Naltrexone, a medication traditionally prescribed in high doses (50 mg or more) to help individuals overcome opioid or alcohol dependence, has recently gained attention for its other uses, including its potential in weight loss. Naltrexone blocks certain receptors in the brain. At high doses, it stops the euphoric feelings that come from drinking alcohol or using drugs. At low doses, it can act differently and affect the body’s natural “feel-good” chemicals called endorphins. Low Dose Naltrexone (LDN) is proving to be a powerful tool for a wide range of conditions, from autoimmune diseases and chronic pain to metabolic health and weight loss. This article delves into the research surrounding LDN and its potential role in weight management.
Understanding Naltrexone and LDN
Naltrexone is an FDA-approved drug primarily used to manage alcohol and opioid dependence. It functions as an opioid receptor antagonist, binding to these receptors in the brain and blocking the effects of opioids and alcohol. This action helps reduce cravings and resolve addiction triggers. While naltrexone is effective in managing cravings and promoting sobriety, it has also been observed to have effects on patients’ weights.
LDN’s mechanism is unique. It temporarily blocks opioid receptors in the brain for a few hours, triggering a rebound effect that increases the body’s endorphin production. Just like your body’s natural endorphins, this produces a “feel-good” and pain-blocking effect. An LDN dosage, about 4.5mg, is roughly one-tenth of the typical amount to treat opioid addiction. Interestingly, an opposite effect of the drug is achieved at this smaller dose.
How LDN May Influence Weight Loss
Low-dose naltrexone is an interesting new option for weight loss. It helps by:
- Controlling Appetite: LDN can help control your appetite. It works on the part of the brain that tells you when you’re hungry or full. LDN influences opioid receptors involved in food cravings and addictive eating behaviors. When people overate, they didn’t get the rush of satisfaction normally associated with eating sugary, fatty food. This reduction in cravings can have a big impact on weight loss.
- Reducing Inflammation: Inflammation in the body can make it hard to lose weight. Chronic inflammation contributes to obesity, insulin resistance, and metabolic syndrome. LDN improves inflammation by blocking the action of Toll-like receptor 4 (TLR4), a receptor found in white blood cells in the immune system.
- Improving Insulin Sensitivity: If your body uses insulin better, you’re likely to store less fat.
- Better Sleep: Good sleep is important for losing weight. Poor sleep can mess up hormones that control hunger and weight. Many patients report improved sleep quality on LDN, which can further reduce inflammation, stabilize mood, and support metabolism.
LDN vs. Wegovy
Wegovy, one brand name for semaglutide, has also emerged as a promising option in the battle against obesity. Originally used as a treatment for type 2 diabetes under the name Ozempic, semaglutide has shown remarkable effectiveness in promoting weight loss.
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- Appetite Suppression: Wegovy helps reduce appetite by acting on the brain regions responsible for hunger.
- Slows Down Stomach Emptying: Semaglutide slows the rate at which food leaves the stomach, increasing feelings of fullness.
Both medications require medical supervision and should be part of a comprehensive weight management plan that includes dietary changes and increased physical activity. Wegovy, by contrast, might be more fitting for individuals with a BMI of 30 or higher, or 27 with an additional weight-related condition, who can tolerate the initial side effects and afford the higher cost. Ultimately, the choice between LDN and Wegovy should be guided by a healthcare provider and tailored to the individual’s health profile, weight loss goals, and lifestyle. LDN also pairs well with GLP-1 agonists (e.g., Saxenda, Wegovy), particularly for patients with PCOS or leptin resistance. Leptin is the hormone that tells your brain when you’re full and regulates fat storage. Many overweight individuals develop leptin resistance, meaning their brain doesn’t recognize signals to stop eating.
Research and Studies on LDN
Research looking into the role of LDN for specific conditions like Crohn’s disease (CD), fibromyalgia, multiple sclerosis (MS), Hashimoto’s hypothyroidism and weight loss is only in its early stages. A 2021 systematic review looked into 191 scientific articles regarding naltrexone’s safety and efficacy in weight loss.
Numerous small-scale studies have been published on the use of LDN in CD. According to quality of life surveys, an impressive 89% showed a positive response to therapy, while 67% achieved disease remission. A 2014 pilot study of 14 children with CD receiving placebo or 0.1mg/kg LDN for 8 weeks also reported positive findings. Of those treated with LDN, 25% achieved disease remission and 67% saw improvements in disease activity. Furthermore, a randomized, double-blind, placebo-controlled study tested the safety and efficacy of LDN over 12 weeks. Out of 40 CD patients, 80% of those treated with LDN had at least a 70-point decline in their Crohn’s Disease Activity Index score compared to 40% of placebo patients. In a recently published study of 256 Norwegians with IBD, researchers found that the use of LDN led to an overall reduction in other treatment drugs.
Results showed a 30% improvement over placebo for reducing FM symptoms. A later study analyzed 31 women with fibromyalgia also using 4.5mg LDN. A 2008 pilot trial of LDN on 40 patients with primary progressive MS found a significant improvement in spasticity after 6 months. In another trial, researchers looked at the effect of LDN on other drug treatments in 341 patients with MS. However, a 2010 pilot study of 4.5mg LDN on 60 MS patients over 8 weeks reported significant improvements in mental health quality of life measures.
One study of 24 opioid addicts undergoing 50mg of naltrexone treatment (i.e. not low dose naltrexone) found some benefit. Again this is theoretical, there is not enough research to make any solid conclusions.
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One idea explores the connection between LDN and appetite. A study using 50mg of naltrexone showed that subjects ate less due to decreased palatability of food. However, this has not be replicated in lower-doses of naltrexone. Another rationale is that LDN impacts insulin and growth-hormone. A study explored this concept in typical naltrexone doses in 12 obese women and six lean women. It appears that naltrexone did help reduce the insulin response in obese women. Other rationales include how it helps with sleep and inflammation and therefore weight management.
Naltrexone and Bupropion Combination
A lot of the research into naltrexone for weight loss focuses on the idea of combining it with another similar medication. Bupropion is a common antidepressant that also helps to reduce tobacco cravings. When naltrexone and bupropion are combined into a single medication, they tend to work together and provide even more useful effects. While naltrexone alone helps to prevent overeating of caloric foods, bupropion helps to boost energy and stabilize your mood.
The combination effect of bupropion and naltrexone on weight loss is not precise. It was proposed theoretically that naltrexone could influence the neurological pathways of the brain, while bupropion would suppress the appetite [19] Two studies have reported that bupropion/naltrexone combination was found to be effective in achieving loss of weight in obese individuals [18, 20]. Bupropion/naltrexone combination produced significant weight loss when compared to either medication alone. The mechanisms through which naltrexone/bupropion combination act in reducing weight are not completely clear. α-melanocyte-stimulating hormone and β-endorphin are released by pro-opiomelanocortin producing neurons present in the hypothalamus. α-melanocyte-stimulating hormone regulates the activation of pro-opiomelanocortin and β-endorphin activates opioid receptors on pro-opiomelanocortin neurons causing autoinhibitory feedback [21]. Bupropion monotherapy results in modest loss of weight by increasing the pro-opiomelanocortin firing [22]. The weight loss caused by bupropion might be achieved by β-endorphin-mediated autoinhibitory feedback loop and adding naltrexone to bupropion would prevent this negative feedback loop and may help in sustained reduction of weight and achieving weight loss.
Advantages of Using Naltrexone for Weight Loss
Naltrexone provides people with a lot of helpful ways to manage their weight. Of course, people using naltrexone still need to eat fewer calories than they burn if they want to lose weight. It won’t magically make pounds fall off while you continue to eat excessively. However, the way it interacts with your body makes it a lot easier and less stressful to lose weight.
- Lowered appetite: People still get food cravings on naltrexone, but these cravings tend to occur less often and are satisfied more easily.
- Reduced incentive to overeat: With naltrexone, most people no longer feel a rush of satisfaction from binging on food.
- Improved mood: Especially if you take a naltrexone/bupropion medication, you’ll find that you feel less stressed and sad.
- Stabilized blood sugar: Naltrexone helps to improve insulin sensitivity, so you have less drastic blood sugar swings.
- More energy: One of the big reasons that people stop dieting is because they feel tired and fatigued.
Potential Side Effects and Concerns of Using Naltrexone for Weight Loss
Though naltrexone has some promising weight loss effects, it’s not a foolproof method. There are some side effects associated with this medication. In a 2017 study, 22% of test subjects chose to leave the study due to the side effects of naltrexone. The most commonly reported issue was gastrointestinal upset and nausea. Some people also had anxiety, headaches, insomnia, or dizziness. Those who take very high doses may be more susceptible to liver damage. In most patients, side effects were strongest right when they started using the medication and calmed down over time. Most commonly, vivid dreams and sometimes nightmares have been observed. However, long-term safety is not known at this time.
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Though all of these side effects can sound concerning, it’s important to keep in mind that naltrexone is still a very safe medication. Extensive reviews were conducted before the FDA approved it, and there is no evidence that it causes serious side effects. In fact, 2019 research found that patients who took naltrexone actually reported less serious health problems than patients who took a placebo medication instead.
Who Can Benefit From Losing Weight With Naltrexone?
Naltrexone isn’t typically prescribed for patients who just gained a few pounds and want to return to their normal weight. Since it’s a serious medication with possible side effects, most doctors do not want to give it to patients who can lose weight with traditional methods. Naltrexone is not safe to take if you are pregnant, nursing children, or have acute liver failure. It is also not prescribed to patients who plan to continue taking opioids, alcohol, or other substances that slow breathing. Taking naltrexone alongside opioids and alcohol can increase the risk of overdose because it lowers your tolerance and blocks some of the effects. If you’re interested in naltrexone, keep in mind that it must be taken under medical supervision.
Dosage and Administration of LDN
Typical LDN doses range from 1.5mg to 4.5mg per day. Providers often start at a low dose (0.5mg) and slowly titrate up to find the individual’s optimal dose. It’s advised to take the product on an empty stomach starting with a loading phase of 1.5mg and slowly titrating to 4.5mg over a few days. Important: Never attempt to split or crush a full-strength naltrexone tablet.
Why LDN Remains a Hidden Gem
LDN has flown under the radar due to its expired patent and low profit potential for pharmaceutical companies. Without corporate sponsorship, large-scale FDA trials are unlikely.
Meta-Analysis of Bupropion and Naltrexone on Weight Loss
A systematic review and meta-regression analysis of randomized controlled trials aimed to present the evidence systematically on the effects of bupropion alone and combined with naltrexone on weight, body mass index (BMI), waist circumferences (WC).
The study adhered to the guidelines outlined by the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) criteria [23]. A comprehensive search was conducted in the PubMed/MEDLINE, Web of Science, SCOPUS, and Embase databases, without any limitations on language or time, covering the period up to February 2023. Furthermore, the search encompassed relevant scholarly articles as well as gray literature. The selection of Medical Subject Headings (MeSH) and Emtree (Embase Subject Headings) was made in order to conduct searches on the online databases: (“Bupropion” OR " naltrexone " OR " Amfebutamone " OR " Wellbutrin " OR “Zyban " OR “Quomen” OR “Zyntabac “) AND (“weight” OR “Waist Circumference” OR “Body Mass Index”) AND (“Clinical Trials as Topic” OR “Cross-Over Studies” OR “Double-Blind Method” OR “Single-Blind Method” OR “Random Allocation” OR “Clinical Trial”). The reference lists of the publications that were obtained and the review papers that were linked were examined manually in order to find any qualifying trials that may have been overlooked.
The process involved two researchers independently eliminating duplicate articles based on titles, abstracts, or the whole texts of the research, followed by the identification and evaluation of pertinent publications. Ultimately, the papers were categorized according to the aforementioned criteria: (1) The study employed a randomized clinical trial design. (2) The intervention involved administering bupropion alone and in combination with naltrexone to individuals aged 18 and older. (3) Baseline and post-intervention measurements of weight, body mass index (BMI), and waist circumference (WC) were collected for both the intervention and control groups. When a research study reported outcomes at multiple follow-up times, the data from the most recent or longest follow-up period was utilized. Excluded from the analysis were studies that contained duplicated data, studies that specifically examined the impact of bupropion on smoking cessation, studies that provided unclear or ambiguous information, studies that utilized bupropion as an intervention in conjunction with other frequently prescribed medications (excluding naltrexone), studies that employed non-randomized trial designs, studies conducted on animals, studies lacking a control group, as well as reviews and meta-analyses. The criteria for inclusion and exclusion of studies, known as the PICOS criteria, were as follows. The study population included of individuals who were 18 years of age or older. The intervention being investigated was the administration of bupropion either alone or in combination with naltrexone. The comparator group included individuals who received a different intervention or a placebo. The variables of interest in this study are weight, body mass index (BMI), and waist circumference (WC). The study design employed in this research investigation is that of randomized clinical trials.
The authors conducted an independent examination of the qualifying studies. The study extracted various key details, including the first author’s name, the study’s location, the publication year, the sample size for both the intervention and control groups, participant characteristics (such as the percentage of men, BMI, age, and health status), the type of outcomes assessed, the duration of the intervention, the dosage and type of intervention administered, as well as the means and standard deviations (S.D.s) of the intended outcomes at baseline, post-intervention, and/or changes between baseline and post-intervention.
The evaluation of the study’s quality is detailed in Table 1. The methodological evaluation of the included randomized controlled trials (RCTs) was conducted using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) [24]. The authors of this study conducted an assessment of potential sources of bias, including blinding of outcome assessment, allocation concealment, participant and staff blinding, random sequence generation, incomplete outcome data, selective reporting, and other bias. Each study was independently rated by two authors, who categorized the risk of bias as low, high, or unclear. In order to reach a consensus, any discrepancies were deliberated over with the involvement of a third author. The current analytic research was assessed for quality using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) grading technique. The GRADE checklist is a robust 10-point grading method that evaluates factors that impact the quality of a study. The scale comprises seven distinct components, namely: (1) risk of bias (2) precision, (3) heterogeneity, (4) directness, (5) publication bias, (6) financing bias, and (7) study design [25].
The data were analyzed using the STATA version 12.0 program. Furthermore, the utilization of Endnote software facilitated the elimination of duplicate articles and the effective management of eligible articles. Various data types were subjected to a predetermined technique for conversion, resulting in the calculation of their mean and standard deviations (S.D.s) as reported in references [26, 27]. In the event that standard deviations are not available, the change was computed utilizing the following method: The formula for calculating the change in standard deviation is derived as the square root of the difference between the sum of the squares of the baseline standard deviation and the final standard deviation, subtracted by twice the product of the baseline standard deviation and the final standard deviation correlation coefficient. The formula utilized for converting the standard error of the mean (SEM) to the standard deviation is as follows: The standard deviation (S.D.) can be calculated by multiplying the standard error of the mean (SEM) by the square root of the total number of participants (n) in each group. The utilization of the random-effects model was employed in the meta-analysis of the research findings. The research weighted according to the conventional inverse variance methodology. The analysis utilized the data obtained from the longest time point, enabling the inclusion of many examinations within a single study group. The evaluation of study heterogeneity was conducted using Q Statistics and I-squared (I2). The study identified varying levels of heterogeneity, categorized as insignificant, low, moderate, and high. These levels were quantified using I2 values, which ranged from 0 to 25%, 26-50%, 5-75%, and 76-100%, respectively [28]. In order to ascertain potential factors contributing to heterogeneity, a predetermined subgroup analysis was performed, taking into account the dosage, duration, and kind of intervention. A sensitivity analysis was conducted in order to ascertain the individual contributions of each research study to the overall mean difference. To assess the presence of publication bias, we employed the Egger’s test, a widely recognized statistical method [29].
The flowchart presented in Fig. 1 illustrates the research selection procedure, incorporating exclusion criteria. The aforementioned electronic databases yielded a total of 2647 articles. Following the elimination of redundant research papers, the cumulative count amounted to 1711. After conducting an evaluation of the titles and abstracts of the research papers, a total of 1668 articles were excluded from the study due to their failure to match the specified inclusion criteria. A total of 43 publications were identified through the implementation of a comprehensive full-text search method throughout the secondary screening process. Eighteen investigations were discontinued based on the aforementioned factors. A total of 25 publications, each containing 33 treatment arms, were deemed eligible for inclusion in the quantitative meta-analysis based on their adherence to the specified qualifying criteria.
According to our survey findings, a total of twenty studies have been done in the United States, while three papers have been published in Canada. Additionally, one study each has been carried out in Israel and the Republic of Korea, respectively. The publications included in this study were published between the time frame of 1999 to 2021, and the duration of the follow-up interventions varied from 8 to 104 weeks. At the baseline, the average age and proportion of male participants varied between 35.2 and 61.6 years and 0-100%, respectively. The doses prescribed in the studies were between 90 and 400 mg per day, and Bupropion alone was used in 7 studies and the combination of this drug with naltrexone was used as the intervention group in the rest of the studies. The mean BMI at the baseline level was between 26.1 and 37.1 in the studies included.