Can zonisamide make you lose weight?

In this article:

• Zonisamide weight loss
• How it works
• Zonisamide vs. topiramate
• Risks
• Maximizing zonisamide benefits

In this article

• Zonisamide weight loss
• How it works
• Zonisamide vs. topiramate
• Risks
• Maximizing zonisamide benefits

Excess body weight increases the risk of a number of health conditions, from insulin resistance and Type 2 diabetes mellitus to high blood pressure and heart disease. If you are overweight, with a body mass index (BMI) of 25 to 29, or have obesity, with a BMI of 30 or more, your healthcare provider may advise you to lose weight. When Interventions like increased physical activity and a reduced-calorie diet aren’t effective, they may recommend weight loss drugs. And while medications like Orlistat, phentermine, and GLP-1s are commonly prescribed, they aren’t for everyone. 

Zonisamide (brand name Zonegran) is an antiepileptic medication that’s approved by the U.S. Food and Drug Administration (FDA) as an add-on treatment to prevent partial seizures in adults with epilepsy. It acts on the central nervous system, (CNS), slowing down electrical activity in the brain to prevent seizures. While zonisamide is not approved for weight loss, clinical trials indicate that it can lead to weight reduction. It is sometimes prescribed off-label for weight loss in obese patients—alone or in combination with the antidepressant bupropion.

So how exactly does zonisamide make your weight change? Read on to find out, plus the benefits, risks, and tolerability of zonisamide for weight reduction.

Does zonisamide cause weight loss?

Although it’s not FDA approved for weight loss, obese individuals taking zonisamide may lose weight over time, with greater weight loss occurring at higher doses, says Eric Smith, DO, bariatric surgeon and Medical Director at POP Recovery Systems.

For example, a randomized controlled trial conducted at Duke University Medical Center found that obese adults who took a daily dose of 400 mg of zonisamide for one year lost around 16 pounds, while those taking a placebo lost about nine pounds. The group taking 200 mg lost about the same amount of weight at their one-year follow-up as the placebo group. Each group received lifestyle counseling, including dietary and exercise recommendations, to prevent weight gain. 

“Weight loss with zonisamide can vary depending on the dose, how long someone takes it, their eating habits, activity level, and age,” notes Dr. Smith. In adults, the main concern is managing side effects and ensuring proper nutrition, he says, adding that there are additional concerns for adolescents because they’re still growing and developing. “Using a drug like this for weight loss in teens—especially outside of its approved use—can be risky and should only be done with very close medical supervision,” he says.

Dr. Smith points out that while weight loss tends to increase with higher doses of zonisamide, that also increases the risk of side effects, including:

• Nausea or vomiting
• Constipation or diarrhea
• Weight loss
• Dry mouth
• Changes in taste
• Heartburn
• Headache
• Dizziness
• Confusion
• Irritability
• Insomnia
• Memory problems
• Burning, numbness, tingling, or pain in the hands or feet
• Uncontrollable eye movements or double vision

How does zonisamide work for weight loss?

Zonisamide is believed to contribute to weight loss by affecting neurotransmitters in the brain that influence appetite and energy expenditure, explains Diala Alatassi, MD, a double board-certified internist and obesity medicine specialist at Endeavor Health.

Dr. Alatassi says zonisamide alters serotonin levels, which are known to affect appetite regulation and energy expenditure. “We know that another seizure medication, topiramate, which is FDA approved for weight loss in combination with phentermine (Qsymia), works in a similar way,” she says. However, more research is needed to establish this relationship.

Zonisamide vs. topiramate for weight loss

Research indicates that both zonisamide and topiramate can lead to weight loss, but their effectiveness may vary depending on individual circumstances. One study found that among adolescents taking psychiatric medications, zonisamide and topiramate resulted in comparable reductions in weight loss.

While both medications can be effective for weight loss, topiramate has been more thoroughly researched.

Risks of zonisamide for weight loss

Dr. Smith says that while zonisamide may offer weight reduction benefits, it’s not without risks, emphasizing that zonisamide isn’t considered a reliable or safe long-term solution for weight loss. “While some people do lose weight, it’s not predictable, and the potential downsides often outweigh the benefits—especially when there are FDA-approved medications designed specifically for weight management that are typically better tolerated,” he says.

Serious adverse events from zonisamide may include:

• Metabolic acidosis (too much acid in the blood)
• Kidney stones and kidney disease
• Suicidal thoughts or behaviors
• Low white blood cell counts
• Rare but serious skin reactions
  

Because of the risk of adverse effects, zonisamide should never be used casually or without close monitoring by a healthcare professional, urges Dr. Smith. What’s more, the efficacy of zonisamide for weight loss can vary significantly from person to person. Your best bet? Consult your healthcare provider to discuss safe and effective options tailored to your needs. 

How to maximize zonisamide benefits

To get the most out of zonisamide while minimizing potential side effects, Dr. Smith offers the following tips:

• Take it as prescribed, at the same time each day, with or without food.
• Drink plenty of fluids to reduce the incidence of kidney stones.
• Avoid alcohol, other sedating medications, and anything that increases your risk of metabolic issues unless cleared by your healthcare provider.
• Get regular lab work to check your kidney function and blood chemistry.
• Make sure you’re meeting your protein and nutrient needs.
• Discuss any dietary supplements and OTC or prescription medications you’re taking with your healthcare provider.

The bottom line? Understanding that zonisamide is not a “magic pill” for weight loss is essential. Losing weight safely and sustainably requires a full picture of your health, including your medical history, current medications, nutritional needs, and long-term goals, says Dr. Smith. “A healthcare provider can help you choose the right tools—whether that’s lifestyle changes, medication, surgery, or a combination—to support healthy weight loss, not just fast results.