The serendipitous discovery of low-dose naltrexone (LDN) spurred a revolution in the background of medicine. Studies reveal it may help people with autoimmune diseases, chronic pain, inflammation, and even cancer. Read on to understand its unique mechanism, potential uses, side effects, and natural synergies.
What is Naltrexone?
The Story of Opioids
Before the concept of low-dose naltrexone was born, high doses of this drug were used in conventional medicine for completely different purposes.
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].
Opioid drugs can provide relief from chronic, intense pain. But they don’t come without risks: high doses can slow or even stop breathing and exaggerate feelings of calm, euphoria, and pleasure when abused.
Opioid drugs include both prescription painkillers like Vicodin and Percocet, as well as drugs of abuse like fentanyl.
Although we are currently seeing the disastrous effects of the opioid epidemic—from doctors over-prescribing opioid painkillers to extremely potent opioids like fentanyl reaching the streets—the concept of reversing opioid activity dates back to a time before this crisis began.
The opioid blocker naltrexone was synthesized in the 60s and approved in the 80s for treating opioid addiction .
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.
Disclaimer: 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 [4, 5].
- A promising alternative for autoimmune diseases, chronic pain, and inflammation
- Increases natural opioids
- Balances the immune system
- May help people with cancer (preliminary research)
- Side effects are rare and mild
- Very few drug interactions
- Off-label use (unofficial)
- Dosing usually must be adjusted to each individual
- Use largely relies on clinical expertise
Around the same time when naloxone was being used for opioid addiction in mainstream clinics, New York-based physician Dr. Bernard Bihari started using the drug in very low doses in the midst of the first AIDS epidemic.
By attempting the impossible— using an opioid blocker to enhance the immune response in people with an ‘untreatable’ disease—Dr. Bihari spurred a lot of attention.
He was initially working with opiate addicts when he observed that high dose naltrexone makes the body triple endorphin production. However, it caused too many side effects, such as insomnia and the inability to handle stress. Few would stay on it.
To re-wind: your opioid-like endorphins are not only released to help you cope with everyday social situations free of fear, pain, and anxiety. They also play an important role in acute stress and the fight-or-flight response .
Interested in the drug’s immune effects, Dr. Bihari started prescribing a range of naltrexone doses to HIV patients. The goal was to find the best dose that would boost endorphins without causing negative effects.
Surprisingly, it turned out that a small naltrexone dose (3 – 5 mg) increased endorphins to the same extent as a high dose .
Next, he ran a 9-month LDN trial in people with AIDS with promising results. After realizing the immune-normalizing benefits of LDN for AIDS, Dr. Bihari uncovered its application for a wide range of autoimmune diseases .
However, it wasn’t until 2007 that the first low-dose naltrexone (LDN) clinical trial was published. All the while, science has been gaining a lot of insight into the intricate workings of endorphins and opioids in the body.
Other LDN studies have been published and the knowledge about its clinical use has grown, gaining attention as a potential treatment for many chronic diseases .
How It Works
Low naltrexone doses block opioid receptors for a short time – about 3 hours. In response, your body increases the production of endorphins. According to Dr. Bihari, a small late-evening dose of naltrexone will boost endorphin production by 300% [6, 1].
Although naltrexone is cleared away by the morning, endorphins stay high all the next day. The endorphin blockage from low-dose naltrexone is mild, short, and essentially increases their activity.
The rise in endorphin levels remains for as long as you’re taking the low dose every night.
Beta-endorphin, one of our main natural opioids, has a long half-life of about 20 hours in the body. It’s unknown for how long other endorphins stay high in the blood.
- Mu receptors are in the brain and help with pain relief.
- Delta receptors may play a role in controlling cancer and the immune system.
There are several other receptor types that may be important for the action of LDN, but these two play the largest role .
The Missing Link Between Cancer, Autoimmunity, and Depression
To understand why LDN may have such profound effects, we need to get to the bottom of how complex disease like cancer, autoimmunity, and mood imbalances are connected to endorphins.
Cancer and autoimmune diseases may be triggered by low blood levels of endorphins, which contributes to immune deficiencies. Similarly, HIV/AIDS is accelerated by a deficiency of endorphins. Of course, they are not the only cause, but they are a piece of the puzzle .
Another interesting concept is the so-called “sickness response” or “sickness behavior”. When people are faced with a disease—be it cancer or depression—they tend to isolate themselves while the body increases inflammation and alters the immune response .
To draw a parallel, sickness behavior is well-known to scientists in the animal world: animals will isolate themselves for a short period of time when faced with an infection or disease to avoid contaminating others.
It turns out that low endorphins may be the culprit of this complex psychological and emotional response in humans. Sickness behavior can become devastating if it stops to serve a purpose and turns into chronic low mood and energy.
Does It Block or Stimulate Endorphins?
The concept of “stimulating by blocking” is not an easy one. Let’s dive a bit deeper.
The hypothalamus is a structure in the base of the brain and part of the limbic system, which orchestrates emotions, motivation, and learning. Low-dose naltrexone blocks opioid receptors in the hypothalamus .
In response to the short-term blockage, the brain begins producing more of a prohormone called proopiomelanocortin during the night. Next, this hormone is broken up into 3 others in the pea-sized “master gland” called the pituitary:
Aside from these direct effects on the brain, LDN may also signal the adrenals to make more enkephalin via another prohormone called proenkephalin.
This is a normal response, as the body interprets blocked receptors as a signal that our endorphins are low. To compensate, it increases their production. For this reason, we can say that LDN increases our natural opioids – endorphins and enkephalins – by blocking.
If the receptors are blocked by a high dose, they don’t get to recover and stay shut off. According to Dr. Bihari, the ideal dose should maximally increase endorphins while minimally blocking them .
Is It Legal?
Despite the persisting scientific efforts, LDN is still being thrown into the “alternative treatments” bucket. But that doesn’t make it illegal.
Naltrexone is a drug licensed and approved by the FDA, meaning that doctors can prescribe it. However, it’s not approved for the indications we focus on in this article. That makes the use of LDN “off-label”, which is completely legal and medically acceptable.
Uses of Low-Dose Naltrexone
1) Autoimmune Conditions
Dr. Bihari first realized that LDN may help people with autoimmune diseases. According to him, LDN has the power to restore immune harmony 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 .
A specific subtype of these T-helper cells are Tregs (5% – 10%), which are responsible for suppressing harmful Th1, Th2, and Th17 overactivation. They prevent the immune system from going into an autoimmune overdrive, or simply said, from attacking itself [11, 12].
Although clinical studies have yet to confirm his clinical findings, Dr. Bihari claims that LDN can help people with a range of autoimmune diseases including lupus, rheumatoid arthritis, eczema, and psoriasis.
The whole basis for these potential benefits stems from boosting endorphins and their subsequent rearranging of cells in the immune system .
The research revealed that LDN also 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.
Their activation underlies common symptoms in autoimmune and other diseases (see “sickness behavior”): fatigue, fever, inflammation, and pain .
The researched conditions are listed below. It’s possible 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.
Multiple Sclerosis (MS)
At first, the evidence to support LDN use in MS seems conflicting. In one study of 96 people with MS, 8 weeks of LDN (4.5 mg/day) did not provide more relief than placebo .
In contrast, LDN improved mental health and quality of life in another study of 60 people with MS, using a similar protocol .
One study tracking back 4 women with MS suggested that LDN is safe and may help slow the disease. Women who took LDN didn’t report any side effects, while their symptoms stabilized or improved, as did their quality of life and fatigue .
In 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 .
Fibromyalgia is not technically classified as an autoimmune disease, although it triggers many of the same symptoms. LDN seems to offer some hope for people suffering from this otherwise hard-to-treat disease [16, 17].
A group at Stanford University found that LDN (4.5 mg/day) significantly reduces pain, fatigue, inflammation, and stress in people with fibromyalgia while boosting mood. LDN was safe and well-tolerated .
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 .
This goes a long way to show the profound physical and emotional effect of endorphins.
2) Pain and Inflammation
By keeping the microglia in a resting state and increasing endorphins, low-dose naltrexone may reduce the pain and inflammation in CRPS .
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. It worked by silencing microglia that trigger inflammation and pain .
LDN may also enhance the pain-relieving effects of acupuncture, which people with CRPS could benefit from. LDN increases the number of receptors for opioids and cannabinoids, which boosts the response to these natural painkillers. Combined, LDN and acupuncture achieve greater synergy .
Pain and Seizure Relief
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. Such an effect is not surprising since naltrexone increases natural opioids .
In addition, LDN reduced the tolerance to morphine in another study in mice. It may thus help people with severe pain stay at a lower morphine dose over a longer period of time .
In one case report, a person with this condition experienced pain relief with LDN (3 – 4.5mg/day). It probably worked by reversing microglial activation and boosting endorphins, which reduced nerve inflammation and pain .
Inflammatory Gut Disorders (IBS and IBD)
Irritable Bowel Syndrome (IBS) can have many hidden causes, but stress, inflammation, and autoimmunity are often 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 just 4 weeks. LDN was safe and didn’t cause any side effects .
In a study of 14 children with Crohn’s, LDN accomplished complete 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 .
In 40 patients with drug-resistant ulcerative colitis, 30% responded to LDN treatment and 20% experienced long-lasting benefits. Many of the long-term responders went into remission while only 3 people relapsed .
LDN has been proposed as beneficial for various cancers. The list is almost endless, 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 spurs too much excitement and is announced a “miracle cancer drug”, have in mind that much of the evidence is either anecdotal or stems from animal studies.
No large-scale clinical studies have confirmed its cancer-fighting effects. What’s more, many animal and human studies used it only as an add-on to conventional treatments.
For example, in mice with ovarian cancer, LDN coupled with chemotherapy (cisplatin) boosted treatment efficacy and reduced side effects .
Low-dose naltrexone is very safe and does not appear to be toxic. Since standard cancer therapy is very rough on healthy cells and can cause severe side effects, the beneficial profile and immune-enhancing action of LDN becomes key.
In one study of 10 advanced cancer patients who failed standard therapy, LDN (5mg/day) was given with alpha-lipoic acid (ALA) and hydroxycitrate. One patient had a great response, five patients had slower cancer progression, and the remaining four died shortly .
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 .
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 
- ALA reduces oxidative stress and inflammation (via NFkB) and selectively induces the death of cancer cells
- Low-dose naltrexone harmonizes the immune response and increases opioid receptors in tumors, making them more responsive to the growth-inhibiting effects of endorphins. It also increases the number and activity of immune cells that can fight off cancer (cytotoxic T cells and natural killer cells)
One study on bone marrow cells highlights this immune-balancing effect. In low doses, naltrexone enhanced the maturation of bone marrow cells by increasing the activity of genes that code for cancer-fighting immune cells (MHC II, CD40, CD83, CD80, and CD86) .
Dr. Bihari’s Experience
Dr. Bihari speaks of witnessing cancer remission 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 .
Other studies of LDN for cancer are currently in progress, some of which are funded by the National Cancer Institute .
4) Fatigue & Nerve Disorders
Anecdotally, low-dose naltrexone may reduce fatigue and overall symptoms in people with Parkinson’s disease. In one small study of 8 people, LDN improved fatigue over 8 months without any side effects .
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 natural endorphins may protect the brain from further damage.
The reports from 15 ALS patients who used LDN are mixed :
- About half didn’t experience any effect or were unsure
- One-third reported moderate efficacy
- One-fifth reported slight efficacy
The benefits included balance and speech improvements, more energy and less phlegm, and easier breathing. However, these reports were subjective and un-blinded .
At first, naltrexone was used in regular, high doses, in an attempt to improve symptoms of autism in children. The opioid system and our endorphins have profound effects on social interactions, which are impaired in autism.
The 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 discovered a better response with low doses.
Some doctors prescribe low-dose naltrexone to children with autism. However, 90% of the published studies were done with high doses. On the other hand, 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.
6) Stress & PTSD
For complex mental health issues, though, it should always be part of an integrated psychotherapeutic approach.
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 .
7) Addictions & Withdrawal
High-dose naltrexone (and naloxone) is still a conventional treatment for opioid use disorders. On the other hand, LDN remains experimental. It may help people with addictions by boosting natural opioids and reducing the need for stronger external triggers such as drugs, alcohol, or cigarettes.
In a study that tracked 10,000 people, LDN improved pain tolerance and interpersonal interactions in post-detox patients .
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 .
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 .
The naltrexone dose was relatively high: 5-fold the dose that Dr. Bihari and other clinical studies of LDN used. 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 .
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 .
The whole concept of low-dose naltrexone started with HIV/AIDS patients, when Dr. Bihari noticed it enhances a compromised immune system. To date, he administered LDN to hundreds of HIV/AIDS patients and claims that some no longer have detectable levels of the virus .
Naltrexone is a very affordable drug that may help millions of people suffering from HIV/AIDS in the developing world. In fact, LDN has already been approved in Nigeria as an AIDS treatment .
Dr. Bihari considers that low naltrexone doses may also help people with other types of chronic infections, such as tuberculosis, Lyme, genital herpes, and even Hepatitis C. The same rationale follows: LDN boosts immunity and the ability to fight off infections.
These claims still rely only on clinical experience, and no large studies have confirmed them.
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Consult with your physician before taking low-dose naltrexone. This medication requires a prescription and should only be used under the guidance of a qualified healthcare professional.
Typical Protocol & Dosage
- LDN is usually taken only once a day before bedtime as 90% of the endorphins are made during the night .
- The dosage typically ranges from 1.5 mg to 5 mg/day*.
- Slow/timed-release naltrexone and LDN capsules that contain calcium carbonate filters should be avoided .
- Pills are the most common form, but topical creams and patches have also been developed; they may work better for children or people who have difficulty swallowing.
- Naltrexone is commercially available only at a 50mg dose, which means that you need to get your prescribed low-dose formulation from a compounding pharmacy .
*Dr. Bihari considers that the dose should be no less than 1.75 – 2 mg/day and no higher than 4.5 – 5 mg/day. He found that 3 mg/day is a good dose that works for most people .
This is where the confusion kicks in, as some studies used so-called “ultra low-doses”, ones that range from 0.125-0.5 mg/day. On the other hand, borderline doses of 0.5-1 mg/day are considered “very low-dose” .
There is no clear benefit to very or ultra-low doses, based on the published studies. However, each person is different and your doctor may consider that doses in this range will work better for you.
Synergies (Lifestyle & Supplements) of LDN
There are many other ways to increase your natural opioids that may work in synergy with low-dose naltrexone. The following will either increase the activation and sensitivity of your receptors or boost your endorphin production:
- Cold exposure 
- High-intensity exercise [47, 48]
- Sleep 
- Sun exposure/UVB [50, 51]
- Warm showers 
- Social interaction 
- Massages 
- Tasty food [54, 55]
- Acupuncture 
- Magnesium [57, 58]
- Butyrate 
- Capsaicin/Chili peppers 
- Acidophilus probiotics 
- Melatonin 
- LLLT 
- Oxytocin 
- Marijuana – THC/CBD 
- Pregnenolone (only in specific cases) 
Depending on your health concerns and lifestyle, some of these may work better than others.
LDN Side Effects and Interactions
Most people didn’t experience any major side effects in the published clinical trials to-date.
Some people experience vivid dreams (or rarely nightmares), which goe away with time. Insomnia is another possible side effect. In such cases, the dosing can be moved to the morning .
Dr. Bihari added that poor sleep is the only side effect he noticed in a very small percentage of people on 3 mg/day. He considers that lowering the dose (to 1.5 – 2 mg/day) is a better solution than moving it to the morning .
You can consider natural calming supplements or lifestyle adjustments to help you overcome sleep issues while on low-dose naltrexone. They include magnesium, melatonin, and hops. Make sure to get enough sunlight during the day and block out blue light at night.
According to the published studies, mild headaches are also possible. Some physicians reported anxiety, but this was mostly in people undergoing opioid withdrawal and probably not related to naltrexone .
There are anecdotes of people with chronic fatigue and mold illness not reacting well to LDN. This could also possibly be due to increased sensitivity. If you fall under this category, speak to your healthcare practitioner.
The only drugs LDN should not be used with are opioid painkillers: codeine, morphine, fentanyl, hydrocodone, methadone. Low doses of naltrexone may block opioid receptors and temporarily reduce their effectiveness .
People who used (or abused) opioids long-term may require 10 days to 2 weeks before LDN treatment. Your doctor will be able to assess this based on your individual case.
People who have had organ transplants and are taking immunosuppressive drugs permanently are cautioned against the use of LDN.
Naltrexone is a drug that blocks opioid receptors and treats opioid addiction. Recent promising research unveiled that low-dose naltrexone (LDN) may help people with autoimmune diseases, pain and inflammation, fatigue, cancer, and autism.
LDN boosts the body’s natural opioids–endorphins and enkephalins–and re-balances the immune system. It offers hope for many people with complex drug-resistant conditions, but clinical trials are yet to verify most of its current uses.
The dosage typically ranges from 1.5 mg to 5 mg/day, taken before sleep. Side effects such as headaches and insomnia are rare and mild. LDN should not be used with opioid painkillers such as codeine, morphine, and methadone.