This article examines why we should be studying the cannabinoids beyond THC and CBD in order to explore their potential medical value.
In legal cannabis markets, two molecules dominate the conversation for both adult use and medical use cannabis: delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Δ9-THC is the dominant cannabinoid found in most adult-use cannabis. Many Cannabis Sativa cultivars have been selectively bred for it, and CBD is the most commonly found cannabinoid in the supplemental market. Both molecules have had successful drug formulations developed for specific medical conditions such as epilepsy (Epidolex; CBD) and reduce nausea from medical conditions or drugs (Dronabinol; Δ9-THC). While these drugs are an important step toward legitimizing cannabinoid-based medicines, they reduce the significance of the other 400 chemical entities within the plant, such as terpenes and other phytocannabinoids. More importantly, the synergistic properties of the molecules working together don’t exist in our current adult-use and medical products. These molecules working together may have led to many of the anecdotal medical successes attributed to Cannabis Sativa. It is a major shift away from the traditional single-molecule compounds in the pharmaceutical industry. While we do not know the effects of every molecule found within the plant, we have research that shows many phytocannabinoids beyond Δ9-THC and CBD have medical benefits. These molecules include the precursor to Δ9-THC, tetrahydrocannabinolic acid (THCA), and a long list of lesser-known cannabinoids such as cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and more.
Exploring cannabinoids beyond Δ9-THC and CBD will allow us to leverage the compounds that Cannabis Sativa contains fully. This is important for furthering the pharmaceutical and herbaceutical medicines brought to market or commoditized. When using most cannabinoid-based drugs, there is a significant side effect: inebriation or being “high.” While individuals who use cannabis frequently don’t mind or enjoy the psychoactive effects of cannabis, it is a side effect that many people don’t enjoy. As with all modern medicines, some side effects are to be expected, but the psychoactive effects of cannabis specifically come from Δ9-THC. Suppose we can develop cannabinoid medicines that reduce or potentially eliminate the psychoactive effects. In that case, we can engage medical professionals, legislatures, and individuals skeptical of the drugs because of this particular side effect. We may do this without losing the therapeutic efficacy of current formulations by exploring other phytocannabinoids present in cannabis.
THCA is the most abundant phytocannabinoid found in the resin glands of Cannabis Sativa. THCA is typically extracted from the plant and converted to Δ9-THC for its psychoactive properties by breaking the carboxyl group off of the molecule through decarboxylation. THCA has potential for medical value, and the research suggests that we should consider it for product development. An article published in the National Library of Medicine showed that THCA dosed at 0.05/0.5 mg/kg may be more effective at reducing lithium chloride (LiCl) induced vomiting compared to Δ9-THC, which did not suppress nausea at the same dosage (1). THCA’s potential doesn’t stop with nausea. According to a scientific journal published in 2012, THCA, Δ9-THC, and CBD were given to mice to study the molecules’ protective properties against MPP+, a neurotoxin that leads to cell death and Parkinson’s disease (2). The study concludes that while no neurite outgrowth (potential nerve restoration) was observed from the cannabinoids, a high concentration increased overall cell counts by 123% from THCA, and THCA protects against MPP+ induced cell death. THCA also has other neuroprotective properties, as discovered by an article published in the British Journal of Pharmacology. This work showed that THCA in mice treated with 3-NPA, a mycotoxin that is a mitochondrial inhibitor, increased mitochondrial mass in neuroblastoma cells, improving motor deficits and preventing striatal degeneration (3).
The cannabinoid called CBN has gained much traction in the commoditized market of both adult-use cannabis and nutraceuticals. In fact, 5-10 mg of CBN can be found in many products marketed as “sleep” or “rest” aides, and unsurprisingly a study published in November 2021 (4), seems to support this. While CBN isn’t the next Ambien, the study performed by the University of Western Australia’s Center for Sleep Science shows that a formulation containing THC, CBN, and CBD at a ratio of 20:2:1 showed an improvement in the 24 participants with insomnia in a sleep journal. The participants specifically noted that it took less time to fall asleep, they slept longer, reduced nighttime wakefulness, and ultimately felt more rested. In addition to their sleep journals, the participants partook in polysomnography measurements (an analysis of brain waves, heart rate, and REM sleep) that did not conclude any difference between the placebo group and the group that took the cannabinoid drug. The potential for CBN doesn’t stop at sleep; there is a potential for CBN to be used in topical applications because of its inhibiting keratinocyte proliferation properties and agnostic effects on the transient receptor potential vanilloid type 2 (TRPV2) cation channels, which are high threshold thermosensors. As published in Advances of Pharmacology chapter 3 (5), these properties of CBN show, there is a potential for the treatment of psoriasis and burn wounds.
CBC, a nonpsychotropic cannabinoid, has different observed effects that need further research. Like CBN, “CBC interacts with transient receptor potential cation channels that inhibit endocannabinoid inactivation, and stimulate the CB2 receptors, but not CB1 receptors” (6). The specific channels that CBC interacts with have a role in inflammation and pain within mammals, specifically nociceptor firing. This significant interaction with the different transient receptor potential (TRP) channels can cause strong anti-inflammatory effects, which are supported by a study published in 2011 (7) where CBC stimulated pathways of antinociception and caused analgesia in mice. What is even more fascinating is that much of the research also shows an additive result on the nociception effects when THC is co-administered with CBC. To further demonstrate the synergistic effects of the cannabinoids, we could look at an article published in 2011 which provided a pharmacological evaluation of CBC’s impact on pain and inflammation. The research showed that CBC significantly reduced lipopolysaccharide (LPS)-induced paw edema in rat models and produced a subset of effects in the mouse tetrad array (series of behavioral paradigms in rodents treated with cannabinoids). What is fascinating is that the tetrad effects were not CB1 receptor mediated. Instead, when Δ9-THC was given alongside CBC, it showed anti-inflammatory effects in the LPS-induced paw edema model because of CB2 receptor activation. In addition to this additive relationship surrounding the anti-inflammatory properties of CBC and Δ9-THC, there was also an observation that higher doses of CBC led to increased psychoactive effects of Δ9-THC, suggesting a potential pharmacokinetic interaction when the two molecules are combined (8).
The list of cannabinoids with potential medical value doesn’t stop here, as relevant research has been performed on other cannabinoids. CBG, which is the decarboxylated form of cannabigerolic acid (CBGA), the “parent molecule” for all other cannabinoids, has promising new research regarding the therapeutic potential in treating neurological disorders. In 2022, diseases such as Huntington’s disease, Parkinson’s disease, multiple sclerosis (MS), and inflammatory bowel disease (IBD), could be reduced in severity based on the in vitro and animal model studies when intaking CBG (9). Cannabitriol (CBT), a cannabinoid that shares a very similar chemical structure to Δ9-THC, has the potential to reduce the psychoactive effects of Δ9-THC (10). Δ9-Tetrahydrocannabivarin (THCV) is another interesting cannabinoid because it does not have the psychoactive properties of Δ9-THC but does have a measurable effect on appetite stimulation and weight gain—further research must be done on this molecule, however, because it can exhibit either agnostic or antagonistic effects on the CB1/CB2 receptors depending on dosage (11). Cannabinoids such as cannabielsoin (CBE), cannabinodivarin (CBV), and cannabiripsol (CBR) have been identified, but no research has yet to be published. Today more cannabinoids are being identified and quantified than ever before. We know of 120+ different cannabinoids, most of which we have done zero dedicated research on.
Cannabis Sativa is among a remarkable variety of plants that may be able to provide us with a broad range of medical developments ranging from a sleep aid to pain management. While we are currently using phytocannabinoids in a way that is very similar to traditional pharmaceuticals—one molecule targeting one ailment or symptom—the future of cannabinoid drugs must explore all of what the plant has to offer. Δ9-THC and CBD have paved a pathway for research—truly valuable research—to become more mainstream in the scientific community. These two molecules have also brought mainstream media attention to the cannabinoid medicines with products specifically designed to treat adolescent epilepsy. But to move cannabinoid-based medicines forward, we must look beyond the obvious most dominant cannabinoids and into the relatively uncommon ones. To provide efficacious medicines with minimal side effects, we need to be exploring the synergistic effects of primary and minor cannabinoids. The cannabis research should not stop here; we must also learn how the different terpene ratios interact with the various cannabinoids.
Anthony DeMeo is the Director of R&D at Somai Pharmaceuticals in Lisboa, Portugal. Direct correspondence to: AD@SomaiPharma.eu.
A. DeMeo, Cannabis Science and Technology® Vol. 5(7), 28-30 (2022).