As attitudes surrounding obesity and body image have evolved since the late 19th century, new weight-loss drugs have exploded in popularity, time and time again. From thyroid hormones to amphetamine to the “fen-phen” craze, the most common options of the past have continuously faced their demise, largely due to unintended health effects. 

There are many possible causes of obesity, which, throughout history, has made it difficult to find a safe and effective solution for everybody, says Frank Greenway, chief medical officer and professor at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, who specializes in obesity treatments. Scientists remain hopeful that the latest type of weight-loss medications—the glucagon-like peptide-1 (GLP-1) agonist class of drugs—will buck the historical trend.

“I don’t think we’ve understood well what these drugs do, and so we get ourselves into problems,” Greenway says of past obesity treatments. “We don’t understand the physiology as well as we’d like.”

Here’s a breakdown of the obesity drugs that have surfaced throughout America’s history.

The stigma surrounding obesity in the United States appeared around the late 1800s, when people viewed it as the “opposite of being careful, prudent, diligent and hardworking,” says Nicolas Rasmussen, author of Fat in the Fifties: America's First Obesity Crisis and On Speed: From Benzedrine to Adderall. This was a period of urbanization and the Industrial Revolution—a time when society placed high value on hard work.

Thyroid hormone extract (which originally came from pigs and cows) was initially used to treat patients with underactive thyroids, until doctors discovered it could also help with weight loss by boosting metabolism. In 1893, researchers published their findings about thyroid extract’s potential as an obesity treatment. It wasn’t long before medical quacks were selling untested and largely ineffective “patent medicines” as diet aids—like Allan’s Anti-Fat and Dr. Gordon’s Elegant Pills.

“The endocrinologists were the doctors who made fat ladies thin,” says Rasmussen, also a professor emeritus at the University of New South Wales in Australia. “That was the way they made money.”

Many in the medical community raised alarms about using thyroid hormones for obesity. Woods Hutchinson, a renowned English-American physician, wrote that prolonged use could lead to “serious and obstinate disturbance of the nervous system.” 

The medical profession began cracking down on doctors giving patients thyroid hormones and the multi-colored pills they prescribed for weight loss, Rasmussen says. Then, legislation passed in 1938 gave the FDA authority to regulate non-prescription use of the drug. Thyroid hormone's reign as the weight-loss drug of choice faded by the end of the decade—when amphetamine came along.

Also in the 1930s came the chemical dinitrophenol, an over-the-counter obesity treatment. French factory workers previously used dinitrophenol to build explosives during World War I, and many lost weight upon exposure to the substance. Along with side effects like fatigue, excessive sweating and increased body temperature, there were also some reported deaths.

Maurice Tainter, a pharmacologist at Stanford University, conducted further testing on animals and human patients, and in 1934 touted dinitrophenol as a safe weight-loss medication, though he acknowledged the risks of consuming it in high doses. By then, Tainter estimated, at least 100,000 Americans had used the drug. 

Other doctors weren’t so confident in dinitrophenol and linked it to cataracts and neuropathy. There were also reports of about 2,500 people losing their vision after taking the drug. In 1938, the FDA described it as “extremely dangerous and not fit for human consumption,” effectively ceasing its use in the U.S.

Around this time, amphetamine was gaining popularity—initially as a nasal decongestant (Benzedrine) and psychiatric treatment. During World War II, the U.S. military purchased amphetamine in the form of Benzedrine Sulfate tablets and supplied them to troops, believing the drug could help combat fatigue and boost morale. The addictive drug’s wartime popularity helped normalize its recreational use after the conflict ended in 1945. And because amphetamine could suppress people’s appetites, it became a common obesity treatment.

Also becoming more and more popular were the latest form of “rainbow pills,” a colorful combination of amphetamines, sedatives, diuretics and thyroid hormones, taken in conjunction with even more pills to mask the side effects.

“As the actual population gets fatter and fatter—which is happening continuously from World War II on—but the beauty standard remains thin, it becomes harder and harder to fit the standard,” Rasmussen says. By the early 1960s, 13 percent of the population was obese. Amphetamine’s primary medical purpose eventually became weight loss. 

However, in 1968, two events spurred the FDA to remove rainbow pills from the market: the publication of a Life magazine exposé, where an investigative reporter posed as a patient at 10 obesity clinics and was given more than 1,500 pills, and a U.S. Senate investigation that found dozens of instances linking rainbow pills to death.

Amid the new “War on Drugs,” President Richard M. Nixon also signed into law the Controlled Substance Act in 1970, declaring amphetamine a Schedule II controlled substance and making it much more difficult for doctors to prescribe the drug.

With the downfall of amphetamine as an obesity medication came a new generation of synthetic versions of the drug used as diet aids—some requiring a prescription, others not. Among them were phentermine and fenfluramine, two treatments that work differently but both help people drop weight. Combined into “fen-phen,” they drove the next weight-loss drug craze in the mid-1990s. 

Between 1988 and 1994, nearly 23 percent of adults were obese, and over a third were overweight, according to the Centers for Disease Control and Prevention. 

Doctors wrote more than 18 million prescriptions for phentermine and fenfluramine in 1996. But the following year, the medical community discovered fen-phen could cause heart valve damage, and it was removed from the market. By 1999, facing mounting injury lawsuits, the makers of fen-phen agreed to pay thousands of consumers a total of $3.75 billion.

Starting in 2005, GLP-1 drugs were prescribed to treat people with Type II Diabetes. In 2014, a year after the American Medical Association designated obesity a disease, a GLP-1 (Saxenda) was approved for weight loss, followed by Wegovy in 2021. This class of drugs mimics the natural GLP-1 hormone and leads to increased feelings of fullness.

While safer compared with past weight loss drugs, understanding the full risks and potential long-term side effects of GLP1s will take time. Some, like Ozempic, are officially approved by the FDA for Type II Diabetes but not weight loss. As of May 2024, 1 in 8 U.S. adults had taken a GLP-1 drug, according to a KFF Health Tracking Poll.

Unlike today’s treatments, which can be quite costly, “Amphetamine had the virtue of being democratic,” Rasmussen says. “Everybody could afford amphetamines, even the brand name ones.”