BIA 10-2474

This is hands down the most important cautionary tale in the whole FAAH space; BIA 10-2474 is essentially the textbook example of what happens when a molecule is dirty off-target. It is included here because understanding it makes you smarter about every other endocannabinoid drug; the selective FAAH inhibitors that came before it were pretty much clean in people, and this one clearly was not. To be blunt, nobody takes this; it is not a research chemical you dose, it is a study you read. The value here is the lesson; promiscuous lipase inhibition inside the brain is exactly the thing you never want, and this compound proved it the hard way in a Phase 1 trial that ended in tragedy. Read it, respect it, and let it sharpen how you think about selectivity.

Not safe; this is a withdrawn investigational compound with a fatal human record. In the January 2016 Bial Phase 1 trial run at Biotrial in Rennes, single ascending doses and lower repeated doses were tolerated in 84 volunteers, but in the 50 mg/day repeated-dose cohort an acute, rapidly progressive neurologic syndrome developed from about the fifth day: headache, cerebellar signs, memory impairment, and altered consciousness, with symmetric MRI lesions, microhemorrhages, and hyperintensities predominantly in the pons and hippocampi.

One participant became brain-dead and died; others were hospitalized, and at least two had residual deficits (memory impairment; a cerebellar syndrome). Preclinical regulatory safety-pharmacology and toxicology studies in rats, dogs, mice, and non-human primates did not predict or explain the event. There is no established safe dose; this compound should be regarded as historical and dangerous, not as a usable research chemical.