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The hemp plant produces hundreds of chemicals that have been found to deliver wellness and health benefits to humans and other mammals. To date, more than 200 terpenes, 20 flavonoids, and 113 cannabinoids have been discovered and isolated from hemp and cannabis—many of which have been investigated in formal research studies and literature reviews. 

Like terpenes, cannabinoids—as a group—demonstrate efficacy in several areas, giving them application in the prevention and treatment of a variety of diseases and conditions. At their core, benefits of cannabinoids include reductions in systemic inflammation, pain relief, and reduced anxiety. However, research is showing a long list of benefits we can potentially attain from cannabinoids.

History of Cannabinoid Research 

The first cannabinoid to be discovered, in the late 1930s, was cannabinol (CBN) by British chemist Robert Cahn. A few short years later, in 1940, American organic chemist Roger Adams and his team at the University of Illinois isolated and synthesized the CBD and CBN molecules and identified tetrahydrocannabinol (THC). In 1942, Adams was awarded a patent for his particular method of isolating CBD. 

Although, technically, Adams and his team are credited with discovering THC, the effort didn’t isolate the molecule from cannabis plants and yielded no information regarding its potential medicinal efficacy. Adams was able, however, to synthesize THC from some of its cannabinoid cousins (typically CBD).  

In all, Adams published 27 studies regarding cannabis in the American Journal of Chemistry. It is theorized that he wasn’t able to fully isolate THC from the plant because of the relatively primitive technology of the time.

The world didn’t learn about the medical benefits of THC until 1964 when Israeli researcher Raphael Mechoulam and his team first isolated and fully synthesized the THC molecule at Hebrew University in Jerusalem—with the help of a then-modern nuclear magnetic resonance spectrometer. 

Mechoulam and his colleagues later discovered that CBD and THC appear to mimic the endocannabinoids 2-AG and anandamide, respectively—and, thus, act as a health supplement when consumed by humans and other mammals.


Theory of Endocannabinoid Deficiency 

The ECS is a network of millions of microscopic cellular receptors found throughout the body. To date, we know of two primary receptor types that bind with cannabinoids from hemp and cannabis: CB1, found mostly in the brain and central nervous system (CNS); and CB2, located primarily in the organs, tissues, and glands of the immune system found throughout the body. 

CB1 receptors are located in the brain and throughout the body, while CB2 receptors are found mostly in the immune and gastrointestinal system. CB2 receptors are also found in the brain but are not found in the density that CB1 receptors are found. Both receptor types are present in the skin, as exemplified in this 2005 research study. This 2008 study provides additional information regarding the distribution of cannabinoid receptors throughout the body. 

The ECS is significant because of its important role in the management of several different bodily systems, including immune response, cognition, mood, appetite, sleep cycles (circadian rhythm), various aspects of metabolism (including energy level), and even libido.  

In 2004, cannabis researcher Dr. Ethan Russo first proposed the theory of Endocannabinoid Deficiency with the publication of his pinnacle research study entitled “Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome, and Other Treatment-resistant Conditions?” that was published in the journal Neuro Endocrinology Letters

Russo and his team concluded, “Migraine, fibromyalgia, IBS [Irritable Bowel Syndrome], and related conditions display common clinical, biochemical, and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.”

2016 study entitled “Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes” that was published in the journal Cannabis and Cannabinoid Research theorized that a deficiency in the ECS could lead to conditions such as Alzheimer disease, Parkinsons disease, and depression.  

The study’s authors stated that “The theory of CED was based on the concept that many brain disorders are associated with neurotransmitter deficiencies, affecting acetylcholine in Alzheimer disease, dopamine in parkinsonian syndromes, serotonin and norepinephrine in depression, and that a comparable deficiency in endocannabinoid levels might manifest similarly in certain disorders that display predictable clinical features as sequelae of this deficiency.”

According to cannabis researcher Mara Gordon, the best mental model for understanding the role of the ECS in human health involves the ECS not necessarily being itself balanced, but rather of it balancing other critical bodily systems and functions, such as immune response or metabolism. 

“It's not that you're balancing out the endocannabinoid system. It's the endocannabinoid system's job to balance out the body,” said Gordon during a 2019 podcast interview

Chemical Variants of PhytoCannabinoids 

Readers have already learned of the two major categories of cannabinoids, the phyto (plant-based) and endo (produced by the body) varieties. Some cannabinoid variants pertain to where a molecule exists within its lifecycle or the environmental conditions to which it has been exposed (including light and air). 

Acidic precursors, indicated by an “A” following the cannabinoid name, are the natural molecules from the plant before activation (decarboxylation) takes place and deliver their own distinct set of medicinal efficacies. Thus, a patient could potentially gain more value from consuming both THCA and THC, depending on dosing and their specific condition. 

“Varin” versions of cannabinoids, indicated by a “V” following the cannabinoid name feature fewer carbon atoms, which changes the half-life of the molecule.

Some users claim that varin cannabinoids feature a shorter duration of efficacy than other cannabinoids. While the efficacy of varins is often quite similar to that of its non-varin siblings, there are sometimes significant—and even polar opposite—differences. For example, while THC delivers psychoactive effects at nearly all dosage levels, THCV is psychoactive only at relatively large doses. Also, while THC is an infamous appetite stimulant, THCV is one of the rare cannabinoids that decreases appetite and may play a pivotal role in the treatment of obesity and type-2 diabetes in the future. 

Cannabigerol (CBG) is a common cannabinoid found in relatively low quantities in hemp and cannabis. It is an excellent example of the progression of chemical morphology that occurs in the life of a cannabinoid molecule. The CBG acidic precursor, CBGA, is responsible for the creation of the acidic precursors CBDA and THCA in turn, morph into CBD and THC under certain environmental conditions (such as the application of heat). 

Adding complexity to the issue is the fact that varins feature their own acidic precursors. Thus, CBGV is produced by CBGVA. CBGVA transmogrifies into THCVA, CBDVA, and CBCVA. Varins exemplify the central role played by CBG and its acidic precursor CBGA.

Entourage Effect Theory (More on entourage effect in understanding the ECS.)

Research has indicated that terpenes interact synergistically with the human endocannabinoid system (ECS) and often enhance the efficacy and potency of cannabinoids and other terpenes. Sometimes this mechanism involves a terpene helping a cannabinoid cross the highly selective blood-brain barrier. 

Due to this synergy, the exact composition of a hemp extract becomes increasingly important. Many wellness professionals and experts theorize that isolates and broad-spectrum hemp products deprive users of some benefits of the entourage effect that are provided by full-spectrum formulations. 

According to Project CBD, the California-based non-profit organization, “Preclinical research indicates that full spectrum...cannabis oil is effective at much lower doses and has a wider therapeutic window than [an] isolate.”

Research Studies 

Hundreds of research studies have been conducted during the past several decades regarding the potential health benefits of a wide range of cannabinoids. 

2018 study entitled “The Consumption of Cannabis by Fibromyalgia Patients in Israel” that was published in the journal Pain Research and Treatment investigated the effectiveness of CBD for those suffering the painful affliction fibromyalgia. Concluded the study, “Nearly all cannabis consumers reported favorable effects on pain and sleep, and few reported adverse effects or feeling of dependence on cannabis.” 

In 2015, a study involving mice entitled “Neuroprotective Properties of Cannabigerol in Huntington's Disease” investigated the neuroprotective qualities of CBG and its potential role in the treatment of Huntington’s disease. Research reported that “CBG was extremely active as a neuroprotectant in mice intoxicated with 3-nitropropionate, improving motor deficits and preserving striatal neurons against 3NP toxicity”. 

Study authors noted, “In conclusion, our results open new research avenues for the use of CBG, alone or in combination with other phytocannabinoids or therapies, for the treatment of neurodegenerative diseases such as HD.” 

2014 study entitled “Colon Carcinogenesis is Inhibited by the TRPM8 Antagonist Cannabigerol, a Cannabis-derived Non-psychotropic Cannabinoid” that was published in the journal Carcinogenesis explored the ability of CBG to fight the formation of cancer cells. The study found that “CBG promoted apoptosis,” a genetically pre-programmed cellular suicide mechanism that some cannabinoids and terpenes can induce in cancer cells. 

In some of the most definitive statements made by an in vivo study of the chemical components of hemp, authors said, “In vivo, CBG inhibited the growth of xenograft tumours as well as chemically induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of CRC cells.” The study concluded, “CBG should be considered translationally in CRC prevention and cure.” 

2015 study entitled “Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function” that was published in the Journal of Neuroimmune Pharmacology investigated the ability of cannabinoids such as CBD and CBN to improve immune function. 

Researchers noted, “It is now recognized that other phytocannabinoids, such as cannabidiol (CBD) and cannabinol (CBN), can alter the functional activities of the immune system.” 

2008 study entitled “Antibacterial Cannabinoids from Cannabis Sativa” that was published in the Journal of Natural Products explored the ability of a variety of cannabinoids, including cannabichromene (CBC), CBD, CBG, and cannabinol to fight bacterial infection. The study reported, “All five major cannabinoids…showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance.” 

Conclusions to the study report that “taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.”

2011 study entitled “Symptom‐relieving and Neuroprotective Effects of the Phytocannabinoid Δ9‐THCV in Animal Models of Parkinsons Disease” that was published in the British Journal of Pharmacology explored the ability of the varin phytocannabinoid THCV to deliver neuroprotection and improve the condition of patients with Parkinson disease (PD). 

The research reported, “In these animals, Δ9‐THCV…caused preservation of tyrosine hydroxylase–positive neurones. This effect probably involved CB2 receptors as it was also elicited by the selective CB2 receptor agonist, HU‐308, and CB2 receptor–deficient mice were more vulnerable to LPS lesions.” 

Study authors concluded by saying, “Given its antioxidant properties and its ability to activate CB2, but to block CB1, receptors, Δ9‐THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms.” 

2010 in vivo study involving mice entitled “The Plant Cannabinoid Δ9‐Tetrahydrocannabivarin Can Decrease Signs of Inflammation and Inflammatory Pain in Mice” that was published in the British Journal of Pharmacology investigated the ability of THCV “to activate CB2 receptors, there being evidence that combined CB2 activation/CB1 blockade would ameliorate certain disorders.”

Concluded the study’s researchers, “THCV can activate CB2 receptors…and decrease signs of inflammation and inflammatory pain in mice partly via CB1 and/or CB2 receptor activation.”

2006 study entitled “Cannabinoid Analgesia as a Potential New Therapeutic Option in the Treatment of Chronic Pain” that was published in the journal Annals of Pharmacotherapy revealed conclusions that “cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management and cannabinoids are a potential addition to the arsenal of treatment options.” 

2005 study entitled “Human Studies of Cannabinoids and Medicinal Cannabis” that was published in the journal Handbook of Experimental Pharmacology explored the human trials that have been conducted into the phytocannabinoids and terpenes produced by herbs such as hemp and cannabis. 

Reported the researchers, “New possibilities in human research have been opened by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries.” The report noted common problems observed in existing human trials, stating, “Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability.”


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