Science of Cannabis

Cannabis produces cannabinoids, including THC and CBD.  In terms of psychological effects, THC is the compound related to the psychoactive component, while CBD has calming/healing properties.  These cannabinoids represent a diverse set of chemical compounds that bind to special receptors in the human body,  making up what we know as the endocannabinoid system. The human body possesses specific binding sites (“locks”) on the surface of many cell types, and our body produces several endocannabinoids (“keys”) that bind to these cannabinoid receptors (CB) to activate or “unlock” them. Once the lock and key bind to each other, it results in an effect on the brain and body.  THC, CBD, and other cannabinoids are able to bind to these cannabinoid receptors to evoke similar effects.

Scientists have identified cannabinoids found in the cannabis plant (phytocannabinoids) that mimic or counteract the effects of some endocannabinoids. Phytocannabinoids and terpenes are manufactured in resin glands (trichomes) present on the flowers and main fan leaves of late-stage cannabis plants. The amount of resin produced and its cannabinoid content varies by plant gender, growing conditions, and harvesting time. The chemical stability of cannabinoids in harvested plant material is affected by moisture, temperature, light and storage, but will degrade over time in any storage conditions. Over 100 phytocannabinoids have been identified in the cannabis plant, many of which have documented medicinal value. Most are closely related or differ by only a single chemical component.

Endocannabinoid System

An Endogenous Cannabinoid System (ECS), commonly referred to as an “Endocannabinoid System,” is found in every animal and regulates a broad range of physiological and cognitive functions. The ECS is also specifically responsible for managing the pharmacological effects of such cannabis compounds on the brain.1, 2 In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds, just as a specific key is needed to open a particular lock. Specialized receptors are located throughout the human body and in various areas of the brain. For instance, there are receptors in the hippocampus of the brain that will, when triggered, effect memory and/or learning. Other portions of the brain that may be affected include the cerebral cortex, which controls decision-making and/or emotional behavior, or the cerebellum, which controls motor control and coordination.

Clinical endocannabinoid deficiency (CEDC) is a proposed spectrum disorder that has been implicated in a range of illnesses, including fibromyalgia, migraine and irritable bowel syndrome. So far, very little clinical research has been conducted on this speculative disorder. It is quite possible that these very common conditions may respond favorably to cannabinoid therapies, but more research is needed.

Cannabinoid Receptors

The primary cannabinoid receptors are identified as Cannabinoid type 1 receptors (CB1-R) and Cannabinoid type 2 receptors (CB2-R). The receptors can be “unlocked” by three kinds of cannabinoids:

• Endocannabinoids – endogenous-fatty-acid cannabinoids produced naturally in the body (e.g., anandamide and 2-AG)
• Phytocannabinoids – concentrated in the oily resin of the buds and leaves of plants such as cannabis (e.g., THC and CBD)
• Synthetic cannabinoids – manufactured by artificial means such as in a laboratory

First detected in the brain, CB1-R is also located in many other organs, connective tissues, gonads, and glands. CB1-R are not found in the medulla oblongata, the part of the brain responsible for respiratory and cardiovascular functions). CB1 receptors play an important role in the coordination of movements, spatial orientation, sensory perceptions, cognitive performance, and motivation.

The most important function of the CB1-R is the reduction of excessive or inadequate signaling by the neurotransmitters in the brain. By the activation of the CB1-R, the hyperactivity or hypoactivity of the messengers (e.g., serotonin, dopamine) is regulated back into balance. For example, when THC binds to CB1-R, activity in the pain circuits are inhibited, resulting in reduced pain. Many other symptoms such as nausea, muscle spasticity, and seizures can be alleviated or diminished with cannabinoid therapy.

CB2-R are primarily associated with the immune system and found outside the brain in places like the gut, spleen, liver, heart, kidneys, bones, and reproductive organs. For example, CBD binds to CB2-R, and good evidence shows CBD may lessen the impact of inflammatory and neuro-inflammatory diseases. Until recently, it was believed that CB2-R played no role with nerve cells or bundles, but studies now show that it also plays an important role in the signal processing of the brain.

A third receptor is the transient receptor potential vanilloid-type 1 (TRPV1). The function of TRPV1 is to detect and regulate body temperature. In addition, TRPV1 is responsible for the sensations of extreme external heat and pain and is subject to desensitization. Therefore, if continuously stimulated, the pathway will eventually slow down or even stop. This raises therapeutic possibilities for agents to effectively treat certain kinds of neuropathic pain.

New vs. Old Science

Since the initial discovery of the CB1 receptor site by Allyn Howlett and William Devane in 1988, it’s been widely believed that CBD, unlike THC, has little binding affinity for the CB1 receptor. Unfortunately, this assumption was not based on science. New data emerging from the international cannabinoid research community indicates that CBD interacts directly with the CB1 receptor site in ways that are therapeutically relevant. CBD parks at a different docking site on the CB1-R that is functionally distinct from THC’s orthosteric binding site. CBD attaches to what’s known as an “allosteric” binding site on CB1-R. When CBD docks at the receptor, it does not initiate a signaling cascade. It does, however, influence how the receptor responds to stimulation by THC and the endogenous cannabinoids. Allosteric modulation of CB1-R changes the conformation (shape) of the receptor, and this can have a dramatic impact on the efficiency of cell signaling.

A positive allosteric modulator that enhances CB1 receptor signaling indicates that CBD could be helpful treating diseases linked to endocannabinoid deficits (such as anorexia, migraines, irritable bowel, fibromyalgia, and PTSD), in addition to treating conditions associated with endocannabinoid excess or overactivity (obesity, metabolic disorders, liver disease, cardiovascular issues).

Entourage Effect

The concept of the entourage effect was introduced in 1998 by Israeli scientists Shimon Ben-Shabat and Raphael Mechoulam. The theory is that cannabinoids within the cannabis plant work together and affect the body in a mechanism similar to the body’s own endocannabinoid system. Basically, these compounds work better together than in isolation.

The longstanding, successful use of cannabis is further proof of its medicinal superiority when compared to products containing isolated, single components of the cannabis plant, or even synthetic cannabinoids trying to replicate the natural components.

Research into the benefits of THC and CBD in isolation is well established. THC demonstrates analgesic, anti-emetic, and anti-inflammatory properties. CBD possesses anti-psychotic, anti-seizure, and anti-anxiety properties. However, evidence is mounting that by isolating these cannabinoids or creating them in a lab, the resulting effects may have limited therapeutic use. When delivered in high concentrations, THC can cause overdosing. Although an acute THC overdose rarely requires medical intervention, the side effects can be very unpleasant. Evidence supports the idea that THC and CBD work better together to create a synergistic effect known as the entourage effect. Therefore, the idea indicates that whole plant cannabis products have more medicinal value than isolated compounds or extracts.

List of Cannabinoids

Cannabidiol (CBD)

Not all cannabinoids are colorless. One of the most brightly yellow-colored cannabinoids is CBD, a very valuable cannabinoid. CBD has tremendous medical potential. This is particularly true when the correct ratio of CBD to THC is applied to treat a particular condition. CBD acts as an antagonist at both the CB1 and CB2 receptors, yet it has a low binding affinity for both. This suggests that CBD’s mechanism of action is mediated by other receptors in the brain and body.

Tetrahydrocannabinol (THC)

Delta-9-tetrahydrocannabinol (THC) is a phytocannabinoid, and typically the most abundant cannabinoid present in cannabis products on the market today. THC can be derived from THCA by non-enzymatic decarboxylation during storage and consumption. It is responsible for the well-documented psychoactive effects experienced when consuming cannabis. When you smoke or ingest cannabis, THC travels into the bloodstream and eventually binds to cannabinoid receptors throughout your body. These receptor sites affect memory, concentration, pleasure, coordination, sensory and time perception, appetite and many more important functions. Mild side effects of larger doses of THC can include anxiety, elation, burning eyes, dry mouth, shaking/trembling, increased heart rate and/or shortness of breath (or at least the perception of such) and short-term memory loss. Smoking or ingesting too much THC in a short period of time can intensify and alter its effects.

Tetrahydrocannabinolic Acid (THCA)

THCA is the main constituent in raw cannabis. THCA converts to Δ9-THC when burned, vaporized, or heated at a certain temperature. THCA, CBDA, CBGA, and other acidic cannabinoids hold the most COX-1 and COX-2 inhibition, contributing to cannabis’ anti-inflammatory effects. This cannabinoid also acts as an antiproliferative and antispasmodic.

Cannabidiolic Acid (CBDA)

CBDA, CBD-acid or CBD-a is the main form in which CBD exists in the cannabis plant, along with THCA (THC-acid). CBD is obtained through non-enzymatic decarboxylation from the acidic form of the cannabinoid, this reaction taking place when the compounds are heated. Heating or catalyzing CBD-a transforms it into CBD, thereby increasing the total CBD level. Research shows higher concentrations of CBDA displayed more pronounced antimicrobial activity than CBD alone.

Cannabidivarin (CBDV)

Like THCV, CBDV differs from CBD only by the substitution of a pentyl (5 carbon) for a propyl (3 carbon) sidechain. Although research on CBDV is still in its initial stages, recent studies have shown promise for its use in the management of epilepsy. This is due to its action at TRPV1 receptors and modulation of gene expression.

Cannabigerol (CBG)

A non-psychoactive cannabinoid, CBG’s antibacterial effects can alter the overall effects of cannabis. CBG is known to kill or slow bacterial growth, reduce inflammation, (particularly in its acidic CBGA form,) inhibit cell growth in tumor/cancer cells, and promote bone growth. It acts as a low-affinity antagonist at the CB1 receptor. CBG pharmacological activity at the CB2 receptor is currently unknown.

Cannabinol (CBN)

CBN is a mildly psychoactive cannabinoid that is produced from the degradation of THC. There is usually very little to no CBN in a fresh plant. CBN acts as a weak agonist at both the CB1 and CB2 receptors, with greater affinity for CB2 receptors than CB1. The degradation of THC into CBN is often described as creating a sedative effect, known as a “couch lock.”

Cannabichromene (CBC)

Evidence has suggested that it may play a role in the anti-inflammatory and anti-viral effects of cannabis, and may contribute to the overall analgesic effects of medical cannabis. A study done in March 2010 showed that CBC along with cannabidiol (CBD) and tetrahydrocannabinol (THC) have antidepressant effects. Another study showed that CBC helps promote neurogenesis.

Tetrahydrocannabivarin (THCV)

THCV is a minor cannabinoid found in only some strains of cannabis. The only structural difference between THCV and THC is the presence of a propyl (3 carbon) group, rather than a pentyl (5 carbon) group, on the molecule. Though this variation may seem subtle, it causes THCV to produce very different effects than THC. These effects include a reduction in panic attacks, suppression of appetite, and the promotion of bone growth.

Basic Terminology

Marijuana – The dried leaves and flowering tops of the pistillate hemp plant that yield THC and are smoked in cigarettes for their intoxicating effect.

Cannabis – A flowering plant from the Cannabaceae family used in for its hemp fibers and oils and medicinal value.

Cannabinoid (CBD) – A cannabinoid is a chemical compound that interacts with a large regulatory system in the body called the Endocannabinoid System (ECS), and yet is considered a non-psychoactive drug according to the CBD is non-psychoactive, according to the National Center for Biotechnology Information. The ECS is responsible for maintaining homeostasis in the body. Homeostasis is the perfect internal balance required for optimum health.  Varying classes exist of the medical chemical compounds of the cannabis herb and CBD (along with Cannabinol – CBN) and was discovered as one in the 1940’s.  The newer the plant the less the CBD and higher the THC. It has milder psychoactive effects compared to THC components.

Hemp – The fiber and oils found in the Cannabis plant and comes from a differing strain than the perceived narcotic compound THC.  It can be refined and leveraged into a variety of products like paper, textiles, clothing, biodegradable plastics, etc.

THC – Tetrahydrocannabinol (THC) is the psychoactive component also referred to as delta-9-tetrahydrocannabinol.  It’s considered to be the most psychoactive Cannabinoid and the active ingredient in Cannabis.

Cannabinoid receptor types 1 and 2 – CB1 receptors are predominantly in the brain within areas like the cerebellum as well as our reproductive systems.  However, CB2 receptors are present in the immune system mostly in the spleen.  Both appear to be the major conduits for the receptiveness of the body to medical marijuana.

CBD – Short for Cannabidiol one of the least psychoactive and most anti-inflammatory Cannabinoids.

Phytocannabinoids – The cannabinoids produced by plants naturally and formed through decarboxylation of their respective 2-carboxylic acids (2-COOH), a process which is catalyzed by heat, light or alkaline conditions.

Endocannabinoids – The cannabinoids produced within the body of humans and animals – a chemical substance in the body belonging to a group resembling organic chemicals found in cannabis.

Synthetic Cannabinoids – A class of chemicals that are different from the cannabinoids found in cannabis but which also bind to cannabinoid receptors. They are often marketed as designer drugs or sold in products with claims that they give the effects of cannabis and are typically produced in a laboratory.

Even today, new uses for cannabinoids are being discovered. For example, scientists recently found that topical cannabinoid-based preparations can be effective in treating antibiotic-resistant skin infections. Transdermal patches and unisex rectal suppositories are now helping patients with arthritis, fibromyalgia, diabetic nerve pain, neuropathic. Progression and further development of cannabis as a novel therapy for various afflictions depends on continued research and development. The science behind marijuana’s ability to help patients cope with a variety of issues, such as anxiety, pain, gastrointestinal issues, etc., has flourished in recent years.  As more evidence on cannabis is unveiled, a wider range of therapeutic uses will emerge.

References:

• Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz (2016). “Targeting the endocannabinoid system: future therapeutic strategies”. Drug Discovery Today.
• Donvito, Giulia; Nass, Sara R.; Wilkerson, Jenny L.; Curry, Zachary A.; Schurman, Lesley D.; Kinsey, Steven G.; Lichtman, Aron H. (31 August 2017).