LDN – yet another set of initials in the MS alphabet jumble. You may have heard people raving about it, and you may have heard doctors shying away from it. So who is right?
Low Dose Naltrexone (LDN) is a more than 10 times lower dose of a FDA-approved medication, Naltrexone (50 mg a day orally), which is indicated for opioid and alcohol dependence. Naltrexone is an opioid receptor antagonist (blocker), which works by blocking harmful chemicals such as heroin from stimulating these receptors in the brain.
Huh? Opioids? Dependence? MS Isn’t Heroin!
In different areas of the human body, and especially the brain, opioid receptors can do more than relieve pain. Primarily, these receptors bind endogenous (originating within the human body) pain-relieving compounds, such as endorphins. Semi-synthetic compounds, like heroin, also stimulate these receptors. There appears to be a feedback loop, where blocking these receptors a little may cause an increase in endorphin production.
Some people believe that these endorphins reduce symptoms of autoimmune diseases such as MS and even modify other chronic diseases. Endorphins also seem to promote healing and repair of tissues as well as have a positive effect on immune cells; opioid receptors are found on immune cells and some cancer cells. Stimulating the opioid receptors may cause programmed cell death (apoptosis) of cancer cells.
Part of the problem in scientifically understanding the effects of LDN is that Naltrexone consumed at lower doses both blocks and stimulates the opioid receptors. This paradox is similar to what happens in the immune system with MS, where it can be confusing because some things that stimulate the immune system can make it worse. This is because the immune system is already selectively stimulated – hence autoimmune – in MS. Because of these factors, more LDN research is needed (and finally proceeding).
Finally Some Hope Finally Some Research
In the 1980s, doctors began prescribing Naltrexone at much lower doses (usually 3 to 4.5 mg a night) for HIV, autoimmune diseases, and cancer, among others. However scientific research did not begin until 2006, when a small, clinical trial of LDN was conducted in 17 people with Crohn’s disease. While LDN was safe and effective in this pilot study, it was open-label, meaning that there was no comparison arm and no placebo or randomization.
In 2008, doctors in Italy published results of a Phase II trial of LDN in 40 people with primary-progressive MS. One of the secondary outcomes of the trial was spasticity, and LDN was found to be generally safe and reduced spasticity.
In 2010, Dr. Bruce Cree and others at University of California, San Francisco, published a double-masked, placebo-controlled, crossover study of LDN in 80 people with MS. In this well-designed study, each person also acted as his or her own “control” because there was a crossover, meaning that each participant received eight weeks of LDN and eight weeks of matching placebo. However, they did not know which one they were receiving at any given time.
LDN was shown to be tolerated well; there were no serious side effects and quality of life improved. Regular MS measures looking for a change in MS disease activity were not studied because of the minimal funding for this study (obtained through patient fundraising).
Although these results are all exciting, one study begun in Ohio in 2007 produced negative results. This study of LDN for MS symptoms and quality of life concluded in 2008 that there was no difference between being treated with LDN or with placebo. It remains unclear why this was a negative study – it could have been linked to issues of study design, patient population used or the number of people enrolled. Of course, the other possibility is that LDN does not have the beneficial effects that some have suggested.
It is also unclear whether LDN actually changes the course of MS (modifies the disease), or whether it helps some of the symptoms, such as spasticity. The improvement in quality of life seen in the UCSF study may be related to the effects on the opioid receptor and a minimal “high” from releasing endorphins.
LDN Side Effects
The most common side effect of LDN is sleep disturbances. This usually improves over time. Although it has not been proven, it is probably better to take LDN at bedtime because there is a brief blockade of opioid receptors between 2 a.m. and 4 a.m. This is believed to produce a prolonged “up-regulation” of vital elements of the immune system via endorphin production.
It is generally recommended that people taking opiates for pain be weaned off them under the direction of their physician prior to starting LDN. This is because Naltrexone blocks opioid receptors, and the LDN may reverse some of the effects. Also, LDN releases additional endorphins, which alone causes some pain relief.
Higher doses of Naltrexone have been shown to cause liver problems and should not be used in people with liver disease. It is unclear whether such low doses of Naltrexone could cause liver problems, too, but research has indicated that LDN is generally safe.
In people taking thyroid replacement medication for an autoimmune disease called Hashimoto’s thyroiditis, LDN should probably be started at even lower doses. If the LDN helps to stop the autoimmune attack on the thyroid, there is a chance that the thyroid hormone levels will go too high. Thyroid hormone levels should be checked frequently and LDN should only be used under the careful supervision of a knowledgeable physician.
If LDN really has a profound effect on the immune system, then it is possible that it has a damaging effect on certain types of immune system diseases. This is why (especially) people taking immunosuppressive and chemotherapies medications should be cautious about the use of LDN.
Practical Issues
How do you get LDN?
Since Naltrexone is FDA-approved at 50 mg, LDN (usually, 1.5 to 4.5 mg) is generally obtained through a compounding pharmacy. There can be variability among compounding pharmacies, and your doctor would know best which pharmacy they want you to use.
Has LDN been proven to help MS?
The only treatments that have been FDA approved for the treatment of MS (and not simply its symptoms) are oral fingolimod, subcutaneous glatiramer acetate, intramuscular subcutaneous interferon beta 1A, subcutaneous Interferon beta 1b, and intravenous (IV) natalizumab.
If I take LDN, should I stop my regular MS disease-modifying agent?
No. There is no reason that you should stop your regular MS medications.
So is LDN a wonder drug or a waste of time?
Only time and more research will tell.
Daniel Kantor, M.D., is the medical director of Neurologique, an organization dedicated to patient care, education, and research in Ponte Vedra Beach, Fla. He is the president of the Florida Society of Neurology and focuses on patient-centered MS care and the interaction between MS and migraine. Based on the success of the study at UCSF, Dr. Kantor is planning an East Coast replication of the study (scientific research always needs to be validated in other research facilities). The study at Neurologique will be starting in the next few months. To contact Neurologique call 904-834-3007 or email info@Neurologique.org. The website is www.Neurologique.org.