The endocannabinoid system (ECS) is a biological system composed of
endocannabinoids, which are endogenous lipid-based retrograde
neurotransmitters that bind to cannabinoid receptors, and cannabinoid
receptor proteins that are expressed throughout the mammalian central
nervous system (including the brain) and peripheral nervous system.
The endocannabinoid system is involved in regulating a variety of
physiological and cognitive processes including fertility,
pregnancy, during pre- and postnatal development, appetite,
pain-sensation, mood, and memory, and in mediating the pharmacological
effects of cannabis. The ECS is also involved in mediating some
of the physiological and cognitive effects of voluntary physical
exercise in humans and other animals, such as contributing to
exercise-induced euphoria as well as modulating locomotor activity and
motivational salience for rewards. In humans, the plasma
concentration of certain endocannabinoids (i.e., anandamide) have been
found to rise during physical activity; since endocannabinoids
can effectively penetrate the blood–brain barrier, it has been
suggested that anandamide, along with other euphoriant neurochemicals,
contributes to the development of exercise-induced euphoria in humans,
a state colloquially referred to as a runner's high.
Two primary endocannabinoid receptors have been identified: CB1, first
cloned in 1990; and CB2, cloned in 1993. CB1 receptors are found
predominantly in the brain and nervous system, as well as in
peripheral organs and tissues, and are the main molecular target of
the endocannabinoid ligand (binding molecule), anandamide, as well as
its mimetic phytocannabinoid, THC. One other main endocannabinoid is
2-arachidonoylglycerol (2-AG) which is active at both cannabinoid
receptors, along with its own mimetic phytocannabinoid, CBD. 2-AG and
CBD are involved in the regulation of appetite, immune system
functions and pain management.
1 Basic overview
1.1 Expression of receptors
Endocannabinoid synthesis, release, and degradation
1.3 Binding and intracellular effects
1.4 Binding and neuronal excitability
2 Functions of the endocannabinoid system
2.1.1 Role in hippocampal neurogenesis
2.1.2 Induction of synaptic depression
2.3 Energy balance and metabolism
2.4 Stress response
2.4.1 Exploration, social behavior, and anxiety
2.5 Immune function
2.5.1 Multiple sclerosis
2.6 Female reproduction
2.7 Autonomic nervous system
2.11 Physical exercise
3 Experimental use of CB1 -/- phenotype
Endocannabinoids in plants
5 See also
7 Further reading
8 External links
The endocannabinoid system, broadly speaking, includes:
The endogenous arachidonate-based lipids, anandamide
(N-arachidonoylethanolamide, AEA) and
these are known as "endocannabinoids" and are physiological ligands
for the cannabinoid receptors.
Endocannabinoids are all
The enzymes that synthesize and degrade the endocannabinoids, such as
fatty acid amide hydrolase or monoacylglycerol lipase.
The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors
that are located in the central and peripheral nervous systems.
The neurons, neural pathways, and other cells where these molecules,
enzymes, and one or both cannabinoid receptor types are all
colocalized collectively comprise the endocannabinoid system.
The endocannabinoid system has been studied using genetic and
pharmacological methods. These studies have revealed that cannabinoids
act as neuromodulators for a variety of processes,
including motor learning, appetite, and pain sensation,
among other cognitive and physical processes. The localization of the
CB1 receptor in the endocannabinoid system has a very large degree of
overlap with the orexinergic projection system, which mediates many of
the same functions, both physical and cognitive. Moreover, CB1 is
colocalized on orexin projection neurons in the lateral hypothalamus
and many output structures of the orexin system, where the CB1
and orexin receptor 1 (OX1) receptors physically and functionally join
together to form the CB1–OX1 receptor heterodimer.
Expression of receptors
Further information on receptor localization: Cannabinoid receptor
type 1 (CB1) and
Cannabinoid receptor type 2 (CB2)
Cannabinoid binding sites exist throughout the central and peripheral
nervous systems. The two most relevant receptors for cannabinoids are
the CB1 and CB2 receptors, which are expressed predominantly in the
brain and immune system respectively. Density of expression varies
based on species and correlates with the efficacy that cannabinoids
will have in modulating specific aspects of behavior related to the
site of expression. For example, in rodents, the highest concentration
of cannabinoid binding sites are in the basal ganglia and cerebellum,
regions of the brain involved in the initiation and coordination of
movement. In humans, cannabinoid receptors exist in much lower
concentration in these regions, which helps explain why cannabinoids
possess a greater efficacy in altering rodent motor movements than
they do in humans.
A recent analysis of cannabinoid binding in CB1 and CB2 receptor
knockout mice found cannabinoid responsiveness even when these
receptors were not being expressed, indicating that an additional
binding receptor may be present in the brain. Binding has been
2-arachidonoylglycerol (2-AG) on the
suggesting that this receptor may be a candidate for the established
In addition to CB1 and CB2, certain orphan receptors are known to bind
endocannabinoids as well, including GPR18,
GPR55 (a regulator of
neuroimmune function), and GPR119. CB1 has also been noted to form a
functional human receptor heterodimer in orexin neurons with OX1, the
CB1–OX1 receptor, which mediates feeding behavior and certain
physical processes such as cannabinoid-induced pressor responses which
are known to occur through signaling in the rostral ventrolateral
Endocannabinoid synthesis, release, and degradation
During neurotransmission, the pre-synaptic neuron releases
neurotransmitters into the synaptic cleft which bind to cognate
receptors expressed on the post-synaptic neuron. Based upon the
interaction between the transmitter and receptor, neurotransmitters
may trigger a variety of effects in the post-synaptic cell, such as
excitation, inhibition, or the initiation of second messenger
cascades. Based on the cell, these effects may result in the on-site
synthesis of endogenous cannabinoids anandamide or 2-AG by a process
that is not entirely clear, but results from an elevation in
intracellular calcium. Expression appears to be exclusive, so that
both types of endocannabinoids are not co-synthesized. This exclusion
is based on synthesis-specific channel activation: a recent study
found that in the bed nucleus of the stria terminalis, calcium entry
through voltage-sensitive calcium channels produced an L-type current
resulting in 2-AG production, while activation of mGluR1/5 receptors
triggered the synthesis of anandamide.
Evidence suggests that the depolarization-induced influx of calcium
into the post-synaptic neuron causes the activation of an enzyme
called transacylase. This enzyme is suggested to catalyze the first
step of endocannabinoid biosynthesis by converting
phosphatidylethanolamine, a membrane-resident phospholipid, into
N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that
phospholipase D cleaves NAPE to yield anandamide. This process
is mediated by bile acids. In NAPE-phospholipase D
(NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium
concentrations, but not abolished, suggesting multiple, distinct
pathways are involved in anandamide synthesis. The synthesis of
2-AG is less established and warrants further research.
Once released into the extracellular space by a putative
endocannabinoid transporter, messengers are vulnerable to glial cell
Endocannabinoids are taken up by a transporter on the
glial cell and degraded by fatty acid amide hydrolase (FAAH), which
cleaves anandamide into arachidonic acid and ethanolamine or
monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and
glycerol. While arachidonic acid is a substrate for leukotriene
and prostaglandin synthesis, it is unclear whether this degradative
byproduct has unique functions in the central nervous system.
Emerging data in the field also points to FAAH being expressed in
postsynaptic neurons complementary to presynaptic neurons expressing
cannabinoid receptors, supporting the conclusion that it is major
contributor to the clearance and inactivation of anandamide and 2-AG
after endocannabinoid reuptake. A neuropharmacological study
demonstrated that an inhibitor of FAAH (URB597) selectively increases
anandamide levels in the brain of rodents and primates. Such
approaches could lead to the development of new drugs with analgesic,
anxiolytic-like and antidepressant-like effects, which are not
accompanied by overt signs of abuse liability.
Binding and intracellular effects
Cannabinoid receptors are G-protein coupled receptors located on the
pre-synaptic membrane. While there have been some papers that have
linked concurrent stimulation of dopamine and CB1 receptors to an
acute rise in cyclic adenosine monophosphate (cAMP) production, it is
generally accepted that CB1 activation via cannabinoids causes a
decrease in cAMP concentration by inhibition of adenylyl cyclase and a
rise in the concentration of mitogen-activated protein kinase (MAP
kinase). The relative potency of different cannabinoids in
inhibition of adenylyl cyclase correlates with their varying efficacy
in behavioral assays. This inhibition of cAMP is followed by
phosphorylation and subsequent activation of not only a suite of MAP
kinases (p38/p42/p44), but also the PI3/PKB and MEK/ERK pathway
(Galve-Roperh et al., 2002; Davis et al., 2005; Jones et al., 2005;
Graham et al., 2006). Results from rat hippocampal gene chip data
after acute administration of tetrahydrocannabinol (THC) showed an
increase in the expression of transcripts encoding myelin basic
protein, endoplasmic proteins, cytochrome oxidase, and two cell
adhesion molecules: NCAM, and SC1; decreases in expression were seen
in both calmodulin and ribosomal RNAs (Kittler et al., 2000). In
addition, CB1 activation has been demonstrated to increase the
activity of transcription factors like c-Fos and
Krox-24 (Graham et
Binding and neuronal excitability
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The molecular mechanisms of CB1-mediated changes to the membrane
voltage have also been studied in detail. Cannabinoids reduce calcium
influx by blocking the activity of voltage-dependent N-, P/Q- and
L-type calcium channels. In addition to acting on calcium
channels, activation of Gi/o and Gs, the two most commonly coupled
G-proteins to cannabinoid receptors, has been shown to modulate
potassium channel activity. Recent studies have found that CB1
activation specifically facilitates potassium ion flux through GIRKs,
a family of potassium channels.
demonstrated that CB1 is co-localized with GIRK and Kv1.4 potassium
channels, suggesting that these two may interact in physiological
In the central nervous system, CB1 receptors influence neuronal
excitability, reducing the incoming synaptic input. This
mechanism, known as presynaptic inhibition, occurs when a postsynaptic
neuron releases endocannabinoids in retrograde transmission, which
then bind to cannabinoid receptors on the presynaptic terminal. CB1
receptors then reduce the amount of neurotransmitter released, so that
subsequent excitation in the presynaptic neuron results in diminished
effects on the postsynaptic neuron. It is likely that presynaptic
inhibition uses many of the same ion channel mechanisms listed above,
although recent evidence has shown that CB1 receptors can also
regulate neurotransmitter release by a non-ion channel mechanism, i.e.
through Gi/o-mediated inhibition of adenylyl cyclase and protein
kinase A. Direct effects of CB1 receptors on membrane excitability
have been reported, and strongly impact the firing of cortical
neurons. A series of behavioral experiments demonstrated that
NMDAR, an ionotropic glutamate receptor, and the metabotropic
glutamate receptors (mGluRs) work in concert with CB1 to induce
analgesia in mice, although the mechanism underlying this effect is
Functions of the endocannabinoid system
Mice treated with tetrahydrocannabinol (THC) show suppression of
long-term potentiation in the hippocampus, a process that is essential
for the formation and storage of long-term memory. These results
concur with anecdotal evidence suggesting that smoking cannabis
impairs short-term memory. Consistent with this finding, mice
without the CB1 receptor show enhanced memory and long-term
potentiation indicating that the endocannabinoid system may play a
pivotal role in the extinction of old memories. One study found that
the high-dose treatment of rats with the synthetic cannabinoid HU-210
over several weeks resulted in stimulation of neural growth in the
rats' hippocampus region, a part of the limbic system playing a part
in the formation of declarative and spatial memories, but did not
investigate the effects on short-term or long-term memory. Taken
together, these findings suggest that the effects of endocannabinoids
on the various brain networks involved in learning and memory may
Role in hippocampal neurogenesis
In the adult brain, the endocannabinoid system facilitates the
neurogenesis of hippocampal granule cells. In the subgranular
zone of the dentate gyrus, multipotent neural progenitors (NP) give
rise to daughter cells that, over the course of several weeks, mature
into granule cells whose axons project to and synapse onto dendrites
on the CA3 region. NPs in the hippocampus have been shown to
possess fatty acid amide hydrolase (FAAH) and express CB1 and utilize
2-AG. Intriguingly, CB1 activation by endogenous or exogenous
cannabinoids promote NP proliferation and differentiation; this
activation is absent in CB1 knockouts and abolished in the presence of
Induction of synaptic depression
The inhibitory effects of cannabinoid receptor stimulation on
neurotransmitter release have caused this system to be connected to
various forms of depressant plasticity. A recent study conducted with
the bed nucleus of the stria terminalis found that the endurance of
the depressant effects was mediated by two different signaling
pathways based on the type of receptor activated. 2-AG was found to
act on presynaptic CB1 receptors to mediate retrograde short-term
depression (STD) following activation of L-type calcium currents,
while anandamide was synthesized after mGluR5 activation and triggered
autocrine signalling onto postsynapic
TRPV1 receptors that induced
long-term depression (LTD). Similar post-synaptic receptor
dependencies were found in the striatum, but here both effects relied
on presynaptic CB1 receptors. These findings provide the brain a
direct mechanism to selectively inhibit neuronal excitability over
variable time scales. By selectively internalizing different
receptors, the brain may limit the production of specific
endocannabinoids to favor a time scale in accordance with its needs.
Evidence for the role of the endocannabinoid system in food-seeking
behavior comes from a variety of cannabinoid studies. Emerging data
suggests that THC acts via CB1 receptors in the hypothalamic nuclei to
directly increase appetite. It is thought that hypothalamic
neurons tonically produce endocannabinoids that work to tightly
regulate hunger. The amount of endocannabinoids produced is inversely
correlated with the amount of leptin in the blood. For example,
mice without leptin not only become massively obese but express
abnormally high levels of hypothalamic endocannabinoids as a
compensatory mechanism. Similarly, when these mice were treated
with an endocannabinoid inverse agonists, such as rimonabant, food
intake was reduced. When the CB1 receptor is knocked out in mice,
these animals tend to be leaner and less hungry than wild-type mice. A
related study examined the effect of THC on the hedonic (pleasure)
value of food and found enhanced dopamine release in the nucleus
accumbens and increased pleasure-related behavior after administration
of a sucrose solution. A related study found that endocannabinoids
affect taste perception in taste cells In taste cells,
endocannabinoids were shown to selectively enhance the strength of
neural signaling for sweet tastes, whereas leptin decreased the
strength of this same response. While there is need for more research,
these results suggest that cannabinoid activity in the hypothalamus
and nucleus accumbens is related to appetitive, food-seeking
Energy balance and metabolism
The endocannabinoid system has been shown to have a homeostatic role
by controlling several metabolic functions, such as energy storage and
nutrient transport. It acts on peripheral tissues such as adipocytes,
hepatocytes, the gastrointestinal tract, the skeletal muscles and the
endocrine pancreas. It has also been implied in modulating insulin
sensitivity. Through all of this, the endocannabinoid system may play
a role in clinical conditions, such as obesity, diabetes, and
atherosclerosis, which may also give it a cardiovascular role.
While the secretion of glucocorticoids in response to stressful
stimuli is an adaptive response necessary for an organism to respond
appropriately to a stressor, persistent secretion may be harmful. The
endocannabinoid system has been implicated in the habituation of the
hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to
restraint stress. Studies have demonstrated differential synthesis of
anandamide and 2-AG during tonic stress. A decrease of anandamide was
found along the axis that contributed to basal hypersecretion of
corticosterone; in contrast, an increase of 2-AG was found in the
amygdala after repeated stress, which was negatively correlated to
magnitude of the corticosterone response. All effects were abolished
by the CB1 antagonist AM251, supporting the conclusion that these
effects were cannabinoid-receptor dependent. These findings show
that anandamide and 2-AG divergently regulate the HPA axis response to
stress: while habituation of the stress-induced HPA axis via 2-AG
prevents excessive secretion of glucocorticoids to non-threatening
stimuli, the increase of basal corticosterone secretion resulting from
decreased anandamide allows for a facilitated response of the HPA axis
to novel stimuli.
Exploration, social behavior, and anxiety
. These contrasting effects reveal the importance of the
endocannabinoid system in regulating anxiety-dependent behavior.
Results suggest that glutamatergic cannabinoid receptors are not only
responsible for mediating aggression, but produce an anxiolytic-like
function by inhibiting excessive arousal: excessive excitation
produces anxiety that limited the mice from exploring both animate and
inanimate objects. In contrast, GABAergic neurons appear to control an
anxiogenic-like function by limiting inhibitory transmitter release.
Taken together, these two sets of neurons appear to help regulate the
organism's overall sense of arousal during novel situations.
Evidence suggests that endocannabinoids may function as both
neuromodulators and immunomodulators in the immune system. Here, they
seem to serve an autoprotective role to ameliorate muscle spasms,
inflammation, and other symptoms of multiple sclerosis and skeletal
muscle spasms. Functionally, the activation of cannabinoid
receptors has been demonstrated to play a role in the activation of
GTPases in macrophages, neutrophils, and BM cells. These receptors
have also been implicated in the proper migration of B cells into the
marginal zone (MZ) and the regulation of healthy
Interestingly, some disorders seem to trigger an upregulation of
cannabinoid receptors selectively in cells or tissues related to
symptom relief and inhibition of disease progression, such as in that
rodent neuropathic pain model, where receptors are increased in the
spinal cord microglia, dorsal root ganglion, and thalamic neurons.
Historical records from ancient China and Greece suggest that
Cannabis indica were commonly prescribed to ameliorate
multiple sclerosis-like symptoms such as tremors and muscle pain.
Modern research has confirmed these effects in a study on diseased
mice, wherein both endogenous and exogenous agonists showed
ameliorating effects on tremor and spasticity. It remains to be seen
whether pharmaceutical preparations such as dronabinol have the same
effects in humans. Due to increasing use of medical Cannabis
and rising incidence of multiple sclerosis patients who self-medicate
with the drug, there has been much interest in exploiting the
endocannabinoid system in the cerebellum to provide a legal and
effective relief. In mouse models of multiple sclerosis, there is
a profound reduction and reorganization of CB1 receptors in the
cerebellum. Serial sections of cerebellar tissue subjected to
immunohistochemistry revealed that this aberrant expression occurred
during the relapse phase but returned to normal during the remitting
phase of the disease. Other studies suggest that CB1 agonists
promote the survival of oligodendrocytes in vitro in the absence of
growth and trophic factors; in addition, these agonist have been shown
to promote mRNA expression of myelin lipid protein. (Kittler et al.,
2000; Mollna-Holgado et al., 2002). Taken together, these studies
point to the exciting possibility that cannabinoid treatment may not
only be able to attenuate the symptoms of multiple sclerosis but also
improve oligodendrocyte function (reviewed in Pertwee, 2001;
Mollna-Holgado et al., 2002). 2-AG stimulates proliferation of a
microglial cell line by a CB2 receptor dependent mechanism, and the
number of microglial cells is increased in multiple sclerosis.
Cannabis in pregnancy
The developing embryo expresses cannabinoid receptors early in
development that are responsive to anandamide secreted in the uterus.
This signaling is important in regulating the timing of embryonic
implantation and uterine receptivity. In mice, it has been shown that
anandamide modulates the probability of implantation to the uterine
wall. For example, in humans, the likelihood of miscarriage increases
if uterine anandamide levels are too high or low. These results
suggest that intake of exogenous cannabinoids (e.g. cannabis) can
decrease the likelihood for pregnancy for women with high anandamide
levels, and alternatively, it can increase the likelihood for
pregnancy in women whose anandamide levels were too low.
Autonomic nervous system
Peripheral expression of cannabinoid receptors led researchers to
investigate the role of cannabinoids in the autonomic nervous system.
Research found that the CB1 receptor is expressed presynaptically by
motor neurons that innervate visceral organs. Cannabinoid-mediated
inhibition of electric potentials results in a reduction in
noradrenaline release from sympathetic nervous system nerves. Other
studies have found similar effects in endocannabinoid regulation of
intestinal motility, including the innervation of smooth muscles
associated with the digestive, urinary, and reproductive systems.
At the spinal cord, cannabinoids suppress noxious-stimulus-evoked
responses of neurons in the dorsal horn, possibly by modulating
descending noradrenaline input from the brainstem. As many of
these fibers are primarily GABAergic, cannabinoid stimulation in the
spinal column results in disinhibition that should increase
noradrenaline release and attenuation of noxious-stimuli-processing in
the periphery and dorsal root ganglion.
The endocannabinoid most researched in pain is palmitoylethanolamide.
Palmitoylethanolamide is a fatty amine related to anandamide, but
saturated and although initially it was thought that
palmitoylethanolamide would bind to the CB1 and the CB2 receptor,
later it was found that the most important receptors are the
PPAR-alpha receptor, the
TRPV receptor and the
Palmitoylethanolamide has been evaluated for its analgesic actions in
a great variety of pain indications and found to be safe and
effective. Basically these data are proof of concept for
endocannabinoids and related fatty amines to be therapeutically useful
analgesics; palmitoylethanolamide is available under the brand names
Normast and PeaPure as nutraceuticals.
Endocannabinoids are involved in placebo induced analgesia
N-arachidonoyl dopamine (NADA) have been shown to act
TRPV1 channels, which are involved in
TRPV1 is activated by the exogenous ligand
capsaicin, the active component of chili peppers, which is
structurally similar to endocannabinoids. NADA activates the TRPV1
channel with an
EC50 of approximately of 50 nM.[clarify] The high
potency makes it the putative endogenous
TRPV1 agonist. Anandamide
has also been found to activate
TRPV1 on sensory neuron terminals, and
subsequently cause vasodilation.
TRPV1 may also be activated by
methanandamide and arachidonyl-2'-chloroethylamide (ACEA).
Increased endocannabinoid signaling within the central nervous system
promotes sleep-inducing effects. Intercerebroventricular
administration of anandamide in rats has been shown to decrease
wakefulness and increase slow-wave sleep and REM sleep.
Administration of anandamide into the basal forebrain of rats has also
been shown to increase levels of adenosine, which plays a role in
promoting sleep and suppressing arousal.
REM sleep deprivation in
rats has been demonstrated to increase CB1 receptor expression in the
central nervous system. Furthermore, anandamide levels possess a
circadian rhythm in the rat, with levels being higher in the light
phase of the day, which is when rats are usually asleep or less
active, since they are nocturnal.
Anandamide is an endogenous cannabinoid neurotransmitter that binds to
cannabinoid receptors. It has been shown that aerobic exercise
causes an increase in plasma anandamide levels, where the magnitude of
this increase is highest at moderate exercise intensity (i.e.,
exercising at ~70–80% maximum heart rate). Increases in
plasma anandamide levels are associated with psychoactive effects
because anandamide is able to cross the blood–brain barrier and act
within the central nervous system. Thus, because anandamide is a
euphoriant and aerobic exercise is associated with euphoric effects,
it has been proposed that anandamide partly mediates the short-term
mood-lifting effects of exercise (e.g., the euphoria of a runner's
high) via exercise-induced increases in its synthesis.
In mice it was demonstrated that certain features of a runner's high
depend on cannabinoid receptors.
Pharmacological or genetic disruption
of cannabinoid signaling via cannabinoid receptors prevents the
analgesic and anxiety-reducing effects of running.[non-primary
Experimental use of CB1 -/- phenotype
Neuroscientists often utilize transgenic CB1 knockout mice to discern
novel roles for the endocannabinoid system. While CB1 knockout mice
are healthy and live into adulthood, there are significant differences
between CB1 knockout and wild-type mice. When subjected to a high-fat
diet, CB1 knockout mice tend to be about sixty percent leaner and
slightly less hungry than wildtype. Compared to wildtype, CB1
knockout mice exhibit severe deficits in motor learning, memory
retrieval, and increased difficulty in completing the Morris water
maze. There is also evidence indicating that these
knockout animals have an increased incidence and severity of stroke
Endocannabinoids in plants
The endocannabinoid system is by molecular phylogenetic distribution
of apparently ancient lipids in the plant kingdom, indicative of
biosynthetic plasticity and potential physiological roles of
endocannabinoid-like lipids in plants, and detection of
arachidonic acid (AA) indicates chemotaxonomic connections between
monophyletic groups with common ancestor dates to around 420 million
years ago (silurian; devonian). The phylogenetic distribution of these
lipids may be a consequence of interactions/adaptations to the
surrounding conditions such as chemical plant-pollinator interactions,
communication and defense mechanisms. The two novel EC-like molecules
derived from the eicosatetraenoic acid juniperonic acid, an omega-3
structural isomer of AA, namely juniperoyl ethanolamide and
2-juniperoyl glycerol (1/2-AG) in gymnosperms, lycophytes and few
monilophytes, show AA is an evolutionarily conserved signalling
molecule that acts in plants in response to stress similar to that in
Endocannabinoid reuptake inhibitor
Cannabinoid receptor antagonist
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^ a b c d e f g Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A,
Gasperi V, Maccarrone M (2014). "Physical activity and the
endocannabinoid system: an overview". Cell. Mol. Life Sci. 71 (14):
2681–2698. doi:10.1007/s00018-014-1575-6. PMID 24526057. The
traditional view that PA engages the monoaminergic and endorphinergic
systems has been challenged by the discovery of the endocannabinoid
system (ECS), composed of endogenous lipids, their target receptors,
and metabolic enzymes. Indeed, direct and indirect evidence suggests
that the ECS might mediate some of the PA-triggered effects throughout
the body. ... the evidence that PA induces some of the
psychotropic effects elicited by the
Cannabis sativa active ingredient
Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and
peacefulness, strengthened the hypothesis that endocannabinoids (eCBs)
might mediate, at least in part, the central and peripheral effects of
exercise . ... To our knowledge, the first experimental study
aimed at investigating the influence of PA on ECS in humans was
carried out in 2003 by Sparling and coworkers , who showed
increased plasma AEA content after 45 min of moderate intensity
exercise on a treadmill or cycle ergometer. Since then, other human
studies have shown increased blood concentrations of AEA ... A
dependence of the increase of AEA concentration on exercise intensity
has also been documented. Plasma levels of AEA significantly increased
upon 30 min of moderate exercise (heart rate of 72 and 83 %), but
not at lower and significantly higher exercise intensities, where the
age-adjusted maximal heart rate was 44 and 92 %,
respectively ... Several experimental data support the hypothesis
that ECS might, at least in part, explain PA effects on brain
functions, because: (1) CB1 is the most abundant GPCR in the brain
participating in neuronal plasticity ; (2) eCBs are involved in
several brain responses that greatly overlap with the positive effects
of exercise; (3) eCBs are able to cross the blood–brain barrier
; and (4) exercise increases eCB plasma levels [64–67].
^ a b c d Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A
(2012). "Wired to run: exercise-induced endocannabinoid signaling in
humans and cursorial mammals with implications for the 'runner's
high'". J. Exp. Biol. 215 (Pt 8): 1331–1336. doi:10.1242/jeb.063677.
PMID 22442371. Humans report a wide range of neurobiological
rewards following moderate and intense aerobic activity, popularly
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endurance exercise may explain why humans and other cursorial mammals
habitually engage in aerobic exercise despite the higher associated
energy costs and injury risks
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was observed when CB1 and HcrtR1 were co-expressed ... In this
study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1
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• Figure 1: Schematic of brain CB1 expression and orexinergic
neurons expressing OX1 or OX2
• Figure 2: Synaptic signaling mechanisms in cannabinoid and
• Figure 3: Schematic of brain pathways involved in food
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gastric emptying, and intestinal motility. ... CB1 is shown to
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corticotrophin-releasing hormone, in the paraventricular nucleus of
the hypothalamus, and with the two orexigenic peptides,
melanin-concentrating hormone in the lateral hypothalamus and with
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Homepage of the ICRS - The International Cannabinoid Research Society
Homepage of the ECSN – The
Endocannabinoid System Network
Recreational and medical applications
Difference between C. indica and C. sativa
Etymology (cannabis, marijuana)
Religious and spiritual use
List of hemp diseases
List of hemp products
List of hemp products (
Hempcrete • Jewelry • Milk
• Oil • Paper)
Hemp for Victory
Hemp Industries Association
The Emperor Wears No Clothes
Extracts by potency
Cannabis in pregnancy
Effects of cannabis
Adult lifetime use by country
Annual use by country
Bootleggers and Baptists
Global Marijuana March
Legality by country
Legal and medical status
Legal history in the United States
Marijuana Anonymous (MA)
Marijuana Control, Regulation, and Education Act
Marihuana Tax Act of 1937
UK: Return to class B
Uruguay: Law No. 19172
Decriminalization of non-medical use
Rescheduling per the Controlled Substances Act
Cannabis political parties
List of British politicians who have acknowledged cannabis use
List of US politicians who have acknowledged cannabis use
Gonzales v. Raich
Ker v. California
Kyllo v. United States
Kyllo v. United States (thermal imaging)
Leary v. United States
Cannabinoid receptor modulators
Agonists (abridged; see here for more): 2-AG
2-AGE (noladin ether)
Antibodies: Brizantin (Бризантин)
2-AGE (noladin ether)
Agonists: Abnormal cannabidiol
Agonists: 2-AGE (noladin ether)
Inhibitors: 4-Nonylphenylboronic acid
Inhibitors: Betulinic acid
Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor)
ARN-272 (FAAH-like anandamide transporter inhibitor)
Cannabinoids (cannabinoids by structure)
TRP channel modulators
Sanshool (ginger, Sichuan and melegueta peppers)
Allyl isothiocyanate (mustard, radish, horseradish, wasabi)
CR gas (dibenzoxazepine; DBO)
CS gas (2-chlorobenzal malononitrile)
Farnesyl thiosalicylic acid
Ligustilide (celery, Angelica acutiloba)
Linalool (Sichuan pepper, thyme)
Methyl salicylate (wintergreen)
Oleocanthal (olive oil)
Paclitaxel (Pacific yew)
Polygodial (Dorrigo pepper)
Shogaols (ginger, Sichuan and melegueta peppers)
Thiopropanal S-oxide (onion)
Umbellulone (Umbellularia californica)
Adhyperforin (St John's wort)
Hyperforin (St John's wort)
Cooling Agent 10
Rutamarin (Ruta graveolens)
Steviol glycosides (e.g., stevioside) (Stevia rebaudiana)
Sweet tastants (e.g., glucose, fructose, sucrose; indirectly)
Rutamarin (Ruta graveolens)
Triptolide (Tripterygium wilfordii)
Sanshool (ginger, Sichuan and melegueta peppers)
Bisandrographolide (Andrographis paniculata)
Camphor (camphor laurel, rosemary, camphorweed, African blue basil,
Capsaicin (chili pepper)
Carvacrol (oregano, thyme, pepperwort, wild bergamot, others)
Dihydrocapsaicin (chili pepper)
Eugenol (basil, clove)
Evodiamine (Euodia ruticarpa)
Homocapsaicin (chili pepper)
Homodihydrocapsaicin (chili pepper)
Low pH (acidic conditions)
Nonivamide (PAVA) (PAVA spray)
Nordihydrocapsaicin (chili pepper)
Paclitaxel (Pacific yew)
Phorbol esters (e.g., 4α-PDD)
Piperine (black pepper, long pepper)
Polygodial (Dorrigo pepper)
Rutamarin (Ruta graveolens)
Resiniferatoxin (RTX) (Euphorbia resinifera/pooissonii)
Shogaols (ginger, Sichuan and melegueta peppers)
Thymol (thyme, oregano)
Tinyatoxin (Euphorbia resinifera/pooissonii)
Cannabigerolic acid (cannabis)
See also: Receptor/signaling modulators • Ion