The global prevalence of obesity and overweight is a significant concern in the field of public health. Addressing and combating these conditions pose considerable challenges. Naltrexone, primarily known for its role in treating opioid and alcohol use disorders, has also garnered attention for its potential effects on weight management. This article explores the effectiveness of naltrexone, both alone and in combination with bupropion, for weight loss, while also addressing safety concerns, side effects, and appropriate usage.
What is Naltrexone?
Naltrexone is a medication approved by the Food and Drug Administration (FDA) for the treatment of opioid addiction and alcohol addiction. It functions as an opioid receptor antagonist, binding to opioid receptors in the brain and blocking the effects of opioids and alcohol, thus reducing cravings. Naltrexone is available in pill form (Revia and generic naltrexone) and as an intramuscular extended-release injection (Vivitrol). Revia and generic naltrexone are typically prescribed for alcohol use disorder, while Vivitrol is approved for addiction to opioids or alcohol.
The Connection Between Naltrexone and Weight Loss
When patients started taking naltrexone to manage addiction, many discovered that they were starting to unintentionally lose weight. Studies have shown that naltrexone can affect appetite. Naltrexone’s ability to block opioid receptors can reduce subjects’ reward feedback system. 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. A 2011 study found that those who took naltrexone were three times as likely to lose 15% of their total body weight.
Combining Naltrexone and Bupropion for Weight Management
A lot of the research into naltrexone for weight loss focuses on the idea of combining it with another similar medication, bupropion. Naltrexone/bupropion (Contrave) combines an opioid receptor antagonist (naltrexone) with a dopamine and norepinephrine reuptake inhibitor (bupropion) in an extended-release tablet. 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. Naltrexone/bupropion has been evaluated in three studies that enrolled more than 4,000 overweight or obese patients with hyperlipidemia or hypertension, and in one study of 505 patients with diabetes.
How Naltrexone/Bupropion Works
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.
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Dosage and Administration of Naltrexone/Bupropion
The dosing of naltrexone/bupropion must be titrated. In week 1, patients should take one 8/90-mg tablet once a day in the morning with a low-fat meal. In week 2, they should increase the daily dosage to one tablet in the morning and one tablet in the evening. During week 3, patients should increase the daily dosage to two tablets in the morning and one tablet in the evening, and in week 4 patients will reach the maximum recommended dosage of two tablets twice a day. Patients with moderate to severe renal impairment should be limited to one tablet twice daily, and patients with moderate hepatic impairment should be limited to one tablet daily.
If patients do not lose 5% of their baseline body weight after 12 weeks, further treatment is unlikely to be beneficial and therapy should be discontinued. If patients achieve clinically significant weight loss after 12 weeks, therapy should be continued for up to one year.
Contraindications and Warnings for Naltrexone/Bupropion
Naltrexone/bupropion is labeled as increasing the risk of depression and suicidal behavior, based on studies of bupropion alone that showed an increase in the incidence of these events. However, clinical trials of the combination compared with placebo found no increase in depression and no increase in suicidality. Naltrexone/bupropion should not be given to children or adolescents. Because it may raise blood pressure and heart rate, it should not be used in patients with uncontrolled high blood pressure. It also should not be prescribed to patients with a known seizure disorder or those already taking opioids. Although one of the goals of weight loss is to decrease the risk of cardiovascular outcomes, patients with active cardiovascular disease, including significant heart failure, history of myocardial infarction, angina, or stroke, were excluded from premarketing studies. A large cardiovascular outcomes study that includes these patients is now ongoing. Bupropion is metabolized in the liver and its use may increase serum levels of some antidepressants, antipsychotics, beta blockers, and antiarrhythmics. Naltrexone/bupropion is pregnancy category X.
Advantages of Using Naltrexone for Weight Loss
While naltrexone alone helps to prevent overeating of caloric foods, bupropion helps to boost energy and stabilize your mood. Naltrexone provides people with a lot of helpful ways to manage their weight. Naltrexone produces clinically significant weight loss when combined with a diet and exercise program. It decreases body weight in patients with diabetes, but its effect on diabetic outcomes is not known. Naltrexone provides people with a lot of helpful ways to manage their 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
A significant proportion of patients will experience adverse effects. It should not be prescribed for patients with preexisting heart disease until the effects are known. 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.
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Common Side Effects of Naltrexone
Gastrointestinal symptoms are common with naltrexone/bupropion. Up to one in three patients will report nausea and 19% will experience constipation, especially early in treatment.
Common side effects of naltrexone use may include:
- Nausea and vomiting
- Dizziness
- Sleepiness
- Sleep disturbances
- Muscle cramps and joint pain
- Headache and toothache
- Flu-like symptoms
- Anxiety and irritability
- Constipation or diarrhea
Severe Adverse Effects of Naltrexone
Severe adverse effects of taking Revia may include:
- Depression
- Hallucinations
- Pneumonia
- Confusion
- Blurred vision
- Dangerous allergic reaction, including swelling of mouth or tongue, chest pain, trouble breathing, and rash
- Hepatitis or liver damage, including dark-colored urine and jaundice
- Injection site reactions, including severe pain, tissue death, blisters, lumps, or open wounds
Precautions and Monitoring
It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant during therapy. If you think you have become pregnant while using this medicine, tell your doctor right away.
Do not take naltrexone and bupropion combination with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid [Marplan®], phenelzine [Nardil®], selegiline [Eldepryl®], tranylcypromine [Parnate®]). Do not start taking naltrexone and bupropion combination during the 2 weeks after you stop a MAO inhibitor. Wait 2 weeks after stopping naltrexone and bupropion combination before you start taking a MAO inhibitor. If you take them together or do not wait 2 weeks, you may have confusion, agitation, restlessness, stomach or bowel symptoms, a sudden high body temperature, an extremely high blood pressure, or severe seizures.
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Do not use naltrexone and bupropion combination if you are also using Zyban® to quit smoking or Aplenzin® or Wellbutrin® for depression, because they also contain bupropion. Also, do not take this medicine if you are using or have used narcotic drugs (eg, buprenorphine, methadone, or other habit-forming painkillers) within the past 7 to 10 days.
This medicine may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. Make sure the doctor knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. If you or your caregiver notice any of these side effects, tell your doctor right away.
You have a higher risk of accidental overdose, serious injury, or death if you use heroin or any other narcotic medicine while you are being treated with naltrexone and bupropion combination. Also, naltrexone prevents you from feeling the effects of heroin if you use it.
Do not stop taking this medicine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. This is to decrease the chance of having certain side effects when you stop the medicine, such as agitation, anxiety, dizziness, a feeling of constant movement of self or surroundings, headaches, increased sweating, nausea, trembling or shaking, trouble with sleeping or walking, or unusual tiredness.
Your blood pressure might get too high while you are using this medicine. This may cause headaches, dizziness, or blurred vision. You might need to measure your blood pressure at home. If you think your blood pressure is too high, call your doctor right away.
This medicine may cause a serious allergic reaction, including anaphylaxis, which can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, swelling of the face, tongue, or throat, trouble breathing, or chest pain.
Serious skin reactions (eg, Stevens-Johnson syndrome) can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills with this medicine.
Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.
Check with your doctor right away if blurred vision, eye pain, or any other change in vision occurs during or after treatment. Your doctor may want your eyes be checked by an ophthalmologist (eye doctor).
This medicine may increase the risk of hypoglycemia (low blood sugar) in patients with diabetes. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. You should check your blood sugar before you start treatment and while you are taking this medicine.
Drinking alcoholic beverages should be limited or avoided, if possible, with this medicine.
Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine. Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
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.
Naltrexone vs. Other Weight Loss Methods
Naltrexone is just one of the many tools available to people looking to lose weight. Traditional methods like counting calories and getting regular exercise can be just as effective. People get the best results from naltrexone when they work with a professional nutritionist to relearn healthy eating habits.
Low Dose Naltrexone (LDN)
Low Dose Naltrexone (LDN) is a lower dosage of naltrexone, typically ranging from 0.5mg to 4.5mg, that has been explored for its potential immune-modulating and anti-inflammatory properties. Unlike traditional naltrexone dosing (50-100mg/day), LDN works not by fully blocking the opioid system, but by temporarily binding to opioid receptors.
Potential Benefits of LDN
LDN has been studied for a wide range of clinical benefits, including chronic pain, autoimmune disease, fibromyalgia, PCOS, and even cancer. Many patients report improved sleep quality on LDN, which can further reduce inflammation, stabilize mood, and support metabolism. LDN also pairs well with GLP-1 agonists (e.g., Saxenda, Wegovy), particularly for patients with PCOS or leptin resistance.
Considerations for LDN
LDN is generally well tolerated, with side effects typically mild and transient. Providers often start at a low dose (0.5mg) and slowly titrate up to find the individual’s optimal dose. It is important to never attempt to split or crush a full-strength naltrexone tablet.
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.
Risks of Taking Revia for Weight Loss
People have begun taking low-dose naltrexone (Revia) or a combination naltrexone/bupropion formula in order to lose weight. Naltrexone/bupropion has been FDA-approved for weight loss in some patients, whereas naltrexone on its own has not been approved and is considered off-label. Taking Revia for weight loss can negatively affect your physical and psychological health, especially for those with a history of dieting. This is because dieting is a risk factor for disordered eating and developing an active eating disorder. In fact, research has shown that about one-quarter of individuals who engage in severe dieting develop an eating disorder. And although dieting on its own doesn’t directly cause an eating disorder, it can increase the likelihood of developing one, especially in those who are predisposed.
Trying to lose weight quickly by taking Revia or other medications can cause a host of side effects and health risks.
Can You Overdose on Naltrexone?
Naltrexone overdose is not common, with even high doses causing relatively benign symptoms. However, the real risk of naltrexone, aside from dangerous weight loss and disordered eating potential, is that of overdosing on opioids. Since naltrexone blocks opioid receptors, people taking this prescription medication are at risk of overdose if they relapse on heroin or a prescription opioid like Vicodin, Percocet, or other chronic pain management medications. This is because they may take a much higher dose in an attempt to overcome the subdued effect caused by naltrexone. The risk of overdose also increases in someone who has been on Revia or Vivitrol for an extended period of time, effectively lowering their tolerance to opioids during the period of abstinence. Returning to opioid use, especially at their previously used dose, can lead to an overdose.
If you suspect that someone has overdosed, call 911 immediately and wait for medical personnel to arrive. In the case of an opioid overdose, administer Narcan (naloxone) if it’s available.
Understanding Naltrexone and Eating Disorders
Using a medication like naltrexone or naltrexone/bupropion to lose weight quickly could increase the risk of developing an eating disorder like bulimia nervosa or anorexia nervosa. Dieting or using a diet pill like naltrexone alone doesn’t necessarily mean that you have an eating disorder or are engaging in disordered eating, but if other symptoms are present, then it could indicate an issue.
Other symptoms of eating disorders include:
- Severe caloric restriction
- Skipping meals
- A preoccupation with food, weight, and thinness
- A pathological drive for thinness
- Distorted body image
- Low self-esteem
- Purging behaviors like laxative use, excessive exercise, and self-induced vomiting
- Binge eating episodes
- Feeling profound shame and guilt related to disordered eating behaviors
- Eating alone or avoiding situations in which food will be present
Naltrexone may be misused by people looking to lose weight thanks to diet culture, which prioritizes weight loss and thinness over health and well-being. Anti-fat bias, or fatphobia, is the intense hatred or fear of people living in larger bodies, and it contributes to the popularity of medications like naltrexone.
Society communicates to us that there is only one “ideal” body type-thinness for women and lean muscle mass for men. However, people of all sizes, shapes, and weights are valid, and there is no such thing as a bodily ideal, though this belief drives many people to engage in disordered eating behaviors and what they perceive as a "healthy diet" in pursuit of thinness. Chronic disordered eating can ultimately lead to a clinical eating disorder, which may require formal eating disorder treatment on an inpatient, outpatient, or virtual basis. If you are looking to heal your relationship with eating and movement, professional treatment may be a great option.
Meta-Analysis of Bupropion and Naltrexone for Weight Loss
A systematic review and meta-analysis investigated the effects of bupropion alone and in combination with naltrexone on weight, body mass index (BMI), and 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. The random-effects model analysis was used to provide pooled weighted mean difference and 95% confidence intervals.
Results of the Meta-Analysis
Twenty five studies with 22,165 participants’ were included in this article. The pooled findings showed that bupropion administration has an effect on lowering weight (WMD: -3.67 kg, 95% CI: -4.43 to -2.93) and WC (WMD: -2.98 cm, 95% CI -3.78 to -2.19) in compared with control groups. The analysis also showed that the effects of the present intervention on weight and WC during the intervention are > 26 weeks and ≤ 26 weeks compared to the other group, respectively.
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