Low Dose Naltrexone, LDN

The story starts in the 1960s when pharmaceutical companies were looking for a substitute for opioids, like morphine, that could reduce pain without the potential for addiction. Naltrexone and naloxone, for injection, were developed to produce similar analgesic effects to morphine, but proved ineffective. 

In the 1970’s, these drugs were repurposed for their ability to temporarily block and reverse the effects of opioids in ER situations of acute drug overdose. 

In the mid 1980’s, physicians began using naltrexone as a therapeutic tool to treat people with drug addiction, to block the associated mood elevation and euphoria from narcotics.  

At that time morphine, opium, and heroin were the major opioids, but today in addition there are, oxycodone, fentanyl, methadone, oxycodone, oxymorphone, and others. These drugs all result in continuous opioid receptor stimulation, but with time tolerance occurs requiring higher and more frequent doses making them subject to abuse, addiction, and potential overdose. 

A pioneer physician, Dr Bihari, an MD addiction specialist and pharmacologist, began prescribing naltrexone, 50-300mg, to block opioid receptors to assist in helping drug addicts maintain drug abstinence. He began noticing that when his patient’s stabilized, were improving, and naltrexone dosing was markedly decreased, his patient’s chronic inflammatory illnesses, autoimmune diseases, and pain, seemed to show recognizable symptom improvement.   

Since that time numerous studies, over 300, by Dr Zagon and Dr Mclaughlin have elucidated research that has revealed that the number of natural opioids and opioid receptors are controlled and carefully regulated maintaining specific ranges, but that low dose naltrexone resulted in a compensatory increase in both opioids and their receptors for hours after the LDN effect was dissipated; as well as that LDN  inhibits multiple cancer pathways, reduces pain sensitivity and inflammation in autoimmune illnesses, and  assists in regulating  excessive insulin production. 

Executive Summary

  • History of Naltrexone: Developed in the 1960s as an opioid alternative. Repurposed in the 1970s for drug overdose treatment. Used in the 1980s to treat drug addiction by blocking opioid-induced euphoria. 

  • Discovery of Low Dose Naltrexone (LDN): Dr. Bihari noticed improved symptoms in patients with chronic conditions when using very low doses of naltrexone. This led to exploring LDN's potential beyond addiction treatment. 

  • Dr Zagon and McLaughlin clarified the mechanism of LDN: Temporarily blocks opioid receptors for 4-6 hours. This blockade triggers increased production of natural opioids and receptors. The resulting higher levels may help with pain relief and immune regulation.  

  • LDN in Cancer Treatment: May slow cancer growth by affecting specific pathways like OGF/OGFr. Enhances the immune system's ability to fight cancer cells. Potentially inhibits new blood vessel formation in tumors and promotes cancer cell death. 

  • LDN and Autoimmune Diseases: Helps regulate overactive immune responses in autoimmune conditions. Modulates Toll-Like Receptors involved in inflammation. Shows potential benefits in various autoimmune diseases, though more clinical studies are needed. 

  • Dosage and Administration: Typically prescribed at 4.5mg or less. Should be prepared by a compounding pharmacy. Usually taken once daily, with specific protocols for cancer treatment (3 days on, 4 days off). 

  • Side Effects and Considerations: Generally mild and temporary, often occurring when starting treatment. May include sleep disturbances, headaches, or mild gastrointestinal issues. Cannot be taken with opioid medications. 

  • Metabolic Effects: Shown to improve hyperinsulinemia and insulin resistance. May help shift metabolism back to aerobic pathways, potentially hindering cancer growth which often relies on anaerobic metabolism. 

  • Current Status and Future Research: LDN use for cancer and autoimmune conditions is considered "off-label". More large-scale clinical trials are needed to definitively prove its effectiveness. Future research should focus on optimal dosing and identifying specific conditions where LDN is most effective. 

  • Practical Considerations: Should be used under healthcare professional guidance. May require adjustments around surgical procedures involving opioid pain management. Can potentially be used alongside other cancer treatments, except certain immunotherapies. 

How LDN Works in Cancer 

Low Dose Naltrexone (LDN) has shown promising effects in cancer treatment, based on both research studies and clinical experience. Here's an overview of what we currently understand: 

Research findings: 

  • Immune system modulation: Studies suggest LDN can enhance the function of natural killer cells and increase the production of endorphins, potentially boosting the immune system's ability to fight cancer. 

  • Anti-proliferative effects: Research indicates LDN may inhibit cancer cell proliferation by modulating opioid growth factor (OGF) receptors. 

  • Anti-inflammatory properties: LDN has been shown to reduce inflammation, which is known to play a role in cancer progression. 

  • Angiogenesis inhibition: Some studies suggest LDN may help reduce the formation of new blood vessels that feed tumors. 

  • Apoptosis promotion: Research indicates LDN might promote programmed cell death (apoptosis) in cancer cells. 

Clinical experience: 

  • Improved quality of life: Many patients report reduced pain, improved sleep, and increased energy levels when using LDN. 

  • Reduced side effects: LDN is often well-tolerated with fewer side effects compared to traditional cancer treatments, and can be integrated simultaneously with most cancer therapies. 

  • Potential tumor stabilization: Some clinicians have observed tumor stabilization or even regression in patients using LDN as part of their treatment regimen.  

Innovative therapeutic approaches to cancer care can offer assistance and benefit to a person’s overall treatment. The use of the drug naltrexone is one such pharmaceutical which while intended for use in drug overdose and addiction medicine has been recognized, when given in very small doses, to have beneficial effects in supportive cancer care. 

The natural opioids, beta-endorphin and enkephalin, are our strongest naturally occurring analgesic substances. They are generated in situations of pain and/or stress to assist in reestablishing homeostasis. They are stored as inactive molecules in the brain, peripheral nervous system, digestive organs, adrenals, and immune cells, until needed. 

When required, the brain’s master hormone regulator, the hypothalamus, releases a specific hormonal messenger, corticotropin releasing hormone (CRH), which initiates the pituitary release of adrenocorticotropin hormone (ACTH), to activate both adrenal hormones, to prepare for fight or flight, and the stored endorphin peptides.  

Endorphins were initially believed to act primarily within the central and peripheral nervous systems to modify pain perception, but studies now demonstrate that most immune cells; monocytes, macrophages and T and B cells, are also capable of creating these active endorphins, primarily beta-endorphin.  

In addition to beta-endorphin and encephalin, there are two other important natural opioids.  

One is a non-analgesic opioid endorphin, called methionine [MEK-5] enkephalin or opioid growth factor (OGF) that plays a completely different and distinctive role related to cell growth.  

The other is dynorphin, which is associated with the development of chronic pain rather than alleviating it.  

Natural pain reducing opioid endorphins act in two different but complementary ways: 

  • These amino acid comprised proteins, or peptides, are produced in one location and released into the blood stream to regulate the physiologic functions in the central and peripheral nervous systems, and are thus considered hormones. 

  • As Neurotransmitters, they act to induce changes in chemical or electrical signals between nerves that effect pain sensitivity.

These actions require the binding of the endorphin to its specific opioid receptor on nerve cells when there is injury or trauma, and interfacing with pain pathways moderating their responses.  

Beta -Endorphin, the most plentiful opioid endorphin, binds in the peripheral nervous system at the Mu opioid receptors, on the surface of nerves, initiating a series of reactions connected to the activation of a protein called Substance P, which is linked to pain recognition and perception. 

In the central nervous system, beta-endorphin also binds at Mu receptors but there inhibits the release of GABA, gamma aminobutyric acid, which reduces nerve excitability and results in increased production of dopamine, a catecholamine neurotransmitter associated with pleasure or reward, modifying both pain perception and pain intensity.  

Other analgesic effects are achieved by the natural opioids, enkephalins and dynorphins. Each of these bind at a different of opioid receptor but affect pain. Enkephalins bind at the DOP or Delta receptor which modifies acute pain, and Dynorphin at KOP or Kappa receptor which appears to be associated with the development of chronic pain. 

Low Dose Naltrexone achieves beneficial effects by modifying the known actions of natural opioids on pain, cancer progression, and the chronic inflammation associated with autoimmune illness, with minimal or negligible side effects.  

The reason for the multiplicity of LDN effects appears related to the biologic activity from its two different molecular configurations or isomers. For example, it is common biochemically for many compounds, natural and manufactured to exist as two molecular structures, both comprised of the same formula, chemically identical but spatially different, existing as superimposable mirror images. 

In most situations, only one form is biologically active. For example, in humans, amino acids have a left and right structure but only the left one can be utilized to create proteins.  The drug ibuprofen has 2 isomers but only one binds to a human receptor to relief pain.  

These configurations, or isomers, of LDN are both biologically active, a Left and Right form, whose functions are: 

Left (Levo) LDN Form 

The Levo LDN form temporarily blocks opioid pain receptors 

 

  •  Natural endorphins bind at opioid receptors initiating pathways that can modify pain perception. LDN is considered an antagonist to these substances by temporarily binding at these same receptors. While this blockade, lasts only a few hours, until the drug is metabolized by the liver, it causes an increase in endorphins and endorphin receptors post blockade, resulting in augmented and extended pain relief. 

  • The Levo form of LDN has been shown, in animal studies, to also temporarily inhibit opioid growth factor (OGF), opioid growth factor receptor (OGFr) interaction affecting cancer cell replication by modulating innate and adaptive immune responses.

  • Both cancer and normal cells express an opioid growth factor (OGF), called (met5) enkephalin. It binds to its opioid growth factor receptor (OGFr) on the cell surface, transfers into the cell, and transported to the nucleus. It transiently blocks this OGF/OGFr link, which appears to increase both OGF and OGFr receptors when the blockage ends.

  • This growth factor/receptor combination plays a role in hindering cancer progression via activation of two cyclin-dependent kinase inhibitory pathways, P16 and P21. The P16 pathway slows DNA replication of cancer cells and P21 pathway links cell damage to preventing further cancer cell replication via P53 tumor suppressor gene.  

  • In laboratory studies, research using cancer cells from almost three dozen different human cancer cell lines has shown that this OFG/OFGr pathway can suppress cancer cell growth in the colon, liver, pancreas, stomach, ovary, squamous head and neck and leukemic cancer cells. 

  • In animal models, LDN also augment the immune response to cancer cells by increasing proinflammatory cytokine messages that increase macrophage activity to engulf and remove abnormal cells, and also increase CD8 T cell lymphocytes (Natural Killer cells) which are capable of killing cancer cells. 

LDN affects the ability of cancer cells to avoid programmed death. 

  • Cancers use multiple evasion tactics to avoid destruction. In the body, apoptosis is the genetically controlled system that regulates cell death in circumstances of abnormal, stressed, aged, or damaged cells. 

This system is regulated by a family of controlling proteins: 

BCL (B-cell lymphoma) proteins that are anti-apoptotic or supportive of cell survival 

BAX proteins are pro-apoptotic, supporting cell death. 

The origination and progression of cancer requires that cells are able to both avoid death and prolong survival and they capable of doing this by manipulating these proteins in a favorable manner to increase BCL anti-apoptotic proteins for continued existence as well as decreasing BAX pro death signaling proteins.

  • Research shows that in cancer, LDN is able through its intermittent receptor blockade effect on OGF/OGFr pathway, to influence the expression of BAX and BCL proteins to increase cell death and decrease cell survival.  

  • The OGF/OGFr pathway also can modulate cancer angiogenesis, or cancer’s development of new blood vessels to supply nutrients and a method of spread. 

  • Ovarian cancer is the leading cause of death from gynecologic cancers, with a large percentage of women having progression or recurrence, even with treatment. Using LDN in ovarian cancer tissue cultures and in mice with these tumors, LDN decreased tumor progression, and while not increasing survival, when given in combination with cisplatin it reduced cisplatin weight loss and increased OGF/OGFr which impacts cancer progression. This research article suggests its potential as a integrative addition in western oncology. 

Right (Dex) Form:  

This structure of naltrexone, in low dose, can modulate immune cell dysfunction that has resulted in persistent overexpression of chronic inflammatory associated autoimmune diseases.   

LDN binds and temporarily blocks some Toll Like Receptors (TLRs), especially (TLR-4) by disrupting signaling to cytokine messengers that are activating pro-inflammatory responses.  

  • Toll like receptors (TLR) are a family of immune receptors that trigger front line immune responses and are expressed on many sentinel defensive cells such as, neutrophils, monocytes, eosinophils, dendritic (surveillance cells) and natural killer (NK) cells. They recognize patterns from foreign molecules; infectious particles called pathogen associated molecular patterns (PAMPS) or damaged cellular material called damaged associated molecular patterns (DAMPS), which when recognized activate a cascade of several pro-inflammatory responses through cell signaling. Toll like receptor-4 (TLR-4) controls and upregulates inflammation by enhancing the response from such inflammatory substances as NF-kB, Interferon, and tissue necrosis factor (TNF) which effect microglia, the main form of immune protection in the brain, mast cells and macrophages, a white blood cell that engulfs pathogens and abnormal cells. 

  • LDN inhibits this activation of cytokine messaging that up regulates pro-inflammatory compounds. Using LDN daily and consistently has been observed to assist in controlling autoimmune disease. 

  • This right isomer of LDN is also an important supportive therapy that can be used for chronic nerve pain. 

Other Beneficial Effects of LDN 

LDN has been shown in research testing to improve hyperinsulinemia and insulin resistance, which offers another complementary effect in cancer.  

Our mitochondria are cellular organelles designed to efficiently convert glucose sugar into chemical energy, called ATP, via an aerobic or oxygen driven pathway. Energy creation, and other cellular metabolic processes, for instance, digestion, cardiovascular and neurologic activities as well as immune actions all produce secondary by products called reactive oxygen and reactive nitrogen species, which are damaging to the body unless neutralized and detoxified.  

In mitochondrial glucose utilization, insulin is necessary to transport sugar across its cellular membranes to be utilized. When available resources for detoxification become limited, energy production is slowed and diminished. In an attempt to compensate, insulin levels are increased (hyperinsulinemia) to drive more glucose into the mitochondria. But this strategy is ineffective, as the insulin receptors develop less sensitivity, (insulin resistance). Insulin excess results in: 

  • Heightened levels of inflammation 

  • Storage of excess unused sugar as fat  

  • Obesity  

  •  Risk of developing diabetes increases 

  • Increased risk of breast, prostate and colon cancers 

Normally, the compound SIRT-1 (silent information regulator -1) acts genetically to regulate the expression of blood sugar balance, mitochondrial function, programmed cell death or apoptosis, and chronic inflammation. But in situations of hyperinsulinemia and insulin resistance, SIRT-1 activity is blocked, inhibiting this ability.  

This effect on SIRT-1, shifts the mitochondria to an alternative energy pathway, that converts glucose to sugar, without oxygen, called glycolysis, which while bypassing the impaired aerobic pathway, is very inefficient. However, it is preferential method to create energy in cancer cells and encourages their growth and progression. 

Biochemical studies and in vivo animal testing  have demonstrated that  

LDN can:  

  • Reverse SIRT-1 repression and restore its regulatory functions, thereby abolishing hyperinsulinemia (insulin excess) and improve insulin resistance and help a shift toward normal aerobic energy creation.  

When SERT-1 one activity is reestablished however, it doesn't change the initial problem of the accumulation of combustion byproducts affecting normal aerobic energy production. 

That solution is provided by the complex pathway of detoxification, which is designed to move these undesirable substances from storage in the body, through the liver and excreting them through the gut or kidneys. 

But if the demand for necessary compounds to accomplish these steps becomes inadequate, then focusing on its causes will commonly point to the initiation by environmental toxins such as heavy metals, organic and inorganic solvents, pesticides and herbicides, petrochemicals and other industrial chemicals in our air and groundwater.  

For a more complete explanation of this process see the article on the website, the initiating causes and downstream effects that are associated with cancer causation. 

Everyone in contemporary society is exposed to some level of environmental burden and everyone needs to be detoxing at some level. As a proactive approach, seeking an experienced Integrative provider can provide testing for the body’s burden and develop specific treatment approaches designed to diminish them. Ultimately, this will allow systems to reboot and reestablish better organ functions. 

For healthy individuals, detoxification can be a beneficial approach to maintaining optimal health. However, cancer patients should avoid detoxification processes during active treatment, as these can adversely impact the metabolism of cancer treatment drugs. 

Once cancer therapy is completed and a person enters ongoing surveillance, specific detoxification protocols can be initiated, but is crucial to start these processes at a very gentle level and slowly increase them. This approach can complement the reactivation of SIRT1 (a protein involved in cellular regulation), which assists in reducing insulin levels and insulin resistance. It also aids in removing chemical compounds that inhibit normal energy production in cells and can be toxic to the body. 

By implementing this strategy and helping the body switch back to aerobic metabolism (using oxygen to produce energy), cancer growth and progression can potentially be hindered. This is because many cancer cells rely heavily on anaerobic metabolism (producing energy without oxygen) and shifting back to aerobic metabolism can create an environment less favorable for cancer growth. 

The use of LDN in this context can support these processes by potentially modulating the immune system and influencing cellular regulation. However, it's important to note that this approach should be undertaken only under the guidance of healthcare professionals and as part of a comprehensive cancer care plan. 

Therapy With LDN  

LDN and opioids cannot be given simultaneously, as the LDN will block the receptor preventing opioid drugs from being effective, and may precipitate withdrawal symptoms 

It must be stated that evidence supporting the use of low dose naltrexone cannot be substantiated by scientifically controlled studies in any disease. Abundant documentation from laboratory research evidence supports its potential benefits, and lack of side effects, but is unlikely that patient studies will be implemented, unless perhaps continued observational experience suggests the importance of pursuing patient specific disease trials. 

Understandably, there are several potential therapy benefits for low dose naltrexone as a complement in cancer treatment, as well as supportive care for autoimmune illnesses. These indications were not tested clinically during the initial clinical trials application, therefore the FDA would require specific LDN clinical testing, patient studies, to document its risk/benefits. This would be prohibitively expensive, and for a drug already generically available, the ability to recoup the costs of clinical trials would make the return on investment negligible. 

Therefore, the use of LDN is an unapproved indication for naltrexone, however there are many drugs being utilized in treatments for indications considered “off label “and LDN is currently being used this way by practitioners familiar with its use. Most experienced providers are affiliated with the nonprofit, LDN Research Trust, which offers expertise in LDN treatment, both in supportive cancer therapies as well as autoimmune illness. Professional guidance is essential so that patients understand realistic expectations for using it, correct dosing methods, management of any side effects and careful monitoring.  The Trust is the most complete patient and physician resource. 

Considerations in Prescribing Low Dose Naltrexone 

LDN is a unique medication having dual functions and abilities by being able to both augment and inhibit immune responses. The question then is how it will know which direction to go in a specific situation. In cancer, abnormal cells are replicating and growing out of the control of the immune system. The goal is to inhibit cancer progression by inhibiting growth and encouraging cancer cell death. This is the action of the LEVO LDN form. 

In autoimmune disease, often the phenomenon of mimicry occurs in which a triggering substance resembles a normal tissue and the immune system attacks both. It creates excessive inflammation, against itself, when it should not.  The solution in this situation is to put the brakes on the immune system, shut down this excessive inflammation and protect organ systems from damage. The DEXTRO form can dampen down and regulate this immune response by curtailing inflammation. 

So, while we understand the effects of each LDN isomer we don’t know what decides its actions but thankfully it does it correctly!  

Dosing, in cancer, is designed to reach a maximum of 4.5mg. It should always be prepared by a certified compounding pharmacy, and always in an immediate release form, using one of several available preparations, oral tablets or capsules, sublingual drops, or troches.  

Dosing is often in the evening, and once daily, unless it interrupts sleep, then am dosing should be used. Usually, in cancer, the initial starting dose is 1.5mg, once daily, for a week, then increase by 1.5 mg weekly until a dose of 4.5mg is achieved.  And while LDN is taken daily in other situations, the cancer dosing is 3 days on and 4 days off, and there should be drug” holidays “during chemotherapy infusion days and the day after.  

LDN can be taken with other medications, as long as they are non-opiate drugs. Contraindications include allergy to ingredients used in compounding, acute hepatitis or withdrawing from opioids. 

CBD has been used together with LDN, and observational information suggests it may enhance its effect. 

Contraindications  

LDN can be used while receiving chemotherapy except with PD-1 checkpoint inhibitors, Opdivo or Keytruda. 

Common side effects are commonly seen with initiation and increases in dosages. 

These include:  

  • Nausea 

  • Abdominal discomfort  

  • Insomnia 

  • Headache 

  • Sleep disturbance  

  • Agitation  

  • Fatigue  

  • Flu like symptoms 

  • Most of the common symptoms listed are transient and occur when initially starting LDN. If they are bothersome, stop LDN for a few days and restart a decreased the dose slowly returning to the original dose as symptoms resolve. 

  • Care should be taken in autoimmune Hashimoto’s thyroid disease, as it might provoke hyperthyroidism , and it might also cause increased muscle spasticity in Parkinson’s disease. 

LDN and Surgical Preparation 

Situations can arise that surgical treatment becomes necessary for either or both diagnosis/and or as a therapeutic modality, and often narcotics are needed post-operatively. 

The half-life of LDN is short, 4-6hours, but pharmacists and physicians recommend stopping LDN two to three days before an elective procedure.  Generally, the narcotic medications for post-op pain recommend dosing every 4-6 hours, in acute pain situations, and to achieve this the LDN needs to be absent and the receptors able to bind the narcotics for maximum effectiveness.  Thus, this time window provides for a rebalancing of the receptors and successful pain control. 

When the narcotics are discontinued, and the time interval is less than 2 weeks being off the LDN, recommencement of the current dosage can be started. If the interval is greater than 2 weeks, resuming the same previous dosage can precipitate side effects such as   insomnia, headache or digestive upset, and these can be reduced or eliminated by starting on a very low dose with slow incremental increases. In clinical experience, it has also been noted that symptomatic improvement can sometimes occur at lower doses than initially used. Perhaps increased receptor sensitivity?  

 

References

Meng, Y., Gao, X., Chen, W., Plotnikoff, N.P., Griffin, N., Zhang, G. and Shan, F., 2017. Methionine enkephalin (MENK) mounts antitumor effect via regulating dendritic cells (DCs). International Immunopharmacology, 44, pp.61-71. 

Sprouse-Blum AS, Smith G, Sugai D, Parsa FD. Understanding endorphins and their importance in pain management. Hawaii Med J. 2010 Mar;69(3):70-1. PMID: 20397507; PMCID: PMC3104618.  

Martin, S. J., McAnally, H. B., Okediji, P., & Rogosnitzky, M. (2022). Low-Dose Naltrexone, an Opioid-Receptor Antagonist, is a Broad-Spectrum Analgesic: A Retrospective Cohort Study. Pain Management, 12(6), 699–709. https://doi.org/10.2217/pmt-2021-0122 

Donahue RN, McLaughlin PJ, Zagon IS. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. Gynecol Oncol. 2011 Aug;122(2):382-8. doi: 10.1016/j.ygyno.2011.04.009. Epub 2011 Apr 30. PMID: 21531450. 

Szczepaniak A, Fichna J, Zielińska M. Opioids in Cancer Development, Progression and Metastasis: Focus on Colorectal Cancer. Curr Treat Options Oncol. 2020 Jan 22;21(1):6. doi: 10.1007/s11864-019-0699-1. PMID: 31970561; PMCID: PMC6976545. 

Preclinical and clinical studies into the bioactivity of low-dose naltrexone (LDN) for oncotherapy 

https://www.sciencedirect.com/journal/international-immunopharmacology 

Author links open overlay panel Na Qu a, Yiming Meng b, Mike K. Handley c, Chunyan Wang a, Fengping Shan d

Ciwun M, Tankiewicz-Kwedlo A, Pawlak D. Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy. Cancers (Basel). 2024 Mar 21;16(6):1240. doi: 10.3390/cancers16061240. PMID: 38539570; PMCID: PMC10968813. 

Sameer AS, Nissar S. Toll-Like Receptors (TLRs): Structure, Functions, Signaling, and Role of Their Polymorphisms in Colorectal Cancer Susceptibility. Biomed Res Int. 2021 Sep 12; 2021:1157023. doi: 10.1155/2021/1157023. PMID: 34552981; PMCID: PMC8452412. 

The LDN Book-3, edited by Linda Elsegood  

The LDN Book -1, edited by Linda Elsegood