Low-dose naltrexone (LDN) describes the off-label use of the medication naltrexone at low doses (usually 4.5 mg) for diseases such as multiple sclerosis. Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is a strong opioid antagonist. Preliminary research has been promising for use of LDN in treating chronic medical conditions such as chronic pain, but at this stage the use of LDN as a treatment is still experimental and more research needs to be done before it can be widely recommended.
Some proponents of low-dose naltrexone have made unproven or pseudoscientific claims about its efficacy in treating a wide range of diseases, including cancer and HIV. Low-dose naltrexone organizations have promoted its use on their webpages. Neurologist and skeptic Steven Novella has criticized these claims, pointing out a lack of clinical trials supporting them.
Approved uses of naltrexone
Naltrexone is an opioid receptor antagonist, meaning it binds to opioid receptors in cells. These receptors bind endogenous pain relieving compounds such as endorphins as well as opioids such as morphine. Naltrexone also works to bind against the effects of heroin, which is synthesized from morphine, and is useful to alleviate opioid dependence.
The U.S. Food and Drug Administration have approved the use of naltrexone for chronic treatment of opioid dependence and for drug detoxification. Recommended dosing for orally-administered naltrexone for this purpose range 50 mg to 150 mg; for comparison, low-dose naltrexone is usually prescribed at 4.5 mg.
Research and potential therapeutic applications
Organizations promoting low-dose naltrexone have advocated it as a treatment for a variety of medical conditions. However, currently no peer-reviewed studies that would justify clinical use of low-dose naltrexone have been published.
Low-dose naltrexone may relieve certain symptoms in multiple sclerosis patients, although medical practitioners often advise against using it as a substitute to proven therapies, and the evidence supporting its use in MS is not robust, as different studies have come to conflicting conclusions. Writing for the National MS Society in 2009, neurologist Alan Bowling called research into low-dose naltrexone "encouraging" but further research needed to be done before any definitive conclusions could be reached. Bowling noted that safety of low-dose naltrexone treatment for multiple sclerosis has not been assessed, and that patients who chose to undergo the treatment should be fully informed of the limited research backing its use. Personal testimonials describing low-dose naltrexone as a cure for multiple sclerosis are not supported by high quality evidence in large randomised, double-blind, placebo-controlled clinical trials. The UK National Health Service concluded that small pilot studies indicate low-dose naltrexone can improve symptoms in multiple sclerosis patients, but that more thorough studies are needed to determine its efficacy and safety. There is not enough evidence to prove it is effective in treating multiple sclerosis. Prescription and medical formulation of low-dose naltrexone in the UK are unlicensed in the treatment of multiple sclerosis.
Although preliminary studies have been published on Crohn's disease, the small size and preliminary nature of the studies prevent drawing "any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease."
One small pilot study found a reduction in fibromyalgia symptoms in patients treated with low-dose naltrexone.
Ultra-low-dose naltrexone can reverse or prevent the development of tolerance to opioids, and its use is being investigated in the combination drug Oxytrex, which combines oxycodone with ultra-low-dose naltrexone. There is some evidence that very low doses of opioid antagonists such as naltrexone reduce the severity of opioid withdrawal.
Mechanism of action
Naltrexone and its active metabolite 6-β-naltrexol are competitive antagonists at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. Clinical doses of naltrexone (50–150 mg) cause the blockade of opioid receptors, which is the basis behind its action in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. The current theory behind low-dose naltrexone's mechanism of action is that by inhibiting opioid receptors, it causes the body to increase production of endorphins and enkephalins in order to compensate for the blocked receptors. These increased levels of endogenous opioids persist after the naltrexone has been eliminated from the body. Thus, regular doses of low-dose naltrexone can be used to increase a patient's endorphin and enkephalin levels.
The mechanism of low-dose naltrexone in reversing or preventing the development of tolerance of opioids involves its high-affinity binding to filamin A. The interaction of naltrexone with microglia cells within the central nervous system is believed to be how the drug exerts its beneficial effects in individuals who suffer from fibromyalgia; this interaction on microglial cells results in a reduction of proinflammatory cytokines as well as neurotoxic superoxides.
Opioid receptors may have other uses in the body than just for modulating pain, and it is on these bases that supporters of LDN promote it as a treatment for selected diseases. Advocates have claimed that increased endorphin production can help with pain, spasticity, fatigue, relapse rate and other symptoms. These claims are not as of yet supported by significant clinical research. 
Preliminary research suggest LDN may have an effect on inflammation. Naltrexone has an antagonistic effect on Toll-like receptor 4 (TLR4), which are found on microglia, which can modulate the body's response to inflammation. It has been hypothesized that LDN may have anti-inflammatory effects through this pathway, and this hypothesis is being pursued through further research.
Unsupported therapeutic use
In addition to proposed uses for low-dose naltrexone that have been studied in clinical research, websites run by low-dose naltrexone advocates make unproven claims of its efficacy in treating other conditions, including: various types of cancer, Alzheimer's disease, HIV/AIDS, rheumatoid arthritis, and others. Skeptic Steven Novella of the Yale University School of Medicine disputed these claims as unsupported by rigorous clinical research, calling many applications pseudoscientific. He further argues that the claim that low-dose naltrexone as an effective treatment for both immune dysfunction and autoimmune diseases is contradictory, and that improving the immune system could make the autoimmune disease worse. Novella also writes that claims of treating a wide range of diseases with different etiologies should be a red flag to be skeptical about these claims, which are likely to be "bogus treatment with claims that are literally too good to be true."
- Younger, J; Parkitny, L; McLain, D (April 2014). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.". Clinical rheumatology 33 (4): 451–9. PMID 24526250.
- Bowling, Allen C. "Low-dose naltrexone (LDN) The "411" on LDN". National Multiple Sclerosis Society. pp. 44–46. Archived from the original on 29 September 2009. Retrieved 14 May 2014.
- Novella, Steven. "Low Dose Naltrexone – Bogus or Cutting Edge Science?". Retrieved 5 July 2011.
- Bourdette, Dennis. "Spotlight on low dose naltrexone (LDN)". US Department of Veteran Affairs. Archived from the original on 10 February 2010. Retrieved 14 May 2014.
- "NALTREXONE HYDROCHLORIDE tablet, film coated". DailyMed. August 2011. Retrieved 12 May 2014.
- Younger, Jarred W.; Mackey, Sean C. (2009). "Low-Dose Naltrexone Reduces the Symptoms of Fibromyalgia". Stanford School of Medicine System Neuroscience and Pain Lab. Retrieved 12 May 2014.
- "Low-Dose Naltrexone". National MS Society. Retrieved 12 May 2014.
- Smith, Katie. "What is the evidence for low dose naltrexone for treatment of multiple sclerosis?". National Electronic Library for Medicines, National Health Service. Retrieved 12 May 2014.
- Segal, D; Macdonald, JK; Chande, N (Feb 21, 2014). "Low dose naltrexone for induction of remission in Crohn's disease.". The Cochrane database of systematic reviews 2: CD010410. doi:10.1002/14651858.CD010410.pub2. PMID 24558033.
- Ngian GS, Guymer EK, Littlejohn GO (February 2011). "The use of opioids in fibromyalgia" (PDF). Int J Rheum Dis 14 (1): 6–11. doi:10.1111/j.1756-185X.2010.01567.x. PMID 21303476.
- Webster LR (August 2007). "Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation". Expert Opin Investig Drugs 16 (8): 1277–83. doi:10.1517/135437126.96.36.1997. PMID 17685875.
- Mannelli P, Gottheil E, Van Bockstaele EJ (2006). "Antagonist treatment of opioid withdrawal translational low dose approach". J Addict Dis 25 (2): 1–8. doi:10.1300/J069v25n02_01. PMID 16785213.
- Shader RI (August 2003). "Antagonists, Inverse Agonists, and Protagonists."Journal of Clinical Psychopharmacology". 2003 Aug; 23 (4): 321–322. doi:10.1097/01.jcp.0000087502.38434.6c. PMID 12920405.
- Burns LH, Wang HY (November 2010). "PTI-609: a novel analgesic that binds filamin A to control opioid signaling". Recent Pat CNS Drug Discov 5 (3): 210–20. doi:10.2174/157488910793362386. PMID 20726836.
- lowdosenaltrexone.org, an example of a website that presents information about possible uses of low-dose naltrexone