When Theory Meets the Complexity of Human Physiology

Yoon Hang Kim, MD, MPH

One of the things I love about medicine is how often our patients humble us. We think we understand how a drug works, we have a beautiful mechanistic explanation—and then the body does something unexpected.

Low-dose naltrexone and gut motility is a perfect example.

The Theory: LDN Should Speed Things Up

Let me walk you through why, on paper, LDN should be a prokinetic agent—meaning it should treat constipation, not cause it.

Your gut has what’s called “tonic opioid restraint.” Essentially, your natural endorphins are constantly putting a gentle brake on intestinal motility. It’s like your foot resting lightly on the brake pedal while driving—you’re still moving, but not at full speed.

When you take an opioid medication (morphine, oxycodone, etc.), you’re slamming that brake pedal to the floor. The drug binds to mu-opioid receptors in your enteric nervous system, inhibits acetylcholine release, and peristalsis grinds to a halt. This is why opioid-induced constipation is such a common and miserable problem.

Now here’s where it gets interesting: opioid antagonists—drugs that block opioid receptors—do the opposite. They release that tonic restraint. The brake pedal lifts. Peristalsis increases. Transit time shortens.

This is exactly how PAMORAs (peripherally acting mu-opioid receptor antagonists) like methylnaltrexone work. They block opioid receptors in the gut and get things moving.

So theoretically, LDN—which is also an opioid antagonist—should have a similar prokinetic effect.

The Evidence: LDN Actually Does Help Constipation

And in fact, the clinical data supports this.

Dr. Leonard Weinstock, a gastroenterologist who has published extensively on LDN, conducted a study looking at LDN in various GI disorders. Among 12 patients with chronic idiopathic constipation treated with LDN 2.5mg twice daily, 7 were markedly improved, and none got worse.

Dr. Weinstock has described using LDN specifically as a prokinetic agent. In one interview, he mentioned treating a patient with constipation and restless leg syndrome who had “a dramatic response” to LDN.

The mechanism makes sense. By transiently blocking opioid receptors in the gut, LDN releases that tonic restraint on the migrating motor complex (MMC)—the “housekeeper wave” that sweeps through your intestines between meals. A more active MMC means better motility.

This is why some SIBO (small intestinal bacterial overgrowth) protocols include LDN as a prokinetic alongside or instead of erythromycin.

The Paradox: Some Patients Get Constipated

Here’s where it gets humbling.

Despite the clear theoretical rationale for LDN being prokinetic, I occasionally see patients who develop constipation on LDN. And I’m not alone—other clinicians report the same thing, though they describe it as “few and far between.”

How do we explain this? I have a few working hypotheses:

Hypothesis 1: The Endorphin Rebound Effect

LDN’s therapeutic magic lies in its transient blockade. You take it at bedtime, it blocks opioid receptors for 4-6 hours, and then your body rebounds by upregulating endorphin production—sometimes dramatically. In most patients, the net effect still favors improved motility. But in some patients—perhaps those with particularly robust endorphin reserves or unusually sensitive gut receptors—the rebound effect might tip the balance toward constipation.

Hypothesis 2: Individual Variation in Receptor Distribution

We know that opioid receptor density varies between individuals. Some people may have a higher concentration of mu-receptors in their enteric nervous system relative to their central nervous system. For these patients, the gut effects of the endorphin rebound might be more pronounced.

Hypothesis 3: Dose-Dependent Effects

LDN operates in a narrow therapeutic window where the blockade is brief enough to trigger rebound but not so prolonged that it acts like full-dose naltrexone. Individual metabolic variation means the same dose can produce different durations of receptor occupancy. In slow metabolizers, even “low dose” naltrexone might act more like standard naltrexone.

Hypothesis 4: It’s Not the LDN

Sometimes what looks like an LDN side effect is actually something else. When a patient with complex chronic illness starts a new medication and develops constipation, we need to consider: thyroid function, magnesium status, changes in activity level, other medications, diet changes, or progression of their underlying condition. The LDN may be a red herring.

What This Teaches Us

This is what I love about medicine when it’s practiced honestly: we hold our theories loosely.

The pharmacology clearly predicts LDN should be prokinetic. The clinical data largely supports this. But the human body is not a simple input-output machine. It’s a complex adaptive system with feedback loops, individual variation, and emergent properties we don’t fully understand.

When I see a patient who gets constipated on LDN, I don’t dismiss them because “that’s not how the drug works.” I take their experience seriously. Maybe I lower the dose. Maybe I add magnesium. Maybe I look for other causes. Maybe I acknowledge that their physiology is doing something our models don’t predict.

This is individualized medicine. Not because it sounds nice, but because it’s the only approach that actually works.

Practical Takeaways

If you’re considering LDN for a motility issue:

1. The evidence supports its use for constipation, particularly in the context of SIBO or when used alongside other prokinetics.

2. Start low and titrate slowly. This allows you to find the dose that optimizes the prokinetic effect without triggering paradoxical responses.

3. Monitor your response. If you develop constipation, don’t assume it’s “just a side effect you have to live with.” It may mean the dose needs adjustment or something else is going on.

4. Work with an experienced clinician. LDN dosing is more art than science, and having someone who understands the nuances can make the difference between success and failure.

5. Remember that your response is valid. If your body does something unexpected, that’s information—not a failure.

The Bigger Picture

I’ve been prescribing LDN for over two decades, and cases like this remind me why I still find this work fascinating. Every patient teaches me something. Every paradox deepens my understanding.

The body is wiser than our theories. Our job is to listen.

Dr. Yoon Hang Kim is a board-certified preventive medicine physician specializing in integrative medicine and LDN therapy. He has presented at multiple LDN Research Trust conferences and practices telemedicine through Direct Integrative Care, serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

www.directintegrativecare.com