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Inhibitor of Fatty Acid Amide Hydrolase - Learning from Tragic Failures.

To the Editor: Kerbrat et al. (Nov. 3 issue)1 describe the central nervous system clinical signs and symptoms in healthy volunteers who received an investigational drug that inhibits fatty acid amide hydrolase (FAAH). Other causes for the illness were ruled out, so drug toxicity was assumed to be responsible for the tragic acute neurologic disorder. Drug accumulation due to prolonged exposure to increased dosages may have led to off-target effects. Would the authors agree that compound-related toxicity rather than mechanism-based toxicity played the main role in these events? One wonders whether preclinical toxicology studies in animals already showed drug-accumulation–related toxic effects. Moreover, it would be interesting to know what oral dose would have been sufficient to inhibit the FAAH to a clinically meaningful degree (e.g., >50% inhibition) in order to substantially increase intrinsic anandamide levels. Could one assume this would be the maximal dose used in a phase 1 trial? If not, why should higher doses be prescribed, as might have happened in this case? Ion Anghelescu, M.D.