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Low-Dose Naltrexone for Weight Loss: Mechanisms, Evidence, and Comparison with Naltrexone/Bupropion Combination Therapy: LDN Weight Loss Integrative Functional Medicine San Antonio TX


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 Inquiry: www.yoonhangkim.com


Low-Dose Naltrexone for Weight Loss: Mechanisms, Evidence, and Comparison with Naltrexone/Bupropion Combination Therapy


Obesity remains a significant public health challenge, contributing to comorbidities such as type 2 diabetes, cardiovascular disease, and metabolic syndrome. Pharmacological interventions, when combined with lifestyle modifications, offer adjunctive support for weight management. Among emerging options, low-dose naltrexone (LDN), typically dosed at 1–5 mg daily, has garnered interest for its potential off-label use in weight loss due to its immunomodulatory and anti-inflammatory effects. Additionally, the fixed-dose combination of standard-dose naltrexone (32 mg) and bupropion (360 mg), marketed as Contrave, is an FDA-approved therapy specifically for chronic weight management. This article reviews the mechanisms and evidence for LDN in weight loss and examines the established naltrexone/bupropion combination.


Low Dose Naltrexone Weight Loss: Mechanisms of Action - LDN Weight Loss Integrative Functional Medicine San Antonio TX

Naltrexone is an opioid receptor antagonist primarily approved at higher doses (50 mg) for opioid and alcohol dependence. At high doses, naltrexone blocks opioid receptors, preventing users from experiencing the euphoric feelings associated with opioids and alcohol. At low doses, LDN is hypothesized to transiently block opioid receptors, leading to a rebound increase in endogenous endorphins, which play a role in mood regulation and pain relief, and modulation of glial cell activity. LDN work includes reducing inflammation and supporting mood regulation. This may reduce systemic inflammation, improve insulin sensitivity, regulate appetite, and enhance sleep quality—all factors implicated in obesity. Low dose naltrexone may support appetite control and reduce food cravings by modulating the opioid system, which is involved in addictive eating behaviors. Proposed pathways include decreased insulin resistance, reduced inflammatory cytokines, and indirect effects on growth hormone secretion, potentially preserving lean muscle mass while promoting fat loss. LDN may also help address leptin resistance, which can impair hunger signals and contribute to overeating. How low dose naltrexone is thought to work for weight loss involves its impact on the opioid system and endorphin release, influencing appetite and metabolic pathways.

In contrast, the naltrexone and bupropion combination targets central nervous system pathways regulating energy balance and is FDA approved for weight loss. Bupropion, a dopamine and norepinephrine reuptake inhibitor, stimulates pro-opiomelanocortin (POMC) neurons in the hypothalamus, promoting satiety and energy expenditure. Naltrexone at standard doses blocks autoinhibitory feedback on POMC neurons, enhancing these effects synergistically. This combination primarily suppresses appetite and reduces food reward, distinct from LDN’s broader anti-inflammatory focus. Weight loss naltrexone (in combination with bupropion) is supported by clinical evidence.


Evidence for Low-Dose Naltrexone in Weight Loss

Evidence supporting LDN for weight loss is largely preliminary and derived from observational data, small trials, and mechanistic studies rather than large randomized controlled trials (RCTs). Systematic reviews indicate limited high-quality data specific to obesity, with most research focusing on LDN’s role in autoimmune or inflammatory conditions. Potential benefits include improved insulin regulation and reduced cravings, particularly in conditions like polycystic ovary syndrome or hypothyroidism-associated weight gain, and LDN may also help regulate blood sugar. LDN may help manage binge eating and reduce cravings for certain foods, which can support healthier eating behaviors. While some individuals report weight loss, successful weight loss with LDN still requires maintaining a caloric deficit and consuming fewer calories than expended. It is important to address eating disorders and ensure medical supervision when taking naltrexone for weight loss, as misuse or unsupervised use can be harmful. However, no large-scale RCTs have confirmed significant, sustained weight loss with LDN monotherapy. Clinical use remains off-label, and effects appear modest, often requiring combination with diet and exercise.


In clinical practice, taking naltrexone may help some individuals lose weight by reducing cravings and supporting healthier eating patterns.


LDN Weight Loss Integrative Functional Medicine San Antonio TX


Review of Naltrexone/Bupropion Combination (Contrave)

The naltrexone/bupropion extended-release formulation combines two medications that work synergistically: naltrexone helps reduce cravings, while bupropion boosts energy and suppresses appetite. Robust evidence from phase III RCTs, including the COR-I, COR-II, COR-BMOD, and COR-Diabetes trials, involving over 4,500 participants, supports its efficacy. These 56-week studies demonstrated placebo-subtracted weight loss of approximately 4.7% (range 3.2–5.2%), with 26–33% more patients achieving ≥5% weight loss compared to placebo when combined with lifestyle interventions. In intensive behavior modification settings, weight loss exceeded 9%. Improvements in cardiometabolic parameters, such as waist circumference, triglycerides, and insulin sensitivity, were also observed. Long-term data suggest sustained benefits, though nausea is a common adverse effect leading to discontinuation in some patients. It is important to use this combination only under medical supervision to manage potential risks and side effects.


Compared to LDN, the standard-dose combination offers more predictable and clinically meaningful weight loss, supported by regulatory approval and larger evidence bases. Naltrexone is also used in the management of substance use disorder, highlighting its established safety profile in clinical use. No direct head-to-head trials exist between LDN and Contrave, but the latter’s targeted central appetite regulation appears superior for primary obesity management.


Potential Side Effects of LDN

Low dose naltrexone (LDN) represents an evidence-based therapeutic intervention typically prescribed at significantly reduced dosages compared to those utilized in opioid or alcohol dependency treatment protocols, and demonstrates excellent tolerability profiles across diverse patient populations. However, as with any pharmaceutical intervention in integrative medicine practice, comprehensive awareness of potential adverse reactions and implementation under qualified healthcare supervision remains paramount to optimal patient outcomes.

The majority of patients receiving low dose naltrexone therapy for weight management, metabolic optimization, or associated endocrine disorders experience only transient, mild adverse effects that align with established clinical research findings. These may encompass cephalgia, gastrointestinal disturbances such as nausea, enhanced dream activity, or minor sleep pattern modifications. Such symptoms characteristically resolve within several weeks as the patient's physiological systems achieve therapeutic adaptation to the prescribed naltrexone dosage. Numerous patients report significant improvements in sleep architecture over time, which provides additional therapeutic support for weight management protocols and comprehensive wellness optimization.


In rare clinical instances, more significant adverse reactions may manifest. These include severe dermatological responses, allergic hypersensitivity reactions, chest discomfort, or respiratory compromise. Should any severe symptomatology or dermatological manifestations occur, immediate medical evaluation becomes critically important for patient safety. While such reactions remain infrequently documented in clinical literature, maintaining vigilant patient monitoring ensures optimal safety protocols throughout the treatment continuum.

LDN demonstrates potential pharmaceutical interactions, particularly with opioid analgesics, and may present contraindications for individuals with specific medical conditions including hepatic or renal dysfunction. Comprehensive disclosure of complete medical history and concurrent medications or nutraceutical supplements to your healthcare provider before initiating low dose naltrexone therapy remains essential for safe clinical practice. This becomes particularly crucial when utilizing LDN for managing severe manifestations of autoimmune pathologies, chronic pain syndromes, or irritable bowel syndrome, as these complex conditions require sophisticated clinical monitoring and integrative treatment approaches.

To optimize therapeutic outcomes while minimizing adverse effects, adherence to evidence-based treatment protocols established by qualified healthcare practitioners becomes fundamental. LDN therapy typically commences at conservative dosages, generally ranging from 1.5mg to 4.5mg daily, often administered at bedtime to support circadian rhythm regulation and sleep quality enhancement. Integration of LDN with caloric restriction protocols, structured physical activity programs, and comprehensive lifestyle modifications can amplify therapeutic benefits for weight management and metabolic syndrome, while simultaneously supporting immune system function and hormonal equilibrium.


Beyond its established role in weight management protocols, LDN has demonstrated significant therapeutic promise for enhancing insulin sensitivity, reducing systemic inflammatory markers, and supporting endocrine balance optimization. Current research investigations continue exploring its therapeutic potential for managing severe symptomatology in conditions such as multiple sclerosis and other autoimmune pathologies, representing exciting developments in integrative medicine applications.

Ultimately, while low dose naltrexone provides a promising evidence-based therapeutic option for individuals managing excess adiposity, metabolic syndrome, or chronic pain conditions, it does not replace comprehensive lifestyle interventions fundamental to integrative medicine practice. A holistic treatment approach incorporating nutritional modifications, regular physical activity protocols, and stress management techniques remains essential for achieving sustained long-term therapeutic success. Through collaborative partnership with qualified healthcare providers and dedicated adherence to established treatment protocols, patients can maximize LDN's therapeutic benefits while maintaining optimal safety profiles. Should any severe symptomatology develop or concerns regarding adverse effects arise, prompt communication with your healthcare provider ensures appropriate clinical guidance and intervention.


Patient Perspectives and Experiences

Many patients struggling with weight management have turned to low dose naltrexone as part of a comprehensive approach, particularly when conventional methods haven't produced lasting results. People dealing with obesity alongside conditions like insulin resistance, PCOS, hypothyroidism, or chronic inflammation frequently report reduced cravings, improved appetite control, better sleep, and enhanced energy levels that support their weight loss efforts.

Clinical observations align with these reports. Patients often describe feeling less driven by food cravings and finding it easier to maintain dietary changes. Some note improvements in mood and reduced emotional eating patterns—factors that often undermine weight loss attempts.

Beyond the number on the scale, practitioners have documented improvements in metabolic markers and overall well-being. For many patients, LDN has helped address the inflammatory and hormonal imbalances that can make weight loss particularly challenging.

Patients sometimes describe LDN as a helpful tool that makes sustainable lifestyle changes feel more achievable. The mechanism appears to involve immune modulation, improved insulin sensitivity, and normalization of appetite signaling.


That said, responses to LDN vary considerably. While many patients benefit, some don't achieve meaningful results. Weight loss with LDN still requires a caloric deficit and commitment to dietary and lifestyle changes—it supports rather than replaces these fundamentals. Consultation with a knowledgeable provider is essential to determine appropriateness and monitor progress.

As research continues, LDN's role in metabolic health and weight management will become better defined—offering another option for patients seeking integrative approaches to sustainable weight loss.


Resources


Low-dose naltrexone shows theoretical promise for weight loss through anti-inflammatory and metabolic pathways, yet evidence remains limited and primarily anecdotal or indirect. In contrast, the naltrexone/bupropion combination (Contrave) is well-substantiated for producing significant, sustained weight loss as an adjunct to lifestyle changes. Clinicians should consider patient-specific factors, including comorbidities and tolerance, when evaluating these options. Further RCTs are needed to clarify LDN's role in obesity treatment.


Meet Dr. Yoon Hang Kim MD MPH Integrative & Functional Medicine and LDN Therapy Expert

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

Direct Integrative Care

Virtual Integrative Functional Tele-Medicine in IA, IL, MO, GA, FL, and TX

Text and Phone 210.981.6106

Toll Free 855.462.0188


References

Greenway, F. L., Fujioka, K., Plodkowski, R. A., Mudaliar, S., Guttadauria, M., Erickson, J., Kim, D. D., & Dunayevich, E. (2010). Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet, 376(9741), 595–605. https://doi.org/10.1016/S0140-6736(10)60888-4

Kulak-Bejda, A., Bejda, G., & Waszkiewicz, N. (2021). Safety and efficacy of naltrexone for weight loss in adult patients – a systematic review. Archives of Medical Science, 17(4), 920–929. https://doi.org/10.5114/aoms.2020.100183

Wadden, T. A., Foreyt, J. P., Foster, G. D., Hill, J. O., Klein, S., O'Neil, P. M., Perri, M. G., Pi-Sunyer, F. X., Rock, C. L., Erickson, J. S., Maier, H. N., Kim, D. D., & Dunayevich, E. (2011). Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: The COR-BMOD trial. Obesity, 19(1), 110–120. https://doi.org/10.1038/oby.2010.147

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

 
 
 

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