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Review
. 2025 Apr 5;14(7):551.
doi: 10.3390/cells14070551.

FAAH Modulators from Natural Sources: A Collection of New Potential Drugs

Catalin Nicoara  1 , Filomena Fezza  2 , Mauro Maccarrone  1   3
Affiliations
Review

FAAH Modulators from Natural Sources: A Collection of New Potential Drugs

Catalin Nicoara et al. Cells. .

Abstract

The endocannabinoid system (ECS) plays a crucial role in maintaining homeostasis by regulating immune response, energy metabolism, cognitive functions, and neuronal activity. It consists of endocannabinoids (eCBs), cannabinoid receptors (CBRs), and enzymes involved in eCB biosynthesis and degradation. Increasing evidence highlights the involvement of the ECS under several pathological conditions, making it a promising therapeutic target. Recent research efforts have focused on modulating endogenous eCB levels, particularly through the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of the major eCB anandamide. Natural substances, including plant extracts and purified compounds, can inhibit FAAH and represent a promising area of pharmacological research. Natural FAAH inhibitors are particularly attractive due to their potentially lower toxicity compared to synthetic compounds, making them safer candidates for therapeutic applications. Phytocannabinoids, flavonoids, and flavolignans have been shown to efficiently inhibit FAAH. The structural diversity and bioactivity of these natural substances provide a valuable alternative to synthetic inhibitors, and may open new avenues for developing innovative pharmacological tools.

Keywords: FAAH; cannabinoids; endocannabinoid system; inhibitors; natural compounds.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Endocannabinoid system and related pathologies.
Figure 2
Figure 2
Chemical structures of the main natural FAAH inhibitors.
Figure 3
Figure 3
Schematic representation of the main ECS elements. AEA: anandamide; 2-AG: 2-arachidonoylglycerol; COX-2: cyclooxygenase-2; CB1R cannabinoid receptor type 1; CB2R cannabinoid receptor type 2; DAGL: diacylglycerol lipase; FAAH: fatty acid amide hydrolase; FAAH-2: fatty acid amide hydrolase-2; 12-LOX: 12-lipoxygenase; MAGL: monoacylglycerol lipase; NAAA: N-acylethanolamine acid amide hydrolase; NAPE-PLD: N-acyl phosphatidylethanolamine-specific phospholipase D; NAT: N-acyltransferase enzymes; PLC: phospholipase C.
Figure 4
Figure 4
Chemical structures of the synthetic FAAH inhibitors listed in Table 1.
See this image and copyright information in PMC

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