Choosing a long-term weight management plan can feel overwhelming, especially with so many options to sort through. Two medications you may consider in your journey are Zepbound® and Contrave®. Zepbound® is a once-weekly injection, while Contrave® is a twice-daily pill. But there’s a lot more to these two weight loss options than just how you take them.

Read on as we break down Zepbound® versus Contrave® across mechanisms, dosing schedules, and clinical outcomes to find the right medication for your health goals.

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How do Zepbound® and Contrave® work for weight loss?

Zepbound® and Contrave® are both FDA-approved to help adults manage their weight long term alongside a reduced-calorie diet and physical activity. But that’s where their overlap largely ends. They belong to different drug classes, act on different pathways, and differ in outcomes.

How Zepbound® works

Zepbound® is an FDA-approved GLP-1 medication for weight loss. Its active ingredient, tirzepatide, is a molecule that mimics two hormones your body naturally produces: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). 

Both GLP-1 and GIP are incretins, hormones that prompt your pancreas to release insulin when blood sugar (glucose) levels run high after a meal. This insulin then travels through the bloodstream and binds to receptors on your cells. Once bound, the insulin triggers a chemical signal that lets glucose enter your cells to be used for energy. By keeping insulin release steady and glucose-dependent, Zepbound® prevents dramatic blood sugar spikes and crashes. This keeps your energy levels stable and helps reduce blood sugar-driven cravings.

GLP-1 and GIP also play distinct roles. For example:

• GLP-1 binds to receptors in your brain’s hunger center (hypothalamus) to suppress appetite signals and quiet food cravings. It also binds to receptors on the vagus nerve and stomach wall to slow down muscle contractions. This physically delays gastric emptying so food stays in your stomach longer and you feel fuller.
• GIP binds to receptors within your brain and fat (adipose) tissue. In the brain, it amplifies the effects of GLP-1. In fat tissue, it triggers a chemical signal that tells your cells to store extra energy safely under your skin (as subcutaneous fat), rather than letting it gather around your organs (as visceral fat). This aids in keeping your metabolism healthy while you lose weight.

How Contrave® works

Contrave® combines two older medications, bupropion and naltrexone:

• Bupropion: This antidepressant medication stimulates neurons in your hypothalamus that tell you to stop eating, which naturally cuts down your appetite.
• Naltrexone: These same “stop eating” neurons release a braking molecule (beta-endorphin) that tries to turn bupropion’s signal off. Naltrexone blocks the opioid receptors on those neurons to prevent beta-endorphin from binding and quieting that signal.

Side-by-side comparison

Here’s a side-by-side comparison of Zepbound® versus Contrave®:

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Zepbound® vs. Contrave®: Weight loss outcomes

To understand how these medications stack up, it helps to look at the landmark clinical trials for each.

Zepbound® (tirzepatide)

The SURMOUNT-1 phase three trial, published in The New England Journal of Medicine in 2022, assessed tirzepatide’s weight loss outcomes over 72 weeks. Average weight loss scaled with dosage:

Contrave® (Naltrexone-bupropion)

The COR-I trial, published in The Lancet in 2010, assessed the active ingredients of Contrave® over 56 weeks. Participants taking the daily target dose (32 mg naltrexone and 360 mg bupropion) achieved an average weight loss of 6.1%, compared to just 1.3% on the placebo.

It’s important to note that only half of the participants finished the trial due to various reasons, including side effects and loss of contact. Because of this, the FDA’s analysis of the same data, which included participants who dropped out early using their last recorded weight, landed lower: an average weight loss of 5.4% compared to the study’s 6.1%.

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How do the side effects and serious risks of Zepbound® and Contrave® compare?

Zepbound® and Contrave® affect the body differently and carry distinct side effect and safety profiles. 

Common Zepbound® side effects vs. common Contrave® side effects

Both medications commonly cause digestive issues like nausea, constipation, and diarrhea. But Contrave® is more likely to cause central nervous system (CNS) symptoms like headaches or dizziness than GI symptoms. Here are some additional common side effects of each medication:

• Zepbound®: Vomiting, stomach pain, and indigestion
• Contrave®: Insomnia, anxiety or irritability, and fatigue

FDA boxed warnings

A boxed warning is the FDA’s most serious safety alert, and each drug has one:

• Zepbound® warns of a potential risk for thyroid C-cell tumors. This was seen in animal studies and hasn’t been proven in humans, but it still requires caution for high-risk individuals.
• Contrave® warns of suicidal thoughts and behaviors, particularly in young adults. This risk is tied to bupropion, which is also used as an antidepressant.

Who shouldn’t take these medications (Contraindications)

A contraindication is a specific medical condition or factor that makes a drug unsafe to use. Here are the contraindications for each medication:

Zepbound® and Contrave® eligibility criteria

Both Zepbound® and Contrave® share the same FDA-approval rules. To qualify for either medication, you must be an adult who meets the following criteria:

• A body mass index (BMI) of 30 or higher, or
• A BMI of 27 or higher, plus a weight-related condition like high blood pressure

Doctors approve both medications for use alongside a reduced-calorie diet and increased physical activity—not as a substitute for them. However, meeting the BMI criteria doesn’t automatically guarantee qualification. Your doctor will look at your full health picture to determine if either medication is right for you.

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Dosages and treatment schedules

When starting treatment, both medications involve gradual dose increases (called titration) to help your body adjust and minimize side effects. Below are the standard titration schedules, but your doctor may customize them based on your needs.

Zepbound® (Once-weekly injection)

Zepbound® begins with a starting dose of 2.5 mg, once weekly for the first four weeks, followed by:

• Titration: From week five onward, the dose increases by 5 mg weekly. If needed, your doctor can increase it by 2.5 mg every four weeks at the earliest.
• Maintenance doses: Patients typically take 5 mg, 10 mg, or 15 mg for weight management (or 10–15 mg for OSA). 

Contrave® (Daily oral tablets)

Each Contrave® tablet contains 8 mg naltrexone and 90 mg bupropion. Week one usually begins with just one tablet in the morning, followed by:

• Titration: Week two increases to one tablet in the morning and one at night, followed by two tablets in the morning and one at night during week three.
• Maintenance dose: Patients typically take two tablets morning and evening (totaling 32 mg naltrexone and 360 mg bupropion daily).

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Access whole-person GLP-1 care at Maven Clinic

Navigating weight management can feel overwhelming, but you don’t have to do it alone. As Lisa, a Maven Clinic patient, shared: “I needed someone to hear me and help me find solutions, and be my cheerleader. I feel more hope about my body than I have in a long time.” 

At Maven Clinic, the prescription is just the beginning. Our specialists deliver evidence-based GLP-1 care tailored to your unique body, lifestyle, and goals. We remain by your side to support your long-term health outcomes.

Discover our approach to GLP-1 care.