Phytocannabinoids: What Are Their Benefits
The Cannabis sativa plant has enjoyed a long history of human use, both for its medicinal and recreational benefits, that dates back to at least 2,600 BCE. It’s become an integral part of our culture and it’s enjoying a recent explosion in interest, with cannabis products becoming increasingly refined and potent. Most of the positive benefits that we look for in cannabis come from naturally occurring phytocannabinoids.
Different Kinds of Cannabinoids
The class of chemical compounds known as cannabinoids can be divided into three basic categories:
- Endocannabinoids – Also known as endogenous cannabinoids, these are produced naturally in the mammalian body. The two primary ones in humans are N-arachidonoylethanolamine (commonly referred to as anandamide or abbreviated to AEA) and 2-Arachidonoylglycerol (commonly abbreviated to 2-AG).
- Phytocannabinoids – Also referred to as pCBs, these are cannabinoids found in the cannabis plant. There are conflicting reports on precisely how many phytocannabinoids exist (as some are present in only trace amounts or cannot be easily identified), but current research places the number at about 120.
- Synthetic cannabinoids – Sometimes known as cannabimimetics, these are cannabinoids that have been synthesized in a laboratory setting.
Unlike other naturally occurring drugs, including caffeine, cocaine, nicotine, or opioids, phytocannabinoids do not contain the element nitrogen, meaning that they are not alkaloids. They also have structural similarities, including the fact that most of them share a dibenzopyran ring and a hydrophobic alkyl chain.
Furthermore, pCBs also interact with terpenoids in the cannabis plant to give the desired effects and benefits. These are both synthesized in the plant’s secretory cells found in their glandular trichomes, which have their highest concentration in unfertilized female flowers before the onset of senescence.
So why does the cannabis plant produce these compounds? How do phytocannabinoids and terpenoids benefit the actual plant? Well, most phytocannabinoids have antimicrobial effects (both antibacterial and antifungal) while terpenoids make the trichomes sticky. As a result, the cannabis plant can trap and neutralize any unwanted insectoid invaders or pathogens before they destroy or harm the plant.
It should also be noted that phytocannabinoids are lipophilic, meaning that they are not water-soluble. Instead, they can be dissolved in fats, lipids, nonpolar solvents, or oils. Consequently, any solvent used in phytocannabinoid extraction will have to fall into one of these categories.
What is the Endocannabinoid System (ECS)?
It’s also important that we quickly go over the endocannabinoid system (also known as the ECS). According to the influential cannabis researcher Vincenzo Di Marzo, the ECS is a “complex endogenous signaling system” that controls functions like “relaxing, eating, sleeping, forgetting, and protecting.” In other words, the ECS is responsible for regulating a complex set of interlinked physiological processes that all work together in a person so they can reach optimal health and wellness. This harmonious state is frequently referred to as homeostasis, meaning that the ECS is also known as a pro-homeostatic system.
This ECS is composed of the endocannabinoids mentioned above, the enzymes that break them down, and cannabinoid receptors that are activated by the endocannabinoids. Researchers have identified two types:
- Cannabinoid 1 receptors (CB1) – These are mostly found in the brain, especially in the limbic system (hippocampus and striatum), basal ganglia, and cerebellum. They are notably absent from the part of the brain stem (the medulla oblongata) that is responsible for cardiovascular and respiratory function.
- Cannabinoid 2 receptors (CB2) – These are found mostly in cells of the immune system, with the greatest concentration being in the spleen. They are also located in the peripheral nervous system.
Both of these are also known as G-protein coupled receptors (or GCPRs). Phytocannabinoids will exhibit different binding affinities for CB1 and CB2 receptors, resulting in different effects and benefits. Additional pharmacological research has also indicated that pCBs have other molecular targets besides these cannabinoid receptors, including other GPCRs like GPR55, GPR18, and opioid/serotonin receptors as well as transistor receptor potential (TRP) channels like TRPV1 (also known as the capsaicin receptor).
Binding Affinity and Reactivity
Let’s take a quick moment to discuss how cannabinoids interact with receptors:
- Agonist – The pCB activates the receptor.
- Antagonist – The pCB binds to the receptor without activating the receptor. In doing so, it will also block other agonists.
There are also three primary types of agonists:
- Full agonist – The pCB fully activates the receptor.
- Partial agonists – The pCB partially activates the receptor.
- Inverse agonists – The pCB binds to the same receptors while triggering a response that is the opposite of other agonists.
How a particular phytocannabinoid benefits the body will depend on its binding affinity and reactivity with the various molecular targets. Furthermore, these pCBs also have various precursor forms that need to be “unlocked” via a process known as decarboxylation.
Decarboxylation: How to Unlock the Benefits of Phytocannabinoids
Raw cannabis plant material does not contain phytocannabinoids in their active forms. Instead, it is made up of cannabinoid acids that need to be “activated” (or decarboxylated) via the application of:
- Light (ultraviolet rays)
- Alkaline conditions
Once these conditions are applied, then the cannabis material becomes activated and the various benefits become accessible. It’s important to note that smoking or baking cannabis material counts as decarboxylation as you are exposing it to substantial energy in the form of heat. Additionally, decarboxylation will occur naturally as time passes, so newly harvested cannabis material will have a different phytocannabinoid-makeup that older material, even if they are the same strain.
In 1964, influential cannabis researchers Y. Gaoni and Raphael Mechoulam identified cannabigerol (CBG) as the chemical precursor to every phytocannabinoid. It fulfills this role because it has the lowest oxidation level for the first step in pCB biosynthesis. In other words, every class of pCB is derived from cannabigerol-type (CBG) compounds; furthermore, how the CBG is cyclized will affect the decarboxylation into an active phytocannabinoid form. This observation aligned with Dr. Mechoulam’s “Law of Stinginess”, in which nature will only make small changes to a preexisting framework in order to maximize the results.
Consequently, let’s take a look at the most common of these decarboxylation reactions:
- CBG (cannabigerol) is derived from CBGA (cannabigerolic acid)
- Δ-9-THC (Δ-9-tetrahydrocannabinol) is derived from THCA (tetrahydrocannabinolic acid)
- Δ-8-THC (Δ-8-tetrahydrocannabinol) is derived from THCA (tetrahydrocannabinolic acid)
- CBN (cannabinol) is derived from THCA (tetrahydrocannabinolic acid)
- THCV (tetrahydrocannabivarin) is derived from THCVA (tetrahydrocanabivarinic acid)
- CBD (cannabidiol) is derived from CBDA (cannabidiolic acid)
- CBDV (cannabidivarin) is derived from CBDVA (cannabidivarinic acid)
- CBC (cannabichromene) is derived from CBCA (cannabichromenenic acid)
- CBGV (cannabigerivarin) is derived from CBGVA (cannabigerovarinic acid)
- CBCV (cannabichromevarin) is derived from CBCVA (cannabichromevarinic acid)
The acid forms all have an extra carboxyl ring or group (-COOH) that is lost during the chemical reaction. Furthermore, the decarboxylated pCB forms are also referred to as neutral phytocannabinoids.
What are the Benefits of Phytocannabinoids?
Now that we’ve gone over some of the fundamentals, let’s take a look at the most abundant phytocannabinoids and their respective benefits.
THC is the superstar of the cannabis plant – it is, by far, the most widely used and studied phytocannabinoid. Officially, it is known as Δ-9-tetrahydrocannabinol (or Δ-9-THC, for short) and its isomer is referred to as Δ-8-tetrahydrocannabinol (or Δ-8-THC, for short). However, we’re just going to refer to it as “THC” in order to simplify the discussion.
THC is the primary “psychoactive” phytocannabinoid; this means that it is the chemical component that causes euphoria and intoxication. Consequently, it is highly prized for its recreational benefits.
It is also a moderate partial agonist of CB1 and CB2 receptors, meaning that it exhibits a mixed agonist-antagonist profile depending on the type of cell, expression of the receptors, and the presence of other endocannabinoids or full agonists. Its CB1 agonism is what causes euphoria and pleasant feelings (remember, CB1 receptors are located in the brain, especially in the “reward center” of the limbic system).
Furthermore, the benefits of THC include:
- Treating chronic pain
- Treating nausea and vomiting
- Protecting brain cells and spatial memories (neuroprotectant)
- Treating symptoms associated with post-traumatic stress disorder (PTSD)
- Treating insomnia and obstructive sleep apnea
- Stimulating ghrelin increase in the hypothalamus (increase appetite)
- Acting as an antimicrobial
- Reducing oxidative stress (antioxidant)
- Decreasing cytokine and chemokine production in the body (anti-inflammation)
- Inhibiting the growth of tumor cells (via angiogenesis)
- Acting as a muscle relaxant and decreasing pain, cramping, and spasticity
Furthermore, the efficacy of THC in treating various medical conditions is moving out of the laboratory and into the real world. For example, in 2013 the Food and Drug Administration (FDA) even approved a large-scale trial to closely examine THC as a painkiller.Interestingly, THCA (tetrahydrocannabinolic acid) also has various medicinal benefits, including acting as an anti-inflammatory, neuroprotectant, anti-tumor agent, and anti-emetic.
Next to THC, CBD is the second most widely studied phytocannabinoid. Due to a recent explosion in research, it has become immensely popular and is undergoing a kind of renaissance at the moment. Furthermore, because the Farm Bill of 2018 has differentiated between “industrial hemp” (less than 0.3% THC) and “marijuana” (more than 0.3% THC), CBD-rich strains of cannabis are now totally legal. As a result, CBD is being included in everything from skin lotions to cheeseburgers!
Various studies have shown that CBD exhibits weak CB1 and CB2 antagonistic effects, although it is also referred to as “extremely versatile pharmacologically”. In fact, of all the phytocannabinoids, CBD exhibits the strongest biphasic effects, meaning that a low dose may result in one effect while a higher dose may result in the opposite effect. For example, a low dose (usually around 10 milligrams) may have a slightly stimulating effect while a high dose (50 milligrams and above) will have sedating effects.
Additionally, in some situations and at certain doses, CBD can act as an inverse agonist of CB1 receptors, meaning that it can actually reverse some of the adverse effects of THC intoxication, including anxiety, tachycardia, sedation, and excessive hunger (the “munchies”).
Furthermore, CBD’s benefits include:
- Acting as an analgesic
- Treating intractable cancer pain in patients unresponsive to opioids
- Acting as a neuroprotectant and antioxidant (even more potent than ascorbate or tocopherol)
- Potentially treating certain forms of cancer (it is cytotoxic to breast cancer cells while being cyto-preservative to normal cell lines)
- Treating rheumatoid arthritis by antagonizing tumor necrosis factor-alpha (TNF-alpha) cells
- Acting as an anticonvulsant
- Treating nausea
- Being used as an antimicrobial, especially against methicillin-resistant Staphylococcus aureus (MRSA) pathogens
- Reducing anxiety
- Potentially being used as an effective antidepressant
Interestingly enough, THC and CBD have the same chemical formula:
That means that there are 21 carbon molecules, 30 hydrogen molecules, and 2 oxygen molecules. The difference between the two is not in the number of molecules, but in how they are structured and arranged. In other words, THC has a cyclic ring whereas CBD has a hydroxyl group. That means that just one chemical bond separates THC from CBD. However, this seemingly tiny bond makes all the difference when it comes to how CBD interacts with the human body.
Finally, CBD and THC are especially effective when combined; this is partially because CBD decreases the adverse effects associated with high doses of THC. This is also a smaller-scale version of the “entourage effect” that you see in cannabis material that has all of its phytocannabinoids and terpenoids intact. In fact, full-spectrum cannabis extracts have exceptionally low mammalian toxicity – they are much less toxic than pure THC.
CBN is an oxidized metabolite of THC. Remember that decarboxylation can occur over time, so CBN concentrations are much higher in aged samples of cannabis (THC turns into CBN).
It is generally a weak psychoactive compound, with a greater affinity for CB2 receptors. Depending on the dosage, it can act as either a moderate agonist or inverse agonist. With CB1 receptors, on the other hand, it is a weak agonist. Interestingly, when given in conjunction with THC, it helped to produce greater sedation at lower doses.
Furthermore, it is also:
One of the most abundant phytocannabinoids in the plant, CBC was first identified in 1966 by Dr. Mechoulam and his team. Interestingly, it does not exhibit any significant affinity for either CB1 or CB2 receptors; instead, it interacts with the ECS by inhibiting the uptake of the endocannabinoid anandamide (or AEA).
Its other benefits include:
- Providing painkilling and analgesic activity
- Acting as a potent anti-inflammatory
- Antimicrobial effects (both antifungal and antibacterial)
- Cytotoxicity in cancer cell lines
Research from animal studies also shows that CBC reduces THC intoxication and may have powerful antidepressant effects.
CBG is a phytocannabinoid that is found in high concentrations in the cannabis plant. Remember that its acid form (CBDA, or cannabigerolic acid) is the chemical precursor for the other pCBs.
CBG has a low affinity for both CB1 and CB2 receptors, although, much like CBC, it affects the ECS by inhibiting AEA uptake. It is also a weak agonist at TRPV1/TRPV2, a potent antagonist at TRPM8, and a potent agonist at TRPA1.
Older research suggests that its gamma aminobutyric acid (GABA) uptake inhibition is greater than both THC and CBD, thereby suggesting that it may be the most potent muscle relaxant of all phytocannabinoids. Additionally, it may be a more potent analgesic than THC and its potential ability to treat breast cancer may be second only to CBD.
Additional benefits of CBG include:
- Modest antifungal effects
- Cytotoxic (at high doses) against human epithelioid carcinoma
- Effective antidepressant in animal research
- Potent anti-MRSA agent
Regular strains of cannabis have very low concentrations of this phytocannabinoid, but recent advances in cannabis horticulture have resulted in chemotypes that are made up of 100% CBG.
CBDV is a propyl analogue of CBD; its side-chain has been shortened by two methylene bridges. It displays a very weak affinity for CB1/CB2 receptors, although it is a weak agonist of TRPV1, TRPV2, and TRPV3 receptors (cation channels).
That being said, research with animal models indicates that CBDV has shown promise in treating autism-like behaviors. Its neuroprotectant properties also help restore hippocampal ECS function in rats that have been prenatally exposed to valproic acid.
Furthermore, CBDV showed tremendous promise as an anticonvulsant (independent of CB1 receptors) in rat and mice models. In fact, it has been approved for preclinical safety and efficacy research in early life seizures in human patients.
THCV is a propyl analogue of THC. The only difference between the two is the length of the lipophilic alkyl chain, although this seemingly minor structural difference results in a phytocannabinoid with a markedly different pharmacological profile.
Currently, the research is not entirely clear on how THCV interacts with CB1 receptors – in vitro (laboratory) studies indicate that it has antagonistic/inverse agonistic effects while in vivo (real-world/clinical) studies indicate that it has agonistic effects. There is a possibility that THCV, much like other phytocannabinoids (most notably CBD) is also biphasic, resulting in different observable effects and pharmacological outcomes dependent on dosage amount. As for CB2 receptors, both in vitro and in vivo studies indicate that it is a partial agonist.
As with CBD, THCV can modulate or decrease the adverse effects of THC intoxication. The other benefits of THCV include:
These results are currently only in animal research models, so THCV will likely be the subject of extensive preclinical research in the coming years.
One of the more recent phytocannabinoid discoveries, there are currently no studies about animal or human consumption of this mysterious pCB. However, it appears in high concentrations in cannabis distillates due its molecular properties.
Let’s take a moment and discuss the relevant background:
- Standard – This is any solution that has a known volume of a given compound.
- Chromatography – This is the science of separation. Generally, samples are prepared in the form of a solution and then this solution is pressed through a column. The physical/mechanical pressure of the column causes the compounds in solution to separate, and then these compounds can be quantified as they exit the column.
- Timing of the exit – When each compound is separated out, the timing of its exit is a measure of how much the column retains a given compound.
Interestingly, CBT has certain qualities which frequently make it the last compound to be pressed out of the column. As a result, final cannabis distillates will usually have higher quantities of this particular phytocannabinoid.
Furthermore, Type III strains (low THC/high CBD) will end up yielding more CBT than Type I strains (high THC/low CBD). To make matters even more confusing, there is another phytocannabinoid known as cannabitriol that is also abbreviated with “CBT”; ultimately, as these pCBs are studied more comprehensively, then their naming and abbreviation conventions will be standardized and any ambiguity will be effectively removed.
A Few Lesser Known Phytocannabinoids
Let’s take a moment to go over a handful of rarer and more esoteric pCBs, including:
- Cannabinodiol (CBND) – This is a fully aromatized analogue of CBD as well as a byproduct of CBD photochemical conversion. The concentration of this phytocannabinoid is quite low in the plant itself, although it is found in the cannabis flowers.
- Cannabielsoin (CBE) – This is a pCB metabolite that is produced via photo-oxidation of CBD and its acid form, CBDA.
- Cannabicyclol (CBL) – This pCB is the product of a photochemical conversion of CBC when heated. This is important to note, as cannabis is frequently smoked for its recreational and medicinal benefits.
In order to properly research and understand these pCBs, they have to be isolated and then administered in animal models of research and then to human subjects. Until then, we can only guess what benefits they may have.
Ongoing Research and Unknown Compounds
These various phytocannabinoids are only scratching the surface; there are still dozens that remain poorly understood and barely researched. What is known, however, is that the complex interplay and interactions of these various phytocannabinoids will result in maximum efficacy and efficiency. This is known as the “entourage effect” and is the primary reason why full-spectrum products are more effective and potent than isolate versions. Consequently, if a producer is looking to maximize their product, then it would be best to create cannabis extracts which preserve the makeup of phytocannabinoids and terpenoids present in the plant.