#19: Low-Dose Naltrexone (LDN) for Long Covid

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On this installment of The Medicine Cabinet series, I tackle the use of Low-Dose Naltrexone (LDN) to treat Long Covid symptoms. Naltrexone is a fascinating drug that works one way at high doses and another way at low doses. In low doses, it can be a potent anti-inflammatory, and it may help reverse autoimmune conditions. 
There's a lot more to it. I explain how LDN works, who should consider it, and obstacles to access. I also share practical tips to dosing that will help you avoid, or at least understand, side effects. 

Links:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313374/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10862402/
https://www.physio-pedia.com/Glial_Cells

Chapters

• 0:00 Intro
• 0:00 How Low Dose Naltrexone works
• 0:59 What makes LDN unique
• 4:00 What are Receptors?
• 6:27 TLR-4 Receptors on Glial Cells
• 9:07 LDN acts on Other Pathways
• 10:20 What does research tell us?
• 12:42 Is LDN right for you?
• 17:34 Compounding Pharmacies
• 19:20 My experience with LDN
• 21:20 TL;DR Summary of LDN
• 24:35 Outro

Transcript

Zeest Khan (00:00)
The contents of this podcast do not constitute medical advice.

Zeest Khan (00:10)
Hello and welcome back. I'm Dr. Zeest Khan, the Long COVID MD. I'm here to help you understand your body and understand healthcare so you can move your own health forward. In today's installment of the Medicine Cabinet series, I'm explaining how low dose naltrexone can help patients with long COVID. I'll cover what LDN is, how it works, how to know if it's right for you, and how to learn what

dose is right for you. I'll share my personal experience with LDN and if this episode is too much for you, you can fast forward to the summary I provide at the end. Check the chapter markers to find the right spot. Let's get started.

In Alice in Wonderland, Alice was sometimes big and she was able to do specific things she couldn't do when she was small. Other times, she became tiny and was able to do things she couldn't do at any other size. Naltrexone is a little bit like Alice and her potions. At a big dose, naltrexone works one way, but at a very small dose, it has a totally different effect.

Like Alice, both sizes helped her for specific needs, and we can approach naltrexone the same way. Naltrexone is an FDA -approved medication used to treat substance use disorder. At doses starting at 50 milligrams, naltrexone blocks the effects of opioids and prevents intoxication by blocking a specific receptor called the mu -opioid receptor.

found in the brain and central nervous system. When these bigger doses of naltrexone bind the mu receptor, that receptor is deactivated and opiates don't work. Naltrexone is therefore used at the 50 milligram range to help reduce opioid cravings and prevent opioid -related overdose.

Now we're going to talk about low dose naltrexone, which works in a very different way. Instead of reducing cravings, low dose naltrexone can reduce inflammation, nerve pain, brain fog, and even fatigue. It also has the potential to calm an overactive immune system. Studies have demonstrated benefit of using LDN in conditions like inflammatory bowel disease,

multiple sclerosis, and complex regional pain syndrome. Many people are using it for fibromyalgia, myalgic encephalomyelitis, and now long COVID. Whether or not you use it, you should know about this medication. Many physicians believe it is a very important mainstay of therapy.

The standard dose of naltrexone works on the mu opioid receptors and those receptors connect to euphoria and pain. Low dose naltrexone works on a few other receptors including one called TLR4 which stands for toll like receptor four. This receptor is found on cells called glia.

that are found in the brain and spinal cord. They affect inflammation, the immune system, and also nerve pain. Receptors are a really important part of the story here. So let's talk about what a receptor is. Receptors are all over the human body and are the primary way signals are passed from one system of your body to another.

You can think of receptors like light switches. You might have a panel on your kitchen wall with several light switches. One could be connected to the kitchen lights, one to the ceiling fan, one to the garbage disposal. You could have a switch that opens your garage door and you could have a switch that powers your printer. In the human body, receptors are like these power switches. Actions in the body are activated or shut off

depending on the position of the receptor. That action could be increasing your heart rate when you're running, or it could be sending fibrin to a cut on your hand in order to build a protective scab. That scab is an example of how receptors control the release of immune and inflammatory cells when they're needed.

But just like in our house, the switches shouldn't be on forever. They should only be on when they're needed and off when they're not needed. So in the examples I used, if you are running or doing an aerobic activity, having an increased heart rate is really gonna help you. But as soon as you stop running, the increased heart rate needs to stop. If it doesn't, you're gonna feel worse.

Likewise, if you have a cut on your hand, you need some clotting material in your bloodstream to go to that site to protect you. If that process doesn't shut off appropriately, you could develop clots and thrombi in your bloodstream.

Receptors are turned on or activated by chemicals called agonists. They are blocked by things called antagonists. Many of the drugs we use are designed to be agonists or antagonists of certain receptors. By manipulating different receptors, our body's power switches, we can amplify or eliminate the downstream actions that that receptor controls.

Naltrexone is used for its ability to bind multiple receptors. The receptors it chooses to bind to seems to depend on the dose of the medication that's used. At standard doses, 50 to 100 milligrams, naltrexone selectively blocks mu opioid receptors.

At lower doses of one to five milligrams, naltrexone, now referred to as low dose naltrexone, preferentially binds to the TLR4 receptor on glial cells. Glial cells are not neurons, but they are an important part of the central nervous system and they support neurons. They're also an important

part of the body's innate immune response. You can think of them as first responders to danger signals in the body. They release all sorts of cells that attack an infection in a very broad and general way until the adaptive immune system builds specific weapons like antibodies that precisely eliminate the infection.

The innate immune response is supposed to subside when those specific weapons are released. In autoimmune conditions, glial cells become chronically activated. They simply don't turn off. And so we get chronic generalized inflammation. Chronically activated glial cells also contribute to neuron dysfunction. And that might be a contributing factor to brain fog.

Low -dose naltrexone binds to TLR4 receptors on glial cells and turns the glial cells off. Low -dose naltrexone tells the body, we don't need these inflammatory compounds right now. By doing so, low -dose naltrexone can shut down glial cells that were contributing to persistent inflammation.

And this is the major benefit of low dose naltrexone. It reduces neuroinflammation by blocking TLR4 receptors on glial cells, specifically on microglial cells. But it doesn't end there. LDN also seems to increase endorphins, making us feel better in several ways, including improving our mood and reducing pain.

at doses less than one milligram, called very low or ultra low dose naltrexone, it also amazingly seems to make opiates work better. A current area of interest is using LDN after surgery to reduce a patient's need for narcotics.

And yes, you heard me right. Naltrexone at standard doses blocks the effect of narcotics. Naltrexone at low doses improves their effect. Now let's take a breath here because we covered a lot.

To summarize what we've learned so far, Naltrexone works one way at high doses by blocking opioid receptors and another way at low doses by reducing inflammation at the level of the brain and the nervous system. There are obviously promising applications for LDN on long COVID patients, but not surprisingly, we don't have much data on our specific population.

We can, however, review the research that we do have. I'll link some sources in the show notes, but in short, LDN has been found to reduce symptoms, reduce inflammatory markers, and improve the quality of life in patients with Crohn's disease. Patients with fibromyalgia, especially those who had an elevated inflammatory marker called ESR,

were found to have a reduction in several inflammatory markers, including TNF -alpha and interleukin -6 after using LDN. Patients with multiple sclerosis using low -dose naltrexone have been studied as well. The data is conflicting, but some studies demonstrate statistically significant improvement of fatigue and quality of life. LDN is also a medication of interest in cancer research.

but that's outside of our focus today. I can say LDN is a hot area of interest in the management of chronic pain. It might be especially useful for chronic regional pain disorder and other chronic nerve pain disorders. Neuropathic pain can be very challenging to treat, and we don't have a lot of medications that help. Right now, we're using gabapentin, which is a fairly old drug, and pregabalin.

Injections and surgical interventions targeting nerves are also options, but they're not always permanent solutions, nor do they come without risks. LDN can be a lifesaver in these situations. This area of research is especially interesting to me as an anesthesiologist, as my field is intimately connected with post -operative pain.

and many people who are researching pain control methods and low dose naltrexone are anesthesiologists.

Who should consider low dose naltrexone and what's the best way to take it? For patients with long COVID, common symptoms that could be helped with naltrexone are brain fog, fatigue, pain, both generalized aches and neuropathic type pain, and signs of generalized inflammation. A common starting dose is half a milligram with the goal of titrating up

to at least four and a half milligrams. The medication comes as a small capsule and has to be filled at a specialty or compounding pharmacy. I'll explain more about that in a little bit. Many people take their dose in the morning, especially those whose sleep is disrupted by naltrexone. Others find it works better for them at night.

Determining the right timing and the right dose are two reasons it's important to work with a healthcare provider who is experienced prescribing low dose Naltrexone. LDN is not something every doctor is familiar with. You need to be properly evaluated to determine if you're a good candidate and to find the right dosing regimen for you.

Now let's talk about safety. It's important to know that low dose naltrexone is a pretty safe medication. The major safety issue is the combination of standard dose naltrexone and opiates. Using opiate medications, however, does not automatically make you ineligible for low dose naltrexone therapy. But you must be under the care of a responsible specialist like a pain physician who can help determine

the best dose for you.

For the bulk of the population, even those with complex illness like long COVID, low dose naltrexone is quite safe. It can, however, have side effects that make it difficult to tolerate, and that can cause people to give up on the drug. I'm here to tell you with low dose naltrexone, slow titration is crucial. You're going to increase your chances of finding maximum benefit

if you can start at a low dose and titrate up slowly. Give the process three to six months. I mean, it can take eight to 10 weeks for you to notice a benefit from the Naltrexone. So it takes time. Pay attention to the improvements, pay attention to the side effects as you go and collaborate with your prescriber. For some people,

Half a milligram is too high of a starting dose, and a dose of 0 .1 milligrams might be better tolerated. Whatever your starting dose, stay on it for at least a week before increasing, and increase the dose slowly. The American Society of Regional Anesthesia, the group of anesthesiologists who focus on nerve -related pain control, suggest their patients stay on their starting dose for a month.

before increasing it.

So how do you know if you're taking too much naltrexone too fast? Since LDN works on the central nervous system, some of the common side effects are insomnia and vivid or disruptive dreams. People with PTSD should be particularly aware of this side effect. LDN can also just make you feel a little odd, mildly dysphoric or jittery.

And even though it's been used in part to help cognition and fatigue, it can make you feel a little slow mentally and a little tired, especially during those periods of increasing the dose. These side effects, along with headache and abdominal pain, often resolve with time. And if they don't, you may have found your current ceiling.

The point is that it is okay. It is in fact very reasonable and probably helpful to take a slow approach to low dose Naltrexone. By giving this process enough time, you'll be able to notice how LDN affects you and you can work with your prescriber to land on a dose that's just right for you.

Low dose naltrexone is not habit forming, but just like titrating up slowly is helpful, if you decide that it's not right for you, it's prudent to wean off instead of stopping altogether.

Now let's talk about specialty pharmacies. Naltrexone is not FDA approved to treat fatigue or brain fog. It is not FDA approved to treat any condition that we've talked about that it might help at these low doses. It is, however, totally reasonable and legal for prescribers to use medications for off -label use.

and to use off -label doses as long as those doses are not dangerous. So using LDN is perfectly fine in that respect.

But because the FDA approved Naltrexone to treat substance use disorder at a dose of 25 to 150 milligrams, commercially made Naltrexone tablets come in multiples of 50 milligrams. When we want to use it at microgram doses, it is not particularly safe nor reliable to use the commercially available tablet.

Instead, many of us get our LDN at specialty pharmacies where pharmacists compound the drug at the specific dose we need. This makes the process safer and tailored to your specific needs. The downside is that in the U .S., most of us have to pay full price for LDN because compounded meds are not covered by our insurance.

I have paid between $100 to $200 a month for my treatment, but prices vary depending on the dose in each capsule and how many capsules you request. For me though, it was worth it. LDN was a game changer. It improved my mental clarity so much, I felt like I was a character in the movie Awakenings, at least during the part after they got their medication and before it wore off.

I was in a deep deep fog and I felt after starting LDN that that fog lifted. I felt like I woke up. I also remember feeling like I was all better. Eventually however I had to slow down on the dose because it did affect my sleep and I titrated back up very slowly. LDN has helped me significantly.

even at doses well under four and a half milligrams. In my body, LDN is very potent and I think of it as a dance partner. Sometimes we have to take it slow, sometimes we're both in the groove and sometimes it steps on my toes. But given the data we have so far on LDN, especially its effects on neuroinflammation and the chronic inflammatory cascade,

I think it's a medication worth dancing with for me. It's a medication I'm gonna continue taking at various doses depending on my needs and always in conjunction with my physician.

That being said, LDN might not benefit everyone. As we clarify subsets of long COVID patients, we'll find what works best for each type of long COVID. There are also real hindrances to acquiring LDN between finding a specialized doctor and a compounding pharmacy. Sometimes both of these are pricey and hard to find.

So let's summarize what we've covered here today. At doses around 50 milligrams, Naltrexone is a drug that blocks opioid receptors in the brain and nervous system, and it's used to treat substance use disorders. At low doses, very low doses, and ultra -low doses, Naltrexone acts very differently. Low dose Naltrexone, or LDN,

refers to doses of naltrexone between one and five milligrams. In that range, naltrexone acts on glial cells, the nervous system's cleanup and defense force. When glial cells are activated, they release inflammatory cytokines and fire up the immune system. In autoimmune conditions, perhaps including long COVID, they become chronically activated. And if they don't turn off,

they can cause neuroinflammation, fatigue, and perhaps immune system dysfunction. Lodosnaltrexone in part turns off those over -activated glial cells, potentially reversing neuroinflammation and immune dysfunction. LDN has been found to help people with inflammatory bowel disease and multiple sclerosis. And some research suggests

that it benefits people with fibromyalgia, particularly those with elevated markers of inflammation in their blood.

Low -dose naltrexone is a promising potential treatment for brain fog, fatigue, and neuropathic pain. It should be prescribed by a healthcare professional who is familiar with the medication as it is not broadly used outside the branches of medicine studying pain. It is not often covered by insurance and has to be compounded at a specialty pharmacy.

The most common side effect is sleep disruption from insomnia or vivid dreams. People with PTSD history or those who are taking opiates should inform their doctor of their history. Neither is a contraindication to using LDN, but it should be tailored appropriately and you should be evaluated to make sure you are an appropriate candidate for this therapy at all.

LDN is a potent medication and long COVID patients tend to be sensitive to meds as it is. Starting with a low dose of LDN and titrating up slowly is a good approach to finding the most effective, most sustainable dose for you. Give the process several months. And if you decide to stop, wean off slowly instead of stopping cold turkey.

I hope this was a helpful summary of the way low dose naltrexone can be used for long COVID symptoms. As with all of my episodes, this is not medical advice. Please consult your own doctor and healthcare team to ensure you are safe as you try new treatments. This has been another episode of the Long COVID MD podcast. I'm Dr. Ziest Khan. Like and follow this podcast on your streaming app.

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Until next time, I hope you're feeling well today and bye for now.