The endocannabinoid system is VERY important because:

• Today's world is VERY inflammatory:
• Environmental Toxins:
• Herbicides
• Insecticides
• Heavy Metals
• Chronic Biological Infections:
• Bacteria
• Viruses
• Fungus
• Molds
• Inflammatory Diet / "Leaky gut"
• Endotoxins
• inflammation is VERY unhealthy:
• Immune Inflammation
• Autoimmune Disease
• Rheumatoid Arthritis
• Irritable Bowel Syndrome (IBS)
• Fibromyalgia/MS
• Skin / Psoriasis/ Eczema
• Chronic Infections
• Brain Inflammation
• Brain Fog / Migraine / Epilepsy
• Anxiety / PTSD
• ADD /ADHD /Autism
• Insomnia

Cannabiniods, though their interaction with the human endocannabinoid system,
support homeostasis and thus optimal health.

Cannabinoids can be classified by function or origin:

• Cannabinoids function in three basic ways:
• Agonists:
• bind to receptors
• Cannabinoid agonists stimulate G protein-coupled receptors (GPCRs) by binding to an "orthosteric" site on the receptor, which initiates a series of micro-conformational changes in the receptor structure, that ultimately leads to G-activation.
• Antagonists:
• block receptors
• Cannabinoid antagonists block activation of G proteins by binding to an "allosteric" site on the receptor that is involved in the G protein activation process, thereby precluding the ability of the orthosteric agonist-mediated conformational stimulus to execute activation.
• Modulators:
• do not bind or block receptors
• Unlike agonists and antagonists (whose action causes direct effects), These cannabinoids, modulate the environment "setting up" indirect effects
• Cannabinoids originate in three different ways:
• Endocannabinoids:
• "endogenous cannabinoids"- cannabis-like molecules (ligands), produced by the body.
• neural modulators (not neural transmitters)
• not stored in the body, so they are synthesized and released on demand.
• produced in post-synaptic neurons, then travel backwards to pre-synaptic neurons in the CB1 receptor (retrograde signaling) to inhibit neurotransmitter release, which influences other chemical reactions, producing a cascade effect.
• In the case of a head injury, or neuropathic pain, where there would normally be an abundance of glutamate, which could cause excitotoxicity (damage or death of neurons by excessive stimulation), this endoocannabinoidal mechanism can inhibit the excitotoxication.
• Two endocannabinoids have been discovered so far.
• Anandamide (aka Arachidonyl Ethanolamide or AEA):
• first endocannabinoid discovered (1992)
• a neural transmitter
• attaches to the same CB receptors as does THC.
• stimulates CB1 and CB2 receptors
• in parts of brain involved in reward, mood
• released during meditation and running
• named Anandamide (the "bliss" molecule)
• named after the word "Ananda" which means "supreme joy" (in Sanscrit)
• associated with "the runners high" effect
• anandamide not only targets the CB1 receptor, but also influences opioid and endorphin receptors.
• Contrary to what many believe, CBD does not turn into THC in the body, rather it simulates some THC effects, because it increases the relative gain of the ECS by upregulating anandamide.
• 2-arachidonoyl-glycerol (2-AG):
• second endocannabinoid discovered (1995)
• functions to "relax", eat, sleep, forget, protect
• endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor
• predominantly found in the Central Nervous System
• released in mothers milk (along with anandamide, but in greater amount)
• can be neuro-endo-immune agonists
• Can also modulate:
• neurotransmission in the brain
• endocrine hormone production
• immune system response
• metabolized in the liver
• Exocannabinoids (Phytocannabinoids):
• formed when cannabinoid acids, such as THCA and CBDA, (naturally found in cannabis plants) are heated, resulting in CO2 being shed (decarboxylation) and neutral phytocannabinoids remaining.
• when taken into the body . . . they can be neurotransmitters or modulators.
• e.g., THC, CBD, CDN
• metabolized in the brain and the sites where they are being used
• Synthetic cannabinoids:
• synthesized in a lab
• e.g. ajulemic acid
• bind to cannabinoid receptors and causes affects

Cannabinoid receptors are a class of cell membrane receptors in the G protein-coupled receptor (GPCR) superfamily, which function as targets (the sites of activity) for cannabinoids in the ECS.

• contain seven transmembrane spanning domains.
• detect molecules outside the cell
• activate internal signal transduction pathways
• ultimately, cause cellular responses
• the largest class of receptors known
• widely dispersed throughout the body:
• Central Nervous System
• Cardio Vascular System
• Immune system
• Bone Marrow
• Intestines
• Bladder
• There are several types of endocannabinoid receptors:
• CB1 Receptors:
• Primarily found in the brain
• The most abundant G-protein-coupled receptor found in the brain
• highly expressed in:
• nociceptive areas of brain (responsible for sensation of pain)
• cerebellum and basal ganglia (regulates motor movements)
• limbic system (having to do with emotion)
• hippocampus (having to do with memory processing)
• reward pathways
• Although they are prominent in the substantia nigra and periaqueductal grey matter . . .
• they have very limited expression in the brainstem.
• not in medullary respiratory center . . .
• so unlike opioids (which have receptors in the medulla) an "over dose" of cannabis can not cause death by respiratory depression.
• expressed primarily on glutamatergic and GABAergic pre-synaptic interneurons, which when activated (depolarized) inhibit GABA-mediated neurotransmission, resulting in limited pre-synaptic calcium ions entry and thus less glutamate being released
• have major neuromodulatory functions, which are involved in:
• pain
• memory
• movement
• emotion
• appetite
• emesis
• seizure threshold
• GI motility/secretion
• Role characterized as "relax, eat, sleep, forget and protect"
• blocking CB1 receptors leads to depression
• There may be many other functions that we are not yet aware of.
• CB1 receptors have been found in the urinary tract and in parts of the reproductive system.
• Researchers believe they will find CB1 receptors in other parts of the body as well.
• CB2 Receptors:
• some expression in central and peripheral nervous system
• greatest expression is in the immune system
• circulating white blood cells
• macrophages
• B cells
• T cells
• the spleen, tonsils and thymus gland
• microglial cells (brain macrophages)
• hematopoietic cells (blood producing cells)
• in the skin (as is CB1)
• gastrointestinal system
• modulates intestinal inflammatory response
• shows great promise for Crohn's disease and IBS
• major immunomodulatory functions involved in pain and inflammation.
• regulates the release of cytokines
• assist in the communication between cells during immune responses
• encourages the appropriate cells to respond to inflammation and infection.
• limits fibrosis (build up of scar tissue)
• CB2 agonists have potential in treating hepatic fibrosis and related conditions
• Non Cannabinoid Receptors:
• TRP (Transient Receptor Potential):
• a superfamily of receptors, with a large number of cation channels
• modulate ion entry driving forces and Ca₂+ and Mg₂+ transport machinery in the plasma membrane, where most of them are located
• have important interactions with other proteins and often form signaling complexes
• Transient Receptor Potential Cation (TRPC) channels - include TRPV and TRPA receptors
• TRPV Receptors (Transient Receptor Potential Vanilloid Receptors):
• ionotropic receptors - form part of a ligand-gated ion channel, so that binding of ligand (e.g. a hormone or neurotransmitter) to the receptor causes opening of the channel, permitting ions to flow through it.
• present in skin
• associated with pain and itch on the skin
• CBD is a TRPV1 agonist
• which is why CBD is good for topical rashes and pain
• works as a sebostatic agent in acne
• While CB1 activation leads to a decrease in intracellular calcium and attenuation of synaptic transmission, anandamide binding to TRPV1 results in elevated calcium levels and potentiated synaptic transmission.
• TRPA Receptors (Transient Receptor Potential Ankyrin Receptors):
• facilitates many signaling pathways such as: sensory transduction, nociception, inflammation and oxidative stress
• Phytocannabinoids activate TRP channels of both TRPV1 and TRPA1 receptors.
• Serotonin Receptors (aka 5-hydroxytryptamine receptors or H-HT receptors):
• a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems
• mediate both excitatory and inhibitory neurotransmission
• activated by the neurotransmitter serotonin, which acts as their natural ligand
• CBD is also an agonist of serotonin 1A receptors
• modulate the release of many neurotransmitters:
• glutamate
• GABA
• dopamine
• epinephrine / norepinephrine
• acetylcholine
• modulate the release of many hormones:
• oxytocin
• prolactin
• vasopressin
• cortisol
• corticotropin
• substance P
• influence various biological and neurological processes:
• aggression
• anxiety
• appetite
• cognition
• learning
• memory
• mood
• nausea
• sleep
• thermo-regulation
• the target of a variety of pharmaceutical and recreational drugs:
• many antidepressants
• antipsychotics
• anorectics
• antiemetics
• gastroprokinetic agents
• antimigraine agents
• hallucinogens
• entactogens

• GABA Receptors (Gamma-Amino Butyric Acid receptors):
• receptors that also control inflammation, pain, reward and anxiety
• Low GABA activity increases sensitivity to THC psychotomimetic effects
• Several terpenes can increase GABA activity
• Terpenes are anecdotally reported to reduce psychotomimetic effects
• Myrcene, alpha-pinene, phytol, and alpha-terpinolene could directly bind and increase activation of the GABA receptor.
• Phytol may also raise GABA levels by inhibiting its metabolism.
• Limonene raised GABA levels in rodents and its metabolites and could directly increase activation of the GABA receptor.
• Linalool could boost GABA activity in cells, even though it doesn't bind directly to the GABA receptor and could potentially have additional antipsychotic actions by inhibiting the NMDA receptor
• PPARs (Peroxisome Proliferator-Activated Receptors):
• a major class of nuclear hormone receptors
• function as transcription factors regulating the expression of genes
• Three types of PPARs have been identified: (α, δ and γ)
• Activation of all isoforms (primarily PPARα and γ), mediate some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumor, gastrointestinal and cardiovascular effects of some cannabinoids.
• often in conjunction with activation of:
• CB1 and CB2 receptors
• the TRPV1 ion channel
• mediate some of the effects of endocannabinoid degradation/transport inhibition
• Researchers believe there are more (yet to be discovered) cannabinoid and non-cannabinoid receptors.

Regulatory Enzymes:

• required for making and breaking down endocannabinoids
• FAAH (fatty acid amide hydrolase) breaks down AEA
• MAGL (monoacylglycerol lipase) breaks down 2AG

Endocannabinoid tone is a term, which reflects the balance of the ECS components.

• the density of active cannabinoid receptors in the brain
• the levels of endocannabinoids and the rate at which they're made and broken down
• the amount of enzymes which make and break down the endocannbinoids

Endocannabinoid tone can be measured relatively, but technology does not exist to measure it absolutely.

• Serum levels of endocannabinoids in the blood may not reflect what is going on in the brain
• Direct measurements, such as spinal taps are too invasive to be practical.
• PET and MRI scans show promise in measuring absolute endocannabinoid tone, but currently can not.

CBD increases "endocannabinoid tone" -

• pools up endocannabinoids
• stimulates the production of 2AG
• achieves higher levels of AEA, by blocking the production of "fatty acid amide hydrolase" (FAAH), the enzyme which breaks down (hydrolyzes) AEA
• stabilizes neuroinflammation
• turns up glutiothione system and turns down the inflammatory processes
• stabilizes activated microglia
• stabilizes overactive glutamate receptors

Clinical Endocannabinoid Deficency (CED):

• a concept introduced by Dr. Ethan Russo in 2001, with subsequent publications in 2004 and 2016.
• According to Russo, If you don't have enough endocannabinoids:
• you may have pain, when you shouldn't.
• You may feel be nauseated, when you shouldn't.
• You may have a lowered seizure threshold.
• Russo theorized that a number of very common diseases seem to fit a pattern, that would be consistent with an endocannabinoid deficiency, specifically: migraine headaches, IBS and fibromyalgia.
• They're all hyperalgesic syndromes . . . the pain is way out of proportion to what it should be.
• The tissues look normal, yet there's something biochemically that's driving the pain.
• Additionally, they occur in the same individuals.
• If someone has a chronic problem with migraine there's a high likelihood they're going to have fibromyalgia at some point in their life; similarly, with the irritable bowel syndrome.
• In Italy, Sarchielli, et al, measured anandamide levels in cerebrospinal fluid.
• They did lumbar spinal taps on subjects with and without migraine headaches
• They found that subjects with migraine headaches had much lower levels than those who didn't.