- “Messenger” molecules synthesized by the body (anandamide and 2-AG).
- Cellular receptor sites to which these molecules bind (CB1 and CB2).
- Enzymes that break the molecules down (FAAH and MAGL).
Two main Cannabinoid (CB) receptors have been identified CB1 and CB2. CB1 receptors are primarily found in the central nervous system where they regulate a wide variety of brain functions. They are concentrated in brain regions responsible for both mental and physiological processes. Example areas (and functions) include the hippocampus (memory), hypothalamus (appetite), cerebral cortex (higher cognition), basal ganglia (movement), cerebellum (motor coordination) and amygdala (emotions).
CB2 receptors are mostly found on immune cells which circulate throughout the body and brain via the bloodstream. They are also found on neurons in a few select brain regions. CB2 receptors are known to be involved in pain relief, anti inflammation and neuroprotection. CB2 receptors are also present in the gut, heart, liver, kidneys, spleen, blood vessels, bones, endocrine glands, lymphatic cells and reproductive organs.
The body’s most prominent Endocannabinoids, namely N-arachidonoylethanolamide (anandamide) and 2 arachidonoylglycerol (2-AG), activate TRPV proteins which are responsible for hot and cold sensations. The heat you experience from eating chilli pepper, for example is a TRPV mediated response. Although CB and TRPV receptors are the major players in the ECS there are at least three other receptors (GPR55, GPR18 and GPR119) that may eventually be considered CB receptors once their functions are fully understood.
Endocannabinoids vs. Phytocannabinoids
Endocannabinoids are produced inside the body as opposed to phytocannabinoids which are produced in plants most commonly and abundantly in Cannabis. The body already uses Endocannabinoid molecules to regulate many functions so we are inherently endowed with many target sites for Cannabis plant compounds to activate. Both types of molecules behave similarly on a functional level. They activate the body’s ECS by binding to receptors found throughout the body across several systems.
Endocannabinoids activate a homeostatic effect bringing the body to a balanced state of health. They are produced by our cells in an “on demand” fashion. Think of the ECS as an “equaliser” of sorts for the body much like an air traffic controller. These innate compounds send signals to the body to set it back to its finely balanced pre set just like an air traffic controller sends signals to pilots to ensure that planes in the surrounding airspace fly safely.
Phytocannabinoids amplify the signals that trigger responses related to everything from hunger and pain to hearing and spatial orientation. When one amplifies a hunger signal for example you get the “munchies”. Plant compounds like THC are also capable of producing intoxication (psychoactive effects) through ECS modulation which Endocannabinoids alone cannot do. This highlights one of the key differences between the compounds produced innately by the body versus those derived from Cannabis.
The enzymes produced by the body, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) rapidly break down Endocannabinoids but are unable to degrade phytocannabinoids in the same way. Specifically psychoactivity is not achieved via the “bliss” molecule anandamide because it is rapidly broken down by the FAAH enzyme. An intoxicating effect does result from THC because it is less susceptible to degradation by this enzyme.
Retrograde Signalling Function
Endocannabinoids function as retrograde signalling molecules. The human body consists of an electrical and chemical messaging system known as the nervous system which transmits signals to and from different parts of the body. The ECS functions throughout the central (brain and spinal cord) and peripheral (everywhere else in the body) nervous systems. This “electrical wiring” system is made up of approximately 86 billion nerve cells called “neurons”.
Endocannabinoids and Neurotransmitters move between neurons to transmit signals in the form of chemical messages. This movement is how the body communicates what needs to happen to control a wide range of bodily functions such as maintaining homeostasis. The split second something in a healthy body gets out of balance the nervous system picks up on it and begins to transmit signals aimed at restoring balance at lightning speed.
Specifically Endocannabinoids and Neurotransmitters function at the gap between neurons called the “synaptic cleft”. At this gap the two cells can be named as the presynaptic (sending) and postsynaptic (receiving) neuron. Normally a presynaptic neuron transmits a signal by releasing neurotransmitters into the synaptic cleft. These compounds bind to receptor sites on a second postsynaptic neuron which then sends the message along its cell body and so the signal passed on.
However Endocannabinoid signalling occurs in a backwards direction (“post to pre”), compared to the regular function of neurotransmitters (“pre to post”). When a signal arrives via neurotransmitters at the postsynaptic neuron the body uses available fat cells (lipid precursors) to create Endocannabinoids which then jump back across the cleft and attach to CB receptor sites of the presynaptic neuron.
Interestingly this retrograde flow means that these compounds are able to influence how neurotransmitters behave before they are activated. This is one of the features that appear to make the ECS so powerful and versatile. However we know that Endocannabinoids are produced in an on demand fashion and then quickly broken down by FAAH and MAGL enzymes. Phytocannabinoids are not broken down in the same manner which provides the basis for Cannabis as a therapeutic tool.
The ECS and Biological Balance
Given its complex nature, The Endocannabinoid system has many functions. It is involved in numerous bodily systems and contributes to the body’s ability to maintain biological equilibrium. Every bodily function requires a specific balance of factors to perform at maximum capacity. When this balance is achieved it is called homeostasis.
Endocannabinoids are the messenger molecules that are critically involved in this internal regulatory response. Pain, stress, appetite, energy metabolism, cardiovascular function, reward and motivation, reproduction and sleep are just a few of the functions targeted through activating Cannabinoid receptors. Unsurprisingly Medical Cannabis compounds have the potential to step in and assist when this delicate biological balance goes awry.
Endocannabinoids have shown promise as therapeutic solutions for pain and inflammatory conditions. Both anandamide and 2 AG play a role in regulating pain neuropathic and inflammatory through CB1 and CB2 receptor pathways. These compounds have been found in pain modulating regions throughout the central nervous system and may have a hand in modulating inflammatory pain through CB2 receptors. When administered exogenously to animals these Endocannabinoids have exhibited pain relieving potential similar to that of exogenous Cannabinoids such as THC and CBD.
2 AG may be heavily involved in controlling anxiety and depressive behaviours. Studies on 2 AG levels in mice indicate that deficiency could be a contributing cause of anxiety and mood disorders. Cannabis compounds with low level psychoactive effects may be beneficial in this regard.
Endocannabinoids play an integral role in modulating the stress response. They are even involved in activating the hypothalamic pituitary adrenal (HPA) axis the body’s central stress regulation system. CBD and CBG may be able to help regulate the behavioural response to stressful stimuli.
- Appetite and Energy Metabolism
Several studies have shown that Endocannabinoids play a role in regulating appetite and hunger by acting as CB1 receptor agonists (compounds that activate these receptors) and antagonists (inhibiting compounds). THC stimulates appetite and is beneficial in combating chemotherapy induced nausea and vomiting (CINV). THCV however hinders appetite. These compounds may prove significant in the fight against obesity, diabetes and eating disorders like anorexia.
Anandamide has been found to regulate sleep stability by activating CB1 receptors. 2 AG may also have the ability to induce REM sleep through CB1 activation. CBN a derivative of THC is the highly sedative Cannabinoid mostly linked with improving sleep.
The ECS is spread prominently throughout the cardiovascular system. Under normal conditions Endocannabinoids have a minor role in cardiovascular regulation but they also have the potential to intervene in instances of hypotension and hypertension. CBD for example may be beneficial due to its impact on stress, high blood pressure and inflammation.
Convincing evidence suggests that the ECS is expressed in the gut. Endocannabinoids may play a role in protecting the gastrointestinal tract from inflammation and other gastric abnormalities through CB1 and CB2 receptor activation both of which are also major targets of Cannabinoids.
The ECS is heavily involved in regulating brain function. At different stages of learning and memory, Endocannabinoids that activate CB1 receptors may be able to modulate stress and anxiety associated with emotional memory. They can also have neuroprotective effects. 2 AG contributes to brain homeostasis as both an anti inflammatory and neuroprotectant. The role of the ECS in healthy brain function makes it an ample target for Cannabis compounds in treating PTSD, addiction, schizophrenia and neurodegenerative disease.
The ECS has been implicated quite prolifically in fighting cancer and promoting healthy cell function. Studies have shown that exogenous Cannabinoids have massive therapeutic potential for limiting cell proliferation and tumour growth. Findings also suggest that endocannabinoids play a role in the healthy function of kidney, liver and bone cells.
- Clinical Endocannabinoid Deficiency (CECD)
First proposed in 2001 as an explanation for the therapeutic properties of Cannabis the theory posits that several illnesses that have been successfully treated with plant based Cannabinoids are the result of a deficiency of the body’s Endocannabinoids. Current research supports this theory indicating that deficiency in the production of Endocannabinoids is a viable explanation for migraine, fibromyalgia, irritable bowel, PTSD and other treatment resistant syndromes. CECD may also play a role in anxiety and mood disorders and it may be the reason more and more people are finding relief from different ailments by using CBD oil.
While much is still unknown about the ECS research is beginning to shine a light on just how integral it is for maintaining homeostasis and how Cannabis plant compounds are able to assist when the body’s delicate biological balance goes awry.
Given the functional similarity of Endocannabinoids and Phytocannabinoids it is hardly surprising to learn that these plant compounds hold tremendous therapeutic potential.
A brightly yellow coloured compound with tremendous medical potential. CBD is able to act therapeutic agent either alone or via a specified CBD to THC ratio in order to treat a wide variety of conditions. It acts as an antagonist at CB1 and CB2 receptors yet has a low binding affinity for both. This suggests that its mechanism of action is mediated by other receptors in the brain and body. CBD’s low affinity for CB1 receptor sites is able to prevent THC from binding there largely limiting or even eliminating the psychoactive effect entirely.
- THC (Tetrahydrocannabinol)
Delta 9 Tetrahydrocannabinol (Δ9 THC) is responsible for the well documented psychoactive effects experienced when smoking or ingesting Cannabis. It is typically the most abundant Cannabinoid present in Medical Cannabis products (although CBD’s popularity has risen drastically). THC can be derived from THCA by non enzymatic decarboxylation during storage and consumption.
This compound enters the bloodstream via the lungs, skin or digestive system and eventually binds to Cannabinoid receptors (most notably CB1) throughout the body. These receptor sites affect memory, concentration, pleasure, coordination, sensory experience, time perception, appetite and many more important functions. Side effects of THC can include anxiety, elation, burning eyes, dry mouth, increased appetite, shaking, elevated heart rate, shortness of breath (or at least the perception of such) and short term memory loss.
- THCA (Tetrahydrocannabinolic Acid)
THCA is the main constituent in fresh plant material and converts to Δ9 THC when burned, vaporised or heated at a certain temperature. THCA, CBDA, CBGA and other acidic Cannabinoids contribute to anti inflammatory effects via abundant COX 1 and COX 2 inhibition. This raw compound also acts as an antiproliferative and antispasmodic.
Non psychoactive CBG’s antibacterial effects can alter the overall effects of Cannabis. It is known to kill or slow bacterial growth, reduce inflammation (particularly in its acidic form, CBGA), inhibit cancerous cell growth and promote bone growth. It also acts as a weak partial agonist at both CB1 and CB2 receptor sites. CBG’s low affinity for CB1 receptors is able to antagonise THC’s psychotropic effects.
CBN is mildly psychoactive produced from the degradation of THC. There is usually very little to none in a fresh plant. It acts as a weak agonist at both CB1 and CB2 receptors with greater affinity for the latter. The degradation of THC to CBN is often described as creating a sedative effect which is why it is known as the “sleepy cannabinoid”.
The Entourage Effect
This phenomenon describes how the collective sum of all Cannabis compounds is required to maximize its therapeutic potential. The information pertaining to the entourage effect varies and is sometimes contradictory. However breeders have long believed that Cannabis shows its true efficacy when combining all of its compounds allowing them to work in synergy and science is slowly starting to catch on.
Cannabis plants contain hundreds of different molecules including Cannabinoids, Terpenoids and Flavonoids which all interact with mind and body to various extents. Two Cannabinoids psychoactive THC and non intoxicating CBD have received the most attention among researchers and consumers although more than 120 have been identified so far. Terpenoids or “Terpenes” are aromatic compounds found in many other plants including herbs, spices, trees and fruits. They give strains their distinctive and unique smells and flavours and also have their own therapeutic properties.
Flavonoids are abundant in nature and have many functions including providing protection and colouration. Cannabis plants produce unique Cannaflavins which have distinct effects. For example Cannaflavin A is a much more powerful anti-inflammatory than aspirin. Flavonoid presence may enhance or inhibit the effects of Cannabinoids and Terpenes. Each individual compound has a specific biochemical effect on the body and unique combinations specific to different strains are known to cause varying effects.
The phrase “Entourage Effect” was first used in 1998 by a group of scientists that included the father of Cannabis research renowned Israeli biochemist Dr. Raphael Mechoulam. More recently the phrase has been popularised by Dr Ethan Russo. In his 2011 paper, “Taming THC: Potential Cannabis Synergy and Phytocannabinoid Terpenoid Entourage Effects” he investigated the interactions between Cannabinoids and Terpenes looking for synergies to treat pain, inflammation, depression, anxiety, addiction, epilepsy, cancer and bacterial infections.
Dr. Russo reported in 2008 that “Good evidence shows that secondary compounds in Cannabis may enhance the beneficial effects of THC” as well as reduce its unwelcome side effects. From that many people have concluded that all of the synergistic effects are beneficial which means that “Full Spectrum” Oil (containing all of the plant’s compounds) makes for the best Cannabis based medicinal products.
As the body of scientific research grows a more thorough understanding of the exact synergistic interplay among the Cannabinoids, Terpenes, Flavonoids and other plant compounds will lead to the sophisticated harnessing of the entourage effect. This knowledge will drive the future of medical products to be developed for specific conditions, needs and desires. Read more about the various plant compounds in Medical Cannabis 101.
