Like other medication classes, anti-obesity medications (AOMs) have seen their fair share of pharmacotherapy withdrawal from the market. Reasons range from concerns about addiction potential to serious safety issues and adverse health outcomes. Although no longer prescribable, discontinued medications are fair game for the ABOM exam, as many of our patients may have tried these. In this blog, we will take a walk down memory lane to some of the more notorious medication withdrawals and things you should know.

Taking a thorough history is an important part of comprehensive obesity management. In determining what patients have trialed in the past for weight loss, it is not uncommon to hear of patients who have been prescribed phentermine/fenfluramine (Fen-Phen), with some having significant success with this combination. In contrast, other patients may be surprised that you are discussing phentermine as a potential option, given their knowledge of Fen-Phen causing heart valve defects. In either scenario, being comfortable with the history of this medication will allow you to provide education and reassurance regarding safety concerns and efficacy more confidently, and barring contraindications, some of these patients may do very well on phentermine therapy.

Let’s look at the backstory on this combination medication. Phentermine was approved in 1959, with fenfluramine gaining approval in 1973. Both were independently marketed and approved for weight loss. However, it wasn’t until the early 1990’s when these medications started being prescribed in combination given their potential synergistic effects, coining the term fen-phen. This pairing was never an FDA-approved single combination medication, but instead each component was separately prescribed in combination and, thus, considered off-label.

Fenfluramine acts as a nonspecific agonist of 5HT-2 receptors, promoting satiety by enhancing serotonergic action within the hypothalamus. Unfortunately, fenfluramine and its active metabolite, norfenfluramine, also stimulate 5-HT2B serotonin receptors located on cardiac valves. This receptor activation was linked to valvular heart disease and was also associated with pulmonary arterial hypertension. Due to these serious safety concerns, the FDA withdrew fenfluramine from the market in 1997. Importantly, the valvular heart disease associated with Fen-Phen was attributed to the fenfluramine component rather than phentermine, which has never been withdrawn from the market. Interestingly, despite these potential significant adverse effects, fenfluramine gained FDA-approval in 2020, under the brand name Fintepla®, for severe, life-threatening refractory seizures disorders, as benefits of this medication outweighed the risks in this particular scenario.

This brings us to lorcaserin (Belviq®). This 5-HT2C selective receptor agonist, found on first-order neurons on the POMC/CART pathway, was thought to be the alternative to fenfluramine, having the beneficial serotonin weight benefits, but not affecting the 5-HT2B receptors associated with valvular disease. However, lorcaserin was removed from the market in 2020 after the FDA determined that a long-term cardiovascular outcomes trial showed a slightly higher incidence of cancer in the treatment group compared with placebo. The mechanism for this is unknown and the signal was observed across multiple cancer types rather than a single specific malignancy.

A few other notable pharmacologic treatments for weight loss that were withdrawn include:

  • Dinitrophenol (DNP): Introduced in 1932, DNP was one of the earliest pharmacologic treatments for obesity (aside from thyroid hormone preparations). It uncoupled oxidative phosphorylation, causing energy to be released as heat and dramatically increasing metabolic rate. Although it produced rapid weight loss, it was associated with severe toxicity, including fatal hyperthermia, and was removed from the market in 1938.
  • Amphetamine: Similar in structure to methamphetamine, amphetamine produced rapid weight loss but also unsurprisingly carried a significant risk of abuse and addiction. Although widely used for obesity treatment beginning in the 1940s, safety concerns and dependence potential led to its fall out of favor by the 1970s.
  • Sibutramine: This medication was withdrawn from the U.S. market in 2010 after the SCOUT trial demonstrated an increased risk of nonfatal myocardial infarction and stroke in patients with preexisting cardiovascular disease. Interestingly, sibutramine has continued to be identified in some over-the-counter weight-loss supplements and counterfeit products, despite its withdrawal due to safety concerns.
  • Ma Huang (Ephedra): Ephedra promoted weight loss through its sympathomimetic effects, increasing the release of norepinephrine and stimulating adrenergic receptors, which increased energy expenditure and suppressed appetite. However, it was associated with serious cardiovascular adverse events, including hypertension, arrhythmias, heart attacks, and strokes, prompting the FDA to ban dietary supplements containing ephedra in 2004.
  • Rimonabant: Rimonabant was a cannabinoid-1 (CB1) receptor antagonist that promoted weight loss by reducing appetite and food reward signaling within the central nervous system. Although it demonstrated meaningful weight-loss efficacy, it was associated with increased rates of depression, anxiety, and suicidal ideation. Due to these psychiatric safety concerns, it was withdrawn from the European market in 2008 and was never approved by the FDA in the United States.

Lastly, after the manufacturer of cellulose and citric acid hydrogel (Plenity®) filed for bankruptcy in 2023, it has since returned to the market and, as of 2026, is available without a prescription. Unlike the other medications discussed in this blog, Plenity® was not withdrawn because of safety concerns, but rather financial struggles during a period when highly effective GLP-1 receptor agonist-based therapies were competing for the same patient population.

An important portion of obesity management involves patient education and addressing concerns that may stem from prior experiences or misconceptions about treatment. Understanding the safety issues associated with historical weight-loss medications, including previously withdrawn therapies that some patients may have used, can help provide valuable context. By bridging these past experiences with the evidence-based treatments available today, we can help patients feel more informed and comfortable with treatment decisions, particularly those who may be hesitant to pursue obesity therapy.

Sample Question

A patient is discussing a prior weight-loss medication with her obesity medicine specialist that she was previously prescribed within the past 10 years. She recalls achieving moderate weight loss but remembers having to discontinue one of her antidepressant medications because of concerns about serotonin syndrome while taking the obesity medication. She also remembers that the medication was later withdrawn from the market. Which of the following was the primary reason for its withdrawal?

A. Valvular heart disease
B. Cancer signal
C. Pulmonary hypertension
D. Hyperthermia and heat-related toxicity
E. Increased suicidal ideation

Next Week: Endoscopic Therapy Guidelines and Procedures

Upcoming: Motivational Interview Question Walk Through and Knowledge Check

For more practice questions, check out the following:

  • Obesity Medicine Board Review Questions (2026): Qs 238 and 247.
  • Obesity Medicine Practice Tests (2026): Qs 287 and 448.

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