Through much of the 2010s, one fish-oil study after another came up empty, Richard Bazinet, a nutrition researcher at the University of Toronto, told me—“null, null, null, null, null.” And then came REDUCE-IT, a trial funded by the pharmaceutical company Amarin to test its fish-oil-based heart drug, called Vascepa. The results, presented in 2018, found that, among high-risk adults already receiving another type of cholesterol-lowering treatment, the drug decreased the risk of heart failure and other serious cardiovascular events by an eye-popping 25 percent. Fish oil, it seemed, was back in business. When the study’s lead author, the Harvard cardiologist Deepak Bhatt, presented his findings at the American Heart Association’s annual meeting in Chicago, the crowd gave a standing ovation. The following year, the FDA approved the drug for the use studied in REDUCE-IT. (The agency had already approved the drug for a different use back in 2013.)

With triumph, though, came controversy. Even at the time of Bhatt’s presentation, some cardiologists noted that the study’s mineral-oil-based placebo—a pill selected because its color and consistency mimic those of fish oil, but whose use in fish-oil studies has been debated—seemed not to be entirely neutral. In fact, the placebo seemed to be harming people. Initially, nothing much came of these concerns. Then, last month, a new analysis published in the journal Circulation substantiated them and then some. It showed, based on elevated levels of several biomarkers in blood-test results, that the placebo may have increased volunteers’ risk of heart attack and stroke. Many researchers found these results to be compelling evidence that Vascepa’s eye-popping success could be due to a bad placebo, not a great drug.

“What’s somewhat shocking about that paper is that it looks like everything got worse in the placebo group and the treatment group stayed the same,” Bazinet told me. “You could have given the subjects a glass of water. Anything would have been better against that placebo.” Steven Nissen, a cardiologist at the Cleveland Clinic who was involved in a different omega-3 trial, called the Circulation study’s findings “extraordinarily disturbing.” Two members of the expert panel that in 2019 recommended that the FDA green-light Vascepa even told Stat’s Matthew Herper that, if they’d had access to the new data at the time, they might not have voted to approve.

To make matters more confusing, the Circulation study—as in, the very study that ignited this controversy—was also funded by Amarin, and one of the study’s 13 authors was Bhatt, the lead author on REDUCE-IT. In a statement, Amarin told me it “continues to stand by the results of REDUCE-IT” and is “very surprised” that the panel members would make such comments based on the Circulation paper. The company stressed that REDUCE-IT’s positive results “could not be explained” by the placebo, and that the effects found in the Circulation study were too minor to “correlate to any meaningful changes in outcomes.” Bhatt agreed, telling me he sees the new paper not as undermining REDUCE-IT but simply as clarifying Vascepa’s biological mechanisms. He defended the use of mineral oil as a placebo, arguing that it alone could not explain the significant risk reductions observed in the trial.

The lead author of the Circulation study, Paul Ridker, declined to comment on the controversial results. But other experts I spoke with were considerably less sanguine than Bhatt. Several would say only that, at this point, the REDUCE-IT results are basically uninterpretable. Nissen, who has in the past called REDUCE-IT “almost certainly a false-positive study,” went so far as to say that he thinks the benefits it found can be “entirely explained by the harms of the placebo” and that Amarin should have known not to use mineral oil. JoAnn Manson, the chief of preventive medicine at Brigham and Women’s Hospital in Boston and the leader of the largest-ever study of vitamin D and omega-3 pills in healthy adults, was more sympathetic to the idea that the Circulation study’s findings likely don’t account for the full 25 percent risk reduction. But she also raised the possibility that the Vascepa, if ineffective, could be dangerous: Some studies have shown that a high daily dosage of fish oil can heighten one’s risk of developing a type of irregular heartbeat. (Amarin called the suggestion that Vascepa could be ineffective and dangerous “a gross distortion of fact,” saying that “the findings of independent, thorough, and impartial scientific and statistical reviews” had determined that the drug’s benefits to the at-risk patients for whom it is designed more than make up for its risks.)

The upshot of all this is that an already murky situation has become a good deal murkier, and there’s no end to the murk in sight. Which is a shame because, in one sense at least, the stakes are higher now than they’ve been in some time: REDUCE-IT suggested that Vascepa could legitimately save lives. If it can’t, that’s more than a scientific scandal; it’s a real, human loss. “I’ve never seen anything like this,” Bazinet told me. “In a way, it’s not surprising. The field’s been controversial all the time, and now we probably have the biggest controversy.”

The only way out of this mess, experts said, is to run a whole new trial comparing Vascepa (or its generic equivalent, icosapent ethyl) with something everyone agrees is a true placebo—one that we can be confident doesn’t harm people. Manson is leading a team applying for NIH funding to run such a study. (She said that Amarin told her it was not open to a replication trial and that the company declined to fund three related studies. When I asked Amarin about this, the company told me it would not replicate REDUCE-IT, because the outcomes “read out robustly,” and that it does not publicly discuss research proposals from third parties.) The study would also investigate a pair of promising leads turned up by her own major study, an ongoing project that has found that although omega-3 did very little for the population as a whole, it might have considerable benefits for Black people and people who don’t eat much fish.