Low-Dose Naltrexone (LDN) as a Treatment for Autoimmune Disease

What conditions is low-dose naltrexone effective for? There are actually two ways to answer this question. The first is what the scientific literature shows, and then the second is what clinical and anecdotal experience of clinicians that are working with LDN shows.

In this episode, we cover:

3:36  How LDN works
10:50  The effectiveness of LDN
17:25  Finding a doctor to work with

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Steve Wright: Good morning, good afternoon, and good evening. You are listening to the Revolution Health Radio Show. I’m your host, Steve Wright, co-author at SCDlifestyle.com. This episode of the RHR podcast is brought to you by 14Four.me. This is a 14-day healthy lifestyle reset program. Chris has put together a really simple, step-by-step, hand-holding program for those of you who are still struggling with sleep issues, weight issues, gut issues — actually basically any health issues — because the 14Four.me program addresses your food, your sleep, your movement, and your stress, all foundational principles for living a long, healthy life and overcoming any sort of chronic conditions you’re still dealing with. If you’re having problems implementing these in your life, please check out 14Four.me. It might be the program for you.

With me is integrative medical practitioner, healthy skeptic, and New York Times bestselling author, Chris Kresser. Chris, how are you doing?

Chris Kresser: Pretty well. How are you, Steve?

Steve Wright: I’m catching up on some sleep, but I’m doing well.

Chris Kresser: All right. Yeah, I heard you’ve been out partying hard at Garth Brooks concerts!

Steve Wright: I can’t say I haven’t been. It’s been good to put on the Stetson, the cowboy boots, and sing some Friends in Low Places.

Chris Kresser: That’s pretty awesome. I have to remember you’re Midwest born and raised, right?

Steve Wright: Yeah, yeah, coming from the rural backwoods of Michigan. Not really that backwoods, but —

Chris Kresser: That’s great.

Steve Wright: — I got the country gene.

Chris Kresser: Good times, good times.

Steve Wright: Yes.

Chris Kresser: All right, so we have a great question this week. It was actually hard for me to believe that I had never covered it. I’ve talked about it on so many different podcasts and in blog articles and stuff, but I realized when we got this question that I had never actually covered this topic in one distinct podcast, so here we go.

Question from Larry: Hi, Chris. My name is Larry Leibowitz. I’m an integrative/functional family physician in Connecticut. I’ve become an avid listener to your podcast, and I find a lot of the material to be extremely useful and very helpful for my practice. As you can imagine, I see a lot of patients with chronic inflammatory conditions. Many of them are autoimmune in nature, and recently I’ve been considering the use of low-dose naltrexone with my patients. I’d be very interested in hearing about your experiences with the medication, some of the successes and/or failures, and in which cases you find it to be the most useful. Thanks. Take care.

Chris Kresser: All right. Yeah, like I said, it’s something we’ve talked about here and there, and it can be really useful for people with autoimmune conditions. I think a lot of folks have heard of it by now, but I want to just take the chance to give a little bit of background, explain how LDN, low-dose naltrexone, works, what kind of conditions it’s been studied in and might be effective for, and we’ll talk about some pros and cons and things to keep in mind if you take it and how you might find a doctor that you can work with to take it.

How LDN Works

As the name implies, low-dose naltrexone is a low dose of a medication called naltrexone that was originally approved back in the ’80s at a higher dose, 50 mg, for the purpose of helping opiate and heroin addicts to get off those drugs, and it works by blocking the reception of opioid hormones. So if you were on a 50 mg dose, you could take any kind of opiate drug and not get high. But the problem was that in addition to not getting high when taking these opiates, people who were taking 50 mg of naltrexone didn’t feel any pleasure at all because the opioid receptors in our brain mediate our experience of pleasure. So at the full dose, naltrexone really reduced that experience of pleasure and, therefore, wasn’t a very sustainable or effective drug.

But around that time in the mid ’80s there was a doctor in New York named Dr. Bihari who was interested in treating cancer and AIDS, which was just becoming something that people were starting to focus on more at that point, of course, and he discovered that a low dose between 3 mg and 4.5 mg of naltrexone had beneficial effects on the immune system. And since then, LDN has been used for autoimmune disease, cancer, and other conditions that involve immune dysregulation. This is important to understand if you’re going to talk to your doctor about LDN because a lot of doctors might be familiar with naltrexone that was used for this purpose and might raise their eyebrows or not be familiar with the fact that a lower dose is used for a completely different purpose. The higher dose is about blocking opioid receptors and detox and getting people off drugs, whereas the low dose is being used now for balancing and regulating the immune system, so it’s important to make that distinction.

Without getting too geeky here, I want to tell you a little bit about how LDN works because it’s interesting, and it, of course, helps to understand how it might benefit you if you have an immune-related condition. And this is ongoing. There are new papers published about the mechanisms of LDN each year, and we’re still learning about this, but so far, there are two main mechanisms that have been identified. One is that, as I said, it regulates the immune system, and it does this primarily by promoting T regulatory cell function. The T regulatory cells, or Tregs, they keep the immune system in balance, and they turn inflammation on and off, depending on what’s needed, and they prevent the immune system from getting stuck in patients with overactive immune systems, like people with allergies or asthma or autoimmune conditions. The way this works is LDN, as I mentioned, it temporarily blockades the opioid receptors in the brain, and when the receptors are blocked, the body thinks more opioids are needed, and so it produces more, and by the time more opioids are produced, LDN is out of the system, the receptors are unblocked and receive those, and that leads to essentially a net increase in opioid production.

So if you’re wondering now, like, what does this have to do with the immune system, we now know that people with autoimmune disease often have low levels of these opioids and that white blood cells, which, of course, are what are driving the immune response, have receptors for these opioids, which, of course, suggests that they play a really important role in the immune system.

So that’s number one, this immune-regulating, balancing mechanism.

Steve Wright: Does the increase in opioids actually then cause a corresponding increase in Treg cells? Is that the point you were making there?

Chris Kresser: Yeah, exactly. And then the Treg cells are the ones that — I mean, they’ve been referred to as the police force of the immune system. I’m not sure that’s the best analogy these days, given what’s been happening, but the idea is that they balance and regulate the immune system and keep both sides in check.

Another more recently discovered mechanism is that LDN reduces inflammation in the central nervous system, and the significance of this is that inflammation in the central nervous system is thought to play a role in a number of different conditions that LDN has been shown to be effective for, like fibromyalgia and chronic pain and depression. In addition to blocking the opioid receptors, LDN blocks something called toll-like receptor 4 that’s found on white blood cells that are called microglia, and the microglia are central nervous system immune cells that produce inflammation, pain sensitivity, fatigue, sleeplessness, mood disorders, and cognitive problems. When those microglia are chronically activated, as they are fibromyalgia and other pain disorders, it results in neurotoxicity and then this whole wide cascade of symptoms that are associated with all these conditions, and LDN essentially blocks that cascade by blocking the receptors on those microglial cells. This probably explains why in some of the studies so far LDN has been shown to reduce something called erythrocyte sedimentation rate, or ESR, which is an inflammatory marker that’s elevated in conditions like fibromyalgia.

Again, to recap, there are two basic mechanisms: balancing and regulating the immune system and then reducing central nervous system inflammation. There probably are other mechanisms, but those are the ones that have been the most clearly defined so far.

Steve Wright: Chris, is there any way for people to test their opiate levels to know if they might be low and LDN would be an ideal —

Chris Kresser: Not that I’m aware of. There are some tests that can look at various kinds of immune cells and the balance between those immune cells, but they’re not widely available and they’re a little bit difficult to interpret, so it’s not something that I think is that useful for the average person or ready for primetime. I think with LDN the best way to determine if you’ll benefit from it is whether you have the conditions that it’s shown to be useful for or any other kind of immune-related condition and then just doing a therapeutic trial, but we’ll talk a little bit more about that in a second.

The Effectiveness of LDN

OK, so what conditions is LDN effective for? There are actually two ways to answer this question. The first is what the scientific literature shows, and then the second is what clinical and anecdotal experience of clinicians that are working with LDN shows. There’s definitely research out there on LDN, but it’s still somewhat limited, and I think clinical and anecdotal experience is further ahead in terms of the breadth of conditions that LDN is being used for and the experience of how effective it can be for those conditions. The studies are also still usually relatively small sample size, not always randomized, not always double-blinded. Part of the reason for this is they’re probably not that well-funded because low-dose naltrexone is off patent, and that means that drug companies don’t stand to make a killing on selling LDN, and it’s unlikely that a whole lot of money is going to be put into it for that reason.

Having said that, the results so far of the studies on LDN have been really encouraging, and they’ve been primarily on cancer, multiple sclerosis, Crohn’s disease, fibromyalgia, and autism. It’s especially effective for Crohn’s with over a 70% remission rate and even complete mucosal healing as evidenced by colonoscopy in some cases. If you know about Crohn’s disease and how nasty it can be and how difficult to treat and how poor the success rates are of the typical treatments, that’s a pretty remarkable statistic, over 70% remission rate with mucosal healing, especially when you consider the fact that there were not documented side effects of LDN in that study compared to placebo.

So that’s what’s in the scientific literature, but anecdotally clinicians are using it for a whole wide range of conditions involving inflammation and immune dysregulation, autoimmune diseases like Hashimoto’s and Graves’, rheumatoid arthritis, lupus, psoriasis, chronic fatigue syndrome, neurodegenerative disorders like Parkinson’s and Alzheimer’s. It’s being extensively used for infertility. There’s a clinic in the United Kingdom that is basically almost entirely focused on using LDN for fertility to treat patients who are struggling with that. And the reason it’s effective for such a broad range of conditions is because of the mechanism of action. As I said, it regulates and balances the immune system and reduces inflammation, and of course, we know that inflammation and immune dysregulation are at the root of many diseases and certainly at the root of autoimmune conditions. Even though there aren’t any studies of LDN on Hashimoto’s, for example, it makes sense that it would work for Hashimoto’s if it’s working for multiple sclerosis and Crohn’s disease because the underlying mechanism of all those conditions is immune dysregulation, autoimmunity. That’s why a lot of clinicians out there feel justified and safe in using LDN for conditions that it hasn’t directly been studied on because, A, the mechanism makes sense and, B, it’s safe and well tolerated and doesn’t have any significant complications or risks or even side effects in many of these studies.

One of the advantages of LDN as a therapy is that it’s low cost. It’s off patent, as I said, which means typically you can get it for about 40 bucks a month, 35 or 40 bucks a month from a compounding pharmacy.

The side effects are pretty minimal, in that in some of the double-blind, placebo-controlled trials, as I said, there was no difference in side effect between placebo and the treatment group, but I will say that in our experience, what we’ve seen in our clinic and other clinicians I know that work with it, there are some side effects that are fairly common, which are temporary sleep disturbance when a patient first starts taking it or vivid dreams and a mild headache, but these usually pass pretty quickly and can often be mitigated by starting with a lower dose, so if 3 mg or 4.5 mg is the ultimate dose that they end up on, starting at, like, 1 mg or 1.25 mg or something and then building up more slowly.

LDN does not have any known abuse potential. It’s not an addictive medication. One of my hesitations or criticisms of a lot of drugs is that they just primarily work by suppressing symptoms and they don’t necessarily improve the function of the body, but LDN is a little different in that respect, in that it works by improving the function, it increases the production of T regulatory cells, which then have that immune-balancing effect and, I think, makes it a little bit safer to use over the long term. Now, of course, if you can achieve results and address your autoimmune condition without using a medication, even one as safe as LDN, then that’s great, but my rubric for a treatment, you know, whether a treatment makes sense, has always been whatever is the most effective and causes the least amount of harm. In many cases, that’s not a drug, but LDN is actually one medication that I think passes that test.

One of the disadvantages of LDN is that there’s still not standardized dose, and really the patient and the prescribing physician just kind of have to figure it out through trial and error. From our experience, we’ve seen most people end up around 2.5 mg to 3 mg; 4.5 mg tends to be too much for people. I’ve seen some patients settle on as little as 1.25 mg or 1.5 mg, but anywhere in the 1 mg or 1.25 mg to 4.5 mg range could be the optimal dose for a given person.

We still need more research. I mentioned that the research we have already is somewhat limited, so we need more research.

Finding a Doctor to Work With

It’s not always easy to get a prescription. A lot of primary care doctors aren’t familiar with it. It’s not covered by insurance. It’s completely off label, but fortunately it’s pretty cheap. Even if people are paying out of pocket, it’s only about 35 or 40 bucks a month.

And although all the studies we have so far show that it’s safe, we don’t have any hard data on really long-term safety, you know, people who have been taking LDN for 10 years or something like that. Of course, that’s true for a lot of drugs, but I’m just pointing that out.

So if you’re interested in LDN, keep in mind it has to be prescribed by a physician, or in some states, a naturopath can prescribe it. You can print out some studies from PubMed. You can go into PubMed.org and search for “low-dose naltrexone,” and there are a bunch of studies that will pop out. You can print those out and take them to your doctor to discuss. There’s a website called LDNinfo.org that has kind of a clearinghouse of information on LDN that you can go to. There’s a Yahoo group about LDN that you can join and talk to folks there and try to find a practitioner in your area.

What I don’t recommend is ordering it from overseas pharmacies. You never know what you’re getting that way, and there have been a lot of studies showing that drugs that come from those pharmacies are not often what they claim to be, and that’s just flat out dangerous and not very smart. Hopefully that goes without saying, but I’m just mentioning it anyway.

And particularly with LDN, it should be obtained from a reputable compounding pharmacy that has some experience in compounding LDN. I mean, there are certain pharmacies that know which binders and fillers make the most sense with it and seem to be the best tolerated, and they just a lot more experience working with patients that are taking it, and it’s a good idea to refer your physician to one of those. Skip’s Pharmacy in Florida is the one that comes to mind that’s been doing it for the longest period of time, so you can look them up on the web. There’s also a list of recommended pharmacies on the LDNinfo.org site that you can make your doctor aware of.

Let’s see. Anything else come to mind? What have you got, Steve?

Steve Wright: I got a question. Have you seen in your patient population that, for instance, say someone settles on 3 mg, do they ever need to change that? Does the effect wear down over time, or do life circumstances sometimes mean that you could get more sensitive or less sensitive to it?

Chris Kresser: Great question. My sort of take is usually, like, let’s use any treatment, whether it’s a supplement or medication for a therapeutic purpose, to reach a therapeutic goal, and once we reach that goal, I’m always interested in seeing if we get people off of stuff, maybe once the immune system comes back into balance and the patient is symptom free. Like we’ve talked about before, the concept of tolerance. You’re an engineer, Steve. You’ve told me about it. It’s easier to maintain something within tolerance, that’s already where it should be, than it is to get it back there in the first place. A patient may want to stop taking LDN or titrate off of it after a while to just test to see if they can maintain the improvement that they’ve gained from it.

On the other hand, if somebody has a condition like Graves’ disease where there’s a real risk of going into a hyperthyroid storm and stroking out and that’s been historically an issue for them and LDN is just completely managing it without any other medication, if you’re going to weigh that against taking PTU or methimazole or pretty toxic medications that often needed for Graves’ or even more invasive, like a surgery to remove the thyroid or to radioactively ablate the thyroid gland, and you’re weighing those against just staying on LDN, of course, you have to talk to your doctor about these questions, but my take on that would be if it were me as a patient, I would rather take LDN on an ongoing basis than to face any of those outcomes. So it just depends on the person.

And the dose can fluctuate, depending, of course, on the background level of immune dysregulation. If maybe someone is gluten intolerant and they don’t know it and they’re eating gluten and they’re taking LDN and they need the full 4.5 mg dose because they kind of have their foot on the accelerator and the brake at the same time, but then they take gluten out of their diet and maybe 4.5 mg is unnecessary or even starts causing some side effects, so that’s possible.

Steve Wright: One more question.

Chris Kresser: Yeah.

Steve Wright: In previous shows and potentially in writing — I’m not sure where I remember you mentioning this — but you’ve said to commit to a timeframe for LDN because not everybody shows symptom reduction or lab test reduction at a specific point in time after starting taking it, so what are your current thoughts on that?

Chris Kresser: Yeah, it’s the same. I mean, it’s really interesting. Some people, like, the next day after they start they feel like a different person, and then other people, it can take three months for them to really feel a significant difference. We don’t really understand why that is yet. And interestingly enough, it doesn’t necessarily correspond to how sick they are or how long they’ve been sick. I’ve seen it where people have been really kind of in bad shape and they respond immediately and other people whose condition was a lot more benign or mild and they didn’t have an immediate response. I don’t know about that, but I do know that it’s common. So I would say probably give it three months before you let it go if you’re going to try it.

A couple other things to consider are that because LDN blocks the opioid receptors, some pain narcotic drugs like Percocet or morphine or tramadol, LDN can decrease their effectiveness so that typically they shouldn’t be taken together. And patients with Graves’ or Hashimoto’s that are taking thyroid meds should be careful because one thing we’ve seen happen is if someone takes LDN and their thyroid function improves, then the dose of medication they were on that was maintaining equilibrium before all of a sudden becomes too high, and that person can go into kind of like a hyperthyroid episode or start feeling heat or not sleeping well or all those typical symptoms. Your doctor should mention this to you when they prescribe it, but that’s something to be aware of and to talk about with your doctor if you’re on a thyroid medication, to be ready to reduce the dose if your thyroid function starts to improve.

A question that often comes up is, OK, are there some natural alternatives to LDN that achieve the same purpose of reducing central nervous system inflammation and promoting T regulatory cell function? Definitely, there are things that achieve both of those goals. In some cases, especially when you put them together, they can do just as good of a job as LDN, but in other cases I’ve seen LDN just be more effective even when someone’s done all these other things. But for Treg cell function, vitamin D is a powerful T regulatory cell promoter, as is glutathione, so those should definitely be in the repertoire. Maintaining adequate levels of selenium and zinc and iodine is important for immune function. Probiotics, especially bacillus species like soil-based organisms, promote Treg cell function. Butyrate, which is a short-chain fatty acid that’s produced by beneficial bacteria in the colon, improves Treg cell function, so prebiotics can actually do that indirectly. Vitamin A is important for immune balance, so cod liver oil. And then for inflammation, we have things like curcumin and boswellia — those are COX inhibitors, selective kinase response modulators, fish oil or EPA and DHA from cold-water fish, of course, and then diet obviously. Whether we’re talking about just a general, overall anti-inflammatory paleo-ish type of diet or whether you’re taking the next step and doing an autoimmune protocol type of diet, those can be important as well.

Steve Wright: Awesome. Well, it sounds like a pretty good round-out there. It seems like if people wanted to try those things, I’ve seen a lot of people try those things and not get success and then get on LDN and through LDN and some of those supplements together, like, really have a brand-new life.

Chris Kresser: Yeah, it can be pretty dramatic. And of course, I don’t want to create any false hope or unrealistic expectations for people, but for some it has definitely been life changing. I have patients who had been on those thyrotoxic drugs for 20 years or more, 25 years. One patient comes to mind who had Graves’ and had been on PTU for 20 years and was able to get off PTU completely and all other medications and just take LDN and feel better than she ever had felt during that period and maintain completely normal thyroid numbers, so it can be pretty dramatic. I have to say, though, that we have had patients who have taken it and experienced nothing at all. So it’s not a miracle, of course. No treatment is, but it helps a lot of people, and it does it pretty affordably and without causing a lot of side effects or complications or risks, and that’s a pretty good combination.

Steve Wright: Yeah, definitely. Awesome.

Chris Kresser: All right.

Steve Wright: Well, if listeners would like their question answered, make sure to go to ChrisKresser.com/PodcastQuestion to submit your questions. Chris and his team are always taking those in and trying to pull the most relevant topics that haven’t already been covered, so if you have submitted questions and you’re wondering, why, guys, haven’t we talked about my question, make sure you listen to the rest of our episodes because there’s quite a treasure trove of information that we’ve covered over, what, like, four or five years now?

Chris Kresser: Yeah, four or five years, somewhere in there. I should know, but something like that. Yeah.

Steve Wright: Awesome. And in between episodes, if you’re not following Chris on social media, this is where you can get updates on the latest articles he’s reading, different things that he’s pulled from around the web, so go to Facebook.com/ChrisKresserLAc and Twitter.com/ChrisKresser. Thanks for listening.

Chris Kresser: All right. Thanks, everyone. Talk to you next time.