​Why Death in a French Clinical Trial Should Make 'Legal High' Users Think Twice

If we don't rapidly move toward marijuana legalization, a similar catastrophe could affect teens or young adults in the United States.
January 19, 2016, 6:00pm
Biotrial general director Francois Peaucelle speaks to the press on January 16, 2016 in Rennes, western France. LOIC VENANCE/AFP/Getty Images

The tragic death on Sunday of a previously healthy man in a French clinical trial might seem like it has little to do with recreational drug use in America. But in fact, a substance similar to the one that killed him and may have caused irreversible brain damage to three other study participants has been found in some so-called "legal highs" sold in the US.

This death—in a closely-monitored clinical setting—should serve as a warning, both to legal high users and to legislators. If we don't rapidly move toward marijuana legalization, a similar catastrophe could affect teens or young adults in the United States, many of whom have no idea that so-called legal highs carry far greater risk potential than the natural plant.

Researchers in France were reportedly studying a drug known as BIA 10-2474, which is manufactured by the Portuguese drug company Bial to treat pain. This was a " phase I" trial, so participants were the first people ever to ingest the substance following animal testing. Such research obviously carries significant risks, but it rarely causes death or lasting harm.

In this case, 108 people had previously received the drug without incident, starting last summer. But five of the unfortunate participants who got it early this year had brain bleeding and showed signs of dying brain tissue, which can cause all types of permanent handicaps—and death. A sixth man who has reportedly shown no symptoms is being kept for observation.

BIA 10-2474 is a type of drug known as an FAAH-inhibitor. That means it prevents the breakdown of the brain's natural marijuana-esque chemicals—the endocannabinoids—ideally keeping them in action longer and producing the calming pain relief people get from marijuana, but without any of the usual impairment.

But FAAH inhibitors are not at all similar to natural weed or even synthetic forms of it—both traditional cannabis and synthetic cannabinoids act directly on the brain's cannabinoid receptors. In contrast, these experimental drugs are indirect. That was supposed to make them safer, and indeed, other companies and institutions have tested them for a range of conditions including Tourette's Syndrome, anxiety, insomnia, pain, and cannabis addiction without incident.

"Without adequate information, it is impossible to advance any hypothesis about the cause of toxicity," Daniele Piomelli, a researcher at the University of California Irvine who has long studied the cannabinoid system, including FAAH inhibitors, told VICE.

"This said, several structurally different FAAH inhibitors have been previously tested for human safety in rigorous Phase 1 clinical trials," Piomelli said. "These include compounds from companies such as Sanofi, Pfizer, Merck, Johnson and Johnson, and others. All these compounds were shown to be safe in humans."

Because none of the other drugs caused problems, Piomelli thinks it's unlikely that there is something uniquely dangerous about the entire class of FAAH inhibitors. "It is more probable that this compound interacts with another, as yet unknown protein that is responsible for the observed toxicity," he suggested, a problem known as "off-target" interaction.

The disastrous outcome, however, demonstrates that at least one FAAH inhibitor is unsafe. And that makes the fact that researchers found an FAAH inhibitor—known as URB597—in "legal highs" sold as "herbal incense" or "potpourri" in Indiana between 2012 and 2013 rather worrying.

Kevin Shanks, a forensic toxicologist at AIT Laboratories in Indianapolis, Indiana, was one of the co-authors of the paper which made the discovery public. He and his colleagues found the substance, typically along with chemicals that directly activate cannabinoid receptors—presumably, as a way to make them more potent—in the following products: Darkness, Darkness Blueberry, Darkness Purple Haze, Funky Green Stuff (Reggie's Blend), and Kite.

"The only FAAH inhibitor that we have ever detected was URB597," he told VICE. "And we haven't seen it since 2013. Could it still be out there? Sure. But we haven't seen it in our casework."

Shanks says he also received an anonymous call around the time of the initial discovery, probably from someone in the legal high business, about another FAAH inhibitor. "I do know that other FAAH inhibitors were being thought about because I received a random phone call from a person inquiring about LY-2183240," he told me. While he does not offer advice to underground chemists, he checked into it later and found that it has "off-target" effects, which means that it might potentially cause similar problems to those seen in the clinical trial. And worse, he found a study showing that the substance had been detected in "legal highs" in Japan.

All of this highlights the fact that legal high users are basically doing their own "first in human" trials—with no knowledge of dose, purity, chemical content, potential side effects, and no medical monitoring. And since manufacturers sell some substances that have never even been tested in animals, at some point this kind of tragedy could happen stateside.

As Piomelli puts it: "'Legal highs' contain all sort of things—cannabinoid agonists [synthetic THC-like substances], FAAH inhibitors, anandamide transport inhibitors [drugs that affect how cannabinoids are moved in the brain], plus, of course many impurities. They are certainly far from being safe. A well characterized cannabis preparation would indeed be safer."

The sad truth behind these legal highs is that the majority of individuals who take them do so not because they prefer them, but for other reasons like avoiding positive drug tests. If weed were legalized and properly regulated, they wouldn't be forced to act as human guinea pigs, exposed to substances that might leave them severely disabled or even dead due to a vain attempt at keeping people from using a drug that is neither toxic nor fatal.

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