Clinicians are increasingly using low-dose naltrexone to treat challenging illnesses such as autoimmune conditions and neurodegenerative disease. LDN is extremely safe and well tolerated, especially compared to the drugs typically used to treat these conditions, making LDN a valuable tool for clinicians and an important focus for ongoing research.
As a practitioner, you may be familiar with the drug naltrexone, which was approved by the FDA in 1984 for treating addiction patients. In doses of 50 to 100 milligrams, naltrexone completely blocks opioid receptors in the brain, preventing patients from experiencing a high when they take opioid drugs.
Soon after the drug’s initial approval, Dr. Bernard Bihari discovered a potential alternate application for naltrexone. He noticed that in AIDS and cancer patients, a much lower dose of naltrexone (about 3 milligrams) had beneficial immune-modulating effects. This discovery gave rise to a grassroots movement of patients and practitioners who had seen LDN work and were calling for additional research and mainstream attention.
Despite the promise of this new treatment, formal research on LDN has been slow to happen, likely because LDN is off patent and therefore not as profitable to drug companies. Even so, our understanding of the mechanisms behind LDN’s effectiveness in various conditions continues to progress, and results from preliminary clinical trials are slowly being published.
In this article, I’ll describe our current understanding of LDN’s mechanisms and review the clinical trials that have been conducted thus far. I’ll also give you a more practical take on LDN from my perspective as a clinician and cover concerns that might be relevant for other clinicians who want to prescribe LDN to their patients.
How does LDN work?
As research on LDN progresses, it appears more and more likely that it functions through a variety of different mechanisms and that the most relevant mechanism might differ depending on the disease that is being treated. But at this point, the two most well-characterized functions of LDN are as an opioid antagonist and an anti-inflammatory.
Increasing endogenous opioid activity
Like its full-dose counterpart, low-dose naltrexone blocks opioid receptors in the brain, the major difference being that LDN is cleared from the system after only a few hours. Most researchers believe that this temporary opioid receptor blockade creates a “rebound effect,” resulting in up-regulated production of the endogenous opioids beta-endorphin and met-enkephalin, as well as increased expression of opioid receptors (1).
How these adaptive changes affect the disease processes that LDN influences is less established. However, several mechanisms have been proposed. First, endogenous opioids are known to have analgesic and stress-relieving effects, which alone could account for some of the symptom relief seen with LDN.
What the latest research says about low-dose naltrexone
Second, we know that immune cells possess opioid receptors, and both endogenous and exogenous opioids have long been considered important immune modulators (2, 3). The exact effects of endogenous opioids on the immune system, however, remain unclear; both increases and decreases in immune cell activity and proliferation have been observed in response to LDN, as well as beta-endorphin and met-enkephalin (4, 5, 6).
These endogenous opioids may also exert therapeutic benefits based on their regulation of cellular proliferation. Met-enkephalin, also known as opioid growth factor (OGF), has been found to regulate the cell cycle by suppressing DNA synthesis via its action on the OGF receptor (7, 8). This so-called “OGF–OGFr axis” is the focus of research on LDN for treating cancer and may also be another mechanism by which LDN modulates immune function.
Reducing inflammation in the CNS
LDN appears to have a second mechanism of action that is independent from the opiate-antagonist pathway described above: suppression of microglial activity. Microglia are the primary immune cells in the central nervous system and are responsible for creating inflammation in response to pathogens or injury. When activated, microglia secrete factors such as pro-inflammatory cytokines, prostaglandins, nitric oxide, and excitatory amino acids (9).
The activation of the microglia and the subsequent release of cytokines—though essential to protecting the brain and CNS—cause symptoms such as fatigue, reduced pain tolerance, sleep and mood disturbances, cognitive disruption, and general malaise, all classically referred to as “sickness behaviors” (10). While these adaptive symptoms may make sense in the short term for promoting rest and recovery, ongoing CNS inflammation is maladaptive and can contribute to a wide range of diseases and syndromes.
Evidence indicates that LDN can suppress microglial activation, likely via its antagonistic effect on toll-like receptor 4 (TLR4), a non-opioid receptor that is found on macrophages such as microglia (11). This mechanism may explain LDN’s effectiveness for conditions like fibromyalgia and other chronic pain disorders, which involve chronic activation of microglial cells.
LDN in the scientific literature
Unfortunately, research on LDN as a treatment for human disease is still extremely sparse. Most of the trials that have been conducted thus far were primarily intended to test the tolerability and safety of LDN, rather than the efficacy, so keep that in mind, but the initial research does show promise. I’ve summarized the existing studies below, and hopefully additional research won’t be far behind.
A small open-label pilot study from 2007 had remarkable results, reporting that 89 percent of participants responded to LDN, and a whopping 67 percent achieved remission (12). This was the first published LDN trial in humans.
Results from two subsequent randomized controlled trials were less dramatic, but still extremely promising. One study from 2011 reported significant improvement in 88 percent of the participants in the LDN group, compared to 40 percent in the placebo group (13). And 33 percent of participants in the LDN group achieved remission, compared to 8 percent in the placebo group, although this difference was not statistically significant.
The second RCT was published in 2013 and looked at the effectiveness of LDN in children with Crohn’s disease (14). They found that of those treated with LDN, 67 percent exhibited improvement, and 25 percent went into remission. In all of these studies, LDN was very well tolerated with no significant difference in side effects compared to placebo.
Fibromyalgia and other conditions
In 2009, a pilot study involving 10 fibromyalgia patients reported a greater than 30 percent reduction in symptoms over placebo in those taking LDN (15). Interestingly, they found that patients with a higher erythrocyte sedimentation rate (ESR) at baseline had greater symptom reduction in response to LDN treatment. ESR is a marker for inflammation, so this observation lends credence to the theory that LDN works by reducing inflammation in the central nervous system.
The second study, a randomized controlled trial involving 31 fibromyalgia patients, was published in 2013. They reported significant improvements in pain, mood, and general satisfaction with life in the LDN group compared to placebo (16). And again, LDN was well tolerated in these studies.
LDN has also been studied in and shown potential efficacy for autism (17), pain (18, 19), depression (20), multiple sclerosis (21, 22, 23), systemic sclerosis (24), and complex regional pain syndrome (25). Additionally, preliminary evidence in vitro and in animal models indicates that LDN may be an effective treatment for cancer, including ovarian cancer and pancreatic cancer (26, 27).
Clinical success using LDN for autoimmune and neurodegenerative diseases
As I mentioned at the beginning of this article, LDN is unusual in that its use has spread as a result of grassroots efforts by patients themselves, rather than the typical top-down marketing of new drugs by pharmaceutical companies. Because of this, clinical and anecdotal evidence for the drug’s effectiveness in a wide variety of conditions still vastly outpaces the scientific literature.
This is initially a cause for concern because we obviously want any treatment we use on patients to be as evidence based and extensively studied as possible. But we do have ample safety data from the approval process of full-dose naltrexone, and all of the evidence we have so far on LDN shows that it is extremely safe and well tolerated. It’s still a judgment call, but the fact that existing treatments for many of these illnesses are demonstrably toxic with significant side effects certainly makes LDN an attractive option.
Conditions that have clinically responded well to LDN but have not been formally studied include autoimmune diseases such as Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, lupus, psoriasis, and ulcerative colitis, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s, and other conditions like chronic fatigue syndrome and even infertility. Because these conditions share the same underlying disease processes of immune dysregulation and inflammation, it’s not a huge surprise that LDN can be an effective treatment, despite the differences in disease presentation.
Practical concerns for prescribing LDN
LDN is generally very well tolerated, but patients may experience insomnia, headaches, or unusually vivid dreams when first starting the medication. These side effects are usually minor and dissipate after a week or two of taking LDN.
Because naltrexone is only produced in 50-milligram tablets, prescriptions for LDN do need to be filled at a compounding pharmacy. A list of reliable compounding pharmacies for LDN, along with filler recommendations, can be found here. Because LDN is off label, it’s unlikely that insurance companies will cover it, but the out-of-pocket cost of LDN is only about $40 per month, making it more affordable than many drugs on the market.
One downside of LDN is that there’s not a standardized dose, and the most effective dose for a given patient may be anywhere from 1.25 to 4.5 milligrams. We typically start patients on 1 to 1.5 milligrams, then gradually increase to 4.5 milligrams and see how they do. From my experience, I’ve seen most people end up around 2.5 to 3 milligrams.
Note that in patients with Hashimoto’s or Graves’, their previous dose of thyroid medication could suddenly be too high as their thyroid function improves on LDN. It may be necessary to reduce their normal thyroid medication to prevent them from becoming hypo- or hyperthyroid.
Finally, be aware that while LDN can be miraculous for some patients, others may see no benefits at all. Unfortunately we don’t know enough yet to determine if there’s a subset of patients that LDN is most likely to help, so the best we can do is try and hope for the best. It can sometimes take a little while for patients to notice improvement on LDN, so we typically allow about three months as a trial period before deciding whether to continue treatment.
Do you have experience using LDN to treat patients with autoimmune disease or other conditions? Let us know in the comments.