The human Endocannabinoid System is an ancient neuromodulatory system found in all vertebrates. It plays a role in a wide variety of functions and processes and it is this breadth of effect that results in medicinal cannabis having such a wide scope of activity across a multitude of symptoms. Understanding the Endocannabinoid System at a basic level helps us, as prescribers, conceptualise the ways in which medicinal cannabis can assist in symptom management, and also some of the ways in which it is not like more traditional pharmaceutical compounds. Understanding the Endocannabinoid System helps to refute one of the frequent criticisms of medicinal cannabis - that ‘anything that can do so many things must do nothing at all.’
The homeostatic role of the Endocannabinoid System explains the key patient-reported benefits of medicinal cannabis, regarding not only improvement in key symptoms such as pain, anxiety and nausea, but also improvement in a feeling of overall wellness and coping ability.
The Endocannabinoid System is a complicated, widespread neuromodulatory system that has effects across a wide variety of systems and is a vital contributor to homeostasis. It plays an important role in CNS development, synaptic plasticity and the response to endogenous and environmental insults. The processes and systems impacted include pain, inflammation and immune activation, mood, appetite, memory, stress, sleep and also general cell maintenance functions.
The Endocannabinoid System involves three key components:
The two main endocannabinoids identified so far, although there may be others, are the lipids arachidonoyl ethanolamide (anandamide / AEA) and 2-arachidonoyl glycerol (2-AG). These two endocannabinoids are produced as needed, not held in reserve. Their precursors are present in lipid membranes and they are released into extracellular space on demand. This contrasts with classical neurotransmitters that are synthesised ahead of time and held in vesicles.
There are two main endocannabinoid receptors:
Transient receptor potential channels (TRP) and peroxisome proliferator activated receptors (PPARs) can also interact with cannabinoids. CB1 and CB 2 are G-protein-coupled receptors and their activation has diverse consequences on cellular physiology including synaptic function, gene transcription and cell motility.
CB1 receptors are particularly abundant in the spinal cord, cortex, basal ganglia, hippocampus and cerebellum. The majority are sited on axon terminals and the pre-terminal segment. Importantly CB 1 receptors are also expressed in adipose tissue, the pancreas, the liver, the GI tract, the heart, skeletal muscle and the reproductive system.
CB2 receptors are expressed at lower levels in the CNS but exist in the microglia and vascular elements. CB2 receptors are particularly abundant in immune tissue, including on B cells, NK cells and neutrophils. Their expression seems to increase in some forms of nerve injury and CB2 expression is highly inducible, increasing up to 100-fold following tissue injury or inflammation (Maresz / Carrier et al, 2005).
There are several other receptor types, including GPR18 and GPR55, that are also known to bind to endocannabinoids. Among these other receptor types the transient receptor potential cation channel subfamily V member 1 (TRPV1) is activated by AEA and is the best-documented regarding its significant role in synaptic transmission and pain regulation. (Zou / Kumar, 2018).
The endocannabinoids act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of post-synaptic transmission. Endocannabinoids are transported into cells by specific uptake systems and degraded by the two key enzymes FAAH (fatty-acid-amide-hydrolase) and MAGL (monoacylglycerol lipase).
The CB1 receptor is encoded by the gene CNR1 and several varying isoforms have been discovered. CBR2 is encoded by the gene CNR2 and two isoforms have so far been coded.
AEA is a high-affinity partial agonist at the CB1R with very low activity at CB2R, whereas 2AG is a full agonist at both families of receptor with moderate to low affinity.
The plant Cannabis Sativa has a history of human use that can be traced back, at least to China 5000 years ago when it was used to treat cramps and pain. Cannabis contains many hundreds of different phytocannabinoids with the two most studied being THC (tetrahydrocannabinol) and CBD (cannabidiol). Issues surrounding recreational use, the fact that cannabis is illegal in some areas and concerns regarding the psycho-active effects of high-dose THC have limited therapeutic use in many countries.
THC agonises both CB1 and CB 2 receptors whilst CBD preferentially agonises CB2. The metabolism of both is incredibly complex. THC, for example, is metabolised by both phase I and phase II enzymes into more than 100 metabolites. THC has psychoactive side-effects which CBD completely lacks. The chemical structure of THC is similar, but not identical to, anandamide whereas CBD more closely mimics 2-AG.
The complexity and breadth of the human Endocannabinoid System explains the widespread symptomatic benefits that patients with certain conditions can experience with appropriately prescribed medicinal cannabis. There are multiple pathways that have been elucidated that connect symptomatic benefit for specific conditions.
One well-recognised use of medicinal cannabis is as an aid to seizure control in severe epilepsy. CB1 inhibits GABA glutamate release from presynaptic terminals leading to a modulation of neurotransmission. This has been proposed as the underlying mechanism of CB1R-mediated neuroprotection against excitotoxicity – a known key pathological process in both epilepsy and neurodegenerative disorders. (Katona, Freund, 2008). This is just one example of a pathway, grounded in the analysis of the human endocannabinoid system, that explains the symptomatic benefit of medicinal cannabis in the management of one patient population. Similar research is elucidating pathways for pain, nausea, appetite stimulation, mood stabilisation, panic modulation and sleep.
The widespread expression and myriad functions of the human Endocannabinoid System supports research aimed at furthering the targeting of specific drug formulations, and also supports the scientific validity of medicinal cannabis as a therapeutic option for a wide variety of patients whose symptoms are sub-optimally managed with conventional therapy.
L.H.Bennett DevjitSrivastava James J.Cox Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity British Journal of Anaesthesia Volume 123, Issue 2, August 2019, Pages e249-e253
F M Leweke, D Piomelli, F Pahlisch, D Muhl, C W Gerth, C Hoyer, J Klosterkötter, M Hellmich & D Koethe “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia” Translational Psychiatry volume 2, page 94 (2012)
Fitzgibbon Marie, Finn David P, Roche Michelle High Times for painful Blues: The Endocannabinoid System in Pain-Depression ComorbidityInternational Journal of Neuropsychopharmacology Volume 19, issue 3, March, 2016.
Maresz K, carrier EJ, Ponomarev ED, et al Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli Journal of Neurochemistry 2005;95:437-445
Zou Shenglong, Kumar Ujendra Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System International Journal of Molecular Science . 2018 Mar: 19(3): 833
Katona I, Freund T.F Endocannabinoid signalling as a synaptic circuit breaker in neurological disease. Nat. Med. 2008;14:923-930
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