Does Low Dose Naltrexone (LDN) Work?

Low dose naltrexone (LDN) has been used since the 1980s in alternative and environmental medical circles. In the past 15 years, LDN has been used more widely in autoimmune disorders like Crohn’s disease and multiple sclerosis and conditions that are associated with neuroinflammation—diseases including fibromyalgia (FM), chronic pain of other types, myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and long COVID (LC).

LDN is widely recommended by chronic complex disease literate practitioners because it is very safe, relatively inexpensive, and is widely believed to decrease core symptoms such as pain, fatigue, and brain fog. However, just because something is popular doesn’t mean it is effective. There was a time when leeches were a thing.

When I began reading about LDN in 2011, I came across the results of an online survey by a group called Cure Together (now part of 23andMe), which rated it as the single most effective remedy for both FM and ME/CFS. But when I introduced LDN to my practice in 2012, most people trying it didn’t notice any improvement, even when we experimented with a number of doses from 1.5–9 mg/day and continued it for up to six months.

There are 61 studies of LDN listed on the ClinicalTrials.gov website, where most researchers register their studies. Many of these have been completed or withdrawn or are on topics not relevant to our discussion. I read 23 of the most relevant studies to see whether LDN is effective for FM, ME/CFS, and long COVID. This blog post is a summary of what I learned. Note that not all studies are references for this post. Some were of such low quality that they didn’t merit mention, and others were reviews that didn’t have any new information.

How Does LDN Work for Inflammation?

Naltrexone is an opioid receptor blocker. At the full dose of 50–100 mg, it has been used for 60 years to reverse the effects of opiate overdose and in treating opiate addiction. In doses of up to 4.5 mg, LDN only partially blocks opioid receptors, and this triggers an increase in endorphins (our naturally produced opioids) which decreases pain (Isman et al., 2024). At this low dose, LDN binds more strongly to another brain receptor called the toll-like receptor 4 (TLR4). TLR4 is a critical part of the innate immune system. This means it is on alert all the time and can respond to any infection, such as bacteria and viruses that enter the body, including through a leaky gut. This is one way in which leaky gut causes generalized inflammation.

TLR4 receptors are located on the microglial cells in the brain. Microglia are the immune cells of the brain, and when they become overactive, they release immune chemicals that cause neuroinflammation. Neuroinflammation is implicated in most types of chronic pain including FM, ME/CFS, inflammatory bowel disease (Crohn’s and ulcerative colitis), low back pain, rheumatoid arthritis, diabetic neuropathy, and chronic regional pain syndrome (Rupp, Young, & Chadwick, 2023). By blocking the effects of TLR4, and blocking the action of mast cells, LDN is thought to decrease neuroinflammation (Marcus, Robbins, Araki, Gracely, & Theoharides, 2024). This may be responsible for some of the positive effects that are reported.

Does LDN work for Chronic Pain

In a systematic review of studies of LDN in these various central pain conditions, the most common dose was 4.5 mg/day, usually given an hour before bed. Note that some people get insomnia from LDN, in which case it is better to take it in the morning. All six studies assessed were relatively small—some were only case reports. All the studies were done differently, and the outcome measures were self-reported. Despite the low quality of the data (self-report measures only), the authors concluded that LDN is mildly helpful for a majority of people with various chronic pain conditions and should be offered as a treatment because it is so well tolerated. In addition to pain, LDN also improved sleep, mood, and overall quality of life for some people.

Even though most studies used the dose of 4.5 mg, to get the best results, one has to be willing to fine-tune the dose based on people’s responses. Marcus and colleagues did a study trying to identify the best dose of LDN in a group of people with hypermobility, many of whom had mast cell activation syndrome, a condition associated with dozens of symptoms triggered by things like food, medications, supplements, and temperature. They concluded that everyone is unique and that there is no most common effective dose for LDN. Some people responded to as little as 0.1 mg and others to as much as 5.6 mg/day (Marcus et al., 2024).

Not all the recent studies of LDN in people with chronic pain have had positive results. In a study of LDN in adults with chronic pain at a university medical center, 87% of the study participants discontinued LDN, 52% due to lack of effectiveness (Irwin, Cooke, Berland, Marshall, & Smith, 2024).

How long does it take LDN to work in Fibromyalgia

Fibromyalgia is the disorder in which LDN seems most often used and for which it may be the most effective. A review of six small studies of 121 people (mostly women) with fibromyalgia treated with LDN showed positive results. The improvements in pain and general FM symptoms were modest (15–30%).  And self-reported data was strengthened by the inclusion of objective measures, including the ability to tolerate cold longer, reduction in proinflammatory cytokines, and increased pain thresholds to pressure and heat (de Carvalho & Skare, 2023). LDN was well tolerated in all the studies.

Many of the studies reported are tabulations of how people in real clinics did on LDN and not gold standard randomized trials. Dr. Karin Due Bruun and colleagues from Denmark conducted a controlled trial of LDN in FM at a dose of 6.0 mg/day. They didn’t find any improvement in the active treatment group with respect to pain but found a small improvement in memory (Due Bruun et al., 2024).

Another randomized controlled trial (RCT) of 52 FM patients from Denmark also failed to find any improvement. However, they only ran the study for two months (Bested et al., 2023). One study suggested that one could see improvement in as little as two weeks (Bruun-Plesner et al., 2020), but clinical experience suggests that response to LDN often takes three to six months.

A retrospective review of patients with chronic pain prescribed LDN at any of the Mayo Clinic locations over a 14-year period found that 65% of people who took LDN reported subjective benefit for pain. Over 60% of those studied had fibromyalgia.

LDN in ME/CFS

A Finnish team did a retrospective chart review of 218 individuals with ME/CFS based on Fukuda and Canadian Consensus Criteria. Seventy-four percent reported an improvement in at least one symptom, and about half improved with respect to two symptoms on a dose of 4.5 mg/day. Symptoms measured included alertness, physical performance, cognition, pain, and fever. Only 7.3% discontinued the treatment due to side effects.

Does LDN Help with Long COVID?

A recent retrospective chart review found LDN equal in impact to amitriptyline and superior to duloxetine in improving shortness of breath, brain fog, pain, and fatigue in people with long COVID (Tamariz, Bast, Klimas, & Palacio, 2024). Another review of real-life patients with LC found LDN helped with fatigue, sleep, and post-exertional malaise (PEM). Again, the improvements were small and extremely variable, with some people improving and others not (Bonilla et al., 2023).

What are the Most Common Side Effects of LDN?

Side effects from LDN are minimal and usually well tolerated, even by people who are moderately to severely ill. The top three side effects are vivid dreams, diarrhea, and headache. Less commonly, people can experience insomnia, nausea, dry mouth, shortness of breath, anxiety, agitation, increased hair growth, increased sweating, and dizziness.

Conclusions

In my opinion, the data on effectiveness of LDN for chronic complex diseases remains inconclusive. Most of the studies showing improvement are retrospective chart reviews of people treated with LDN. Several of the randomized controlled trials didn’t show any benefit. RCTs are considered more accurate because people don’t know whether they are receiving the active drug or the placebo.

• Despite the low level of evidence of benefit, the risk of trying LDN is very low.
• If you discuss LDN with your prescriber, make sure you are able to adjust the dose to what you can tolerate. People often start at 1.5 mg/day and increase in 1.5-mg increments until they notice either a positive or negative change. This is relatively easy since LDN is compounded anyway.
• Make sure you are ready to commit to a three-to-six-month trial. Although you might see positive changes sooner, they can be very slow for some.
• The size of reported improvements is small—15–35% in most cases, so use a symptom tracking app and your wearable tracker so that you can feel confident in your perception of whether you are benefiting or not. It is hard to keep track of all your symptoms in your head for six months.

According to https://www.clinicaltrials.gov/, there are only four trials under way that will build on our knowledge—one each in long COVID, diabetic neuropathy, fibromyalgia, and chronic regional pain syndrome. There is also a trial starting called the LIFT trial comparing LDN with pyridostigmine, a drug which may improve function in people with orthostatic intolerance.

Did you know that I host a program with 2 x live sessions each month in which you can learn more about topics such as LDN.  The program is called Live! with Dr. Stein.  These sessions provide actionable management strategies for people with chronic complex diseases. You will get science based information and the chance to ask your questions of me and my growing community of life long learners. Subscribers to Live! are granted free access to amazing experts on a wide variety of topics - The Expert Speaker Series is approximately monthly.

References

Bested, K., Jensen, L. M., Andresen, T., Tarp, G., Skovbjerg, L., Johansen, T. S. D., . . . Bendiksen, A. (2023). Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study. The Pain Report, 8(4), e1080. doi:https://dx.doi.org/10.1097/PR9.0000000000001080

Bonilla, H., Tian, L., Marconi, V. C., Shafer, R., McComsey, G. A., Miglis, M., . . . Geng, L. N. (2023). Low-dose naltrexone use for the management of post-acute sequelae of COVID-19. International Immunopharmacology, 124(Pt B), 110966. doi:https://dx.doi.org/10.1016/j.intimp.2023.110966

Bruun-Plesner, K., Blichfeldt-Eckhardt, M. R., Vaegter, H. B., Lauridsen, J. T., Amris, K., & Toft, P. (2020). Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships. Pain Medicine, 18, 18. doi:https://dx.doi.org/10.1093/pm/pnaa001

de Carvalho, J. F., & Skare, T. (2023). Low-Dose Naltrexone in Rheumatological Diseases. Mediterranean Journal of Rheumatology, 34(1), 1-6. doi:https://dx.doi.org/10.31138/mjr.34.1.1

Due Bruun, K., Christensen, R., Amris, K., Vaegter, H. B., Blichfeldt-Eckhardt, M. R., Bye-Moller, L., . . . Toft, P. (2024). Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial. The Lancet Rheumatology, 6(1), e31-e39. doi:https://dx.doi.org/10.1016/S2665-9913(23)00278-3

Irwin, N. M., Cooke, D., Berland, D., Marshall, V. D., & Smith, A. M. (2024). Efficacy and Safety of Low Dose Naltrexone for Chronic Pain. Journal of Pain & Palliative Care Pharmacotherapy, 38(1), 13-19. doi:https://dx.doi.org/10.1080/15360288.2024.2302550

Isman, A., Nyquist, A., Strecker, B., Harinath, G., Lee, V., Zhang, X., & Zalzala, S. (2024). Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain, Behavior, & Immunity Health, 36, 100733. doi:https://dx.doi.org/10.1016/j.bbih.2024.100733

Marcus, N. J., Robbins, L., Araki, A., Gracely, E. J., & Theoharides, T. C. (2024). Effective Doses of Low-Dose Naltrexone for Chronic Pain - An Observational Study. Journal of Pain Research, 17, 1273-1284. doi:https://dx.doi.org/10.2147/JPR.S451183

Rupp, A., Young, E., & Chadwick, A. L. (2023). Low-dose naltrexone's utility for non-cancer centralized pain conditions: a scoping review. Pain Medicine, 24(11), 1270-1281. doi:https://dx.doi.org/10.1093/pm/pnad074

Tamariz, L., Bast, E., Klimas, N., & Palacio, A. (2024). Low-dose Naltrexone Improves post-COVID-19 condition Symptoms. Clinical therapeutics, 46(3), e101-e106. doi:https://dx.doi.org/10.1016/j.clinthera.2023.12.009