INSIGHTS | PERSPECTIVES
GRAPHIC: V. ALTOUNIAN/SCIENCEscience.org SCIENCErological disorders (Alzheimer’s,
Parkinson’s, and Huntington’s
diseases) by limiting inflam-
matory cytokine release from
activated microglia, which can
be harmful to neurons (see the
figure). Alternatively, THC can
dampen errant synaptic neuro-
transmission by CB 1 R activation,
which might improve cogni-
tion. Long-term, low-dose THC
treatment in a mouse model
of Alzheimer’s disease rescued
memory deficits, neuronal mor-
phology, and aberrant gene tran-
scription ( 11 ). This duality of
correcting synaptic neurotrans-
mission and protecting neurons
from degeneration is a typical
example of cannabinoid poly-
pharmacology: beneficial effects
at more than one cellular target
( 1 ). This also exemplifies bipha-
sic responses to cannabinoids,
manifesting as beneficial effects
at low concentrations and harm-
ful effects at high concentrations.
Apart from the multitarget na-
ture of these compounds, these
biphasic effects may depend on
biased cannabinoid action at
different CB 1 R populations and,
hence, on the baseline (patho)
physiological substrate these molecules act
on. A further obstacle to the therapeutic use
of THC per se is that CB 1 Rs, unlike CB 2 Rs, of-
ten exacerbate inflammation ( 1 ).
Cannabinoid therapy is also potentially ap-
plicable for the management of neuropathic
pain, induced by a lesion or disease of the so-
matosensory nervous system, because damp-
ening excitatory neurotransmission at the
level of spinal neurocircuits can reduce hy-
peralgesia in rodents ( 12 ). Another druggable
target emerges in inflammatory pain because
of peripheral sensitization in the skin, where
accumulation of anandamide facilitates pain
processing and proinflammatory signaling
through TRPV1 on primary sensory afferents
(Ad and C fibers). TRPV1 activation increases
the transcription of nerve growth factor
receptors [tropomyosin receptor kinase A
(TrkA) and p75], whose activation augments
pathological touch sensitivity. Thus, inacti-
vating TRPV1 by sequential activation and
desensitization, as some phytocannabinoids
do ( 1 ), might be medically relevant.
In contrast to the transient and reversible
effects of THC on synaptic neurotransmission
at mature synapses, the situation is different
during pre- and postnatal brain develop-
ment. The precisely timed activation of CB 1 R,
CB 2 R, and likely GPR55 is critical for cell fate
decisions during organ development. In the
brain, cell-autonomous signaling contributes
to neurite outgrowth ( 13 ). Alternatively, inter-
cellular endocannabinoid action determines
the size of neural stem cell pools and lineage
commitment of daughter cells, their migra-
tion, synaptogenesis, and synapse mainte-
nance in vertebrates. Thus, the coincidence
of THC exposure with these processes, which
occur in the human brain from the second
trimester during pregnancy until late ado-
lescence, can imprint adverse and life-long
modifications on the structural integrity of
the brain. Accordingly, exposure of (pre-)
adolescent children to Cannabis is associated
with an increased number of hospitalizations
for neurological complications ( 14 ).
Like CB 2 R on neural stem cells, the acti-
vation of CB 1 R in adipocytes, TRPV1 in pan-
creas, or GPR55 in skin and salivary gland
defines tissue size by modulating the rate of
cell proliferation during organ development.
Thereafter, CB 1 R (or TRPV1) activation in dif-
ferentiating progeny also determines cell sur-
vival. These findings support the exploration
of phytocannabinoid-based therapy for dis-
orders in which errant cell-cycle regulation
is pathogenic, including cancer. A leading
concept is that possible antitumoral effects of
THC (and likely CBD) may involve increased
ceramide production, triggering autophagy-
mediated cancer cell death ( 15 ).Increasing knowledge of en-
docannabinoid mechanisms and
Cannabis constituents has led to
the development of synthetic can-
nabinoids, encompassing THC
analogs and structurally un-
related compounds such as
high-affinity and selective CB 1 R
antagonists and inhibitors of a
variety of lipases and hydrolases
that catalyze endocannabinoid
synthesis and inactivation. Some
of these synthetic ligands have
already entered clinical practice
(e.g., rimonabant, nabilone, orli-
stat) or are in clinical trials (e.g.,
ABX-1431). Thus, the expanding
repertoire of drugs targeting the
endocannabinoid system and
the endocannabinoidome is of
broad therapeutic appeal.
Given the abundance and sub-
cellular partitioning of CB 1 R and
CB 2 R and the endocannabinoid
enzymatic machinery, organ-
specific targeting by synthetic
ligands remains a key pharmaco-
logical challenge. Dissecting how
subcellular pools of CB 1 R bring
about differential drug action
and define functional outcome
will be key to improving disease-
specific applications. Similarly,
delivering single components versus phyto-
cannabinoid mixtures requires decisions on
targeting specific signaling pathways rather
than harnessing the pleiotropy and synergy
of coadministered phytocannabinoids ( 1 ).
Nonetheless, the expanding knowledge of the
endocannabinoid system is lifting phytocan-
nabinoids from fringe utilization to poten-
tially safe and effective medicines in adults. jREFERENCES AND NOTES- J. S. Brodie et al., Trends Pharmacol. Sci. 36 , 802 (2015).
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ACKNOWLEDGMENTS
The authors are supported by the European Research Council
(ERC-2015-AdG-695136; T.H.), the Austrian Research Fund
(P 34121-B; E.K.), and the Tri-Agency of the Canadian Federal
Government (CERC programme, Canada Foundation for
Innovation Leaders Fund, and Sentinelle Nord-Apogée pro-
gramme; V.D. ).
10.1126/science.abf6099Homodimeric CB 1 ROuter mitochondrial
membraneReduced ATP (neuron)
Reduced ROS (glia)GIRK PI3K ACERKSRCJNKAC, adenylyl cyclase;
ATP, adenosine triphosphate;
CBD, cannabidiol; CB 1 R, CB 1
cannabinoid receptor;
ERK, extracellular signal–regulated
kinase; GIRK, G protein–coupled
inwardly rectifying potassium
channel; JNK, c-Jun N-terminal
kinase; PKA, protein kinase A; PI3K,
phosphatidylinositol 3-kinase;
ROS, reactive oxygen species;
STAT3, signal transducer and
activator of transcription 3; THC,
D^9 -tetrahydrocannabinol; VDCC,
voltage-dependent calcium channel.Exocytosis Proliferation DifferentiationVDCCAKT STAT 3??
?Soluble AC PKAGbg Gai/oTHC CBD?Inner mitochondrial membraneComplex 1EndocannabinoidsGai /oCannabinoid signaling
Endocannabinoids signal through G protein–coupled receptors to control exocytosis,
proliferation, differentiation, and respiration. In disease, phytocannabinoids (only
THC and CBD are shown for simplicity) can affect CB 1 R signaling, although the
mechanisms are not fully elucidated. Many of these signaling principles could also
apply to CB 2 R which, for example, regulates cytokine release.1450 17 DECEMBER 2021 • VOL 374 ISSUE 6574