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Review
. 2020 Sep;22(3):259-269.
doi: 10.31887/DCNS.2020.22.3/vdimarzo.

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

Vincenzo Di Marzo  1
Affiliations
Review

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

Vincenzo Di Marzo. Dialogues Clin Neurosci. 2020 Sep.

Abstract
in English, Spanish, French

The endocannabinoid (eCB) system encompasses the eCBs anandamide and 2-arachidonoylglycerol, their anabolic/catabolic enzymes, and the cannabinoid CB1 and CB2 receptors. Its expansion to include several eCB-like lipid mediators, their metabolic enzymes, and their molecular targets, forms the endocannabinoidome (eCBome). This complex signaling system is deeply involved in the onset, progress, and symptoms of major neuropsychiatric disorders and provides a substrate for future therapeutic drugs against these diseases. Such drugs may include not only THC, the major psychotropic component of cannabis, but also other, noneuphoric plant cannabinoids. These compounds, unlike THC, possess a wide therapeutic window, possibly due to their capability of hitting several eCBome and non-eCBome receptors. This is particularly true for cannabidiol, which is one of the most studied cannabinoids and shows promise for the treatment of a wide range of mental and mood disorders. The eCBome plays a role also in the microbiota-gut-brain axis, which is emerging as an important actor in the control of affective and cognitive functions and in their pathological alterations. .

El sistema endocannabinoide (SeCB) incluía los eCB anandamida y 2-araquidonoilglicerol, sus enzimas anabólicas / catabólicas y los receptores cannabinoides CB1 y CB2. Su expansión para incluir algunos mediadores lipídicos similares al SeCB, sus enzimas metabólicas y sus dianas moleculares (Fig. 1), forma el endocannabinoidoma (eCBoma). Este complejo sistema de señalización está profundamente involucrado en la aparición, la progresión y los síntomas de los principales trastornos neuropsiquiátricos y proporciona un sustrato para futuros fármacos terapéuticos contra estas enfermedades. Tales drogas pueden incluir no solo THC, el principal componente psicotrópico de la cannabis, sino también otros cannabinoides vegetales no euforizantes. Estos compuestos, a diferencia del THC, poseen una amplia ventana terapéutica, posiblemente debido a su capacidad de actuar sobre varios receptores eCBoma y no eCBoma. Esto es particularmente cierto para el cannabidiol, que es uno de los cannabinoides más estudiados y que aparece prometedor para el tratamiento de una amplia gama de trastornos mentales y del estado de ánimo. El eCBoma también tiene un papel en el eje microbiota-intestino-cerebro, que se perfila como un actor importante en el control de las funciones afectivas y cognitivas y en sus alteraciones patológicas.

Le système endocannabinoïde (eCB) comprend les récepteurs cannabinoïdes CB1 et CB2 et les endocannabinoϊdes endogènes l’anandamide et le 2-arachidonoylglycérol ainsi que leurs enzymes anaboliques/cataboliques. L'endocannabinoϊdome (eCBome) est formé de ce système eCB et de plusieurs médiateurs lipidiques de type eCB, leurs enzymes métaboliques et leurs cibles moléculaires (Fig. 1). Ce système de signalisation complexe est profondément impliqué dans l'apparition, la progression et les symptômes des principaux troubles neuropsychiatriques et offre une base pour le développement de futurs traitements contre ces maladies. Ces médicaments peuvent contenir du THC, le principal composant psychotrope du cannabis, et aussi d'autres cannabinoïdes végétaux non euphorisants dont la fenêtre thérapeutique est large, contrairement au THC, peut-être en raison de leur capacité à atteindre plusieurs récepteurs eCBome et non eCBome. C’est particulièrement vrai pour le cannabidiol, l'un des cannabinoïdes les plus étudiés qui s'avère prometteur pour traiter un large spectre de troubles mentaux et de l'humeur. L'eCBome joue également un rôle dans l'axe microbiote-intestin-cerveau, acteur important dans le contrôle des fonctions affectives et cognitives et des pathologies qui y sont liées.

Keywords: anxiety; autism; cannabinoid; depression; eating disorder; endocannabinoid; lipid mediator; schizophrenia.

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Figures

Figure 1.
Figure 1.. The endocannabinoidome and its interactions with plant cannabinoids. (A) Endocannabinoidome mediators and receptors and their suggested involvement in neuropsychiatric disorders. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are often accompanied by their congeners, the N-acylethanolamines (NAEs), such as N-palmitoyl-, N-oleoyl-, N-linoleoyl- and N-docosahexaenoyl-ethanolamine (PEA, OEA, LEA, and DHEA) and the 2-AcGs, such as 2-oleoyl- and 2-linoleoyl-glycerol (2-OG, 2-LG). These congeners modulate targets other than cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), such as transient receptor channel type 1, type 2 and type 4 (TRPV1, TRPV2, TRPV4), peroxisome proliferator-activated nuclear receptor (PPAR)α, and γ, T-type Ca2+(Cav3 channels, and orphan G-protein coupled receptors (GPR), such as GPR18, GPR55, GPR110, and GPR119. Other long-chain fatty acid amides, such as primary amides, N-acylated amino acids (lipoamino acids), and some N-acyl-neurotransmitters (N-acyl-dopamines and N-acyl-serotonins) have also been identified as elements of the expanded endocannabinoid system with promiscuous targets. Endocannabinoidome targets have been implicated in the etiology of neuropsychiatric disorders, as indicated. (B) The endocannabinoids anandamide and 2-AG, their congeners, and the various long-chain fatty acid amides often share receptors and anabolic/catabolic enzymes, although these may have different substrate selectivity. Fatty acid amide hydrolase (FAAH) breaks down all long-chain N-acylethanolamines, N-acyl-taurines, and N-acyl-glycines; FAAH-2 (so far found only in human tissues) has a preference for OEA and LEA; N-acylethanolamine acid amidohydrolase (NAAA) recognizes saturated N-acylethanolamines such as PEA; monoacylglycerol lipase (MAGL) is specific for long-chain 2-AGs, especially those that are unsaturated, and so do α, β-hydrolases 6 and 12 (ABHD6, ABHD12), which also have non-endocannabinoidome ester substrates. In addition, some oxidizing enzymes of the arachidonate cascade, such as cyclooxygenase-2 (COX2), recognize the polyunsaturated fatty acid-containing endocannabinoid congeners. Several metabolic products of these congeners have their own receptors. Plant cannabinoids modulate receptors and enzymes of the endocannabinoidome and have been proposed as treatments for neuropsychiatric disorders, as shown. ABH4, α, β-hydrolase-4; Abn-CBD, abnormal cannabidiol; ADHD, attention-deficit/hyperactivity disorder; AN, anorexia nervosa; ASD, autism spectrum disorder; BED, binge eating disorder; CBD, cannabidiol; CBDA, cannabidiolic acid; CBDV, cannabidivarin; CBDVA, cannabidivarinic acid; CBG, cannabigerol; CBGA, cannabigerolic acid; CoA, coenzyme A; EMT, endocannabinoid membrane transporter; GDE1, glycerophosphodiester phosphodiesterase 1; lyso-PLC, lyso phospholipase C; NAPE-PLD, N-acyl-phosphatidylethanolamine-specific phospholipase D; NATs, N-acyl-transferases; OA, oleamide; PA, phosphatidic acid; PG, prostaglandin; PLA, phospholipase A; PLC, phospholipase C; PLD, phospholipase D; PTPN22, tyrosine-protein phosphatase nonreceptor type 22; PTSD, posttraumatic stress disorder; sn-1-DAG lipase, sn-1-specific diacylglycerol lipase; sPLA2, secretory phospholipase A2; THC, ∆9-tetrahydrocannabinol; THCA, ∆9-tetrahydrocannabivarinic acid; THCV, ∆9-tetrahydrocannabivarin; TRPM8, transient receptor potential melastatin type-8
Figure 2.
Figure 2.. Chemical structures of D9-tetrahydrocannabinol (THC), ∆9-tetrahydrocannabivarin (THCV), cannabidiol (CBD), and cannabidivarin, the four most clinically studied plant cannabinoids in the context of neuropsychiatric disorders
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