Vaping THC may be behind many of the serious lung diseases that have been tied to e-cigarette use––raising concerns about an increasingly popular way of consuming marijuana, which many consumers view as a relatively safe habit.

Up to 450 people have developed illnesses and at least four people have died after using e-cigarettes, Centers for Disease Control and Prevention (CDC) officials said on a call with reporters Friday. While the CDC and Food and Drug Administration (FDA) have not found a device, product or substance that is linked to all cases, a paper published Friday in the New England Journal of Medicine suggests that many sick individuals vaped THC, a compound in marijuana, before developing an illness, either instead of or in addition to nicotine. CDC and public-health officials confirmed this finding.

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The investigation threatens to shatter many people’s perceptions of marijuana as safe and natural, an opinion that has gained steam as the drug is legalized in more and more states. A 2018 Gallup poll found that Americans largely view both marijuana and e-cigarettes as less harmful than cigarettes, and that more than 40% of respondents thought marijuana was “not too” or “not at all” harmful. But a growing number of illnesses apparently tied to vaping THC may change some users’ minds—and remove the health halo that often surrounds vaping.

The recent illnesses have surprised Ziva Cooper, research director of the University of California Los Angeles Cannabis Research Initiative. “If you had called me a month ago and asked me about the risks of vaporizing relative to smoking, I would have had a very different answer based on the literature thus far,” Cooper says. “This is an issue that deserves immediate attention.”

E-cigarettes work by heating substances—most often liquid nicotine, but also marijuana flowers or compounds suspended in oils—into aerosols that can be inhaled. Although it’s a source of debate, this process is thought to be healthier than traditional smoking, since burning substances such as tobacco or marijuana creates byproducts that can harm the lungs and overall health. Cooper says a handful of studies on vaping cannabis have suggested that using e-cigarettes is less harmful to the lungs than smoking marijuana.

Perhaps in part because of that belief, vaping marijuana has grown increasingly popular. In Colorado—the poster child of legal marijuana use—there was a 78% increase in the number of marijuana concentrates (a category that includes vape products) sold to consumers from 2017 to 2018, according to state Department of Revenue data. (Marijuana flowers still make up a larger share of the total market, the data shows––but the proportion is changing as concentrate sales rise.)

And it’s not just legal users who are vaping marijuana: About 13% of high school seniors said they had in a federal survey released in December 2018. And the CDC has specifically warned consumers against using “bootleg” vape pen cartridges.

By 2022, U.S. cannabis concentrates sales, driven by vaping products, are projected to hit $8.4 billion—only slightly less than sales of marijuana flowers, according to a report from marketing firm Arcview, which focuses on the cannabis industry.

It’s likely that the processing of THC, rather than the compound itself, is the cause of recent lung issues, says Jacob Borodovsky, an epidemiologist at Washington University School of Medicine in St. Louis who has studied vaping. To produce vape pen liquid, THC is suspended in an oil solution that often also includes chemicals to alter the flavor or consistency of the mixture, which users then heat and inhale. “If I had to bet money on whether or not THC is causing these lung-related issues, I wouldn’t put it on the THC compound itself,” Borodovsky says. “I would put it on the way in which the THC is prepared and delivered.”

Since the regulatory process for vape oils is “pure chaos right now,” it’s hard to know which chemicals have been added, and even if what’s on the label is accurate, he says. The FDA, for example, has issued multiple warnings to companies making inaccurate claims about the contents of products containing CBD, another compound in marijuana.

The FDA is now testing more than 100 product samples used by patients who developed lung diseases after vaping, in an effort to find out exactly what’s in them and what could be causing illnesses. New York state health officials on Thursday pointed to vitamin E acetate, an unauthorized additive in some marijuana vape pods, as a focus of their investigation. But on Friday, an FDA spokesman said, “No one substance, including Vitamin E acetate, has been identified in all of the samples tested” by the agency.

The spokesperson added: “Importantly, identifying any compounds that are present in the samples will be one piece of the puzzle but will not necessarily answer questions about causality.”

While the FDA attempts to stop cannabis products from making health claims, it does not regulate THC vaping products––in part because marijuana remains illegal under federal law. And though some states require companies to submit to random independent testing of their products, Borodovsky says, there’s little oversight before something goes to market—and even less for the “black and gray market companies” that have popped up as the industry has grown. “Just because it says lab-tested on the label, don’t believe that,” he says.

Products that contain less than 0.3% THC do not fall under Drug Enforcement Administration purview. And those that contain more are subject to a byzantine regulatory system that can prevent even scientists from studying their contents.

Since marijuana is classified as a Schedule I drug under federal law, the same category as heroin and LSD, researchers need special permission to work with it, and they’re limited to studying products that come from the only facility approved to grow marijuana for research: the University of Mississippi, which traditionally doesn’t produce things like vape oils and edibles. “We cannot study [some] products that are available to the public, which is a significant barrier to understanding the public-health implications,” Cooper, the UCLA cannabis researcher, says.

As the investigation into lung diseases continues, the CDC is advising consumers to “consider not using e-cigarettes,” and particularly avoid products that have been altered or purchased on the street.

Cooper agrees that people should be careful, and notes that plants may be a safer alternative to more processed products. “There’s enough concern for there to be a general statement that people should be very cautious about vaping,” she says. “It’s safer, if you’re going to vape, to go with plant product with a known device.”