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INTRODUCTION

The psychoactive and medicinal properties of Cannabis species have been appreciated for millennia. However, only recently have we developed an understanding of the compounds present in cannabis that produce these effects. The primary psychoactive compounds in cannabis are the phytocannabinoids, which are meroterpenoids typically synthesized from olivetolic acid and geranyl pyrophosphate. Δ9-Tetrahydrocannabinol (THC) is the phytocannabinoid responsible for the characteristic psychoactivity of Cannabis. Another major phytocannabinoid, cannabidiol (CBD), may have distinct therapeutic benefits. The effects of other phytocannabinoids are less well understood. THC produces its effects by engaging the endocannabinoid system, an endogenous signaling system comprised of endogenous cannabinoids (endocannabinoids), endocannabinoid receptors, and the enzymes responsible for endocannabinoid synthesis and degradation. The endocannabinoid system is widespread throughout the body and is involved in regulation of stress, pain, reward, metabolism, and inflammation, among other physiological actions.

ABBREVIATIONS

Abbreviations

ABHD: α/β hydrolase domain-containing protein

AEA: anandamide

2-AG: 2-arachidonoyl glycerol

ALT: alanine aminotransferase

CBC: cannabichromene

CBCA: cannabichromenic acid

CBD: cannabidiol

CBDA: cannabidiolic acid

CBGA: cannabigerolic acid

CBN: cannabinol

CBNA: cannabinolic acid

COX-2: cyclooxygenase-2

DAG: diacylglycerol

DAGL: diacylglycerol lipase

eCB: endocannabinoid

FAAH: fatty acid amide hydrolase

GIRK: G protein-coupled inwardly rectifying K+ channel

GPCR: G protein-coupled receptor

LTD: long-term depression

MAGL: monoacylglycerol lipase

MAP kinase: mitogen-activated protein kinase

NAPE-PLD: N-acyl phosphatidylethanolamine–specific phospholipase D

NArPE: N-arachidonoyl phosphatidylethanolamine

NREM: non–rapid eye movement

7-OH-CBD: 7-hydroxy-cannabidiol

11-OH-THC: 11-hydroxy-tetrahydrocannabinol

PAG: periaqueductal gray

PLC: phospholipase C

PPAR: peroxisome proliferator-activated receptor

REM: rapid eye movement

THC: Δ9-tetrahydrocannabinol

THCA: Δ9-tetrahydrocannabinolic acid

THCV: Δ9-tetrahydrocannabivarin

TRPV1: transient receptor potential channel vanilloid 1

VTA: ventral tegmental area

ENDOGENOUS CANNABINOIDS

The endocannabinoids (eCB) are defined as endogenously produced molecules that bind to cannabinoid receptors. The prototypical eCBs are arachidonate-derived signaling lipids that are produced by cells throughout most organ systems in the body but have been primarily studied within the nervous system (Blankman and Cravatt, 2013; Hillard, 2015, 2018). The lipophilic eCB molecules often associate with protein binding partners, such as fatty acid binding proteins or albumin in the blood, to facilitate transport through aqueous compartments. eCBs exert their actions through a family of receptors as discussed below.

Anandamide

The first eCB to be discovered was N-arachidonoylethanolamine (AEA; Figure 26–1) and was given the name anandamide in reference to the Sanskrit word ānanda for bliss (Blankman and Cravatt, 2013). AEA is an arachidonic acid molecule conjugated to an ethanolamine group. Within the brain, AEA is believed to be synthesized and mobilized in a varying, but continuous, manner and not undergo vesicular storage, a process often referred to as “on-demand” synthesis. AEA is a high-affinity (low nM) but low-efficacy agonist at the cannabinoid receptors, making it a partial agonist (Hillard, 2015), and is also known to act as an agonist at transient ...

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