Does Naltrexone Cause Diarrhea? And How to Manage It

Diarrhea is one of the more common gastrointestinal side effects of naltrexone, reported by roughly a quarter to a third of people taking it depending on the formulation and dose. In one head-to-head trial, 30% of participants on oral naltrexone experienced diarrhea, alongside fatigue and appetite changes as equally frequent complaints.¹ The good news is that for many people the effect is temporary, and the mechanism behind it points toward straightforward management strategies.

How Often It Happens

Pinning down a single number for diarrhea incidence on naltrexone is tricky because studies use different doses, formulations, and patient populations. In a randomized trial comparing oral naltrexone to an extended-release injectable form for opioid use disorder, diarrhea affected 30% of the oral group and 25% of the injectable group.¹ In surveys of patients taking low-dose naltrexone for gastrointestinal conditions, about 61% reported some kind of side effect, with gastrointestinal complaints making up a sizable chunk. A third of those who had side effects described them as short-lived, resolving on their own within the first few weeks.²

Diarrhea tends to be more common in the early days and weeks after starting the drug. For many people, the gut adjusts. But not for everyone: in that same low-dose naltrexone survey, about 27% of patients who experienced side effects ultimately discontinued the medication because of them.² That said, diarrhea is only one of the GI complaints people report. Nausea, cramping, and appetite changes all show up too. A large pharmacovigilance analysis of alcohol-use-disorder medications found that oral naltrexone was associated with roughly four times the expected rate of nausea reports and about twice the expected rate of vomiting reports compared to other drugs in the safety database.³ So if you are experiencing GI trouble on naltrexone, diarrhea may be part of a broader picture rather than the sole issue.

Why Naltrexone Upsets the Gut

Naltrexone works by blocking opioid receptors, which most people associate with the brain. But opioid receptors are scattered throughout the digestive tract too, particularly a type called mu-opioid receptors. These receptors play a significant role in regulating how quickly food moves through your intestines. When opioids activate those receptors, everything slows down, which is why constipation is one of the most predictable side effects of opioid painkillers. Naltrexone does the opposite: by blocking those same receptors in the gut wall, it removes the braking mechanism. Intestinal transit speeds up, and water is not reabsorbed as efficiently, which produces looser and more frequent stools.

Research on peripherally active opioid receptor antagonists, a class that includes naltrexone’s cousin methylnaltrexone, confirms that blocking mu-opioid receptors in the gut doesn’t just affect motility. These drugs also influence intestinal permeability, the tightness of the junctions between cells lining the gut wall.⁴ When those junctions become more permeable, fluid can leak into the intestinal lumen more freely, contributing to diarrhea. This dual effect on motility and permeability helps explain why GI symptoms from naltrexone can feel more disruptive than a simple case of loose stools.

The key insight is that naltrexone’s GI side effects are not a sign of toxicity or allergic reaction. They are a predictable pharmacological consequence of blocking opioid receptors that happen to live in the gut as well as the brain. Your gut was using those receptors to regulate transit, and naltrexone temporarily renegotiates that arrangement.

Oral Versus Injectable Naltrexone

Naltrexone comes in two main delivery forms: a daily oral tablet (typically 50 mg for addiction treatment) and a monthly extended-release injectable (marketed as Vivitrol). You might assume the injectable version, which bypasses the stomach entirely, would spare you the GI trouble. The reality is more nuanced.

In the randomized trial mentioned earlier, diarrhea rates were slightly lower with the injection (25%) than with oral naltrexone (30%), but both groups still reported it as one of their most common adverse events.¹ This makes pharmacological sense: once naltrexone enters the bloodstream, it reaches opioid receptors in the gut wall regardless of how it got into the blood. The oral form may produce a sharper initial wave of GI symptoms because the drug passes directly through the stomach and intestines before absorption, giving it an early chance to interact with local receptors on the way through. The injection avoids that first-pass contact with the GI lining but still delivers systemic drug that reaches the gut via the bloodstream.

Where the formulations differ more starkly is in nausea and vomiting. The pharmacovigilance analysis found that oral naltrexone carried about twice the reporting odds for vomiting compared to injectable naltrexone, whose vomiting rate was statistically no different from baseline.³ So if your main complaint is nausea or vomiting rather than diarrhea, switching to the injectable form may provide meaningful relief. For diarrhea specifically, the benefit of switching is more modest.

Low-Dose Naltrexone Is a Different Story

Low-dose naltrexone, or LDN, typically uses doses between 1.5 mg and 4.5 mg, a fraction of the standard 50 mg tablet. It has become popular in off-label use for conditions like fibromyalgia, Crohn’s disease, and irritable bowel syndrome. Because the dose is so much lower, you might expect the GI side effect profile to be gentler, and it is, but not absent.

In a survey of patients taking LDN for gastrointestinal disorders, about 61% still reported some side effect. Neurological complaints like vivid dreams and sleep disturbance were actually more common than GI symptoms at these low doses, though 32 out of 121 patients did report one or more gastrointestinal side effects.² That is a lower proportion than what you see at full doses, which makes intuitive sense: fewer receptors are being blocked at any given moment. But the fact that GI effects still show up at 4.5 mg underscores how sensitive the gut’s opioid system is to even small perturbations.

Paradoxically, LDN is being studied as a treatment for inflammatory bowel diseases. In a randomized placebo-controlled trial of low-dose naltrexone in active Crohn’s disease, 88% of participants on naltrexone had a clinically meaningful improvement in disease activity compared to 40% on placebo, and a third of the naltrexone group achieved endoscopic remission.⁵ Fatigue was the only side effect reported at higher rates in the placebo group than the naltrexone group; the drug did not seem to worsen GI symptoms in these Crohn’s patients. Animal research has echoed these findings, showing that low-dose naltrexone improved markers of intestinal inflammation in a rat model of Crohn’s disease.⁶

The likely explanation is that at very low doses, naltrexone briefly blocks opioid receptors and then clears, triggering a rebound upregulation of the body’s own endorphin system. That rebound may dampen inflammation through pathways that are distinct from the motility effects seen at higher doses. So while full-dose naltrexone can cause diarrhea by speeding up the gut, low-dose naltrexone may actually calm an inflamed gut in people with autoimmune bowel conditions. Whether someone experiences diarrhea or improvement depends heavily on the dose and the underlying condition.

Your Genes Might Determine How Bad It Gets

Not everyone on the same dose of naltrexone has the same experience with diarrhea, and researchers are beginning to understand why. A study in people being treated for alcohol use disorder found that genetic variations in the OPRM1 gene, which encodes the mu-opioid receptor, seemed to interact with genes involved in dopamine signaling to predict who would develop GI side effects. In other words, the specific version of the opioid receptor you carry, combined with how your dopamine system is wired, appears to influence whether naltrexone gives you significant gut trouble.⁷

This research is still in its early stages, and no one is running a genetic panel before prescribing naltrexone in routine practice. But the finding is noteworthy because some of the genotype combinations that predicted stronger GI effects also predicted better therapeutic response to naltrexone for reducing drinking.⁷ That is frustrating for patients: the same biological wiring that makes naltrexone more effective at reducing cravings may also make diarrhea more likely. It suggests that GI sensitivity to the drug is not random bad luck but a sign that the medication is actively engaging the opioid system, gut receptors included.

Practical Ways to Manage It

If you are dealing with naltrexone-related diarrhea, there are several approaches worth discussing with your prescriber before deciding to stop the medication.

Give it time: A meaningful fraction of GI side effects resolve on their own within the first few weeks. In the low-dose naltrexone survey, about a third of patients with side effects described them as short-lived.² If you can ride out the initial adjustment period, the diarrhea may settle without intervention.
Take it with food: Eating a meal before or alongside your dose can slow the rate at which naltrexone hits your GI tract, reducing the peak local concentration in the intestines. This is standard guidance for most medications that cause nausea or diarrhea.
Start low and titrate up: If your prescriber is open to it, beginning at a lower dose and gradually increasing over a week or two gives the gut time to adjust. This is especially relevant for full-dose oral naltrexone, where the jump from nothing to 50 mg can be jarring.
Consider the injectable form: As noted, the injection does not eliminate diarrhea, but it avoids the direct first-pass GI exposure and may reduce nausea and vomiting specifically.
Stay hydrated: Diarrhea pulls water and electrolytes out of your body. Oral rehydration solutions or simply drinking more water and consuming foods with potassium and sodium can prevent the secondary problem of dehydration from compounding the discomfort.

One question patients sometimes have is whether taking an over-the-counter anti-diarrheal like loperamide (Imodium) would undercut naltrexone’s therapeutic effect. Loperamide is itself an opioid agonist, but it is “peripherally restricted,” meaning it activates opioid receptors in the gut without crossing into the brain in meaningful amounts. A rat study exploring this interaction found that loperamide given alongside oral naltrexone did not alter naltrexone blood concentrations.⁸ In fact, loperamide appeared to enhance naltrexone’s therapeutic effect in that study, possibly by reducing the local GI interaction that limits oral naltrexone’s absorption. This is animal data and should not be treated as clinical guidance without talking to your doctor, but it does suggest that loperamide and naltrexone are not necessarily working against each other. Your prescriber can help you weigh whether occasional loperamide use is appropriate in your specific situation.

Naltrexone and the Gut Microbiome

Opioids are known to reshape the bacterial communities living in the intestines, which feeds into a cycle of inflammation and barrier dysfunction. Research in mice has demonstrated that morphine causes a significant shift in gut microbial composition, with a notable expansion of certain bacterial groups that can promote inflammation. When researchers co-administered naltrexone alongside morphine, the animals’ microbiome reverted to a pattern resembling the placebo group, suggesting that blocking opioid receptors can prevent opioid-driven microbial disruption.⁹

This finding is relevant in two ways. First, for people taking naltrexone as part of recovery from opioid use, the drug may actually be helping to restore healthier gut bacteria that opioids disrupted. Second, it raises the question of whether naltrexone on its own, in people who are not opioid users, might independently alter the microbiome. The evidence here is thinner. A study of people in addiction treatment found no significant differences in gut microbial diversity between those taking opioid antagonists and those not taking any opioid-related medication. This suggests that naltrexone alone, in the absence of opioids, does not dramatically reshape the microbiome in the way that opioids themselves do.

For the average person starting naltrexone for alcohol use disorder, the microbiome angle is probably not the main driver of their diarrhea. The direct pharmacological effect on gut motility and permeability is a more immediate explanation. But if you are transitioning from chronic opioid use to naltrexone, your gut bacteria are going through their own adjustment, which could amplify GI symptoms during the transition period.

When Diarrhea on Naltrexone Needs Medical Attention

Most naltrexone-related diarrhea is uncomfortable but not dangerous. It is a known pharmacological effect, and for many people it diminishes over time. There are situations, however, where you should contact your prescriber rather than toughing it out.

If diarrhea is severe enough to cause signs of dehydration, such as dizziness, dark urine, or a rapid heartbeat, that is a reason to seek help promptly. If you notice blood in your stool, that is not a typical naltrexone side effect and warrants evaluation for other causes. Persistent diarrhea lasting more than a few weeks without any sign of improvement may indicate that your body is not adjusting, and a dose change or formulation switch might be warranted. And if you are taking naltrexone alongside other medications that can also cause GI effects, the combined burden may need to be reassessed.

It is also worth keeping in mind that not all diarrhea that starts after beginning naltrexone is caused by naltrexone. Dietary changes, stress, infections, and underlying GI conditions can all coincide with a new medication start. If your symptoms do not match the typical pattern of early-onset, self-limiting diarrhea that gradually improves, your doctor may want to investigate other explanations before attributing everything to the drug.

Comparing Naltrexone to Other Medications in Its Class

If you are being treated for alcohol use disorder, naltrexone is not your only pharmacological option, and the GI side effect profiles of the alternatives differ in interesting ways. The same pharmacovigilance analysis that flagged naltrexone’s nausea signal found that acamprosate, another commonly prescribed medication for alcohol use disorder, carried about four times the expected rate of diarrhea reports, while its nausea rate was actually lower than average.³ Disulfiram, the third major option, showed elevated rates of abdominal pain but no significant signal for diarrhea or nausea.

So the GI trade-offs look roughly like this: naltrexone leans toward nausea and vomiting with moderate diarrhea risk, acamprosate leans heavily toward diarrhea with less nausea, and disulfiram primarily causes stomach pain. None of these medications are free of GI effects, but knowing the different profiles can help you and your prescriber choose the best fit for your body. Someone already prone to loose stools might tolerate naltrexone’s GI profile better than acamprosate’s, while someone who struggles with nausea might find the opposite.

These comparisons reinforce an important point: GI side effects from medications that act on the nervous system are not unusual or alarming. They reflect the basic reality that the gut has its own extensive network of receptors for the same neurotransmitters targeted by these drugs. Your intestines are not passive plumbing; they are an active participant in the pharmacology of almost any centrally acting medication, and diarrhea is one of the more common ways they register the change.