Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function

Biol Psychiatry. 2009 Jul 1;66(1):9-16. doi: 10.1016/j.biopsych.2008.10.047. Epub 2008 Dec 21.


Background: Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity.

Methods: Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function.

Results: Carriers of FAAH 385A, associated with reduced enzyme and possibly increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison with C385 homozygotes. Similarly divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. The 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity.

Conclusions: Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Delta(9)-tetrahydrocannabinol, and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amidohydrolases / genetics*
  • Analysis of Variance
  • Anxiety / genetics*
  • Brain / anatomy & histology
  • Brain / blood supply
  • Brain / physiology*
  • Brain Mapping
  • Cannabinoid Receptor Modulators / genetics
  • Endocannabinoids
  • Female
  • Genetic Variation / genetics*
  • Genotype
  • Humans
  • Image Processing, Computer-Assisted / methods
  • Magnetic Resonance Imaging / methods
  • Male
  • Middle Aged
  • Oxygen / blood
  • Psychiatric Status Rating Scales
  • Regression Analysis
  • Reward*
  • Signal Transduction* / genetics


  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Oxygen