🧪The Hidden Medicine Cabinet
Why One Old Drug Might Hold Keys to Our Chronic Illness Crisis
Old medicine's
gentle whisper calms the storm—
immune balance found
With every article and podcast episode, we provide comprehensive study materials: References, Executive Summary, Briefing Document, Quiz, Essay Questions, Glossary, Timeline, Cast, FAQ, Table of Contents, Index, Polls, 3k Image, Fact Check and
Comic at the very bottom of the page.
When a 50-year-old addiction medication starts reversing autoimmune diseases, clearing brain fog, and helping cancer patients—maybe it's time we stopped thinking about medicine the way pharmaceutical companies want us to.
We live in an age of medical gaslighting disguised as evidence-based care. Millions of people suffer from conditions that conventional medicine can't explain, won't treat, or dismisses as psychological. Long Covid patients know this intimately—told their debilitating symptoms are "just anxiety" while their immune systems wage war against their own bodies.
But what if I told you there's a medication sitting in medicine cabinets right now that's helping people with everything from autoimmune diseases to cancer to chronic fatigue? A drug so old it's generic, so cheap it costs pennies, and so effective at low doses that Big Pharma has zero financial incentive to study it properly?
Welcome to the strange world of Low Dose Naltrexone (LDN), where a medication designed to treat heroin addiction at high doses becomes a powerful immune modulator when used at 1/10th the standard amount. It's a perfect microcosm of everything broken about our healthcare system—and everything hopeful about medicine when profit isn't the primary motive.
The Broken Epistemology of Modern Medicine
Let's start with a uncomfortable truth: our medical system is designed around patentable solutions to isolated problems. Got high blood pressure? Here's a pill. Autoimmune disease? Here's an immunosuppressant that costs $50,000 a year. Depression? Try this SSRI that may or may not work better than a placebo.
This reductionist approach falls apart completely when confronted with the reality of chronic illness. These conditions don't fit into neat diagnostic boxes because they stem from systemic dysfunction—dysregulated immune systems, chronic inflammation, mitochondrial problems, and gut microbiome disasters that cascade through interconnected biological networks.
LDN works precisely because it targets these fundamental imbalances rather than suppressing symptoms. At doses between 1.5-4.5mg (compared to 50mg for addiction treatment), naltrexone briefly blocks opioid receptors, triggering the body to produce more endorphins and upregulate receptor sensitivity. More importantly, it modulates immune function by inhibiting Toll-like receptor 4 (TLR4), a key player in chronic inflammation.
Think of TLR4 as a smoke detector in your immune system. When it's working properly, it identifies real threats and sounds appropriate alarms. But when it gets stuck in the "on" position—triggered by infections, toxins, stress, or even certain foods—it creates the persistent, low-grade inflammation that drives autoimmune diseases, cancer progression, and post-viral syndromes like Long Covid.
The Long Covid Connection
Long Covid has become the poster child for medical gaslighting, with millions of patients told their symptoms are psychological while mounting evidence points to measurable biological dysfunction. Post-viral syndromes aren't new—we saw similar patterns after the 1918 flu pandemic and H1N1. What's different now is our ability to understand the mechanisms.
The research reveals aberrant monocytes loaded with viral spike protein invading tissues months after infection. T-cell exhaustion preventing the immune system from clearing reactivated viruses like Epstein-Barr. Chronic neuroinflammation affecting everything from cognition to autonomic function. These aren't vague, psychosomatic complaints—they're measurable immune dysfunction.
Yet patients report significant improvements with LDN, often starting with dramatic clearing of brain fog within weeks. Why? Because LDN addresses the underlying immune dysregulation rather than suppressing individual symptoms. It's not masking the problem; it's helping restore normal immune function.
The Patent Problem
Here's where the story gets infuriating. Naltrexone went generic decades ago, which means there's no financial incentive for pharmaceutical companies to fund the massive clinical trials needed for FDA approval of new indications. A company might spend $500 million proving LDN works for autoimmune diseases, only to watch competitors sell identical generic versions the day after approval.
This creates a catch-22: without large randomized controlled trials, LDN remains "off-label" and "unproven" by conventional standards. But off-label prescribing represents about 20% of all prescriptions written—it's a normal part of medical practice when the clinical evidence supports it and patients aren't responding to standard treatments.
The tragedy is that thousands of people are suffering from conditions that might respond to a safe, inexpensive medication while we wait for a profit motive that will never materialize. It's a perfect example of how our healthcare system prioritizes shareholder value over patient outcomes.
The Autoimmune Epidemic
Autoimmune diseases have tripled in developed countries over the past few decades, affecting over 50 million Americans. The conventional approach treats these as separate conditions requiring different specialists and expensive biologics that suppress immune function—often with serious side effects.
But what if most autoimmune diseases are variations on a theme? What if they're all manifestations of the same underlying problem: an immune system that's lost the ability to distinguish self from non-self, creating chronic inflammation that damages whatever tissues are most vulnerable in each individual?
The LDN research suggests exactly this. By modulating fundamental immune pathways rather than suppressing them entirely, LDN appears to help restore immune balance. Patients with mixed connective tissue disease, inflammatory bowel conditions, multiple sclerosis, and other autoimmune diseases report significant improvements—not just symptom management, but actual disease modification.
One case study particularly stands out: a woman with multiple autoimmune conditions and recurrent breast cancer who saw dramatic improvement in her quality of life after adding LDN, high-dose vitamin D, and dietary changes. Her anxiety resolved to the point where she no longer needed benzodiazepines. This isn't just treating a disease—it's restoring health at a systems level.
The Cancer Question
Perhaps most intriguingly, LDN appears to have anti-cancer properties through multiple mechanisms. It concentrates in the liver and inhibits TLR9, reducing inflammatory signals like IL-6 that promote cancer progression. At low doses, it affects gene expression in ways that promote apoptosis (programmed cell death) in cancer cells while potentially sensitizing tumors to conventional treatments.
The case studies are remarkable: a patient with liver metastases achieving long-term disease-free status after adding LDN when chemotherapy failed. An end-stage kidney cancer patient with widespread metastases showing no evidence of disease on follow-up scans after combining LDN with melatonin, mistletoe, and dietary changes.
These are anecdotal reports, not controlled trials. But they're consistent with the biological mechanisms and suggest LDN might work synergistically with other treatments to improve outcomes in cancer patients who have few options left.
The Path Forward
The LDN story reveals both the promise and the problems of modern medicine. We have a safe, inexpensive medication with compelling biological rationale and thousands of success stories across multiple conditions. We also have a regulatory and economic system that makes it nearly impossible to generate the evidence that would make it standard of care.
This leaves patients and providers in an impossible position: wait for studies that may never happen, or use clinical judgment to try treatments that make biological sense and have excellent safety profiles. Increasingly, both patients and providers are choosing the latter.
The broader lesson isn't just about LDN—it's about recognizing that chronic illness often requires a fundamentally different approach than acute care. Instead of suppressing symptoms with expensive medications, we need to identify and address root causes: immune dysfunction, chronic infections, nutritional deficiencies, toxic exposures, and stress.
LDN works because it's part of this systems approach, often combined with dietary changes, targeted nutrients, infection treatment, and lifestyle modifications. It's not a magic bullet—it's a tool in a comprehensive toolkit for restoring health rather than just managing disease.
The question isn't whether LDN works—the biological mechanisms are clear and the clinical observations are consistent. The question is whether our medical system can evolve beyond its current profit-driven paradigm to embrace treatments that prioritize healing over revenue.
Until then, patients will continue to advocate for themselves, seek out knowledgeable providers, and share their stories with others who are suffering unnecessarily. Because sometimes the most revolutionary act is simply refusing to accept that your suffering is inevitable, imaginary, or untreatable.
The medicine cabinet of the future might look surprisingly like the medicine cabinet of the past—if we're brave enough to look beyond the marketing.
Link References
The LDN Book, Volume 3 is both a resource for practitioners, pharmacists and patients and a renewed call for further research on the healing potential of this generic drug
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STUDY MATERIALS
Briefing
Executive Summary:
The provided sources explore the therapeutic potential of Low-Dose Naltrexone (LDN) in treating a range of inflammatory and autoimmune conditions, with a specific focus in one source on its effect on Natural Killer (NK) cell function in Long COVID patients. LDN, a μ-opioid receptor antagonist at higher doses, exhibits different mechanisms at lower doses, including counteracting the inhibitory function of opioid receptors on TRPM3 ion channels and increasing endorphin release. The research highlights compromised TRPM3 function in NK cells from Long COVID patients and suggests that LDN treatment may restore this function, potentially contributing to improved immune responses and reduced disability. The second source provides broader context on LDN's applications, pharmacology, and its role in addressing various systemic factors implicated in chronic illnesses, including the microbiome, endocrine system, and peptides. Both sources underscore the anti-inflammatory and immune-modulatory effects of LDN and the challenges associated with its off-label use.
Key Themes and Important Ideas/Facts:
1. Low-Dose Naltrexone (LDN) Pharmacology and Mechanism of Action:
Naltrexone (NTX) is a μ-opioid receptor antagonist primarily used at higher doses (50-100 mg) for addiction treatment.
At low doses, NTX has different actions.
LDN (specifically the levo-naltrexone isomer) acts as an antagonist for opiate/endorphin receptors, leading to increased endorphin release.
"To summarize the past ten years of research, LDN is effective because levo-naltrexone is an antagonist for the opiate/endorphin receptors, leading to increased endorphin release." (The LDN Book 3)
LDN counteracts the inhibitory function of opioid receptors on TRPM3 ion channels, thereby restoring TRPM3 function and reestablishing Ca2+ influx.
"Notably, as a μ-opioid receptor antagonist, NTX counteracts the inhibitory function of opioid receptors on TRPM3 ion channels, thereby restoring TRPM3 function and reestablishing Ca2+ influx" (Sasso et al., 2025)
Opioid receptors are widely distributed in various tissues, including immune cells, and can exert both immunomodulatory and immunosuppressive effects.
2. TRPM3 Ion Channels and Their Role in NK Cells:
TRPM3 (Transient Receptor Potential Melastatin 3) ion channels are discussed as being functionally impaired in NK cells from Long COVID patients.
TRPM3 channels are involved in Ca2+ influx, which is crucial for various cellular functions, including immune cell activity.
The study by Sasso et al. (2025) specifically investigated endogenous TRPM3 ion channel function in NK cells from healthy controls (HC), Long COVID patients, and Long COVID patients treated with LDN using whole-cell patch-clamp experiments.
3. Long COVID and NK Cell Dysfunction:
The Sasso et al. (2025) study focused on assessing TRPM3 function in NK cells from Long COVID patients.
The study's objective was to determine if LDN could restore impaired TRPM3 function in these cells.
Long COVID patients in the study exhibited significantly lower quality of life and higher disability scores across multiple domains compared to healthy controls (based on SF-36 and WHODAS assessments).
See Table 2 in Sasso et al. (2025) for detailed comparisons across SF-36 and WHODAS domains, showing statistically significant differences between Long COVID groups and healthy controls in areas like physical functioning, physical role, pain, social functioning, mobility, life activities, and participation in society.
4. LDN's Impact on TRPM3 Function in Long COVID NK Cells:
The Sasso et al. (2025) study presents data suggesting that LDN treatment is associated with restored TRPM3 ion channel function in NK cells from Long COVID patients.
The figures illustrate the current obtained in response to TRPM3 modulation (using PregS and ononetin) in NK cells from the different groups, visually demonstrating a difference in response between the Long COVID group and the HC and LDN-treated Long COVID groups.
5. Broader Applications of LDN and its Anti-inflammatory/Immune-Modulatory Effects:
"The LDN Book 3" emphasizes LDN's use in treating a wide range of inflammatory conditions.
"Low dose naltrexone has been shown to be one of the keys to the future of medicine for many disease processes that are inflammatory in nature." (The LDN Book 3)
LDN is considered an efficacious pain control agent.
LDN is discussed as a potential treatment for various conditions, including but not limited to those featured in "The LDN Book" series (e.g., multiple sclerosis, various cancers, drug-resistant depression, virally damaged tissues, longevity, mixed connective tissue disease, mold illness and CIRS, ophthalmic conditions).
LDN has been shown to have positive benefits in immune diseases affecting the GI system (Crohn's disease, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome).
"As can be seen from the extensive research gathered by the LDN Research Trust, LDN has been shown in many studies to have positive benefits in immune diseases that center on the GI system..." (The LDN Book 3)
LDN decreases damaging inflammatory cytokines.
"LDN decreases the damaging inflammatory cytokines produced in the gut..." (The LDN Book 3)
One paper cited in "The LDN Book 3" showed a reduction of inflammatory cytokines with the use of oral LDN in ten weeks, including IL-1, IL-6, TNFα, and others.
"We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN), transforming growth factor. TGF-β, tumour-necrosis factor TNFα , and granulocyte-colony stimulating factor (G-CSF)." (The LDN Book 3, citing another paper)
LDN supports the immune system to improve the balance of the microbiome.
LDN can help balance hormones, including stress hormones, and has a balancing effect on the HPA axis.
"LDN is known to help balance stress hormones as well. LDN has a balancing effect on the HPA axis and all the body’s hormones." (The LDN Book 3)
LDN is discussed in the context of its interaction with the microbiome, endocrine system, peptides, and other systemic factors influencing chronic illness.
6. Peptides and Their Connection to Immune Function and Healing:
The concept of peptides as short chains of amino acids with diverse physiological roles is introduced.
Peptides are discussed as controlling and modulating most bodily systems, including immune function, hormone production, healing, and aging.
Immune modulating peptides, often secreted by or affecting the pineal-thymic-immune axis, are highlighted for their ability to normalize a dysfunctional immune system, shifting it away from an inflammatory and autoimmune state.
Specific peptides like thymosin alpha-1, thymogen, vilon, thymosin beta 4 (TB4), and BPC-157 are mentioned for their immune-modulatory and healing properties.
The C-terminal tripeptide of MSH, KPV, is presented as a potent anti-inflammatory and antimicrobial peptide, orally bioavailable and effective for conditions like mast cell activation syndrome (MCAS) and neuroinflammation.
7. Challenges and Considerations for LDN Use:
LDN is largely used in an unlicensed (off-label) way for many of the conditions discussed.
The primary reason for the lack of licensing for LDN for these conditions is the financial disincentive for drug companies to invest in clinical trials for an inexpensive, generic drug.
"The fundamental problem with repurposing such an old drug is that it is available generically —relatively inexpensively—and even if a drug company were to invest millions in a clinical trial, there would be very limited protection for an end-product, therefore no way to recoup the cost of the trial." (The LDN Book 3)
Prescribers using LDN off-label must consider the legal framework and ensure proper patient consent and risk/benefit assessments are conducted and documented.
Compounding pharmacies play a crucial role in providing LDN in appropriate dosages and forms (e.g., oral liquid, sublingual drops, capsules, tablets), as commercial preparations for low doses are not widely available.
Compounding for ophthalmic use is particularly challenging due to the requirement for sterile preparations.
8. Potential Synergy of LDN with Other Therapies:
"The LDN Book 3" suggests that LDN can be part of a broader approach to addressing chronic illness, potentially used in conjunction with dietary changes, stress management techniques (like breathing exercises), and peptide therapies.
LDN's effects on the microbiome, hormones, brain function, and energy production are seen as supportive of overall health and the ability to implement other beneficial lifestyle changes.
Caveats and Limitations:
The Sasso et al. (2025) study included a small sample size (N=9 per group).
There was a statistically significant age difference between the LDN group and the other groups in the Sasso et al. (2025) study, which is acknowledged as a potential confounder.
"The LDN Book 3" presents information from various practitioners and researchers, reflecting clinical experience and research findings, but the level of evidence for specific claims may vary.
The information regarding peptides and their specific effects is presented as part of a broader treatment strategy within "The LDN Book 3" and may require further independent verification.
Conclusion:
The provided sources offer valuable insights into the potential therapeutic mechanisms and applications of Low-Dose Naltrexone. The Sasso et al. (2025) study provides preliminary evidence suggesting that LDN may restore impaired TRPM3 ion channel function in NK cells of Long COVID patients, potentially contributing to improved immune function in this population. "The LDN Book 3" complements this by highlighting LDN's broader anti-inflammatory and immune-modulatory effects and its potential role in addressing systemic imbalances that contribute to chronic illnesses. While the off-label nature of LDN use presents challenges, the collective information suggests a promising area of research and clinical application for this medication in various chronic inflammatory and autoimmune conditions. Further larger, controlled studies are needed to confirm these findings and fully elucidate the mechanisms and efficacy of LDN in different patient populations.
Quiz & Answer Key
Quiz
What is the primary prescription use of naltrexone hydrochloride (NTX) at daily doses of 50-100 mg?
In the context of the electrophysiological experiments described, what is the function of L-aspartic acid in the intracellular pipette solution?
According to the provided data, what statistically significant demographic difference was observed between the study groups?
How are WHODAS scores converted from the initial five-point scale, and what does a lower score indicate?
Based on Figure 1, how does PregS typically affect the current amplitude in NK cells from healthy controls?
How does naltrexone, as a μ-opioid receptor antagonist, counteract the inhibitory function of opioid receptors on TRPM3 ion channels?
What does the presence of red lines in Figure 2 D-F indicate in the scatter plots?
According to The LDN Book 3, what is the fundamental problem preventing pharmaceutical companies from investing heavily in clinical trials for LDN?
Based on the information in The LDN Book 3, what is the primary difference between a peptide and a protein based on amino acid chain length?
According to the excerpts from The LDN Book 3, what is one reason why eye exams may be an early warning system for autoimmune disorders?
Quiz Answer Key
The primary prescription use of naltrexone hydrochloride (NTX) at daily doses of 50-100 mg is for the treatment of alcohol or opioid dependence.
L-aspartic acid is added to the intracellular pipette solution to reduce the risk of chloride current involvement in TRPM3 assessment and to distinguish the reversal potential of Cl- currents from cation currents.
A statistically significant difference in age was observed among the groups, primarily due to the older average age in the LDN treatment group compared to the other groups.
WHODAS scores are converted from the five-point scale to a percentage from 0% to 100%, with lower scores indicating less disability and 100% representing full disability.
Based on Figure 1, PregS typically stimulates TRPM3, leading to an increase in the current amplitude in NK cells from healthy controls.
As a μ-opioid receptor antagonist, naltrexone counteracts the inhibitory function of opioid receptors, thereby restoring TRPM3 function and reestablishing Ca2+ influx.
In Figure 2 D-F, red lines indicate cells sensitive to ononetin, characterized by a reduction in current amplitude after its application.
The fundamental problem is that naltrexone is available generically and inexpensively, offering limited patent protection for an end-product and no way for a drug company to recoup the cost of a clinical trial if they were to invest millions.
By definition, a peptide is a compound made of two or more amino acids linked in a chain; if the chain is longer than 40 amino acids, it is called a protein.
Eye exams may be an early warning system because the same underlying pathophysiological changes found in the eye (such as inflammation and cytokine profiles) are also present in the rest of the patient's body and are associated with autoimmune disorders.
Essay Questions
Discuss the methodology of the electrophysiological patch-clamp experiments described in the source material, including the solutions used, the equipment, and the voltage protocol, and explain the purpose of each component.
Analyze the findings regarding quality of life and disability scores (SF-36 and WHODAS) presented in Table 2, comparing the three participant groups and discussing the implications of the statistically significant differences observed.
Explain the proposed mechanism by which low-dose naltrexone (LDN) impacts TRPM3 ion channel function, referencing the role of μ-opioid receptors and Gβγ protein subunits.
Synthesize the information provided in The LDN Book 3 regarding the use of LDN in the context of unlicensed (off-label) prescribing, outlining the considerations and steps a prescriber should take when making a decision to use LDN in this manner.
Drawing upon the information from The LDN Book 3, describe the concept of peptides and their diverse roles in the human body, providing specific examples of immune-modulating peptides and their purported effects.
Glossary of Key Terms
μ-opioid receptor antagonist: A substance that blocks the activity of mu (μ)-opioid receptors. Naltrexone is an example.
TRPM3 (Transient Receptor Potential Melastatin 3): An ion channel involved in regulating calcium influx into cells.
LDN (Low-Dose Naltrexone): Naltrexone prescribed at doses significantly lower than those used for opioid or alcohol dependence.
NK (Natural Killer) cells: A type of cytotoxic lymphocyte critical to the innate immune system.
Electrophysiological experiments: Techniques used to measure the electrical activity of cells, such as patch-clamp.
Patch-clamp: A technique used in electrophysiology to measure the flow of ions across the membrane of a single cell.
PregS (Pregnenolone sulfate): A neurosteroid that can act as an agonist for TRPM3 ion channels, stimulating their activity.
Ononetin: A compound that can act as an inhibitor for TRPM3 ion channels, blocking their activity.
I–V curve (Current-Voltage curve): A graph that plots the electrical current across a membrane as a function of the applied voltage, used to characterize ion channel activity.
HC (Healthy controls): Individuals included in a study who do not have the condition being investigated, serving as a comparison group.
Long COVID: Persistent symptoms that continue for weeks or months after the initial SARS-CoV-2 infection.
WHODAS (World Health Organization Disability Assessment Schedule): A standardized tool used to assess disability across various life domains.
SF-36 (36-item Short-Form Health Survey): A widely used patient-reported survey that measures quality of life across eight health domains.
GPCR (Guanine nucleotide-binding protein-coupled receptors): A large family of transmembrane receptors that play diverse roles in cell signaling.
Ca2+ (Calcium): A vital ion involved in numerous cellular processes, including immune cell function and ion channel activity.
Unlicensed (Off-label) Use: Prescribing a medication for a condition, dosage, or age group not specifically approved by regulatory authorities.
Isomers: Molecules with the same chemical formula but different structural arrangements.
Endorphins/Met-enkephalins: Natural opioid peptides produced by the body.
Microbiome: The collection of microorganisms living in a particular environment, such as the human gut.
Dysbiosis: An imbalance in the composition or function of the microbiome.
Peptide: A compound consisting of two or more amino acids linked in a chain. Generally shorter than a protein.
Protein: A large molecule made up of one or more long chains of amino acids. Generally longer than a peptide (more than 40 amino acids).
HPA axis (Hypothalamus, Pituitary and Adrenal glands): A complex set of interactions between endocrine glands that controls stress response, mood, energy levels, and more.
Cytokines: Small proteins secreted by cells that influence the immune system and cell communication; can be pro-inflammatory or anti-inflammatory.
TRP channel: Transient Receptor Potential channel, a diverse group of ion channels involved in sensing various stimuli.
Immunomodulatory: Having the ability to modify or regulate the immune system.
Immunosuppressive: Having the ability to suppress the immune system.
CIRS (Chronic Inflammatory Response Syndrome): A multi-system, multi-symptom illness often associated with exposure to biotoxins like mold.
Mycotoxins: Toxic compounds produced by certain types of fungi (molds).
Leaky Gut: Increased permeability of the intestinal lining, allowing larger molecules to pass into the bloodstream.
Leaky Brain: Increased permeability of the blood-brain barrier.
MSH (Melanocyte-Stimulating Hormone): A peptide hormone involved in various functions, including skin pigmentation, inflammation, and neuroprotection.
KPV: The C-terminal tripeptide fragment of MSH, noted for potent anti-inflammatory and antimicrobial effects.
MCAS (Mast Cell Activation Syndrome): A condition where mast cells inappropriately release chemical mediators, leading to various symptoms.
Th1/Treg: Types of T helper cells associated with cell-mediated immunity and immune tolerance.
Th2/Th17: Types of T helper cells associated with humoral immunity, allergic reactions, and inflammation.
Thymosin alpha-1 (TA1), Thymogen, Vilon: Immune-modulating peptides associated with stimulating Th1/Treg responses.
BPC-157 (Body Protection Compound-157): A peptide with healing, anti-inflammatory, and organoprotective effects.
Aqueous humor: The fluid filling the space between the cornea and the lens in the eye.
Vitreous humor: The gel-like substance filling the large space behind the lens and in front of the retina in the eye.
Uvea: The middle layer of the eye wall, consisting of the iris, ciliary body, and choroid; forms the blood-ocular barrier.
Blood-ocular barrier: A barrier that restricts the passage of substances from the bloodstream into the eye.
Hypercoagulability: An increased tendency of blood to clot.
Lumbrokinase, Nattokinase: Enzymes that can help break down fibrin and reduce blood clotting.
Timeline of Main Events
Early 20th Century: Chemist Dr. Emil Fischer is considered the founder of peptide chemistry and likely coined the term "peptide." He envisioned the synthesis of proteins from animal organs.
Early 20th Century: Researchers Sir William M. Bayliss and Dr. Ernest Starling discover secretin, a peptide hormone. For this discovery, they were nominated for a Nobel Prize in Physiology.
1920s: Insulin, a peptide/protein, is isolated and begins to be used therapeutically in people with diabetes, marking a significant breakthrough.
1965: Scientists in China successfully synthesize insulin, fulfilling Dr. Emil Fischer's earlier vision. Insulin becomes widely used in medicine.
1984: Naltrexone, at a full dose of 200mg daily, is licensed for use in treating alcohol or opioid dependence.
Mid-2000s (Approx.): Dr. Yusuf M. (JP) Saleeby encounters low-dose naltrexone (LDN) when a patient asks him to research it for autoimmune thyroiditis. He begins using LDN in his integrative medicine practice.
2009: A study on yoga, yogic breathing, and other breathing techniques is noted with regard to longevity and their effect on biomarkers like the HPA-axis.
2017: A study led by Dr. Tolahunase (YMLI study) shows significant improvements in biomarkers of cellular aging and metabolic biomarkers after 12 weeks of Yoga and Meditation-Based Lifestyle Intervention in a healthy adult cohort.
2022 (October): "The LDN Book 3" is first printed, published by the LDN Research Trust.
2024/2025 (Implicit): The research paper "Low-Dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients" is published, describing experiments conducted to investigate the effect of LDN on natural killer cells from long COVID patients. The paper includes details about participant recruitment, sample preparation, electrophysiological experiments, and statistical analysis performed to assess TRPM3 ion channel function.
Ongoing: Research into exosomes (decellularized nanoparticles) as a potential drug delivery system is described as being in its early stages. The connection between LDN and exosomes is noted as less evident currently.
Ongoing: Clinical use of LDN for a wide range of diseases continues, despite LDN not yet having a pharmaceutical license for these conditions. This involves off-label prescribing, which requires careful consideration of risk and benefit by clinicians.
Ongoing: Research and understanding of peptides continue, highlighting their role in controlling and modulating most bodily systems and their potential as optimization and replacement therapies.
Cast of Characters
Dr. Emil Fischer: German chemist, considered the founding father of peptide chemistry. He likely originated the term "peptide" and envisioned protein synthesis. Winner of the 1902 Nobel Prize in Chemistry.
Sir William M. Bayliss: Researcher who, along with Dr. Ernest Starling, discovered secretin. Nominated for a Nobel Prize in Physiology.
Dr. Ernest Starling: Researcher who, along with Sir William M. Bayliss, discovered secretin. Nominated for a Nobel Prize in Physiology.
Dr. Bernard Bihari: Pioneering clinician who initially used low-dose naltrexone (LDN) for the treatment of HIV and later for late-stage cancer.
Dr. Mark Shukman: Renowned psychiatrist who first described "Tired Brain Syndrome," characterized by specific signs of brain inflammation.
Ritchie C. Shoemaker: Author, mentioned in connection with mold illness/CIRS and the potential genetic predisposition due to HLA haplotype.
Dr. Tolahunase: Leader of a 2017 study on the effects of Yoga and Meditation-Based Lifestyle Intervention (YMLI) on cellular aging biomarkers.
Linda Elsegood: Editor of "The LDN Book 3" and likely involved with the LDN Research Trust, the publisher of the book.
Pamela W. Smith: Likely a medical professional (MD, MPH, MS), wrote the foreword for "The LDN Book 3," expressing hope about LDN's potential for healing.
J. Stephen Dickson BSC (HONS), MRPharmS: Author of Chapter One in "The LDN Book 3" on the pharmacology and best clinical practices of LDN. A pharmacist in the UK involved in stabilizing the LDN supply chain and standardizing prescription methods. Also involved in technology companies related to pharmacy.
Elizabeth Livengood: Author of Chapter Two in "The LDN Book 3" on drug-resistant depression.
Sarah J. Zielsdorf: Author of Chapter Three in "The LDN Book 3" on virally damaged tissues.
Yusuf M. (JP) Saleeby, MD: Author of Chapter Four in "The LDN Book 3" on LDN and longevity. A functional & integrative physician who uses LDN in his practice. Author of the epilogue in "The LDN Book 3".
Deanna Windham: Author of Chapter Five in "The LDN Book 3" on mixed connective tissue disease.
Kent Holtorf: Author of Chapter Six in "The LDN Book 3" on mold illness and CIRS.
Sebastian Denison, RPh, FAAR: Author of Chapter Seven in "The LDN Book 3" on ophthalmic conditions. A compounding pharmacist involved in HRT, veterinary, pain, and sports compounding, as well as pharmacy education.
Dr. Jennifer Rickner, PharmD, RP Compounding Pharmacist and LDN Specialist: Provided an endorsement for "The LDN Books."
Steve Hoffart, PharmD Compounding Pharmacist: Provided an endorsement for "The LDN Book 3."
Nat Jones, R.Ph. FAPC Clinical Compounding Pharmacist: Provided an endorsement for "The LDN Book 3."
Dr. Mark Mandel: Mentioned as "my hero" by Linda Elsegood in the dedication of "The LDN Book 3." His specific role is not detailed in the excerpts.
Sasso, Eaton-Fitch, Smith, Muraki, Marshall-Gradisnik: Authors of the research paper "Low-Dose naltrexone restored TRPM3 ion channel function in natural killer cells from long COVID patients." They are credited with the research and publication of the study findings. (Note: Eaton-Fitch and Smith are mentioned in the context of previous research cited in the paper).
This timeline and cast of characters are based solely on the information provided in the excerpts.
FAQ
What is low-dose naltrexone (LDN)?
Naltrexone hydrochloride (NTX) is a medication primarily used at standard doses (50-100 mg daily) to treat alcohol or opioid dependence. It functions as a competitive antagonist of mu (μ)-opioid receptors, which are distributed throughout the body, including the central nervous system, gastrointestinal tract, and immune cells. LDN refers to naltrexone used at significantly lower doses than those typically prescribed for addiction. This lower dosing regimen has been explored for its potential therapeutic effects on a wide range of conditions, many of which involve inflammation or immune dysfunction.
How does LDN differ from standard-dose naltrexone in its mechanism of action?
While standard doses of naltrexone completely block opioid receptors, low doses appear to work through a different mechanism. Naltrexone is composed of two isomers (different shapes with the same chemical components). Recent research suggests that one isomer, levo-naltrexone, binds to immune cells, while the other binds to opioid receptors. At low doses, levo-naltrexone acts as an antagonist for opiate/endorphin receptors, leading to increased release of endorphins. Additionally, as a μ-opioid receptor antagonist, LDN is thought to counteract the inhibitory function of opioid receptors on TRPM3 ion channels, which are important for immune cell function, thereby restoring TRPM3 function and calcium influx.
What are TRPM3 ion channels and why are they relevant in the context of long COVID and LDN?
TRPM3 (Transient Receptor Potential Melastatin 3) are ion channels that play a role in various cellular functions, including immune cell activity. In natural killer (NK) cells, a type of immune cell, TRPM3 function appears to be impaired in individuals with long COVID. Opioid receptors can inhibit TRPM3 ion channels. By blocking these opioid receptors at low doses, LDN may help restore the normal function of TRPM3 channels in NK cells, potentially contributing to the therapeutic effects observed in long COVID patients.
How was TRPM3 function assessed in the study involving long COVID patients and LDN?
The study utilized whole-cell patch-clamp electrophysiology experiments on freshly isolated NK cells from healthy controls, individuals with long COVID, and individuals with long COVID receiving LDN treatment. This technique allows researchers to measure the electrical currents flowing through ion channels. They used pharmacological modulators, specifically pregnenolone sulfate (PregS) to stimulate TRPM3 activity and ononetin to inhibit it, to assess the functional response of the TRPM3 channels in the NK cells from each participant group.
What were the key findings regarding TRPM3 function in the study?
The study found that TRPM3 ion channel function was restored in natural killer (NK) cells from long COVID patients who were treated with LDN, compared to long COVID patients not receiving LDN. This restoration of function was indicated by increased TRPM3 current amplitude and increased sensitivity to ononetin inhibition, bringing the NK cell function closer to that observed in healthy controls.
Beyond its effects on TRPM3 channels, what are some other proposed mechanisms by which LDN may exert its therapeutic effects?
LDN is thought to influence various biological systems. It can modulate the immune system by affecting inflammatory cytokines and altering the balance of immune cells. It has also been suggested to help balance hormones by influencing the HPA axis and increasing endorphins. Additionally, LDN may support gut health by improving the microbiome and decreasing cravings for unhealthy foods. It is also believed to improve mitochondrial function, leading to increased energy production.
Is LDN an FDA-approved treatment for long COVID or other conditions besides addiction?
No, the use of LDN for conditions other than opioid or alcohol dependence is considered unlicensed or "off-label." This means that while naltrexone is an FDA-approved drug, its use at low doses for a wide range of other conditions has not undergone the formal clinical trial process required for specific drug licensing for those conditions. The reasons for this are varied but often relate to the financial disincentives for pharmaceutical companies to invest in trials for older, generic drugs.
What considerations should practitioners and patients be aware of when considering LDN for off-label use?
When considering LDN for off-label use, practitioners should have a direct conversation with the patient to make a joint clinical decision, documented in the patient's record. They should assess potential interactions with other medications and establish a formal review period. A risk-benefit analysis should be completed, considering the expected benefits, potential risks (such as in pregnancy), and strategies to mitigate those risks. Patients should be informed that LDN in this context is an unlicensed use of the drug. The availability of LDN for off-label use typically requires compounding by specialized pharmacies.
Table of Contents with Timestamps
Introduction and Overview
00:00 - Welcome to Heliox and The Deep Dive
Introduction to the podcast's mission and today's focus on Low Dose Naltrexone (LDN) across multiple conditions
Understanding LDN Fundamentals
01:48 - The Basics of Low Dose Naltrexone
Explanation of naltrexone isomers, antagonist effects, and the critical importance of dosage
02:54 - Licensing Challenges and Off-Label Use
Why LDN lacks official approval for most conditions despite clinical evidence
Core Mechanisms and Immune Function
05:11 - Immune System Dysfunction and Chronic Inflammation
The connection between poorly functioning immunity and chronic disease
05:37 - TLR4 and the Inflammatory Cascade
How Toll-like receptors trigger inflammation and LDN's role in modulation
Long COVID Deep Dive
07:21 - Long COVID as Post-Infectious Syndrome
Historical parallels and the broken epistemology of symptom dismissal
08:41 - Reactivated Infections and T-Cell Exhaustion
EBV, Lyme, and other pathogens in long COVID pathology
09:10 - The Endosome Battleground
Cellular defense mechanisms and mucosal immunity
10:16 - Clinical Observations with LDN in Long COVID
Reported improvements in brain fog, fatigue, and muscle pain
Autoimmune Diseases
11:06 - Mixed Connective Tissue Disease (MCTD)
Detailed examination of autoimmune triggers and diagnostic criteria
12:51 - Environmental and Lifestyle Triggers
Microbiome, nutritional deficiencies, infections, and toxins as disease drivers
14:44 - Case Study Success
Multi-modal treatment approach including LDN, vitamin D, and dietary changes
Cancer Applications
15:17 - LDN's Anti-Cancer Mechanisms
Inflammation pathways, IL-6 suppression, and dose-dependent effects
16:35 - Gene Expression and Cell Cycle Control
Low-dose effects on apoptosis and cancer cell vulnerability
17:00 - Remarkable Case Studies
Liver metastases, kidney cancer, and ovarian cancer survivor experiences
Mold Illness and CIRS
18:18 - Chronic Inflammatory Response Syndrome
Traditional vs. enhanced protocols incorporating LDN and peptides
19:00 - T-Cell Exhaustion and Immunosenescence
Core immune dysfunction in mold-related illness
19:45 - Biomarkers and MSH Deficiency
C4A, melanocyte-stimulating hormone, and MARCoNS infections
20:22 - KPV Peptide Therapy
Advanced anti-inflammatory treatments without immune suppression
Ophthalmic Applications
22:08 - Eye Disease and Immune-Mediated Inflammation
Unexpected connections between LDN and ocular health
22:41 - OGF/OGFR System Discovery
Tissue growth regulation and naltrexone's surprising dual action
23:25 - Topical Applications
Eye drops for dry eye, macular degeneration, and surgical healing
Practical Implementation
24:04 - Forms and Dosing Strategies
Liquid, sublingual, and capsule options with timing considerations
24:44 - Drug Interactions and Special Populations
Safety considerations for CFS/ME, MS, and Lyme patients
25:47 - Finding Qualified Providers
Resources and compounding pharmacy requirements
Synthesis and Future Directions
25:52 - The Common Thread
Interconnected systems and fundamental imbalances underlying chronic disease
26:36 - Integrated Treatment Approaches
LDN as part of comprehensive healing protocols
27:23 - Paradigm Shift Question
Moving from symptom-chasing to systemic balance restoration
Total Runtime: 28:08
Index with Timestamps
Addiction treatment 03:10
Antagonist effects 02:18
Anti-U1 RNP antibody 12:15
Apoptosis 16:45, 18:08
Autoimmune diseases 00:53, 11:06, 12:02, 15:00
Autophagy 18:08
Benzodiazepines 15:10
Biomarkers 19:37
Blood ocular barrier 23:18
Brain fog 10:40, 12:36, 19:37
C4A levels 19:37
Cancer progression 15:51, 16:01
Case studies 14:48, 17:00
Cell cycle control 16:35
Chirality 03:17
Chronic fatigue 10:56, 12:36, 25:05
Chronic inflammation 01:13, 05:21, 06:32, 15:57, 19:34
CIRS 18:22, 18:56, 19:16
Clinical trials 04:05
Compounding pharmacies 23:52, 25:46
Crohn's disease 13:12
Cytokines 13:25, 23:01
Dosage importance 02:54, 16:09
Dry eye 23:25, 23:45
Dysbiosis 13:00
Endorphins 02:28, 02:39, 24:28
Endosome 09:10, 09:33
Epigenetic triggers 12:21, 12:40, 13:43
Epstein-Barr virus 08:41
Exosomes 18:10
Eye drops 23:35, 23:45
Fibromyalgia 08:26
Gene expression 16:20, 16:35
Generic drug 03:57, 04:18
Gut health 12:53, 13:09
IL-6 15:48, 15:51
Immune dysfunction 01:13, 05:15, 18:31, 19:01
Immunosenescence 19:01, 19:11
Inflammation pathways 03:10, 15:35
Isomers 01:51, 01:56
KPV peptide 20:22, 20:28
Levonaltrexone 02:12
Licensing challenges 03:50, 04:14
Liver metastases 17:02
Long COVID 00:53, 07:21, 08:05, 10:16
Low dose naltrexone 00:46, 02:54, 16:14
Lyme disease 08:53, 14:02, 25:29
Macular degeneration 23:45
MARCoNS 20:05, 20:14
MCTD 11:13, 12:02, 12:21
Melatonin 17:22
Microbiome 12:53, 13:25
Mixed connective tissue disease 11:13
Mold exposure 14:02, 18:22
Monocytes 09:43, 09:48
MSH deficiency 19:45, 19:55
Multiple sclerosis 25:16, 25:24
Mucosal immunity 09:33, 09:36
MyYD88 06:11
Naltrexone concentration 15:41
NFKB 06:13, 06:16, 07:01
Off-label use 01:08, 04:27, 04:40
OGF/OGFR system 22:41, 22:46
Ophthalmic conditions 22:08
Patent protection 04:01
Peptide therapies 18:47, 20:22, 26:47
Post-infectious conditions 07:39
Raynaud's phenomenon 12:12
Sleep disruption 14:18, 14:27
T-cell exhaustion 08:59, 09:01, 19:01, 20:54
Telomeres 17:53
Th1/Th2 balance 19:16, 19:22
Thyroid function 13:47, 13:54
TLR4 05:31, 05:37, 07:01
TLR9 15:42
Toll-like receptors 05:40, 22:17
Topical applications 23:25, 23:51
Toxin exposure 12:36, 14:07, 18:32
Ulcerative colitis 13:12
VIP peptide 20:42, 20:46
Vitamin D deficiency 13:35, 13:37, 15:01
Poll
Post-Episode Fact Check
✅ ACCURATE CLAIMS:
LDN Mechanism: Naltrexone has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain - PMC, confirming the podcast's explanation of TLR4 inhibition.
TLR4 Pathway: Naltrexone can inhibit toll-like receptor activity and was shown to be an equi-potent inhibitor of LPS-induced TLR4 downstream signalling and induction of pro-inflammatory factors WileyFrontiers.
Research Foundation: Low Dose Naltrexone helps regulate the immune system, benefiting patients with a variety of autoimmune and related diseases, with LDN use tested in clinical trials Conditions that are helped by Low Dose Naltrexone (LDN) LDN Research Trust - The Low Dose Naltrexone Charity.
Typical Dosing: The typical dosage of LDN in published research is 4.5 mg The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain - PMC, supporting the podcast's low-dose emphasis.
⚠️ LIMITATIONS:
Evidence Quality: The podcast relies heavily on anecdotal reports and case studies. While LDN has emerged as a potential analgesic option that has been minimally explored Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions: A Fourteen-Year, Enterprise-Wide Retrospective Analysis - PMC, robust clinical trial data remains limited.
Off-label Use: The extensive off-label applications discussed are accurate but should be clearly distinguished from FDA-approved uses.
❌ UNVERIFIED CLAIMS:
TRPM3 Function: The title mentions "TRPM3 Function" but this specific mechanism wasn't substantiated in available research.
Specific Long COVID Claims: While mechanistically plausible, the dramatic improvements described lack peer-reviewed validation.
Overall Assessment: The podcast presents scientifically grounded mechanisms but extrapolates beyond current evidence quality. The TLR4 pathway and anti-inflammatory effects are well-documented, but clinical outcomes remain largely anecdotal.
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Mind Map
Fun fact: The total annual cost of LDN for all current users is probably less than what one pharmaceutical company spends on advertising a single blockbuster drug for one month.