Weight loss is a complex journey, often requiring a multifaceted approach. In recent years, the pharmacological treatment of obesity has advanced significantly, offering a range of medications to aid in weight management. Among these options, the combination of naltrexone/bupropion (Contrave) and topiramate has garnered attention. This article aims to provide a comprehensive overview of these medications, their mechanisms of action, efficacy, and potential side effects, to help individuals make informed decisions about their weight loss journey.
The Evolving Landscape of Weight Loss Medications
Prior to 2012, the options for pharmacological weight loss interventions were limited. However, the landscape has since expanded, with the emergence of glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and dual receptor agonists like Mounjaro (tirzepatide) and Zepbound, indicated for type 2 diabetes and obesity, respectively. With a growing number of weight loss medications available, patients may wonder about the most effective option for them.
Determining candidacy for weight loss medications begins with assessing Body Mass Index (BMI). The doctor and patient should discuss the patient’s current health issues, other medications, and family medical history. The average weight loss varies from 5% to 21%, with some people losing more and some people losing less.
Contrave: A Dual-Action Approach to Weight Loss
Contrave is an FDA-approved prescription medication that combines bupropion and naltrexone to help adults with obesity or overweight lose weight when used alongside diet and exercise. It works by reducing appetite and food cravings through its dual action on hunger-related and reward pathways in the brain.
How Contrave Works
Contrave contains two active medications, bupropion and naltrexone, that work together to help you lose weight.
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- Bupropion: An antidepressant that affects the brain's neurotransmitters, particularly dopamine and norepinephrine. By influencing these neurotransmitters, bupropion can help reduce food cravings and control appetite, which can be helpful for people who struggle with emotional eating or managing portion sizes.
- Naltrexone: An opioid antagonist that binds to opiate receptors in the brain and blocks the pleasurable effects associated with substances like opioids and alcohol. When used in Contrave, naltrexone helps reduce cravings for high-calorie, unhealthy foods by blocking the reward response that typically drives people to overindulge in such foods. This effect can make it easier for individuals to stick to a healthier diet plan.
Efficacy of Contrave
Clinical trials have demonstrated the effectiveness of naltrexone/bupropion in promoting weight loss. A study by Greenway et al. (2010) found that patients treated with naltrexone/bupropion experienced a mean weight loss of 5.0-9.3% over 56 weeks. In clinical trials, around 40% of adults lost at least 5% of their weight after a year when using Contrave alongside lifestyle changes.
Side Effects of Contrave
Common side effects of Contrave include nausea, constipation, and headache. However, it's important to note that taking high doses of Contrave can raise your risk of seizures. If you have a seizure or any serious side effects, contact your doctor. They may lower your dose or stop the medicine. Don’t take Contrave right after a high-fat meal, as it can cause too much of the drug to enter your body at once and trigger seizures. Contrave contains bupropion, an antidepressant. Antidepressants may cause suicidal thoughts in some patients. If you or someone you know is experiencing any mental health symptoms while taking Contrave, seek medical advice from a healthcare professional immediately.
Contraindications
Healthcare providers may avoid prescribing Contrave for people with:
- A history of seizures
- Eating disorders (such as anorexia or bulimia nervosa)
- Mood disorders (like bipolar disorder or major depressive disorder)
- Hypertension (high blood pressure)
- Type 1 or type 2 diabetes
- Hypoglycemia (low blood sugar)
- Alcohol or substance abuse
- Liver problems or hepatitis
- Kidney problems
- Heart disease
- Glaucoma
- Use of other Bupropion-containing products
Contrave may not be prescribed to pregnant women, women who are trying to conceive, or women who are breastfeeding.
Topiramate: An Anticonvulsant with Weight Loss Effects
Topiramate (brand name Topamax) is an anticonvulsant and migraine medication that has also been shown to promote weight loss.
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How Topiramate Works
While the exact mechanisms of action are not fully understood, topiramate is thought to work through appetite suppression (reduced calorie intake), preventing the body from storing excess fat and lowering some fat and cholesterol levels. It might also affect the brain's reward system, potentially preventing binge eating.
Efficacy of Topiramate
Topiramate’s (brand name Topamax) weight loss potential was first observed in patients treated for epilepsy. A study by Kramer et al. (2010) found that topiramate led to a mean weight loss of 7.3% over 56 weeks in patients with obesity (BMI ≥ 35 kg/m²). Some patients may lose an average of 5-10% of body weight.
Side Effects of Topiramate
However, side effects such as paresthesia, taste disturbance, and memory impairment may limit its use in some patients. Other common side effects include abnormal sensations, dizziness, altered taste, insomnia, constipation, and dry mouth.
Topiramate: Modes of Action
Topiramate's modes of action, based on in vitro and in vivo animal trials, include:
- Blocking voltage-dependent sodium channels.
- Increasing the frequency of GABA activation of GABAA receptors.
- Acting as a glutamate antagonist at the AMPA/kainite subtype of glutamate receptor.
- Inhibiting carbonic anhydrase.
Several of the adverse effects of topiramate may be related to its inhibitory effect of carbonic anhydrase.
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Topiramate and Metabolic Acidosis
In addition to paresthesias, the carbonic anhydrase inhibitor activity of topiramate can contribute to a metabolic acidosis and type 3 renal tubular acidosis. However in the metabolic acidosis, plasma bicarbonate levels are seldom less than 18 mM. The acidosis can usually be resolved by reducing the dose of topiramate and administration of sodium bicarbonate if needed.
Topiramate and Pregnancy
Topiramate has been shown to be teratogenic in animal studies. In humans there is an increased risk of oral clefts, and because of this the medication has a category D designation and should absolutely not be used in pregnant women.
Phentermine-Topiramate (Qsymia): A Synergistic Combination
Qsymia is an FDA-approved medication for long-term weight loss that combines phentermine and topiramate in a new formulation. Phentermine is an appetite suppressant, while topiramate can help increase feelings of satiety. The main difference is summation of effect without summation of side effects.
Phentermine
Phentermine is the oldest and most widely used weight loss medication. It was originally used as a short-term medication to jump-start weight loss, but now newer medical guidelines have added it to long-term therapy. Side effects include headache, overstimulation, high blood pressure, insomnia, rapid or irregular heart rate, and tremor.
Efficacy of Phentermine-Topiramate
The initial clinical approval trials offer evidence that this fixed drug combination offers synergistic potential for effective, robust and sustained weight loss with mean weight loss of at least 10% of baseline achieved and sustained for up to 2 years in over 50% of subjects treated.
Concerns About Phentermine
The potential for abuse with phentermine is a major concern among providers which may preclude prescribing this agent for weight loss. The validity of this concern has been investigated in a recently published study.
Other Weight Loss Medications
GLP-1 Agonists
GLP-1 agonists have demonstrated significant weight loss potential in clinical trials. A notable example is liraglutide (Saxenda), which was found to induce a mean weight loss of 5.6-8.0% over 56 weeks in a study by Pi-Sunyer et al. Semaglutide has shown even more promising results, with a mean weight loss of 14.9% over 68 weeks. Common side effects of GLP-1 agonists include gastrointestinal issues such as nausea, vomiting, and diarrhea.
Orlistat
Orlistat is a lipase inhibitor that comes in a capsule. Undigested fat is then passed through the body. Some patients may lose about 5% of their body weight. An over-the-counter formulation is available at 60 mg capsules with each fat-containing meal.
Setmelanotide
Setmelanotide is a melanocortin-4 receptor agonist indicated for chronic weight management in adult and pediatric patients six years and older, with obesity due to certain rare genetic disorders.
Plenity
A medical device rather than a medication, Plenity was FDA-cleared in 2019 for people with a BMI of 25 to 40. It consists of a capsule that releases a biodegradable, super-absorbent hydrogel into the stomach. The gel helps to increase satiety, enabling the person to eat less.
The Importance of a Comprehensive Approach
It's essential to recognize that medications are most effective when used as part of a comprehensive treatment plan that includes lifestyle and behavioral modifications, increased physical activity, and a healthy diet. All weight loss medications work best in the context of a healthy eating plan and exercise. A treatment plan for obesity can comprise multiple forms of treatment, including medications, diet, exercise, and/or surgery.
The Role of Healthcare Professionals
With prescription medications, a healthcare professional can weigh all factors affecting the patient’s lifestyle and BMI and monitor progress and side effects. It’s essential to discuss your options with your healthcare provider and consider your medical history, potential side effects, and individual preferences when choosing the most suitable medication for your weight loss goals.
Future Directions in Obesity Pharmacotherapy
With fervent consumer demand for weight loss medications, combined with rising obesity rates, more medications are bound for the market in the coming years. Pharmaceutical platform Ozmosi predicts one to two GLP-1 launches annually starting in 2026. specifically for obesity. Lilly is developing at least two new options. The first, orforglipron, is an oral GLP-1 inhibitor that completed a Phase 3 clinical trial in early 2025. It could provide a welcome alternative for people who do not want injections. The other, retatrutide, targets GLP-1, GIP, and glucagon. At this writing, it is in Phase 3 clinical trials. Amgen is developing MariTide, a monoclonal antibody designed to increase GLP-1 receptor activity while reducing GIP receptor activity. The once-monthly injection entered Phase 3 clinical trials in March 2025. Researchers continue to study hormones that play a role in appetite for other ways to target obesity with medication. Those of interest include not only GLP-1, but also peptide tyrosine-tyrosine (PYY) and cholecystokinin (CCK). With more options available, doctors will be increasingly able to personalize treatments.
Addressing Metabolic Adaptation and Weight Regain
AOMs may counter the effects of metabolic adaptation and prevent weight regain. After weight reduction, the body metabolically adapts, often causing an increase in hunger hormones and a decrease in satiety hormones and resting metabolic rate, all of which can contribute to weight regain.
Over-the-Counter Options and Supplements
The only over-the-counter medicine for weight loss currently approved by the FDA is Alli (orlistat). Other over-the-counter products are considered supplements. While no specific vitamin or supplement is considered a “treatment” for obesity or overweight, certain ones help support metabolic health. For example, studies suggest that calcium and vitamin D may play a role in regulating belly fat.
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