The Endocannabinoid System
The 'ECS' is thought to connect the physical and emotional responses to stress with appetite and energy regulation. It is thought to affect a wide variety of physiologic processes including nociception (pain sense), motor control, memory and learning, appetite, food intake, and energy balance... read more
Biomedical research on cannabis began in earnest in the latter part of the last century primarily because of the prevalence of overweight and obesity in both adults and children. Knowledge of the ECS may lead to better treatment for cardiovascular disease and type 2 diabetes associated with being overweight.
The ECS is a complex endogenous signaling system (produced by the brain) comprised of Cannabinoid receptors (CB1 and CB2), Endocannabinoid ligands, and proteins that are involved with endocannabinoid synthesis. Endocannabinoid receptors are found mostly in the brain, but also in tissues, glands such as the liver, gastrointestinal tract and skeletal muscles.
Pharmaceutical companies are primarily interested in the inactivity mode of the ECS receptors.
The ECS is thought to connect the physical and emotional responses to stress with appetite and energy regulation. It is thought to affect a wide variety of physiologic processes including nociception (pain sense), motor control, memory and learning, appetite, food intake, and energy balance.
Cannabis contains a
number of cannabinoids, of which the most abundant are THC ( D
9-tetrahydrocannabinol), CBD (cannabidiol) and CBN (cannabinol). The
active ingredient, which gets you high, is THC. In the plant, CBD is a
precursor and CBN a metabolite of THC. As cannabis gets older, THC
gradually breaks down to CBN.
THC is the substance found to have most psychoactive effect, and also the most effect on symptoms such as pain or bronchospasm. CBN and CBD are not psychoactive themselves; however CBD can take the edge off a THC high, tending to relax the user rather than increasing anxiety and paranoia. CBD has also been found to have anticonvulsant properties (potential value in treating epilepsy, MS, muscle spasms etc), and recently published research has indicated CBD to be effective in reducing neurotoxic brain damage following strokes or head trauma.
mechanism of action also suggests CBD may offer some protection against
ecstasy-derived neurotoxicity (long-term depletion of serotonergic
receptors), although this has not specifically been investigated. CBD
is normally present in significant quantities in hashish (cannabis
resin), although in most herbal cannabis or "skunk" the levels of CBD
are usually low or absent.
cannabis offers some advantages over oral preparations (rapid onset of
action, ability to control dose), the smoke contains carcinogens, tars
and other lung irritants which may cause respiratory diseases and lung
The lack of an
effective filter in "roaches" and the deep
inhalation techniques used by cannabis smokers increases this risk.
However the study of
smoke composition quoted by the BMA and others
referred to poor quality herbal cannabis smoked "neat", and the
relevance of these results to tobacco/hash spliffs or high-THC
varieties is questionable.
At least one pharmaceutical company is developing alternative quick-acting delivery systems for plant-derived cannabinoid combinations, avoiding the need for smoking.
In standard neurotransmission, the pre-synaptic neuron
releases neurotransmitter into the synaptic cleft which binds to
cognate receptors expressed on the post-synaptic neuron. Upon binding,
the neuron depolarizes.
This depolarization facilitates the influx of calcium into the
neuron; this increase in calcium activates an enzyme called transacylase which
catalyzes the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine,
a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine
(NAPE). Experiments have shown that multiple phospholipases cleave
NAPE to yield anandamide.
In NAPE-phospholipase D (NAPEPLD) knockouts, the PLD-mediated
cleavage of NAPE is reduced, not abolished, in low calcium
concentrations, suggesting multiple, distinct pathways are involved in AEA
biosynthesis (Leung et al., 2006).
Once released into the extracellular space by a putative
endocannabinoid transporter, messengers are vulnerable to glial
inactivation. Endocannabinoids are uptaken via a putative transporter
and degraded by fatty
acid amide hydrolase (FAAH) which cleaves anandamide and MGLL, which cleaves 2-AG to arachidonic acid
and arachidonic acid & glycerol, respectively (reviewed in Pazos et
al., 2005). While arachidonic acid is a substrate for leukotriene and prostaglandin
synthesis, it is unclear whether this degradative byproduct has novel
functions in the CNS (Yamaguchi et al., 2001; Brock, T., 2005).
Emerging data in the field also points to FAAH being expressed in the postsynaptic neuron, suggesting it also contributes to the clearance and inactivation of anandamide and 2-AG by endocannabinoid reuptake.
Binding & Signal Transduction
While there have been some papers that have linked
concurrent stimulation of dopamine and CB1 receptors to an acute rise
in cAMP production, it is accepted that CB1 activation causes an
inhibition of cyclic
adenosine monophosphate (or cAMP) when activated alone.
This inhibition of cAMP is followed by phosphorylation and
subsequent activation of not only a suite of MAP kinases 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 showed an increase in the expression of 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 al., 2006).Endocannabinoid Binding & Alterations in Neuronal Excitability
The molecular mechanisms of CB1-mediated changes to the membrane voltage have also been studied in detail. CB1 agonists reduce calcium influx by blocking the activity of voltage-dependent N-, P/Q- and L-type calcium channel.
In addition to acting on calcium channels, Gi/o and Gs,
subunits of G
protein-coupled receptors, activation has also been shown to
channel activity. Recent studies have found that CB1 activation
facilitates GIRK, a potassium channel belonging to the Kir3 family.
Corroborating Guo and Ikeda, Binzen et al. performed a series
of immunohistochemistry experiments that demonstrated CB1 co-localized
with GIRK and Kv1.4
potassium channels, suggesting that these two may interact in
In the central nervous system, CB1 receptors, for the most part,
influence neuronal excitability indirectly, by reducing the impact of
incoming synaptic input.
This mechanism ("presynaptic inhibition") is believed to occur when a neuron ("postsynaptic") releases endocannabinoids in a retrograde fashion, binding to CB1 receptors expressed on nerve terminals of an input neuron ("presynaptic"). CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent input from the presynaptic neuron has less of an impact 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 Still,
direct effects of CB1 receptors on membrane excitability have been
reported, and strongly impact the firing of cortical neurons In
a series of behavioral experiments, Palazzo et al. demonstrated that NMDA, 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
Together, these findings suggest that CB1 influences neuronal excitability by a variety of mechanisms, and these effects are relevant to perception and behavior.
CB1 -/- Phenotype
Neuroscientists often utilize transgenic CB1 knockout mice (i.e. the mice have had the gene encoding the CB1 receptor deleted or removed) to discern novel roles for the ECS. While CB1 knockout mice are healthy and live into adulthood, there are some differences among mice without CB1 and wild-type (i.e. "normal" mice with the receptor intact); When under 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 and seizure (Parmentier et al., 2002; Marsicano et al., 2003).
Mice treated with tetrahydrocannabinol 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 smoked preparations of Cannabis attenuates short-term memory. Indeed, 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. Recent research reported in a 2005 Journal Of Clinical Investigation article indicate that the high-dose treatment of rats with the synthetic cannabinoid, HU-210 over a period of a few 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.
Emerging data suggests that THC
acts via CB1 receptors on hypothalamic nuclei, thus directly increasing
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 have
higher-than-normal levels of hypothalamic endocannabinoids.
Similarly, when these mice were treated with an endocannabinoid
antagonist, 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 (or "normal") mice.
While there is need for more research, these results (and others) suggest that exogenous cannabinoids (as from smoking marijuana) in the hypothalamus activates a pathway responsible for food-seeking behavior.
Sweet taste receptors are found in the intestine and pancreas, where they help regulate nutrient absorption, insulin secretion and energy metabolism.
If endocannibinoids also modulate the responses of pancreatic and intestinal sweet receptors, the findings may open doors to the development of novel therapeutic compounds to combat metabolic diseases such as obesity and diabetes. Monell Chemical Senses Center (2009, December 23). Enhanced sweet taste: Endocannabinoids act directly on tongue taste receptors.
ECS and Multiple
Historical records from ancient China and Greece
suggest that preparations of Cannabis Indica were commonly
prescribed to ameloriate multiple sclerosis-like symptoms such as
tremors and muscle pain; unfortunately, however, treatment with marinol has shown the same
Due to the illegality of 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 (Cabranes et al., 2006). 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 (Cabranes et al., 2006).
There is recent data indicating that CB1 agonists promote the
in vitro survival of oligodendrocytes, specialized support
glia that are involved in axonal myelination, 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-arachidonylglycerol stimulates proliferation of a microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.
Human Female Reproduction
The developing embryo expresses cannabinoid receptors
early in development that are responsive to anandamide which is
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 proper intake of exogenous cannabinoids (e.g. marijuana) 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. More...
In the adult brain, the endocannabinoid system facilitates neurogenesis ("birth of new neurons") 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.
Very recent data suggests that the maturing granule cells are dependent on a reelin, a molecular guidance cue, for proper migration through the dentate gyrus (Gong et al., 2007). NPs in the hippocampus have been shown to possess FAAH and express CB1 and utilize 2-AG.
Intriguingly, CB1 activation by endogenous or exogenous promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.