Cannabidiol (CBD) is still a big mystery in many ways. How it works and what effect it has on the body is not precisely known, partially because far more clinical trials need to take place before we can say anything for sure, and partially because research on cannabinoids – even the non-psychoactive/non-intoxicating ones – is still restricted in many parts of the world. Yes, we have studies, but many of them are animal or in vitro studies. There are some studies carried out on humans, especially in recent times; but far more research still needs to take place. The human brain is just as big (or perhaps an even bigger) mystery than CBD. How the human brain works, how it evolved and why humans and other highly-developed mammals have consciousness are subjects of intense study and debate, and will likely confound scientists and philosophers for many years to come. Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014“. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. – Own work As we have noted many times throughout the blog posts, the conditions pages and the Leafwell book, the endocannabinoid system (ECS) plays a fundamental role in homeostasis. The ECS is involved in fertility, appetite regulation, pregnancy, pre- and postnatal development, pain sensation, mood, the pleasurable effects of voluntary exercise and the formation of memory. The ECS, it seems, plays an important part in the development and plasticity of the human brain throughout a person’s lifetime. There is a good reason why mammalian bodies produce their own cannabinoids, in particular anandamide and 2-arachidonoylglycerol (2-AG). When the ECS is disrupted, or if a person’s genetics do not encode cannabinoid receptors or endocannabinoids properly, health problems occur. The ECS can be disrupted by injuries or illnesses, which can form a part of an inflammatory event (e.g. a long-term viral or bacterial infection) that can cause both short- and long- term changes to the functioning of the ECS. Age also plays a factor in how the ECS functions, just as the brain changes over the course of one’s lifetime. Keeping the ECS “in balance” could therefore help overcome or theoretically even prevent conditions that affect the human brain as it ages. There are several neurological and mood disorders where disruption to the ECS is seen. Some of these conditions are genetic and can occur at any age, whilst others are more likely to occur as we age (although there may still be a genetic component). Some are also autoimmune conditions. There are several studies and reports suggesting that CBD and other cannabinoids (including THC in some instances) may be useful for the treatment of neurological and mood disorders such as: Epilepsy, particularly childhood forms of epilepsy such as Dravet syndrome and Lennox-Gastaut syndrome. Parkinson’s Disease Multiple Sclerosis (MS) Traumatic Brain Injuries (TBI) / Stroke Alzheimer’s Disease Depression Anxiety Post-Traumatic Stress Disorder (PTSD) Bipolar Disorder Schizophrenia Migraine / Headache Chronic Pain Trigeminal Neuralgia (TN) Autoimmune Encephalitis There are several reasons why CBD works for the above conditions. CBD’s Effect on Cannabinoid Receptors CBD has a low affinity for the cannabinoid receptors, CB1 (found mostly in the brain, spine, lungs and gastrointestinal tract) and CB2 (found mostly in the gastrointestinal system, immune system and to some extent in the brain), and is an indirect antagonist of these receptors. CBD may, however, increase CB1 receptor density. CBD may both inhibit the effects of THC, as well in increase its duration of effect, depending upon dosage and personal physiology. Cannabinoids such as THC act as a partial agonist of CB1 receptors, which is why it has a psychoactive effect. CBD, meanwhile, does not necessarily have the same intoxicating effects as THC, although it is arguable that it has what could be best described as a “non-intoxicating psychoactive effect”. The pharmacological effects of CBD have also been attributed to peroxisome proliferator-activated receptor gamma (PPARG, aka glitazone), receptor agonism. Author: Dolleyj. From https://commons.wikimedia.org/wiki/File:Agonist_%26_Antagonist.jpg Licensed under the Creative Commons Attribution-Share Alike 3.0 Unported CBD is also an antagonist of the G protein-coupled receptor, GPR55, and an inverse agonist of GPR3, GPR6 and GPR12. CBD may inhibit fatty acid amide hydrolase (FAAH). This may allow a greater amount of anandamide to be available in the bloodstream, which is captured by CB1 receptors. Coupled with the increased CB1 receptor density, this is one of the many possible reasons why CBD may help for pain, depression and anxiety. For conditions such as Alzheimer’s, MS, Parkinson’s, TBI/stroke and epilepsy, attenuation of CB1 and CB2 receptors (which can be achieved by CBD, THC and other cannabinoids in various ways) may: Help reduce neuroinflammation Facilitate neurogenesis Attenuate excitotoxicity Attenuate hypothermia – CBD and THC may reduce body temperature Calcium channel blocker Sodium channel blocker Attenuation of motor and autonomic deficits in those with spinal cord injuries Enhancing anandamide signalling – disruption of which is implicated in autism CBD’s Effect on Serotonin Receptors The other reason why CBD may have antidepressant, anxiolytic and neuroprotective effects is because it is a partial agonist of the 5HT1A serotonin receptor – a receptor targeted by many current antidepressants. CBD also modulates resting cerebral regional blood flow (rCBF) in the brain – another potential reason for CBD’s anxiolytic effects. Author: Pancrat. From https://commons.wikimedia.org/wiki/File:Serotonin_facilitation_dors_horn.png Licensed under the Creative Commons Attribution-Share Alike 3.0 Unported CBD’s Effect on Opioid Receptors CB1 receptors and opioid receptors are found in many of the same areas of the brain. Indeed, the two systems may even “talk” to one another. CBD has been found to be an allosteric modulator (meaning it indirectly influences the effects of a primary ligand) of the mu- and delta- opioid receptors. Both CBD and THC may reduce opioid cravings, as well as act as an indirect modulator of opioid receptors. This helps explain why cannabis may be used to reduce or replace opioids for chronic pain. CBD’s Effect on Dopamine Receptors Cannabis exerts effects on the mesolimbic dopamine system. CBD is also an inverse agonist of the GPR6 receptor, depletion of which increases dopamine levels. This could prove very useful for conditions such as Parkinson’s. Dopamine dysregulation is also implicated in the development of schizophrenia. Coupled with CBD’s ability to modulate rCBF, this may be one reason why CBD could be used for disorders involving psychosis. From https://commons.wikimedia.org/wiki/File:Dopamine.svg CBD’s Effect on the Transient Receptor Potential Vanilloid 1 (TRPV) Receptors Some of CBD’s antiseizure, painkilling/distracting and temperature-lowering effects could be due to it activating and desensitizing TRPV1 receptors. “ … [C]annabinoids can increase or decrease neuronal excitability depending on neurotransmitter and brain region affected.” CBD’s Effect on Glutamate N-Methyl-D-Aspartic Acid (NMDA) Receptors To quote ‘Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction’: “Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs.” CBD seems to have an indirect influence on NMDA receptors, as it affects CB1 receptors, which couples with NMDA receptors and can either dampen or increase NMDA receptor activity. CBD molecular structure. We hope the above has been helpful in explaining how and why CBD could potentially help for so many neurological conditions. Much of the science into precisely how and why CBD and other cannabinoids work for so many neurological conditions, as well as what part the ECS plays in it, still needs to be discovered. Many of the studies referenced in the links above are on rodents or human cell lines in labs. Much more research needs to be carried out to see which precise sets of cannabinoids are useful, at which dosage and for which segment of the population. Let’s hope the research gets to be carried out.