The Leaf THE LEAF November-December 2017 | Page 10

Endocannabinoid System
The cannabinoid CB1 receptor is the most
important for psychoactive effects, but has a
role in a number of therapeutic effects as well,
particularly pain. THC is a potent partial
agonist of CB1. However, the effect of CBD
has been more difficult to determine.
Originally CBD was considered to be a low-
potency antagonist at CB1. However, in 2015,
new results showed that CBD can also bind to
an allosteric site on the CB1 receptor. At this
site, CBD acts as a high potency (IC50=304
nM) negative allosteric modulator, which
could reduce both the efficacy and potency of
CB1 activation by THC.
Cannabinoid CB2 receptor activation has
many effects (too many to list here), although
inflammation is an important one.
Here are more details on roles of the CB2
receptor. Like with CB1, THC is a potent
partial agonist at the CB2 receptor. CBD
opposes activation by THC, since it is an
antagonist/inverse agonist. However, it is not
particularly potent.
Besides direct actions on the cannabinoid
receptors, Phytocannabinoids can modulate
levels of endocannabinoids. In fact, treatment
with CBD increased blood anandamide
levels. This could be due to either inhibition
of the anandamide-metabolizing enzyme or
via
inhibition
of
anandamide
reuptake/transport.
Fatty acid amide hydrolase (FAAH) is the
enzyme that metabolizes anandamide.
Although inhibition of FAAH by CBD is
frequently cited for the increase in
anandamide, it not a very potent inhibitor
(IC50=15.2 μM). Another study saw very
little inhibition of FAAH, even at very high
concentrations, bringing into question
whether this is how CBD raises anandamide
levels.
Fatty acid binding proteins (FABPs) are
intracellular proteins that facilitate the
removal of endocannabinoids by shuttling
them from the cell membrane to the
intracellular enzymes that break them down.
Both THC and CBD bind multiple FABPs
with Ki (binding affinity) values in the 1 to 3
μM range. THC and CBD can compete with
anandamide for binding to the FABPs, which
raises anandamide levels. This is the more
likely mechanism of how Phytocannabinoids
raise endocannabinoid levels.
Atypical Cannabinoid Receptors
GPR18 is a G protein-coupled receptor with
effects on blood pressure and immune
function.
THC is a potent full agonist of GPR18
(EC50=960 nM). However, receptor
activation is opposed by CBD, which potently
inhibited THC-induced actions mediated
through GPR18 (IC50=18 nM).
GPR55activation lowers blood pressure, is
anti-inflammatory, and can block some types
of pain. GPR55 regulates energy intake and
expenditure, which could impact diseases
such as obesity and diabetes. It is also
expressed in bone cells with a possible role in
osteoporosis. GPR55 activation decreased
neurodegeneration in models of multiple
sclerosis.
GPR55 is activated by THC under at least
some experimental conditions. The potency
of THC at GPR55 (EC50=8 nM) was nearly
as low as for the CB1 receptor. CBD opposes
the activation of GPR55 by acting as a fairly
potent antagonist (IC50=445 nM).
So far, I have not seen any studies of
THC/CBD and the third atypical cannabinoid
receptor, GPR119.