Low Dose Naltrexone (LDN) is quickly becoming a favourite medication amongst naturopathic doctors and functional medicine doctors for the treatment of Chronic Fatigue Syndrome (Myalgic Encephalopathy), Fibromyalgia, many autoimmune diseases, and cancer. You may be wondering how one medication is able to treat such a wide range of disease? The answer is in the mechanism of how LDN works.
Mechanism of Action
Naltrexone comes in a 50:50 mixture of two different enantiomers (i.e. two molecules that are mirror images of each other) called Levo-Naltrexone and Dextro-Naltrexone.
The Levo-Naltrexone is able to bind and block opiate receptors (endorphin receptors). When taken in low doses, this blockade lasts for only a few hours, at which time, the body is tricked into thinking it is deficient in endorphins. This results in a rebound increase in endorphin production and release that lasts all day long. These elevated levels of endorphins are able to positively modulate the immune system in order to restore proper immune activity and halt the progression of autoimmune disease.
The Dextro-Naltrexone, on the other hand, is able to bind and block immune cells including Toll-Like Receptors (TLRs) which suppresses the release of cytokines and nuclear factor kappa beta (NF-kB). The end result is a suppression of inflammation and downregulation of oncogenes (a gene that can trigger cancer).
Naltrexone has been around since the 1980s for the treatment of opiate and alcohol addiction. The doses we use for addiction (50-100mg) don’t appear to work for immune regulation as these large doses overwhelm the receptors and result in a persistent blockade. In order to receive the anti-inflammatory and immune regulating benefit of this medication, very low doses are used (typically 0.5-4.5mg).
For the vast majority of my patients who have been prescribed LDN, it is free of any major side effects. Most commonly, some people may experience transient vivid dreams or insomnia for a few days after starting the medication, which soon subside. Very rarely, patients may experience digestive upset such as nausea, constipation, or diarrhea.
If you are experiencing prolonged side effects from LDN, speak with your doctor about changing your dose. In very sensitive patients, doses of LDN need to be started low and increased very slowly, in 0.5mg increments.
There are two conditions that would prevent a person from being able to use LDN safely. First, if you have had an organ transplant, you cannot take LDN due to the immune strengthening effect of LDN which would theoretically put you at risk of transplant rejection.
The second contraindication would be if you require the use of narcotic pain medication on a frequent basis. Due to the blockade on the opiate receptors, using LDN could lead to a dangerous withdrawal reaction. However, in an emergency situation where an opioid needs to be used, no withdrawal effects are expected to arise due to the short half-life of LDN in the body. After using an opiate pain medicine, a plan needs to be formulated with your doctor on when LDN therapy can safely be resumed.
LDN for Autoimmune Disease
Crohn’s disease is the most researched condition for which LDN has been used. LDN has been shown to be effective in the treatment of Crohn’s disease in both pediatric as well as adult populations. Great news – it is also compatible with other medications used to treat inflammatory bowel disease!
In a study published in the American Journal of Gastroenterology in 2007, seventeen patients who had active Crohn’s disease were given 4.5mg every night for 12 weeks. At the end of the study, 67% of those patients were in remission with a further 22% experiencing improvement in their condition. What this means is that 89% of participants in the study exhibited a response to LDN therapy. Another study looking at LDN therapy in children with moderate to severe Crohn’s disease showed a 92% response rate with 25% of the children in remission after 8 weeks of therapy.
LDN appears not to only help Crohn’s sufferers with their symptoms, but it also results in beneficial changes to health of the intestines. A study that looked at both symptoms and mucosal healing found that after 12 weeks on LDN therapy, 88% of patients were responsive to the medication with a reduction in symptoms and 78% of patients exhibited an edoscopic response to treatment with 33% achieving remission based on endoscopy scores.
Almost a third of patients with inflammatory bowel disease (IBD) are non-responsive to IBD drugs or relapse over time. A recent study published in 2018 looked specifically at how well LDN worked in patients who were not responding to conventional therapy. At the end of 12 weeks, LDN induced clinical improvement in 74.5% of participants and remission in 25.5%.
One of the most popular uses of LDN has been in the treatment of multiple sclerosis (MS). A study done in Milan, Italy showed that of 35 patients with primary progressive MS who completed the six month trial with LDN, only one patient experienced progression in neurological disability.
Another placebo-controlled study looked at quality of life measures in MS patients taking 4.5mg of LDN. After only 8 weeks, LDN significantly improved the mental health of the patients.
LDN for Chronic Pain
Recent literature in pain medicine supports the notion that chronic nerve pain conditions such as Complex Regional Pain Syndrome, Fibromyalgia, Reflex Sympathetic Dystrophy, and Diabetic Peripheral Neuropathy are autoimmune based.
The mechanism of how LDN can help with chronic pain comes down to inactivation of glial cells. Glial cells are a type of cell that makes up about 80% of the Central Nervous System (CNS, i.e. brain and spinal cord). Their function is to provide immune protection to the CNS. Under normal conditions, these glial cells remain inactive. However, when there is an infection or injury, the glial cells will activate which will cause a release of inflammatory chemicals such as cytokines, interleukins, and free radicals. It is thought that LDN may help prevent the activation of glial cells thereby reducing inflammation and pain.
Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal pain that is often accompanied by sleep disturbances, profound fatigue, and mood disorders. The first study to demonstrate an effect of LDN in fibromyalgia was published in 2009. This study showed that LDN reduced subjective symptoms by more than 30% compared to placebo in 6 out of 10 patients. Further, the LDN resulted in improved pain thresholds to movement and heat. Interestingly, the fibromyalgia patients with higher baseline ESR (erythrocyte sedimentation rate, a marker of inflammation) levels tend to have a greater reduction in their pain when taking LDN. ESR may be a great baseline test to use to determine whether a fibromyalgia patient should consider using LDN therapy as part of their treatment protocol.
Since that time, a newer study with a better design (double-blind, placebo-controlled), supported the earlier findings that LDN is useful in reducing pain in fibromyalgia. Similar to the original research, this study showed almost a 30% reduction in baseline pain. Further, the LDN was also associated with improved satisfaction with life, and improved mood (although there were no improvements in fatigue or sleep).
Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome that involves activation of glial cells and a sensitization of the CNS. Although there are no formal studies at this time supporting the use of LDN in CRPS, two case reports exist that show dramatic improvements in pain with LDN in CRPS. In the first patient, after 2 months on LDN therapy, he required less frequent ketamine infusions for his pain, his pain severity decreased, he recovered from flares more quickly, had more energy, and his sleep significantly improved. The patient also no longer needed a cane to walk, which he was using for 6 years prior to initiating the LDN therapy. The second case report was in a 12 year old female with CRPS. Similar to the first case report, within a couple months of starting on LDN, her pain dramatically improved and she was able to reduce her dose of ketamine pain reliever.
LDN for Cancer
Dextro-Naltrexone is thought to be able to suppress oncogene activation which can trigger cancer. In low doses, naltrexone is thought to reduce tumor growth by interfering with cell signaling and modifying the immune system. This anti-cancer activity has sparked interest in using LDN for the treatment of cancer. In vitro research has indicated that treatment with LDN may enhance the effect of chemotherapy agents in those undergoing therapy.
Another in vitro study looking at LDN’s effect on ovarian cancer also shows potential benefit of this medication in cancer care. When Naltrexone was administered for 6 hours every 2 days to a tissue culture of human ovarian cancer cells, tissue growth was reduced compared to controls. Moreover, exposure to naltrexone in combination with standard chemotherapy medications showed an enhanced anticancer action in comparison to the chemotherapy alone. The same researchers also investigated the effects of LDN on mice with ovarian tumors and found that the tumor progression was slowed. Similarly to the tissue culture, the LDN seemed to have a synergistic effect with the chemotherapy medication cisplatin.
A case study on a patient with terminal pancreatic cancer was published in 2006 that gives us some insight into how profound of an effect LDN can have in cancer. The patient was told by a university oncology center in 2002 that his cancer was terminal and there was little hope for survival. Four years later, after starting a treatment regimen of intravenous alpha lipoic acid with LDN, he was back at work, symptom free, and without much progression of his cancer.
At this time, using LDN for autoimmunity, chronic pain, and cancer is still an off-label use of naltrexone. Unfortunately there is no incentive for pharmaceutical companies to put LDN through the rigorous trials needed to achieve this as naltrexone is a generic medication that is unable to be patented. In the meantime, there are some universities and private researchers that are looking into the many health benefits of LDN. As time goes on, I truly hope we learn more about additional conditions that may receive benefit from LDN therapy.
Yours in health,