By CannEvolv

The Endocannabinoid System

• What is the ECS?
• What are Endocannabinoids?
• CB1 Receptors
• CB1 and THC
• CB2 Receptors
• CB2 Activation
• How Does Cannabis Affect the ECB?
• Why You Might Need Cannabis Supplements
• Conclusion

Humans, along with most living things on the planet, have an Endocannabinoid system incorporated into their biology. The Endocannabinoid System (ECS) evolved 600 million years ago and has been an integral part of biological survival ever since.

It is an evolutionary wonder.

The ECS helps regulate biological systems in what is known as homeostasis. The ability to adapt and stay healthy in changing conditions.

Homeostasis - The tendency toward a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes.

The ECS regulates system functions on a cellular level. Helping with various aspects including cardiovascular, immune, and nervous systems within the body.

Understanding what the endocannabinoid system does for us on a cellular level helps us as consumers make more informed decisions for ourselves on what we choose to medicate with when it comes to Cannabis.

What is the endocannabinoid system (or ECS)?

It is a system of neuromodulatory lipids and Receptors distributed throughout the whole body. The ECS is comprised of Cannabinoid-1 type receptors known as CB1, and Cannabinoid-2 type receptors known as CB2.

Although these are not the only receptors affected, CB1 and CB2 seem to have a special affinity for cannabinoids.

These two receptors have a multitude of functions that affect thing like

• Appetite
• Anxiety
• Learning
• Metabolism
• Memory
• Motor Coordination
• Emotion
• Other functions of the nervous system.

The CB1 receptor mainly affects the central nervous system while the CB2 receptor is more of a peripheral nervous system modulator, though there is some cross over between the two.

Both CB1 and CB2 receptors are responsible for inhibiting adenylyl cyclase and calcium channels while activating MAPK’s and potassium channels.

What Are Endocannabinoids? Does My Body Make Cannabis?

Our bodies produce cannabis-like chemicals that interact with the endocannabinoid system. These naturally produced cannabinoids are named endocannabinoids.

• Endo - within (your body)
• Cannabinoid - a chemical compound

The main two Endocannabinoids produced within the body are anandamide and 2-Arachidonoylglycerol (2-AG).

• Anandamide is an lipid mediator and immune modulator that also acts as an endogenous agonist of CB1. It is similar to THC in its affinity for the CB1 receptors.
• 2-AG is an endogenous agonist of the CB1 and CB2 receptors.

Anandamide has been shown to be released in mice after running for a period of time. Scientists posit this is the same reason humans experience what is known as a "runner's high"from physical exercise.

CB1 Receptors

CB1 receptors are seven transmembrane G-protein-coupled receptors which modulate neurotransmitter release.

These receptors are found throughout the body with the most density of CB1 receptors in the brain and spinal cord.

Activation of CB1 leads to retrograde inhibition of the neuronal release of

• Acetylcholine
• Dopamine
• GABA
• Histamine
• Serotonin
• Glutamate
• Cholecystokinin
• D- aspartate
• Glycine
• Noradrenaline

CB1 receptors can be found mainly in the central nervous system (in the brain and spinal cord), but is spread throughout the peripheral nervous system as well.

So… What the hell does that mean?

This means CB1 receptors help control brain and central nervous system functions. It acts as a neurotransmitter “gatekeeper” responsible for relaying information from the outside of the cell to the inside. This signaling allows neurotransmitters to be released into the synapse which then cause various biological responses.

The CB1 receptor influences:

• Sleep
• Anxiety
• Metabolism
• Digestion
• Memory
• Pain Perception
• Motor Functions

CB1 controls Glutaminergic and GABAergic activity. This means it is in charge of energizing and calming down the central nervous system. It plays a critical role in striking a balance between glutamate (Energizing) and GABA (Calming).

Glutamate – a neurotransmitter which is the major mediator of excitatory signals.

GABA – an inhibitory neurotransmitter that calms the central nervous system.

An imbalance of glutamate can cause Hyperalgesia (more pronounced pain), Anxiety, Fibromyalgia, Insomnia, Lethargy, Brain fog, etc.

An imbalance of GABA can cause Depression, Alzheimer’s, Mood Disorders, Epilepsy, Anxiety, Schizophrenia, Dystonia, etc.

These two neurotransmitters work together so an imbalance in one causes a domino effect in health problems.

CB1 receptors can be found in:

The brain:

• Cerebellum
• Pituitary Gland
• Basal ganglia
• Hippocampus (memory)
• Dorsal Horn
• Hypothalamus (Metabolism)

In the body:

• Pancreas
• Skin
• Heart
• Lungs
• White blood cells,
• Spleen
• Adrenals
• Endocrine gland
• Reproductive parts,
• Gastrointestinal tracts
• Urinary tract

CB1 and THC

CB1 is the main target of THC and is the reason we feel “high” when consuming cannabis. The stimulation of this receptor causes several biological responses in the consumer having to do with the limbic and reward circuitry.

THC binds to CB1 receptors in the ventral tegmental area. This disinhibits dopaminergic signaling and results in a reward response. The feeling of being high.

“These cannabinoid-induced actions on glutamatergic neurotransmission in multiple brain regions go hand in hand with their effects on motor activity, reward function, cognition and neuroprotection or neurotoxicity.” - The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently

It is important to note here that studies have shown trace amounts of THC have just as much therapeutic effect as larger doses, while larger doses will overwhelm the system and can cause things like anxiety, high heart rate, and paranoia.

The biphasic property of THC is why dosage is so important, because a small dose can have the opposite effect than a large dose.

“Our findings suggest that a low dose of THC produces subjective stress-relieving effects in line with those commonly reported among cannabis users, but that higher doses may non-specifically increase negative mood.” - Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress

THC has similar biological effects as Anandamide, an endocannabinoid within our bodies. It is one of the naturally occurring chemicals which are a CB1 agonist. Anandamide is thought to be the main reason for the feeling of a “runner’s high” after vigorous physical activity. Anandamide is a stress-responsive endocannabinoid.

CB1 is being closely studied for other things like addiction treatment as well.

"..endocannabinoids serve as mediators of short- and long-term neuronal plasticity. Thus, in addition to being the target for Δ9THC, the principal psychoactive component of cannabis, CB1 cannabinoid receptors are also central to important normal behavioral pathways. The behaviors involved are diverse and include: movement, sensory learning, analgesia, anxiety, and appetitive behaviors, to name a few. At the current time, the most relevant of these for therapeutic manipulation are obesity (with involvement of both central and peripheral mechanisms – alternatively homeostatic and hedonic mechanisms) and craving-based disorders, such as alcohol and tobacco dependency. As our understanding of the basic biology of the endocannabinoid system develops, it is likely that additional therapeutically beneficial manipulations of this system will be developed, as we have seen with the CB1 receptor antagonist, rimonabant." -- Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength

CB1 and CBD

Cannabidiol (CBD) acts on CB1 receptors as a negative allosteric modulator. This means it can mitigate the effects of THC and help control your high. It does this by modulating peripheral receptors which influence the CB1 receptor making THC less likely to bind to CB1.

This is great news for researchers and patients because it allows us to take therapeutic doses of cannabinoids without as much of the psychoactive effect.

CB2 Receptors

CB2 receptors are seven transmembrane G-protein-coupled receptors, much like CB1. These receptors inhibit adenylyl cyclase and modulate cAMP levels.

CB2 receptors are responsible for cytokine release in the immune system. It acts as a moderator of immune responses like inflammation, and cell proliferation/survival. This gives researchers reason to believe therapies which target the CB2 receptors a possibility for treating various neurodegenerative diseases.

“The presence of CB2 receptors in microglia in the human Alzheimer's diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies." - The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

CB2 Receptors Have Effects On:

• Inflammation
• Cell Proliferation
• Pain
• Neuroprotection

Where CB2 Receptors Are Found:

• Microglial Cells
• Skin Cells
• Pancreas
• Liver
• White blood cells
• Tonsils
• Spleen

The research on CB2 is still in its infancy but is being studied for various neurodegenerative diseases such as Huntington's and Alzheimer's disease. The CB2 receptor shows promise as a neuroprotective and anti-inflammatory target for new therapies. Since activating CB2 receptors is non-psychoactive (unlike CB1 receptors) it is being carefully considered by scientists for new drugs.

Since drugs acting on CB2 receptors modulate immune cell migration, they represent a promising pharmacological platform for developing anti-inflammatory therapeutics, but this possibility comes across as a daunting challenge. Indeed, we must first gain a better understanding of the differential pharmacology of endogenous, synthetic and plant-derived cannabinoids acting at CB2 receptors, not to mention cell type-specific effects. - CB2 receptor-mediated migration of immune cells: it can go either way

CB2 Receptor Activation

CB2 has an over an 60% homogeneity with the CB1 receptor so many of the things that activate CB1 will also tend to interact with CB2.

A popular piece of misinformation is that CBD is a CB2 agonist, but CBD shows little affinity for CB2. CBD does however bind to TRPV1 receptors which causes an analgesic reaction by desensitizing the receptor, causing us to feel less pain. This is the same receptor that capsaicin (spiciness) activates.

CB2 receptors are being studied for a myriad of diseases along with CB1 receptors.

"Apart from the regulation of inflammatory processes, some experimental designs also suggest that CB2 receptors may play a role in nociception (Jhaveri et al., 2007; Whiteside et al., 2007), gastrointestinal function (Wright et al., 2008), neural progenitor cell proliferation and axon guidance (Palazuelos et al., 2012; Duff et al., 2013), and synaptic transmission (Kim and Li, 2015; Li and Kim, 2016), among other functions." - CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease

How Does Cannabis Affect The Endocannabinoid System?

The various compounds found within cannabis have a synergistic effect when used together.

Along with THC and CBD, there are at least ninety different cannabinoids present in the plant (that we know about). These cannabinoids along with aromatic chemicals known as terpenes work together as a therapeutic team.

All of these compounds act as neuromodulators and add to the "entourage effect" of cannabis.

When consumed, cannabis compounds mimic natural biological processes which activate cell responses. These responses have an array of effects on the consumer including, but not limited to, modulation of neurotransmitters associated with central nervous system responses (sensory input, information processing and motor output), and peripheral nervous system responses like inflammation.

Why You Might Need Cannabis Supplements

As with any biological system, the endocannabinoid system ages and becomes dis-regulated with time. Inhibition of the ECS can be detrimental to mental health as it is responsible for neuroplasticity and neurogeneration. Compounds found within the cannabis plant have been considered to aid in protecting against neurodegenerative diseases like Alzheimer's disease.

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls — and is affected by — normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. - Endocannabinoid signalling and the deteriorating brain

Some consider including cannabis as a possible neuroprotective supplement as well as a hormone regulator to help support an aging Endocannabinoid System.

Conclusion

As we can see, the Endocannabinoid System is vital to our survival. It is responsible for a multitude of biological signaling and responses.

Being able to study and manipulate the ECS via CB1 and CB2 receptors shows very promising data in many different studies.

Applications of therapeutic models indicate the ECS can possibly be used to help biological functions including but not limited to:

• Neuroinflammation
• Neurodegeneration
• Acute Inflammation
• Gastrointestinal Function
• Depression
• Anxiety

The ECS is a biological system which ages and eventually may need supplementary help.

Compounds found within the cannabis plant can help support an aged ECS by mimicking endocannabinoids like 2-AG and anandamide.

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