Written by justis berg
08 September 2010


Fat Attack

By Dan Gwartney


Is Being Fat a Headache? Migraine Drug Causes Fat Loss

People love newspapers because they can learn most of a story from the headlines. Imagine this one— FDA approved drug effective at weight loss. Despite the public demand, that hasn’t been front page news for some time. Drugs developed for weight loss usually demonstrate adverse side effects before the FDA finishes its tortoise race to approval.

In the United States, the accepted practice of medicine depends upon treating illnesses and injuries using methods and materials developed through evidence-based clinical science. The downside to Western-style science is the same as its upside— it is very specific. The ideal of science is to observe the reaction caused by a single change in a controlled environment, like a test tube. This is impossible in humans, as we are not uniform and the body is a complex interplay of chemical and behavioral reactions.

To examine experimental effects in humans, scientists look for a specific change (e.g., cholesterol levels, fever, weight loss, etc.), when one variable is changed (e.g., taking a drug). While this allows for a very concrete conclusion, such as aspirin reduces fever or insulin lowers blood sugar, it tends to blind the scientists to other effects that may be taking place.

If a pharmaceutical corporation develops a drug that is effective and can be marketed profitably, it submits data to the Food and Drug Administration (FDA) for approval. If the FDA is satisfied there is sufficient evidence from clinical trials to justify claims and satisfy safety concerns, then the drug is approved for a specific use. The company cannot market the drug for any other purpose without performing additional studies and repeating the approval process for the new claim(s); approval is not guaranteed and typically takes years, costing millions of dollars.

As drugs are released into clinical practice, observations made by physicians in clinics and hospitals, or researchers in labs, suggest other effects that may be caused by a drug. If doctors believe there is an unmet need that may be fulfilled by a drug approved for another condition, they typically are allowed to prescribe that drug for uses other than what the manufacturer states or the FDA has approved. Prescribing a drug for a purpose other than what it is approved for is referred to as an “off-label use.”1 With rare exceptions, physicians are considered to have the authority to prescribe any FDA-approved drug for any condition they believe can be safely and effectively treated by the drug, regardless of the recognized claims. A blatant exception is the class of anabolic steroids. There are some added risks to the doctor and patient, as such use is not verified by clinical trials and the drug may not be safe when used by unstudied groups (e.g., children, diabetics, pregnant women, etc.). Physicians who prescribe off-label risk legal jeopardy if an unforeseen side effect arises, as off-label use may not be considered “standard practice.”

Even though pharmaceutical companies are not allowed to advertise off-label uses to physicians or the public, the news media and word-of-mouth create significant demand. One such example is the current trend in using drugs designed to treat diabetes, asthma, fertility problems, depression, and other disorders for assisting in weight loss.2,3 A good friend of mine living in California informed me of a growing trend among doctors to prescribe topiramate for weight loss, with reportedly good results.

Topiramate is an older drug, originally prescribed to prevent seizures in epileptics; later it was found to be effective in reducing migraine attacks.4 As physicians became more sensitive to treating the patient and not the disease, they became aware that weight loss was a common experience. Several side effects are associated with topiramate that potentially contribute, including: headache, nausea, diarrhea, and anorexia.5

In the interest of responsible medicine, several studies observed potential weight loss in patients prescribed topiramate, attempting to define a mechanism of action (how it caused weight loss).6-9 During the last decade, a number of studies consistently demonstrated weight loss among the overweight and obese; along with the weight loss, insulin sensitivity improved. Though it remains unclear exactly how the weight loss occurs, a decreased appetite and reduced voluntary food intake appears to be the primary change. The improvement in insulin sensitivity seems to be related to the degree of weight loss, rather than any direct effect of topiramate on insulin release, insulin-related signaling, or receptor-mediated events.

Though it is helpful to be able to refer to these studies as evidence supporting the use of topiramate in promoting weight loss through appetite suppression, responsible clinicians should continue to explore how topiramate is accomplishing this feat. This is critical as physicians not familiar with the drug may be prescribing it, unaware of drug interactions, side effects, risks, and dosing. Even more harrowing is the probability that some consumers acquire the drug via the Internet or black market sources that do not provide proper guidance, monitoring, or even the guarantee of unadulterated topiramate (legitimate drug versus impure counterfeits or placebos).

Some may look to the pharmaceutical industry, placing responsibility on the original patent holders, but all patents for topiramate have expired and the drug is often encountered as a generic. Thus, no corporate entity has any financial incentive to look further into the actions of topiramate when used as an anorexic (appetite suppressant).

Fortunately, some clinicians remain scientifically inquisitive. A group of German physicians followed six patients being treated with topiramate for frequent migraines.10 Migraines are particularly painful and debilitating headaches that can occur rapidly; at times, the pain is so severe that intravenous painkillers are necessary.

This group (five women, one man) ranged from normal weight to obese, aged 26-61 years, were treated with topiramate for 20 weeks; no recommendations were provided relative to changes in diet or exercise. Topiramate dosing was titrated (adjusted) upward gradually with each patient, beginning at 25 mg daily; the dose was increased each week by 25 mg (daily dose) to determine the best outcome (preventing migraines versus the appearance and management of side effects). The average final dose was 50 mg taken twice a day; the maximum dose was 100 mg twice daily.

Despite the gradual introduction of the drug, and screening of the patients, side effects still occurred, including: tingling in the hands, difficulty concentrating, dizziness, and anomia (difficulty recalling names or words).10 As some patients could not tolerate the drug past 20 weeks, the doctors only analyzed data for that time period. Remember, these people were taking topiramate to avoid debilitating migraine headaches, not just weight loss.

Despite the variable dosing and small number of subjects, several significant effects were recorded in this group. Still, in 20 weeks the group lost on average 7 percent of body mass, with the greatest loss being nearly 15 percent. Assuming the method used to measure body fat was accurate (Tanita Bioimpedance Analyzer), fat loss was disproportionately high. Whereas average total body mass was reduced by 7.2 percent, fat mass dropped 11.6 percent. The average waist circumference (distance around the belly) dropped just under two inches; all this occurred without being instructed to change diet or exercise habits.

When body fat drops, one expects leptin concentration to decrease; and so it did, by 40 percent. Leptin is a hormone released from fat cells that reduces appetite and increases calorie burning in normal people. In the obese, the body becomes less sensitive to leptin’s signal, due to the over-abundance of fat and fat-related hormones.11 Fat loss due to most any cause is associated with a reduction in leptin which allows the body to respond to the energy-store signal more appropriately. Another hormone originating from fat cells is adiponectin. Obese people produce less adiponectin, and its increase during weight loss is associated with better cardiovascular and metabolic health.12

As dramatic as the decrease in leptin (40 percent) was, adiponectin’s rise was even more astounding, increasing 70 percent. The overall effect of these changes in the fat cell’s hormonal signaling promotes greater health and easier weight loss. The rise in leptin observed in this study conflicts with an earlier study which failed to show a significant rise.9

Dr. Barry Sears enlightened the world of insulin’s central role in weight management.13 When insulin concentration is high, the body stores fat and resists fat loss. Controlling insulin concentrations through moderate carbohydrate intake (the Zone® diet) proved to be effective for many. Advocates of low-fat diet programs (e.g., Dr. Dean Ornish) suggest many of the benefits are the consequence of weight loss rather than carbohydrate restriction.14

Even in the absence of any dietary guidelines or change in eating habits, the patients receiving topiramate experienced improved insulin response, reflected by a 38 percent reduction in insulin resistance.10 One major contributor to insulin resistance, which can progress to type 2 diabetes, is visceral fat— a specific type of fat that surrounds the internal organs of the digestive system.15,16 People with excess visceral fat often demonstrate many of the obesity-related metabolic disorders, even if they are normal weight. This is why men with big bellies and skinny legs die of heart disease in their 50s, while grandmas with sausage arms and thunder thighs are still going in their 80s.

The authors of the study believed that the loss of abdominal fat, as shown by the reduction in waist circumference, was indicative of a loss of visceral fat. Visceral fat is also a source of inflammatory cytokines, messenger hormones that affect the liver negatively, as well as contributing to cardiovascular and metabolic harm.17 Unfortunately, concentrations of the two primary inflammatory cytokines (IL-6 and TNF-alpha) did not decrease as might be expected, if visceral fat stores were significantly depleted.10 It is possible visceral fat did decrease without affecting the cytokines measured, or the fat loss observed may have come from the subcutaneous fat stores.

An interesting observation made during the study was that a hormone called VEGF sharply spiked during the first two weeks, preceding the other reactions of the subjects to topiramate.10 VEGF regulates the “leakiness” of the blood vessels; when VEGF is elevated, the capillaries “leak.” Normally, the capillaries allow enough “leaking” for the blood to interact with the fluid that surrounds cells. This promotes the flow of nutrients and oxygen to cells in exchange for waste products like lactic acid and carbon dioxide. This is particularly important for the brain, as it has to compete with the organs, muscle, and other tissue for glucose (sugar). When VEGF increases, the brain has easier access to sugar; when VEGF is low, the brain starves, as it cannot compete with the insulin-sensitive tissue of the body for circulating glucose.18 Hypoglycemia (low blood sugar) stimulates the release of VEGF as a protective mechanism.

The authors postulated that the spike in VEGF (177 percent increase) allowed an influx of glucose that convinced the brain that it is in a state of energy surplus. VEGF returned to original concentration as insulin resistance was corrected. This suggests that weight gain in the insulin resistant may be due in part to the brain struggling against insulin-stimulated muscle and fat for circulating glucose.10 As glucose availability to the brain improves, brain-based signals that promote weight loss are generated. This finding suggests that some component of topiramate’s efficacy as a weight loss agent, primarily through appetite suppression, is created by improving glucose access to the brain by making the blood vessels leakier. VEGF injection has been shown to have this effect in animal studies; low VEGF is associated with weight gain in type 2 diabetics.19

Topiramate is currently one of the “hot drugs” in the weight loss circuit. Though it has been shown to be effective, causing weight loss by suppressing the appetite, it carries a number of risks. Even for patients taking this drug to avoid excruciating headaches, topiramate can be difficult to tolerate. While it holds hope for those struggling to lose weight, it is not an appropriate agent for athletes or bodybuilders. Cutting calories in the environment of a demanding physical activity can lead to muscle loss and impaired performance. Hopefully, pharmaceutical companies will explore the mechanism by which topiramate suppresses the appetite, so that a more tolerable treatment can be developed.



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