Low-Dose Naltrexone (LDN) For Immune System Optimization

Low-dose Naltrexone (LDN) is the re-purposing, at a micro dose (1.75 mg - 4.5 mg each night at bedtime), of already FDA-approved Naltrexone 50 mg.

Naltrexone 50 mg was approved in 1984 for the treatment of heroin addiction and in 1990 for the treatment of alcoholism.  It works by acting as a non-selective opioid receptor antagonist.  What that means is that Naltrexone binds to all of the body's different types of opioid receptors (Mu, Kappa, Delta and Zeta [aka Opioid Growth Factor receptor/OGFr]), thereby preventing external opioids, such as heroin, or endogenous opioids, such as beta-endorphin and met-enkephalin, from having access to the receptors.  Opioid receptors are found throughout the body, with a high concentration in the central and peripheral nervous system, digestive tract, liver, pancreas and kidneys.  Moreover, nearly every cell in the immune system has opioid receptors, and researchers believe that the exquisite harmony that our immune system exhibits when it functions properly is orchestrated by the body's endogenous opioids.

In the mid-1980s, as the AIDS epidemic began in New York City, Dr. Bernard Bihari, who had served as the city's Deputy Health Commissioner and ran its addiction treatment programs, discovered the clinical effects of low-dose Naltrexone.  He knew that at 50 mg, Naltrexone causes the body's endogenous opioids to increase by up to 300%.  It does this by sending a false signal to the body; the blockade of the opioid receptors by Naltrexone causes the body to sense a lack of endogenous opioids and to produce more of them.  But, because Naltrexone at 50 mg continuously blocks the body's opioid receptors for about 24 hours, the body cannot enjoy the effects of the increased level of endogenous opioids (beta-endorphin and met-enkephalin) that the blocking elicits.

At a low dose of Naltrexone, however, the body can have access to the increased level of beta-endorphin and met-enkephalin caused by the blockade of opioid receptors.  Dr. Bihari discovered that the same increase in beta-endorphin and met-enkephalin levels is caused by Naltrexone at 50 mg, at 10 mg, at 5 mg, and at 3 mg.  But, at a dose of 3 mg to 5 mg, Naltrexone does not continuously block the opioid receptors the entire next day; it is cleared from the body in a few hours.  Thus, as soon as the body clears the low-dose Naltrexone, it can enjoy the rebound effect of the increased level of beta-endorphin and met-enkephalin triggered by LDN's brief blocking of opioid receptors.

What is the effect of LDN on immune system function? 

  • First, the blockade of opioid receptors by LDN and the ensuing rebound effect of elevated endogenous opioid levels causes increased production and improved function of T lymphocytes (CD4+, CD8+, CD25, T reg), B lymphocytes and Natural Killer (NK) cells.  These immune cells are critical to the body's defense response against pathogens and abnormal cells in the body.  In HIV positive patients, for example, Dr. Bihari found that LDN spared them from the devastation in the number of CD4+ cells that is typical as HIV infection progresses towards AIDS. 
  • Second, LDN causes increased production of met-enkephalin, which acts on the zeta opioid receptor, also known as Opioid Growth Factor receptor (OGFr); another name for met-enkephalin is Opioid Growth Factor (OGF).  Moreover, LDN's blockade of OGFr causes OGFr to increase both in number and sensitivity.  The OGF/OGFr interaction regulates growth and healing in both normal cells and abnormal ones (i.e. cancer).  Cancer cells themselves have OGF receptors, and when either LDN or met-enkephalin bind to a cancer cell's OGF receptor, they induce death of the cancer cell, known as apoptosis.  By contrast, when OGF binds to OGFr in a damaged normal cell, it promotes growth and healing. 
  • Third, LDN acts on the neurological and innate immune system signalling pathways responsible for inflammation by binding to Toll-Like Receptor 4 (TLR4), down-regulating but not eliminating the production of pro-inflammatory cytokines (IL-6, IL-12, TNF-alpha, NF-kB). 
  • Additionally, LDN tends to shift the adaptive immune response from Th2 (humoral) to Th1 (cell-mediated). 
  • Thus LDN helps to normalize inflammation responses that become unregulated and fail to return to homeostasis, as is the case in the chronic inflammatory states involved in autoimmune diseases.

In the 35 years since Dr. Bihari discovered its clinical effects, LDN has been used by tens of thousands of patients worldwide for many conditions that have immune system involvement, or are associated with immunological dysfunction, such as cancer, autoimmune diseases, chronic pain syndromes, infectious diseases, and depression. 

Of relevance to the Covid-19 pandemic that the world is undergoing, LDN may offer multifaceted protection against the disease:  it could help counteract or prevent the cytokine storms that are involved in severe cases of Covid-19, boost the ability of the body's immune cells to clear or prevent the infection, and promote the healing of tissue damaged by the infection.

Indeed, the Frontline Covid-19 Critical Care Alliance (FLCCC) includes LDN among its first-line treatments for Long-Haul Covid-19 Syndrome.


An interview of Dr. Bernard Bihari in which he recounts how he discovered the effects of LDN and explains its mechanism of action. He used it first to treat AIDS patients, and then later cancer, multiple sclerosis, and other autoimmune patients:

The transcript of the above interview of Dr. Bihari

A video about doctors who are using LDN to treat cancer:

A YouTube channel with many patient cases and interviews with doctors who prescribe LDN

The presentations on the above channel by Dr. Burt Berkson and Dr. Jill Smith are especially interesting -- Berkson presents some 'hopeless' cancer cases that demonstrate the power of LDN (along with alpha-lipoic acid) to induce the body to heal itself, and Smith very clearly explains its mechanism of action.  Dr. Smith's research on LDN focuses on using it to treat Crohn's disease and ulcerative colitis:

LDN's mechanisms of action (1, 2

Published studies of LDN

An informational site curated by one of Dr. Bihari's colleagues, Dr. David Gluck

LDN prescribing doctors