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THE ULTIMATE GUIDE TO CANNABINOIDS

The Ultimate Guide to Cannabinoids

WRITTEN BY: LEX PELGER

JAN 11, 2022

You have many ways to define cannabinoids – but the clearest definition is: cannabinoids are molecules that bind to the cannabinoid receptors.

In humans, the cannabinoid receptors are widespread. CB1 receptors, the first discovered, occur in all of the highest parts of the brain. That’s why tetrahydrocannabinol (THC) affects people in such a multitude of ways. Everyone has different concentrations of CB1 receptors in various brain areas. Then the CB2 receptors are found in every organ of the body and are intimately tied up with the immune system.

These receptors of our endogenous cannabinoid system help to balance out the entire body and mind. The endocannabinoid system is often referred to as our system of homeostasis, of balance. And the cannabinoids – whether found in the plant (phytocannabinoids) or produced within the body (endocannabinoids) or even made in the lab (synthetic cannabinoids) – are what bind to those receptors.

How Many Cannabinoids are There?

Of the approximately 420 chemical compounds that can be found in the cannabis plant, more than 120 cannabinoids have been identified. The most studied phytocannabinoids are THC and CBD. The strongest effects of cannabinoids also tend to occur in the highest concentrations in both the recreational cannabis and the agricultural hemp varieties of the plant. But besides CBD and THC, there’s much more to be discovered about some of the other phytocannabinoids produced by the cannabis plant.

Potential Benefits of Cannabinoids

The most common benefits of phytocannabinoids that we hear about are for stress, sleep, and occasional inflammation. Cannabidiol, or CBD’s ability to balance someone’s endocannabinoid system – as well as interact with a large number of other neurotransmitters and signaling systems – means that it helps many different people in a variety of ways.

All of that being said, we do not mean for any of the science below to be taken as treatment for medical conditions. The minor cannabinoids found in our products occur at varying levels and it is only the doses of CBD (and THC in our Reserve products) that we are formulating to keep at a constant level. These products are dietary supplements and not intended to treat, cure, or prevent any disease. This information is offered for educational purposes only.

Phytocannabinoids vs. Endocannabinoids

We will cover some of the major phytocannabinoids below – but what are the endocannabinoids that they work with?

The two most famous are anandamide (AEA) and 2-AG. These two neurotransmitters might not have the same shape as a phytocannabinoid, but they bind to the cannabinoid receptors and make a host of changes across the body. These endocannabinoids go far back in evolutionary history and every mammal (as well as most of the rest of the tree of life) contains an endocannabinoid system.

The endocannabinoids are especially involved with the neuronal, the hormonal, and the immune systems – three of the most mysterious and most important systems in the body and mind. The endocannabinoids seem to help hold everything together.

List of major phytocannabinoids

CBDA – Cannabidiolic acid

The acid forms of the cannabinoids are their raw form inside of the plant. To convert a cannabinoid like cannabidiolic acid CBDA to CBD, all it takes is some gentle heating. But while they might appear quite similar, the acid forms have a whole different range of effects in the body and mind. That’s why THCA won’t cause the psychoactives effects of THC from consuming a cannabis leaf.

Those acid forms of the cannabinoids need to be converted so that they can cross the blood-brain barrier. But that doesn’t keep CBDA from being a great cannabinoid of health, especially for our guts.

CBDA is the most abundant cannabinoid in Nature – but there’s less than 100 total studies on it. First isolated in 1955, it was the first cannabinoid acid ever found. The early research focused on its sedative properties and its strong antibiotic effects. Research in animal models suggest its help in combatting nausea as well as stress.

Currently, many people across the United States are juicing hemp plants and drinking the juice to enhance their gut health. One of the major cannabinoids they would be consuming in this manner would be CBDA.

THCA – Tetrahydrocannabinolic acid

The acid form of, or precursor to THC is tetrahydrocannabinolic acid (THCA). Despite also not being well researched, what’s known so far is exciting. As this review points out, THCA, or raw cannabis, interacts with a number of molecular targets and work in animal models shows it to have anti-inflammatory, immunomodulatory, and neuroprotective effects.

In brain cells, THCA has been shown to bind to the PPARγ receptors that control genetic transcription. This positive side effect to turn on and off genes allows THCA to produce signaling molecules that protect brain cells, reduce neuroinflammation, and modulate the microglial cells that act as guardians of the brain.

CBG – Cannabigerol

However, everything begins with cannabigerol (CBG). Often referred to as the mother molecule, CBG is the first cannabinoid produced by the plant in its biosynthetic process. CBG usually only remains for a transient amount of time before being converted into a downstream molecule like THC, CBD, and CBC.

You might call CBG the “stem-cell” of cannabinoids. Only found in trace amounts in the plant, CBG has not been particularly well studied since its isolation. However, researchers have already found an intriguing number of medical uses.

Compared to the greatly psychoactive THC, CBG binds only slightly to the CB1 receptors in the brain. It also appears to interact with the CB2 receptors of the body – but whether it functions as an agonist or antagonist (activator or blocker) is still unclear.

We know CBG inhibits the reuptake of several neurotransmitters such as anandamide, serotonin, and norepinephrine – though not with as strong an effect as THC or CBD. However, CBG does inhibit GABA uptake more effectively than both of these and since GABA is the main inhibitory neurotransmitter of the brain, this might explain the anti-anxiety effects found for CBG.

Though clinical studies are lacking, preclinical research suggests anti-inflammatory properties and scientists confirmed that CBG helps in animal models for bladder issues and inflammatory bowel disorders. Like THC, it also appears effective in helping to lower glaucoma’s high eye pressure and CBG might be a more potent painkiller than THC. However, brain health and neuroinflammation is probably its most interesting area. An intriguing cannabinoid in many ways and most certainly worthy of greater study.

CBC – Cannabichromene

Depending upon the conditions in the plant, CBG undergoes conversion to any number of the other cannabinoids. One of the most exciting of these understudied molecules is cannabichromene (CBC). Most often found in freshly harvested cannabis, CBD is especially concentrated in young plants and in the leaves of more mature ones.

CBC was often misidentified as CBD until the late 70’s because they share almost the same retention time in gas chromatography. Now CBC is considered a minor cannabinoid because it usually only occurs as a maximum of 5% of the cannabinoid fraction in most strains. However, mutants in Afghan hashish and Korean fiber varieties have been found with up to 30% of CBC acid (CBCA).

CBC’s been long proven as an anti-inflammatory, an antimicrobial, and a modest painkiller via several mechanisms of action. An excellent recent pharmacological evaluation of CBC in the classic mouse tetrad assay of cannabinoid activity, found that at quite large doses, CBC caused significant locomotor suppression, catalepsy, painkilling and hypothermia. And in one of the most intriguing studies of relevance for the many diseases of neurodegeneration, DiMarzo & Shinjyo demonstrated that CBC increased the viability of adult neural stem cells in mice.

Also, a 2012 study found that CBC helped with diarrhea (gastrointestinal hypermotility) without decreasing the transit time. These were intriguing results, because the current drugs for this condition are often associated with constipation – though the mechanisms of this action are still mysterious because they seem to occur independently of the cannabinoid receptors. One more mystery surrounding the mechanisms of how cannabinoid’s contribute their help.

CBDV & THCV – Cannabidivarin & Tetrahydrocannabivarin

The varin forms of CBD and THC are simply the originals with a shorter tail. Tetrahydrocannabivarin (THCV) tends to occur at the highest levels in the South African varieties of cannabis known as Durbans and is said to impart a different flavor to the psychoactive experience. Cannabidivarin (CBDV) has been studied the most for conditions like epilepsy and autism.

CBDV, originally discovered in 1969, took more than 40 years to first be studied in animals. In 2012, anticonvulsant effects on two in-vitro models and four rodent models of epilepsy were demonstrated, while also showing compatibility with the existing epilepsy meds.

In addition, CBDV demonstrated no negative effects on motor control. That lab followed up this research in 2013 by looking at extracts from the whole plant and finding a significant reduction in seizures. CBDV’s mechanism of action are still unknown, though it might be activation of the TRPV1 channels that are expressed in the brain.

THCV, first discovered by Gill in 1970, only saw 5 papers published on it in the next three decades and mass confusion still reigns about its pharmacology. Even papers in the primary literature seem to trip up in confusion when trying to define exactly how THCV acts on the CB1 receptor.

recent systematic review stated, “It remains to be established how THCV produces apparent CB1 receptor activation in vivo but not in vitro at doses above those at which it can block CB1 receptors both in vivo and in vitro.”

However, the effect of activating CB2 may prove even more fruitful. Along with the reports of the CB2 receptor agonists as effective against many types of pain (inflammatory, neuropathic, postsurgical, etc.), a 2010 study by Bolognini specifically on THCV found help in mice for inflammatory pain. Since the effects were attenuated by an antagonist of both CB1 and CB2, it suggests that this phytocannabinoid might be packing an important one-two punch.

The experiment also suggested that some of the effects, like with THC itself, may be mediated by other than the two known cannabinoid receptors and hints at more endocannabinoid elegance to be uncovered.

CBN – Cannabinol

So we end appropriately with cannabinol (CBN) – the first cannabinoid isolated but in the plant itself, the final stage in the degradation of THC. In 1896, Wood, Spivey and Easterfield, the early team of cannabinoid chemists in Cambridge, extracted CBN as the first cannabinoid to ever be obtained in the pure form. Initially – and incorrectly – CBN was thought to be the psychoactive ingredient many had been hunting for.

However, Ames shares the eerie tragedies that ended their work: “The difficulties of chemical studies of cannabis appear to have been enhanced by a series of unfortunate accidents to chemists engaged in such work. Wood, Spivey and Easterfield … were not able to complete their program because of a series of tragic accidents. Wood barely escaped with his life when he took some cannabinol at the time he was preparing zinc ethyl. He lost consciousness, the zinc ethyl ignited and he was rescued from the burning room only with much difficulty. Easterfield was killed by a violent explosion while attempting to hydrogenate cannabinol. Spivey similarly perished while engaged in a synthetic study of the nitro-cannabinolactone.”

 

After these difficulties, it took another 44 years for Dr. Cahn to figure out the structure of cannabinol (CBN). Oftentimes, CBN was mistaken for THC, whose correct structure was not known until decades later.

Contrary results persist to this day. As McPartland and Russo report, “CBN potentiates the effects of THC in man, yet it antagonizes the effects of THC in mice.” Similarly, on dopamine and norepinephrine levels, CBN has been reported to increase, to decrease, and to have negligible effects.

Rare in fresh cannabis, CBN is the degradation product that results from cannabis bud exposed to the air. The THC oxidizes into the much less potent CBN, which makes it useful to date a cannabis sample. When Russo et al analyzed the 800 grams of cannabis found in the 2,700 year old tomb of a shaman, they found mostly CBN, indicating the ancient herb to have once been THC-heavy cannabis.

Often maligned as an indicator of old improperly stored cannabis, CBN is now being seen as a potent therapeutic molecule primarily because of its strength of sedation. SteepHill Labs reports, “The consumption of 2.5mg to 5mg of CBN has the same level of sedation as a mild pharmaceutical sedative, with a relaxed body sensation similar to 5mg to 10mg of diazepam.

CBN is synergistic with both CBD and THC for inducement of sleeping, and when mixed in the correct ratios, CBN becomes an effective sleep aid of 5-6 hours duration.” It’s the reason that aged cannabis makes you more sleepy than fresh bud – but that’s ideal if you’re ingesting for slumbering purposes.

In addition, like the others, CBN demonstrated anticonvulsantanti-inflammatory and potent antimicrobial effects against MRSA. On pain, CBN’s as effective as THC by some measures and when administered together they potentiate each other, their synergistic effects hinting at action via at a novel cannabinoid receptor. The anti-inflammation effects show help in the treatment of asthma in mice and as a topical, CBN reduces the eye pressure of glaucoma.

It also raises testosterone production in the testes and increases follicle-stimulating hormone in the plasma. Recently, some researchers claimed to be the first to demonstrate CBN causing increased feeding patterns. CBN is one more minor cannabinoid that seems like it’s soon going to be making a major splash.

How Our CBD Products take advantage of Cannabinoids

The CBD-rich hemp extract products of CV Sciences take advantage of these minor cannabinoids by harnessing extraction techniques that get as much of the plant into our products as possible. We believe that even minor levels of these cannabinoids enhance health, balance your endocannabinoid system, and help the CBD to work better. Try them today to see what CBD and the minor cannabinoids can do for you.

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