A Functional Medicine Model for Chronic Pain, Fatigue, Brain Fog, and Sleep Disruption — And Why Matching Dose to Physiology Matters More Than Protocol

Yoon Hang "John" Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Lecture Transcript — LDN Research Trust Webinar

Introduction

Good afternoon, everyone. I am so grateful to Linda Elsegood and the LDN Research Trust for this opportunity to share my sentiments and knowledge about LDN. I want to start by sharing a story. I didn't plan on becoming an LDN expert.

What happened is that one of my smartest patients — I tend to get them because I have an integrative and functional medicine practice where the minimum time you can see me is about thirty minutes, and most of the time more than that — one day said to me, "I have Hashimoto's thyroiditis. I've done research, and I heard there's this thing called LDN." That was twenty-some years ago. I said to her, "I don't know, but I will research."

And I did research. What I found was that LDN had a lot of promise and almost no side effects. It's just an amazing tool. And then I kind of got kidnapped into the world of LDN. That patient's Hashimoto's antibodies went to normal, and she didn't even need to start medication. That was an example of how LDN can be super powerful. I was educated by a patient. I did two residencies and two fellowships, and the topic of LDN never came up. That's a shame, because LDN is actually better than many medications — especially when it comes to neuropathy. But the conventional world is failing to recognize that.

A Personal Story: LDN and My Own Health

Recently, I had a surgical procedure. In the background, I had a precancerous tumor that I knew had to come out, but because of how the system works, I couldn't coordinate the surgery at a time of my choosing — which would have been about a year earlier. So I had about a year knowing this precancerous lesion was progressing toward potential malignancy.

Those of us who know about LDN know that it is an immune modulator, meaning it has the capability to help the best things occur within the immune system. I use LDN as taught by Dr. Berkson, who combined LDN with alpha-lipoic acid — in his case intravenous, as well as oral — and sometimes vitamin C. I've been getting very reliable results. Patients contact me seven years later, several years later, saying they have no evidence of disease or that they're in remission. I'm very humbled and grateful.

In my own case, I believe LDN helped slow the conversion of my precancerous lesion to cancer. I'm not making a medical claim — I'm sharing my belief based on twenty years of LDN practice.

After the surgery, I had all kinds of pain, but the worst was neuropathy — nerve pain. Before surgery, we stop LDN because they may give us opioids, and there's a theoretical interaction that can hurt patients, even causing them to wake up in the middle of surgery. So I stopped taking it for a week. But as soon as I was done with surgery, I could feel terrible nerve pain. I know that LDN is a potent, novel anti-inflammatory that specifically benefits nerve pain, and I use it that way in my practice.

I started taking LDN around the clock after surgery. My neuropathy not only got better — it disappeared. I believe that any post-surgically related neuropathy from surgical injury to the nerves was avoided because of LDN. Again, I'm not making a medical claim. I'm sharing my experience.

The third part of the story: after surgery, which was the most difficult experience of my life, I took LDN at neuropathy doses, which tend to be a little higher — 6 milligrams four times a day. And I got to experience what endorphin deficiency feels like. What I felt was nausea, but I also felt like the sensation of death — the zeal for life just seeping out of me. I'm glad I was concerned about this possibility, so I had addressed potential endorphin deficiency about three weeks before surgery. Sometimes knowing too much is a problem because you think about all these things, but I did experience endorphin deficiency symptoms at the dose I was taking. And that brings us to today's topic.

Today's Topic: Endorphin Deficiency and the LDN Sweet Spot

Today's talk is straightforward, and I'm hoping everyone will walk away an expert in dosing. The topic is Endorphin Deficiency and the LDN Sweet Spot — a functional medicine model for chronic pain, fatigue, brain fog, and sleep disruption, and why matching dose to physiology matters more than protocol.

I am Yoon Hang Kim. I'm a physician trained in family medicine, preventive medicine, and public health. Today I operate as an integrative medicine, functional medicine, and lifestyle expert, and I run an integrative medicine company called Direct Integrative Care.

Disclosure

I am the owner of my own telemedicine practice, which is an integrative, functional medicine, and lifestyle medicine practice that focuses on LDN therapy. I have published extensively on LDN. Currently, I have two books: LDN Primer, which focuses on the general public, and LDN for Clinicians, Researchers, and Empowered Patients, which is meant to be more of a reference textbook. I also help to run the LDN Support Group and the website ldnsupportgroup.org, and more recently I've started a Skool-based LDN support group as well.

Learning Objectives

By the end of this talk, I would like you to be able to describe what endorphin deficiency looks like — in terms of chronic pain, fatigue, poor sleep, and reduced stress tolerance. I want you to understand LDN as a transient opioid blockade followed by compensatory upregulation of endogenous opioid production. Before COVID-19, this mechanism worked for probably 99.999% of people. But there are always what we call canaries in the coal mine who behave completely differently. In my practice, I always tell patients, "You are not an average bear — you may not be inside the bell curve."

We will also talk about intolerance, early warning signs, worsening when people begin LDN, and who needs ultra-low-dose naltrexone. These days, ultra-low-dose naltrexone starts at one microgram, but I'm finding patients who cannot tolerate even one microgram and have to go to nanogram doses, and a few need to go to picogram doses. We will also talk about what happens when the compensatory upregulation pathway is poisoned or simply does not work.

Why This Matters: LDN as People's Medicine

The conditions that LDN is capable of treating — chronic pain, fatigue, sleep disruption, brain fog, autoimmune conditions, long COVID, mast cell activation syndrome, and other chronic inflammatory states — are widespread. Modern medicine has come a long way, especially in the last ten to twenty years, with the availability of biological agents and immunotherapy. But in the United States, we have a very chaotic healthcare system. Either you can afford insurance or you can't. Either you have "Cadillac" insurance or high-deductible insurance. And depending on that, your ability to access medication differs greatly.

I'll use myself as an example. My physician called in a prescription. I went to pick it up, and the pharmacist said, "Dr. Kim, your co-pay is going to be $1,500 every month. Would you like to pay that through credit card?" I asked her to help me find an alternative in the same drug class — and there was one for $4 per month. You can guess what I chose.

I've seen many cases where patients are given some special program, and a year into it the funding mysteriously disappears, and then they're withdrawing from something. That's why I've always thought of LDN as people's medicine. For about a dollar, most people can access it. For patients who cannot afford even a dollar, I prescribe the 50-milligram tablet and walk them through a 1:100 dilution. Fifty milligrams diluted 1:100 becomes 0.5 milligrams, or 500 micrograms. Another dilution brings it to 5 micrograms. And so on. There's not a lot of other medication I can confidently say, "Go ahead and dilute it," and then teach them how. As most of you may know, the word "doctor" comes from the Latin word docere, which means "to teach." I love that aspect of medicine.

Endorphin Deficiency Phenotype

Think of endorphin deficiency as a phenotype or syndrome — not as an ICD code. The worst way to think about it is as an ICD code, and that's where we're going wrong with the treatment of conditions like mast cell activation syndrome. Endorphin deficiency syndrome is a syndrome, and we're seeing a lot of it now.

The way you identify low endorphin tone is through clinical questions. We don't yet have easily available assays. There are proxy measures, and those proxy measures are these questions: Do you have pain amplification? Nonrestorative sleep? Stress intolerance? Low emotional resilience?

Endorphins are, of course, involved in fighting pain. The joke I've heard from my mentors is that opioid receptors were not made for pharmaceutical companies to benefit — they were made for endorphins so that we can regulate our own pain. Nonrestorative sleep and lack of endorphin have a linear relationship. I share with patients that we are like a rechargeable battery. What happens to a rechargeable battery as it ages? It cannot hold its charge. I believe that's what happens to us — we lose our biochemical charge, and then people develop nonrestorative sleep. If you're getting nonrestorative sleep, everything else is harder.

With stress intolerance and low emotional resilience, patients with low endorphin tone tell me that even one drop — one nanogram — of LDN causes tears to come. They feel like hope is evaporating right in front of them. And then about two hours later, they're better. That makes perfect sense, because the half-life of LDN is about four to six hours.

The Endorphin Depletion Loop

How do you get to endorphin deficiency? Chronic pain is one path. Not being able to sleep is another. When you have a lot of pain, your central nervous system says, "This is our new normal. You should have pain all the time." And the body says, "Yes, commander." We see this in different patterns, including what we used to call RSD — now called CRPS. That's an example of the body teaching itself to be in pain. If you're in pain all the time, of course you deplete endorphin. If you deplete endorphin, of course you develop endorphin deficiency syndrome, where poor sleep is one of the outcomes.

The clinical symptom pattern is a cluster: fatigue, pain, brain fog, poor sleep, emotional distress — I prefer that term over "fragility" — dysphoria, profound malaise, and stress intolerance. Just think of it as a syndrome. Endorphin deficiency syndrome. Ask yourself: is there a chance this person may have low endorphin tone?

LDN Dosing: The Standard Range

We know about 1.5 to 4.5 milligrams as the classic LDN range. The 50-milligram dose, of course, is for opioid or alcohol use disorder and is not typically thought of as an immunomodulator. But there are studies that examined 5, 25, and 50 milligrams of naltrexone for tinnitus — all were helpful, with 50 milligrams potentially the most helpful. The LDN range is interesting because there are two things going on: the chemistry of the drug, and the dosing pattern triggering biological responses not usually seen with the full 50-milligram dose.

Here's how it works: you take LDN at time zero. Within thirty minutes, there's a blockade lasting four to six hours. Normally, you rebound — when there's a blockade, the body's natural compensatory mechanism upregulates endogenous opioid production, sometimes by making more receptors or increasing receptor sensitivity. After blockade, you're supposed to have improved endorphin tone.

For LDN and neuroimmune modulation, there are at least two pathways: the opioid receptor pathway and the Toll-like receptor 4 pathway for microglial modulation. But this is a very partial picture. When I researched why LDN works so well for MCAS, I found that Toll-like receptor 4 is also present on mast cells. So it's not just one thing. As we get to know LDN better, we will likely find third and fourth pathways.

Does LDN Cause Endorphin Deficiency?

Some people say, "I took LDN and all my symptoms got worse. It's terrible. I'm gonna quit." The best way to think about it: the first step is endorphin blockade — that's true. Does it deplete endorphin? I'm not sure that's exactly what's going on, but blockade is true. If the body is able to overcome it, then LDN may enhance endogenous opioid function.

Think about it this way: if you get people to lift weights, they develop more strength and bigger muscles. But what happens if they have myopathy — disease of the muscle? Then that may not happen. That's an important analogy. It's the reason why some people feel worse with LDN, especially when the dosing is wrong or too high. Too low is not usually an issue, but too high is.

One of the things I love is that even at one microgram, a patient might say, "Oh my God, I'm all better." Case closed. I tell them I'll increase the dose as tolerated. Other people report vivid dreams, maybe one to two weeks of sleep difficulty, or feeling more tired — but it usually resolves within one to two weeks at a stable dose.

The canary-in-the-coal-mine patients — about one percent or less — have persistent insomnia, dysphoria, or pain flares. For these people, the easiest thing is to start right, which is what we're going to talk about. If you don't start right, stop LDN. Stop for one week or until you feel normal. Then come back with a smaller dose — a microgram dose. That's a pretty easy, practical way of managing it, and that's what I do in my practice.

The LDN Sweet Spot: Dose Makes Medicine or Poison

The idea of a sweet spot comes from Paracelsus, who said in Roman times, "The dose makes the poison." But it should also say the dose makes the medication. Depending on the dose, a substance can be medicine or poison.

Even ten or twenty years ago, I reserved microgram dosing for highly sensitive patients. Now, with MCAS — mast cell activation syndrome — becoming an epidemic in plain sight, I use one microgram more and more. In children, I also like to use one microgram, because I'm a parent. When adult patients have side effects, you can talk to them. When babies have side effects, that's more difficult. I explain to parents that we're going to take a slower, safer approach, and I've never had a parent object.

The Scoring System: Who Needs What Dose?

This is the heart of this talk. I've come up with a very simple way to determine starting dose, and I want to share it with all of you. It's also in both of my books.

There are four scoring levels based on three questions. If a patient scores zero points, I give them a choice: do you want 0.5, 1.5, or even 4.5 milligrams? These people have no issues. If they score 10 points, I offer 100 micrograms — they have some endorphin reserve intact. If they score 20 points, I offer 10 micrograms — these people have probably moderate depletion. If they score 30 points, their endorphin reserves are severely depleted, and I start them on 1 microgram.

The three questions:

Question 1: Are you sensitive to medication? If yes, 10 points. If no, 0 points.

Question 2: Are you highly functional in your life? If yes, 0 points. If no, 10 points.

Question 3: Have you been ill more than six months? If yes, 10 points. If no, 0 points.

So if someone comes in saying, "I'm sensitive to medication, I'm not very functional in my life, and I've been ill more than six months" — that's 30 points. Automatically, one microgram. With the warning: if you develop endorphin deficiency symptoms, stop the LDN and give me a call so we can discuss it.

This scoring approach was not needed pre-COVID, at least in my practice. Pre-COVID, most people tolerated 0.5 milligrams. Some may recall when everyone started at 1.5 milligrams, and I advocated for 0.5. Since then, I've gone to 0.1 milligrams, because LDN is such a wonderful and important tool that I do not want people to abandon it because we got the dose wrong and they suffered. In the LDN support groups, I see this all the time: "I'm gonna quit. I had a bad reaction. This is terrible." That's why I wrote the books — so people can evaluate for endorphin deficiency and start accordingly.

Some people say this approach takes too long. It doesn't. If you start with one microgram, you can increase as early as every three to seven days. Within a month, they'll be at four micrograms. If they tolerate it, I make a jump to ten micrograms, then twenty, thirty, forty. After that, one hundred micrograms, then milligram doses. Within about three to four months, we catch up. But I don't usually lose people because of side effects.

Clinical Examples

Example 1: A 45-year-old female with fibromyalgia for eight years. Highly medication sensitive — even half doses of most prescriptions cause side effects. Unable to work. Struggles with daily activities. Medication sensitive? Yes — 10 points. Highly functional? No — 10 points. Ill more than six months? Yes — 10 points. Total: 30 points. I would start this individual at one microgram, with instructions: if you have side effects, stop and let me know.

Example 2: A 52-year-old with Hashimoto's thyroiditis, diagnosed two years ago. Not sensitive to medication. Works full time. Exercises regularly. Medication sensitive? No — 0 points. Highly functional? Yes — 0 points. Ill more than six months? Yes — 10 points. Total: 10 points. I would start this person on 100 micrograms.

Example 3: A 38-year-old interested in LDN for immune support. No chronic illness. No medication sensitivity. Fully functional. Medication sensitive? No — 0 points. Highly functional? Yes — 0 points. Ill more than six months? No — 0 points. Total: 0 points. I would offer this person a starting dose of 1.5 to 4.5 milligrams. I'll tell them that when I took 4.5 milligrams without preparation, I stayed up all night stretching. I wanted to know what happens so my patients can avoid taking it too aggressively, and so I can recognize what it does.

Clinical Pearls

Start low. Hold and observe. Anytime it goes wrong, stop LDN until the patient feels normal, then restart at a lower dose. You will arrive at the ideal dose — the lowest dose that gets the benefit without side effects.

Match the dose to the physiology. Early reactions are feedback, not failure. Think about a sweet spot, not a ceiling. When people say 4.5 milligrams is the ceiling — it's not. There are no dosing studies that say 4.5 is the only effective dose. Some studies, like the tinnitus study, suggest that higher doses of naltrexone may have benefits for nerve pain. That's consistent with what I'm experiencing.

Document the symptom trajectory. If cases are complex or patient conditions are complex, start lower, not higher. Timing can make a difference: start by taking it with food, perhaps at dinnertime. If it makes you sleepy, go to sleep. If it causes insomnia, take it in the morning or at lunchtime.

Common Questions Addressed

What if someone is a non-responder at standard doses?

If someone has been a non-responder at 1.5, 3, and 4.5 milligrams without side effects, it is not logical to lower the dose. More likely, the answer is to go higher: 6, 9, 12, 15, even 25 milligrams. In my practice, I march through the doses. If nothing works, I'll go all the way up to 45 milligrams. Another approach for non-responders is to stop completely, allow the receptors to reset, and begin the process again.

What about starting at 6 milligrams (the Norwegian approach)?

In my practice, I look at it very carefully because the side effects of LDN are real. If you stay up all night retching, you're going to see LDN as a torture device. It's possible that some populations have better endorphin reserve, but I can't guarantee that 100% of anyone will have their endorphins intact. Starting at 6 milligrams is a shortcut — it avoids the careful titration. But what happens to people with endorphin deficiency? They're going to suffer, and they're going to quit.

I've heard patients describe it: "I felt like I was inches from death. I knew logically that wasn't true, but it just felt that way." Or, "I felt all the joy in my life just leaving." Tears. Hopelessness. Many of these patients already have very significant conditions. To let someone feel that way — I just can't do it. The tenet of medicine is: first, do no harm. I know those doses can do harm to some people, so I won't take that approach.

Even if an Olympic athlete came in wanting LDN for performance, I would still start at 4.5 milligrams. That's the practice norm. King Hammurabi said that if a doctor practices within community standard, the doctor is not responsible for a bad outcome, but if the doctor does his own thing outside community guidelines, then he is responsible. That principle is still true today.

Who needs ultra-low doses?

Ultra-low-dose candidates are medication-sensitive people with chronic fatigue, long COVID, fibromyalgia, MCAS, sleep cycle disruption, autonomic dysregulation, or low endorphin reserve linked to emotional state. These are the patients who tell me that even one nanogram more will make a difference — they stop and just start crying, then two hours later feel smooth, and at four hours are normal. That timeline uncannily approximates the half-life of LDN.

I have patients who cannot tolerate one microgram. They go to nanogram LDN. Two of them cannot tolerate nanogram, so I'm using picogram doses. To put that in perspective: a milligram is one-thousandth of a gram. A microgram is one-millionth. A nanogram is one-billionth. A picogram is one-trillionth of a gram.

If someone has side effects at 0.25 milligrams, should they reduce the dose?

No. In my practice, I tell them to stop. Just stop. If you have compromised endorphin repletion, even 0.25 milligrams or one microgram will deplete them further. They'll have all the bad side effects I described. I don't tell them to suffer through it. I tell them, "Let's work smarter." Stop, then restart at a lower dose.

How long to stop?

I tell them to try a week, but the real answer is: stop until you feel normal.

Is it possible to be fine at first, then develop side effects after a few days?

Yes. That is the textbook definition of endorphin deficiency. You start fine because you have some reserve, but after a few days the blockade has depleted what little you had.

Is it worth pushing through side effects?

It depends. If your ability to create endorphin is intact, then after a couple of days you'll be okay. In my own situation, I had endorphin deficiency but I was also able to replete after two days of unhappiness. The danger of pushing through is that patients may give up on LDN entirely — throw the baby out with the bathwater. I've seen too many people quit LDN prematurely.

Think of it this way: Is LDN sufficient to make things better by itself? About one-third of the time, yes — LDN does amazing things on its own. Another third, no matter what I do, it doesn't seem to work. But the other third, if I combine LDN with a specialty ketogenic diet, methylene blue, or ketotifen — all of a sudden it's a game changer.

Can LDN help with autoimmune diseases? Can patients come off immunosuppressants?

I think LDN alone is often enough. If it's not, I recommend a ketogenic diet or the modified paleo diet by Terry Wahls. The more important question is: have I seen patients achieve remission? Absolutely. About ten percent of patients achieve remission with LDN alone. When I combine it with ketosis, the response rate goes up to about sixty percent — excellent control, not cure.

Why are we seeing lower doses needed since COVID?

I believe whatever COVID did to us falls into three scenarios: you got COVID, you got the COVID vaccine, or you were simply exposed to COVID. Unless you lived in a bubble. COVID's initial symptoms weren't necessarily respiratory — loss of smell and diarrhea were among the earliest signs. COVID was a very different virus. It went to our digestive system, which is rich in nerves — the enteric plexus. It penetrated the central nervous system. If you put those things together, I think COVID caused immune modulation, but not in a good way. Our immune systems probably became more chaotic, which is why we're seeing much more mast cell activation syndrome. Everyone's immune system has probably been altered.

Can LDN prevent or cure cancer? Dementia?

"Cure cancer" is language that gets people in trouble. Even with chemotherapy and surgery, they don't say "cure" — they say "remission." No evidence of disease times five years equals remission. The same applies to autoimmune disease. Prevention? I believe so, and I shared my personal experience at the beginning of this talk. Dementia? Absolutely — I use LDN as a cornerstone treatment for dementia. But these are complex conditions. You can't just say, "I gave them LDN, done, go home." There are different supporting protocols.

Could fillers or solutions cause side effects?

It's possible. You should always consider additives or fillers. One of the easiest solutions is to ask the compounding pharmacy to put it in olive oil, at least in the U.S. Olive oil is pretty inert. Naltrexone is a quaternary amine, meaning it's hydrophobic and lipophilic. Putting it in water isn't really practical because it lasts maybe two weeks — water is a harsh environment for naltrexone. Its lipophilic nature is actually why it's so wonderful for treating the nervous system, because the nervous system is lipid-based.

Why do some people need higher doses, like 10 milligrams?

Because we are unique. We are not produced in a factory where everyone is made the same way. Different people respond differently to different things. For nerve pain after my surgery, I was taking 6 milligrams of LDN four times a day to get the post-surgical nerve pain under control. They were going to give me gabapentin, which can be helpful for some people, but I just don't like taking medications if I don't have to. That's why I practice the medicine I practice.

LDN for long COVID?

When COVID-19 first appeared, the theory was that cytokine storms were killing people, and steroids were the only thing that really worked early on — before we had antibodies, medications, or vaccines. The patients who were in my active care and my family members were all instructed to use LDN aggressively plus wear KF94 masks. I don't think one person in my active care developed COVID. In my practice, LDN is always the starting point for long COVID. Then there are other things like methylene blue that I may add for mitochondrial support.

LDN for small fiber neuropathy?

Small fiber neuropathy induced by long COVID is something I see a lot. There are trials underway. A 2024 trial looked at biopsy-proven small fiber neuropathy, started patients on 4.5 milligrams, and found that all five symptom domains improved. Another 2024 study found it worked about 25 percent of the time. My question is: how expensive is LDN? What great harm does it do? If there's not great harm and it's not going to break the bank — and there are no other treatments for small fiber neuropathy that work really well — it's worth considering.

What about vivid dreams on LDN?

Leave them alone unless you're getting night terrors or nightmares. Vivid dreams often indicate good REM sleep, which is necessary for recovery. That's actually one of the things LDN was designed to do. Before COVID, LDN used to be my go-to agent for sleep. Now it's too unpredictable — some people develop insomnia.

What about methylene blue?

I think of methylene blue at three levels. The lowest dose supports mitochondria. The middle dose supports the serotonin system and the immune system. The highest dose is antimicrobial. For anyone interested, I have a very active blog called IFM Synergy — ifmsynergy.com — with about 180 articles published on many topics, most about LDN, and also on MCAS and methylene blue.

Conclusion

To summarize: match the dose to the patient's physiology. Use the three-question scoring system to determine starting dose. Start low when in doubt. Early reactions are feedback, not failure. Think sweet spot, not ceiling. When things are complicated, that's when you need a clinician who is willing to learn and willing to listen.

LDN is people's medicine. For about a dollar, you can access a tool that can be life-changing. I don't want anyone to miss that opportunity because we got the dose wrong.

If you'd like to see me, you have to live in one of the states where I'm licensed: Iowa, Illinois, Missouri, Georgia, Florida, or Texas. You can find me at yoonhangkim.com. For clients outside the U.S., educational consultations are actually easier — I provide education, create a work product, and patients can take that to their own doctor for discussion. I can even speak with their doctor directly.

Everything I write in LDN Primer is also available for free on my blog at ifmsynergy.com. Both books — LDN Primer and LDN for Clinicians, Researchers, and Empowered Patients — are available on Amazon.

Thank you for your time, and thank you to the LDN Research Trust for the opportunity to share this with you.