To learn more about the evidence supporting the use of low-dose naltrexone (LDN) to treat autoimmune conditions, see the book excerpt below.

For assistance finding a doctor familiar with prescribing LDN:

• www.LDNScience.org/patients/find-a-doctor 
• www.ldnresearchtrust.org/LDN_Prescribers

Many rheumatologists and other specialists are still quite reluctant to prescribe LDN, likely because the drug is not yet approved for use in treating inflammation and doctors are not familiar with the supporting studies.  Fortunately many integrative or functional medicine physicians are more comfortable prescribing low-dose naltrexone to patients with psoriatic arthritis, rheumatoid arthritis, IBD, and ankylosing spondylitis. See the Institute for Functional Medicine to find a practitioner.

There are also ongoing clinical trials for LDN to treat arthritis, and you may be able to enrol as a study participant. See e.g.:  VA study of LDN to treat rheumatoid or psoriatic arthritis

———- Excerpt from The Keystone Approach  ———-

The Science of Low-Dose Naltrexone

Naltrexone is a pharmaceutical that has been used for decades to treat opioid addiction, but more recently it has shown great promise as a medication for various inflammatory diseases. When taken in very low doses, naltrexone can regulate the immune system and reduce pain.[1]

In one of the earliest studies on low-dose naltrexone (LDN), researchers found that it could reduce muscle spasms associated with multiple sclerosis (MS).[2] In 2010, a placebo-controlled study at the University of California, San Francisco, also found that LDN significantly reduced pain and improved quality of life in MS patients.[3]

Low-dose naltrexone has also been found to significantly reduce pain in some people with fibromyalgia.[4] The treatment does not work for everyone, but a small double-blind trial at Stanford University reported that the majority of fibromyalgia patients taking LDN had at least a 30 percent reduction in pain.[5]

Aside from these pain-relieving effects, LDN may actually be able to reduce underlying inflammation, particularly in the gut. There is good evidence for this from double-blind, placebo-controlled trials in Crohn’s disease.[6] In one such study, when patients were examined by endoscopy after taking naltrexone for three months, 78 percent showed significant intestinal healing, compared to just 28 percent of those taking a placebo.[7] Even more starkly, one-third of the patients taking naltrexone achieved remission, compared to 8 percent of those on the placebo. These extraordinary effects suggest that naltrexone can actually disrupt the inflammatory process in the gut.

Although most of the controlled trials in Crohn’s disease have so far originated from a single research institution, other gastroenterologists have also reported success in some patients.[8] A case report from the Cleveland Clinic, for example, describes a 14-year-old girl who had suffered from abdominal pain for three years and had intestinal damage consistent with Crohn’s disease. After four weeks of LDN treatment, her symptoms were significantly reduced, and by three months an endoscopy showed complete healing of the damaged intestinal lining.[9] A 2018 study found that LDN induced clinical improvement in three-quarters of patients with inflammatory bowel disease and induced remission in one-quarter of patients.[10] Physicians in Australia also reported that LDN was successful in treating five out of 14 Crohn’s patients, and four of those patients also showed gut healing on an endoscopy.[11]

It was initially suggested that naltrexone has this powerful anti-inflammatory effect because it boosts natural endorphins and it is these endorphins that regulate the immune system.[12] More recently, another mechanism has come to light, one that is particularly relevant to psoriasis and various forms of inflammatory arthritis.

This newly discovered mechanism is entirely separate from the opioid/endorphin system. It is instead based on the fact that naltrexone can directly interfere with the activation of immune cells by bacterial toxins such as lipopolysaccharide.[13]

Naltrexone does this by binding to and blocking a receptor called TLR4.[14] This receptor is normally how “first-responder” immune cells (such as mast cells) can detect the presence of lipopolysaccharide and other bacterial by-products. When lipopolysaccharide binds to TLR4 on the surface of cells, this triggers the release of inflammatory mediators. In effect, TLR4 receptors are the eyes that allow a variety of different immune cells to see bacterial by-products in the intestines and in the bloodstream. Naltrexone blindfolds these cells and stops them from overreacting to the presence of bacteria.

The TLR4 mechanism suggests that the extraordinary effects seen in Crohn’s disease could also apply in several other autoimmune diseases. This is particularly true in those conditions where TLR4 clearly plays a role, including psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. In each of these conditions, mutations in the TLR4 genes are more common than in the rest of the population,[15] and there is a higher than normal level of TLR4 receptors on immune cells.[16] When bacterial by-products bind to TLR4 receptors, this also triggers the production of the precise inflammatory mediators that are the hallmarks of psoriasis and inflammatory arthritis.[17] Naltrexone could disrupt this process and thereby calm the immune system.

Interestingly, in the fibromyalgia clinical study, the patients with the greatest drop in pain on LDN treatment were those who started out with the highest level of inflammation, shown by erythrocyte sedimentation rate (ESR). According to the researchers performing the study, this suggested “that the clinical effect of LDN may be physiologically associated with the reduction of inflammation.”[18] The researchers further commented that “the observed relationship between ESR and LDN response raises the intriguing possibility that other chronic conditions characterized by high ESR may also benefit from LDN therapy.” Psoriasis and inflammatory arthritis are unquestionably conditions characterized by high ESR levels, and ESR is in fact used by rheumatologists to monitor disease severity. The pain-reducing and anti-inflammatory effects of low-dose naltrexone thus hold great promise for those with these conditions.

In the United States, naltrexone is already approved by the FDA to treat addiction, so physicians are allowed to prescribe it “off-label” for other uses. When used to treat inflammatory diseases, the dose is far lower than that used for addiction (1.5–4.5 mg compared to 50–100 mg). As a result, the prescription must be filled at a specialist compounding pharmacy that can prepare capsules containing low doses. The dose is often titrated, meaning one starts at a dose of 1.5 mg or 2 mg and then increases to 3 mg after several weeks. The dose is only increased further if necessary.

The side effects of LDN reported in the clinical studies so far are headache, difficulty sleeping, and vivid dreams, but it has also been reported that these side effects can be minimized by keeping the dose at or below 3 mg per day.[19] LDN cannot be used in conjunction with opioids, because it causes withdrawal symptoms, but rheumatologists have been prescribing LDN in combination with methotrexate and biologics. At the time of writing, several clinical trials are underway to determine the efficacy of LDN in treating conditions such as rheumatoid and psoriatic arthritis.

LDN is not yet an FDA-approved treatment option for autoimmune disease, but as explained by Stanford researchers, “Our replicated observation that low-dose naltrexone affects levels of pain, together with the low cost and tolerable nature of low-dose naltrexone, makes it a promising target for future investigation.”[20]

See also:

anti-inflammatory supplements for psoriatic arthritis, RA, and AS

Curcumin for autoimmune disease 

How to choose the highest quality fish oil supplement

References

[1] Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., … & Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[2] Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., … & Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[3] Cree, B. A., Kornyeyeva, E., & Goodin, D. S. (2010). Pilot trial of low‐dose naltrexone and quality of life in multiple sclerosis. Annals of neurology, 68(2), 145-150.

[4] Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

[5] Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

[6] Smith, J. P., Bingaman, S. I., Ruggiero, F., Mauger, D. T., Mukherjee, A., McGovern, C. O., & Zagon, I. S. (2011). Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Digestive diseases and sciences, 56(7), 2088-2097.

Smith, J. P., Stock, H., Bingaman, S., Mauger, D., Rogosnitzky, M., & Zagon, I. S. (2007). Low-dose naltrexone therapy improves active Crohn’s disease. The American journal of gastroenterology, 102(4), 820-828.

Smith, J. P., Field, D., Bingaman, S., Evans, R., & Mauger, D. (2013). Safety and tolerability of low dose naltrexone therapy in children with moderate to severe crohn’s disease: a pilot study. Journal of clinical gastroenterology, 47(4), 339.

[7] Smith, J. P., Bingaman, S. I., Ruggiero, F., Mauger, D. T., Mukherjee, A., McGovern, C. O., & Zagon, I. S. (2011). Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Digestive diseases and sciences, 56(7), 2088-2097.

[8] Jackson, B. D., Lewis, D. J., Beswick, L., Van Langenberg, D., Sparrow, M., & Gibson, P. R. (2013). Apparent efficacy and safety of low dose naltrexone in australian patients with active Crohn’s disease. Journal of Gastroenterology and Hepatology, 28, 99.

Shannon, A., Alkhouri, N., Mayacy, S., Kaplan, B., & Mahajan, L. (2010). Low‐dose naltrexone for treatment of duodenal Crohn’s disease in a pediatric patient. Inflammatory bowel diseases, 16(9), 1457.

[9] Shannon, A., Alkhouri, N., Mayacy, S., Kaplan, B., & Mahajan, L. (2010). Low‐dose naltrexone for treatment of duodenal Crohn’s disease in a pediatric patient. Inflammatory bowel diseases, 16(9), 1457.

[10] Lie, M. R., Giessen, J., Fuhler, G. M., Lima, A., Peppelenbosch, M. P., Ent, C., & Woude, C. J. (2018). Low dose Naltrexone for induction of remission in inflammatory bowel disease patients. Journal of translational medicine, 16(1), 55.

[11] Jackson, B. D., Lewis, D. J., Beswick, L., Van Langenberg, D., Sparrow, M., & Gibson, P. R. (2013). Apparent efficacy and safety of low dose naltrexone in australian patients with active Crohn’s disease. Journal of Gastroenterology and Hepatology, 28, 99.

[12] Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

[13] Wang, X., Zhang, Y., Peng, Y., Hutchinson, M. R., Rice, K. C., Yin, H., & Watkins, L. R. (2016). Pharmacological characterization of the opioid inactive isomers (+)‐naltrexone and (+)‐naloxone as antagonists of toll‐like receptor 4. British journal of pharmacology, 173(5), 856-869.

Stevens, C. W., Aravind, S., Das, S., & Davis, R. L. (2013). Pharmacological characterization of LPS and opioid interactions at the toll‐like receptor 4. British journal of pharmacology, 168(6), 1421-1429.

[14] Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., … & Rice, K. C. (2008). Non‐stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll‐like receptor 4 (TLR4). European Journal of Neuroscience, 28(1), 20-29.

[15] Smith, R. L., Hébert, H. L., Massey, J., Bowes, J., Marzo-Ortega, H., Ho, P., … & Warren, R. B. (2016). Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis. Archives of dermatological research, 308(3), 201-205.

Assassi, S., Reveille, J. D., Arnett, F. C., Weisman, M. H., Ward, M. M., Agarwal, S. K., … & Mayes, M. D. (2011). Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5. The Journal of rheumatology, 38(1), 87-98.

[16] Xu, D., Yan, S., Wang, H., Gu, B., Sun, K., Yang, X., … & Wang, X. (2015). IL-29 enhances LPS/TLR4-mediated inflammation in rheumatoid arthritis. Cellular Physiology and Biochemistry, 37(1), 27-34.

Yang, Z. X., Liang, Y., Zhu, Y., Li, C., Zhang, L. Z., Zeng, X. M., & Zhong, R. Q. (2007). Increased expression of Toll‐like receptor 4 in peripheral blood leucocytes and serum levels of some cytokines in patients with ankylosing spondylitis. Clinical & Experimental Immunology, 149(1), 48-55.

Garcia–Rodriguez, S., Arias–Santiago, S., Perandrés–López, R., Castellote, L., Zumaquero, E., Navarro, P., … & Zubiaur, M. (2013). Increased gene expression of Toll‐like receptor 4 on peripheral blood mononuclear cells in patients with psoriasis. Journal of the European Academy of Dermatology and Venereology, 27(2), 242-250.

De Rycke, L., Vandooren, B., Kruithof, E., De Keyser, F., Veys, E. M., & Baeten, D. (2005). Tumor necrosis factor α blockade treatment down‐modulates the increased systemic and local expression of toll‐like receptor 2 and toll‐like receptor 4 in spondylarthropathy. Arthritis & Rheumatology, 52(7), 2146-2158.

[17] Hu, F., Li, Y., Zheng, L., Shi, L., Liu, H., Zhang, X., … & Yang, Y. (2014). Toll-like receptors expressed by synovial fibroblasts perpetuate Th1 and th17 cell responses in rheumatoid arthritis. PLoS One, 9(6), e100266.

Begon, É., Michel, L., Flageul, B., Beaudoin, I., Jean-Louis, F., Bachelez, H., … & Musette, P. (2007). Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. European Journal of Dermatology, 17(6), 497-506.

[18] Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

[19] Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., … & Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[20] Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low‐dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double‐blind, placebo‐controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.