Is Medical Marijuana Natural?

One of the most amazing aspects of medical cannabis treatment is the fact that our bodies have internal systems designed to be able to interact with the medicinal compounds found in cannabis. ​Cannabis Sativa is a naturally-growing plant that can be found across the world. Cannabis itself has been used medicinally for hundreds of year, with some accounts dating all the way back to Ancient Egypt.

Although cannabis is natural in itself, cannabis would not be nearly as impactful as other treatment options if it was not for the internal mechanisms that truly allow cannabis to spread its relief across the body and impacting multiple conditions and symptoms in its path.

Due to the complexity of the endocannabinoid system (ECS) we decided to break this resource down into two sections: General Understanding of the Endocannabinoid System & Detailed Breakdown of the Endocannabinoid System.

What Are the Internal Mechanisms That Allow Cannabis to Work?

Generally speaking, there are a few key compounds and systems in the human body that allow cannabis to work its medicinal magic:

 

The Endocannabinoid System

The ECS, comprised of cannabinoid receptors, endocannabinoid molecules, and their metabolic enzymes, is a crucial molecular system that the body uses to help maintain homeostasis - an internal mechanism responsible for stability, balance, or equilibrium within the cell or the body. This balance allows cells, organs, and systems to function optimally. The ECS is found within all vertebrates, i.e. animals with a backbone or spinal column.

Cannabinoid Receptors

When cannabis is consumed, cannabinoids bind to receptor sites throughout our brain (CB-1 Receptors) and body (CB-2 Receptors). Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds to receptors in the brain whereas CBN has a strong affinity for CB-2 Receptors located throughout the body. It is important to remember that molecules like cannabinoids and other neurotransmitters rarely interact with only one receptor type; they often interact with many. While cannabinoids may activate the same cannabinoid receptors as endocannabinoids, they will likely interact with several other receptors and therefore have distinct effects.

Endocannabinoids

While cannabinoids are the chemical compounds secreted by cannabis flowers that provide relief to an array of symptoms including pain, nausea, anxiety ,and inflammation, cannabinoids actually imitate our naturally produced endocannabinoids that activate to maintain internal stability and health. To put a complex system simply, they mediate communication between cells, and when there is a deficiency or problem with our ECS, unpleasant symptoms and physical complications occur.

The two primary endocannabinoids involved with cannabis treatment are:

2-AG: is the most abundant endocannabinoid found in the body, and like anandamide, is thought to play an important role in the regulation of appetite, immune system functions and pain management. It is also thought that 2-AG may also play a role in the inhibition of cancer cell proliferation.

Anandamide: is created on-demand naturally to be used when needed to maintain homeostasis. Anandamide has been shown to be a mood enhancer, in addition to regulating feeding and suckling behavior, along with baseline pain levels and sleep patterns.

 
 

Detailed Break Down of ECS

History of Endocannabinoid System

While human-use of cannabis dates back centuries, it was not until the 1940s that we truly began to understand the foundations of the cannabis plant, with the discovery of cannabinoids. This discovery jump-started an industry of scientists leading research into cannabis, culminating in 1964 when the Israeli organic chemists, Yehiel Gaoni and Raphael Mechoulam, characterized and synthesized tetrahydrocannabinol (THC) produced by the cannabis plant for the first time. It would take another 20 years before the first cannabinoid (CB) receptors were discovered in the late 1980s, and were found to compromise a new series of homeostatic regulatory mechanisms within the body; this newly found system was named the endocannabinoid system.

 

What is the Endocannabinoid System?

Although the endocannabinoid system may not be widely or publicly understood, it is a very complex regulatory system that is found within all complex animals - from fish to humans. The diverse regulatory functions of the endocannabinoid system include:

  • Memory

  • Digestion

  • Motor function

  • Immune response and Inflammation

  • Appetite

  • Pain

  • Blood pressure

  • Bone growth

  • Protection of neural tissues, among others.

 

There are three main components that make up the endocannabinoid system:

  • Endocannabinoid receptors: Found on the surface of cells, they transmit information about changing conditions to the inside of the cell. There are two major cannabinoid receptors, aptly named CB1 and CB2 Receptors.

  • Endogenous Endocannabinoids: Small, naturally-produced molecules that activate cannabinoid receptors. The two major endocannabinoids, anandamide and 2-AG are synthesized on demand, meaning they get made and used exactly when they’re needed, rather than packaged and stored for later use. According to Leaf Science, 2-AG is found at higher concentrations in the brain, while anandamide has a role in reward, mood, appetite, pain relief, and reproduction, and is found at higher concentrations in other areas of the body.

  • Enzymes that either synthesize or metabolize these endocannabinoids: Responsible for breaking down endocannabinoids after they are used. According to Backes, the two major enzymes are FAAH, which breaks down anandamide, and MAGL, which conversely breaks down 2-AG. These enzymes ensure that endocannabinoids get used when needed, but no longer than necessary, distinguishing endocannabinoids from many other molecular signals in the body.

 

Most consequentially, according to Leafly, the endocannabinoid system is responsible for helping maintain homeostasis, the concept that most biological systems are actively regulated to maintain conditions within a narrow range. For example, our body does not desire the temperature to be too hot or too cold, nor blood sugar levels to be too high or too low; for our cells to maintain optimum performance, our body desires ideal conditions that do not fluctuate wildly. When an event brings a cell out of its preferred homeostatic state, the endocannabinoid receptors, endocannabinoids, and the enzymes that synthesize and metabolize the endocannabinoids all play a role in bringing things back to homeostasis.

What are CB1 and CB2 Receptors?

There are two primary cannabinoid receptors in the endocannabinoid system, simply named CB1 and CB2. According to Backes, CB1 receptors are one of the most abundant receptor types in the brain and are the receptors that interact with THC to elicit the psychoactive effects. In contrast, CB2 receptors are more abundant outside of the nervous system in places like the immune system. Altogether, CB1 and CB2 receptors are distributed throughout the central nervous and immune systems, and within many other tissues, including the:

  • Brain

  • Gastrointestinal System

  • Reproductive and Urinary Tracts

  • Spleen

  • Endocrine System

  • Heart

  • Circulatory System.

 

It is now understood that cannabinoid interactions extend beyond the CB1 and CB2 receptors. Cannabinoids also interact with other CB-type and related receptors and ion channels. According to Backes and Project CBD, these include:

  • Serotonin Receptors - at high concentrations, CBD directly activates the 5-HT1A serotonin receptor, implicated in a range of biological and neurological processes, including (but not limited) to anxiety, addiction, appetite, sleep, pain perception, nausea, and vomiting. CBDA also has a strong affinity for the 5-HT1A receptor, and possibly even more so than CBD.

  • TRPV1 - known to mediate pain perception, inflammation, and body temperature, CBD directly interacts and binds to TRPV1 receptors. Anandamide is also a TRPV1 agonist.

  • PPARS - [peroxisome proliferator-activated receptors] activation of the PARR-gamma has an anti-proliferative effect as well as an ability to induce tumor regression in human lunger cancer cell lines; PPAR-gamma activation also degrades a key molecule linked to the development of Alzheimer’s disease. Furthermore, PPAR receptors also regulate genes that are involved in: energy homeostasis, lipid uptake, insulin sensitivity, and other metabolic functions including a benefit for diabetics.

  • GPR55 - receptor linked to energy homeostasis and metabolic dysregulation associated with diabetes and obesity

  • Allosteric Modulator - CBD interacts with the GABA-A receptor in a way that enhances the receptor’s binding affinity for its principal agonist, GABA, by changing the shape of the GABA-A receptor in a way that amplifies the natural calming effect of GABA. As a negative allosteric modulator of the CB1 receptor, CBD lowers the ceiling on THC’s psychoactivity.

  • GPR18 - regulates disparate physiological functions that range from intraocular pressure to cellular migration and which include endometriosis and some forms of metastatic disease

  • GPR119 - functions as a “fat sensor” to reduce food intake and weight gain

  • GPR30 - responds to estrogen with rapid signaling

 

How Does Cannabis Affect the Endocannabinoid System?

More than 700 chemical constituents are produced within the cannabis plant, however phytocannabinoids (cannabinoids) and terpenoids (terpenes) are the principle active ingredients that provide patients with medical relief.

 

While the body produces its own cannabinoids in the form of endocannabinoids, phytocannabinoids are produced by cannabis in the form of cannabinoid acids such as THCA, CBDA, CBGA, CBCA, CBGVA, THCVA, CBDVA, and CBCVA. Once these phytocannabinoids are heated, they will convert into their chemically neutral and more widely recognized forms of THC, CBD, CBG, CBC, CBGV, THCV, CBDV, and CBCV.

 

With most cannabinoids you will not experience the psychoactive "high" many associate with cannabis, aside from THC and possibly THCV. Although the cannabinoids are not intoxicating inherently, the presence and combination of different cannabinoids can influence how THC affects you; for example, CBD influences the way that THC interacts with CB1 receptors and will decrease the effect of THC when used in combination.

 

Terpenes are the fragrant oils secreted in cannabis trichomes - and in other plants - and offer users a variety of medical benefits. There are eight (8) primary terpenes found in cannabis, including pinene, limonene, myrcene, beta-caryophyllene, linalool, terpinolene, ocimene, and humulene. Terpenes have unique attributes that contribute to the overall composition of a strain, adding a dimension to each one's "personality."

 

A fascinating aspect of cannabinoids, terpenes, and the interaction with the endocannabinoid system is what is referred to as the "Entourage Effect." In essence, the entourage effect theory states that cannabinoids and terpenes are more medically beneficial when used synergistically, allowing the cannabinoids and terpenes to work in conjunction to boost the symptomatic benefits.

 

Phytocannabinoids are relatively nontoxic, and for this reason it requires extremely high lethal-dose requirements in humans that makes it virtually impossible to overdose on cannabis.

What Does the Endocannabinoid System Do?

Endocannabinoids effectively modulate the flow of neurotransmitters, keeping the nervous system running smoothly. They are also directly linked to the mechanisms underlying memory and learning. Furthermore, as discussed above and reinforced by Backes, endocannabinoids appear to be profoundly connected with the concept of homeostasis and help to redress specific imbalances presented by disease or by injury. Backes states that endocannabinoids’ role in pain signaling has led to the hypothesis that endocannabinoid levels may be responsible for the baseline of pain throughout the body; the value of proper “endocannabinoid tone” within the body appears to play a significant role in maintaining the general physical and emotional well-being of a person.

 

According to Backes, it is the activation of CB1 receptors that is responsible for the psychoactive effects of cannabis, as THC is mimicking an endocannabinoid by binding to this receptor. The brain functions affected by the endocannabinoid system include:

  • Decision-making

  • Cognition

  • Emotions

  • Learning

  • Memory

 

As well as regulation of:

  • Bodily Movement

  • Anxiety

  • Stress

  • Fear

  • Pain

  • Body Temperature

  • Appetite

  • Sense of Reinforcement or Reward

  • Blood-brain Permeability

  • Motor control

 

Importantly, the one brain region that does not express many CB1 receptors is the brain stem, which is responsible for respiration and circulation. This is significant as this characteristic is attributed as the primary reason overdose risk is practically non-existent compared to opioid overdoses.

 

CB2 expression has been identified in key regions of the brain, including the hippocampus responsible for memory and spatial recognition. According to Backes, in the hippocampus, CB2 receptors appear to modulate self-activity and information flow between brain networks, potentially assisting in the selection of inputs that may guide complex behavior. CBD has also been shown to modulate midbrain reward circuitry, responsible for sensory stimulus.