Science - USA (2021-12-17)

SCIENCE science.org

By Erik Keimpema^1 , Vincenzo Di Marzo2,3,

Tibor Harkany1,4

S

ince its first mention ~4000 BCE,

Cannabis sativa has evolved through

selective cultivation from being a

source of durable fiber (hemp) to a

plant enriched in bioactive ingredi-

ents. Currently, >100 potentially bio-

active phytocannabinoids from Cannabis

spp. have been cataloged, yet their precise

structure-function relationships are mostly

unclear ( 1 ). D^9 -Tetrahydrocannabinol (THC)

and cannabidiol (CBD) are primarily studied,

particularly because high-grade Cannabis

subspecies can produce over 20% yield of

either compound. The variety of bioactive

constituents in C. sativa, together with their

defined ratios, suggests that they have poten-

tial application in many illnesses ( 1 ). Possibly

due to many phytocannabinoids producing

similar pharmacological effects through dif-

ferent mechanisms, selecting which to study

for a disease remains a formidable challenge.

THC action in humans is dependent on the

CB 1 cannabinoid receptor (CB 1 R) ( 2 ), which

is the most abundant G protein–coupled

receptor (GPCR) in the brain, as well as its

ortholog, CB 2 R. When activated, CB 1 R in the

plasma membrane signals through G(i/o) pro-

teins to inhibit either Gai-mediated SRC–sig-

nal transducer and activator of transcription

(STAT) or Gbg-mediated adenylyl cyclase,

AKT, or extracellular signal–regulated kinase

(ERK) cascades. For excitable cells, such as

neurons, activated CB 1 R inhibits Ca2+ influx

through voltage-gated Ca2+ channels, thus re-

ducing neurotransmitter release.

Although most studies focus on THC be-

cause of its psychostimulant effects, CBD is

another abundant (up to 40 to 50% of total

phytocannabinoid content) and yet non-

psychotropic Cannabis component. CBD

is thought to have anti-inflammatory and

tissue-protective effects. This is because CBD

action is putatively mediated by more than

one receptor, including transient receptor

potential cation channel V1 (TRPV1), GPCR

55 (GPR55), and peroxisome proliferator-

activated receptor–g (PPARg). Additionally,

CBD enhances antioxidant cellular de-

fenses by scavenging hydroxyl radicals and

can counteract THC action intracellularly,

through CB 1 Rs on mitochondrial membranes

( 3 ). Indeed, CBD opposes the THC-induced

disruption of oxidative phosphorylation, at

the level of complex I ( 3 ), thereby protecting

from the deleterious consequences of THC-

induced reduction in cellular respiration.

Notably, these potential cellular and molecu-

lar sites of action are not limited to the brain

but apply to, e.g., pancreas, muscle, liver, and

gut—suggesting that cannabinoids may have

applications in diverse settings.

It is important to recognize that C. sativa

is more than just THC and CBD. Many phy-

tocannabinoids that exist in lesser amounts

(e.g., cannabivarin, cannabigerol, and THC

acid) ( 4 ) in plant preparations could indi-

vidually be biologically powerful and even

supersede or modify THC and/or CBD ac-

tion. Thus, the continued structure-function

study of phytocannabinoids is warranted.

Accordingly, combinations of phytocannabi-

noids might deliver relief to disorders with

complex etiology ( 1 ).

Receptor-mediated actions of phytocan-

nabinoids, particularly THC, center on dis-

placing high-affinity endocannabinoids,

innate ligands that bind CB 1 R, CB 2 R, and al-

ternative receptors including TRPV1, GPR55,

and PPARg. Two such molecules, 2-arachi-

donoylglycerol (2-AG) and arachidonoyl-

ethanolamide (anandamide), with their re-

spective biosynthetic and catabolic enzyme

machineries, form the molecular backbone

of the endocannabinoid system (5, 6). 2-AG

and anandamide are functionally redundant.

Yet, endocannabinoid signaling can adopt

cell-type–specific configurations to support

cell-autonomous (e.g., self-inhibition in neu-

rons), intercellular (e.g., metabolic interplay),

and intracellular (e.g., cellular respiration

through CB 1 R on mitochondria) signaling

in the brain and in peripheral tissues. Such

functional flexibility is made possible by the

different half-lives (minutes versus hours)

and tissue distributions of 2-AG and anan-

damide, together with the diversity of avail-

able receptors. These arrangements allow for

systemic actions of endocannabinoids and

their modulation by THC and CBD ( 1 ).

An expanding catalog of endocannabinoid-

like molecules are being recognized for their

modulation of TRP channels, PPARs, and or-

phan GPCRs. This “endocannabinoidome” of-

fers a more comprehensive physiological sub-

strate for phytocannabinoid action than the

core endocannabinoid system. Moreover, the

array of endogenous CB 1 R and CB 2 R ligands

now includes allosteric modulators derived

from steroids and hemoglobin fragments,

which can antagonize THC intoxication ( 7 )

and reduce neuropathic pain ( 8 ), respectively.

Functional interrogation of 2-AG action

on CB 1 Rs in the brain revealed that endocan-

nabinoids modulate synaptic plasticity by

limiting Ca2+-dependent neurotransmitter

release ( 9 ). This mechanism relies on CB 1 Rs

partitioned at presynaptic termini with endo-

cannabinoid ligand production in postsynap-

tic neurons. Because endocannabinoids are

eicosanoid lipids that travel by nonvesicular

diffusion, their activity-dependent produc-

tion and fast degradation ensure phasic avail-

ability and short-lived action. Accordingly,

neuropsychiatric effects of THC-containing

Cannabis preparations (e.g., euphoria, hypo-

motility, and amnesia) occur through CB 1 R

hyperactivity at the plasma membrane and

intracellularly, which disrupts temporal pre-

cision and prolongs endocannabinoid-depen-

dent synaptic inhibition. In the adult brain,

the near-complete recovery of endocannabi-

noid action (and reinstatement of synaptic

neurotransmission) may take hours to weeks

after THC consumption. Yet, given that only

a small fraction of first-time consumption

progresses to chronic heavy use, Cannabis is

classified as moderately addictive in adults.

A prominent clinical niche being explored

for cannabinoid medicines is treatment-

resistant epilepsy ( 10 ). Phytocannabinoids

that trigger CB 1 R-mediated signaling at glu-

tamatergic synapses dampen neuronal hy-

perexcitability in epileptic foci in rodents and

humans. Repeated epileptic seizures provoke

neurodegeneration in, e.g., the hippocampus.

Therefore, although still speculative, rescu-

ing neurons from oxidative damage and mi-

tochondrial dysfunction by, e.g., CBD, could

partly underpin the substantial reduction in

seizure frequency seen in clinical trials ( 10 ).

Phytocannabinoids may also have appli-

cations in diseases associated with aging.

This is largely because aging tissues contain

increased amounts of immune cells, which

remove cellular debris or extracellular (pro-

teinaceous) deposits. THC-induced activation

of CB 2 Rs during aging may offer relief in neu-

MEDICINE

B iological basis of cannabinoid medicines

Mechanistic insights into cannabinoid signaling could improve therapeutic applications

(^1) Department of Molecular Neurosciences, Center for Brain
Research, Medical University of Vienna, Vienna, Austria.
(^2) Institute of Biomolecular Chemistry, Consiglio Nazionale
delle Ricerche, Pozzuoli, Italy.^3 Institut Universitaire de
Cardiologie et de Pneumologie de Québec and Institut sur
la Nutrition et les Aliments Fonctionnels-Centre NUTRISS,
Université Laval, Québec, Canada.^4 Department of
Neuroscience, Karolinska Institutet, Solna, Sweden.
Email: [email protected]
17 DECEMBER 2021 • VOL 374 ISSUE 6574 1449