Is Low Dose Naltrexone (#ldn) Stimulating Autoimmunity?

Naltrexone (#ldn) is usually used in 50mg doses as a drug to help heroin or opium addicts, by blocking the effect of such drugs.  By blocking opioid receptors, naltrexone also blocks the reception of the opioid hormones (endorphins) that the brain and adrenal glands produce.   Many body tissues have receptors for the endorphins, including virtually every cell of the body’s immune system.

FDA-approved naltrexone, in a low dose (only 3mg), can boost the immune system, helping those with HIV/AIDS, cancer, and Autoimmune Diseases. The Immune System is “uncontrolled”in Autoimmune conditions. Boosting an uncontrolled Autoimmune response is a bad thing.

LDN is currently under experimental use for many conditions.  Preliminary results in theory are very encouraging: Naltrexone increases the body’s production of the beta and metenkephalin endorphins and blood tests have indicated that it can double or even triple the activity of natural killer cellsNaturalkillercells(also known as NK cells, K cells, and killercells) are a type of lymphocyte (a white blood cell) and a component of innate immune system. NK cellsplay a major role in the host-tissue rejection of both tumours and damaged cells.

Oh, but Doc, this is Low-Dose Naltrexone. My response: A single spark can ignite a forest fire.

A wealth of experimental data suggest that T cells are self-restricted or self-regulated. Immune regulators of the NEI Supersystem cannot be too high or too low as the self-regulation is dose-dependent. Artificially suppressing or stimulating the levels has detrimental effects on the immune response.

LDN works by suppressing the immune system. Eventually, to quote, Dr. Ian Malcolm of Jurassic Park:

… the kind of control you’re attempting simply is… it’s not possible. If there is one thing the history of evolution has taught us it’s that life (the immune system) will not be contained. Life (the immune system) breaks free, it expands to new territories and crashes through barriers, painfully, maybe even dangerously, but, uh… well, there it is.

There are three different methods by which the body fights infections.  While cellular immunity (Th1) directs Natural Killer T-cells and macrophages to attack abnormal cells and microorganisms at sites of infection inside the cells, humoral immunity (Th2) results in the production of antibodies used to neutralize foreign invaders and substances outside of the cells. T helper 17 cells (Th17) are a subset of T helper cells producing interleukin 17 (IL-17). They are developmentally distinct from Th1 and Th2 cells. Th17 cells are associated with autoimmune disease. The Th17 effector cells are triggered by IL-6 and TGF beta or IL-23 and IL-1β.

woman on fire
Are you on fire?

In many cases, all three arms of the immune system fight an infection.  At other times, only one is predominantly needed to control an infection.  A healthy immune system is both balanced and dynamic: it should be balanced between Th1 and Th2 and Th17 activity, switching back and forth between the three as needed.  This allows for a quick eradication of a threat and then a return to balance before responding to the next threat.  The inability to respond adequately with a Th1 response can result in chronic infection and cancer; an overactive Th2 response can contribute to allergies, various degenerative syndromes and autoimmune disease is a consequence of a Th17 response.  In autoimmune illnesses, all of the arms of the immune system are active, creating the inflammation and tissue injury in autoimmune disease.

A failure of the Th1 arm of the immune system and an overactive Th2 arm is implicated in a wide variety of chronic illnesses.  These include autoimmunity, CFS, candidiasis, multiple allergies, multiple chemical sensitivities (MCS), viral hepatitis, Hashimoto’s thyroiditis, cancer and other illnesses.  If these three arms of the immune system could be balanced by stimulating Th1 and decreasing Th2, then many of the symptoms associated with these chronic illnesses would diminish or disappear and we would have found the answer to immune restoration and balance or the equivalent of a cure. Unfortunately, where Th1 and Th2 leaves off, Th17 takes over and most treatments don’t take account of Th17. This is definitely the case for Low Dose Naltrexone (LDN).

While correct in theory, it is incorrect in terms of how the immune system functions. Most view the immune system only in terms of Th1, Th2 and rarely if ever include Th17. Cytokines, chemokines, neurotransmitters and hormones that control the Th1, Th2 and Th17 responses direct the immune response. Hormones are always thought of as only involved in sex and reproduction. However, progesterone, estriol and testosterone are immune suppressive. While two of the estrogens – estrone, and estradiol are immune stimulating. Not to mention the inflammatory hormone Etiocholanolone, which is rarely tested for and drives the Th17 response. Yes, Etiocholanolone is a hormone made from DHEA that drives Th17. All too often low DHEA is thought to be an adrenal problem, when it is actually being converted into etiocholanolone. Neurotransmitters work both to alert the immune system to an area of the body in distress and signal the immune system that the work is over. Again, rarely tested for. Collectively, this is known as the NEI Supersystem.

Th1 cells secrete INF-gamma and IL-2, which activate macrophages and cytotoxic T-cells to kill intracellular organisms; Type Th2 cells secrete IL-4, IL-5, and IL-10, which help B cells to secrete protective antibodies. Th17 cells are triggered by IL-6, IL-17, IL-1β, and IL-23 to clear out damaged tissue damaged by autoimmunity or the uterine lining during menstrual cycles or miscarriages.

Interferon gamma (IFNγ) is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells and NK cells. Among the effects of increased IFNγ are:

  • Promotes NK cell activity
  • Increases antigen presentation and lysosome activity of macrophages.
  • Activates inducible nitric oxide synthase (iNOS)
  • Induces the production of IgG2a and IgG3 antibodies from activated plasma B cells
  • Causes normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells.
  • Promotes adhesion and binding required for leukocyte migration
  • Induces the expression of intrinsic defense factors.
  • IFNγ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFNγ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells.

I recommend calming and quieting the immune system so it can respond appropriately when needed.

Low Dose Naltrexone works by stimulating suppression of the immune response. When immune suppression occurs, those using LDN don’t feel the pain and discomfort with their immune system being suppressed. It’s a win/winsituation. The patient isn’t feeling any pain and the Doctor isn’t getting asked by the patient isn’t feeling any better.

Low Dose Naltrexone works by Stimulating Suppression of the Immune system.

Parsing the Benefits of LDN

It’s worth mentioning LDN “stimulates” suppression. Proponents will parse it to “LDN works by stimulating an immune response.” Conveniently leaving off the end of the statement. “LDN works by stimulating an immune response to calm down or stop inflammatory immune responses (AKA – suppression).” Technically they are correct. By convention today, there is an agreement to only look at one aspect when publishing medical studies. They publish a study showing LDN works by stimulating a immune response. End of story. They assume those in the know reading this study would understand the consequences of this “stimulation.” However, the average person or Doctor(s)  (Don’t assume Doctors know much about the immune system) doesn’t know or care how it works. They only want to know will it give relief. Consequences be damned.

Fact: Inflammation is an immune response.

In answer to “a common anecdotal report is that people don’t get the common cold as much. Technically, they are correct. But??? They are equating not getting sick to a normal healthy immune system. After seeing the results from the Stimulated Cytokine lab test. I realized the reason they not getting sick is because their immune system is so fatigued or suppressed that no symptoms are generated. They come to my office reporting they feel like crap but they “never get sick”. “How can I be so healthy but feel so bad?”

Those using LDN usually report a blissful period where their inflammation (see fact above) subsides. Usually for a four to six month period; then other components of the immune system become overstimulated without the feedback control from the components that LDN suppressed. They have had half a year for smoldering inflammation doing further damage to their body. The good news is they will not feel it. The bad news is they will now seek help from a Doctor that will recommend immune stimulating supplements. Exacerbating the condition and the damage being done.

Alternative / Functional treatments focus on Stimulating the Immune Response.

Naltrexone Treatment by Immune Stimulation

A possible line of therapy being investigated by the medical community is to reintroduce some of these cytokines to people who have severe immune deficiencies.  This approach can be tricky because large amounts of any particular cytokine can have serious side-effects. This approach fails to recognize fatigued cells that are too exhausted to produce immune cells cause the deficiencies. How is stimulating the immune system beneficial?

The immune system by design provides your body with numerous layers of protection with a multiple backups. The system is set up so that if the responsible system is unable to handle the job and bigger, stronger system is recruited. Thus, if the basic Th1 or Th2 systems are fatigued to respond, the Th17 system is alerted to come in and take care of business.

Naltrexone Stimulation of the Immune System

Naltrexone treatment increases NK cell cytolytic activity and cytokine production in the spleen. Chronic naltrexone administration enhanced both basal and the cytokine-modulated NK cell cytolytic activity and IFN-γ production.

Naltrexone treatment increased the production of IL-2, IL-4, IL-6, and IL-18 and the basal and cytokine-activated NK cell cytolytic activity and IFN-γ production in the splenocytes. Chronic administration of naltrexone stimulates the production of cytokines and NK cell cytolytic activity in splenocytes. Naltrexone does not block IL-1β.,

Naltrexone Stimulation of NK cells

Natural killer cells are a T cells that share properties of both T cells and natural killer cells. NK cells can also produce many different cytokines as well as chemokines.  T cells are inherently cross-reactive, and this versatility and specificity is a hallmarks of adaptive immunity. T cells are prone to be autoreactive and thus able to induce autoimmunity.  Increasing the NK cell avtivity results in enhanced alloreactivity  and autoimmunity.

IL-2 promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen.

IL-2 does not specify the type of Th differentiation that occurs; instead, IL-2 modulates expression of receptors for other cytokines and transcription factors, thereby either promoting or inhibiting cytokine cascades that correlate with each Th differentiation state. In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells.

IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects. Some common side effects:

  • Flu-like symptoms (fever, headache, muscle and joint pain, fatigue)
  • Nausea/vomiting
  • Dry, itchy skin or rash
  • Weakness or shortness of breath
  • Diarrhea
  • Low blood pressure
  • Drowsiness or confusion
  • Loss of appetite

More serious and dangerous side effects sometimes are seen with increased IL-2, such as capillary leak syndrome, breathing problems, serious infections, seizures, allergic reactions, heart problems or a variety of other possible complications.

T-cell recognition is essential for protection against microbial pathogens, recognition of self-peptides by T cells that have escaped negative selection in the thymus can lead to autoimmune disease. A disregulated T cell interaction can initiate autoimmunity. Thus, antigen recognition by T cells must be tightly regulated in order to ensure protection against pathogens and tumors, avoiding activation of self-reactive T cells.

NK cell cytolytic activity has been shown to be activated by interferon-γ (IFN-γ), which has a number of opioid-like effects. Various other cytokines are also known to increase NK cell cytolytic activity and lymphocyte proliferation. Of these cytokines, interleukin (IL)-2, IL-12, and IL-18 stimulate NK cell cytolytic activity. Other cytokines like IL-4 and IL-6 are known to regulate NK cell proliferation and differentiation. Cytokines IFN-γ, IL-2, IL-4, IL-6, IL-12, and IL-18 have been shown to also affect the function of other immune cell populations in splenocytes.

Alcohol consumption is also known to suppress Lectin-induced production of various cytokines, including IL-2, IL-6, and IL-4 from splenocytes. Initially, Naltrexone therapy counteracts the suppressive effects of alcohol on NK cell cytolytic activity for the first couple of weeks allowing increase production of IL-2, IL-6, and IL-4 from splenocytes.

Naltrexone Stimulation of Chemokines

Naltrexone is an opioid antagonist when administered the first couple of weeks, but shows δ-opioid-like activity following chronic long-term administration. With constant use naltrexone selectively promotes the δ-opioid receptor activity and enhances NK cell cytolytic activity response to β-endorphin. Naltrexone disrupts the feedback control that results in enhanced NK cell cytolytic response.

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1 beta, induce an intense fever. The central action on body temperature (Tb) of MIP-1 beta with that of interleukin-6 (IL-6), has been implicated in the mechanism underlying the pathogenesis of fever along with etiocholanolone. This is potentiated by the presence of lipopolysaccharide.

Naltrexone increases in neutrophil-associated myeloperoxidase activity and chemokine mRNA expression, including macrophage inflammatory protein-1 alpha (MIP-1α) and -2 (MIP-2).

LDN could enhance both morphological and functional maturation of bone marrow dendritic cells (BMDCs). Their main function is to process antigen material and present it to the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems. LDN markedly up-regulates expression of key surface molecules, which will trigger a chain of cell mediated responses. In addition to this, LDN also markedly upregulate production of cytokines IL-12 and TNF-α, which will trigger Th1 cell response.

Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response.

Interleukin (IL-1), tumor necrosis factor α (TNFα), IL-3, and IL-6 collaborate with GM-CSF. β-endorphin increased the number of macrophage colonies when bone marrow cells were cultured in the presence of GM-CSF plus lipopolysaccharide (LPS). Naloxone and Naltrexone, an antagonist of endorphins for opioid-receptors, completely abolishes the effect of β-endorphin. Both Naloxone and Naltrexone stimulates suppression of the production of GM-CSF.

Naltrexone Stimulates Suppression of Cytokines

Naltrexone and naloxone stimulates suppression of microglia activation, reduces the production of re- active oxygen species and other potentially neuroexcitatory and neurotoxic chemicals.

Naltrexone causes a significant decrease of IL-12 and IL-10 production by macrophages. With chronic dosages, IL-12 remaines significantly suppressed. As for IL-10, naltrexone seems to partially prevent the IL-10 reduction. Naltrexone significantly inhibited the production of TNF-alpha induced by LPS.

Naltrexone Stimulates Suppression of Chemokines

The anti-inflammatory effect of opioid antagonists naltrexone and naloxone also extend to the periphery, as evidenced by stimulates suppression of TNF-alpha, MCP-1, and other inflammatory agents in peripheral macrophages.

Stimulated Cytokine Testing on LDN Patient

The lab results shown below are from a woman using Naltrexone therapy. Despite feeling better on the Autoimmune protocol recommended to her, she stopped doing the Autoimmune protocol after deciding to start Naltrexone.

After starting the Naltrexone, things changed drastically. A lot of the old symptoms reappeared and some got worse. She was experiencing severe pain on right side of body from neck and shoulder down to her hip and ankle. Her low back was really bad, and she could hardly walk being constantly achy and sore. She could not get out of bed, and had diarrhea a couple of times a week. When she gets a flair up – it can occur for no reason and they are lasting longer. Unfortunately, she failed to mention the LDN therapy.

Naltrexone Induced Ischemia

Ischemia is a restriction in blood supply to tissues causing a shortage of oxygen and glucose needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue.

Neurons that demonstrate particular vulnerability to ischemic challenges have been termed “selectively vulnerable neurons”.  Of the entire brain, the neurons of the hippocampus are the most vulnerable.

This would result in problems with endocrine system, (thyroid, hormone, adrenal) as the blood-brain-barrier would be further compromised as a results of compromised (ischemic) blood flow to the pituitary, hypothalamus and hippocampus.

Exogenous ligands, i.e. naltrexone, that activate the δ receptors mimic the phenomenon known as ischemic preconditioning. Ischemia preconditioning/hypoxia preconditioning (IPC/HPC) is a phenomenon whereby brief ischemia/hypoxia “preconditions” cells and increases cellular resistance against subsequent lethal ischemia/hypoxia injury. Short periods of transient ischemia are induced the downstream tissues are robustly protected. This serves as a protective mechanism to restrict blood flow around an inflamed area of the body to prevent inflammation or microbes from spreading throughout the body. It is intended for short periods until the immune system is able to control the situation. If longer-duration interruption of the blood supply is then effected, ischemic damage from the lack of oxygen, glucose and elimination of cellular waste products occurs. Naltrexone and naloxone with δ activity mimic this effect.

Naltrexone Reduces Liver Enzymes

Naltrexone significantly reduces the elevation of serum glutamate-oxalacetate transaminase (SGOT) and glutamate-pyruvate transaminase (SGPT) (as index of hepatic function) induced by LPS.

Is LDN right for you?

The comments and posts you are reading saying how good they feel is because their immune status matches how LDN supports their imbalanced cytokines and chemokines. LDN works only for those with the correct immune status that Naltrexone or Naloxone supports.

If you do not match that cytokine or chemokine profile. LDN will only increase the damage and further disrupt your body’s ability to control the immune system. If you are using LDN and not satisfied with the way you are feeling. It is probably not right for you.

It is possible to get the immune system back under control. It is not a quick process but steady progress is experienced giving you the faith and confidence you need to know you did the right thing. One should never guess when it come to the immune system. Call today to have your Stimulated Cytokines and NEI Supersystem tested.

Are Edible Enemies contributing to poor health and inflammation? Lectins cause a plethora of damage to the body, promoting chronic inflammation and sensitivity. Take the Edible Enemy Quiz to test your knowledge on lectins.

Use the Lectin Control Formula to reduce the inflammatory response that occurs due to lectin consumption. Take two capsules with each meal.

3 Replies to “Is Low Dose Naltrexone (#ldn) Stimulating Autoimmunity?”

  1. I have a daughter 40 yers old who was diagnosed with RRMS and has been on LDN 4.5 for about three years and is doing fairly well. I also have a 39 yo daughter who is mildly retarded and from a hospital screw up of an IV push of Phenergan started to hear voices and is now on 10mg of Abilify and does not hear voices anymore while on Abilify but still has daily anxiety. I am thinking of trying her on LDN after reading some articles on using LDN for that treatment but have also now read your article and am asking about this testing you wrote about. I live in PA. Thank you for any feedback. My best, Sandy Reid

    1. Hi Sandra, One has to be careful with diagnosis associated with MS. Does she actually have MS antibodies from a spinal tap. When one digs a little deeper on using MRIs to diagnosis MS, any ol’spot will do. That does not mean it is MS. The “Relapsing – Remitting” also brings this more questionable. The ubiquitous symptoms can be attributed to any diagnosis. I always ask. In order for RRMS to be occur – what must occur in the body for it to manifest? The symptoms of RRMS are remarkably similar to those conditions cause by problems with control of abdominal blood flow alter blood flow to the brain. Dr. Dave

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