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FAAH

FAAH — fatty acid amide hydrolase — is the enzyme that degrades anandamide (AEA, N-arachidonoylethanolamine), the first-discovered endocannabinoid. Where MAGL governs 2-AG, FAAH governs anandamide; together they set the tone of the endocannabinoid system from the degradation side.

Effect of inhibition

Raising anandamide by blocking its breakdown produces anxiolytic and analgesic effects in the preclinical literature. Because anandamide is released on demand at active synapses, inhibiting its hydrolysis amplifies signalling where signalling is already happening, rather than flooding the whole system the way an exogenous agonist does. That selectivity is the pharmacological argument for the approach.

Natural inhibitors

• Yangonin — a kavalactone from kava (Piper methysticum). Has CB1 binding affinity of its own; anxiolytic.
• Guineensine — a piperidine alkaloid from black pepper (Piper nigrum). Reported as both an FAAH inhibitor and an endocannabinoid reuptake inhibitor.
• Macamides — N-benzylamide alkaloids from maca (Lepidium meyenii). FAAH inhibition; neuroprotective.
• Biochanin A — an isoflavone from red clover and soy. FAAH inhibitor; also oestrogenic.

The Piperaceae pattern

Two of the four natural FAAH inhibitors above come from the pepper family: yangonin from kava and guineensine from black pepper. Black pepper additionally supplies piperine, a general bioavailability enhancer, and β-caryophyllene, a CB2 agonist. A single plant family therefore contributes a reuptake inhibitor, an enzyme inhibitor, a receptor agonist and an absorption enhancer — which is the sort of convergence that makes the family worth treating as a unit rather than as four unrelated ingredients.

Cautions

• Kava carries a genuine hepatotoxicity signal in the literature, disputed as to mechanism and to the role of preparation method, and it is the reason kava was withdrawn from several markets. It is not resolved by the fact that yangonin is interesting.
• Biochanin A is oestrogenic; that is a systemic effect independent of the enzyme activity.
• The most-publicised FAAH inhibitor of recent years was BIA 10-2474, which caused one death and lasting neurological injury in a 2016 French Phase I trial. Chemoproteomic profiling proved this was caused by off-target covalent inhibition of unrelated serine hydrolases (ABHD6, PNPLA6) rather than FAAH inhibition itself. Selective FAAH inhibitors (such as PF-04457845) and natural human genetic FAAH variants (C385A / rs324420) confirm that selective FAAH inhibition is safe in humans.

Comprehensive monograph

For the complete molecular biology of FAAH, its catalytic Ser241–Ser217–Lys142 triad, the non-cannabinoid NAE family (PEA, OEA), lysosomal NAAA, and the full endocannabinoidome, see The Expanded Endocannabinoid System and FAAH Science. For enzyme kinetics and serine hydrolase cross-reactivity, see Enzyme Inhibition Kinetics and Molecular Transporters.

See also: The Expanded Endocannabinoid System and FAAH Science · MAGL · Anandamide and 2-AG · Cannabinoid Oilahuasca · Enzyme Inhibition Kinetics and Molecular Transporters · Kava · Black Pepper · Maca · Stack Substances

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