Phytocannabinoids are a class of compounds found in plants (phyto-) that act upon the endocannabinoid system. The vast majority of phytocannabinoids are found in the species cannabis sativa, but other cannabinoids have been found elsewhere in the plant kingdom, such as piper nigrum (black pepper) and echinacea purpurea (purple coneflower).
Acidic vs. Neutral Cannabinoids
Cannabis plants produce cannabinoids in their acidic forms. These compounds are believed to convey antioxidant, anti-pest, and antimicrobial1 properties to the plant. When heated, acidic cannabinoids lose their acid group, a process called decarboxylation, which transforms them into neutral cannabinoids. For example, tetrahydrocannabinolic acid, THCA, is converted to tetrahydrocannabinol, THC, when heated. A small amount of conversion from the acidic to neutral form will also occur over time at room temperature. Preparations of cannabis intended to contain the acidic cannabinoids will almost always contain at least a low level of naturally occurring neutral cannabinoids.
While acidic cannabinoids possess medicinal properties, almost all of the research on phytocannabinoids has investigated the neutral forms. These neutral cannabinoids possess a wide array of physiologic effects, and none have been found to be toxic or capable of causing serious injury or death from overdose.
In addition to the physiologic effects summarized briefly in this chapter, several of the cannabinoids have been shown to possess antimicrobial and antioxidant properties2, like they do on the plant.
Delta-9-tetrahydrocannabinol (THC) is the most well-known and studied phytocannabinoid. THC is responsible for the psychoactive effects of cannabis, as well as many of the medicinal properties. THC works by interacting with the endocannabinoid system’s CB1 and CB2 receptors. By stimulating these receptors, THC can mimic the function of the endocannabinoids our bodies produce to regulate physiology and maintain health.
Like endocannabinoids, the effects of THC vary in different bodily tissues. In the brain, THC can protect neurons, promote cell growth, regulate neuroplasticity (a process involved in learning and forgetting), and cause psychoactive effects including euphoria, changes in memory, mood, coordination, and perception.
THC has been shown to have numerous medicinal effects, including relief of pain, inflammation, spasticity, nausea, anxiety, itching, seizures, and much more. Most strains of medical cannabis contain predominately THC and very low levels of the other cannabinoids, though breeders have been working hard to produce strains that contain higher levels of the other cannabinoids and their medicinal properties.
The acidic form of THC is non-psychoactive, based on animal studies3 and anecdotal human reports. The little research on THCA has demonstrated anti-inflammatory properties via decreased production of tumor necrosis factor alpha (TNF-a4) and inhibition of COX enzymes5, and anti-nausea properties in mice at doses much lower than it’s neutral counterpart, THC6. THCA does not appear to stimulate the CB1 or CB2 receptors, but some of its activity may be indirectly dependent on their function. In my clinical practice, I have been impressed by the anti-seizure properties of THCA in extraordinarily low doses.
Cannabidiol (CBD) has become an exciting focus of medical research, popular media, and legislation related to cannabis. CBD is considered a “non-psychoactive” cannabinoid, although it can alter one’s consciousness to some extent. CBD has been shown to relieve anxiety, depression, pain, seizures, psychosis, inflammation, spasm, nausea, and more7. CBD has numerous mechanisms of action in the body, and others are likely to be discovered. It antagonizes GPR55, alpha-1 adrenergic, and mu-opioid receptors, activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, and inhibits the uptake of norepinephrine, dopamine, serotonin, GABA, and anandamide, and influences mitochondrial calcium stores, to name a few 8. Unlike pharmaceutical magic bullets with single mechanisms of action, CBD is a pharmacologic shotgun with a surprising safety profile and great therapeutic potential.
Interestingly, very little of CBD’s activity depends on the CB1 and CB2 receptors, though it has been shown to modify the effects of other substances at these receptors, including its close relative THC. Combining CBD and THC decreases the psychoactivity and other side effects of THC, while enhancing some of THC’s benefits9. The largest body of human clinical research has been performed on a 1:1 ratio of CBD and THC in an oral spray (nabiximols)10.
With the explosion of media coverage on CBD’s benefits to children with intractable seizures, the falsehood that CBD is the “medicinal” component and THC is the “intoxicating” component of this plant has spread across the globe. On the contrary, science has clearly shown that both THC and CBD have medical value, and that they work quite well together.
Like THCA, scientists have not thoroughly explored the physiologic effects or therapeutic potential of cannabidolic acid (CBDA). CBDA has demonstrated anti-nausea properties in mice at very low doses11 and anti-inflammatory effects via COX enzyme inhibition12. CBDA is a potent inhibitor of the COX-2 enzyme, the same mechanism of action as the drug Celebrex. It is likely that CBDA shares some of the diverse mechanisms of action and pharmacologic properties with its neutral counterpart CBD.
Over time, THC oxidizes and is converted into cannabinol (CBN). Ultraviolet light and heat may accelerate this process. CBN is much less psychoactive than THC13, and due to its lower potency, it has not been the subject of much recent research. Some patients report they prefer CBN-rich products for promoting sleep or relaxation without impairment, though others have infrequently reported higher concentrations of CBN associated with a stimulating effect. These reports are likely complicated by the breakdown and evaporation of other compounds in the herb, so without more research it is difficult to discern the therapeutic value of CBN itself. Even when cannabis is stored in ideal conditions, THC will gradually convert to CBN, and the medicinal effect will change over time.
CBG and CBGA
Cannabigerolic acid (CBGA) is the precursor cannabinoid that is later converted into THCA, CBDA, or CBCA. Like the other cannabinoids, CBGA is decarboxylated into CBG by heat and time, but few cannabis strains have any significant amount of CBGA in the mature flowers. Some strains have been identified that lack the enzyme which converts CBGA into the other cannabinoids, and some growers have discovered techniques of early harvesting common strains to increase the yield of CBGA.
Very little research has explored the effects of CBG, and even less CBGA. CBG has low activity at the cannabinoid receptors, stimulates TRPV1, TRPA1, and a2-adrenergic receptors,14,15, and inhibits the uptake of the neurotransmitters serotonin, norepinephrine, and GABA16. CBG has also been shown to relieve pain, erythema, and inhibit lipoxygenases, enzymes that produce inflammatory molecules, more potently than THC17.
Cannabichromene (CBC) is also rarely found in substantial quantities in mature cannabis flowers. It has been shown to decrease pain18 and inflammation19 and to have strong antimicrobial effects20. CBC also activates the TRPA1 receptor and weakly inhibits the reuptake of the endocannabinoid anandamide, but has very little activity at the CB1 or CB2 receptors.21 It causes sedation in dogs and rodents, but has not been shown to cause any psychoactive effects in monkeys or humans.22 There is some evidence that co-administration of CBC with THC could increase the effects of THC.23
Tetrahydrocannabivarin (THCV) is also rarely found in substantial quantities in cannabis flowers, though some breeders have developed strains that emphasize this cannabinoid. On it’s own, it is considered 25% as psychoactive as THC24, with a faster onset25 and shorter duration. In rats it has been shown to block the effects of THC at the CB1 receptor at low doses, but stimulate the receptor at higher doses, and is a partial agonist at CB2. It is being studied as a treatment for obesity and diabetes due to its effects on decreasing food intake and increasing energy expenditure.26
By Dustin Sulak, DO
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