A History of Weight-Loss Drugs: From Thyroid Pills and Fen-Phen to GLP-1s

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History

Phentermine: short-term weight-loss pill, risks and rules FDA approved for weight managementPrescriptionPillOrlistat (Xenical and Alli): how the fat-blocker works FDA approved for weight managementPrescriptionPillQsymia (phentermine/topiramate): uses, risks and REMS FDA approved for weight managementPrescriptionPillContrave (naltrexone/bupropion): how it works and its warnings FDA approved for weight managementPrescriptionPill

A history of weight-loss drugs from FDA records: dinitrophenol, amphetamines, fen-phen, sibutramine and Belviq withdrawals, orlistat, and the GLP-1 era from Saxenda to Foundayo.

Fact-checked against FDA labels and official sources; not yet reviewed by a licensed clinician. This page is education, not medical advice. Talk to your doctor before starting, stopping or changing any treatment.

Key takeaways

  • Dinitrophenol was widely used for weight loss in the early 1930s, but federal regulators could not stop its sale until the 1938 Food, Drug, and Cosmetic Act.[2]
  • Fenfluramine, approved in 1973, and dexfenfluramine were withdrawn in 1997 after fen-phen was linked to heart-valve disease.[8]
  • In the SCOUT trial, major cardiovascular events occurred in 11.4% of people on sibutramine vs 10.0% on placebo; the FDA recommended against its use in October 2010.[11]
  • The FDA asked for lorcaserin (Belviq) to be withdrawn on February 13, 2020, after cancer was diagnosed in 7.7% of users vs 7.1% on placebo.[24]
  • Wegovy, approved on June 4, 2021, later became the first weight-loss medicine approved to reduce the risk of heart attack and stroke (March 2024).[29]

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

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.

SCOUT trial: heart attack, stroke, cardiac arrest or cardiovascular death over 3.4 yearsValues in %
SCOUT trial: heart attack, stroke, cardiac arrest or cardiovascular death over 3.4 years
ItemValue
Sibutramine11.4%
Placebo10%

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.

CAMELLIA-TIMI 61: patients diagnosed with cancer over 5 yearsValues in %
CAMELLIA-TIMI 61: patients diagnosed with cancer over 5 years
ItemValue
Lorcaserin (Belviq)7.7%
Placebo7.1%

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

YearDrugWhat happenedStatus in 2026
1930s-1938Dinitrophenol (DNP)Popular from the early 1930s; federal power to stop sales arrived with the 1938 Food, Drug, and Cosmetic ActBanned; sold illegally online
1947MethamphetamineApproved for weight loss in the U.S.Schedule II
1959PhentermineInitial U.S. approvalApproved, short-term use; Schedule IV
1961-1968“Rainbow pills”Multi-drug combinations sold for weight lossGone
1973Fenfluramine (Pondimin)Approved as an appetite suppressantWITHDRAWN 1997 for weight
Mid-1990sDexfenfluramine (Redux)ApprovedWITHDRAWN 1997
1997Fen-phenHeart-valve report in 24 women (never approved as a combination)Fenfluramines withdrawn
1997Sibutramine (Meridia)Approved November 22WITHDRAWN 2010
1999Orlistat (Xenical)Approved April 23Approved
2000PhenylpropanolamineFDA advisory; companies asked to stop marketingREMOVED
2004EphedraBanned in supplements (rule effective April 12)BANNED
2007Alli (orlistat 60 mg)First over-the-counter weight-loss medicine, February 7Approved, OTC
2010SibutramineFDA recommends against use after SCOUT (October 8)WITHDRAWN
2012Qsymia; BelviqQsymia approved July 17; Belviq approvedQsymia approved; Belviq WITHDRAWN 2020
2014Contrave; SaxendaApproved September 10 and December 23Approved
2020Belviq; ImcivreeBelviq withdrawn February 13; Imcivree approved November 25Belviq WITHDRAWN; Imcivree approved
2021WegovyApproved June 4Approved
2023ZepboundApproved November 8Approved
2024Wegovy; ZepboundHeart-risk reduction (March 8); sleep apnea (December 20)Approved uses
2025Wegovy; Wegovy tabletsMASH (August 15); tablets approved December 22Approved
2026Wegovy HD; FoundayoHigher dose March 19; Foundayo April 1Approved
Sources in the references: Drugs@FDA, FDA safety communications and reviews, the Federal Register, DEA, and peer-reviewed histories; checked on 2026-10-06.
How long withdrawn weight-loss drugs were on the U.S. marketValues in years
How long withdrawn weight-loss drugs were on the U.S. market
ItemValue
Phenylpropanolamine (1960-2000)40 years
Fenfluramine (1973-1997)24 years
Sibutramine (1997-2010)13 years
Lorcaserin (2012-2020)8 years
Dinitrophenol (1933-1938)5 years

Approximate years between first U.S. marketing for weight loss and withdrawal or removal. Some harms took decades to recognize.

Source: Muller TD et al., Nature Reviews Drug Discovery 2022 (Table 1); FDA withdrawal records (checked on October 6, 2026)

What a century of drugs teaches

Five lessons from weight-loss drug history

  1. Rare harms show up lateValve disease, strokes and cancer signals appeared only after wide use or large outcome trials.
  2. Weight loss is not the only outcomeSibutramine lowered weight but raised heart risk; Wegovy lowered both weight and heart risk.
  3. Combinations need their own proofFen-phen was never approved as a combination.
  4. "Natural" is not safe by defaultEphedra was banned, and DNP and sibutramine still turn up in illegal products.
  5. 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.

Records in this article

Related guides

Questions to ask a professional

  • How do the risks of today's medicines compare with the ones that were withdrawn?
  • What long-term safety data exist for the medicine I am considering?
  • Could any supplement I take contain hidden drug ingredients?
  • How will we monitor for side effects if I start a weight-loss medicine?

Frequently asked questions

What was the first weight-loss drug?

Thyroid hormones and, in the early 1930s, dinitrophenol (DNP) were among the first drugs used to cause weight loss. Both were abandoned because of serious harm; DNP could only be stopped by federal regulators after the 1938 Food, Drug, and Cosmetic Act.

Why was fen-phen taken off the market?

In 1997, a Mayo Clinic report linked fenfluramine-phentermine to heart-valve disease in 24 women. Fenfluramine and dexfenfluramine were withdrawn that year. Phentermine alone was not withdrawn and is still approved for short-term use.

Which weight-loss drugs have been withdrawn in the U.S.?

Among others: fenfluramine and dexfenfluramine (1997), phenylpropanolamine (removed from products after a 2000 FDA advisory), sibutramine (Meridia, 2010) and lorcaserin (Belviq, 2020). Ephedra was banned in supplements in 2004, and DNP was stopped after 1938.

Is phentermine safe if fen-phen was dangerous?

The heart-valve problems were linked to fenfluramine and dexfenfluramine, which were withdrawn. Phentermine is still FDA approved for short-term use and is a Schedule IV controlled substance. Whether it suits you is a question for your clinician.

When were GLP-1 medicines approved for weight loss?

Saxenda (liraglutide) in December 2014, Wegovy (semaglutide) in June 2021, Zepbound (tirzepatide) in November 2023, Wegovy tablets in December 2025 and Foundayo in April 2026.

References

  1. Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery, 2022. doi:10.1038/s41573-021-00337-8 · PMID 34815532 (accessed October 6, 2026) Review
  2. Colman E. Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regulatory Toxicology and Pharmacology, 2007. doi:10.1016/j.yrtph.2007.03.006 · PMID 17475379 (accessed October 6, 2026) Review
  3. Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. Journal of Medical Toxicology, 2011. doi:10.1007/s13181-011-0162-6 · PMID 21739343 (accessed October 7, 2026) Review
  4. Colman E. Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Annals of Internal Medicine, 2005. doi:10.7326/0003-4819-143-5-200509060-00013 · PMID 16144896 (accessed October 6, 2026) Review
  5. Rasmussen N. America’s first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present. American Journal of Public Health, 2008. doi:10.2105/AJPH.2007.110593 · PMID 18445805 (accessed October 6, 2026) Other
  6. Controlled Substances: Alphabetical Order (CSA schedules). U.S. Drug Enforcement Administration, Diversion Control Division. (accessed October 6, 2026) Government page
  7. Phentermine hydrochloride tablets: prescribing information. Via DailyMed (generic labeler), 2026. (accessed October 6, 2026) Drug label
  8. Clinical review, NDA 212102 Fintepla (fenfluramine): background on the 1997 market withdrawal of fenfluramine and dexfenfluramine. U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  9. Connolly HM, Crary JL, McGoon MD, et al.. Valvular heart disease associated with fenfluramine-phentermine. New England Journal of Medicine, 1997. doi:10.1056/NEJM199708283370901 · PMID 9271479 (accessed October 6, 2026) Other
  10. Drugs@FDA: Meridia (sibutramine), NDA 020632 (approved 1997-11-22; discontinued). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  11. James WP, Caterson ID, Coutinho W, et al.. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects (SCOUT). New England Journal of Medicine, 2010. doi:10.1056/NEJMoa1003114 · PMID 20818901 · NCT00234832 (accessed October 6, 2026) Randomized trial
  12. FDA Drug Safety Communication: FDA Recommends Against the Continued Use of Meridia (sibutramine). U.S. Food and Drug Administration, 2010. (accessed October 6, 2026) Government page
  13. Questions and answers about FDA’s initiative against contaminated weight loss products. U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  14. Drugs@FDA: Xenical, NDA 020766 (original approval 1999-04-23). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  15. Drugs@FDA: Alli, NDA 021887 (original approval 2007-02-07). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  16. Kernan WN, Viscoli CM, Brass LM, et al.. Phenylpropanolamine and the risk of hemorrhagic stroke. New England Journal of Medicine, 2000. doi:10.1056/NEJM200012213432501 · PMID 11117973 (accessed October 6, 2026) Other
  17. Phenylpropanolamine-Containing Drug Products for Over-the-Counter Human Use; Tentative Final Monographs (70 FR 75988). Federal Register (FDA), 2005. (accessed October 6, 2026) Government page
  18. Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk (69 FR 6788). Federal Register (FDA), 2004. (accessed October 6, 2026) Government page
  19. Drugs@FDA: Qsymia, NDA 022580 (original approval 2012-07-17). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  20. Drugs@FDA: Contrave, NDA 200063 (original approval 2014-09-10). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  21. Drugs@FDA: Saxenda, NDA 206321 (original approval 2014-12-23). U.S. Food and Drug Administration. (accessed October 7, 2026) Government page
  22. Drugs@FDA: Imcivree, NDA 213793 (original approval 2020-11-25). U.S. Food and Drug Administration. (accessed October 6, 2026) Government page
  23. NDA 213793/S-009 approval letter (acquired hypothalamic obesity). U.S. Food and Drug Administration, 2026. (accessed October 7, 2026) Government page
  24. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. U.S. Food and Drug Administration, 2020. (accessed October 6, 2026) Government page
  25. Drugs@FDA: Wegovy, NDA 215256, approval history. U.S. Food and Drug Administration. (accessed October 7, 2026) Government page
  26. Wilding JPH, Batterham RL, Calanna S, et al.. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine, 2021. doi:10.1056/NEJMoa2032183 · PMID 33567185 · NCT03548935 (accessed October 7, 2026) Randomized trial
  27. Drugs@FDA: Zepbound, NDA 217806. U.S. Food and Drug Administration. (accessed October 7, 2026) Government page
  28. Jastreboff AM, Aronne LJ, Ahmad NN, et al.. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine, 2022. doi:10.1056/NEJMoa2206038 · PMID 35658024 · NCT04184622 (accessed October 7, 2026) Randomized trial
  29. FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight. U.S. Food and Drug Administration, 2024. (accessed October 7, 2026) Government page
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Facts checked on October 6, 2026

Educational information, not medical advice. Talk with a qualified healthcare professional about your own situation. In an emergency call 911.

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