An investigation into the botched French clinical trial that left one person dead and put five in the hospital has found evidence of brain damage in subjects who took high doses of the experimental pain and mood disorder medication known as BIA 10-2474, according to a report released early March.
Conducted by the Portuguese pharmaceutical company Biotrial in France, the early-stage study was halted in January when the side effects surfaced. The clinical trial was the first time the drug had been tested in humans.
Investigators found that people who got high cumulative doses of the drug sustained damage to their brains, specifically the hippocampus and pons, NPR reports. In contrast, subjects who got lower doses had no consistent adverse reactions. The report stressed that the patients’ symptoms and injuries were “completely unusual, with no relatedness to a known disease or toxicity.” They underlined “the astonishing and unprecedented nature” of the accident that caused a reaction in the brain “unlike anything seen before,” according to the Guardian.
Past experiments in rats, mice, dogs and monkeys involved doses up to 650 times those given to human subjects. While some animals suffered brain damage or died when given extremely high doses, there were no consistent signs indicating the drug would be unsafe for humans.
BIA 10-2474 is part of a family of FAAH-enzyme inhibitors that can have an impact on pain and anxiety by boosting the endocannabinoid system involved in appetite control, pain sensation, mood and memory. In the small French study, 90 people took the experimental drug at different doses. The six who were hospitalized, including the one participant who died, had received the highest dose, which was 10 to 40 times higher than the dose needed for the drug to be effective.
At those high doses, the investigators believe the molecule may have suppressed the target enzyme too much, preventing it from breaking down other chemicals. This consequence may have allowed a chemical like anandamide, which is present in chocolate in tiny amounts, to build up to dangerous concentrations in the brain. Another idea is that the molecule produced toxic byproducts in the brain. The investigators ruled out any manufacturing problem, saying there was no shared genetic weakness among the victims.
“We don’t know by what mechanism the molecule caused these lesions, and I fear we won’t know it for a long time since they couldn’t have been due to the endocannabinoid system that was targeted by the molecule,” Dr. Bernard Begaud, who leads the scientific committee investigating the incident, told the French publication Sciences et Avenir.
Also investigating the case is the Food and Drug Administration, which said that while there have been studies on the potential benefits of FAAH inhibitors on a number of neurological disorders, the results of this trial marks the first time a person has died from exposure to FAAH inhibitors.