In short: For most of the last century, weight-loss drugs followed the same cycle: a promising pill, wide use, then harm and withdrawal. Dinitrophenol in the 1930s, amphetamines and “rainbow pills” in the 1950s and 1960s, fen-phen in the 1990s, sibutramine in 2010 and lorcaserin in 2020 were all pulled or restricted for safety reasons. A few older medicines survived with limits, such as phentermine (short-term only) and orlistat. The pattern changed with GLP-1 medicines: Saxenda in 2014, Wegovy in 2021 and Zepbound in 2023 produced larger losses, and Wegovy became the first weight medicine shown to lower heart attack and stroke risk. Today’s pills, Wegovy tablets and Foundayo, were approved in December 2025 and April 2026.
This page tells that story from FDA notices, approval records, the Federal Register, DEA scheduling and peer-reviewed research. It is history, not advice: whether any medicine fits you is a decision for you and your clinician. For today’s options side by side, see every FDA-approved weight-loss medication compared, and for the wider story of diets, surgery and programs, our history of weight loss.
A century of weight-loss drugs in four numbers
- 1938the year a new federal law finally let regulators stop sales of dinitrophenolColman E, Regulatory Toxicology and Pharmacology 2007
- 18 million+U.S. prescriptions for fenfluramine and phentermine in 1996, a combination the FDA never approvedConnolly HM et al., NEJM 1997
- 5drugs or drug groups for weight loss withdrawn or banned in the U.S. since 1997: fenfluramine, dexfenfluramine, phenylpropanolamine, sibutramine, lorcaserinFDA and Federal Register records
- 2021Wegovy approved, beginning the GLP-1 era of larger average weight lossDrugs@FDA
Checked on October 6, 2026
Before 1938: thyroid extracts and a dangerous “metabolism booster”
The first drug treatments for obesity tried to speed up the body’s energy use. A 2022 review of anti-obesity drug discovery in Nature Reviews Drug Discovery lists thyroid hormones, amphetamines and dinitrophenol among the treatments of the last century that were abandoned because of serious side effects. Giving thyroid hormone to someone whose thyroid works normally can push the heart and metabolism into overdrive, which is why it is not a weight-loss treatment today.
2,4-Dinitrophenol (DNP) (BANNED). In the early 1930s, DNP, an industrial chemical, became a popular weight-loss drug, largely through the work of Stanford pharmacologist Maurice Tainter. It works by making cells waste energy as heat. An FDA reviewer’s 2007 history describes its therapeutic margin as “razor thin”: thousands of people suffered irreversible harm before physicians abandoned it. Federal regulators had no power to stop patent-medicine sellers until the Food, Drug, and Cosmetic Act passed in 1938. DNP never went away: a 2011 review counted 62 published deaths, and it is still sold illegally online as a “fat burner”. Our fat burners guide explains why such products are dangerous.
1940s to 1960s: amphetamines and “rainbow pills”
After the 1938 law, the FDA approved several amphetamine and amphetamine-like drugs for obesity in the 1940s and 1950s, according to a 2005 history by an FDA medical officer in the Annals of Internal Medicine. Methamphetamine was approved for weight loss in the U.S. in 1947, and phentermine and phendimetrazine followed in 1959, according to a 2022 review in Nature Reviews Drug Discovery. These drugs curb appetite by stimulating the nervous system. Their popularity helped drive what historian Nicolas Rasmussen calls “America’s first amphetamine epidemic”, which peaked around 1969. From 1961 to 1968, “rainbow pills”, colorful combinations of several drugs taken together, were sold in the U.S. for weight loss and were linked with palpitations, raised blood pressure and deaths, according to the same review.
Regulators responded with limits rather than outright bans. The FDA restricted labeling to short-term use and added warnings about abuse and addiction, and these drugs are now controlled substances. The Drug Enforcement Administration lists amphetamine and methamphetamine in Schedule II (the strictest category for drugs with medical uses), benzphetamine and phendimetrazine in Schedule III, and phentermine and diethylpropion in Schedule IV. Phentermine, with an initial U.S. approval in 1959, is still prescribed, and its label limits it to short-term use as part of a broader plan. Our appetite suppressants guide covers it today.
1973 to 1997: fenfluramine, fen-phen and the heart-valve crisis
Fenfluramine (Pondimin) and dexfenfluramine (Redux) (WITHDRAWN 1997). Fenfluramine, an amphetamine relative that acts on serotonin, was approved in the U.S. in 1973 as an appetite suppressant. In the 1990s, doctors began prescribing it together with phentermine, a pairing known as “fen-phen” that the FDA never approved as a combination. Its close relative dexfenfluramine (Redux) was approved in the mid-1990s, and long-term use of these drugs spread quickly. In 1996, U.S. prescriptions for fenfluramine and phentermine passed 18 million.
In August 1997, doctors at the Mayo Clinic reported unusual heart-valve disease in 24 women who had taken fen-phen and had no history of heart problems; eight also had new pulmonary hypertension, and five had needed heart surgery. Fenfluramine and dexfenfluramine were withdrawn from the U.S. market in 1997 because of valve disease, and in 1999 the FDA listed both in the Federal Register as withdrawn for reasons of safety or effectiveness. Phentermine itself was not withdrawn. In a twist, fenfluramine returned in 2020 under a new name, Fintepla, approved for seizures in a rare childhood epilepsy, Dravet syndrome, with heart monitoring. It has no weight-loss approval.
1997 to 2010: sibutramine, orlistat and over-the-counter scares
Sibutramine (Meridia) (WITHDRAWN 2010). Approved on November 22, 1997, sibutramine was meant to be a safer appetite drug. It became the subject of SCOUT, a large trial of its long-term cardiovascular effects, which enrolled 10,744 older adults with heart disease, type 2 diabetes or both. Over an average of 3.4 years, heart attacks, strokes, cardiac arrest or cardiovascular deaths occurred in 11.4% of the sibutramine group and 10.0% of the placebo group, a 16% higher risk, while extra weight loss with the drug was small. On October 8, 2010, the FDA recommended against continued use and asked the maker to withdraw it, and the company stopped U.S. marketing. The FDA still finds sibutramine hidden in products sold as supplements.
| Item | Value |
|---|---|
| Sibutramine | 11.4% |
| Placebo | 10% |
Hazard ratio 1.16. Nonfatal heart attack 4.1% vs 3.2%; nonfatal stroke 2.6% vs 1.9%. The FDA recommended against continued use in October 2010.
Source: James WP et al., New England Journal of Medicine 2010 (SCOUT, 9,804 randomized adults) (checked on October 6, 2026)
Orlistat (Xenical, Alli) (still approved). Orlistat took a different route: it blocks part of the fat in food from being absorbed rather than acting on the brain. Xenical was approved on April 23, 1999, and a half-strength version, Alli, became the first over-the-counter weight-loss medicine on February 7, 2007. Its digestive side effects are well known, but it has stayed on the market. See our orlistat and Alli pages.
Phenylpropanolamine (PPA) (REMOVED 2000). PPA was sold for decades in over-the-counter diet aids and cold remedies. A Yale case-control study of 702 stroke patients, published in 2000, found that women who used PPA appetite suppressants had about 16 times the odds of a bleeding stroke. In November 2000, the FDA issued a public health advisory and asked all drug companies to voluntarily stop marketing products containing PPA, and stores and manufacturers removed them; a 2005 Federal Register notice proposed making the removal permanent.
Ephedra (BANNED IN SUPPLEMENTS 2004). Ephedra, a plant source of ephedrine alkaloids, was a common ingredient in weight-loss supplements. On February 11, 2004, the FDA published a final rule declaring supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk of illness or injury, including heart attack, stroke and death; it took effect on April 12, 2004. Our supplements guide explains why supplements are not FDA approved for weight loss.
Rimonabant (never approved in the U.S.). This drug blocked the brain’s cannabinoid receptors to reduce appetite. It was sold in Europe from 2006 to 2009 before being withdrawn over depression and suicidal thoughts, according to the 2022 review, and it never reached the U.S. market.
2012 to 2020: new combinations, and one more withdrawal
A new generation of medicines arrived in the 2010s. Qsymia (phentermine plus topiramate) was approved on July 17, 2012, and Contrave (naltrexone plus bupropion) on September 10, 2014. Both are still approved. Saxenda (liraglutide), approved on December 23, 2014, was the first GLP-1 medicine for weight management and a sign of what was coming; its approval extended to teens aged 12 and older in December 2020. Imcivree (setmelanotide), approved on November 25, 2020, treats rare genetic forms of obesity confirmed by testing.
Lorcaserin (Belviq) (WITHDRAWN 2020). Approved in 2012, lorcaserin acted on a serotonin receptor more selectively than fenfluramine had. A large safety trial, CAMELLIA-TIMI 61, followed 12,000 patients for five years. Cancer was diagnosed in 462 patients (7.7%) on lorcaserin and 423 (7.1%) on placebo, with several cancer types more frequent with the drug. On February 13, 2020, the FDA asked the maker to withdraw Belviq and Belviq XR from the market, and the company did so.
| Item | Value |
|---|---|
| Lorcaserin (Belviq) | 7.7% |
| Placebo | 7.1% |
462 vs 423 patients among about 12,000 in the trial. The FDA said the risk of cancer outweighed the benefits.
Source: FDA, request for withdrawal of Belviq and Belviq XR (February 13, 2020) (checked on October 6, 2026)
2021 to 2026: the GLP-1 era
On June 4, 2021, the FDA approved Wegovy (semaglutide 2.4 mg), a weekly injection; in its main trial, average weight change was -14.9% with Wegovy and -2.4% with placebo. Its approval was extended to adolescents 12 and older in December 2022. Zepbound (tirzepatide), which acts on two gut hormone receptors, followed on November 8, 2023, with average losses up to -20.9% vs -3.1% on placebo. Then the uses widened. In March 2024, Wegovy became the first weight-loss medicine approved to reduce the risk of heart attack, stroke or cardiovascular death in adults with heart disease and obesity or overweight, based on the SELECT trial. Zepbound was approved for moderate to severe obstructive sleep apnea in adults with obesity in December 2024, and Wegovy for a form of fatty liver disease with liver scarring (MASH) in August 2025.
The newest chapter is pills and higher doses. Wegovy tablets were approved on December 22, 2025, a higher-dose Wegovy and an Imcivree approval for acquired hypothalamic obesity followed on March 19, 2026, and Foundayo, a daily small-molecule pill, on April 1, 2026. Our GLP-1 guide explains how these medicines work, and oral GLP-1s covers the pills.
The GLP-1 era brought its own problems. Shortages led to compounded copies, which the FDA says are not reviewed for safety, effectiveness or quality, and to counterfeits. Read our guide to compounded GLP-1s before considering one.
Approval and withdrawal timeline
| Year | Drug | What happened | Status in 2026 |
|---|---|---|---|
| 1930s-1938 | Dinitrophenol (DNP) | Popular from the early 1930s; federal power to stop sales arrived with the 1938 Food, Drug, and Cosmetic Act | Banned; sold illegally online |
| 1947 | Methamphetamine | Approved for weight loss in the U.S. | Schedule II |
| 1959 | Phentermine | Initial U.S. approval | Approved, short-term use; Schedule IV |
| 1961-1968 | “Rainbow pills” | Multi-drug combinations sold for weight loss | Gone |
| 1973 | Fenfluramine (Pondimin) | Approved as an appetite suppressant | WITHDRAWN 1997 for weight |
| Mid-1990s | Dexfenfluramine (Redux) | Approved | WITHDRAWN 1997 |
| 1997 | Fen-phen | Heart-valve report in 24 women (never approved as a combination) | Fenfluramines withdrawn |
| 1997 | Sibutramine (Meridia) | Approved November 22 | WITHDRAWN 2010 |
| 1999 | Orlistat (Xenical) | Approved April 23 | Approved |
| 2000 | Phenylpropanolamine | FDA advisory; companies asked to stop marketing | REMOVED |
| 2004 | Ephedra | Banned in supplements (rule effective April 12) | BANNED |
| 2007 | Alli (orlistat 60 mg) | First over-the-counter weight-loss medicine, February 7 | Approved, OTC |
| 2010 | Sibutramine | FDA recommends against use after SCOUT (October 8) | WITHDRAWN |
| 2012 | Qsymia; Belviq | Qsymia approved July 17; Belviq approved | Qsymia approved; Belviq WITHDRAWN 2020 |
| 2014 | Contrave; Saxenda | Approved September 10 and December 23 | Approved |
| 2020 | Belviq; Imcivree | Belviq withdrawn February 13; Imcivree approved November 25 | Belviq WITHDRAWN; Imcivree approved |
| 2021 | Wegovy | Approved June 4 | Approved |
| 2023 | Zepbound | Approved November 8 | Approved |
| 2024 | Wegovy; Zepbound | Heart-risk reduction (March 8); sleep apnea (December 20) | Approved uses |
| 2025 | Wegovy; Wegovy tablets | MASH (August 15); tablets approved December 22 | Approved |
| 2026 | Wegovy HD; Foundayo | Higher dose March 19; Foundayo April 1 | Approved |
What a century of drugs teaches
Five lessons from weight-loss drug history
- Rare harms show up lateValve disease, strokes and cancer signals appeared only after wide use or large outcome trials.
- Weight loss is not the only outcomeSibutramine lowered weight but raised heart risk; Wegovy lowered both weight and heart risk.
- Combinations need their own proofFen-phen was never approved as a combination.
- "Natural" is not safe by defaultEphedra was banned, and DNP and sibutramine still turn up in illegal products.
- Approval is ongoingThe FDA keeps reviewing safety after approval, and labels change.
These lessons help explain why today’s medicines carry long labels and why supplements that promise drug-like results deserve suspicion. They also explain why InstaTuck’s medication pages never rank medicines and always link to the FDA label.
Thinking about a medicine yourself? Our questions to ask before starting a GLP-1 help you prepare for the conversation, the weight-loss pills hub covers every oral option, and what’s new in weight loss in 2026 picks up the story from here.