Multiple news outlets referred to this “limit.” For healthy adults, the number is 400 milligrams per day, and it comes from sources like the Food and Drug Administration and the International Food Information Council. Four hundred milligrams amounts to around four cups of coffee in the old-style sense of the phrase, an eight-ounce mug in a diner. It’s more like one Starbucks venti.

When it comes to caffeine, a drug that’s part of the everyday lives of 90 percent of Americans and a source of great joy—sometimes the actual best part of waking up—that limit can seem less like an admonition than a challenge. Black Insomnia claims to have 702 milligrams of caffeine in a 12-ounce cup. That’s around five times as much as a home-brew, and three times as much as Starbucks’s dark roast. And no serious coffee drinker would stop at 12 ounces. Fill two venti cups with Black Insomnia and you’re at 2,340 milligrams, or about six times the “limit.”

With options like this before us, where does the 400 milligram limit come from, and how seriously should it be taken?

Esther Myers says seriously. She is a specialist in systematic research reviews, and over the past year she and colleagues at the International Life Sciences Institute have been working on the most exhaustive review of evidence on the safety of caffeine to date. This week the team is presenting the findings in Chicago at a conference called Experimental Biology.

Myers explained that the oft-cited 400-milligram limit has been out of date for a while. It came from the last research review, which was done in 2003 by Health Canada. Her colleagues were surprised to learn it had been that long, and that even at the time the review wasn’t really comprehensive. So they did a systematic review, meaning they followed a comprehensive, transparent protocol defined by the Institute of Medicine.

The team scoured more than 700 studies on the safety of caffeine at various levels and noted whether adverse health effects occurred above, below, or at 400 milligrams. Those health effects ranged spanned cardiovascular, musculoskeletal, reproductive, and behavioral domains. And it seems that for healthy adults, 400 milligrams is indeed a safe daily limit. For pregnant women, it’s safer to use 300 milligrams or less.

Above those levels the team found evidence of links to everything from depression and dysphoria (general unhappiness) to anxiety to hypertension to higher proportions of sperm with DNA damage.

So does that mean that 500 milligrams a day is definitely unsafe?

“No,” said Myers. “There’s a great deal of inter-individual variability in how people respond to caffeine. That’s one of the research gaps. We need to better identify differences and identify people who are more sensitive.”

The most important finding of this research was, apparently, how little we know for certain about this drug that’s all around us. Myers’s team highlights a particular need for a better understanding of how caffeine affects less-than-healthy adults. There is also much more to be determined about how the health effects of caffeine vary depending on how, when, and with what frequency it’s consumed. No matter how much we learn about caffeine, even as one of our most studied and consumed drugs, there will always be more questions.