The serendipitous discovery of low-dose naltrexone (LDN) spurred a revolution in the background of medicine. Although still an experimental and unapproved approach, scientists are researching if LDN can help people with autoimmune diseases, chronic pain, inflammation, and fatigue. Read on for more about its potential uses.

Disclaimer: LDN is not FDA-approved for pain or any other indication. It is still a highly experimental approach. The aim of this post is to outline scientific research for informational purposes only. If you are interested in LDN, it is important to talk to your healthcare provider about its possible effectiveness, side effects, and risks.

What is Naltrexone?

Naltrexone is a drug that blocks the activity of opioids in the brain. Your body normally produces endorphins and enkephalins, natural opioids that contribute to feel-good sensations. In fact, these chemicals are the body’s most powerful reward and pleasure system [1, 2].

The opioid blocker naltrexone was synthesized in the 60s and approved in the 80s for treating opioid addiction [1].

Doctors gave naltrexone to opioid addicts in recovery to prevent relapse. The rationale was to completely shut off the ‘high’ of abused narcotics. By blocking all receptors in advance, naltrexone renders narcotics powerless.

Opioid drugs are strong painkillers that can cause addiction if abused. Naltrexone was used to block their effects and treat addiction in the past.

Note: Naltrexone shouldn’t be confused with naloxone (Narcan), although both drugs are opioid blockers. You may have heard about naloxone kits (spray or injection) that can save lives in opioid overdose. Naloxone is a better choice for reversing overdose because it starts to act faster and lasts for a shorter time, as is desirable in emergency situations. Naltrexone, on the other hand, takes a couple of hours just to kick in [3, 4].

Snapshot

Proponents

Used off-label for autoimmune diseases, chronic pain, and inflammation

Claimed to increase natural opioids and balance the immune system

Limited studies suggest side effects are mostly rare and mild

Likely few drug interactions

Skeptics

Large-scale studies lacking

Not enough data to rate effectiveness

Unapproved, unofficial use (off-label)

Dosing usually has to be adjusted to each individual

Use largely relies on clinical expertise

Long-term safety unknown

Potential Uses of Low-Dose Naltrexone

Insufficient Evidence for

The following purported benefits are only supported by limited, low-quality clinical studies.

There is insufficient evidence to support the use of LDN for any of the below listed uses. LDN should never be used as a replacement for approved medical therapies.

1) Autoimmune Conditions

Anecdotes

According to Dr. Bihari, LDN might support a healthy immune response by rebalancing T-helper cells, the so-called “master cells” of the immune system. People with autoimmune issues tend to have impaired T-helper cell function [5].

A specific subtype of these T-helper cells are Tregs (5% – 10%), which are thought to be responsible for suppressing harmful Th1, Th2, and Th17 overactivation. Scientists think they prevent the immune system from going into an autoimmune overdrive and attacking itself [6, 7].

The whole hypothetical basis for these potential effects stems from Dr. Bihar’s claims about LDN boosting endorphins. Higher endorphins are thought to subsequently rearranging of cells in the immune system. This mechanism hasn’t been proven [5].

Although Dr. Bihari claimed that LDN can help people with a range of autoimmune diseases (including lupus, rheumatoid arthritis, eczema, and psoriasis), clinical studies have yet to verify his claims.

Scientists are also investigating whether LDN blocks the activation of microglia, a type of immune cell in the brain and nervous system. Microglia normally stay in a resting state and are woken up only by brain damage or infection [1].

Their activation is considered to underlie common symptoms in autoimmune and other diseases (see “sickness behavior”): fatigue, fever, inflammation, and pain [8].

Conditions that have been at least partially researched are listed below.

Some doctors claim that LDN may also help with other diseases with an autoimmune component, such as Hashimoto’s. Anecdotally, it improves thyroid health, lowers antibodies and the need for additional drugs. Research is completely lacking to support these uses, though.

LDN is hypothesized to affect autoimmune disorders by boosting endorphins and rebalancing the immune system via T-helper cells. Clinical trials are yet to confirm this.

Multiple Sclerosis (MS) Studies

The evidence to support LDN use in MS is conflicting. Future trials are yet to determine its safety and effectiveness.

In one study of 96 people with MS, 8 weeks of LDN (4.5 mg/day) did not provide more relief than placebo [9].

In contrast, LDN improved mental health and quality of life in another pilot study of 60 people with MS, using a similar protocol [10].

One study tracked 4 women with MS prescribed LDN, suggesting that it might be safe under medical supervision. Women who took LDN didn’t report any side effects and their symptoms stabilized or improved, as did their quality of life and fatigue. We can’t, however, draw any conclusions from a report on four people [11].

Evidence on LDN in MS patients is mixed. Larger trials should investigate this further.

Rheumatoid Arthritis & Fibromyalgia Research

As with MS, there’s insufficient evidence to rate LDN for rheumatoid arthritis and fibromyalgia. Only a couple of small studies have been carried out, while proper clinical trials are lacking.

In a low-quality study of 10 people with rheumatoid arthritis, LDN reduced joint pain and swelling. A few weeks after they stopped taking LDN, most experienced periods of severe stress and disease worsening [8].

Fibromyalgia is not technically classified as an autoimmune disease, although it triggers many of the same symptoms. Initial LDN research seems to offer some hope for people suffering from this otherwise hard-to-treat disease, but it’s too early to say whether it works [12, 13].

A group at Stanford University found that LDN (4.5 mg/day) reduces pain, fatigue, inflammation, and stress in people with fibromyalgia while boosting mood. LDN was safe and well-tolerated [14].

Another small clinical trial uncovered that people with fibromyalgia have lower endorphins or a “low opioid tone.” LDN reversed their low levels, thereby improving pain tolerance. Interestingly, it also enhanced the patients’ ability to relate interpersonally and engage in relationships [15].

On the one hand, this hints at the potentially profound physical and emotional effect of endorphins.

On the other hand, these findings indicate that scientists are still just scratching the surface. Much more research on the impact of LDN on people with fibromyalgia and autoimmune diseases is needed.

LDN is being researched for boosting opioids and relieving pain, fatigue, and stress in people with fibromyalgia, but the data are inconclusive.

2) Pain and Inflammation

There is not enough evidence about the use of LDN for chronic pain conditions. However, some doctors prescribe LDN off-label for this indication. Proper clinical research is needed to support this experimental practice.

CRPS

Complex regional pain syndrome (CRPS) is a form of chronic pain that can be excruciating. Limited research suggests that it is worsened by SIBO, obstructive sleep apnea, and microglial activation in the brain [16].

By keeping the microglia in a resting state and increasing endorphins, low-dose naltrexone is hypothesized to reduce the pain and inflammation in CRPS. Yet, no clinical trials back up this use [16].

A lot of people with CRPS experience a movement disorder called dystonia, which causes painful muscle contractions. In a report, LDN lowered pain and dystonia in two people with CRPS. The authors claimed that it worked by silencing microglia that trigger inflammation and pain [17].

However, we can’t know if LDN affects CRPS symptoms based on this case report. Its safety and effectiveness need to be explored in proper human studies.

Some researchers are also investigating whether LDN can also enhance the pain-relieving effects of acupuncture, which people with CRPS might benefit from [18].

In animals and cells, LDN increases the number of receptors for opioids and cannabinoids, which might theoretically boost the response to these natural painkillers. Combined, LDN and acupuncture are hypothesized to achieve greater synergy, but clinical trials haven’t tested this yet [18].

LDN has yet to be clinically researched in people with complex regional pain syndrome (CRPS). It’s hypothesized to silencing microglia and boosting internal cannabinoids.

Other Types of Pain

Another group of researchers think that LDN may enhance the effects of cannabinoids and opioids on pain. In 10 people, ultra-low-dose naltrexone enhanced the painkilling effect of an opioid drug, buprenorphine. They concluded that such an effect is not surprising since LDN appears to increase natural opioids. However, their findings haven’t been replicated [19].

In addition, LDN reduced tolerance to morphine in another study in mice. Thus, clinical trials should examine if it can help people with severe pain stay on lower morphine dose over a longer period of time [20].

Seizures

The effects of LDN on seizures are unknown. Human data are lacking.

In mice, LDN increased the anti-seizure effects of opioids and cannabinoids. These findings suggest that future studies might focus on people with epilepsy, especially those who use medical cannabis [21].

The anti-seizure potential of LDN is being researched in animals, but we don’t know how it affects people with epilepsy.

Nerve Inflammation

Transverse myelitis is an inflammation of the spinal cord that can severely damage nerve insulation, myelin. It also causes nerve pain that rarely responds to any medication [22].

In one case report, a person with this condition experienced pain relief with LDN (3 – 4.5mg/day). The authors hypothesized that it might reverse microglial activation and boost endorphins, which would reduce nerve inflammation and pain. However, it’s impossible to know if LDN has any effect on this condition based on a single case. Both animal and human studies are needed [22].

Inflammatory Gut Disorders (IBS and IBD)

Despite some promising small studies, there’s not enough data to determine whether LDN helps people with IBS or IBD.

Irritable Bowel Syndrome (IBS) is claimed to have many hidden causes, but stress, inflammation, and autoimmunity are often said to be a large part of it.

In one study of 42 people with IBS, ultra-low doses of naltrexone (0.5 mg/day) reduced pain and provided overall symptom relief in 76% of the cases after 4 weeks. LDN was deemed to be safe and side effects were not reported [23].

Similarly, a couple of small studies have suggested that low-dose naltrexone may help relieve symptoms of Irritable Bowel Disease (IBD), which encompasses Crohn’s and ulcerative colitis [24].

In a study of 14 children with Crohn’s, LDN caused remission in one-fourth of the cases, while two-thirds improved. An 8-week course of treatment also improved their overall and social quality of life. Future studies are needed to verify these findings [25].

In 40 patients with drug-resistant ulcerative colitis, 30% responded to LDN treatment and 20% experienced long-lasting improvements. Many of the long-term responders went into remission while 3 people relapsed. Larger, better-designed studies are needed [24].

LDN is still an experimental approach for IBD and IBS, despite some early promising research.

3) Fatigue & Nerve Disorders

Aside from sporadic clinical anecdotes, only a couple of small studies looked at the effects of LDN on fatigue and nerve disorders. More research is needed to determine its safety and effectiveness.

Anecdotally, low-dose naltrexone is said to reduce fatigue and overall symptoms in people with Parkinson’s disease. In one small study of 8 people with Parkinson’s, LDN improved fatigue over 8 months without reported side effects [26].

Other clinical anecdotes mention that LDN may help people with incurable degenerative illnesses such as ALS (Lou Gehrig’s Disease) and PLS. These diseases may have an autoimmune component, so certain doctors believe that LDN may protect the brain from further damage by increasing natural endorphins. Yet, scientific data are lacking.

Reports from 15 ALS patients who used LDN are mixed [27]:

About half didn’t experience any effect or were unsure

One-third reported moderate efficacy

One-fifth reported slight efficacy

“Efficacy” included improvements in balance and speech, more energy and less phlegm, and easier breathing. However, these reports were subjective, un-blinded, and had many other limitations [27].

It’s unknown whether LDN can help with chronic fatigue and progressive nerve disorders. The available research produced mixed findings.

4) Autism

At first, naltrexone was researched in regular, high doses, in an attempt to see if it can improve symptoms of autism in children. The research rationale was that the opioid system and endorphins have profound effects on social interactions, which are impaired in autism.

For example, one such study used about 15 mg/day for a 66-lbs child – way above the “low-dose” benchmark [28, 29].

These early studies did report increased endorphins and improved symptoms in autistic children who received naltrexone. The doses ranged from 5 to 50 mg/day, used every other day.

A couple of researchers then suggested that some children with low doses may respond better to low doses, though even these studies had several flaws and inconclusive findings [28, 29].

All in all, 90% of the published studies were done with high doses.

Nonetheless, some doctors prescribe low-dose naltrexone to children with autism. They claim that only low doses have the potential to boost stress resilience, social bonding, emotional well-being, mood, and immunity.

Dr. Jaquelyn McCandless, an LDN advocate, reported positive effects of LDN formulated as a transdermal cream in children with autism after 8 weeks. Each patch contained 3mg of naltrexone and was given between 9 and 12 pm.

She also included a couple of adults with Crohn’s Disease and one with Chronic Fatigue Syndrome to test the 4.5mg patch. According to her, “everyone responded positively.”

However, Dr. McCandless did not conduct a proper clinical study. Rather, this was a mere clinical observation, which had a high potential for bias. A placebo effect was also likely. We need proper clinical trials to know whether LDN can help some people with autism.

Some physicians claim that LDN helps with autism and prescribe it off-label, but there’s no solid evidence to back this up.

5) Stress & PTSD

The effects of LDN on stress and PTSD are being researched, but no clinical research is yet available to back up its use.

Even doctors who prescribe LDN based on experience say that it should always be part of an integrated psychotherapeutic approach for complex mental health issues.

Some researchers believe that, by raising natural opioid activity, LDN may increase resilience to stress and fine-tune some emotional imbalances. Its immune-balancing effects are also described as having a potentially positive impact on mood [30].

In one study, LDN (2 – 6 mg/day) helped 11 out of 15 people with severe, trauma-related dissociative disorders and post-traumatic stress disorder (PTSD). They reported a clearer perception of both their own body, their inner life, and their surroundings. These findings have not been replicated and no other trials have been carried out [31].

LDN is hypothesized to improve emotional and mental perception of reality, which is key for overcoming trauma and PTSD. Yet, proper clinical trials are lacking.

6) Addictions & Withdrawal

High-dose naltrexone (and naloxone) is still a conventional treatment for opioid use disorders. On the other hand, LDN remains experimental and controversial. There’s not enough evidence to determine whether it works.

Some scientists think it may help people with addictions by boosting natural opioids and reducing the need for stronger external triggers such as drugs, alcohol, or cigarettes. This theory hasn’t been verified.

Opioids

In a study that tracked 10,000 people, LDN improved pain tolerance and interpersonal interactions in post-detox patients [15].

In 127 people undergoing a 6-day methadone taper, very-low-dose naltrexone (0.125 – 0.25 mg/day) with another drug (clonidine) reduced the intensity and stress of withdrawal. It lowered cravings, anxiety, restlessness, bone and muscle aches, and sweating [32].

Alcohol and Cigarettes

In one study with 130 heavy-drinking smokers, the combination of medium-dose naltrexone (25 mg/day) and the smoking-cessation drug varenicline reduced cigarette and alcohol cravings, as well as the intensity of the “high” from both substances [33].

The naltrexone dose was relatively high: 5-fold the dose that Dr. Bihari and other clinical studies of LDN used. Scientists consider that this initially higher dose may help stop smoking and drinking to start with, after which the dose can be lowered to boost natural opioid activity. More research is needed [33].

Cocaine

The effects of LDN on cocaine addiction in humans are unknown. In rats, LDN with a dopamine-blocking drug (L-tetrahydropalmatine) prevented cocaine abuse relapse. It reduced drug-seeking behavior and increased endorphins without causing fatigue and sedation. Human trials are required [34].

Limited evidence points at the potential of LDN for helping people overcome drug, cigarette, and alcohol addiction, but more research is needed.

Possibly Ineffective for

LDN for HIV/AIDS is highly controversial. The only data about its use comes from Dr. Bihari’s opinions. His claims rely only on clinical experience, and no studies have confirmed them. Thus, LDN is considered an unproven approach to HIV/AIDS management.

The whole concept of low-dose naltrexone started with HIV/AIDS patients, when Dr. Bihari formulated his theory that it enhances a compromised immune system. He claimed to have administered LDN to hundreds of HIV/AIDS patients, some of which allegedly no longer had detectable levels of the virus [35].

Having in mind that naltrexone is a very affordable drug and that millions of people suffer from HIV/AIDS in the developing world, clinical trials are warranted. In fact, one study mentions that LDN has been approved in Nigeria as an AIDS treatment [36].

Dr. Bihari considered that low naltrexone doses may also help people with other types of chronic infections, such as tuberculosis, Lyme, genital herpes, and even Hepatitis C. According to him, the same rationale follows: “LDN boosts immunity and the ability to fight off infections.” Yet LDN has not been researched at all in people with these types of chronic infections.

Dr. Bihari proclaimed LDN effective against HIV and other infections, but no clinical trials to support his claims.

Cancer

LDN does not treat cancer. It was never properly researched in cancer patients and should not be recommended due to a lack of data.

Nonetheless, LDN has been popularly proposed as beneficial for various cancers–the list is almost endless and covering bladder, breast, colorectal cancer, brain, liver cancer, lung, blood and bone marrow, skin, cancers of the reproductive organs, and many others.

But before LDN is announced a “miracle cancer drug,” have in mind that the evidence is either anecdotal or stems from animal studies. There’s no proof that it can do anything for people with cancer.

No proper clinical studies have examined its effects on cancer. What’s more, many animal studies used it only as an add-on to conventional treatments.

For example, in mice with ovarian cancer, LDN coupled with chemotherapy (cisplatin) was studied for its potential to increase treatment efficacy and reduce side effects [37].

The use of LDN in people with cancer is not evidence-based and should not be recommended.

ALA/LDN Protocol

In one study of 10 advanced cancer patients who failed standard therapy, LDN (5mg/day) was given with alpha-lipoic acid (ALA) and hydroxycitrate as part of end-of-life (palliative) care. The sample was extremely small and the study was not blinded or randomized [38].

ALA/LDN appeared to be safe in the study. Some patients were given this combination in addition to chemotherapy. One patient was described as a responder, five patients were said to have had slower cancer progression, and the remaining four died shortly. These improvements were not ascribed to ALA/LDN, since patients were receiving other therapies as usual [38].

Long-term survival of a person with advanced cancer treated with LDN and alpha-lipoic acid has been reported. The man had pancreatic cancer and metastases to the liver. He was alive and well almost 7 years later — far beyond expectations. But it’s impossible to know which factors impacted his survival, and LDN might not have been a relevant one [39].

Three other similar pancreatic cancer cases were described. One was doing well 3 years later, and the other two had confirmed remissions after 5 and 4 months of treatment. Other factors that could’ve impacted survival were not described [39]

Some researchers are looking at the following pathways that the ALA/LDN protocol may affect in cells and animals [39, 40]:

ALA on oxidative stress and inflammation (via NFkB) in cancer cells

LDN on the immune response and opioid receptors in tumors, which might theoretically change their response to the growth-inhibiting effects of endorphins and the number and activity of immune cells that may be involved in cancer (cytotoxic T cells and natural killer cells)

Scientists are investigating its immune effects in bone marrow cells (via genes that code for immune cells–MHC II, CD40, CD83, CD80, and CD86) [41].

LDN and alpha-lipoic acid are being researched in cancer, but no large-scale trials have been conducted.

Dr. Bihari’s Experience

Dr. Bihari spoke of witnessing cancer improvements in his patients prescribed LDN. He also observed that, in contrast, high doses of naltrexone may have the opposite effects and worsen cancer growth, probably by reducing opioid activity. Whether there is truth in his claims remains to be determined [35].

Other studies of LDN for cancer are currently in progress, some of which are funded by the National Cancer Institute [35].

Further Reading