The Endocannabiniod Receptor System
Endocannabinoid Receptor System:
The endocannabinoid system (ECS) is a complex regulatory system found within all complex animals, from fish to humans. The ECS regulates diverse functions such as memory, digestion, motor function, immune response, inflammation, appetite, blood pressure, bone growth, and protection of neural tissues. The ECS works by maintaining homeostasis (physiological stability) and helping to redress imbalances presented by disease or injury. If disease or injury is prolonged, your body may not produce appropriate amounts of endocannabinoids. In order to remedy endocannabinoid deficiency, we can supplement with a 1:1 ratio diet of Omega 3 : Omega 6, phytocannabinoids (THC, CBD, CBG, etc...) and terpenes. These act as endocannabinoids and re-activate the receptors to achieve homeostasis. The ECS is comprised of three principal elements: Endocannabinoid receptors, Endocannabinoids, and enzymes that synthesize and/or metabolize these endocannabinoids.
Endocannabinoids: Neurotransmitters that regulate homeostasis. Endogenous cannabinoids Anandamide and 2-AG are created and released by our bodies’ ECS. We can supplement with exogenous cannabinoids to correct imbalances causing disease and tissue injury by inhaling or ingesting phytocannabinoids such as THC, CBD, CBG, and terpenes such as …. A diet rich in omega 3 and omega 6 will also stimulate the ECS.
Phytocannabinoids: Cannabinoids produced by plants. These can be found in Sensimilla , Hemp, and Ruderalis species. Known cannabinoids are THCa - THC - CBN - CBDa - CBD - CBCa - CBC - CBGa -CBG - THCV - THCV - CBDVa - CBDV - CBL - CBDP - THCP.
IMPORTANT NOTE:
Repeated high doses of THC over time can decrease the amount of C receptors which are responsible for XXX. This is ultimately counter productive to ECS function and can increase your tolerance to medication, including THC and CBD (requiring higher doses) thereby increasing pain, nausea, inflammation or other symptoms present.
High doses of THC can cause imbalances of the ECS in the body which in turn reduces its receptor density (receptor down regulation).
To prevent receptor down regulation, it is best to incorporate at least 4% more weight of CBD to THC to balance out the receptors.
Rule of thumb:
Use minimum effective dosage to address medicinal need and the shortest possible treatment course to reduce chance of developing dose tolerance issues. Use our inhalation, consumable, and sensitization guides for more information.
Endocannabinoid Receptors:
The two primary receptors in the ECS are CB1 and CB2. The different binding mechanisms of these 2 receptor types creates the Entourage Effect , which is when the cannabinoids and terpenes in the plant (especially CBD & THC) work synergistically in the body to give users relief from different ailments. These receptors are distributed throughout the brain, spleen, kidney, lungs, heart as well as the central nervous system, immune system, gastrointestinal system, reproductive system, urinary system, endocrine system, circulatory system, integumentary system, skeletal system, and respiratory system.
Some research indicates THC directly activates and regulates these receptors, with CBD indirectly activating these receptors through directly activating adenosine, serotonin, and dopamine receptors.
CB1: Responsible for psychoactive activity. Informally called the THC receptor because the THC family of cannabinoids are the only compounds that robustly activate the CB1 receptor.
CB1 receptors regulate the central nervous system, gastrointestinal system, vascular system, reproductive organs, lungs, muscles.
Responsible for the psychoactive high.
Modulates the release of inhibitory and excitatory neurotransmitters across the synapse.
CB2: Are found more in the body and less in the brain.
CB2 receptors regulate bones, skin, spleen, immune system, apoptosis, and hematopoietic blood cells (platelets, red blood cells, and white blood cells).
Also found in immune cells such as T cells, B cells, macrophages, and monocytes.
Regulate the release of cytokines (immunomodulatory proteins) linked to inflammation and general immune function.
CB2 has high activity within the hippocampus, by modulating self activity and information flow between brain networks (potentially assisting the selection of inputs that guide complex behaviors).
CB2 also modulates the mid brain reward system.
TRPV-1: “Capsaicin Receptors”: Regulates body temperature and pain transmission.
PPAR: Peroxisome Proliferator Receptors: Regulate metabolic functions, fatty acid storage, glucose metabolism, and progression of malignancies.
Adenosine Receptors:
Activated / Regulated by CBD
CNS neuromodulator
Facilitates sleep
Dilates blood vessels
When adenosine activates it decreases the release of Serotonin
5-HT Receptors (Serotonin):
Activated / Regulated by CBD
Mediates Inhibitory & Excitatory Neurotransmission
Dopamine Receptors:
Activated / Regulated by CBD
Regulates motivation, pleasure, cognition, memory, learning, motor control
Modulates Neuroendocrine Signaling
Orphan Cannabinoid Receptors:
Cannabinoid interactions extend beyond CB1 and CB2 receptors, there are orphan receptors and ion channels that interact with cannabinoids as well. The orphan receptors include GPR55, GPR18, GPR 30, GPR119. They are called orphans because the endogenous ligands (molecules that bind to the large molecules like receptors) have not been conclusively identified. There are also Transient receptor potential vanilloid type channel (TRPV1), and the alpha and gamma peroxisome proliferator-activated nuclear receptors.
GPR55: Linked to energy homeostasis and metabolic dysregulation associated with diabetes and obesity.
GPR18: Regulates physiological functions such as intraocular pressure, cell migration, endometriosis, and some metastatic diseases.
GPR30: Hormone regulation. Responds to estrogen with rapid signaling.
GPR119: Functions as a fat censor to reduce food intake and weight gain.
Endocannabinoids:
After the discovery of the endocannabinoid receptors, researchers quickly started the search for the substances produced within the body that were binding to them. In the early 1990’s scientists quickly found the endocannabinoids, anandamide and 2-AG.
Anandamide:
Sanskrit for Bliss. This is known as the bliss molecule.
Synthesizing enzyme:
N-arachidonoyl phosphatidylethanolamine (NAPE)
Metabolizing enzyme:
Fatty Acid Amide Hydrolase (FAAH)
2-AG:
Synthesizing enzyme:
Phospholipase C (PLC)
Diacylglycerol lipase (DAGL)
Metabolizing enzyme:
Phospholipase C (PLC)
Diacylglycerol lipase (DAGL)
Monoacylglycerol lipase (MAGL)
All endocannabinoids are derivatives of polyunsaturated fatty acids and closely related to omega-3 fatty acids. Because they are fats, endocannabinoids are not water soluble and have difficulty moving efficiently through the body so they are biosynthesized on demand from precursor molecules and work locally.
Endocannabinoid Activity:
Endocannabinoids control the release of neurotransmitters across the synapse. They do so by serving as primary messengers in retrograde signaling (Signaling sent back to nucleus) between neurons from postsynaptic neuron back across the synapse to the presynaptic neuron.
In less scientific terms, endocannabinoids are produced on demand, released across the synapse, activate receptors, and then taken into cells where they are rapidly metabolized to maintain physiological stability.
This allows the endocannabinoids to modulate the flow of neurotransmitters, keeping our nervous system running smoothly and directly linked to the mechanisms underlying memory and learning.
Endocannabinoids role in pain signaling have created a hypothesis that endocannabinoid levels may be responsible for the baseline of pain throughout the body, allowing us to believe phytocannabinoids are useful in treating chronic and severe pain.
This also gives us an idea that the constant release of our endocannabinoids could provide relief from muscle tightness, multiple sclerosis, neuropathic pain, inflammation, and aid in appetite.
The value of proper endocannabinoid levels within the mind and body play a significant role in maintaining physical and mental homeostasis.
Endocannabinoid Activity cont…
CB1: Receptors are expressed throughout the brain, where endocannabinoids and CB1 receptors combine to form a circuit breaker, modulating the release of both inhibitory and excitatory neurotransmitters across the synapse.
When THC is used, the CB1 receptors are activated and thus create psychoactive effects, because THC is mimicking the endocannabinoid (anandamide (bliss)) by binding to this receptor.
CB2: Receptors found primarily in immune cells, blood cells, tonsils, and spleen. They control the release of cytokines (immunoregulatory proteins) linked to inflammation and general immune function.
These receptors can also be found in the hippocampus where they modulate self activity and information flow between brain networks, in which could play a role assisting the selection of inputs they guide complex behaviors. It’s also been shown to modulate mid-brain reward like self administration of cocaine.
The Brain: Cannabinoid Receptors
Cannabinoid Receptors are located in six different regions of the brain and are known to regulate the functionality of these regions. CB1 receptors are not located in the brainstem, which is responsible for controlling breathing and heart rate. This means that cannabinoids do not have the ability to produce an overdose by shutting down the body’s breathing and blood circulatory system, both of which are possible with opioid overdoses.
The National Cancer Institute states: “Because cannabinoid receptors, unlike opioid receptors, are not located in the brain stem areas controlling respiration, lethal doses from cannabis and cannabinoids do not occur.”
Brain regions with Cannabis Receptors:
Hippocampus - memory, learning, cognition
Cerebellum – responsible for motor coordination and muscular activity
Cerebral cortex – responsible for cognition, memory, attention, and perception
Basal ganglia – responsible for movement and procedural learning
Hypothalamus – responsible for appetite, temperature regulation, sleep, and mood
Amygdala – responsible for emotional reactions and decision-making