01 February 2003
Lancet Neurology, Volume 2, Number 2
Tetrahydrocannabinol, the psychoactive constituent of cannabis, acts via CB1 cannabinoid receptors and has various effects, including a lowering of anxiety. Researchers have now developed drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. “Inhibitors of anandamide hydrolysis such as those identified in our study may provide an innovative mechanism to treat anxiety and depression, one that may offer advantages in terms of efficacy and/or side-effect profile over existing therapies”, comments senior author Daniele Piomelli (University of California, Irvine, CA, USA).
Piomelli and colleagues developed compounds that are potent, selective, and systemically active inhibitors of fatty acid amide hydrolase (FAAH), which degrades the endogenous cannabinoid ananamide. In rats, the inhibitors showed benzodiazepine-like properties in standard behavioural tests of anxiety. The behavioural effects were accompanied by increased brain concentrations of anandamide and were prevented by blocking the CB1 receptor with antagonists (Nat Med 2003: 9: 76–81).
Maurice Elphick (School of Biological Sciences, Queen Mary, University of London, UK) thinks that inhibitors of FAAH could be used in the future for treatment of human disorders such as chronic anxiety and pain. “However”, he says, “the selectivity of this approach may be dependent on endogenous production of endocannabinoids in relevant brain regions.” At the moment, he stresses that whether endocannabinoid synthesis is increased in human beings as a consequence of anxiety or pain is unknown. “Relevant to this study is the recent paper by Sipe and co-workers (Proc Natl Acad Sci USA 2002 99: 8394–99) reporting that humans with a mutated version of FAAH have an increased likelihood of street drug use and problem drug/alcohol use. This provides further important evidence that in humans, FAAH plays an important role in normal human brain function”, he adds.
“There is much basic research still to be done and, of course, our hypothesis
needs to be validated in phase II clinical studies”, warns Piomelli. Important
open questions include: What regions of the brain are involved in the anxiolytic
actions of the FAAH inhibitors? What additional neurotransmitter systems
might be engaged? And how are anxiolysis and analgesia connected? “Moreover,
from a translational perspective, we need to identify specific therapeutic
targets as well as clinical candidates for preclinical toxicology and,
eventually, human testing. Optimistically, this may happen within 2 years”,
© Copyright 2003, Lancet Neurology