Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects predictive of addictive potential. In collaboration with Dr. Alex Makriyannis, we have developed and patented a novel FAAH inhibitor, AM3506, and are currently characterizing its pharmacological/therapeutic profile. Last year we reported that AM3506 normalizes the elevated blood pressure and inappropriately increased cardiac contractility of both anesthetized and conscious spontaneously hypertensive rats (SHR) via a centrally mediated reduction in sympathetic tone, without affecting these parameters in normotensive animals. Additionally, AM3506 does not induce metabolic side effects including hyperglycemia/glucose intolerance, which are seen with other FAAH inhibitors, such as URB597, or in FAAH-/- mice, and are due to inhibition of FAH in the liver and the consequent increase in hepatic anndamide levels that result in activation of hepatic CB1 receptors. The unique lack of such side effects with AM3506 is due to its very rapid metablism by the liver, resulting in ts inabiliity to block FAAH in the liver. This unique pharmacologic profile suggests that AM3506 may have theraputic potential in hypertension. These results have been published in Chemistry &Biology. Endocannabinoids acting via CB1 receptors in the amygdala have been implicated in the extinction of aversive memories (Nature 418:530, 2002), a process that plays a central role in post-traumatic stress syndrome (PTSD). Because AM3506 causes marked elevation of anandamide levels in the brain, Dr. Andrew Holmes group, in collaboration with our lab, tested the effects of AM3506 in a mouse model of fear extinction. Systemic or intra-amygdala administration of AM3506 facilitated fear extinction, and this effect was reversed by CB1 antagonist treatment. AM3506 treatment increased anandamide levels in the basolateral amygdala, and modified the expression of extinction-related kinases and phosphatases. In human subjects, individuals carrying a low-expressing FAAH variant showed quicker habituation in a fear-related fMRI task as well as lower stress reactivity in a personality test. These results raise the possible therapeutic use of AM3506 in PTSD. These findings have been submitted for publication with Dr. Holmes as corresponding author. Endocannabinoids and CB1 receptors have also been implicated in the control of pain responses as analgesic mediators. In collaboration with Dr. Yun Guan (Johns Hopkins Univ) we examined the analgesic properties of AM3506 in a rat model of neuropathic pain. Preliminary findings indicate that AM3506 treatment causes significant, CB1 receptor-mediated reduction in mechanical allodynia, but does not affect thermal hypersensitivity. These findings highlight the selectivity of anandamide action on different modalities of neuropathic pain.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Alcohol Abuse and Alcoholism
Zip Code
Pacher, Pal; Steffens, Sabine; Haskó, György et al. (2018) Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 15:151-166
Valenta, Ines; Varga, Zoltan V; Valentine, Heather et al. (2018) Feasibility Evaluation of Myocardial Cannabinoid Type 1 Receptor Imaging in Obesity: A Translational Approach. JACC Cardiovasc Imaging 11:320-332
Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma et al. (2016) Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. Neuropsychopharmacology 41:1598-609
Gaskari, Seyed Ali; Liu, Hongqun; D'Mello, Charlotte et al. (2015) Blunted cardiac response to hemorrhage in cirrhotic rats is mediated by local macrophage-released endocannabinoids. J Hepatol 62:1272-7
Kunos, George; Volkow, Nora D (2013) Preface to the special issue of psychopharmacology: 10ýýyears of the Jacob P. Waletzky Award. Psychopharmacology (Berl) 229:383-4
DePoy, Lauren; Daut, Rachel; Brigman, Jonathan L et al. (2013) Chronic alcohol produces neuroadaptations to prime dorsal striatal learning. Proc Natl Acad Sci U S A 110:14783-8
Gunduz-Cinar, O; MacPherson, K P; Cinar, R et al. (2013) Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18:813-23
Bashashati, M; Storr, M A; Nikas, S P et al. (2012) Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. Br J Pharmacol 165:1556-71
Engeli, Stefan; Bluher, Matthias; Jumpertz, Reiner et al. (2012) Circulating anandamide and blood pressure in patients with obstructive sleep apnea. J Hypertens 30:2345-51
Heilig, Markus; Warren, Kenneth R; Kunos, George et al. (2011) Addiction research centres and the nurturing of creativity: the National Institute on Alcohol Abuse and Alcoholism. Addiction 106:1052-60

Showing the most recent 10 out of 18 publications