An interesting review article appeared only a few months ago in a journal called Alternative Therapies (in Health and Medicine). Although the journal title may sound wishy-washy it is a peer reviewed journal with some interesting papers within. This paper in particular ‘The Endocannabinoid System and its Modulation by Cannabidiol (CBD)’ is one of the more thorough looks at the endocannabinoid system we have seen; a review encompassing some well-known research into the system. However, we must remember that despite the often-touted miracle discovery of the endocannabinoid system, this is still a new area of research and much more work needs to be done in the field before we can draw definitive conclusions about how the system works in its entirety and the full role (endo) cannabinoids play in human health. I have summarised this review below, extracting the most important parts. The paper is linked above if you would like to delve into the full article and follow the citations. It should be noted that some of the original authors of this paper are involved in the cannabis industry to varying degrees. Academics must declare conflicts of interest on all publications as they have done here. Having said this, their citations are of generally good quality, peer-reviewed research.
The endocannabinoid system (ECS) is a signalling system with multiple parts, many of which are likely unknown as of writing. Based on current evidence, the ECS is present in all animals and is affected by diet, sleep, stress and a host of other factors including exposure to our own natural endocannabinoids and phytocannabinoids like cannabidiol (CBD). Understanding how the ECS works and how we can modify its activity may offer tremendous therapeutic potential in the treatment of a wide range of health disorders ranging from mental health issues to pain, nerve damage, metabolic diseases like diabetes and brain disorders like Parkinson’s Disease.
Interest in the use of phytocannabinoids derived from cannabis has increased tremendously over the last few years, driven largely by changes to laws regarding the consumption of cannabis in the USA. Heightened research interest surrounding the mechanism of action of tetrahydrocannabinol (THC), the primary psychoactive ingredient of cannabis and other compounds like cannabidiol (CBD) has resulted from increased consumer interest. Phytocannabinoids interact with enzymes, endogenous ligands and receptors that collectively embody the endocannabinoid system (ECS). The ECS is one of the most evolutionarily conserved signalling systems currently known to science and thought to be 600-million years old. The system is present in every studied animal species with the exception of insects. Its primary function is to restore balance (homeostasis) following cellular stress. As such, the system is a constant flux of up and down regulation. The ECS is incredibly far reaching and interacts with myriad other body systems in some capacity, being involved in pain perception, mood, appetite, memory and reward processing.
Following on from ground-break working involving isolation of THC and early research into its mechanism of action, the G-protein coupled receptor to which THC acts as a partial agonist was discovered and dubbed cannabinoid receptor 1 (CB1). Only a few years later in 1992, the endogenous cannabinoid (endocannabinoid) anandamide-N-arachidonoylethanolamide (AEA) was identified. A second endocannabinoid 2-arachidonoylgylcerol (2-AG) as well as a second cannabinoid receptor (CB2) were discovered in the mid 1990’s. These two receptors and two endocannabinoids have seen increased research interest, partly due to the explosion of consumer interest in cannabis derivatives like CBD.
Endocannabinoids are fatty-acid neurotransmitters that act as the signalling molecules of the endocannabinoid system. They produce most of their effects by acting through receptors. While AEA and 2-AG are the most well studies endocannabinoids, other endocannabinoid-like compounds exist that function in similar ways including oleoyl ethanolamine (OEA) and palmitoyl ethanolamine (PEA). Endocannabinoids share some structural similarity with phytocannabinoids (those found in cannabis) but generally have less affinity for the cannabinoid receptors. Like their ‘phyto’ counterparts they interact with a range of receptors, not just cannabinoid receptors. AEA and 2-AG are regulated by different systems, allowing the two molecules to exert different effects even within the same cell. Pathological and normal physiological conditions can alter the levels of either or both molecules simultaneously.
AEA is a high affinity, partial agonist of both CB1 and CB2 receptors. AEA inhibits adenyl-cyclase activity within cells via both receptors – this appears to be a common effect of cannabinoids.
2-AG is very similar in chemical structure to AEA but it is a moderate affinity, full agonist at both CB1 and CB2. It is synthesised by different enzymes to AEA. 2-AG is the most abundant endocannabinoid in the central nervous system (CNS) and plays a major role in CNS development and synaptic plasticity.
Endocannabinoid System Receptors
The cannabinoid receptors (CB1 and CB2) are 7-transmembrane domain GPCRs. These two receptors differ in their protein make-up, distribution, signalling mechanisms as well as other characteristics. Interestingly, despite being dubbed cannabinoid receptors, the only cannabinoids currently known with high affinity for either receptor are THC and THCV (tetrahydrocannabivarin). CBD actually has negligible affinity for both receptors. Other ‘non-cannabinoid’ receptors also play a role in the ECS as detailed below.
CB1 is the most abundant and densely concentrated receptor in the human CNS. They are particularly prevalent in nociceptive (relating to the perception or sensation of pain) areas of the brain and spinal cord but can also be found on immune system cells, fat tissues, liver, muscle, lungs and the kidneys. Interestingly, these receptors are entirely absent from areas of the brain stem which control respiration and cardiac activity which is one of the reasons cannabis doesn’t suppress breathing or stop the heart even in large quantities. Conversely, opioids do affect this area of the brain stem and respiratory depression is the key cause of death in cases of opioid overdose.
CB2 receptors are mainly located in the periphery as opposed to the more central expression of CB1. CB2 can be found mainly on immune tissues, lymphoid tissues as well as the heart and liver. The abundant expression of this receptor in immune tissues highlights the role of the ECS in immune system regulation and modulation of CB2 may be particularly useful in combating inflammatory-based disorders.
The discovery of the GPR55 receptor represents a new generation of research that has started to show the ECS is much more complicated than previously thought. Researchers have hypothesised that the GPR55 receptor may be the ‘third’ cannabinoid receptor due to its affinity for both endo- and phytocannabinoids. GPR55 is expressed widely through the brain and periphery and is involved in the regulation of multiple processes including motor activity, nociception, energy expenditure, anxiety modulation and bone metabolism to name only a few.
Commonly called ‘Serotonin receptors’, these are a class of GPCRs and ligand-gated ion channels found mainly in the central and peripheral nervous system. Serotonin is the predominant endogenous ligand within our bodies and is related to histamine, dopamine and adrenaline. 14 different types of this receptor exist which allows serotonin to exert a wide range of effects in the body. Serotonin is typically associated with the regulation of pain, nausea, anxiety, addiction and appetite. There is emerging evidence that CBD interacts with the serotonin receptor which may influence pain perception. As both the ECS and serotonin systems have overlapping control of things like stress and emotional processing, more research effort is being spent to work out how they interact.
Adenosine receptors are a group of GPCRs to which adenosine binds as an endogenous ligand. Caffeine is known to act as an exogenous antagonist producing the stimulating effects of coffee. In humans, 4 types are known— A1, A2A, A2B and A3. These different receptor types possess distinct areas of expression, different means of regulation, and different signalling mechanisms. Adenosine receptors provide broad anti-inflammatory effects. Additionally, adenosine modulates synaptic plasticity and neurotransmitter release.
Endocannabinoid System Functions
In addition to acting as neurotransmitters (molecules which transmit information along nerves), endocannabinoids also act as autocrine and paracrine regulators. For example, in the presence of inflammatory bowel disease (IBD), endocannabinoids interact with various gut receptors (both cannabinoid and non-cannabinoid) on the cells that produce endocannabinoids (autocrine regulation) as well as nearby immune cells (paracrine regulation) to reduce additional infiltration and inflammation caused by said immune cells. On top of this role in inflammatory processes, a growing body of work suggests endocannabinoids play a role in normal gut function. AEA for example inhibits gut motility, delays gastric emptying and reduces gastric secretions all indicative of a role in energy balance – these are similar functions to appetite-regulating hormones such as Peptide YY. Additionally, CB1 receptor agonism has been shown across a variety of models to be anti-emetic (anti-vomiting) and can reduce nausea. Conversely, antagonism of the CB1 receptor induces emesis. CBD has been shown to produce anti-nausea effects by indirect agonism of serotonin receptors.
Food Intake and Reward
The control of food intake, energy expenditure and reward involve a delicate interplay between central neurons and peripheral organ systems. An incredibly complex orchestra of processes which we are still unravelling. Hormones and other peptides play a vital role and cannabinoids show similar functional profiles such that they may be putatively included in the category of orexigenic molecules – molecules which stimulate appetite.
Administration of AEA, an endocannabinoid, has been shown to stimulate appetite in various rodent models. Additionally, CB1 receptors are expressed in key hypothalamic brain areas associated with energy regulation. Interestingly, much like the hunger hormone ‘ghrelin’ levels of endocannabinoids gradually increase over time until feeding is commenced, at which point levels drop again.
Cannabinoid-dopamine interactions appear to play an important role in feeding and the dopaminergic system is important in controlling reward processing including the rewarding aspect of food. Leptin, a key energy-balance hormone, has also been shown to regulate hypothalamic levels of endocannabinoids. One of the more common side effects of CBD is changes to feeding behaviour and weight, and effects on these feeding systems and hormones are likely culprits.
Pain and Inflammation
Cannabinoid receptors are present on nociceptors and other sensory neurons in pain processing pathways in the brain and spinal cord, often found together with opioid receptors. Activation of CB1 receptors in these areas has been shown to inhibit pain signals to higher brain regions and modulate pain signals in descending pain pathways.
Numerous preclinical studies have demonstrated the beneficial effects of cannabinoids, including CBD, in animal models of acute pain, chronic pain, and neuropathic pain, some demonstrating opioid-sparing effects. Human studies investigating CBD-induced analgesia in humans, however, are few.
Although reductions in pain have reported in numerous animal models, the mechanism(s) for this analgesic effect are still being investigated and are currently not well understood. Their effects on pain may be linked to their anti-inflammatory effects as shown in other rodent models. Ultimately CBD-induced analgesia as well as the compounds effects on inflammation are likely down to a complex interplay of mechanisms.
Endocannabinoids are involved in local and central regulation of reproduction and are present in most reproductive fluids and tissues. A properly functioning ECS helps orchestrate nearly all reproductive events from gamete production and fertilisation to successful pregnancy, birth, and lactation.
Interestingly, pharmacological antagonism of CB1 blocks ECS signalling and leads to failure of pregnancy. High levels of maternal anandamide appear detrimental to placental and foetal development. The enzymatic degradation of anandamide appears to be an early marker of spontaneous abortion and may even be useful as a diagnostic tool for monitoring of early pregnancy.
Hypothalamic-Pituitary-Adrenal (HPA) Axis
Studies of the endocannabinoid system support its importance in modulation of the hypothalamic-pituitary-adrenal (HPA) axis, including regulation of mood and anxiety and extinction of fear learning. Cannabinoid action on neuroendocrine functioning, including ACTH levels, is mediated by CB1 signalling in the hypothalamus. Alternately, pre-treatment with the CB1 antagonist Rimonabant, prior to a stressor, has been shown to blunt HPA function in a mouse model.
The Entourage Effect
In the CBD and wider cannabis industry the term ‘entourage effect’ has been coined to describe the so-called synergistic effects of consuming multiple phytocannabinoids simultaneously. This idea is not exclusive to cannabis nor to cannabinoids as synergism exists in multiple biological examples. The term actually originated to describe how endocannabinoid-like mediators could increase the biological activity of the endocannabinoid 2-AG at the CB1 receptor. Although there is strong evidence that terpenes, cannabinoids and phytocannabinoids interact and can change the activity of each other at receptors, there is no clinical evidence that the entourage effect exists with regard to cannabis – that is to say, no clinical study has shown a synergistic effect of taking multiple phytocannabinoids in unison. Research hopes to address this directly in the near future.
Based on current studies, CBD is a very well tolerated substance with few significant side effects even when consumed at high doses of 1,500 mg per day on consecutive days. This is not to say that CBD is side-effect free. The most commonly reported side effects include fatigue, dry mouth and changes to appetite and weight. Having said this, when CBD is used to treat medical conditions, the low side-effect profile can improve the likelihood of patients continuing treatment in comparison to FDA pharmaceutical drugs.
It should be noted that the route of administration as well as if cannabinoids are given as extracts or in isolate can all effect physiological outcomes. When given as a broad-spectrum extract, a linear dose-response curve is observed but when CBD is given as an isolate, a bell-shaped-dose-response curve is seen. Not only does the dose-response profile change but so can the side-effect profile. This may point towards the ‘entourage effect’ being a real response with cannabis extracts but further studies are required to prove this definitively.
The endocannabinoid system (ECS) is an extensive endogenous signalling system. The ECS is seemingly ubiquitous in animal species and modulated by diet, sleep, exercise, stress, and a multitude of other factors, including exposure to phytocannabinoids, like CBD. Modulating the activity of this system may offer tremendous therapeutic promise for a diverse scope of diseases, ranging from mental health disorders, neurological and movement disorders, pain, autoimmune disease, spinal cord injury, cancer, cardiometabolic disease, stroke, TBI, osteoporosis, and others. CBD and other cannabis derivates are not miracle cures or cure-all remedies. Instead they are interesting compounds with diverse therapeutic values. While clinical evidence in humans remains lacking, the next decade will see markedly more publications potentially unlocking the full power of cannabidiol in the context of human health.
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