Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Fatty Acid Amide Hydrolase

  • Filomena Fezza
  • Monica Bari
  • Domenico Fazio
  • Mauro Maccarrone
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101566


Historical Background

A membrane-associated enzyme activity from rat liver that hydrolyzes N-acylethanolamine (NAE) species containing unsaturated and monounsaturated acyl chains was first described in 1985 by Schmid and colleagues (1985). Subsequently, an enzyme activity with similar properties that breaks the sleep-inducing substance cis-9-octadecenamide (oleamide) was reported and suggested to represent a general mechanism for terminating NAEs signaling in vivo. Nonetheless, the actual enzymes involved in NAEs metabolism remained unknown until the late 1990s, when Cravatt and colleagues purified this amidohydrolase activity from rat liver membranes (Cravatt et al. 1996). This enzyme, named fatty acid amide hydrolase (FAAH; E.C., was shown to be specifically inhibitable (Deutsch et al. 1997), was recombinantly expressed, and was found to hydrolyze several endogenous NAEs, including the neuromodulator/neurotransmitter N-arachidonoylethanolamine (anandamide, AEA), the anti-inflammatory compound N-palmitoylethanolamine (PEA), and the appetite-suppressing agent N-oleoylethanolamine (OEA). To date, FAAH has emerged as a key component of the “endocannabinoid system,” a complex ensemble of lipid signals (like AEA, PEA, and OEA), their metabolic enzymes, transporters, and receptor targets that impact on several human health and disease conditions (Maccarrone et al. 2015).

It should be noted that AEA was the first “endocannabinoid” (i.e., endogenous agonist of cannabinoid receptors) to be isolated in 1992 and found to share binding properties with the psychoactive ingredient of the cannabis (Cannabis sativa) plant, Δ9-tetrahydrocannabinol. Both endocannabinoids and other NAE-related substances are the subject of growing interest in pharmacology for their multiple therapeutic applications. Unfortunately, their rapid inactivation prevents as yet an effective medical use; thus, inhibitors of their degradation are urgently needed. In this context, accumulated evidence indicates that genetic or pharmacological blockade of FAAH produces analgesic, anxiolytic, and anti-inflammatory phenotypes, clearly pointing to this enzyme as a promising therapeutic target (Maccarrone et al. 2015).

FAAH Properties: Gene, Structure, and Selectivity

FAAH is an integral membrane protein (Fig. 1) of 579 amino acids and is encoded by a gene that has been mapped in chromosomes 1, 4, and 5 of human, mouse, and rat, respectively.
Fatty Acid Amide Hydrolase, Fig. 1

Three-dimensional structure of rat FAAH modeled into a lipid bilayer. The enzyme is a homodimer of 63-kD subunits

Faah gene has been cloned from rat, mouse, and human sources, showing sequence homology between 82% and 91% (Fig. 2).
Fatty Acid Amide Hydrolase, Fig. 2

Comparison of amino acid sequences from human (black), mouse (red), and rat (green) Faah genes (homologies are highlighted in yellow). Mouse and rat Faah genes share 91% amino acid identity, whereas human Faah gene shares 82% and 84% identity with rat and mouse Faah genes, respectively

Remarkably, multiple transcription sites have been identified in the Faah promoter, suggesting a species-specific regulation (Table 1).
Fatty Acid Amide Hydrolase, Table 1

Faah gene regulatory elements



Response element (consensus sequence)






↑ FAAH expression in primary Sertoli cell




Ikaros-binding site (TGGGAA/T)

↑ FAAH expression in T lymphocytes



CRE-like site (TGACGTA)

↑ FAAH expression in T lymphocytes

Among them, estrogen response elements (EREs) have been identified in mouse, where they allow regulation of FAAH expression by estrogen. Of note, histone demethylase LSD1 has been shown to modulate such a regulation through an epigenetic mechanism, pointing to FAAH as the first molecular target of estrogen as yet identified (Grimaldi et al. 2012). Instead, human FAAH is regulated by progesterone and leptin that activate Ikaros and cAMP response element (CRE)-like sites, respectively (Grimaldi et al. 2012, and references therein).

FAAH serves as the major metabolic regulator of many bioactive lipids (Fig. 3) and its distribution is consistent with a key role in terminating NAEs signaling at their sites of action.
Fatty Acid Amide Hydrolase, Fig. 3

Chemical structures of prominent NAEs

FAAH has an optimal alkaline pH (around 9) and is bound to intracellular membranes (Fezza et al. 2008). The X-ray crystal structure of rat FAAH (rFAAH) in complex with the irreversible inhibitor methoxy arachidonyl fluorophosphonate (MAFP, shown in Fig. 4) has been resolved, by using a catalytically active mutant (ΔTM-rFAAH) where the first 29 amino acids were deleted. Such a mutant crystallized as a homodimer with a globular shape and retained the ability to bind membranes (Bracey et al. 2002).
Fatty Acid Amide Hydrolase, Fig. 4

Chemical structures of representative FAAH inhibitors

The crystal structures of ΔTM-rFAAH also revealed that this enzyme possesses different channels to access both the membrane and cytoplasmic compartments of the cell, possibly to facilitate substrate binding, product release, and catalytic turnover (Blankman and Cravatt 2013). Later on, ΔTM-rFAAH was further engineered by replacing its active site residues with a “human-like” catalytic pocket, thus generating a human/rat chimera (h/rFAAH) that exhibits the same inhibitor profile as authentic hFAAH, valuable to guide innovative drug design efforts (Mileni et al. 2008). More recently, small-angle X-ray scattering analysis of ΔTM-rFAAH in solution, along with molecular dynamics simulations, has demonstrated that FAAH activity is regulated by the surrounding lipid environment, most notably by membrane cholesterol that aids AEA entrance into the active site of the enzyme (Dainese et al. 2014).

Although FAAH is a member of the “amidase signature” family of serine hydrolases, it is the only well-characterized mammalian enzyme containing the unusual serine–serine–lysine (Ser241-Ser217-Lys142) catalytic triad, in contrast to the serine–histidine–aspartate triad typical of most serine hydrolases. In particular, experimental and computational studies indicate that Lys142 acts as a key base and acid in distinct steps of the catalytic process. In the early phase of the catalysis, neutral Lys142 activates Ser241 nucleophile for attack on the substrate carbonyl, an event that leads to the formation of a tetrahedral intermediate (Fezza et al. 2008).

FAAH acts on a wide range of NAEs, yet it preferentially hydrolyzes arachidonoyl and oleoyl substrates (arachidonoyl threefold better than oleoyl). Additionally, primary amides are hydrolyzed twofold faster than ethanolamides. Extensive structure activity relationship (SAR) studies carried out with AEA and NAE-related compounds, along with the use of various structurally different inhibitors, have suggested that both the alkyl chain and the “polar head” of the substrate are important for the interaction with the active site. In particular, 20 carbon ethanolamide substrates are hydrolyzed more slowly when the number of double bonds decreases. Instead, introduction of a methyl group in the ethanolamine portion of AEA (e.g., in methanandamide) yields a substrate that is no longer hydrolyzed by FAAH, thus being useful in many experimental setup (Blankman and Cravatt 2013).

In addition, FAAH shows a high esterase activity toward the substrate 2-arachidonoylglycerol (2-AG), another major endocannabinoid. Yet, mice lacking Faah gene (Faah −/− ) still hydrolyze 2-AG, but not AEA or OEA, suggesting that FAAH is not the key 2-AG metabolic enzyme. At any rate, the unusual enzymatic profile of FAAH, a serine hydrolase that cleaves both amide and ester substrates, seems to warrant a correct regulation of endocannabinoid tone in vivo, where lipid esters are far more abundant than lipid amides (Blankman and Cravatt 2013).


The spectrum of FAAH inhibitors comprises structurally different, potent, and selective compounds that have prompted investigations into the metabolic and physiologic effects of augmented NAE signaling (Fowler 2015). In particular, the opportunity to selectively increase the tone of endocannabinoids and NAE-related substances only in those tissues where such an enhancement can be beneficial could lead to therapeutic benefits with limited (if any) detrimental effects, compared to direct pharmacological activation of receptor targets. Indeed, FAAH inactivation allows significant elevation in AEA, PEA, and OEA levels, producing analgesic and anti-inflammatory effects without cognitive alterations typically associated to stimulation of AEA-binding type 1 cannabinoid receptors (Blankman and Cravatt 2013).

To date, selective and in vivo active FAAH inhibitors have been described and reported in the patent literature, based on extensive SAR studies. The main classes of patented FAAH inhibitors are reported in Table 2, along with their therapeutic applications, effective doses, and administration routes. It should be stressed that selectivity of FAAH inhibitors has always to be ascertained compared to other elements of the endocannabinoid system (i.e., enzymes, transporters and receptors), as well as to unrelated serine hydrolases, in order to rule out relevant off-targets of these compounds and subsequent unwanted side effects of their administration (Bisogno and Maccarrone 2013).
Fatty Acid Amide Hydrolase, Table 2

Main classes of patented FAAH inhibitors


IC50 value

Use, dose, and route



Oxazolyl-ketones [replacement of the phenylhexyl group of OL-135 with a piperidine ring] Open image in new window

2 nM toward human FAAH

Reduces anxiety, pain, sleep disorders, eating disorders, inflammation, and movement disorders (e.g., multiple sclerosis). From about 0.05 to about 50 mg/kg daily by intravenous infusion; from about 0.05 to about 20 mg/kg daily by topical administration; from about 0.1 to about 10 mg/kg daily by oral administration

Janssen Pharmaceutica N.V. Oxazolyl piperidine modulators of fatty acid amide hydrolase. US 20100292266; 2010

Carbamate inhibitors

URB937 Open image in new window

27 nM toward peripheral FAAH

Inhibits peripheral FAAH; increases peripheral AEA levels; attenuates behavioral responses, indicative of persistent pain of inflammation and peripheral nerve injury; and does not inhibit FAAH activity in the central nervous system. From about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg by oral, nasal, pulmonary. or transdermal administration

The Regents of the University of California, Università degli Studi di Urbino “Carlo Bo,” Università degli Studi di Parma. Peripherally restricted FAAH inhibitors. WO2012015704; 2012

ARN2508 Open image in new window

31 nM toward rat FAAH 12 nM toward rat COX-1430 nM toward rat COX-2

Reduces intestinal inflammation, where a pure FAAH inhibitor was weakly active and the COX inhibitor flurbiprofen even aggravated inflammation. Simultaneous blockade of FAAH and COX-1/COX-2 results in a combination of profound anti-inflammatory and tissue-protective actions

Fondazione Istituto Italiano di Tecnologia, the Regents of the University of California; Alma Mater Studiorum—Università di Bologna. Multitarget FAAH and COX inhibitors and therapeutically uses thereof. WO2014023643; 2014

Aryl ureas

JNJ-42119779 Open image in new window

nM ranges toward human and rat FAAH

Is effective in the spinal nerve ligation (Chung) model of neuropathic pain. 20 and 60 mg/kg per os

Janssen Pharmaceutica N.V. Heteroaryl-substituted spirocyclic diamine urea modulators of fatty acid amide hydrolase. WO2010141817; 2010

Azole derivatives

2-(4-(1H-imidazol-4-yl)phenyl)cyclopropanecarboxamide derivatives Open image in new window

1.0 nM toward human FAAH 5.5 nM toward rhesus monkey

Shows rapid and significant brain penetration in rats. A radiolabeled derivative of this compound was synthetized and investigated as potential 11C PET tracer. The resulting compound, MK-3168, exhibits good brain uptake and FAAH-specific signal in PET studies on rhesus monkey. MK-3168 was also proposed as a good PET tracer for imaging FAAH in the human brain, suitable for clinical applications. 2 mg/kg per os

Merck Sharp & Dohme Corp. Imidazole derivatives useful as modulators and imaging agents of FAAH. WO2010101724; 2010


JNJ-40413269 Open image in new window

5.3 nM toward human FAAH

Shows excellent pharmacokinetic properties and is effective in the rat spinal nerve ligation (Chung) model of neuropathic pain. 10–100 mg/kg by oral administration

Janssen Pharmaceutica N.V. Arylhydroxyethylamino-pyrimidines and triazines as modulators of fatty acid amide hydrolase. WO2009105220; 2009

Tetrahydronaphthyridine derivatives

1,2,3,4-tetrahydro-2,6-naphthyridines Open image in new window

<100 nM toward human FAAH

Reduces pain, anxiety, depression, inflammation, cognitive disorders, weight and eating disorders, Parkinson’s disease, Alzheimer’s disease, spasticity, addiction, glaucoma, and other diseases. 0.1–10 mg/kg/h by injection for from about 1 to about 120 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered. The maximum total dose is about 2 g/day for a 40–80 kg human patient

Renovis Inc. Compounds useful as FAAH modulators and uses thereof. WO2009011904; 2009

Miscellaneous classes

N-alkyl-4-oxazolecarboxamide derivatives Open image in new window

From 20 to 180 nM toward rat brain FAAH

No specific information is available on dose and administration

Allergan, Inc. Fatty acid amide hydrolase inhibitors for treating pain. WO2012145737; 2012

Historically, the first compound able to block FAAH activity was phenylmethylsulfonyl fluoride (PMSF), a nonselective serine hydrolase inhibitor; afterward other inhibitors, such as MAFP (Fig. 4), were also used, but it turned out to be rather unselective (Bisogno and Maccarrone 2013; Fowler 2015).

Early studies following the initial FAAH characterization led to the design of substrate-derived inhibitors including aldehydes, α-ketoamides, α-ketoesters, and trifluoromethyl ketones (Bisogno and Maccarrone 2013; Fowler 2015). These compounds possess electrophilic carbons and hence may form covalent hemiketals with the catalytic nucleophile of the enzyme. The systematic replacement of trifluoromethyl ketones with various monocyclic and bicyclic heterocycles led to α-ketoheterocycle derivatives of oleic acid and allowed to demonstrate that the presence of the oxazole group improved potency against FAAH. Moreover, studies on the length and degree of saturation of the fatty acid chain of candidate substances showed the highest potency with chain lengths of 8–12 carbon atoms, while the introduction of both a phenhexyl chain on the C2 and a pyridyl group on the C5 of an oxazole moiety yielded the most widely recognized α-ketoheterocycle derivative, that is, a lead compound called OL-135. This compound produces analgesia in all pain models examined so far, including tail flick, formalin test, mild thermal injury, and spinal nerve legation. The co-crystal X-ray structures of OL-135 bound to FAAH confirmed the covalent/reversible nature of the inhibitory mechanism. Furthermore, enol carbamates have also been described as noncompetitive/reversible inhibitors of FAAH, and the compound ST4070 (Fig. 4) was shown to be the most potent for the management of neuropathic pain (Marco et al. 2015). Furthermore, the aim to achieve a prolonged pharmacological activity in vivo has boosted research efforts to develop irreversible inhibitors that covalently bind to and modify FAAH. The most relevant in this class, URB597 (Fig. 4), was designed and synthesized as the lead compound of the carbamate-based FAAH inhibitors. Liquid chromatography-mass spectrometry analysis provided support to the ability of carbamate-based inhibitors to covalently modify the active site of FAAH by site-specific carbamylation of Ser241. This compound is active in animal models of acute, inflammatory, and neuropathic pain and protects mice against experimental colitis, besides showing anxiolytic and antidepressant-like effects. Furthermore, Pfizer developed piperidine/piperazine urea-based inhibitors and synthesized a series of compounds including the PF-3845, a highly selective compound with anti-hyperalgesic effects in the complete Freund’s adjuvant model of inflammatory pain.

Further chemical modification of PF-3845 culminated in the discovery of PF-04457845 (Fig. 4) that, despite its excellent pharmacokinetic properties in mice, rats, and dogs, unfortunately failed in phase II clinical trials to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Other piperazinyl urea-based inhibitors were described, and JNJ-1661010 was reported to exert analgesic activity in both mild thermal injury and spinal nerve ligation models of neuropathic pain and to increase brain AEA levels. Mass spectrometry data of JNJ-1661010 suggested the formation of a stable complex between the inhibitor and the enzyme, and for this reason JNJ-1661010 was considered a prototype of “slowly reversible” FAAH inhibitors.

FAAH and Disease

To date, it has been largely described the physiological and pathological function of endocannabinoids and NAE-related substances in health and disease. They participate in the interplay of pro-inflammatory and anti-inflammatory factors, in the neurodegenerative processes and related pathologies, in mental disorders, in endocrine and reproductive systems, as well as in many others (Pertwee 2015). It is noteworthy that the in vivo levels of NAEs are mainly controlled by FAAH that is therefore considered a potential marker of disease and a novel target for therapeutic drugs.

Increased FAAH activity has been detected during inflammatory processes weakening in turn reducing AEA ability to temper inflammation. For example, FAAH increased in peripheral platelets of human female migraineurs, as well as in the intestinal mucosa of patients with inflammatory bowel disease where it is expressed at abnormally high levels (see Maccarrone et al. 2015 for review).

In neurodegenerative diseases, FAAH alterations are nonhomogeneous and closely linked to the type of pathology. In Alzheimer’s disease (AD), FAAH overexpression was observed and was directly related to Aβ deposition in astrocytes, whereas a reduction of FAAH activity was observed in a mouse model of Parkinson’s disease (PD) (Fernández-Ruiz et al. 2015).

Decreased FAAH activity was also reported in brain and peripheral lymphocytes from (pre)Huntington’s disease (HD) patients, as well as in a mouse model of HD (Bari et al. 2013, and references therein). It should be noted that low FAAH activity in HD lymphocytes was due to blockage of enzyme activity by a cytosolic and irreversible inhibitor, rather than to downregulation of protein expression. Interestingly, FAAH activity in lymphocytes represents an easily accessible peripheral marker of what apparently occurs in the brain (Bari et al. 2013). Similarly, a drop in FAAH activity, but this time also expression, in peripheral lymphocytes was associated to impaired fertility of women who spontaneously miscarried or fail to become pregnant after in vitro fertilization and embryo transfer (Maccarrone et al. 2015, and references therein). Reduced activity and expression of FAAH was found also in the ventral striatum of alcohol-dependent (non)suicides, compared to psychiatrically normal controls, an observation supported by increased alcohol self-administration in rats pretreated with the FAAH inhibitor URB597 (Hansson et al. 2007). In addition, an increased vulnerability to drug and alcohol abuse in humans has been recently attributed to a single nucleotide polymorphism (C385A) in the Faah gene that led to reduced FAAH activity and expression due to the reduced stability of the protein. This polymorphism seems to be associated with eating disorders and obesity; whereby, it influences weight loss and insulin resistance and impacts on anorexia nervosa (Ando et al. 2014). Incidentally, FAAH expression was measured in visceral adipose tissue of obese patients and was shown to negatively correlate with visceral fat mass, thus proving evidence for a concomitant dysregulation of the endocannabinoid system with the onset of human abdominal obesity. Furthermore, a significant relationship has been recently reported between C385A polymorphism and obesity associated to cardiometabolic risk, as well as to childhood trauma with affective phenotypes (Lazary et al. 2016). Overall, increased FAAH activity and/or expression is often linked to alterations in inflammatory processes, due to the release of arachidonic acid (a well-known precursor of many pro-inflammatory agents) as metabolic product of AEA breakdown. Conversely, a reduction of FAAH often leads to increased AEA levels and thus to a prolonged action of this substance at its target receptors that trigger in turn signaling pathways often related to the cognitive sphere and to pathologies of the central nervous system. In the case of FAAH overactivity, inhibitors can be used as effective drugs, better if highly selective toward the target and tissue-/cell-specific. In the case of FAAH downregulation, inhibitors can be used only in experimental setup aimed at challenging scientific hypotheses, thus as proofs of concept and not as therapeutics. At any rate, the development of potent and selective FAAH inhibitors, endowed with good in vivo activity, has allowed major advances in our understanding of FAAH properties, biological activity, and therapeutic potential.


A number of exogenous compounds that activate endocannabinoid-binding receptors are commercially available (e.g., Bedrocan®, Bedrobinol®, Bediol®, Bedica®, Cesamet®, Marinol®, Sativex®) in an ever-growing number of countries (e.g., the United Kingdom, Canada, New Zealand, and the United States of America). Furthermore, PEA is currently marketed to cure neuropathic (Normast®) and pelvic (Pelvilen®) pain and is one of the main components of the Physiogel® cream used for inflamed or irritated skin of subjects with atopic dermatitis. Yet, due to frequent unwanted side effects of these compounds, a remarkable series of potent FAAH inhibitors has been developed in the last two decades, and many of them have moved into clinical trials to establish their efficacy for human therapy. In this context, one should always keep in mind that detailed profiling of any new drug is essential, as reminded once again earlier this year (in January) by the “Bial trial disaster.” Here, in a phase I clinical trial conducted with the as-yet-experimental FAAH inhibitor BIA10–2474, one volunteer patient died and other four reported serious brain injuries. Additionally, species specificity should be considered; whereby inhibitors very effective on rodent FAAHs may not be as effective on the human enzyme, due to subtle but relevant structural differences in the protein structures (Bisogno and Maccarrone 2013).

In conclusion, further research is warranted to translate in vitro experiments into safe clinical trials of FAAH inhibitors and to be finally exploited as innovative therapeutics for different human pathologies.



We are grateful to Prof. Enrico Dainese (University of Teramo, Teramo, Italy) for kindly providing FAAH three-dimensional structure. This study was partially supported by the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2012 to F.F. and PRIN 2010–2011 to M.M.).


  1. Ando T, Tamura N, Mera T, Morita C, Takei M, Nakamoto C, Koide M, Hotta M, Naruo T, Kawai K, Nakahara T, Yamaguchi C, Nagata T, Ookuma K, Okamoto Y, Yamanaka T, Kiriike N, Ichimaru Y, Ishikawa T, Komaki G, Japanese Genetic Research Group For Eating Disorders. Association of the c.385C>A (p.Pro129Thr) polymorphism of the fatty acid amide hydrolase gene with anorexia nervosa in the Japanese population. Mol Genet Genomic Med. 2014;2:313–8.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bari M, Battista N, Valenza M, Mastrangelo N, Malaponti M, Catanzaro G, Centonze D, Finazzi-Agrò A, Cattaneo E, Maccarrone M. In vitro and in vivo models of Huntington’s disease show alterations in the endocannabinoid system. FEBS J. 2013;280:3376–3388.PubMedCrossRefGoogle Scholar
  3. Bisogno T, Maccarrone M. Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov. 2013;8:509–22.PubMedCrossRefGoogle Scholar
  4. Blankman JL, Cravatt BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev. 2013;65:849–71.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 2002;298:1793–6.PubMedCrossRefGoogle Scholar
  6. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7.PubMedCrossRefGoogle Scholar
  7. Dainese E, De Fabritiis G, Sabatucci A, Oddi S, Angelucci CB, Di Pancrazio C, Giorgino T, Stanley N, Del Carlo M, Cravatt BF, Maccarrone M. Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH. Biochem J. 2014;457:463–72.PubMedCrossRefGoogle Scholar
  8. Deutsch DG, Omeir R, Arreaza G, Salehani D, Prestwich GD, Huang Z, Howlett A. Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase. Biochem Pharmacol. 1997;53:255–60.PubMedCrossRefGoogle Scholar
  9. Fernández-Ruiz J, Romero J, Ramos JA. Endocannabinoids and neurodegenerative disorders: Parkinson’s disease, Huntington’s chorea, Alzheimer’s disease, and others. Handb Exp Pharmacol. 2015;231:233–59.PubMedCrossRefGoogle Scholar
  10. Fezza F, De Simone C, Amadio D, Maccarrone M. Fatty acid amide hydrolase: a gate-keeper of the endocannabinoid system. Subcell Biochem. 2008;49:101–32.PubMedCrossRefGoogle Scholar
  11. Fowler CJ. The potential of inhibitors of endocannabinoid metabolism for drug development: a critical review. Handb Exp Pharmacol. 2015;23:95–128.CrossRefGoogle Scholar
  12. Grimaldi P, Pucci M, Di Siena S, Di Giacomo D, Pirazzi V, Geremia R, Maccarrone M. The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1. Cell Mol Life Sci. 2012;69:4177–90.PubMedCrossRefGoogle Scholar
  13. Hansson AC, Bermúdez-Silva FJ, Malinen H, Hyytiä P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M. Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology. 2007;32:117–26.PubMedCrossRefGoogle Scholar
  14. Lazary J, Eszlari N, Juhasz G, Bagdy G. Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma. Eur Neuropsychopharmacol. 2016;26:1020–8.PubMedCrossRefGoogle Scholar
  15. Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36:277–96.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Marco EM, Rapino C, Caprioli A, Borsini F, Laviola G, Maccarrone M. Potential therapeutic value of a novel FAAH inhibitor for the treatment of anxiety. PLoS ONE. 2015;10:e0137034.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Mileni M, Johnson DS, Wang Z, Everdeen DS, Liimatta M, Pabst B, Bhattacharya K, Nugent RA, Kamtekar S, Cravatt BF, Ahn K, Stevens RC. Structure-guided inhibitor design for human FAAH by interspecies active site conversion. Proc Natl Acad Sci U S A. 2008;105:12820–4.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Pertwee R.G. Endocannabinoids and Their Pharmacological Actions. In: Handb Exp Pharmacol. Springer. 2015;231:1–37. doi 10.1007/978-3-319-20825-1.Google Scholar
  19. Schmid PC, Zuzarte-Augustin ML, Schmid HH. Properties of rat liver N-acylethanolamine amidohydrolase. J Biol Chem. 1985;260:14145–9.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Filomena Fezza
    • 1
  • Monica Bari
    • 1
  • Domenico Fazio
    • 1
    • 4
  • Mauro Maccarrone
    • 2
    • 3
  1. 1.Department of Experimental Medicine and SurgeryTor Vergata University of RomeRomeItaly
  2. 2.Department of MedicineCampus Bio-Medico University of RomeRomeItaly
  3. 3.European Center for Brain Research/IRCCS Santa Lucia FoundationRomeItaly
  4. 4.Unit of Basic and Applied BioscienceUniversity of TeramoTeramoItaly