Targeting FAAH has been suggested to treat pain, inflammatory gastrointestinal diseases and cognitive disorders as depression or anxiety (Ghosh et al., 2015; Gunduz-Cinar, Hill, McEwen, & Holmes, 2013; Panlilio, Justinova, & Goldberg, 2013; Sałaga, Sobczak, & Fichna, 2014; Ulugöl, 2014)
Mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with anorexia and bulimia (Monteleone et al., 2009).
The endocannabinoid synthesizing enzyme NAPE-PLD was upregulated and the endocannabinoid degrading enzyme FAAH was downregulated in autistic children (Siniscalco et al., 2014), suggesting raised levels of endocannabinoids. Treatment with GcMAF normalized NAPE-PLD and FAAH levels and reduced macrophage activation (Siniscalco et al., 2014) further underlining the involvement of the endocannabinoid system in Autism.
Mutations in CB1 (the major cannabinoid receptor) and FAAH (the major endocannabinoid degrading enzyme) were found to be associated with Anorexia and bulimia (Monteleone et al., 2009).
Functional Gastro-Intestinal Disorders
In humans, a Single Nucleotide Polymorphism (SNP) in Fatty Acid Amide Hydrolase (FAAH), C385A or rs324420 is associated with increased risk of Functional Gastro-Intestinal Disorders in general (P=0.01) and more specifically with diarrhea-type Irritable Bowel Syndrome (IBS)(P=0.008) and mixed-type IBS (P=0.01). As this mutation reduces functional expression of FAAH and FAAH is the major degrading enzyme for Anandamide this suggests the involvement of the endocannabinoid system in gastro-intestinal function (Camilleri et al., 2008). In mice, selective inhibition of FAAH inhibited colonic motility (Fichna et al., 2014)
In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic cannabinoid but also displaying endocannabinoidactivity), which in turn blocks re-uptake of Anandamide (Mallet et al., 2008).
In human patients, high CB1 expression in pancreatic cancer cells was associated with reduced survival. Similarly, low levels of endocannabinoid-degrading enzyme FAAH and MAGL were associated with reduced survival. Interestingly, Anandamide and 2AG levels were unchanged in pancreatic cancer. Finally, contrary to CB1 expression in cancer cells, low CB1 in nervous tissue was associated with increased cancer pain, but also increased survival (Michalski et al., 2008). The mechanistic value of these correlations remains to be elucidated
psychosis and Schizophrenia
DAGL and NAPE are downregulated while MAGL and FAAH are upregulated in subjects who had a first episode of psychosis (Bioque et al., 2013).
Bioque, M., García-Bueno, B., Macdowell, K. S., Meseguer, A., Saiz, P. A., Parellada, M., … FLAMM-PEPs study—Centro de Investigacio´n Biome´dica en Red de Salud Mental. (2013). Peripheral endocannabinoid system dysregulation in first-episode Psychosis. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38(13), 2568-2577. https://doi.org/10.1038/npp.2013.165
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Fichna, J., Sałaga, M., Stuart, J., Saur, D., Sobczak, M., Zatorski, H., Timmermans, J.-P., Bradshaw, H.B., Ahn, K., and Storr, M.A. (2014). Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 470–481.
Ghosh, S., Kinsey, S. G., Liu, Q.-S., Hruba, L., McMahon, L. R., Grim, T. W., … Lichtman, A. H. (2015). Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. The Journal of Pharmacology and Experimental Therapeutics, 354(2), 111-120. https://doi.org/10.1124/jpet.115.222851
Gunduz-Cinar, O., Hill, M. N., McEwen, B. S., & Holmes, A. (2013). Amygdala FAAH and Anandamide: mediating protection and recovery from stress. Trends in pharmacological sciences, 34(11), 637-644. https://doi.org/10.1016/j.tips.2013.08.008
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Monteleone, P., Bifulco, M., Di Filippo, C., Gazzerro, P., Canestrelli, B., Monteleone, F., Proto, M.C., Di Genio, M., Grimaldi, C., and Maj, M. (2009). Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects. Genes Brain Behav. 8, 728–732.
Panlilio, L. V., Justinova, Z., & Goldberg, S. R. (2013). Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug Addiction. Pharmacology & therapeutics, 138(1), 84-102. https://doi.org/10.1016/j.pharmthera.2013.01.003
Sałaga, M., Sobczak, M., & Fichna, J. (2014). Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 52, 173-179. https://doi.org/10.1016/j.ejps.2013.11.012
Siniscalco, D., Bradstreet, J.J., Cirillo, A., and Antonucci, N. (2014). The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of Autism-derived macrophages. J. Neuroinflammation 11, 78.
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