Low Dose Naltrexone Review for MS Reveals High Safety Profile, Mixed Results on Benefits in Multiple Studies

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One of the most widely disputed treatments for multiple sclerosis is low dose naltrexone (LDN). While a plethora of patient testimonies and anecdotal evidence suggest immense benefits of LDN for multiple sclerosis, many clinicians are wary due to the lack of FDA approval outside of treating heroin and alcohol addiction.

Starting with the basic biology of LDN, the opiod antagonist drug is suggested to protect oligodendrocytes from cell death by reducing inflammation in the brain as a result of inducible nitric oxide synthase (iNOS) inhibition. In other words, less oligodendrocyte apoptosis means a greater potential for myelination, the key activity that could restore myelin damaged in multiple sclerosis. An alternative explanation for LDN activity is that low doses (less than 5 mg/day) of naltrexone cause the drug to act as an opiate agonist to regulate neurotransmitter activity between neurons.

Regardless of the mode of action, “Low Dose Naltrexone Therapy in Multiple Sclerosis,” published in the journal Medical Hypotheses, reports that over 70,000 LDN capsules are dispensed from a single pharmacy in only 8 months. Such a high demand for LDN resulted in the first trial for LDN initiated in December 2006 (completed in August 2007 and published in September 2008).

Led by researchers in Milan, Italy, the trial was a six-month, multi-center pilot Phase 2 trial that treated 40 patients with primary progressive multiple sclerosis (PPMS), a more severe form of the disease. “A significant reduction of spasticity was measured at the end of the trial,” wrote Dr. Gironi, lead author of the study “A Pilot Trial of Low-Dose Naltrexone in Primary Progressive Multiple Sclerosis,” published in the journal Multiple Sclerosis. Dr. Gironi further described, “Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.”

In this study, patients were dosed with 2 mg oral LDN at bedtime for four weeks. Patients were monitored by their clinicians via phone call, and the dose was increased to 4 mg if warranted. In-person follow-up visits allowed clinicians to track the progress of patients. Only one patient experienced a progression of neurological disability, and adverse events did not interfere with daily living for the patients who remained in the study.

Around the same time as the study in Milan, psychologist David Pincus announced a study to treat patients with either PPMS or relapsing-remitting multiple sclerosis. This trial was a 16-week trial with 36 patients. Unfortunately, at the close of the study, Dr. Pincus acknowledged problematic outcomes in the study. “We did not exclude patients on existing immunosuppressants,” stated Dr. Pincus. “The existing immunosuppressants may have inhibited the LDN effects in this population.” There was no apparent difference between placebo-treated and LDN-treated patients in terms of symptoms or energy levels.

The first placebo-controlled trial for LDN in multiple sclerosis was conducted by the University of California, San Francisco in early 2007 with neurological researcher Bruce Cree, MD as the lead. “A Randomized Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone” was a Phase 3 study that dosed 80 patients with either 4.5 mg of naltrexone or placebo for eight weeks before treatment was crossed-over.

“We are grateful to the MS patients for participating in this study and wish to specially acknowledge the efforts of SammyJo Wilkinson of LDNers.org and the other fundraisers who made this trial possible,” said Dr. Cree in an acknowledgement to the World Congress on Treatment and Research in Multiple Sclerosis. “To our knowledge, this is the first patient-funded clinical trial in MS.”

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Published in the journal Annals of Neurology, the article “Pilot Trial of Low-Dose Naltrexone and Quality of Life in Multiple Sclerosis” described the results of the trial. Treatment with LDN was associated with a significant improvement on parts of the mental health quality of life measures portion of the multiple sclerosis quality of life (MSQoL) score. No imaging was conducted to see if pathological disease progression was affected.

Around the same time of publication, a second placebo-controlled trial was published, but this time it was from two universities in Iran. This trial was similar in setup to the UCSF trial, but 96 relapsing-remitting or secondary progressive multiple sclerosis (SPMS) patients were treated. “The Effect of Low-Dose Naltrexone on Quality of Life of Patients with Multiple Sclerosis: A Randomized Placebo-Controlled Trial” indicated patients experienced no added benefit of treatment with LDN relative to placebo. Overall, MSQoL was not different between the two groups.

Scientists are not quite sure why clinical studies are revealing insignificant benefits of LDN therapy for multiple sclerosis, despite anecdotal evidence outside the clinical trial setting. To better understand the mechanism of action, researchers have conducted animal studies using experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis. “Prevention and Diminished Expression of Experimental Autoimmune Encephalomyelitis by Low Dose Naltrexone (LDN) or Opiod Growth Factor (OGF) for an Extended Period: Therapeutic Implications for Multiple Sclerosis,” an article published in Brain Research, found that support cells in the nervous system (astrocytes and oligodendrocytes) are protected by LDN treatment. In fact, in the study, LDN helped to halt EAE progression, reverse the neurological deficits experienced by the afflicted mice, and prevent neurological dysfunction for an extended period of time.

If more successful clinical trials are conducted and the FDA approves LDN for multiple sclerosis therapy, patients would benefit from more than just a reduction of symptoms. As reported by “The Use of Low-Dose Naltrexone (LDN) as a Novel Anti-inflammatory Treatment for Chronic Pain,” which was published in Clinical Rheumatology, LDN costs an average of $35 per month assuming no insurance coverage. The low cost relative to other medications is attributed to its generic status. Another major benefit is the low side effect profile. Clinical trials for a wide range of diseases have shown no incidences of ulcers, renal insufficiency, medication interference, or withdrawal symptoms. The most common side effect is an increase in vivid dreams that may go away over time.

Yet LDN is accompanied by a list of disadvantages, in addition to the lack of clinical studies. Insurance companies will not cover LDN for off-label uses, although the low price mitigates this concern. Since not all patients have access to LDN (4.5 mg), some patients create their own dose by dividing commercially available 50-mg tablets. Fortunately, it is unlikely a patient could overdose on LDN, but the danger of inconsistent dosing remains. Additionally, no long-term safety studies have been conducted for LDN — only naltrexone. Although researchers indicate that a lower dose of medication seems as though it would have fewer side effects, the difference in mechanistic action may bring on unforeseen safety issues. Until more trials are conducted and LDN provides a clear benefit without any adverse events, multiple sclerosis patients will continue to wait and see if one more potentially life-saving treatment is approved.

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Maureen Newman is a science columnist for BioNews Texas. She is currently a PhD student studying biomedical engineering at University of Rochester, working towards a career of research in biomaterials for drug delivery and regenerative medicine. She is an integral part of Dr. Danielle Benoit's laboratory, where she is investigating bone-homing therapeutics for osteoporosis treatment.
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    • Debbie says:

      Judy – you don’t need to volunteer. You simply contact any local Compounding Pharmacy and ask them for a list of doctors in your area who prescribe LDN. It has been having phenomenal success with a multitude of autoimmune disorders.

      I take it myself and it has been a life-changer. In 15 months I’ve gone from nearly bedridden to being able to speed walk nearly four miles…plus a variety of other benefits.

      Do yourself a favor and try it! It’s great!

      • Brenda Luka says:

        wonderful… I also have been taking it for 7 years with no adverse side effects! studies are far to few for this fantastic drug…. I suspect the drug companies are paying off positive feedback as it doesn’t serve their interests!! I have been my own advocate… difficult to get doctors to educate themselves about LDN as the drug companies do most of the educating about their drugs.. patent has run out and it is not a money maker anymore! I really hope people who would benefit from it have the opportunity to try Naltrexone! All the best to you as you continue to improve!!

  1. SRainbolt says:

    It is NOT Lose Dose Naltrexone it’s Low Dose Naltrexone! Geez. Also you don’r have to buy 50mg pills and take chances of getting the wrong dosage. This is why you should be taking your LDN RX to a compounding pharmacy! They put capsules together for you with the appropriate amount of medication along with a filler! You can choose you filler, normally it’s calcium carbonate I think but you could have something else helpful like acidophilus used as your filler – YOU CONTROL WHAT YOU PUT IN YOUR BODY so you choose. DO NOT take this article seriously Lose Dose Naltrexoine… pffftttt & patients are left having to divide “…50 mg pills…danger of inconsistent dosing remains” pffftttt Scare tactic B.S.!

  2. Bucca says:


    I have had MS for approx 25 yrs and unfortunately now am in a wheelchair, my dr. doesn’t have any ideas was to what to try next. I just take solumedrol 1000mg infusions 1 month along with the usual plethora of other pills: baclofen, methocarbamol, etc.

    I guess what I’m wondering is in what way is the LDN helping you?

  3. RHW says:

    I take LDN for my MS and — combined with a Swank diet and exercise — have noticed a huge improvement in my condition.

    No side effects like dreams, but it does seem to stimulate my libido, which is a rather good side effect.

  4. Eshaya says:

    Hello .i just start LDN (3.5) .but i have tecifdera too .is it ok to take both of them .or just take LDN.need your opinion please .thank you.please e mail me .

    • Bonnie O'Donnell says:

      My daughter took tecfidera for 2 years. She took the white blood count test upon starting and was sort of monitored during treatment for that. However, she showed negative for the JV Virus at the start but they never monitored her for the JV Virus (simple blood test) during treatment which we now find out should be tested regularly. She was recently tested for the virus and is now POSITIVE. This virus can be activated due to immosuppresants (Tecfidera)and lead to PML. She no longer is taking Tecfidera…what I’ve read about LDN seems more positive with no side effects (other than possible dreams)…it doesn’t make the drug companies any money since it is a generic drug so they don’t want to pursue it…I’m sure you’ve seen all the recent commercials about Tecfidera…it’s all about the $$$…Hope this helps you..if you stay on Tecfidera make sure you are tested regularly for the JV Virus…God bless

  5. heena dhawan says:

    I take techfidra for 1.5years. Now i take ldn also from 1.5months.. I take techfidra during lunch time & at night ldn4.5mg. Condition is ok.

  6. Dave says:

    Was diagnosed with MS in AUG of 2014, (however now realize I’ve had it much longer)… I’ve been taking LDN since FEB of 2015… as of now I’ve had no relapses or such … although I have not progressed, I haven’t really improved… the quality of my life is pretty much normal with the exception of the lengthy walking (and jogging) I used to enjoy… my walks on average is limited from 1 to 2 miles, at best… I take a multi-vitamin (alive—American) and Vitamin “D3” (15,000 IU’s per/week)my diet is much better than it used to me… I researched the many meds my neurologist asked me to look into and they were horrendous!!! I was appalled at the many serious (and sometimes severe) side affects I encountered… what a true blessing I came across LDN… 3 neurologists would not prescribe it to me… I had to see a “friendly to LDN” family doctor… anyway, my question is, what can I do to improve my walking for longer periods? is it possible to improve so dramatically that I could start jogging again? any advice or recommendations would be greatly appreciated…
    Thank you!

  7. Mo says:

    guessing Mayo clinic won’t to mention at appt though. I am tired of these crazy drugs being pushed on us, My Dr. didn’t even go over meds with me, i was just diagnosed. So am tyring to figure out what I’m going to take.

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