About the cannabis plant
Cannabis is a genus of plants belonging to the cannabacae family. Some consider the cannabis genus to comprise a single species: hemp (consisting of the subspecies Cannabis Sativa, Cannabis Indica, and Cannabis Ruderalis).
Cannabis – or hemp – is an aromatic herb with its origins in Central Asia, although it’s cultivated worldwide. It has been used for thousands of years for its strong fibers, nutritious seeds, multi-use oils, and medicinal qualities.
Many medical and industrial cannabis products are created from the plant’s strains, specifically bred to produce minimal levels of psychoactive compounds. These strains satisfy the UN Narcotics Convention guidelines and ensure that products are safe for consumption without unwanted side effects.
Estimates of upwards of 63,000 kilograms of cannabis are produced each year legally around the world. Recent interest in the health benefits of cannabis has led to an increase in global production. There are now an estimated 183 million cannabis users worldwide – a figure that increases year-on-year, mainly as mainstream healthcare professionals recognize the plant’s positives.
About the endocannabinoid system
The endocannabinoid system, or ECS, is a complex biological cell-signaling mechanism within the body. It is composed of endocannabinoids, which are lipid-based neurotransmitters that bind to cannabinoid receptors and cannabinoid receptor proteins found through the central and peripheral nervous systems.
While the endocannabinoid currently remains under preliminary research, it is thought to be involved in the regulation of various cognitive and physiological processes, including:
• Immune system activity
• Pain sensation
• Cognitive processing
The endocannabinoid system is active and exists within your body, even if you don’t use cannabis. It is complicated, and researchers have yet to determine how it functions entirely. However, belief suggests the ECS’s primary role is to maintain homeostasis or the stability of your body’s environment. For example, if an injury or illness affects your homeostasis, your endocannabinoid system starts operating to help your body return to its ideal operational levels.
It is believed that CBD interacts with the ECS by preventing endocannabinoids from being broken down. The interaction allows the endocannabinoids to have a much more significant effect on your body, thereby helping to reduce pain, nausea, and other symptoms.
There are many active cannabinoids within the Cannabis plant. Isolating them helps doctors and the medical community understand the differences between them and their potential therapeutic benefits.
What are cannabinoids?
Cannabinoids are compounds that occur naturally within the cannabis plant. There are almost 500 different compounds within the plant, although only 86 can be considered actual cannabinoids. These compounds interact with specific cannabinoid receptors present on the surface of cells within the human body and are found in different nervous system areas.
To expand the idea, cannabinoids are all molecules with a C-21 terpenophenolic skeleton. Of these, scientists have isolated 86 individual molecules. Researchers base the effects of cannabinoids on their relative affinity to the cannabinoid receptors CB1 and CB2. CB1 receptors are primarily present in neural tissues and account for cannabis’ psychoactive effects. Present in the immune system, CB2 receptors are responsible for the immunoprotective and pain-modulating impact of cannabis.
Cannabinoids are separated into the following sub-classes:
- Cannabigerol (CBG)
- Cannabinodiol (CBDL)
- Cannabicyclol (CBL)
- Cannabielsoin (CBE)
- Cannabitriol (CBT)
- Cannabidiol (CBD)
- Tetrahydrocannabinol (THC)
- Cannabichromene (CBC)
Different cannabinoids have different effects. The way they are differentiated is often based on their degree of psychoactivity. For example, THC, CBN, and CBDL are known to have varying degrees of psychoactivity, and in many places, these cannabinoids are considered controlled substances.
Other cannabinoids, such as CBD, CBC, and CBG, are not psychologically active and instead have medicinal properties. These cannabinoids have been at the forefront of cannabis research in recent years, as healthcare experts increasingly recognize the role of some cannabinoids for medical purposes.
1. What is THC (Delta-9-Tetrahydrocannabinol)?
THC is the principal psychoactive ingredient in cannabis. The compound produces the “high” associated with smoking the plant, although it is consumed in oil, edible, capsule, or tincture form. Cannabis containing high amounts of THC is considered illegal in many countries worldwide, although it is legal for medicinal purposes in some areas.
Δ9 Tetrahydrocannabinol (THC) is the most researched cannabinoid and responsible for the psychoactive effects of cannabis. The impacts of THC range from alterations in cognition and memory to euphoria and sedation.
THC can readily diffuse through cell membranes and quickly enter highly vascularized tissues such as the heart and muscles as a fat-soluble molecule. Eventually, THC ends up in adipose tissue, where it can remain for a long time.
The pharmacokinetics of THC depends on administration. Oral inhalation creates psychotropic effects within minutes that last for 2-3 hours. Oral ingestion involves a 30-90 minute activation window with peak effects occurring at 2-3 hours and the entire experience lasting 4-12 hours.
THC binds to the CB1 cannabinoid receptors, which is where most of its effects take place. Predominant in neural tissues, CB1 receptors reside in the basal ganglia, limbic forebrain, hypothalamus, and stomach. Much of the euphoria and sedation perceived with THC is due to CB1 receptors’ ability to stimulate dopamine production. This stimulation occurs through CB1’s ability to heterodimerize (pair up) with dopamine receptors in the brain.
Analgesia has been reported with THC. The mechanism for analgesic effects seems to be the activation of CB1 receptors in the amygdala, which work to dissociate pain rather than decrease its intensity. THC has also been shown to be effective at reducing neuropathic pain.
In appetite management, CB1 receptors in the brain and stomach work together to stimulate ghrelin production while down-regulating peptide tyrosine-tyrosine (PYY). Ghrelin is notable in its capacity to induce appetite and is increased by the mechanistic target of rapamycin (mTOR) pathway, which THC activates. PYY is a peptide released in the gut in response to feeding and reduces appetite.
The appetite-stimulating effects of THC make it a possible co-therapy for cancer and AIDS patients who experience issues with cachexia and pain-management.
Finally, CB1 receptor activation has therapeutic value for being protective against epileptic seizures. Through its action on CB1 receptors, THC appears to suppress glutamate signaling and the nerve excitation that precedes epileptic attacks.
Because THC is a psychoactive compound, it presents considerable risks to those who take it. Specifically, THC impairs motor function, memory, and perception in the short term. High blood pressure, visual hallucinations, and anxiety may occur depending on the individual and dose in question.
2. What is Δ8THC (Delta-8-Tetrahydrocannabinol)?
The only molecular difference between Δ8 and Δ9 THC is the position of the double bond. Specifically, where Δ9 has a double bond between carbons 9 and 10, Δ8 has the bond between carbons 8 and 9.
Chemically, Δ9 is easily oxidized into cannabinol (CBN), whereas Δ8 is a much more stable variant. The change in the carbon double bond position makes Δ8 biologically active but a significantly weaker psychotropic than Δ9 THC.
Legally, the phenomenological effects conferred by “Delta 8,” as it is commonly known, are subdued enough to allow its sale in the US and elsewhere.
A study evaluated Δ8 THC in pediatric oncology as a benign measure to reduce vomiting. While there were only 8 participants, vomiting was reduced entirely in all subjects post-antineoplastic therapy. Additionally, children were administered much higher (18 mg/m2) doses of Δ8THC than adults receive of Δ9THC (5-10 mg/m2) with no side effects.
3. What is THCV (Tetrahydrocannabivarin)?
Similar to THC, tetrahydrocannabivarin (THCV) is a potent psychoactive cannabinoid. Curiously, THCV’s effects are based on it being a CB1 receptor neutral antagonist. THCV blocks many of THC’s effects on these receptors while promoting other effects.
A study evaluating THCV’s effect on insulin sensitivity in mice found that THCV may ameliorate insulin sensitivity and glucose tolerance while restoring insulin sensitivity to the insulin-resistant liver. Additional human studies offer evidence that THCV may be a treatment option to manage glycemic control.
Unlike THC, THCV is an appetite suppressant. The primary mechanism for appetite suppression is THCV’s action as a CB1 receptor antagonist, blocking the hormone ghrelin’s stimulation and simultaneous down-regulation of peptide PYY. THCV’s appetite suppressive effects make it a possible co-treatment for obesity and weight gain in the same way Δ9 THC potentially helps treat cachexia.
4. What is CBD (cannabidiol)?
After THC, the next most common compound in cannabis is CBD (cannabidiol). While CBD does not cause the euphoric or mind-altering “high” associated with THC, it is useful in combating various medical conditions, including:
• Sleep disorders
Where the effects of THC come from its activation of CB1 receptors, cannabidiol (CBD) works as an inverse agonist on CB1 and CB2 receptors. Specifically, CBD is an active CB2 antagonist and can block the effects of THC in high amounts.
CBD’s mechanism as a CB2 antagonist is responsible for its anti-inflammatory and non-psychotic effects. CBD seems to be an antipsychotic, with the proportion of CBD to THC moderating the psychotic effects of cannabis consumed.
As a reducer of neuroinflammation, CBD works to block peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is involved in modulating energy metabolism and promoting inflammation in Alzheimer’s and other neurodegenerative diseases.
CBD has gathered attention for its ability to treat epilepsy. THC helps weaken epileptic seizures through its action on CB1 receptors. In contrast, CBD operates by desensitizing the transient-receptor potential channel (TPV1) calcium channels. These channels contribute to episodes through excessive stimulation of neural tissues, causing abnormal electrical activity in the brain.
5. What is CBN (Cannabinol)?
CBN is essentially a by-product of the breakdown of THC. It lacks the psychoactive qualities of THC and the anti-inflammatory qualities of CBD. It is typically found in poorly preserved or degraded cannabis. While most cannabis research has focused on CBD and THC in recent years, some experts believe CBN could also be medicinally beneficial.
Cannabinol (CBN) forms during complete oxidation of THC-class cannabinoids. When plants age or become exposed to air, heat, or ultraviolet light, THC converts to CBN. CBN is mildly psychoactive and only found in trace amounts in young cannabis plants.
While much weaker in effect than THC or CBD, CBN acts as an agonist on both the CB1 and CB2 receptors. However, CBN has a much higher preference for CB2 receptors, causing its effects. While technically psychoactive, due to CBN’s minimal action on CB1 receptors, the scientific community considers it non-psychoactive.
Because it exists in trace amounts, CBN is not consumed in large enough quantities to account for significant effects. More research is needed to illuminate CBN’s impact.
6. What is Cannabinodiol (CBDL)?
Cannabinodiol (CBDL), while found in trace amounts of cannabis, is a psychoactive cannabinoid. Curiously, CBDL forms during the full aromatization of CBD, which is not psychoactive. The proposed mechanism for CBDL’s psychoactive effects is that it introduces a double bond to CBD during aromatization, forming CBDL.
The double bond present in cannabinoids is a significant indicator of their affinity to CB1 receptors and psychoactive effects. As previously noted, the double bond placement, for instance, on carbons 8, or 9, produces structurally similar molecules with various degrees of influence.
More research is needed to confirm the degree and specificity of the effect from CBDL. However, it remains a potential candidate for cannabinoid-based therapies for epilepsy, appetite control, inflammation, and pain.
7. What is CBE (Cannabielsoin)?
First mentioned in medical journals in 1973, cannabielsoin (CBE) has been studied further as a potential non-psychoactive cannabinoid. Found in trace amounts in cannabis strains, CBE is one of CBD’s metabolic products during ingestion.
While CBE is not a controlled substance and supposedly harmless due to being non-psychoactive, CBE may play a part in the entourage effect of cannabis. The entourage effect is a proposed mechanism whereby the combination of terpenes, flavonoids, and trace cannabinoids are responsible for a synergistic effect from cannabis. The entourage effect is more potent than THC or CBD alone.
Additionally, because different concentrations of cannabinoids have other agonist properties at cannabinoid receptors, higher concentrations of non-psychoactive cannabinoids such as CBD, CBE, and CBG may “tame” the psychoactive effects of THC.
8. What is CBL (Cannabicyclol)?
Similar to CBE, cannabicyclol (CBL) is non-psychoactive and exists in trace amounts in cannabis plants. In the same way CBN forms from THC when exposed, CBL forms from CBC degradation when cannabis plants are exposed to light or oxidized.
Studies on CBL have not established a direct therapeutic value. However, due to CBL’s structural similarity to other trace non-psychoactive cannabinoids, it may exhibit similar effects compared to CBD. At best, CBL contributes to the entourage effect, with current research indicating that it functions best when consumed alongside other cannabinoids.
9. What is CBG (Cannabigerol)?
Cannabigerol (CBG) is not psychoactive. While CBG exists in minuscule amounts in cannabis plants, it has higher proportions the younger the plant is. Due to possible benefits, CBG has recently been cultivated in certain cannabis strains to bring about its non-psychoactive effects, similar to CBD.
CBG binds to both CB1 and CB2 receptors as an inverse agonist and has an affinity for CB2 receptors. It is not psychoactive and maybe more potent than CBD, although research in this area is lacking.
In terms of therapeutic applications, CBG has garnered attention as a therapeutic aid to inflammatory bowel disease, a non-psychoactive alternative to glaucoma, and protective against Huntington’s disease. These studies were all done on animals, and it is not conclusive how powerful these effects, or side effects, are in humans.
CBG forms during the decarboxylation of cannabigerolic acid (CBGA).
10. What is CBGA (Cannabigerolic Acid)?
Cannabigerolic Acid is the precursor to other cannabinoids. Analogous to stem cells in a growing child, CBGA is present in high quantities at the beginning of a plant cycle and differentiates into THC, CBD, and other cannabinoids.
Specifically, CBGA converts to THCA, CBDA, and CBCA. These are the precursor molecules to THC, CBD, and CBC, respectively.
11. What is THCA (Tetrahydrocannabinolic Acid)?
The precursor to THC, tetrahydrocannabinolic acid (THCA), is present in raw cannabis plants. Molecularly, THCA features a carboxyl group, which makes the cannabinoid as a whole non-intoxicating, as it can not pair with cannabinoid receptors.
Heating cannabis up initiates decarboxylation, removing the carboxyl group from THCA and converting it to THC. Air, heat and ultraviolet rays over time can also remove the carboxyl group, forming THC, which eventually degrades further to CBN.
Because THCA is non-psychoactive, research is looking to establish the potential of THCA as a therapeutic alternative to THC. Specifically, THCA shows promise as being neuroprotective and immunoprotective.
Its novel therapeutic properties, especially as a protective agent, are not dependent on cannabinoid receptors. Instead, THCA seems to operate in cyclooxygenase 1 and 2 (COX-1,2) enzyme and tumor necrosis factor-alpha (TNFA) receptor pathways.
12. What is CBDA (Cannabidiolic Acid)?
Similar to THCA, cannabidiolic acid (CBDA) forms during the decarboxylation of CBD. CBDA’s therapeutic value comes from its inability to bind to cannabinoid receptors. Instead, CBDA seems to work in the same way as nonsteroidal anti-inflammatory drugs (NSAIDS) through COX-2 inhibition.
Additionally, a study looking at the effects of low doses of CBDA (compared to CBD) in rats saw that CBDA reduced nausea significantly. While the anti-inflammatory and anti-nauseating properties seem to operate at low doses, evidence of these effects in humans is lacking.
13. What is CBCA (Cannabichromenic Acid)?
Cannabichromenic acid (CBCA) is the precursor to cannabichromene (CBC) and cannabicycloclic acid (CBLA). CBC is formed through the decarboxylation of CBCA, while CBLA forms during exposure to UV light.
Little research is available to support either the efficacy or abuse of CBCA, and it is mostly known as a precursor to CBC and, eventually, CBL.
14. What is CBC (Cannabichromene)?
Like THC and CBD, cannabichromene (CBC) stems from CBGA, which is the precursor to CBCA, and through decarboxylation forms CBC. CBC is non-psychoactive due to poor affinity to CB1 receptors in the brain.
CBC does seem to have an affinity for non-cannabinoid receptors such as transient receptor potential-vanilloid type-1 (TRPV1) and transient receptor potential ankyrin type-1(TRPA1), which play a role in pain perception. Additional studies have noted CBC’s role in reducing inflammation and neural stem progenitor cell (NCPC) growth; however, studies on humans are lacking.
15. What is CBT (Cannabitriol)?
Cannabitriol (CBT) is structurally similar to THC and biosynthesizes from the precursor molecule THCA. CBT exists in trace amounts in cannabis plants, and it is uncertain whether CBT exhibits personal effects or contributes to the entourage effect.
If CBT does exhibit specific effects at dose, researchers speculate that these effects would be psychoactive as CBT would bind to CB1 receptors in the brain.