The Endocannabinoid System – A Wee Primer

This is just a basic primer and bullet points of the mechanics and pictures of moments and
systems, in time. They do not explain the full function of the EC system which is always on the
quest for homeostasis, balance, equilibrium… and through this, allows us to be fully engaged in the
flow of life.

There are other systems that cannabinoids engage with e.g. the micro biome in the gut: another
form of life in the mycology and bacteriology, 90% of which is foreign DNA, that function together to
keep the body alive and the energy of life flowing through it.

Where Cannabinoids help is that they govern just about everything that happens within the major
organs and muscles, the immune system and the nervous system. They govern reactions that take
place at the cellular level, and also at the macro level on how we think about the nature of reality
and the flow of life.

The endocannabinoid system helps guide the processes, that bring equilibrium to the body. They
need the link to clean food that has been grown in a nutrient and life dense soil, clean water that
hasn’t been chemicalised, and clean air, so that cannabinoids can function effectively. They are
just one factor in a complex, flowing whole.

The legalisation of cannabinoids is just one aspect of this bigger picture. Where, if we can obtain
that equilibrium in the individual, it then, hopefully affects in a symbiotic relationship, all the other\relationships that the individual has; with themselves, with each other, within in society, and with the natural world.

The above are just snapshots that are necessary to bring the scientific or clinical evidence that
support the efficacy of cannabinoids, when we call for legalisation.

OK, enough preachy waffling… Hope this helps.

The EndoCannabinoid System (ECS)

• Endocannabinoids and their receptors are found throughout the body: in the brain, organs,
connective tissues, glands, and immune cells.
In each tissue, the cannabinoid system performs different tasks, but the goal is always the same:
homeostasis, the maintenance of a stable internal environment despite fluctuations in the
external environment.1
• It has almost been 30 years since the initial discovery of the Endocannabinoid system in 1988,
by Allyn Howlett and William Devane. “In 1990, Miles Herkenham and his team mapped the
locations of a cannabinoid receptor system in several mammalian species, including man.” 2
• This system has two major receptors:
“Mammalian tissues are now known to express at least two types of cannabinoid receptor. These
are CB1 receptors, cloned in Tom Bonner’s laboratory in 1990, and CB2 receptors, cloned by
Sean Munro in 1993.” 3
Endocannabinoids are created in the body through fatty acids. Omega-3 fatty acids are 4
essential for this.5

• The CB1 receptor is widely expressed in the nervous system, with particular high levels in the
neocortex (higher cognition), hippocampus (memory), basal ganglia (movement), cerebellum
(motor coordination), the hypothalamus (appetite), the amygdala (emotions) and brainstem . 6
CB1 receptors are also found in nerve endings where they act to reduce sensations of pain.

• The CB2 receptor has a more limited pattern of expression than the CB1 receptor.
They are found almost exclusively in cells and tissues of the immune system. (e.g., B- and Tlymphocytes, macrophages, and spleen, tonsils, lymph nodes etc) In general, when CB2 7
receptors are activated, they work to reduce inflammation and activate the immune system.

• There are two main enzymes that stimulate the ECS receptors, named Anandamide and 2-
Arachidonoylglycerol (2-Ag). (The equivalents of THC)
Anandamide comes from the Sanskrit word Ananda, which means bliss. Anandamide essentially
means the bliss molecule. 2-AG is present in the brain at concentrations 170 times greater than anandamide. CBD’s slow the breakdown of Anandamide.

• Endocannabinoids confer neuroprotection in several types of brain injury.8

• CB1 and CB2 receptors recognise and respond to three kinds of cannabinoid agonists (turn-on
keys): endogenous fatty-acid cannabinoids; phytocannabinoids; and synthetic cannabinoids.

What do the CB1 and CB2 Receptors do in the body? 9

• Chronic stress

Although stress responses can be life-saving in the face of a threat, chronic stress often
has negative health effects. The ECS is the central mediator of the stress response. The
ECS regulates the release of stress-induced neurotransmitters including the systemic
release of norepinephrine and cortisol. The ECS plays a role in the stress alterations of
mood, cognition, and activation of the hypothalamic-pituitary-adrenal axis. The ECS may
also mediate some of the dysmetabolic effects glucocorticoids on lipid metabolism, leading
to hepatic steatosis and potentially contributing to the metabolic syndrome. Therefore, the
ECS is an important control point and therapeutic target to reduce the deleterious effects of
chronic stress.

• Obesity

CB1-R is important for energy balance in the body. With fasting or starvation, anandamide
and 2-AG levels increase in the limbic forebrain and, to a less significant extent, in the
hypothalamus. CB1-R activation increases food intake and effects energy metabolism
through coordination of the mesolimbic reward system and the hypothalamus’ appetite
control pathway. [9, 13] This receptor also promotes food intake by increasing odour
detection via stronger odour processing in the olfactory bulb. Some obese people may have
excess CB1-R activation. Obese and overweight individuals may have a mutation in FAAH,
the enzyme that degrades AEA. This can lead to increased levels of AEA (15-fold increase
in FAAH “knock-out” mice) and stimulation of the hypothalamic appetite control center.
It is uncertain if there is a regulatory feedback loop between the ECS and obesity. Wild-type
mice that develop diet-induced obesity have a hyperactive ECS, with an increase in
receptor availability and an increase in circulating ECs. In pre satiated mice, an
intra hypothalamic injection of AEA induced substantial hyperphagia. Inactivation of CB1-R
receptors decreases plasma insulin and leptin levels, ultimately leading to more efficient
energy metabolism.

• Nervous system

The ECS obviously plays a significant role in the normal functioning of the brain, spinal
cord, and peripheral nervous system. Therefore, the ECS can either cause or become altered by diseases of the neurologic system. For example, hyperactivity of the ECS reduces dopaminergic tone in the basal ganglia, contributing to the pathophysiology of Parkinson disease. Other diseases with potentially significant ECS interactions include multiple sclerosis, seizure disorders, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and psychiatric diseases such as schizophrenia.

• Pain

Pain is already a well established and important therapeutic target for ECs. CB1 agonists
act on nociceptive interneurons in the dorsal horn of the spinal cord to alleviate pain. In
addition, CB2 selective agonists have proven to be helpful in reducing inflammation and
undoing established inflammation hypersensitivity involved in peripheral pain and skin

• Heart and blood vessels

CB1-R activation aids in vasodilation and cardiac contractility, regulating blood pressure
and improving left-sided heart function. CB2 has been implicated in the inflammation in
atherosclerotic plaques. In this regard, CB2 activation is a therapeutic strategy for
reducing atherosclerotic plaque inflammation and reducing vulnerability to rupture and

• Cancer

Both cannabis and the ECS are anti-inflammatory, anti proliferative, anti-invasive, anti
metastatic, and pro-apoptotic in most cancers, in vitro and in vivo, in animals. In some
cancers, the EC’s are pro-proliferative and anti-apoptotic, but in the majority they show cell
cycle arrest, autophagy, apoptosis, and tumour inhibition. At present, cannabinoid cancer
therapy is limited to nausea and pain, but future studies are needed to determine its full
chemotherapeutic potential.

• Gastrointestinal system

Activation of CB-1 receptors and, to a lesser extent, CB2 receptors, by AEA also reduces
gastrointestinal motility and secretions. CB1-R receptor activation inhibits pro-inflammatory
responses in the colon.

• Liver

CB1-R receptors aid in modulating hepatic lipogenesis. Activation in the liver leads to fatty
acid synthesis, causing hepatic steatosis and diet-induced obesity. In addition, the CB1-R
promotes hepatic fibrosis and contributes to the hemodynamic abnormalities in cirrhosis.
By reducing inflammatory cell infiltration and lipid peroxidation, CB2-R receptor activation is
protective against hepatic ischemia-reperfusion injury. Targeting the hepatic ECS may have therapeutic potential in a variety of liver diseases.

• Reproductive system

The ECS has a role in reproduction. The CB1-R is found in the male (Leydig cells) and the
female (ovary, ducts, uterus). Furthermore, normal folliculogenesis and spermatogenesis
may require the ECS. The CB1-R is also present in the placenta and is necessary for
embryo implantation. [22] The use of cannabis is associated with implantation failure,
spontaneous miscarriage, foetal growth restriction, and premature birth in humans. Future
research efforts will be needed to unravel the full complexity of the ECS involvement in the
process of reproduction.

• Skeletal system

In addition to immunomodulatory pathways, CB2-R receptors are involved in maintaining
proper bone mass. CB2-R receptors are abundant in osteocytes, osteoclasts, and
osteoblasts. CB2-R agonists enhance endocortical osteoblast reproduction and activation,
while inhibiting osteoclastogenesis.

The PhytoCannabinoids

• Phytocannabinoids are cannabinoids that occur naturally in the cannabis plant. The classical
cannabinoids are formed through decarboxylation of their respective 2-carboxylic acids (2-
COOH), a process which is catalysed by heat, light or alkaline conditions.10

• The identification and synthesis of THC, by Mechoulam and his colleague Y. Gaoni, took place in
Israel in 1964.11

• Delta-9-tetrahydrocannabinol, or THC, is the most psychoactive and certainly the most famous of
these substances, but other cannabinoids such as cannabidiol (CBD) and cannabinol (CBN) are
gaining the interest of researchers due to a variety of healing properties.
Most phytocannabinoids have been isolated from cannabis sativa, but other medical herbs, such
as echinacea purpura, have been found to contain non-psychoactive cannabinoids as well.12

• Cannabis Sativa may contain over one hundred different cannabinoids, including THC, which all
work synergistically to produce better medical effects and less side effects than THC alone.13

• There is a difference between endocannabinoids and phytocannabinoids : 14
The chemical structures of the endocannabinoids are different from the phytocannabinoids,
although there is evidence that they may fold in a way that resembles THC in 3-D space.

• THC binds to both CB1 and CB2 receptors, activating them just like an endocannabinoid.

• CBD does not bind directly to cannabinoid receptors. Instead, CBD works by inhibiting an
enzyme called FAAH, which is responsible for the breakdown of anandamide. When FAAH is
inhibited, it cannot break down anandamide at its normal rate. This leads to a buildup of
anandamide in the brain.15


• Terpenes are volatile aromatic molecules that evaporate easily especially under heat.
• Cannabis synergy and phytocannabinoid terpenoid and entourage effects17
• Cannabinoid-terpenoid interactions could produce synergy with respect to treatment of pain,
inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections
• Cannabinoid-terpenoid interactions amplify the beneficial effects of cannabis while mitigating
THC-induced anxiety.18

Raw cannabis is good : 19

• One can make the best use of the therapeutic properties of marijuana, through ingestion.
• Raw cannabis activates the brain’s cannabinoid system, more effectively, which in turn, triggers
the release of antioxidants. These antioxidants will effectively get rid of the damaged cells in the
body, and this is something that dried cannabis, can’t do.
• Raw cannabis consumption makes the cells in the body, more efficient.

Further Info.

• The Prime PubMed app from Unbound Medicine
• Journal of Neuroscience
• Marijuana, Science, and Public Policy20
Crucial: The 1995 Marijuana Rescheduling Petition by Jon Gettman21
• Science and Technology related cannabis news. The LEAF Online.
• Dr. Robert Melamede / Dr. Julie Holland – The Endocannabinoid System

• Dr. Ethan Russo. The ECS and Terpenes.

• Fantastic overview of Cannabinoids. Probably one of the best videos out there!!
Clinical Application of Cannabinoids and Terpenes | M. Gordon, Cannafest 2015

The Brain
• Cannabinoids mediate neurogenesis, neuronal plasticity, and learning.
(The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation
and Neurogenesis ) 22
Cannabinoids may directly influence a person’s open-mindedness and ability to move beyond
limiting patterns of thought and behaviour from past situations.
The Body
• Diabetes and Metabolic diseases
Pharmacologic options targeting the ECS may provide a novel, effective approach to the
prevention and management of Cardio Vascular Disease, type 2 diabetes and obesity.
(CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy
balance, metabolism, and cardiovascular health ) 23
• MS
My MS, My Symptoms. Report 201724
People with MS’ experiences of cannabis and symptom management strategies.

6 Piomelli D. 2003. The molecular logic of endocannabinoid signalling. Nat Rev Neuroscience
7 See 4
11 The Discovery of the Endocannabinoid System
13 See 10

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