The same way that only tobacco produces nicotine, only cannabis produces cannabinoids. We live in controversial times, where we are trying to harness the therapeutic potential of cannabinoids while trying to bring them out of a proverbial “dark age” of prohibition. In any case, cannabinoids are what make cannabis cannabis. They are what makes the plant special, unique, and of particular interest to humans.

Cannabinoids are not like caffeine or theobromine, which are active constituents found in a lot of plants; coffee, tea, and guarana all contain caffeine. Cacao, tea, and Yerba Mate all contain theobromine. But we don’t know of a single other plant species in the world that produces cannabinoids; there’s only one — and that’s cannabis.

These phytochemicals and secondary plant metabolites that we call cannabinoids have a special place in the hearts of humans. 

Why?

Humans have used cannabis for thousands of years, for reasons ranging from medicinal all the way to industrial. 

Cannabinoids have been at the centre of all medical inquiry into the plant, they are the reason we become intoxicated when we use cannabis, and the study of cannabinoids themselves led to some of the most important medical discoveries of the 21st century.

Cannabinoids: The reason we know about the endocannabinoid system at all

Drops of water create ripples on a book.

Before we jump right into cannabinoid science, let’s have a brief look at the history of cannabinoid research.

It was only about 30 years ago that humans discovered what is arguably the most pivotal system in the human body; the endocannabinoid system, and we have cannabinoid research to thank for it.

Here’s the TL;DR version of the story:

At the end of the 19th century, CBN was first isolated and identified by R.S. Cahn from a red oil extract of cannabis. A few decades later, in the 1940s, a team of researchers led by R. Adams in the USA first isolated CBD. But it wasn’t until 1964 that Raphael Mechoulam isolated and identified THC for the first time.

From this point, scientists began asking definitive questions; if THC affects humans so, then there must be a receptor somewhere in the body or brain that generously receives THC. And it was through this inquiry that a team of scientists at St Louis University confirmed the existence of cannabinoid receptors.

Once scientists discovered the existence of cannabinoid receptors, it was only logical to wonder why they were there. Cannabinoid receptors surely did not grace human brains solely for the arrival of THC, did they?

And that’s exactly the question that Mechoulam and his team went to work on again in the early 90s. After laboriously examining cannabinoid receptors and their locations in the brain, Mechoulam and his team discovered the first endogenous cannabinoid: anandamide. 

Cool story. But so what?

This was an historical moment in modern medicine, as it marked the discovery of, until then, an unknown aspect of human physiology: the endocannabinoid system. The picture was far from complete, but it symbolised a ligand-receptor signalling system that was otherwise unheard of. 

That signalling system is what we now call the endocannabinoid system, and we have cannabis research to thank for the miraculous discovery of this part of human anatomy. 

The many cannabinoids of cannabis

The more the opportunities open up for cannabis research, the more we are realizing that these discoveries were only the tip of the iceberg.

By the 90s, researchers had only isolated and identified a few major cannabinoids, namely THC, CBD, and CBN. It’s worth noting here that the abhorrent lack of research into cannabis was largely due to the difficulty in obtaining research cannabis.

And this was largely due to strict, prohibitionist movements on the plant.

Now, we are coming out of a notorious scientific slumber; as legalization becomes more widespread, so too does the opportunity for research. In the last two decades, we have discovered more about cannabis than in all the years of research combined. And we have learned something truly special about cannabis; it’s not just about THC.

In fact, there are over 400 chemical constituents in a single specimen of cannabis, of which over 60 are cannabinoid compounds. The rest of them are other cannabis metabolites such as terpenes, terpenoids and flavonoids. We won’t go into all of them in this article, but hopefully the following list of cannabinoids shines some light on the true complexity of cannabis. 

Delta-9-Tetrahydrocannabinol — THC: The “stoned” molecule

Delta-9-tetrahydrocannabinol, otherwise known as THC, is cannabis’ most abundant cannabinoid . It’s also the one that most cannabis users chase, as it’s the one responsible for the euphoric, cerebral high associated with cannabis. 

THC’s chemical formula: C₂₁H₃₀O₂.

THC has a very special affinity for both CB1 and CB2 receptors in the brain and body. Its chemical structure is almost reminiscent of anandamide (the endogenous cannabinoid we mentioned earlier), and it more or less mimics anandamide when it comes into contact with CB receptors. It’s for this reason that users feel relaxed, hungry, painless, and sleepy after ingesting THC. 

What about THC as a medicine?

In terms of its medical uses, THC is mostly used in the clinical setting to suppress nausea (especially that created by chemotherapy), to reduce pain, to induce sleepiness, and is used in conjunction with CBD in the treatment of epilepsy. 

Thanks to THC’s affinity for CB receptors, it effectively reduces nociception (the physical identification of pain), making it an effective painkiller.  Although we don’t know why THC has anti-seizure properties, the endocannabinoid system has been implicated in a variety of different epilepsy models. And there is hard evidence at last that it is an effective remedy.

Cannabidiol — CBD: The medicine molecule

Cannabidiol, otherwise known as CBD, is the second-most abundant cannabinoid. In recent times, it has received arguably more attention than THC.

Both marijuana (high THC varieties) and industrial hemp (low THC varieties) are sources of CBD. Typically, the cannabis industry extracts CBD from industrial hemp, as hemp usually has higher levels of CBD and it’s easier to acquire a license to grow hemp than cannabis.

CBD is starting to gain a lot of credibility in the world of medical cannabis.

Why?

Because it’s non-psychoactive. THC’s psychoactive nature creates a lot of apprehension and confusion in its applications as a medicine, but CBD overcomes that hurdle.

With many of the same therapeutic uses as THC, it’s also non-intoxicating, giving it more credibility as a therapeutic substance.

Unlike THC, CBD has no real affinity for CB receptors (it has low affinity, but not much at all). Instead, it executes its tasks in more roundabout ways.

For example, CBD is able to elevate mood by increasing serum levels of anandamide. It does this by inhibiting an enzyme called FAAH, which is responsible for the breakdown of anandamide.

Okay — that was a lot of scientific jargon.

The human body naturally produces anandamide. When it’s circulating, you feel relaxed, happy, somewhat forgetful, and somewhat hungry. It’s the human body’s natural “feel good” molecule.

By inhibiting this enzyme, anandamide is more readily available to the individual. And anandamide is responsible for feelings of wellbeing and relaxation. 

Because CBD has piqued the interests of scientists so much, there is a multitude of therapeutic applications for which it is currently being researched:

These qualities implicate CBD in the treatment of so many medical conditions, it’s impossible to list them all.

But here are a few so you can get an idea:

Cannabinol — CBN: The sedative molecule

A child yawns in cross-legged position.

Cannabinol, a.k.a. CBN, was the first cannabinoid to be isolated from cannabis, which is interesting because it isn’t present in huge amounts.  CBN is produced by the degeneration of THC due to light and heat. Basically, the older a piece of cannabis gets, the more likely it is to contain higher levels of CBN.

CBN is mildly psychoactive, although not as much as THC.

For the record, it’s the only other psychoactive cannabinoid that we know about.

It’s highly sedative and is said to produce the “couch-lock” effect that often happens to cannabis users. Like THC, CBN has a strong affinity for CB receptors, although it is more attracted to CB2 than CB1. It also acts as an agonist to the TRPV2 receptor. The TRPV2 protein plays a role in nociception (pain recognition), and so it’s thought that CBN might have a role to play in pain reduction.

However, CBN’s most obvious therapeutic application is in the treatment of insomnia. Because of its highly sedative nature, it can put someone into a deep, restful, dreamless sleep.

Cannabigerol — CBG: The anti-stress molecule

CBG is altogether hard to come by in common marijuana, but is far more prevalent in industrial hemp. There are many geneticists experimenting with high CBG hemp strains, as there is reason to believe that this cannabinoid may treat anxiety and depression.

Here’s what we know.

Like CBD, CBG is a CB1 receptor antagonist. This means that when CBG binds to the CB1 receptor, it blocks the action of that receptor and stops anything from binding to it (like THC). CBD does this too, and that’s why it’s touted as the “opposite” of THC.

It’s speculated that CBG’s actions are primarily associated with the 5HT1A-receptor. This receptor plays a regulatory role in serotonin release, which is the brain’s antidepressant. CBG also has a role to play at the adrenoceptor, having an effect on the levels of adrenaline and noradrenaline that circulate through the central nervous system. For those who don’t know, adrenaline and noradrenaline are the body’s hormonal response to danger and prepare the body for action. 

Like many other cannabinoids, CBG’s primary therapeutic actions seem to be mood management, pain reduction, and reduction of inflammation — especially in the bowels and intestines.

Cannabichromene — CBC: The bowel molecule

Once upon a time, CBC was one of the most abundant cannabinoids found in cannabis plants — at least according to a study on landraces in the 1970s. Since then, cannabis genetics have changed drastically, and plants now typically contain more THC than CBC. In any case, CBC is abundantly found in cannabis, especially in tropical varieties, and is one of the better-studied cannabinoids. It is part of a long list of non-psychoactive cannabinoids.

There are a lot of therapeutic applications for CBC, many of which overlap with THC and CBD. Here are a few of the ways that CBC is used in medicine.

  1. For pain reduction

In a 2010 study published in the British Journal of Pharmacology, researchers found that CBC and CBD both significantly reduced nociception in mice

  1. For depression

In another 2010 study, scientists investigated CBC for its effects on those with depression. Researchers concluded that CBC had “significant” effects on indicators of depression.

  1. To improve intestinal motility

Inflammation-induced hypermotility (diarrhoea) was reduced after administration of CBC, according to a 2012 study on murine models. CBC normalized hypermotility without reducing bowel transit time. This is significant because many anti-diarrhoea drugs cause constipation because of the dramatic reduction in bowel transit time. This is of importance for those with inflammatory bowel conditions such as Crohn’s Disease. 

Cannabinoid acids: THC-A and CBD-A

THC-A and CBD-A don’t get nearly enough of a mention as they deserve. These are the acidic forms of the cannabinoids that we have now come to know and love. Essentially, all cannabinoids are present in their acidic forms when the plant is harvested. Heat and light contribute to the degradation of these acids, thereby converting them into CBD and THC.

Most of this degradation occurs during one of two processes: smoking or decarboxylation. When users smoke cannabis, they apply enough heat to convert THC-A into THC, thereby producing a psychoactive effect. Decarboxylation occurs when cannabis flowers are heated (mostly in an oven) to “activate” the compounds before making tinctures, edibles, or extracts. 

Most users “require” the transformation of THC-A into THC — because THC-A is non-psychoactive! 

And a lot of people love that stoned feeling, right?

With that in mind, THC-A and CBD-A have their own plethora of therapeutic applications. For starters, THC-A is up to 30 times more bioavailable to the body than THC. This means that users can get 30 times the benefits of raw cannabis compared to dried, smoked, or processed cannabis. CBD-A is up to 18 times more bioavailable than its non acidic form, CBD.

It isn’t easy to consume large amounts of THC-A and CBD-A. There has to be access to a lot of raw plant material for this to happen, and typically, the best way to ingest these compounds is via juicing. You can only imagine how much cannabis is required to make a glass of cannabis juice.

…A lot.

Needless to say, these cannabinoid acids show us how complex cannabis is — and how much opportunity there is to harness the power of cannabis.

Cannabis: More than just cannabinoids

A girl holds LED light concept.

As we mentioned earlier, of the 400-odd compounds in a specimen of cannabis, only about 60 of them are cannabinoids. 

So what about the other 340 chemical entities? 

Well, cannabis is one of the most complex plants on the planet, and cannabinoids aren’t the only active compounds of interest to humans. 

Terpenes: Cannabis’ aromatherapy

“Terpenes” is a word commonly thrown around by the cannabis industry as of late, and these chemicals are the aromatic compounds of cannabis. They’re what make cannabis smell like “skunk”, “diesel” or “kush”. Terpenes are the reason cannabis has its characteristic smell. You could consider terpenes to be something like the aromatherapy of cannabis.

Cannabis contains hundreds of terpenes, although the most common ones are myrcene (mango smell), pinene (pine smell), limonene (lemon smell), caryophyllene (the peppery smell), and linalool (lavender smell). Each terpene has its own effect on human cells and receptors, and therefore elicits a different effect. Many cannabis geneticists attribute the difference in strain effects to the different composition of terpenes.

For example, limonene, a highly citrus-like aroma, is speculated to have anxiolytic properties. Linalool, on the other hand, is the active aromatic compound in lavender, as is thought to relax the central nervous system.  

Every strain of cannabis has its own aromatherapy profile, and therefore can have different effects when used. This is exactly why some strains are relaxing, others are energizing, and some elicit a great mood for creativity.

Flavonoids: Nature’s antioxidant-rich food dye

Alongside terpenes, cannabis also contains a range of flavonoids. Flavonoids are typically antioxidant compounds that contribute to the colour of plants other than green (chlorophyll wins the medal for that). Vegetables that are purple, red, or yellow can thank flavonoids for their colour. And typically, the darker a plant is, the more flavonoids it contains. 

There are many flavonoids that have pharmacological actions. For example, quercetin is a flavonoid found in many vegetables and is antioxidant and antifungal. Flavonoids originating from cannabis are called cannaflavins, and so far, only a few have been isolated and identified: Cannaflavin A, Cannaflavin B, and Cannaflavin C.

The entourage effect — What truly makes cannabis cannabis

A man stares up at the milky way.

You can think of cannabinoids, terpenoids, and flavonoids as fingers on a hand. If you cut the fingers off the hand, the hand stops working, right?

Well, that’s the essence of “the entourage effect”.

We have mentioned a lot of different chemical compounds someone might expect to in any given strain of cannabis. But when they are isolated, they aren’t really cannabis, are they? It’s all about the togetherness dude, as one hippie said once upon a time, just a few hours ago.

 “The entourage effect” is the phrase used to describe the synergistic actions of all the compounds present in a specimen of cannabis. 

The entourage effect is essentially a property of all whole plant medicines (those that haven’t been standardized to an exact dose of an active component). Each plant contains a unique composition of compounds that when taken all together, produce an effect specific to that particular plant. And cannabis has its very own entourage effect.

So far, research has been primarily concerned with the actions of singular compounds such as THC, CBD, etc. Given the difficulty in studying hundreds of compounds’ behaviour concurrently, it has been extremely difficult to make scientific conclusions about the entourage effect. But Ethan Russo’s research delves into this, and sheds light on why cannabis can have so many different effects for so many different people. 

In a single joint or edible, cannabinoids, terpenoids, flavonoids, and a myriad of other secondary metabolites synergistically produce what a user might call a “therapeutic effect” or a “high”. There’s no knowing whether that effect was created by a single cannabinoid, or multiple cannabinoids, or the combined effect of hundreds of different chemical entities. This is the essence of the entourage effect. 

Cannabis and cannabinoid research are arguably only in their infancy, as we are only just beginning to uncover the complexity of cannabis. To date, there has likely never been a plant that sparked as much curiosity and controversy as cannabis. And it is likely that we will be uncovering scientific data about cannabis and its effects in the body for decades to come.

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