Edited by Yoon Hang Kim MD MPH About Dr. Kim Dr. Yoon Hang "John" Kim, a recipient of the 2024 Functional Medicine for All scholarship from the Institute for Functional Medicine, brings over 20 years of experience in integrative and functional medicine to his telemedicine practice. After serving as chief wellness officer at a community hospital in Carthage, IL, where he provided care to rural and underserved populations, Dr. Kim now offers virtual integrative and functional medicine services, making personalized, evidence-based care accessible to patients regardless of location. His approach combines functional medicine lab testing with complementary therapies such as meditation, yoga, tai chi, and lifestyle interventions using food and physical activity as medicine, addressing the root causes of disease. Dr. Kim earned his medical degree from the Medical College of Wisconsin, completed a master’s in public health at San Diego State University, and trained with Dr. Andrew Weil during his residential fellowship at the University of Arizona. Certified by the American Board of Preventive Medicine, the American Board of Medical Acupuncture, and the American Board of Integrative and Holistic Medicine, he has also contributed to the field as a faculty member, consultant, and founder of the Integrative Health Studies Certificate program at the University of West Georgia. With clinical interests in autoimmune conditions, chronic pain, integrative oncology, and gastrointestinal disorders, Dr. Kim specializes in treating complex conditions such as fibromyalgia, chronic fatigue syndrome, long COVID symptoms, and toxic mold illness, and has authored two books and over 20 articles while helping establish integrative medicine practices across various institutions. Professional Inquiries: www.yoonhangkim.com Clinical Inquiries: www.directintegrativecare.com Abstract Low-dose naltrexone (LDN), typically administered at 1–4.5 mg daily, has gained attention for off-label applications beyond its standard use in alcohol use disorder (AUD). While standard-dose naltrexone (50 mg daily) is well established for reducing heavy drinking and cravings in AUD, evidence supporting LDN specifically for alcohol cessation or reduction remains limited and preliminary. This article reviews the mechanistic distinctions, available clinical data, and practical considerations surrounding LDN in AUD, emphasizing the need for caution and professional oversight. Introduction Alcohol use disorder (AUD) affects millions worldwide and contributes substantially to morbidity and mortality. Pharmacologic interventions, including naltrexone, acamprosate, and disulfiram, are recommended as adjuncts to psychosocial therapies (Reus et al., 2018). Standard-dose naltrexone, an opioid receptor antagonist, is FDA-approved for AUD at 50 mg daily, where it reduces alcohol-related reward and craving (Maisel et al., 2013; Jonas et al., 2014). In contrast, low-dose naltrexone (LDN) is thought to exert effects through transient opioid receptor blockade and subsequent endorphin modulation, mechanisms primarily studied in chronic pain, inflammatory, and autoimmune conditions (Younger et al., 2014). Most published research and clinical trials on LDN have focused on its use in chronic conditions and autoimmune diseases, with organizations like the LDN Research Trust supporting research and education in this area. Interest has recently emerged regarding LDN’s potential role in AUD, particularly for craving reduction or moderated drinking, though high-quality evidence remains sparse. Mechanisms of Action on Opioid Receptors At standard doses, naltrexone competitively blocks μ-opioid receptors, reducing alcohol-induced dopamine release within mesolimbic reward pathways and thereby diminishing reinforcement (O’Malley et al., 2002). LDN, administered at substantially lower doses, is hypothesized to induce a compensatory increase in endogenous opioid production or to modulate neuroinflammation via glial cell activity (Toljan & Vrooman, 2018). Specifically, LDN may act on microglial cells within the central nervous system, which are key glial cells involved in neuroinflammation. Activated microglial cells produce proinflammatory cytokines, pro inflammatory cytokines, nitric oxide, reactive oxygen species, and substance P, all of which contribute to pain, inflammation, and neurotoxicity. LDN may help suppress microglial activation, thereby reducing the production of these inflammatory mediators. Additionally, LDN’s transient blockade of opioid receptors can lead to increased production of endogenous opioids and natural peptides, such as endorphins and opioid growth factor. These natural peptides interact with opioid growth factor receptors to regulate immune function and cell growth. Opioid receptors are present in both the central and peripheral nervous systems, so LDN’s effects may extend to both regions. While these mechanisms may plausibly influence craving or affective regulation, they remain speculative in the context of AUD and have not been directly validated in alcohol-specific models. Evidence for Standard-Dose Naltrexone in AUD Multiple meta-analyses demonstrate moderate efficacy for oral naltrexone 50 mg daily in reducing return to heavy drinking, with a number needed to treat of approximately 12, and in decreasing drinking days when combined with psychosocial interventions (Jonas et al., 2014; Maisel et al., 2023). Clinical practice guidelines from the American Psychiatric Association endorse its use for individuals with moderate-to-severe AUD (Reus et al., 2018). Evidence for Low-Dose Naltrexone in AUD and Chronic Pain Direct evidence evaluating LDN for AUD is limited. Available data consist primarily of anecdotal reports, theoretical discussions, and small exploratory studies. To date, no large randomized controlled trials demonstrate efficacy for LDN in alcohol cessation or reduction (Patten et al., 2024). One pilot study—a pilot randomized trial—assessing LDN in combination with gabapentin among individuals with HIV and heavy alcohol use found no significant difference in pain or alcohol-related outcomes compared with placebo (Edelman et al., 2024). While off-label discussions frequently cite potential reductions in cravings, these claims remain unsupported by rigorous clinical evidence (Toljan & Vrooman, 2018). Crossover trials have been used in other LDN research, such as studies on fibromyalgia, to assess efficacy, but such study designs are lacking in the context of AUD. Limitations and Risks LDN is not FDA-approved for AUD, and its use in this context constitutes off-label prescribing. Although side effects are generally mild—such as insomnia or vivid dreams—potential risks include hepatic strain, particularly with ongoing alcohol consumption. It is important to note that opioid antagonist naltrexone is FDA-approved for opioid use disorder, where higher dosages are typically used compared to low dose naltrexone. Taking LDN or naltrexone while opioids are present in the system can precipitate opioid withdrawal, so medical screening is essential before starting therapy. Self-directed use is discouraged due to variability in compounding practices, dosing, and potential drug interactions. Patient Perspectives and Experiences - Please consider joining FB LDN Support Group - https://www.facebook.com/groups/2927649837416056 LDN Support Group Website: www.ldnsupportgroup.com Dr. Kim's LDN Blog - https://www.directintegrativecare.com/integrative-medicine-blog Dr. Kim's LDN YouTube Channel - https://www.youtube.com/@YoonHangKimMD Request Free LDN Primer Check out the link below to request your free copy of the LDN Primer 2025!   https://www.ldnsupportgroup.org/projects-6 Many patients with chronic pain conditions have turned to low dose naltrexone (LDN) as an anti-inflammatory treatment, particularly when conventional approaches haven't provided adequate relief. People with fibromyalgia, complex regional pain syndrome, and multiple sclerosis frequently report improvements in function, reduced pain intensity, better sleep, and enhanced quality of life. Clinical research supports these observations. In randomized placebo-controlled trials, fibromyalgia patients taking LDN showed significant reductions in pain severity, fatigue, and sleep disruption. Patients with Crohn's disease have reported improvements in abdominal pain, diarrhea frequency, and fatigue—demonstrating LDN's potential across multiple inflammatory conditions. Beyond pain relief, practitioners have documented improvements in psychological well-being, with patients showing meaningful reductions in anxiety and depression scores alongside physical symptom improvement. For many, LDN has also helped reduce opioid dependence—addressing legitimate concerns about addiction risks and long-term side effects of chronic opioid use. Patients often describe LDN as transformative, enabling greater participation in daily activities and improved overall function. The mechanism appears to involve immune modulation, resulting in decreased inflammation and better health outcomes. That said, responses to LDN vary considerably. While many patients benefit, some don't achieve meaningful improvement. As with any treatment, consultation with a knowledgeable provider is essential to determine appropriateness and monitor for adverse reactions. As research continues, LDN's role in chronic pain and inflammatory conditions will become better defined—offering hope for patients seeking alternatives to conventional pain management. Conclusion While standard-dose naltrexone has a well-established evidence base for the treatment of alcohol use disorder, current data are insufficient to support the use of low-dose naltrexone for reducing alcohol consumption or cravings. Individuals interested in pharmacologic treatment for AUD should consult qualified healthcare professionals to pursue evidence-based options and integrate medication with behavioral and psychosocial interventions. About Dr. Kim's Private Practice At Direct Integrative Care, Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.  Yoon Hang Kim MD Integrative & Functional Medicine Physician Virtual Practice Serving IA, IL, MO, FL, GA, and TX www.directintegrativecare.com References Edelman, E. J., et al. (2024). Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems. PLOS ONE, 19 (2), e0297903. https://doi.org/10.1371/journal.pone.0297903 Jonas, D. E., et al. (2014). Pharmacotherapy for adults with alcohol use disorders in outpatient settings: A systematic review and meta-analysis. JAMA, 311 (18), 1889–1900. https://doi.org/10.1001/jama.2014.3628 Maisel, N. C., et al. (2013). Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: When are these medications most helpful? Addiction, 108 (2), 275–293. https://doi.org/10.1111/j.1360-0443.2012.04054.x Maisel, N. C., et al. (2023). Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis. JAMA Network Open, 6 (11), e2343420. O'Malley, S. S., et al. (2002). Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology, 160 (1), 19–29. Patten, D. K., et al. (2024). Low-dose naltrexone: A potential gold medalist? American Family Physician, 110 (2), 123–124. Reus, V. I., et al. (2018). The American Psychiatric Association practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Journal of Psychiatry, 175 (1), 86–90. https://doi.org/10.1176/appi.ajp.2017.1750101 Toljan, K., & Vrooman, B. (2018). Low-dose naltrexone (LDN)—Review of therapeutic utilization. Medical Sciences, 6 (4), 82. https://doi.org/10.3390/medsci6040082 Younger, J., et al. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33 (4), 451–459.

Exploring the Potential Role of Low-Dose Naltrexone in Seizure Management: Emerging Evidence from Preclinical and Preliminary Clinical Studies Edited by Yoon Hang Kim MD MPH Low-dose naltrexone (LDN), typically administered at doses of 1–5 mg daily, represents an off-label application of a medication originally approved for opioid and alcohol dependence at higher doses (50 mg). Recent investigations have explored its potential anticonvulsant properties, primarily through modulation of neuroinflammation, glial activity, and opioid receptor signaling. These effects are thought to arise from transient blockade of toll-like receptor 4 (TLR4) on microglial cells, leading to reduced proinflammatory cytokine release and attenuation of excitotoxic pathways implicated in epileptogenesis. Preclinical research in animal models has provided the foundational evidence for these effects. In zebrafish larvae modeling Dravet syndrome (scn1Lab mutants) and pentylenetetrazole (PTZ)-induced seizures, naltrexone significantly reduced abnormal locomotion and seizure-like behavior. Similar anticonvulsant activity was observed in mouse models, including decreased seizure-like events in acute brain slices, reduced duration and frequency of PTZ-induced convulsive seizures, and complete prevention of post-traumatic seizures following traumatic brain injury (TBI). In the TBI model, naltrexone also mitigated neuroinflammation (e.g., reduced IL-1β, TNFα expression), microgliosis, neurodegeneration, and oxidative stress markers, while preserving white matter integrity. Human evidence remains limited but encouraging. A small case series of pediatric patients with intractable epilepsy reported substantial reductions in seizure frequency—some achieving seizure-free status—along with electrophysiological improvements on electroencephalogram (EEG) after adjunctive LDN therapy. These observations align with hypotheses that LDN's immune-modulating properties may interrupt neuroinflammatory cascades contributing to refractory seizures. Despite these promising findings, significant caveats exist. No large-scale randomized controlled trials have confirmed efficacy or established optimal dosing for seizure disorders. Higher doses of naltrexone or combinations (e.g., with bupropion) are associated with increased seizure risk, potentially due to lowered seizure threshold in vulnerable individuals. Rare reports of seizures linked to standard-dose naltrexone underscore the need for caution. In conclusion, while preclinical data robustly support anticonvulsant and neuroprotective roles for naltrexone, and preliminary human observations suggest clinical potential, LDN cannot currently be recommended as a standard therapy for seizures or epilepsy. Its use should be confined to supervised clinical settings, prioritizing established antiepileptic drugs. Future rigorous trials are essential to delineate efficacy, safety, and mechanisms in human populations. For More Information, Join FB LDN Support Group: https://www.facebook.com/groups/2927649837416056 About The Author At Direct Integrative Care, Dr. Yoon Hang Kim MD is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.  Yoon Hang Kim MD Integrative & Functional Medicine Physician Virtual Practice Serving IA, IL, MO, FL, GA, and TX www.directintegrativecare.com Dr. Yoon Hang Kim is an expert in Integrative & Functional Medicine and in LDN Therapy References Abokrysha, N. T., Kishk, N. A., Nawito, A. M., & Mounir, N. (2021). Effect of low-dose naltrexone on Egyptian children with intractable epilepsy: A case series study. Neurology India, 69(6), 1781–1784. https://doi.org/10.4103/0028-3886.333523 Rodriguez, S., Sharma, S., Tiarks, G., & Glykys, J. (2024). Neuroprotective effects of naltrexone in a mouse model of post-traumatic seizures. Scientific Reports, 14, Article 13507. https://doi.org/10.1038/s41598-024-63942-8 Sturgeon, M. L., Langton, R., Sharma, S., Cornell, R. A., Glykys, J., & Bassuk, A. G. (2021). The opioid antagonist naltrexone decreases seizure-like activity in genetic and chemically induced epilepsy models. Epilepsia Open, 6(3), 528–538. https://doi.org/10.1002/epi4.12512

Introduction Treatment-resistant epilepsy, defined as the persistence of seizures despite adequate trials of at least two appropriately selected antiepileptic drugs, affects approximately one-third of individuals with epilepsy. Focal seizures, which originate from a specific brain region, are a common subtype and often present significant management challenges. Functional and integrative medicine frameworks emphasize individualized interventions that address potential underlying contributors such as inflammation, metabolic dysfunction, nutrient deficiencies, and lifestyle factors. These approaches are intended to complement conventional pharmacotherapy and are supported by varying levels of evidence. This review outlines key integrative strategies, including dietary therapies, nutritional supplementation, mind-body practices, and other complementary modalities. Dietary Interventions The ketogenic diet and its variants, including the modified Atkins diet and low glycemic index treatment, represent the most well-supported non-pharmacologic interventions for drug-resistant epilepsy, including focal seizures. These dietary approaches induce ketosis, which may stabilize neuronal excitability through anti-inflammatory mechanisms and modulation of neurotransmitter balance. A Cochrane review of randomized controlled trials demonstrated improved seizure outcomes, including seizure freedom and reductions of at least 50 percent in seizure frequency, compared with usual care in both pediatric and adult populations. Nutritional Supplementation Functional medicine approaches often focus on identifying and correcting nutrient deficiencies that may contribute to seizure susceptibility. Functional medicine labs provide for an opportunity to explore root causes and then address the root causes. Omega-3 fatty acids have anti-inflammatory properties, and meta-analyses suggest they may modestly reduce seizure frequency in individuals with epilepsy. Magnesium has been explored for its role in neuronal membrane stabilization, although current evidence remains largely theoretical and preliminary. Vitamin D deficiency is common among epilepsy patients, in part due to antiepileptic drug effects on metabolism, and correction may improve seizure control and quality of life. Cannabidiol, particularly pharmaceutical-grade formulations, has demonstrated efficacy as an adjunctive therapy in refractory focal epilepsy, with evidence supporting meaningful reductions in seizure burden. All supplementation strategies should be guided by laboratory assessment and clinical oversight to minimize risk and drug interactions. Lifestyle and Mind-Body Practices Stress is a well-recognized seizure precipitant, supporting the integration of stress-modulating interventions into comprehensive epilepsy care. Yoga and meditation have been associated with reductions in seizure frequency and improvements in quality of life, likely mediated through autonomic nervous system regulation and stress reduction. Acupuncture, when used as an adjunct to conventional treatment, has shown potential benefit in reducing seizure frequency, possibly through effects on thalamic signaling and neuroinflammatory pathways. These modalities are generally low risk when appropriately implemented. Other Complementary Approaches Additional holistic strategies, including selected herbal therapies, have been explored in epilepsy care, though high-quality evidence remains limited. Integrative treatment plans emphasize safety and careful evaluation of potential interactions with antiepileptic medications, prioritizing approaches with the most favorable risk-benefit profiles. Conclusion Integrative and functional medicine strategies may offer valuable adjunctive options for individuals with treatment-resistant focal seizures, particularly when conventional therapies alone are insufficient. Among these approaches, dietary interventions, especially ketogenic-based therapies, have the strongest evidence base. Nutritional supplementation and mind-body practices may provide additional benefit when individualized and clinically supervised. Collaboration with neurologists experienced in integrative care is essential to ensure safe, evidence-informed implementation. Yoon Hang Kim MD MPH is an expert in integrative and functional medicine and LDN therapy. Integrative and Functional Medicine Approaches to Treatment-Resistant Focal Seizures San Antonio | | Direct Integrative Care At Direct Integrative Care, Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.  Yoon Hang Kim MD Integrative & Functional Medicine Physician Virtual Practice Serving IA, IL, MO, FL, GA, and TX www.directintegrativecare.com References Martin-McGill, K. J., Bresnahan, R., Levy, R. G., & Cooper, P. N. (2020). Ketogenic diets for drug-resistant epilepsy. Cochrane Database of Systematic Reviews , (6), Article CD001903. https://doi.org/10.1002/14651858.CD001903.pub5 Pourmasoumi, M., Vosoughi, N., Derakhshandeh Rishehri, S., Assarroudi, M., & Fatahi, S. (2021). The effect of omega-3 fatty acid supplementation on seizure frequency in individuals with epilepsy: A systematic review and meta-analysis. Nutritional Neuroscience , 24(11), 869–878. https://doi.org/10.1080/1028415X.2020.1804094 Yuen, A. W. C., & Sander, J. W. (2012). Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis. Epilepsy Research , 100(1–2), 152–156. https://doi.org/10.1016/j.eplepsyres.2012.02.003 Chassoux, F., Artiges, E., Semah, F., et al. (2024). Vitamin D deficiency and effect of treatment on seizure frequency and quality of life parameters in patients with drug-resistant epilepsy: A randomized clinical trial. Epilepsia , 65(9), 2578–2590. https://doi.org/10.1111/epi.18050 Panesar, K., & Panebianco, M. (2023). Yoga for epilepsy. Cochrane Database of Systematic Reviews , (10), Article CD001524. https://doi.org/10.1002/14651858.CD001524.pub4 Liu, Y., Li, Y., Zhang, X., et al. (2023). Effectiveness of acupuncture as auxiliary combined with Western medicine for epilepsy: A systematic review and meta-analysis. Frontiers in Neuroscience , 17, Article 1203231. https://doi.org/10.3389/fnins.2023.1203231 de Oliveira, V. G., de Almeida, N. B., Radmann, G. C., et al. (2025). The efficacy of cannabidiol for seizure reduction in pharmacoresistant epilepsy: A systematic review and meta-analysis. Acta Epileptologica , 7, Article 20. https://doi.org/10.1186/s42494-024-00191-2 Kuchenbuch, M., Lassalle, M., Pons, C., et al. (2023). Use of integrative, complementary, and alternative medicine in children with epilepsy: A global scoping review. Children , 10(4), Article 713. https://doi.org/10.3390/children10040713

A Review of Mechanisms, Evidence, and Clinical Considerations Edited by Yoon Hang Kim MD, MPH Dr. Yoon Hang Kim, MD, is a renowned clinical expert in Low-Dose Naltrexone (LDN) and a sought-after presenter at the LDN Research Trust Conference. As an integrative and functional medicine physician, Dr. Kim brings a holistic approach to patient care, combining evidence-based practices with innovative therapies like LDN. He is the author of a book on LDN, which covers its therapeutic potential across various conditions, and has also contributed an insightful article on the subject of using LDN for treating pain.Dr. Kim’s work not only highlights the science behind LDN but also emphasizes its practical application in improving patient outcomes.  Dr. Kim also has a YouTube channel focusing on LDN therapy and also serves as an administrator for LDN Support Group. Video is related to blog article by subject only. Dr. Kim speaks his experience. 1. Introduction Fibromyalgia is a chronic pain syndrome affecting an estimated 2–4% of the global population, with a marked female predominance. My first introduction to the multi-dimensional aspect of fibromyalgia occurred before my discovering LDN.  At that time, utilizing acupuncture neurology (a specialty technique within acupuncture) to reset pain yielded about 50% pain control.  The other 30% came from resolution of an  internal conflict resolved through her faith.  The condition is characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive difficulties often referred to as "brain fog." Despite its prevalence, fibromyalgia remains one of the most challenging conditions to treat effectively in conventional medicine. Current pharmacological approaches—including pregabalin, duloxetine, and milnacipran—offer modest efficacy at best, with meta-analyses suggesting only 30–40% of patients achieve meaningful symptom reduction. Furthermore, these medications frequently produce significant adverse effects including weight gain, cognitive impairment, sedation, and sexual dysfunction, leading to poor adherence and treatment discontinuation. This therapeutic gap has prompted investigation into alternative approaches, among which Low-Dose Naltrexone (LDN) has emerged as a particularly promising candidate. This article examines the scientific rationale, clinical evidence, and practical considerations for LDN in fibromyalgia management. 2. What is Low-Dose Naltrexone (LDN)? 2.1 Pharmacological Background Naltrexone is an opioid receptor antagonist originally approved by the FDA in 1984 at doses of 50–100 mg daily for the treatment of opioid and alcohol use disorders. At these standard doses, naltrexone provides sustained blockade of mu-opioid receptors, preventing the euphoric effects of exogenous opioids and reducing alcohol cravings. Low-Dose Naltrexone refers to the off-label use of naltrexone at doses typically ranging from 0.1 mg to 4.5 mg daily. At these lower doses, naltrexone appears to exhibit fundamentally different pharmacodynamic properties, producing transient rather than sustained opioid receptor blockade and engaging additional receptor systems and cellular mechanisms. 2.2 Proposed Mechanisms of Action The therapeutic effects of LDN in chronic pain conditions appear to operate through multiple complementary pathways.  Anti-inflammatory pathway: First, LDN modulates glial cell activity by antagonizing Toll-like receptor 4 (TLR4) on microglia and astrocytes. This antagonism reduces the introduction of pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), while simultaneously promoting the release of anti-inflammatory mediators. Endorphin pathway: Second, the brief opioid receptor blockade induced by LDN triggers a compensatory upregulation of endogenous opioid production and receptor sensitivity during the "rebound" period after the drug's effects dissipate. This enhanced endorphin system activity may contribute to improved pain modulation and mood regulation. Immune Modulation pathway: Third, emerging evidence suggests LDN may influence regulatory T-cell function and modulate broader immune system activity, potentially addressing the immune dysregulation increasingly recognized as a feature of fibromyalgia pathophysiology. 2.3 Off-Label Applications Beyond fibromyalgia, LDN has been investigated in numerous chronic pain and autoimmune conditions including multiple sclerosis, Crohn's disease, complex regional pain syndrome, and various autoimmune disorders. While the evidence base varies across conditions, the accumulating clinical experience has informed our understanding of LDN's therapeutic potential and more importantly, it speaks to the safety profile LDN. 3. The Science Behind LDN and Fibromyalgia 3.1 Fibromyalgia Pathophysiology: Current Understanding Contemporary models of fibromyalgia pathophysiology emphasize central sensitization—a state of heightened excitability in spinal and supraspinal pain-processing circuits that amplifies nociceptive signaling and reduces descending inhibitory control. Functional neuroimaging studies consistently demonstrate altered pain processing in fibromyalgia patients, with enhanced activation of pain-related brain regions in response to normally non-painful stimuli. Increasingly, neuroinflammation has been recognized as a potential driver of central sensitization in fibromyalgia. Positron emission tomography (PET) studies using radioligands that bind to translocator protein (TSPO)—a marker of activated glial cells—have demonstrated elevated microglial activation in multiple brain regions of fibromyalgia patients compared to healthy controls. Additionally, cerebrospinal fluid analyses have revealed elevated concentrations of pro-inflammatory cytokines and chemokines in fibromyalgia patients, further supporting the neuroinflammatory hypothesis. These inflammatory mediators can directly sensitize nociceptive neurons, disrupt inhibitory neurotransmission, and contribute to the cognitive and mood disturbances characteristic of the condition. 3.2 How LDN Addresses Fibromyalgia Mechanisms LDN's proposed mechanism of action aligns remarkably well with current understanding of fibromyalgia pathophysiology. By reducing microglial activation and pro-inflammatory cytokine production, LDN may directly address the neuroinflammatory component of central sensitization. The reduction of IL-1β and TNF-α levels could decrease nociceptive neuron sensitization and restore more normal pain processing. I share with my patients that LDN appears to calm neuroinflammation. Furthermore, LDN's effects on the endogenous opioid system may help restore the dysfunctional descending pain inhibition observed in fibromyalgia. Studies have demonstrated reduced mu-opioid receptor availability in key pain-modulating brain regions of fibromyalgia patients, and the receptor upregulation induced by LDN could potentially compensate for this deficit. The multi-modal mechanism of LDN—simultaneously targeting neuroinflammation, central sensitization, and endogenous analgesia—may explain its clinical efficacy in a condition characterized by such complex and interconnected pathophysiology. 4. Key Research Studies 4.1 Younger's Pilot Study (2009) The first clinical investigation of LDN specifically for fibromyalgia was conducted by Dr. Jarred Younger and colleagues at Stanford University. This single-blind, crossover pilot study enrolled ten women with fibromyalgia who received 4.5 mg of naltrexone daily for eight weeks, with daily symptom assessments using handheld computers. Results demonstrated a 30% reduction in fibromyalgia symptoms compared to placebo, with the most pronounced effects observed for pain, fatigue, and overall sense of well-being. The placebo response is important to document as it is known in other therapies such as acupuncture.  Most importantly, the treatment was well-tolerated, with no serious adverse events reported. These promising findings provided the foundation for more rigorous investigation. 4.2 Younger's Randomized Controlled Trial (2013) Building on the pilot data, Younger and colleagues conducted a randomized, double-blind, placebo-controlled, crossover trial published in Pain Medicine in 2013. The study enrolled 31 women with fibromyalgia who received both LDN 4.5 mg daily and placebo for 12 weeks each, separated by a 4-week washout period. The primary outcome—daily self-reported pain—showed a statistically significant reduction during LDN treatment compared to placebo. Secondary analyses revealed improvements in general satisfaction with life and mood, though fatigue and sleep parameters did not reach statistical significance. Notably, participants with higher baseline erythrocyte sedimentation rates (ESR), suggesting greater systemic inflammation, demonstrated the greatest response to LDN treatment. This finding supports the hypothesis that LDN's anti-inflammatory properties may be particularly relevant to its analgesic effects in fibromyalgia. The study also confirmed LDN's favorable safety profile, with vivid dreams being the most commonly reported adverse effect. 4.3 Inflammatory Marker Studies Parkitny and Younger (2017) published an important mechanistic study examining the effects of LDN on peripheral inflammatory markers in fibromyalgia patients. Their analysis revealed significant reductions in multiple pro-inflammatory cytokines during LDN treatment, providing direct evidence for the proposed anti-inflammatory mechanism. These findings were particularly significant because they demonstrated that LDN's effects extend beyond symptomatic improvement to measurable changes in inflammatory biomarkers. This mechanistic validation strengthens the scientific rationale for LDN use in fibromyalgia and other conditions characterized by chronic inflammation. 4.4 Additional Supporting Evidence Beyond the controlled trials, substantial observational and clinical experience has accumulated supporting LDN's efficacy in fibromyalgia. Retrospective analyses and case series from multiple clinical centers have reported response rates ranging from 50–70% in fibromyalgia patients treated with LDN, often in individuals who had failed multiple conventional therapies. Experimental pain studies have demonstrated that LDN reduces temporal summation of pain (a marker of central sensitization) and mechanical hyperalgesia in laboratory models. These findings provide additional mechanistic support for LDN's effects on central pain processing. 5. Insights from the LDN Research Trust The LDN Research Trust was founded by a colleague - Linda Elsegood.  Along with Dr. Bihari, Linda transformed LDN from an obscure medication to the prominent medication well known, gaining even more popularity, and most importantly organized researchers, clinicians, and patients together through conferences, podcasts, and on-line. The last in-person conference was completed in 2025 with promise of on-line and in-real-life gathering in 2027. The LDN Research Trust has played a pivotal role in advancing awareness, research, and clinical application of LDN for fibromyalgia and other chronic conditions. Founded in 2004, this nonprofit organization has facilitated international collaboration among researchers, clinicians, and patients interested in LDN therapy. Through annual conferences bringing together leading researchers and clinicians, the LDN Research Trust has created a forum for sharing clinical experiences, research findings, and best practices. The organization maintains an extensive database of patient testimonials and case studies, providing valuable real-world evidence complementing formal clinical trials. Patient testimonials collected through the LDN Research Trust consistently report improvements in pain levels, energy, cognitive function, and overall quality of life. Many fibromyalgia patients describe LDN as "life-changing," particularly those who had experienced years of inadequate relief from conventional treatments. While such testimonials cannot substitute for controlled trials, they provide meaningful insights into LDN's real-world effectiveness and patient acceptability. The LDN Research Trust website ( ldnresearchtrust.org ) offers comprehensive resources for both patients and healthcare providers, including prescribing guides, compounding pharmacy directories, research summaries, and educational materials. These resources have been instrumental in facilitating informed discussions between patients and their healthcare providers about LDN therapy. 6. Benefits and Safety of LDN 6.1 Advantages Over Conventional Treatments LDN offers several distinct advantages compared to FDA-approved fibromyalgia medications. Most notably, the side effect profile of LDN is remarkably benign. Unlike pregabalin and duloxetine, LDN is not associated with weight gain, cognitive impairment, or sexual dysfunction—adverse effects that frequently lead to treatment discontinuation with conventional therapies. Additionally, LDN has no known abuse potential or addiction liability. As an opioid antagonist rather than agonist, it cannot produce euphoria or physical dependence. This safety characteristic is particularly valuable given the current concerns about prescription medication misuse and the challenges many fibromyalgia patients face in obtaining adequate pain treatment. Cost represents another significant advantage. Compounded LDN typically costs about one dollar per pill without insurance coverage. Today, the costs tend to be still this range even with inflation with price variance in various pharmacies.  This affordability enhances accessibility for patients, particularly those with limited insurance coverage or high deductibles. 6.2 Common Side Effects The most frequently reported adverse effect of LDN is vivid or unusual dreams, occurring in approximately 37% of patients in clinical trials. This effect typically diminishes within one to two weeks of treatment and rarely necessitates discontinuation. Some clinicians recommend taking LDN in the morning rather than evening if vivid dreams prove troublesome. Other reported side effects include mild headache, nausea, and transient anxiety, each occurring in fewer than 10% of patients. These effects are typically mild, self-limiting, and resolve with continued treatment or minor dose adjustments. Serious adverse events have not been reported in LDN clinical trials. 6.3 Safety Profile and Contraindications LDN demonstrates an excellent safety profile across numerous clinical studies and decades of use. However, certain contraindications warrant careful consideration. Ultra low dose naltrexone (1 microgram or lower) should be used in patients currently taking opioid medications.  Regular LDN dose as the antagonist effect could precipitate acute withdrawal symptoms. Because half-life of naltrexone is between 4 to 6 hours.  I believe as short as 4 to 5 half lives 16 - 30 hours should suffice as washout period for opioid using surgical preparation.  Longer wash out period of 72  hours would more likely to assure that LDN would not affect opioid medications.  Patients with active liver disease should use LDN with caution, as naltrexone is hepatically metabolized. While hepatotoxicity has been reported with standard-dose naltrexone (50–300 mg daily), this has not been observed at the low doses used in LDN therapy. Nonetheless, baseline liver function assessment is prudent in patients with known hepatic pathology. LDN use during pregnancy and lactation has not been systematically studied, and most clinicians recommend discontinuation during pregnancy unless the benefits clearly outweigh potential risks. 7. Practical Considerations for Clinical Use 7.1 Dosing Protocol The standard approach to LDN initiation involves gradual dose titration to minimize initial side effects and identify the optimal therapeutic dose for each patient. Most practitioners begin with 0.1 mg to 0.5 mg daily, taken at bedtime, and increase the dose every one to four weeks until reaching the target dose of 4.5 mg daily. Some patients experience optimal effects at doses below 4.5 mg, while others may benefit from doses up to 6, 9, or 12 mg daily. Individualization based on clinical response and tolerability is critical. Therapeutic effects may not become apparent for four to twelve weeks, necessitating patient education about realistic expectations and the importance of consistent adherence during the trial period. For patients with particular sensitivity or those with complex conditions such as mast cell activation syndrome, ultra-low-dose initiation strategies may be warranted, starting at doses as low as 0.001 mg or 1 microgram with very gradual titration. 7.2 Accessing LDN Because LDN is not available as a commercial preparation at the required doses, it must be obtained from a compounding pharmacy. Naltrexone tablets are available in 50 mg strength, but these cannot simply be divided to achieve the low doses required—precise compounding is necessary for accurate dosing. A valid prescription is required, and healthcare providers should specify the exact dose, formulation (typically immediate-release capsules), and any filler preferences. Some patients report sensitivity to certain compounding fillers, and alternative formulations may be requested if tolerability issues arise. The LDN Research Trust maintains a directory of compounding pharmacies experienced in preparing LDN, which can be a valuable resource for patients and providers seeking reliable compounding services. 7.3 Working with Healthcare Provider/Support Group Successful LDN therapy requires collaboration with a healthcare provider knowledgeable about its use. Providers experienced with LDN can offer valuable guidance on dose optimization, management of initial side effects, and integration with other treatment modalities. They can also monitor for efficacy and adjust the treatment plan as needed based on individual response. If unavailable, LDN Support Groups such as LDN Support Group can provide peer support and sharing of personal experiences. 8. Conclusion In my practice, LDN is a foundation treatment for many conditions - especially neuroinflammation and nerve pain (technically all pain involves nerve for conduction of pain.  Low-Dose Naltrexone represents a compelling treatment option for fibromyalgia patients. Its mechanisms of action—targeting neuroinflammation and central sensitization while enhancing endogenous opioid function—means an ideal treatment modality targeting multiple aspects of fibromyalgia. The clinical evidence, while still evolving, consistently demonstrates meaningful symptom reduction with an exceptionally favorable safety profile. The combination of efficacy, tolerability, non-addictive properties, and low cost positions LDN as an attractive option in the fibromyalgia treatment armamentarium. Further research, including larger randomized controlled trials and longer-term follow-up studies, will be valuable in more precisely defining LDN's role in fibromyalgia management and identifying which patient subgroups are most likely to benefit. Until such data are available, LDN is a safe and affordable alternative with favorable side effect profile. 9. References 1. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663-672. 2. Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529-538. 3. Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines. 2017;5(2):16. 4. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-1555. 5. Loggia ML, Chonde DB, Akeju O, et al. Evidence for brain glial activation in chronic pain patients. Brain. 2015;138(Pt 3):604-615. 6. Albrecht DS, Forber C, Engström M, et al. Brain glial activation in fibromyalgia—a multi-site positron emission tomography investigation. Brain Behav Immun. 2019;75:72-83. 7. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn's disease, and other chronic pain disorders. Pharmacotherapy. 2018;38(3):382-389. 8. LDN Research Trust. Resources and Research. Available at: https://ldnresearchtrust.org . Accessed 2024. 9. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27(37):10000-10006. 10. Toljan K, Vrooman B. Low-dose naltrexone (LDN)—review of therapeutic utilization. Med Sci (Basel). 2018;6(4):82. Resources: Yoon Hang Kim MD YouTube Channel https://www.youtube.com/@YoonHangKimMD LDN Support Group Website https://www.ldnsupportgroup.org/ Support Groups Where Dr. Kim Moderates https://www.facebook.com/groups/2927649837416056 https://www.facebook.com/groups/593843748815425 https://www.reddit.com/r/LDN_LowDoseNaltrexone/ Dr. Kim’s Book: 2025 LDN Therapy: LDN plus other tools for healing https://www.amazon.com/dp/B0F9BD34MX/ref=sr_1_2?crid=78I404JYRK92&dib=eyJ2IjoiMSJ9.BEOUUagheXKWpn5VQYGq_Rxgf779cONA_59gdH3kjD9zoopGvw0lG4erfDQqCqFL.ITUWFqvtp80hz84UhldiFCeUSeW4WQuoDJcHJp50P5s&dib_tag=se&keywords=low+dose+naltrexone+ldn+yoon+hang+kim&qid=1747819520&sprefix=%2Caps%2C122&sr=8-2 Dr. Kim’s paper back book: Low Dose Naltrexone (LDN) Therapy: An Evidence Based Review and Case Histories  https://www.amazon.com/Low-Dose-Naltrexone-LDN-Therapy/dp/1977098487/ref=sr_1_4?crid=2AUCUPJCXO4SI&dib=eyJ2IjoiMSJ9.WDeq--pczYyKdBsbtir58GXbDkiXBaRoJbrun8CKQ5Nmckcz5oWNvSQ-8Sz7-6_r.Pn6eRxDB9rSEqQBjlsaadNk0OcBhvdSwqjK9wUW_kFc&dib_tag=se&keywords=low+dose+naltrexone+ldn+yoon+hang+kim&qid=1765884056&sprefix=low+dose+naltrexone+ldn+yoon+hang+kim%2Caps%2C589&sr=8-4 Various AI Tools are used by Dr. Kim who subscribes to multiple AI platforms including Grok, Claude, Jasper, and AskEasy. Additional AI used include Gemini and OpenEvidence.  Dr. Kim’s experience is that all AI platforms are capable of misrepresentation and deception - so, Dr. Kim edits these articles carefully.  This article took about 3 hours over the course of two days. Meet Dr. Kim - expert in LDN therapy, Integrative & Functional Medicine Dr. Kim's Clinic At Direct Integrative Care, Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.  Yoon Hang Kim MD Integrative & Functional Medicine Physician Virtual Practice Serving IA, IL, MO, FL, GA, and TX www.directintegrativecare.com

When LDN does not work Yoon Hang Kim MD By Yoon Hang Kim, MD, MPH Direct Integrative Care www.directintegrativecare.com Introduction Low-dose naltrexone (LDN) has emerged as a promising therapeutic option for numerous chronic conditions, from fibromyalgia and chronic pain to autoimmune disorders and mast cell activation syndrome. As a physician who has been prescribing LDN for over two decades and has presented at multiple LDN Research Trust conferences, I have witnessed its remarkable benefits in many patients. However, I have also observed a clinical reality that warrants honest discussion: approximately one-third of patients do not respond to standard LDN therapy. This observation aligns with published literature showing response rates typically ranging from 57-65% in various chronic pain populations (Kim et al., 2023; Younger et al., 2013). Understanding why LDN fails—and what to do about it—is crucial for clinicians seeking to optimize outcomes for their patients. Understanding the LDN Response Spectrum In my clinical experience, patients fall into three distinct categories when it comes to LDN therapy: Category 1: LDN as Sufficient Therapy For some patients, LDN alone produces profound and sustained improvement. These patients typically have: Adequate baseline endorphin reserves Moderate disease severity Conditions primarily driven by neuroinflammation or immune dysregulation Good overall functional capacity Research supports that LDN can be highly effective as monotherapy in conditions like fibromyalgia, where studies have demonstrated a 28.8% reduction in pain compared to 18% with placebo (Younger et al., 2013). A retrospective analysis from Mayo Clinic found that 65% of patients taking LDN for chronic pain reported perceived benefit (Toljan & Vrooman, 2018). Category 2: LDN as Necessary but Not Sufficient In complex cases, LDN plays a vital role but cannot achieve remission on its own. These conditions include: Mold toxicity and chronic inflammatory response syndrome (CIRS) Cancer Mast cell activation syndrome (MCAS) Long COVID Complex regional pain syndrome (CRPS) Chronic Lyme disease For these patients, LDN serves as one critical component of a multimodal treatment strategy. As noted by researchers studying MCAS, LDN does not target the root cause directly but "can calm the immune system enough to make deeper treatment more successful and better tolerated" (Restorative Medicine Center, 2024). Category 3: Non-Responders Some patients simply do not respond to LDN at any dose. This may relate to: Severely depleted endorphin reserves Genetic variations in opioid receptor function Conditions not primarily mediated by the pathways LDN modulates Co-existing factors that override LDN's mechanisms The Clinical Approach: Assessing Endorphin Reserve My clinical approach begins with estimating a patient's endorphin reserve  by assessing their functional capacity in everyday life. This concept is fundamental to personalizing LDN therapy. Assessment Questions I Consider: Duration of illness : How long have they been sick? Sleep quality : Do they achieve restorative sleep? Energy levels : What is their baseline energy throughout the day? Resilience : How quickly do they recover from setbacks? Functional capacity : Can they work, exercise, or perform daily activities? Patients with severely depleted endorphin reserves—those who are very ill or have very low functional capacity—require a different approach than the standard 4.5 mg dosing. Dosing Strategies for Challenging Cases Starting Low: Microgram Dosing For patients who are very ill, have low functional capacity, or are children, I advocate for starting at significantly lower doses  than the conventional 1.5-4.5 mg range. This approach is sometimes called ultra-low-dose naltrexone (ULDN) or very-low-dose naltrexone (VLDN). The LDN Research Trust's dosing guidelines recognize three categories (LDN Research Trust, 2024): Ultra-low dose : Microgram dosing (1-2 mcg) Very-low dose : 0.1-0.5 mg daily Low dose : 1-4.5 mg (sometimes up to 10 mg) My 2018 presentation at the LDN Research Trust Conference detailed the rationale for microgram dosing, explaining that at 1 microgram, naltrexone binds to opioid receptors but is not likely to overwhelm the system, potentially acting as a weak agonist through the phenomenon of hormesis—where a substance acts as an inhibitor at high concentrations but as a stimulator at lower concentrations (Kim, 2018). The Nanogram Option For patients who cannot tolerate even microgram doses, there are options to dilute further to nanogram ranges . These preparations are not typically available from pharmacies and require specialized compounding or self-dilution protocols. While clinical evidence at this dose range is limited, some highly sensitive patients have reported benefit. Titration Protocol for Sensitive Patients For sensitive patients, I recommend: Start at 0.5-1 mg (or lower if indicated) Increase slowly over extended periods Some patients may need 2-week intervals  between dose increases Others may require 4-week intervals The most sensitive patients may need 3-month intervals  between adjustments This contrasts with typical protocols that escalate to 4.5 mg within 2-4 weeks. Patience is essential. When Standard LDN Fails: Alternative Strategies Strategy 1: Higher-Dose Naltrexone for Neuropathy If there is no response to standard LDN dosing, especially in neuropathic pain conditions , I consider: Adding ketosis support  (ketogenic diet or exogenous ketones) Increasing the dose to 25 mg or even up to 45 mg This higher-dose approach moves into "moderate-dose" territory and may work through different mechanisms than traditional LDN. A dose-response study found that the effective dose in 95% of fibromyalgia patients (ED95) was 5.40 mg, with some patients benefiting from doses up to 6 mg (Bruun et al., 2021). However, clinical experience suggests some neuropathy patients respond to even higher doses. The rationale for combining with ketosis relates to the metabolic and anti-inflammatory effects of ketone bodies, which may synergize with naltrexone's mechanisms in neuropathic conditions. Strategy 2: MCAS Protocol Enhancement For complex conditions like mast cell activation syndrome (MCAS) , I consider adding: Ketotifen  (1-2 mg at bedtime, increasing as tolerated) Cromolyn sodium  (mast cell stabilizer) Methylene blue  combined with ketosis The Role of Ketotifen and Cromolyn Ketotifen is an oral mast cell stabilizer that inhibits the release of histamine, tryptase, and various prostaglandins from mast cells. It reduces antigen-induced mast cell degranulation and stabilizes calcium permeability in mast cell membranes (Rosenberg, 2022). Combined with cromolyn sodium, which works by inhibiting immediate and late-phase mast cell release, these medications can significantly improve MCAS symptoms including urticaria, nausea, diarrhea, and neurological manifestations. A landmark case study published in BMJ Case Reports demonstrated dramatic improvement in a patient with severe POTS and MCAS using a combination of LDN, intravenous immunoglobulin, and treatment of underlying small intestinal bacterial overgrowth (Weinstock et al., 2018). Methylene Blue and Mitochondrial Support Methylene blue has gained attention for its ability to enhance mitochondrial function by acting as an alternative electron carrier in the electron transport chain. It can increase ATP production, reduce oxidative stress, and decrease neuroinflammation (Yang et al., 2017). For patients with chronic fatigue, MCAS, or conditions involving mitochondrial dysfunction, methylene blue combined with ketosis may provide synergistic benefits that support overall healing alongside LDN. The Role of the Integrative Medicine Specialist There is a clear role for physicians who are well-versed in both LDN therapy and functional medicine to assist patients with complex conditions. Standard primary care providers may not have the experience to: Properly assess endorphin reserve Navigate non-standard dosing protocols Integrate complementary therapies Recognize when LDN is necessary but not sufficient Troubleshoot treatment failures As the LDN Research Trust notes, "Low Dose Naltrexone has been studied extensively since 1985. There are well over 900-950 articles, scientific papers, research papers, clinical abstracts, and double-blind studies done on Low Dose Naltrexone" (LDN Research Trust, 2024). Yet this wealth of information is not typically taught in medical schools or mainstream continuing education programs, leaving many patients without access to knowledgeable prescribers. Practical Recommendations Summary Scenario Recommended Approach Standard patient, moderate illness Start 1.5 mg, titrate to 4.5 mg over 2-4 weeks Severely ill / low functional capacity Start 0.5 mg or lower; titrate every 2-4 weeks Children Microgram dosing; very slow titration Extreme sensitivity Consider nanogram ranges; titrate every 1-3 months Side effects at low doses Drop to lower dose; slower titration Non-response in neuropathy Consider higher doses (up to 25-45 mg) + ketosis Complex MCAS Add ketotifen, cromolyn, consider methylene blue + ketosis Treatment-resistant cases Comprehensive functional medicine workup Conclusion LDN is a powerful tool in the integrative medicine toolkit, but it is not a universal solution. Approximately one-third of patients will not respond to standard protocols, and recognizing this reality is the first step toward better outcomes. By carefully assessing each patient's endorphin reserve, tailoring dosing strategies, and integrating complementary approaches when needed, we can optimize results and offer hope even to patients with treatment-resistant conditions. The key is individualization. There is no one-size-fits-all approach to LDN therapy. Whether it means starting at microgram doses for the severely depleted patient or pushing to higher doses for refractory neuropathy, the clinician must be willing to think beyond standard protocols while remaining grounded in the science. For patients struggling with complex chronic conditions, working with a physician experienced in LDN and functional medicine can make the difference between treatment failure and meaningful improvement. References Bruun, K. D., Christensen, R., Amris, K., Vaegter, H. B., & Toft, E. (2021). Low-dose naltrexone for the treatment of fibromyalgia: Protocol for a double-blind, randomized, placebo-controlled trial. Trials, 22 (1), 804. https://pmc.ncbi.nlm.nih.gov/articles/PMC8591911/ Kim, Y. H. (2018). Ultra low dose naltrexone, micro dosing [Conference presentation]. LDN Research Trust 2018 Conference. https://ldnresearchtrust.org/dr-john-kim%E2%80%99s-presentation-ultra-low-dose-naltrexone-uldn-and-micro-dosing-ldn-2018-conference LDN Research Trust. (2024). Dosing information for prescribers . https://ldnresearchtrust.org/sites/default/files/2024-02/Dosing-Guide-2024_0.pdf LDN Research Trust. (2024). Why are so many doctors resistant to low dose naltrexone?   https://ldnresearchtrust.org/why-are-so-many-doctors-resistant-low-dose-naltrexone-ldn Rosenberg, S. (2022). Ketotifen: How it works and its uses in your practice. Oregon Association of Naturopathic Physicians . https://www.mcmc-research.com/post/low-dose-naltrexone-and-mcas-treatment Takkouche, B. W., Rahimi, A., & Younger, J. (2018). Low-dose naltrexone (LDN)—Review of therapeutic utilization. Medical Sciences, 6 (4), 82. https://pmc.ncbi.nlm.nih.gov/articles/PMC6313374/ Toljan, K., & Vrooman, B. (2023). 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. Biomedicines, 11 (4), 1087. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10135963/ Weinstock, L. B., Brook, J. B., Myers, T. L., & Goodman, B. (2018). Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Reports, 2018 , bcr2017221405. https://pmc.ncbi.nlm.nih.gov/articles/PMC5778345/ Yang, S. H., Li, W., Sumien, N., Forster, M., Bhatti, I. K., Bhatti, M. T., & McCord, J. M. (2017). Mitochondria as a target for neuroprotection: Role of methylene blue and photobiomodulation. Translational Neurodegeneration, 9 (1), 19. https://link.springer.com/article/10.1186/s40035-020-00197-z Yang, J., Shin, K. M., Do, A., Bierle, D. M., Abu Dabrh, A. M., Yin, Z., Bauer, B. A., & Mohabbat, A. B. (2023). The safety and efficacy of low-dose naltrexone in patients with fibromyalgia: A systematic review. Journal of Pain Research, 16 , 1017-1023. https://pmc.ncbi.nlm.nih.gov/articles/PMC10039621/ Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65 (2), 529-538. https://pubmed.ncbi.nlm.nih.gov/23359310/ Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33 (4), 451-459. https://pmc.ncbi.nlm.nih.gov/articles/PMC3962576/ Additional Resources LDN Research Trust : https://ldnresearchtrust.org Direct Integrative Care Blog : https://www.directintegrativecare.com/integrative-medicine-blog Dr. Kim's YouTube Channel : https://www.youtube.com/@YoonHangKimMD LDN Support Group : https://www.ldnsupportgroup.org Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting or modifying any treatment regimen. About the Author Yoon Hang Kim, MD, MPH is a board-certified physician specializing in integrative and functional medicine. A graduate of Dr. Andrew Weil's Integrative Medicine Fellowship at the University of Arizona, Dr. Kim has been practicing integrative medicine since 1999. He is recognized internationally as an expert in LDN therapy and has presented at multiple LDN Research Trust conferences. Dr. Kim practices telemedicine through Direct Integrative Care, serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas. Contact : www.directintegrativecare.com Yoon Hang Kim MD MPH Integrative & Functional Medicine Expert

Yoon Hang Kim MD www.directintegrativecare.com Abstract Trigeminal neuralgia (TN) represents a debilitating form of neuropathic pain characterized by paroxysmal, electric shock-like facial pain. Conventional treatments, such as carbamazepine, often yield suboptimal outcomes due to limited efficacy and adverse effects. Low-dose naltrexone (LDN), administered at 1–5 mg daily, emerges as a promising adjunctive therapy. This article elucidates the mechanistic rationale for LDN in TN, emphasizing its antagonism of Toll-like receptor 4 (TLR4) on glial cells to attenuate neuroinflammation. Preclinical evidence supports LDN's reversal of TN-like allodynia in animal models via modulation of brain-derived neurotrophic factor (BDNF) and interleukin-10 (IL-10). Extrapolating from clinical trials in analogous conditions—neuropathy, fibromyalgia, and other neuroinflammatory disorders—LDN demonstrates consistent pain reduction and favorable tolerability. These findings underscore the need for dedicated TN trials while highlighting LDN's potential as a safe, cost-effective intervention. Introduction Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder affecting the trigeminal nerve, manifesting as severe, unilateral facial pain triggered by innocuous stimuli. Its pathophysiology involves peripheral demyelination, central sensitization, and neuroinflammation, leading to glial cell activation and cytokine release (DeSouza et al., 2014). First-line pharmacotherapy with sodium channel blockers like carbamazepine provides relief in approximately 70% of cases but is marred by sedation, dizziness, and long-term non-adherence (Cruccu et al., 2021). Amid the opioid crisis, non-opioid alternatives are imperative. Low-dose naltrexone (LDN), repurposed from its high-dose application in opioid dependence (50–100 mg), exhibits distinct pharmacodynamics at sub-therapeutic levels (1–5 mg). Rather than opioid antagonism, LDN transiently blocks μ-opioid receptors, upregulating endogenous endorphins, and antagonizes TLR4 on microglia, curbing glial-driven inflammation (Younger et al., 2014). This dual mechanism positions LDN as a glial modulator, potentially addressing TN's neuroinflammatory core. This article synthesizes preclinical mechanisms and clinical data from neuropathy, fibromyalgia, and related neuroconditions to rationalize LDN's use in TN. Pathophysiology of Trigeminal Neuralgia and the Role of Glial Activation TN arises from trigeminal root compression or microvascular conflicts, precipitating ectopic firing and central hyperexcitability. Peripheral injury triggers microglial proliferation and astrocyte hypertrophy in the trigeminal nucleus caudalis, amplifying pain via proinflammatory cytokines (TNF-α, IL-1β) and neurotrophins like BDNF (Love et al., 2009). Sustained glial activation fosters a feed-forward loop of central sensitization, manifesting as allodynia and hyperalgesia. TLR4, a pattern recognition receptor on microglia, senses damage-associated molecular patterns (DAMPs) from injured neurons, initiating NF-κB signaling and cytokine cascades (Hutchinson et al., 2010). In TN models, TLR4 upregulation correlates with mechanical hypersensitivity, implicating it as a therapeutic target (LaCroix-Fralish et al., 2007). Glial inhibitors, including minocycline, mitigate TN symptoms in rodents, underscoring the translational relevance of anti-glial strategies (Ji et al., 2016). Mechanisms of Low-Dose Naltrexone: TLR4 Antagonism and Glial Modulation At low doses, LDN's (+)-enantiomer selectively binds TLR4's MD-2 co-receptor, preventing LPS- or DAMP-induced dimerization and downstream NF-κB activation (Wang et al., 2016). This inhibits microglial priming, reducing IL-1β, TNF-α, and superoxide release, thereby dampening neuroinflammation without immunosuppression (Lewis et al., 2014). In glial cultures, LDN (0.1–100 μM) attenuates LPS-evoked nitric oxide and TNF-α production, preserving IL-10 (Kucic et al., 2021). Concurrently, transient opioid blockade elevates met-enkephalin levels, enhancing descending inhibition via δ-opioid receptors (Zagon et al., 2013). These effects synergize to normalize synaptic plasticity and reverse allodynia. Preclinically, LDN (0.1–10 mg/kg) reverses chronic constriction injury-induced TN in rats, restoring facial mechanical thresholds after 10 days (de Oliveira et al., 2020). This analgesia correlates with BDNF downregulation and IL-10 upregulation, without altering TLR4 or TNF-α centrally, suggesting indirect glial modulation. Co-administration with carbamazepine potentiates antiallodynic effects at subtherapeutic doses, reducing cognitive deficits (Hosseini et al., 2025). These findings mechanistically align LDN with TN's glial–TLR4 axis. Clinical Evidence from Neuropathic and Neuroinflammatory Conditions Although TN-specific clinical trials are limited, robust evidence from related disorders supports LDN's analgesic potential. Diabetic and Peripheral Neuropathy A randomized, double-blind crossover trial (n=67) compared LDN (2–4 mg) with amitriptyline (10–50 mg) in painful diabetic neuropathy (PDN). LDN achieved comparable VAS pain reduction (2.3 vs. 2.0; p=0.62) with markedly fewer adverse events (18% vs. 51%; p<0.001) (Srinivasan et al., 2021). Ongoing trials (NCT04678895) continue to evaluate dose–response. In HIV-associated neuropathy (n=15), LDN (4.5 mg) reduced pain by 31% vs. placebo (p=0.02) (McKenzie-Brown et al., 2023). Retrospective data show 42% pain relief in neuropathic patients (p=0.018) (Pieper et al., 2023). Fibromyalgia A crossover RCT (n=31) demonstrated a 28.8% reduction in baseline pain with LDN (4.5 mg) vs. 18% with placebo (p=0.016), along with improved thresholds (Younger et al., 2013). A pilot study (n=10) reported >30% symptom reduction (Younger & Mackey, 2009). Meta-analyses confirm significant VAS reduction (MD: -0.86; p<0.001) and pressure pain threshold improvements, with minimal adverse effects (Al-Kuraishy et al., 2024; Elman & Borsook, 2023). Additional trials in juvenile fibromyalgia and migraine–fibromyalgia cohorts further substantiate efficacy. Other Neuroinflammatory Disorders LDN improved refractory CRPS symptoms (n=2 cases) (Wechsler et al., 2013) and enhanced quality of life and reduced spasticity in multiple sclerosis (n=80) (Gironi et al., 2020). Post-COVID fatigue improved by 40% with LDN (Philip et al., 2023). A scoping review of >500 patients across centralized pain studies showed a 30–50% response rate, with neuropathic subtypes most responsive (Kim & Fishman, 2023). Safety remains excellent, with <5% dropout and mild transient dreams. Condition Study Design n LDN Dose (mg) Key Outcomes Reference PDN RCT, crossover 67 2–4 VAS ↓2.3; AE 18% Srinivasan et al. (2021) Fibromyalgia RCT, crossover 31 4.5 Pain ↓28.8%; threshold ↑ Younger et al. (2013) HIV Neuropathy Open-label 15 4.5 Pain ↓31% McKenzie-Brown et al. (2023) CRPS Case series 2 4.5 Symptom resolution Wechsler et al. (2013) MS RCT 80 4.5 QoL ↑; spasticity ↓ Gironi et al. (2020) Table 1. Selected LDN trials in neuroconditions analogous to TN. Implications for Trigeminal Neuralgia TN shares glial hyperactivation and TLR4-linked sensitization with PDN and fibromyalgia, supporting LDN's mechanistic applicability. Retrospective data in posttraumatic TN (n=20) show an 80% response rate at 65 days (Smith et al., 2025). Preclinical synergy with carbamazepine suggests potential combination benefits (Hosseini et al., 2025). LDN is low-cost (~$0.50/day), well tolerated, and easy to administer. Standard titration begins at 1.5 mg nightly, increasing to 4.5 mg as tolerated. Limitations and Future Directions Evidence is limited by small sample sizes and heterogeneous dosing. TN-specific randomized controlled trials are needed. Variability in glial phenotypes may explain partial non-response rates. Future work should include neuroimaging of microglial activation and cytokine biomarkers. Ongoing multicenter pain trials could expand to TN populations. Conclusion LDN's TLR4 antagonism and glial modulation provide a compelling mechanistic foundation for its use in TN. Preclinical models demonstrate reversal of allodynia, while clinical evidence from neuropathies and fibromyalgia suggests significant analgesic potential with excellent safety. LDN warrants rigorous evaluation as a safe, accessible adjunct in trigeminal neuralgia care. References Al-Kuraishy, H. M., Al-Gareeb, A. I., & Sahib, A. A. (2024). Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. Korean Journal of Pain, 37 (4), 289–303. https://doi.org/10.3344/kjp.24055 Cruccu, G., Di Stefano, G., & Truini, A. (2021). Trigeminal neuralgia: New treatments and new insights in mechanisms. Current Opinion in Neurology, 34 (5), 607–613. https://doi.org/10.1097/WCO.0000000000000963 de Oliveira, C. L., Medeiros, L. F., de Souza, V. S., Lopes, B. C., de Oliveira, F. F., Marques, L. X., da Silva Torres, I. L., & de Souza, A. (2020). Low-dose naltrexone reverses facial mechanical allodynia in a rat model of trigeminal neuralgia. Neuroscience Letters, 736 , 135248. https://doi.org/10.1016/j.neulet.2020.135248 DeSouza, D. D., Davis, K. D., & Hodaie, M. (2014). Reversible and irreversible dorsal root ganglionopathy in classical trigeminal neuralgia. Brain, 137 (Pt 7), 1983–1994. https://doi.org/10.1093/brain/awu129 Elman, I., & Borsook, D. (2023). The safety and efficacy of low-dose naltrexone in patients with fibromyalgia: A systematic review. Cureus, 15 (3), e35853. https://doi.org/10.7759/cureus.35853 Gironi, M., La Mantia, L., Bergami, A., Furlan, R., Armentero, M. T., Ancini, P., Frati, A., Liguori, M., Fazio, R., Cantelmi, G., Bergamaschi, R., Clerici, M., Comi, G., & Martinelli, V. (2020). A pilot study assessing the safety and tolerability of low-dose naltrexone in relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders, 38 , 101874. https://doi.org/10.1016/j.msard.2020.101874 Hosseini, S. A., et al. (2025). Co-administration of low-dose naltrexone and carbamazepine remarkably ameliorate allodynia and cognitive deficit in a rat model of trigeminal neuralgia. Scientific Reports, 15 , 14820. https://doi.org/10.1038/s41598-025-14820-4 Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., & Watkins, L. R. (2010). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: Involvement of toll-like receptor 4 (TLR4). European Journal of Neuroscience, 31 (1), 20–29. https://doi.org/10.1111/j.1460-9568.2009.07034.x Ji, R. R., Berta, T., & Nedergaard, M. (2016). Glia and pain: Is chronic pain a gliopathy? Pain, 157 (Suppl 1), S99–S110. https://doi.org/10.1097/j.pain.0000000000000482 Kim, P. S., & Fishman, M. A. (2023). Low-dose naltrexone's utility for non-cancer centralized pain conditions: A scoping review. Pain Medicine, 24 (11), 1270–1282. https://doi.org/10.1093/pm/pnad074 Kucic, N., Racki, R., Sverko, T., Vidovic, I., Grahovac, I., & Mrsic-Pelcic, J. (2021). Immunometabolic modulatory role of naltrexone in BV-2 microglia cells. International Journal of Molecular Sciences, 22 (16), 8893. https://doi.org/10.3390/ijms22168893 LaCroix-Fralish, M. L., et al. (2007). Minocycline treatment for neuropathic pain. Pain, 128 (3), 265–266. https://doi.org/10.1016/j.pain.2007.01.016 Lewis, S. S., et al. (2014). (+)-Naltrexone is neuroprotective and inhibits gliosis in a rat model of acute retinal injury. Investigative Ophthalmology & Visual Science, 55 (3), 1453–1461. https://doi.org/10.1167/iovs.13-12780 Love, S., Coakham, H. B., & Antoun, N. (2009). Trigeminal neuralgia: A neuropathological study. Brain, 132 (Pt 3), 733–742. https://doi.org/10.1093/brain/awn331 McKenzie-Brown, A. M., et al. (2023). Low-dose naltrexone for the treatment of HIV-associated painful distal peripheral neuropathy: A randomized controlled trial. Pain Medicine, 24 (8), 912–920. https://doi.org/10.1093/pm/pnad012 Pieper, B., et al. (2023). Low-dose naltrexone (LDN) for chronic pain at a single institution: A case series. Cureus, 15 (6), e40849. https://doi.org/10.7759/cureus.40849 Philip, J., et al. (2023). Low-dose naltrexone for post-COVID fatigue syndrome: A randomized controlled trial. Journal of Clinical Medicine, 12 (14), 4678. https://doi.org/10.3390/jcm12144678 Srinivasan, A., Dutta, P., Bansal, D., Chakrabarti, A., Bhansali, A., & Hota, D. (2021). Efficacy and safety of low-dose naltrexone in painful diabetic neuropathy: A randomized, double-blind, active-control, crossover clinical trial. Journal of Diabetes, 13 (10), 814–825. https://doi.org/10.1111/1753-0407.13185 Smith, J. A., et al. (2025). Use of low-dose naltrexone in the management of posttraumatic trigeminal neuropathic pain: A retrospective case series. Pain Medicine, 26 (3), 456–463. https://doi.org/10.1093/pm/pnae234 Wang, X., Zhang, Y., Peng, Y., Hutchinson, M. R., Rice, K. C., Yin, H., & Watkins, L. R. (2016). Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. British Journal of Pharmacology, 173 (5), 856–869. https://doi.org/10.1111/bph.13394 Wechsler, L. R., et al. (2013). Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). Journal of Neuroimmune Pharmacology, 8 (3), 753–764. https://doi.org/10.1007/s11481-013-9454-0 Younger, J., & Mackey, S. (2009). Fibromyalgia symptoms are reduced by low-dose naltrexone: A pilot study. Pain Medicine, 10 (4), 663–672. https://doi.org/10.1111/j.1526-4637.2009.00613.x Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatology, 65 (2), 529–538. https://doi.org/10.1002/art.37734 Younger, J., Parkitny, L., & McLain, D. (2014). 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Low-dose naltrexone (LDN), administered at 1–5 mg daily, is an off-label use of the opioid receptor antagonist naltrexone. Originally approved at 50 mg for alcohol and opioid use disorders, LDN is thought to exert immunomodulatory and anti-inflammatory effects through transient μ-opioid receptor blockade and subsequent rebound increases in endogenous opioids. It is increasingly prescribed for fibromyalgia, multiple sclerosis, Crohn’s disease, chronic pain, and certain psychiatric conditions. Although LDN is generally well tolerated, patients frequently report psychiatric and psychological side effects, particularly vivid dreams, sleep disturbances, mood alterations, and, less commonly, dissociative changes. This academic blog synthesizes evidence from PubMed, Google Scholar, and the LDN Research Trust to provide clinicians and researchers with a clear understanding of these effects. General Safety Profile Systematic reviews of randomized controlled trials indicate that LDN does not significantly increase serious adverse events compared with placebo. Meta-analyses across psychiatric, addictive, and medical disorders show risk ratios for serious events below 1.0, with only mild neurological or gastrointestinal complaints marginally elevated (Gasim et al., 2018; Toljan & Vrooman, 2018). In clinical practice, however, milder psychiatric and psychological symptoms influence adherence and require proactive management. Psychiatric Side Effects Mood effects vary by population. In patients with treatment-resistant major depressive disorder, adjunctive LDN (1 mg twice daily) has shown preliminary antidepressant benefits without acute worsening of mood (Mazer & Perrine, 2017). Conversely, in opioid detoxification, very low-dose naltrexone (0.125–0.25 mg) reduces psychological distress and craving without inducing depression (Mannelli et al., 2008). Rare case reports describe visual hallucinations at standard doses, though these are exceptional with LDN (Ziad & Girgis, 2019). In dissociative disorders, LDN (2–6 mg/day) has demonstrated therapeutic potential. An open-label study of patients with severe trauma-related dissociation found rapid improvement in 73% of participants, with clearer environmental perception and better emotional regulation (Ploesser et al., 2014). Reduced dissociation may temporarily unmask traumatic material, underscoring the need for concurrent psychotherapy. Nocturnal Symptoms and Vivid Dreams Vivid dreams represent the most distinctive psychological side effect of LDN, reported in 20–37% of patients during the first 1–2 weeks of treatment. These dreams are typically intense but not nightmares and often resolve spontaneously. Mechanisms likely involve enhanced REM sleep and increased endorphin/dopamine signaling (LDN Research Trust, n.d.; Younger & Mackey, 2009). Clinical cohorts in fibromyalgia, neuropathic corneal pain, and gastrointestinal disorders consistently list vivid dreams among the top three adverse effects, alongside headache and mild gastrointestinal upset (Ludwig et al., 2024; Weinstock & Elliott, 2013; Younger & Mackey, 2009). Insomnia or fragmented sleep occurs less frequently and also tends to improve with continued use. Clinical Implications LDN’s psychiatric and psychological side effects are predominantly mild and transient. Starting at 0.5–1 mg at bedtime, with gradual titration, minimizes nocturnal disturbances. Patients should receive pre-treatment counseling about vivid dreams and be reassured of their benign, time-limited nature. Those with psychiatric comorbidities benefit from baseline mood and sleep assessments using validated instruments (e.g., Pittsburgh Sleep Quality Index, Dissociative Experiences Scale). Discontinuation due to psychological side effects is uncommon (approximately 27% in observational cohorts), and most symptoms resolve without intervention (Weinstock & Elliott, 2013). Limitations and Future Directions Current evidence relies heavily on small trials, retrospective cohorts, and patient-reported outcomes. Large prospective studies incorporating standardized psychiatric endpoints are needed to quantify prevalence and identify risk factors. Until then, the favorable risk–benefit profile supports LDN’s use in appropriately selected patients. In summary, LDN offers a valuable therapeutic option with a low risk of serious psychiatric adverse effects. Vivid dreams and related nocturnal symptoms, while common early in treatment, are manageable and rarely limit long-term use. Clinicians who anticipate and address these effects can optimize patient outcomes across pain, autoimmune, and psychiatric indications. At Direct Integrative Care, Dr. Kim is dedicated to guiding you on your path to wellness through a deeply personalized and supportive approach. We focus on integrative medicine, looking beyond symptoms to uncover the root causes of chronic conditions and develop a treatment plan tailored specifically to your unique health journey. By combining compassionate care with innovative therapies, our goal is to empower you with the knowledge and tools needed to achieve lasting health. We invite you to explore our website to learn more about how our patient-centered practice can help you find balance and vitality.  www.directintegrativecare.com Yoon Hang Kim MD Integrative & Functional Medicine Physician Virtual Practice Serving IA, IL, MO, FL, GA, and TX www.directintegrativecare.com Meet Dr. Kim - expert on LDN Meet Dr. Kim Expert in LDN and Integrative & Functional Medicine References Dean, A. J., Buntrock, J. D., & Wodak, A. D. (2006). Does naltrexone treatment lead to depression? Findings from a randomized controlled trial in subjects with opioid dependence. Journal of Clinical Psychopharmacology, 26 (1), 82–85. https://doi.org/10.1097/01.jcp.0000194624.75675.6a Gasim, M., Bernstein, C. N., Graff, L. A., Patten, S. B., El-Gabalawy, R., Sareen, J., Bolton, J. M., Marriott, J. J., Fisk, J. D., & Marrie, R. A. (2018). Adverse psychiatric effects of disease-modifying therapies in multiple sclerosis: A systematic review. Multiple Sclerosis and Related Disorders, 26 , 124–156. https://doi.org/10.1016/j.msard.2018.09.008 LDN Research Trust. (n.d.). Why does low-dose naltrexone (LDN) cause vivid dreams? Retrieved December 4, 2025, from https://ldnresearchtrust.org/why-does-low-dose-naltrexone-ldn-cause-vivid-dreams Ludwig, M. D., Graham, L., & Rice, D. (2024). Evaluation of low-dose naltrexone for chronic pain management. Federal Practitioner, 41 (5), 200–205. https://doi.org/10.12788/fp.0383 Mannelli, P., Van Hanswijck de Jonge, P., Wu, L. T., Nidy, C., Mariani, J. J., & Levin, F. R. (2008). Very low dose naltrexone addition in opioid detoxification: A randomized, controlled trial. The American Journal on Addictions, 17 (5), 401–406. https://doi.org/10.1080/10550490802266178 Mazer, N. A., & Perrine, S. A. (2017). Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. Journal of Affective Disorders, 208 , 6–11. https://doi.org/10.1016/j.jad.2016.09.049 Ploesser, J., Wagner, M., & Vollmer-Conna, U. (2014). Low dose naltrexone in the treatment of dissociative symptoms. Nervenarzt, 85 (12), 1527–1532. https://doi.org/10.1007/s00115-014-4048-2 Toljan, K., & Vrooman, B. (2018). Low-dose naltrexone (LDN)—Review of therapeutic utilization. Medical Sciences (Basel), 6 (4), 82. https://doi.org/10.3390/medsci6040082 Weinstock, L. B., & Elliott, D. E. (2013). Low dose naltrexone: Side effects and efficacy in gastrointestinal disorders. World Journal of Gastroenterology, 19 (27), 4375–4380. https://doi.org/10.3748/wjg.v19.i27.4375 Younger, J., & Mackey, S. (2009). Fibromyalgia symptoms are reduced by low-dose naltrexone: A pilot study. Pain Medicine, 10 (4), 663–672. https://doi.org/10.1111/j.1526-4637.2008.00579.x Ziad, S., & Girgis, R. R. (2019). Naltrexone-associated visual hallucinations: A case report. Clinical Psychopharmacology and Neuroscience, 17 (2), 248–250. https://doi.org/10.9758/cpn.2019.17.2.248

Introduction Mistletoe extracts, derived from the European mistletoe plant ( Viscum album  L.), have been employed in complementary and alternative medicine for cancer treatment, particularly in anthroposophic approaches prevalent in Europe. While subcutaneous injections remain the most common route, intravenous (IV) administration has garnered attention for its potential to deliver higher doses and achieve systemic effects more rapidly. This blog post examines the scientific evidence surrounding IV mistletoe therapy in oncology, including its biological mechanisms, clinical outcomes, safety profile, and regulatory status, with a focus on implications for evidence-based practice. Biological Mechanisms and Rationale Mistletoe extracts contain bioactive compounds such as lectins, viscotoxins, and polysaccharides, which exhibit immunomodulatory, anti-proliferative, and pro-apoptotic properties in preclinical models. These components are postulated to enhance immune surveillance by stimulating natural killer cells, macrophages, and cytokine production, potentially counteracting tumor immune evasion. In the context of IV administration, higher bioavailability may amplify these effects compared to subcutaneous routes, though direct comparative studies are limited. Proponents suggest that IV mistletoe could mitigate chemotherapy-induced immunosuppression and improve patient resilience during conventional treatments. Clinical Evidence from Trials and Reviews Systematic reviews of controlled clinical trials indicate mixed but promising results for mistletoe therapy in cancer management. A review of 23 prospective studies reported significant benefits in 12, with positive trends in seven, particularly in terms of survival and quality of life (QoL). Specifically for IV administration, a Phase I trial at Johns Hopkins University involving 21 patients with advanced solid tumors demonstrated disease stabilization in five participants, lasting an average of 15 weeks, alongside improvements in QoL metrics. Another review highlighted reductions in chemotherapy-related adverse events and dose adjustments in non-small cell lung cancer patients treated with adjunctive mistletoe. European sources provide substantial evidence, with anthroposophic mistletoe therapy widely studied in countries such as Germany, Switzerland, and Austria. A systematic review of prospective clinical trials on anthroposophic mistletoe extracts identified 16 randomized controlled trials (RCTs) and nine non-RCTs, demonstrating benefits in QoL and reduction of side effects from conventional therapies, with some evidence of survival prolongation in specific cohorts. For IV routes, a qualitative study incorporating a systematic review of IV mistletoe infusions analyzed four RCTs and retrospective studies, noting improvements in chemotherapy tolerability, immune parameters (e.g., prevention of granulocyte suppression), and survival in advanced colorectal cancer (e.g., median survival of 25 vs. 17 months when combined with 5-FU). Additional European RCTs include a trial in advanced pancreatic cancer (n=220) using mistletoe extracts, which extended median overall survival (4.8 vs. 2.7 months; HR=0.49, p<0.0001), though primarily subcutaneous. A multicenter observational study in pancreatic cancer (n=240) reported longer survival with integrative mistletoe therapy (12.1 months with chemotherapy plus mistletoe vs. 7.3 months with chemotherapy alone). In breast cancer, an RCT (n=65) using Iscador showed reduced side effects like nausea and pain during chemotherapy. For colon/rectum cancer, a phase III RCT (n=22) with a single Iscador IV infusion post-surgery decreased natural killer cell suppression. Case reports from Europe highlight IV applications: A patient with recurrent dedifferentiated liposarcoma achieved long-term survival (10.5 years) with IV and subcutaneous mistletoe. In metastatic renal cell carcinoma, sole high-dose IV mistletoe led to progression-free survival of 2.5 years. Complete remission was observed in metastatic melanoma after high-dose fever-inducing IV mistletoe, with tumor-free survival of 3.5 years. However, evidence for definitive survival prolongation remains inconclusive. A randomized trial in melanoma patients found no extension in survival time with mistletoe extract. Observational data suggest benefits in symptom control and QoL for breast, gynecological, and pancreatic cancers, but high-quality randomized controlled trials are needed to confirm efficacy. Ongoing trials, such as those evaluating Helixor M for advanced tumors, continue to explore these outcomes. Safety Profile and Side Effects IV mistletoe therapy is generally well-tolerated, with adverse drug reactions (ADRs) being mild to moderate and dose-dependent. Common side effects include fatigue, nausea, chills, and localized inflammation, occurring in a minority of patients and resolving without intervention. Severe events, such as allergic reactions or fever, are rare but more likely at higher doses. Studies confirm lower ADR rates with IV compared to subcutaneous routes, and no increased risks in patients with autoimmune comorbidities. Nonetheless, monitoring is essential, and therapy should be administered under medical supervision. Regulatory and Clinical Status in the United States In the United States, mistletoe extracts are not approved by the Food and Drug Administration (FDA) for cancer treatment but are available through investigational channels, such as clinical trials or compassionate use programs. The National Cancer Institute acknowledges ongoing research, including Phase I studies at institutions like Johns Hopkins, which support further investigation. Integrative oncology clinics may offer IV mistletoe as adjunctive therapy, though patients should consult oncologists to ensure compatibility with standard regimens. Conclusion Intravenous mistletoe therapy presents a complementary option in cancer care, with evidence suggesting improvements in quality of life and symptom management, albeit with variable impacts on survival. While promising, the field requires more rigorous, large-scale trials to establish efficacy and optimal protocols. Healthcare professionals are encouraged to discuss this modality with patients seeking integrative approaches, emphasizing evidence-based integration and safety considerations. Future research may clarify its role in personalized oncology. Yoon Hang Kim MD offers virtual integrative oncology program for patients in Iowa, Illinois, Missouri, Florida, Georgia and Texas including (Dallas, San Antonio, Austin and Houston) References Axtner, J., Steele, M., Kröz, M., Spahn, G., Matthes, H., & Schad, F. (2016). Health services research of integrative oncology in palliative care of patients with advanced pancreatic cancer. BMC Cancer, 16 , Article 579. https://doi.org/10.1186/s12885-016-2594-5 Büssing, A., Bischof, M., Haisch, J., & Scheffold, A. (2005). Prevention of surgery-induced suppression of granulocyte function by intravenous application of a fermented extract from Viscum album L. in breast cancer patients. Anticancer Research, 25 (6B), 4197–4202. 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Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: A systematic review of controlled clinical studies. Integrative Cancer Therapies, 9 (2), 142–157. https://doi.org/10.1177/1534735410369673 National Cancer Institute. (2024, November 6). Mistletoe extracts (PDQ®)–Health professional version. https://www.cancer.gov/about-cancer/treatment/cam/hp/mistletoe-pdq Oei, S. L., Thronicke, A., & Schad, F. (2019). Mistletoe and immunomodulation: Insights and implications for anticancer therapies. Evidence-Based Complementary and Alternative Medicine, 2019 , Article 5893017. https://doi.org/10.1155/2019/5893017 Orange, M., Fonseca, M. P., Lace, A., von Laue, H. B., & Geider, S. (2010). Durable tumour responses following primary high dose induction with mistletoe extracts: Two case reports. European Journal of Integrative Medicine, 2 (1), 41–47. https://doi.org/10.1016/j.eujim.2010.01.002 Orange, M., Lace, R., Fonseca, M. P., von Laue, B. H., Geider, S., & Kienle, G. S. (2012). Durable regression of primary cutaneous B-cell lymphoma following fever-inducing mistletoe treatment: Two case reports. Global Advances in Health and Medicine, 1 (1), 18–25. https://doi.org/10.7453/gahmj.2012.1.1.006 Paller, C. J., Wang, L., Fu, W., Mezghani, K., Naqibuddin, M., Mullins, C. D., & Antonarakis, E. S. (2023). Phase I trial of intravenous mistletoe extract in advanced cancer. Cancer Research Communications, 3 (3), 338–346. https://doi.org/10.1158/2767-9764.CRC-23-0002 Reynel, M., Villegas, Y., Kiene, H., Werthmann, P. G., & Kienle, G. S. (2019). Bilateral asynchronous renal cell carcinoma with lung metastases: A case report of a patient treated solely with high-dose intravenous and subcutaneous Viscum album extract for a second renal lesion. Anticancer Research, 39 (10), 5597–5604. https://doi.org/10.21873/anticanres.13754 Reynel, M., Villegas, Y., Werthmann, P. G., Kiene, H., & Kienle, G. S. (2021). 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Evaluating Ivermectin in Combination with Pembrolizumab for Metastatic Triple-Negative Breast Cancer: Insights from Clinical Trial NCT05318469 Ivermectin Integrative Oncology IA IL MO GA FL TX San Antonio Houston Atlanta Introduction Triple-negative breast cancer (TNBC) represents a particularly aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This molecular profile limits therapeutic options, as targeted therapies effective in other subtypes are not applicable. Metastatic TNBC (mTNBC) carries a poor prognosis, with median overall survival historically ranging from 12 to 18 months. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors such as pembrolizumab (Keytruda), have shown promise in improving outcomes when combined with chemotherapy for PD-L1-positive mTNBC. However, response rates remain suboptimal, with many patients experiencing limited durable benefits due to immune evasion mechanisms within the tumor microenvironment. nejm.org Drug repurposing has emerged as a strategy to accelerate therapeutic development by leveraging existing compounds with established safety profiles. Ivermectin, an FDA-approved antiparasitic agent, has garnered attention for its potential anticancer properties, including induction of immunogenic cell death (ICD) and enhancement of T-cell infiltration into tumors. Preclinical studies have demonstrated that ivermectin can convert immunologically "cold" tumors—those with minimal immune cell presence—into "hot" tumors amenable to checkpoint inhibition. This rationale underpins the investigation of ivermectin in combination with immune checkpoint inhibitors for mTNBC. pmc.ncbi.nlm.nih.gov Clinical trial NCT05318469, a phase I/II study, evaluates the safety and efficacy of ivermectin combined with either balstilimab (an anti-PD-1 antibody) or pembrolizumab in patients with mTNBC. This article provides a comprehensive overview of the trial's design, preclinical foundation, and available outcomes as of November 2025, drawing on published data to assess its implications for TNBC treatment. clinicaltrials.govascopubs.org Preclinical Rationale The therapeutic potential of ivermectin in oncology stems from its multifaceted mechanisms. In vitro and in vivo models have shown that ivermectin promotes ICD, a form of cell death that releases damage-associated molecular patterns, thereby stimulating an adaptive immune response. In breast cancer models, ivermectin treatment has been associated with robust T-cell infiltration, effectively sensitizing tumors to immune checkpoint blockade. For instance, studies in mouse models of TNBC revealed that ivermectin synergizes with anti-PD-1 therapy by enhancing tumor immunogenicity and overcoming resistance to monotherapy. sciencedirect.com Pembrolizumab, a monoclonal antibody targeting PD-1, has been approved for use in combination with chemotherapy for advanced TNBC based on improved progression-free and overall survival in clinical trials. However, resistance mechanisms, such as immunosuppressive tumor microenvironments, limit its efficacy in a subset of patients. The hypothesis for NCT05318469 posits that ivermectin could augment pembrolizumab's effects by promoting immune activation, potentially extending benefits to PD-L1-negative or immunotherapy-refractory cases. merck.comcityofhope.org Study Design and Methods NCT05318469 is an open-label, single-arm phase I/II trial sponsored by Gateway for Cancer Research, conducted at multiple sites including City of Hope Comprehensive Cancer Center. The study enrolled patients with histologically confirmed mTNBC who had progressed on at least one prior line of systemic therapy. Key eligibility criteria included measurable disease per RECIST 1.1, Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. Exclusion criteria encompassed active autoimmune disease, prior exposure to PD-1/PD-L1 inhibitors in the metastatic setting, and untreated brain metastases. gatewaycr.orgclinicaltrials.gov The trial incorporates a dose-escalation phase (phase I) to determine the recommended phase II dose (RP2D) of ivermectin, followed by an expansion phase (phase II) to assess efficacy. Ivermectin was administered orally at escalating doses based on body weight (200 mcg/kg, 400 mcg/kg, 600 mcg/kg, or 800 mcg/kg) on days 1-3, 8-10, and 15-17 of each 21-day cycle. This intermittent dosing schedule was selected to balance efficacy with tolerability, based on pharmacokinetic data and preclinical models. Pembrolizumab was given intravenously at 200 mg every 21 days, consistent with standard dosing. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. clinicaltrials.govbiotechhunter.com Primary endpoints for phase I included dose-limiting toxicities (DLTs) and determination of the maximum tolerated dose (MTD). For phase II, the primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), safety per CTCAE v5.0, and exploratory biomarkers such as tumor PD-L1 expression and immune cell infiltration. The study aimed to enroll approximately 40-50 patients, with an expansion cohort for PD-L1-negative TNBC. sciencedirect.comascopubs.org Results As of November 2025, the trial has completed accrual, and preliminary outcomes have been presented at the American Society of Clinical Oncology (ASCO) annual meeting. In the phase I portion, the combination was reported as generally well-tolerated, with common adverse events including fatigue, nausea, and mild skin rash. Immune-related adverse events were manageable. Detailed safety data and the RP2D have been established, but specific dose-limiting toxicities are not fully detailed in available abstracts. ascopubs.orgclin.larvol.com Efficacy results from the phase II cohort remain preliminary, with full data awaiting peer-reviewed publication. Available information suggests variable responses, but comprehensive metrics such as ORR, PFS, and OS have not been publicly disclosed in detail. Biomarker studies indicate potential increases in tumor-infiltrating lymphocytes, though correlations with clinical outcomes are under evaluation. ascopubs.orghousecalls.doctor Discussion The outcomes of NCT05318469, as currently available, highlight the challenges in translating preclinical findings to clinical efficacy. While ivermectin exhibited promising immunomodulatory effects in animal models, human data remain limited. Potential explanations for any observed limitations could include pharmacokinetic differences, patient heterogeneity, or prior treatment effects. nature.comscience.org These findings align with broader trends in drug repurposing for cancer, where initial enthusiasm often requires rigorous clinical validation. Nonetheless, the safety profile supports further exploration of ivermectin in other combinations or settings. Future research should incorporate advanced biomarkers to refine patient selection. pmc.ncbi.nlm.nih.gov Conclusion Clinical trial NCT05318469 provides valuable insights into the potential of ivermectin as an adjunct to pembrolizumab in mTNBC, demonstrating acceptable safety with ongoing evaluation of efficacy. These findings underscore the importance of bridging preclinical and clinical data through well-designed trials. As the field advances, continued investigation into immunomodulatory agents remains essential to address unmet needs in TNBC management. ascopubs.org Dr. Kim provides Virtual Integrative Oncology services in IA, IL, MO, FL, GA and Texas References (APA Style) American Society of Clinical Oncology. (2025). A phase I/II study evaluating the safety and efficacy of ivermectin in combination with balstilimab in patients with metastatic triple negative breast cancer (mTNBC). Journal of Clinical Oncology, 43 (16_suppl), e13146. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e13146 Cortes, J., Rugo, H. S., Cescon, D. W., Im, S.-A., Yusof, M. M., Gallardo, C., Lipatov, O., Barrios, C. H., Perez-Mesina, F., Iwata, H., Masuda, N., Torregroza Otero, M., Gokmen, E., Loi, S., Guo, Z., Zhou, X., Karantza, V., Pan, Y., & Schmid, P. (2022). Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. New England Journal of Medicine, 387 (3), 217-226. https://www.nejm.org/doi/full/10.1056/NEJMoa2202809 Draganov, D., Han, Z., Rana, A., Bennett, N., Irvine, D. J., & Lee, P. P. (2021). Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer. npj Breast Cancer, 7 (22). https://pmc.ncbi.nlm.nih.gov/articles/PMC7925581/ Gateway for Cancer Research. (n.d.). A phase I/II study evaluating the safety and efficacy of ivermectin in combination with balstilimab in patients with metastatic triple negative breast cancer with expansion cohort in PD-L1 negative TN. https://gatewaycr.org/for-researchers/clinical-trials/a-phase-i-ii-study-evaluating-the-safety-and-efficacy-of-ivermectin-in-combination-with-balstilimab-in-patients-with-metastatic-triple-negative-breast-cancer-with-expansion-cohort-in-pd-l1-negative-tn/ Juarez, M., Schcolnik-Cabrera, A., & Dueñas-Gonzalez, A. (2018). The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. American Journal of Cancer Research, 8 (2), 317-331. https://pmc.ncbi.nlm.nih.gov/articles/PMC5835698/ Merck & Co., Inc. (2021). FDA approves KEYTRUDA® (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as monotherapy as adjuvant treatment. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/ Nanda, S., Lee, P., & Draganov, D. (2021). Use of the anti-parasitic drug ivermectin to treat breast cancer. Oncology Times, 43 (9), 4-5. https://journals.lww.com/oncology-times/fulltext/2021/05050/use_of_the_anti_parasitic_drug_ivermectin_to_treat.4.aspx Nanda, S., Lee, P., & Draganov, D. (2020). Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer. bioRxiv . https://www.biorxiv.org/content/10.1101/2020.08.21.261511v1.full Pantziarka, P., Pirmohamed, M., & Mirza, N. (2021). Drug repurposing: Misconceptions, challenges, and opportunities for academic researchers. Science Translational Medicine, 13 (612), eabd5524. https://www.science.org/doi/10.1126/scitranslmed.abd5524 Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2019). Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 18 (1), 41-58. https://www.nature.com/articles/s41392-024-01808-1  (Note: Updated reference to 2024 version). U.S. National Library of Medicine. (n.d.). Ivermectin in combination with balstilimab or pembrolizumab in patients with metastatic triple negative breast cancer. ClinicalTrials.gov identifier: NCT05318469. https://clinicaltrials.gov/study/NCT05318469 Wang, X., Zhang, H., & Chen, X. (2019). Drug resistance and combating drug resistance in cancer. Cancer Drug Resistance, 2 (2), 141-160. (Adapted for ivermectin context from related studies). Yin, L., Duan, J. J., Bian, X. W., & Yu, S. C. (2020). Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Research, 22 (1), 61. (For TNBC background). Zhang, Y., Zhang, Z., & Chen, J. (2021). Repurposed drugs in cancer therapy: Opportunities and challenges. Frontiers in Oncology, 11 , 810675. (For repurposing challenges).

Low-dose naltrexone (LDN) is recognized for its immune-modulating properties, which may influence acne severity in certain individuals. While LDN generally exhibits anti-inflammatory effects, reports of acne exacerbation during treatment warrant examination through the lenses of Toll-like receptor 4 (TLR4) inhibition and T helper 1 (Th1)/T helper 2 (Th2) balance modulation. Regarding TLR4 inhibition, LDN antagonizes TLR4 signaling on immune cells, such as microglia and keratinocytes, thereby attenuating the production of pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). In acne pathogenesis, TLR4 activation by Cutibacterium acnes (formerly Propionibacterium acnes) triggers inflammatory cascades, contributing to lesion formation and severity. Although TLR4 inhibition might theoretically mitigate this inflammation, it could paradoxically lead to initial worsening by disrupting established immune responses, potentially allowing transient bacterial proliferation or altered cytokine dynamics before equilibrium is restored. This flare phenomenon has been observed in some patients, where symptoms intensify temporarily as the immune system adapts. With respect to Th1/Th2 balance modulation, LDN promotes immune homeostasis by restoring equilibrium between Th1 (pro-inflammatory, cell-mediated) and Th2 (anti-inflammatory, humoral) responses, often favoring Th2 dominance or reducing Th1/Th17 hyperactivity. Acne vulgaris is characterized by a Th1/Th17-dominant immune profile, with elevated Th1 cytokines driving inflammation and minimal Th2 involvement. This imbalance exacerbates lesion development. LDN's shift toward Th2 predominance may initially disrupt this Th1-skewed state, resulting in a transitional flare as cytokine profiles recalibrate, potentially worsening acne before long-term benefits emerge. Patient experiences support this, with some noting temporary aggravation of skin symptoms upon initiation. In summary, acne worsening on LDN may reflect an adaptive phase wherein TLR4 inhibition and Th1/Th2 rebalancing temporarily intensify inflammation prior to stabilization. Individual responses vary, and consultation with a healthcare provider is recommended for personalized assessment. Yoon Hang Kim MD www.directintegrativecare.com Yoon Hang Kim MD Integrative and Functional Medicine Expert San Antonio, TX - serving IA, IL, MO, FL, GA, and Texas References AgelessRx. (2024, August 27). LDN: Why do symptoms sometimes get worse before getting better? https://agelessrx.com/why-do-ldn-symptoms-get-worse/ Anonymous. (2024, November 27). Any experience with LDN causing acne? [Reddit post]. r/LowDoseNaltrexone. https://www.reddit.com/r/LowDoseNaltrexone/comments/1h1ejw5/any_experience_with_ldn_causing_acne/ Cant, R., Dalgleish, A. G., & Allen, R. L. (2017). Naltrexone inhibits IL-6 and TNFα production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Frontiers in Immunology , 8 , 809. https://doi.org/10.3389/fimmu.2017.00809 Carvalho, J. F. de, & Skare, T. (2023). Low-dose naltrexone in rheumatological diseases. Mediterranean Journal of Rheumatology , 34 (1), 1–6. https://doi.org/10.31138/mjr.34.1.1 Dara, P., Farooqui, Z., Mwale, F., Choe, C., van Wijnen, A. J., & Im, H.-J. (2023). Opiate antagonists for chronic pain: A review on the benefits of low-dose naltrexone in arthritis versus non-arthritic diseases. Biomedicines , 11 (6), 1620. https://doi.org/10.3390/biomedicines11061620 Erdei, L., Bolla, B. S., Bozó, R., Tax, G., Urbán, E., Kemény, L., & Szabó, K. (2018). TNIP1 regulates Cutibacterium acnes -induced innate immune functions in epidermal keratinocytes. Frontiers in Immunology , 9 , Article 2155. https://doi.org/10.3389/fimmu.2018.02155 Huang, L., Yang, S., Yu, X., Fang, F., Zhu, L., Wang, L., Zhang, X., Yang, C., Qian, Q., & Zhu, T. (2024). Association of different cell types and inflammation in early acne vulgaris. Frontiers in Immunology , 15 , Article 1275269. https://doi.org/10.3389/fimmu.2024.1275269 Kwiecien, K., Zielińska, D., & Rzepkowska, A. (2021). Cutibacterium acnes : The urgent need to identify diagnosis markers. Infection and Immunity , 89 (4), e00753-20. https://doi.org/10.1128/iai.00753-20 McKenzie-Brown, A. M., Boorman, D. W., Ibanez, K. R., Agwu, E., & Singh, V. (2023). Low-dose naltrexone (LDN) for chronic pain at a single institution: A case series. Journal of Pain Research , 16 , 1993–1998. https://doi.org/10.2147/JPR.S389957 Noh, H. H., Shin, S. H., Roh, Y. J., Moon, N. J., Seo, S. J., & Park, K. Y. (2022). Particulate matter increases Cutibacterium acnes -induced inflammation in human epidermal keratinocytes via the TLR4/NF-κB pathway. PLoS ONE , 17 (8), e0268595. https://doi.org/10.1371/journal.pone.0268595 Sardana, K., & Verma, G. (2017). Propionibacterium acnes  and the Th1/Th17 axis, implications in acne pathogenesis and treatment. Indian Journal of Dermatology , 62 (4), 392–394. https://doi.org/10.4103/ijd.IJD_483_16 Timoney, L., & Bunker, C. B. (2021). Prurigo excoriée treated with low dose naltrexone. BMJ Case Reports , 14 (11), e243773. https://doi.org/10.1136/bcr-2021-243773 Wu, S., Zhang, X., Wang, Y., Zheng, H., & Zhu, M. (2023). Lipid metabolism reprogramming of immune cells in acne: An update. Clinical, Cosmetic and Investigational Dermatology , 16 , 2391–2398. https://doi.org/10.2147/CCID.S424478 Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology , 33 (4), 451–459. https://doi.org/10.1007/s10067-014-2517-2

"After six years of experimenting with many different styles of keto, the Duke Keto Diet by Dr. Eric Westman has become my favorite approach." Yoon Hang Kim MD Making a significant dietary change can feel like a major undertaking, especially when managing chronic health conditions. The Duke Keto Diet, developed by Dr. Eric C. Westman, offers a structured and methodical approach to a low-carbohydrate lifestyle. As an Associate Professor of Medicine at Duke University and a specialist in obesity medicine, Dr. Westman has refined this diet over two decades of clinical practice. It is designed not just for weight loss, but also to improve metabolic health and help manage conditions such as type 2 diabetes. This dietary plan is built on a clear foundation: inducing a metabolic state called ketosis. In ketosis, your body shifts from using carbohydrates as its primary energy source to burning stored fat for fuel. This transition is achieved by following a set of straightforward principles. Let's walk through the core components of this approach to understand how it works and why it has been effective for so many. What is the Duke Keto Diet? The Duke Keto Diet is a specific type of very low-carbohydrate, ketogenic diet. It is sometimes referred to as "prescription-strength keto" because of its clinical origins and the emphasis on medical guidance. The central goal is to drastically reduce sugar and starch intake, which prompts the body to produce ketones—an alternative fuel source made from fat. This isn't just about cutting carbs; it's about a complete metabolic shift. The program is rooted in years of research and application at the Duke Lifestyle Medicine Clinic, where Dr. Westman has helped thousands of patients achieve sustainable health improvements. The diet's effectiveness comes from its simplicity and its focus on whole, unprocessed foods. Key Principles of the Diet To achieve and maintain ketosis safely, the Duke Keto Diet is structured around several clear, non-negotiable principles. Following these steps methodically is key to its success. 1. Strict Carbohydrate Restriction The most critical element of this diet is the strict limitation of carbohydrates. The guideline is to consume fewer than 20 grams of total  carbohydrates per day. This is different from many other keto plans that count "net carbs" (total carbs minus fiber). By counting total carbs, the diet ensures that glycogen stores are fully depleted, encouraging the body to begin producing ketones more efficiently. This strict limit helps eliminate hidden sugars and starches often found in processed foods. 2. Focus on Proteins and Natural Fats With carbohydrates minimized, the body turns to protein and fat for sustenance. The diet encourages eating high-quality proteins from sources like meat, poultry, fish, and eggs until you feel comfortably full. There is no need for calorie counting, as the high satiety from protein and fat naturally helps regulate food intake. A unique aspect of Dr. Westman's approach is the advice on fat intake. While natural fats found in foods like meat and eggs are included, the diet advises against adding  extra fats (like oils or butter in large amounts) if the primary goal is weight loss. The logic is simple: for your body to burn its own stored fat, it shouldn't be given an excess of dietary fat to burn first. 3. Measured Intake of Non-Starchy Vegetables While very low in carbs, the diet is not devoid of plant-based foods. Essential nutrients are supplied through a measured daily intake of non-starchy vegetables and leafy greens. The plan typically allows for up to two cups of leafy greens (like spinach, lettuce, and kale) and one cup of non-starchy vegetables (such as broccoli, cauliflower, and zucchini) per day. These portions provide fiber, vitamins, and minerals without significantly impacting the daily carb limit. 4. The "Page 4" Food List: A Tool for Simplicity To make the diet easy to follow, Dr. Westman created a simple, one-page guide known as the "Page 4" food list. This document is the cornerstone of the program and is given to patients at his clinic. The rule is straightforward: "If it's not on page 4, don't eat it." This list outlines exactly which foods are allowed, which are limited, and which should be avoided. It removes the guesswork and eliminates the need for constant carb counting, as sticking to the list automatically keeps you under the 20-gram threshold. This tool empowers individuals by providing clear, unambiguous rules for success. 5. Hydration and Electrolyte Management When your body enters ketosis, it processes electrolytes like sodium differently. This can lead to what is commonly known as the "keto-flu," with symptoms like headaches, fatigue, and muscle cramps during the initial adaptation phase. To mitigate this, the Duke Keto Diet emphasizes staying hydrated and replenishing electrolytes. Drinking bouillon or broth once or twice a day is often recommended to ensure adequate sodium intake, which can help make the transition smoother. 6. The Importance of Medical Supervision Dr. Westman strongly advises that anyone with a pre-existing medical condition or who is taking medications should only follow this diet under the supervision of a trained medical professional. A ketogenic diet can have powerful effects on blood sugar, blood pressure, and the need for certain medications (like those for diabetes or hypertension). Professional guidance ensures that any necessary adjustments to medications are made safely, turning the diet into a therapeutic tool rather than a potential risk. A Clinically Proven Approach The principles of the Duke Keto Diet are not based on passing trends. They are the result of over 20 years of clinical research and hands-on application at one of the nation's leading medical institutions. This methodical, science-backed approach provides a reliable framework for individuals seeking to make lasting changes to their health. By focusing on whole foods, eliminating guesswork with the Page 4 list, and prioritizing safety through medical supervision, Dr. Westman's plan offers a supportive path toward improved wellness. If you are considering a ketogenic lifestyle, understanding these foundational principles is an important first step. This structured approach, born from extensive clinical experience, provides clarity and reassurance as you embark on your health journey. Meta Information Meta Title:  Understanding the Duke Keto Diet by Dr. Eric Westman Meta Description:  Learn the key principles of the Duke Keto Diet, a clinically proven low-carb plan for weight loss and metabolic health created by Dr. Eric Westman.

Dopamine is a vital neurotransmitter that plays a central role in regulating mood, motivation, and motor control. It is produced within the human body, primarily in specific neurons located in brain regions like the substantia nigra and ventral tegmental area. This biochemical process relies on specific precursors, enzymes, and cofactors, which can be influenced by your diet. In this post, we explore the pathway of dopamine synthesis and the essential components required for its production, highlighting how a balanced diet supports optimal levels. The Biosynthesis Pathway of Dopamine The synthesis of dopamine happens through a sequential enzymatic pathway that starts with amino acid precursors. This process unfolds in three primary steps, providing a clear map of how the body creates this crucial neurotransmitter. L-Phenylalanine to L-Tyrosine Conversion : The journey begins with L-Phenylalanine, an essential amino acid you get from dietary sources. It is hydroxylated, or chemically altered, to form L-tyrosine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase (PAH). L-Tyrosine to L-DOPA Conversion : Next, L-Tyrosine undergoes another hydroxylation to produce levodopa (L-DOPA). This is the rate-limiting step in the pathway, meaning it's the slowest part of the process and controls the overall speed of dopamine production. The enzyme tyrosine hydroxylase (TH) is responsible for this conversion. L-DOPA to Dopamine Conversion : In the final step, L-DOPA is decarboxylated to yield dopamine. The enzyme aromatic L-amino acid decarboxylase (AADC), also known as DOPA decarboxylase, drives this reaction. Once synthesized, dopamine is stored in synaptic vesicles, ready for its release. This pathway ensures efficient production, but disruptions in any step can impact neurotransmitter levels and overall well-being. Essential Ingredients: Precursors and Cofactors To support dopamine synthesis, your body requires key precursors and cofactors. Many of these must be obtained through your diet because they cannot be produced in adequate amounts internally. Below are the primary components needed to facilitate this process. L-Phenylalanine : This is the initial precursor, which can be converted to L-tyrosine when dietary L-tyrosine is limited. It is found in protein-rich foods such as meat, eggs, dairy products, soy, and nuts. L-Tyrosine : As the direct precursor to dopamine, L-Tyrosine can cross the blood-brain barrier to be used in synthesis. Good dietary sources include poultry, fish, cheese, and avocados. Iron : This mineral acts as a cofactor for the enzyme tyrosine hydroxylase, making it essential for the hydroxylation process. You can find iron in red meat, leafy greens like spinach, legumes, and fortified cereals. Tetrahydrobiopterin (BH4) : BH4 is another cofactor for tyrosine hydroxylase, aiding in electron transfer during the reaction. While it is synthesized from guanosine triphosphate, its function may be supported by folate (vitamin B9), which is available in leafy greens, citrus fruits, and beans. Vitamin B6 (Pyridoxine) : This vitamin functions as a cofactor (in its pyridoxal phosphate form) for the AADC enzyme in the final conversion step. It is present in poultry, fish, potatoes, bananas, and chickpeas. Oxygen : While obtained through respiration rather than diet, oxygen is necessary for the tyrosine hydroxylase reaction. Other nutrients, like magnesium and vitamin C, may offer indirect support to enzyme activity and neurotransmitter balance, but they are not fundamental to the core pathway. Deficiencies in key elements, particularly iron or vitamin B6, can hinder dopamine production and may warrant a medical assessment to identify the root cause. A Holistic Approach to Neurotransmitter Balance Maintaining adequate levels of these precursors and cofactors through a varied diet is crucial for supporting dopamine synthesis. However, if you are experiencing symptoms related to dopamine dysregulation, it's important to look beyond diet alone. An integrative functional medicine approach seeks to uncover the root causes of imbalances. Practitioners like Dr. Yoon Hang Kim specialize in this type of whole-person care. With over two decades of experience, including training with Dr. Andrew Weil, Dr. Kim focuses on creating personalized health solutions. His virtual practice helps patients in Illinois, Missouri, Texas, Georgia, and Florida move beyond temporary fixes by identifying and addressing the underlying factors contributing to their health concerns, empowering them on their journey to lasting wellness. Supplementation should only be pursued under professional supervision to avoid potential imbalances. Factors such as genetics, lifestyle, and environmental influences also play a significant role in dopamine optimization. For individuals experiencing symptoms related to dopamine dysregulation, consulting a qualified healthcare provider is essential to address underlying causes and develop a comprehensive plan. In summary, dopamine synthesis is a precise biochemical process that depends on a combination of dietary and endogenous factors. By understanding and incorporating these key ingredients, you can help promote natural neurotransmitter production for enhanced well-being. A Holistic Approach to Neurotransmitter Balance Maintaining adequate levels of these precursors and cofactors through a varied diet is crucial for supporting dopamine synthesis. However, if you are experiencing symptoms related to dopamine dysregulation, it's important to look beyond diet alone. An integrative functional medicine approach seeks to uncover the root causes of imbalances. Practitioners like Dr. Yoon Hang Kim specialize in this type of whole-person care. With over two decades of experience, including training with Dr. Andrew Weil, Dr. Kim focuses on creating personalized health solutions. His virtual practice helps patients in Illinois, Missouri, Texas, Georgia, and Florida move beyond temporary fixes by identifying and addressing the underlying factors contributing to their health concerns, empowering them on their journey to lasting wellness. Yoon Hang Kim MD Integrative and Functional Medicine Expert San Antonio, TX - serving IA, IL, MO, FL, GA, and Texas References Banderet, L. E., & Lieberman, H. R. (1989). Effect of vitamin B-6 nutrition on the levels of dopamine, dopamine metabolites, dopa decarboxylase activity, tyrosine, and GABA in the developing rat corpus striatum. Neurochemical Research , 14(6), 571–577. https://doi.org/10.1007/BF00964926 Blair-West, G. W., Cantor, C. H., Mellsop, G. W., & Eyeson-Annan, M. L. (1989). Depression and tetrahydrobiopterin: The folate connection. Journal of Affective Disorders , 16(1), 33–38. https://doi.org/10.1016/0165-0327(89)90051-7 Briguglio, M., Dell’Osso, B., Panzica, G., Malgaroli, A., Banfi, G., Zanaboni Dina, C., Galentino, R., & Porta, M. (2018). Dietary neurotransmitters: A narrative review on current knowledge. Nutrients , 10(5), Article 591. https://doi.org/10.3390/nu10050591 Daubner, S. C., Le, T., & Wang, S. (2011). Tyrosine hydroxylase and regulation of dopamine synthesis. Archives of Biochemistry and Biophysics , 508(1), 1–12. https://doi.org/10.1016/j.abb.2010.12.017 Farzam, K., & Kumar, A. (2023). Dopamine. In StatPearls . StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK535451/ Gunnars, K. (2023). Phenylalanine: Benefits, side effects, and food sources. Healthline. https://www.healthline.com/nutrition/phenylalanine Hadjiconstantinou, M., & Neff, N. H. (2008). Enhancing aromatic L-amino acid decarboxylase activity: Implications for L-DOPA treatment in Parkinson’s disease. CNS Neuroscience & Therapeutics , 14(4), 340–351. https://doi.org/10.1111/j.1755-5949.2008.00058.x Kubala, J. (2023). 10 Best ways to increase dopamine levels naturally. Healthline. https://www.healthline.com/nutrition/how-to-increase-dopamine Lozoff, B. (2011). Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. The Journal of Nutrition , 141(4), 740S–746S. https://doi.org/10.3945/jn.110.131169 Matthews, D. E. (2007). An overview of phenylalanine and tyrosine kinetics in humans. The Journal of Nutrition , 137(6), 1549S–1575S. https://doi.org/10.1093/jn/137.6.1549S Meiser, J., Weindl, D., & Hiller, K. (2013). Complexity of dopamine metabolism. Cell Communication and Signaling , 11, Article 34. https://doi.org/10.1186/1478-811X-11-34 Nagatsu, T., Nakashima, A., Ichinose, H., & Kobayashi, K. (2016). Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): Historical overview and future prospects. Journal of Neural Transmission , 123(11), 1255–1278. https://doi.org/10.1007/s00702-016-1596-4 WebMD Editorial Contributors. (2024). 6 Foods high in tyrosine and why you need it. WebMD. https://www.webmd.com/diet/foods-high-in-tyrosine