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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.
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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
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ENDOGENOUS CANNABINOIDS
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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.
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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 ...