar, S. M. A., Pearl, V., Lundberg, J. O., Weitzberg, E., & Ahluwalia, A. (2013). Physiological role for nitrate-reducing oral bacteria in blood pressure control. Free Radical Biology and Medicine, 55, 93–100. https://doi.org/10.1016/j.freeradbiomed.2012.11.013
Lancaster, J. R. Jr., & Buettner, G. R. (1999). The biological lifetime of nitric oxide: Implications for the perivascular dynamics of NO and O₂. Proceedings of the National Academy of Sciences, 96(14), 8356–8361. https://doi.org/10.1073/pnas.96.14.8356
Ley, R. (2001). Panic, hyperventilation and perpetuation of anxiety. Journal of Affective Disorders, 61(1-2), 103–114. https://doi.org/10.1016/S0165-0327(00)00336-0
Lin, M. T., Lin, C. H., & Chiu, W. T. (2000). Nitric oxide regulates body temperature, neuronal activation and interleukin-1β expression in the hypothalamus during immune stress. Neuroscience, 97(3), 525–536. https://doi.org/10.1016/S0306-4522(00)00035-5
Lundberg, J. O., Weitzberg, E., & Lundberg, J. M. (1995). High nitric oxide production in human paranasal sinuses. Nature Medicine, 1(4), 370–373. https://doi.org/10.1038/nm0495-370
Mayo Clinic. (n.d.). Restless legs syndrome - Symptoms and causes. Mayo Clinic. Retrieved May 5, 2025, from https://www.mayoclinic.org/diseases-conditions/restless-legs-syndrome/symptoms-causes/syc-20377168
Melis, M. R., Argiolas, A., & Gessa, G. L. (1996). Dopamine agonists increase nitric oxide synthase activity in the paraventricular nucleus of the hypothalamus. European Journal of Neuroscience, 8(5), 1191–1196. https://doi.org/10.1111/j.1460-9568.1996.tb00725.x
Mortensen, S. P., Nyberg, M., Winding, K., & Saltin, B. (2012). Role of nitric oxide and prostanoids in the regulation of leg blood flow and systemic blood pressure in humans. Journal of Physiology, 590(17), 4341–4350. https://doi.org/10.1113/jphysiol.2012.237578
Münzel, T., Gori, T., Bruno, R. M., & Taddei, S. (2013). Aging, nitric oxide, and endothelial dysfunction. Journal of the American Heart Association, 2(1), e000973. https://doi.org/10.1161/JAHA.114.000973
Patton, S. M., Misra, S., & Connor, J. R. (2023). Effects of iron-deficient diet on sleep onset and spinal reflexes in a mouse model of restless legs syndrome. Frontiers in Neurology, 14, 1160028. https://doi.org/10.3389/fneur.2023.1160028
Phillips, B., Young, T., Finn, L., Asher, K., Hening, W. A., & Purvis, C. (2000). Epidemiology of restless legs symptoms in adults. Archives of Internal Medicine, 160(14), 2137–2141. https://doi.org/10.1001/archinte.160.14.2137
Schaad, U. B., Sailer, J., Tippler, B., & Forsythe, S. J. (2009). Circadian variation in exhaled nitric oxide in healthy children. European Journal of Medical Research, 14(Suppl 4), 6. https://doi.org/10.1186/2047-783X-14-S4-6
Schormair, B., Zhao, C., Bell, S., Tilch, E., Salminen, A. V., Pütz, B., ... & Winkelmann, J. (2017). Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: A meta-analysis. The Lancet Neurology, 16(11), 898–907. https://doi.org/10.1016/S1474-4422(17)30327-7
Souza, A. D., Rajagopal, K. V., Ankolekar, V. H., Souza, A. D., & Kotian, S. R. (2016). Anatomy of maxillary sinus and its ostium: A radiological study using computed tomography. CHRISMED Journal of Health and Research, 3(1), 37–40.
Tarantini, S., Valcarcel-Ares, N. M., Yabluchanskiy, A., Tucsek, Z., Toth, P., & Csiszar, A. (2021). Neurovascular coupling in aging and Alzheimer’s disease: Contributions of astrocytes and endothelial nitric oxide. Frontiers in Physiology, 12, 729201. https://doi.org/10.3389/fphys.2021.729201
Weitzberg, E., & Lundberg, J. O. (2002). Humming, nitric oxide, and paranasal sinus obstruction. JAMA, 288(7), 857. https://doi.org/10.1001/jama.288.7.857
Winkelmann, J., Schormair, B., Lichtner, P., Ripke, S., Xiong, L., Jalilzadeh, S., ... & Trenkwalder, C. (2007). Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nature Genetics, 39(8), 1000–1006. https://doi.org/10.1038/ng2092
Zhu, P., Pfrender, E., Steffeck, A., Reczek, C., Zhou, Y., Thakkar, A., Gupta, N., Willbanks, A., Lieber, R., Roy, I., Chandel, N. S., & Peek, C. B. (2025). Immunomodulatory role of the stem cell circadian clock in muscle repair. Science Advances, 11(10), eadq8538. https://doi.org/10.1126/sciadv.adq8538
I also welcome feedback and discussion on this essay. Feel free to contact me directly at brian@vitaltoolboxes.com.
* Brian Dentry has been an independent researcher and journalist for over 25 years, and worked extensively for organizations such as the Asian Development Bank Institute and the Mainichi Shimbun.
