Low-dose naltrexone

Low-dose naltrexone (LDN) is the off-label, experimental use of the medication naltrexone at low doses for diseases such as Crohn's disease, Hashimoto's disease, and multiple sclerosis, but evidence for recommending such use is lacking.

Naltrexone is typically prescribed for opioid dependence or alcohol dependence, as it is a strong opioid antagonist. It has been hypothesized that low-dose naltrexone might operate as an anti-inflammatory agent and therefore could be used to treat some chronic conditions involving immune system dysregulation.

Action of naltrexone at normal dose
Naltrexone and its active metabolite 6-β-naltrexol are competitive antagonists at μ-opioid and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. Standard therapeutic doses of naltrexone block these receptors, which does two things; it prevents inhibition of GABA receptors (normally, signaling through the GABA receptors inhibits the activity of neurons; many recreational drugs inhibit GABA and thus "free up" neuronal activation; preventing inhibition of GABA allows GABA's normal inhibition activity to take place) and it blocks dopamine release (many recreational drugs stimulate dopamine release, which is part of the brain's reward system that creates pleasure).

Hypothesized action at low doses
Low-dose naltrexone refers to doses about 1/10th the size of the dose used normally, typically 4.5 mg or within a couple of milligrams of that value. It is hypothesized that if there are any effects, low-dose naltrexone may inhibit opioid receptors and therefore cause the body to increase production of endorphins and upregulate the immune system; it may also antagonize Toll-like receptor 4 that are found on macrophages, including microglia, possibly resulting in the reported anti-inflammatory effects. Researchers have also examined "ultra-low-doses" of naltrexone at microgram, nanogram, and picogram doses, that are co-administered with opioid analgesics with the goal of increasing pain relief and reducing side effects.

Research
Multiple studies have shown that low-dose naltrexone has promise as a treatment for chronic pain, some autoimmune disorders and cancers. As of 2014, no peer-reviewed studies supporting low-dose naltrexone for multiple sclerosis (MS) have been published. Clinical trials for treatment of fibromyalgia were initiated in 2021.

Prescription and medical formulations of low-dose naltrexone are not licensed or approved in the UK, EU and USA.

Low-dose naltrexone is also being studied in long COVID. However, efficacy has not been shown.

In 2017, Raknes and Småbrekke published a drug utilization cohort study on Norwegian patient and prescriber characteristics, and dispense patterns, following a 2013 television documentary on low-dose naltrexone. They reported drawing upon the Norwegian Prescription Database and sales data not recorded in NorPD from the only Norwegian LDN manufacturer, with the caveat that these sources could not encompass the total. Their findings included that "Twenty percent of all doctors and 71% of general medicine practitioners registered in Norway in 2014 prescribed LDN at least once."

A 2018 therapeutic utilization review concluded that low-dose naltrexone may be an appropriate option for treatment of fibromyalgia and irritable bowel disease, but that "Proper clinical trials are needed in order to establish evidence that could lead to correct indications, mode of administration, and other aspects necessary for effective clinical pharmacology of [low-dose naltrexone]."

A 2023 systematic review published in the Australian Journal of General Practice found that preliminary research into the use of low-dose naltrexone as a treatment for fibromyalgia is promising. All clinical studies examined showed statistically significant improvements in pain and pain tolerance with mild side effects, however, sample sizes were small and further research is needed.

As the UK's National Health Service noted in 2020, "...trials are necessary to draw firm conclusions on the efficacy of [low-dose naltrexone]."