Basics: THCP — Shedding Light on a Lesser-Known Cannabinoid
It’s been more than 50 years since the discovery of THC. Since then, more than 150 phytocannabinoids have been identified in nature, with nearly 90 of them originating from the cannabis plant.1,2 Interestingly, scientists have discovered that cannabinoids are also produced by other flowering plants such as rhododendron, and even some fungi can produce cannabinoid compounds.3 Despite identifying a vast number of these compounds, there are still many mysteries surrounding cannabinoids and their therapeutic potential. Whilst CBD and THC tend to get the most attention, an increasing focus by scientists on less common cannabinoids is leading to new and exciting discoveries.
In late 2019, a group of Italian scientists uncovered two previously unidentified naturally occurring phytocannabinoids known as delta-9-tetrahydrocannabiphorol (THCP) and cannabidiphorol (CBDP).4 These newly identified cannabinoids were discovered within a strain of cannabis known as FM2, named for its federal producer, Farmaceutico Militare, and its two primary constituents, CBD and THC. Interestingly, in Italy, medical cannabis is produced under a federally run program that grows and processes two distinct strains of cannabis for medical patients: FM1 (low CBD, high THC) and FM2 (balanced CBD and THC).5 What makes these discoveries so intriguing is that even though these cannabinoids are newly identified, they’ve likely been hidden within the cannabinoid profile of FM2 the whole time. Thanks to new technologies and laboratory techniques, less common cannabinoid homologs such as THCP, often called minor cannabinoids, are now detectable and even quantifiable. This research is still in its infancy, but the identification and characterization of minor cannabinoids should be of great interest to health care and research professionals alike. Assuming these cannabinoids are present in other strains of cannabis, their presence could help to explain the variable psychological and physiological effects of different strains.
Before a discussion of the results of the research, it should be noted that the CBDP and THCP were both identified within FM2 in very small quantities. According to standards set forth by Italy’s Military Chemical Pharmaceutical Institute, FM2 extract contains a standardized concentration of 5.9% CBD and 4.2% THC. For comparison, researchers extrapolated that their sample of FM2 extract likely contained roughly 0.024% CBDP and 0.003% THCP.4 These percentages are extremely minute, which may help explain the relatively late discovery of THCP and CBDP. Due to the very low concentration of these homologs in FM2, THCP was synthesized in the laboratory for the experiments discussed in this article.
The researchers used in vitro binding assays to predict THCP’s affinity (or attraction) for the cannabinoid receptors type 1 and type 2 (CB1 and CB2). These receptors are widely distributed throughout the body and brain, where they interact with endogenously produced molecules known as endocannabinoids. CB1 and CB2 are also the primary receptors with which phytocannabinoids THC interact. When compared with THC, THCP was found to have 33 times greater affinity for CB1 and five times greater affinity for CB2.4 This increased affinity for CB1 gives THCP the potential to potently elicit some of the classical effects of THC, such as analgesia and euphoria. While THC is known to be a partial agonist of CB receptors with moderate affinity, THCP’s enhanced affinity for CB1 is more comparable to that of synthetic cannabinoids, which can often be full agonists at CB receptors.1,6 Full agonists at CB1 carry an increased risk of adverse effects such as overt sedation, hypertension, renal failure, drug-induced psychosis, and seizures.6,7 THCP hasn’t yet undergone G-protein studies to assess how strongly it elicits a response on the cellular level, which would distinguish its activity between partial and full agonist.
Binding affinity is only one pharmacologic property that drives therapeutic response. To understand how THC differs from THCP, the C3 alkyl chain on the THC structure must be considered. This side chain is thought to be an important factor influencing the pharmacologic activity of cannabinoids—also known as the pharmacophore.1,7,8 With a longer seven-carbon alkyl side chain, THCP was shown to have enhanced affinity and increased activation for CB1 and CB2 receptors via a series of tests on mice known as the tetrad test. The tetrad tests showed THCP had similar biological activity as THC, but at lower doses. THCP appeared to be at least twice as potent as THC at eliciting analgesia, catalepsy, hypothermia, and sedation in mice.4 More research is needed to understand how enhanced activation translates to therapeutic benefits or hazards in humans.
Another important pharmacologic consideration of THCP is safety. Given its enhanced activity at CB1, THCP could also carry an increased risk of adverse effects. Some synthetic cannabinoids, such as nabilone (Cesamet), have a modified C3 alkyl side chain similar to that of THCP. Nabilone is known to be more receptive than THC at CB1 and CB2 and is also generally thought to carry with it an increased risk of adverse effects, including drowsiness, dizziness, and even hallucinations.9
These adverse effects are less common when the plant is consumed whole, due to something known as competitive agonism, by which THC will compete with THCP for the CB1 and CB2 receptors.1 If THCP were isolated and consumed alone, it could hypothetically carry with it more risk of adverse effects compared with THC or whole-plant cannabis. In addition to greater affinity and greater efficacy, it’s also possible that the longer sidechain of THCP could result in a longer duration of activity compared with that of other cannabinoids, but that remains to be studied.
Last, when considering biological activity of THCP, it may be important to consider its potential metabolism. When THC is taken orally, much of the drug is metabolized to 11-hydroxydelta-9-THC, an active metabolite with considerably more psychoactivity than THC itself.10 Assuming oral THCP undergoes similar first-pass metabolism, then hypothetically THCP metabolism could produce a highly active psychoactive metabolite, but this hasn’t been studied.
There are other minor cannabinoids that recently have also been stealing the spotlight from THC and CBD. Delta-9-tetrahydrocannabivarin (THCV), the three-carbon homolog of THC, shows affinity for CB1 and CB2, but because of the shorter side chain, it may act as an antagonist at CB1. THCV’s ability to block or alter endocannabinoid signaling is thought to have potential therapeutic utility in type 2 diabetes, hypertriglyceridemia, and obesity.11 While studies have reported variable activity of THCV in vivo, the therapeutic implications of CB1 antagonism could be interesting.12
The same team of Italian researchers that discovered THCP has also recently identified and classified the novel cannabinoid delta-9-tetrahydrocannabutol (THCB) from the FM2 strain. THCB is a four-carbon homolog of THC found to have substantial affinity for CB1 (three times greater than THC) and similar affinity as THC for CB2. The tetrad test performed on mice administered THCB suggests similar but different activity than THC or THCP.13 The therapeutic utility of THCB remains unclear and will require additional studies.
CBDP, the other novel cannabinoid discovered in late 2019 by Citti and colleagues, wasn’t run through the same affinity and activity tests as THCP.4 Because CBD is known to have starkly different pharmacologic activity compared with THC, including limited affinity for CB1 and CB2 receptors, it’s difficult to predict how CBDP’s activity will differ from CBD’s.12 More research will need to be done before scientists can make assertions about CBDP.
The identification of novel cannabinoids shows that despite extensive existing research on THC, many complexities of the cannabis plant remain to be elucidated. The last year has brought multiple newly characterized cannabinoids, and this trend is likely to continue. With cannabis going mainstream, there’s been an explosion of conversation, funding, and research. Cannabis cultivators, entrepreneurs, geneticists, plant biologists, and pharmacologists are now expanding their focus to include these and other minor cannabinoids.14 With the waves of deregulation and legalization spreading around the world, expect scientists to continue to unravel the mysteries hidden within this plant.
— Codi Peterson, PharmD, is a hospital-based pharmacist specializing in pediatrics and emergency medicine. He has a passion for educating patients and health care professionals alike, with experience teaching nurses, patients, paramedics, and respiratory therapists. His primary focus is increasing awareness about the therapeutic potential of medical cannabis and endocannabinoid health. Peterson is currently obtaining his master of science in medical cannabis science and therapeutics from the University of Maryland School of Pharmacy.
— Joseph Friedman, RPh, MBA, is a pharmacist with a master’s degree in business administration. From December 2015 to December 2019, Friedman owned and operated the only medical cannabis dispensary in the state of Illinois that had multiple pharmacists and a nurse on staff. Friedman made history in the fall of 2016 by being the first medical cannabis dispensary in the nation to work with two Illinois-based colleges of pharmacy (Roosevelt University and Chicago State University) to have their fourth-year pharmacy students do one of their required Advanced Pharmacy Practice Experiences clinical rotations in a medical cannabis dispensary. Friedman hosts the Medical PotCast show and the CRx Podcast via the Pharmacy Podcast Network and is a frequent presenter at pharmacy conventions across the nation. He works tirelessly advocating for the need of pharmacist involvement in the US cannabis industry.
1. Shahbazi F, Grandi V, Banerjee A, Trant JF. Cannabinoids and cannabinoid receptors: the story so far. iScience. 2020;23(7):101301.
2. Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016;33(12):1357-1392.
3. Gülck T, Møller BL. Phytocannabinoids: origins and biosynthesis. Trends Plant Sci. 2020;25(10):985-1004.
4. Citti C, Linciano P, Russo F, et al. A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-tetrahydrocannabiphorol. Sci Rep. 2019;9(1):20335.
5. Paolillo C. The national production of active substances of plant origin based on cannabis. Italian Ministry of Health website. http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=4588&area=sostanzeStupefacenti&menu=organismo. Published December 15, 2016. Accessed December 8, 2020.
6. Cohen K, Weinstein AM. Synthetic and non-synthetic cannabinoid drugs and their adverse effects-a review from public health prospective. Front Public Health. 2018;6:162.
7. Martin BR, Jefferson R, Winckler R, et al. Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists. J Pharmacol Exp Ther. 1999;290(3):1065-1079.
8. Bow EW, Rimoldi JM. The structure-function relationships of classical cannabinoids: CB1/CB2 modulation. Perspect Medicin Chem. 2016;8:17-39.
9. Tsang CC, Giudice MG. Nabilone for the management of pain. Pharmacotherapy. 2016;36(3):273-286.
10. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770-1804.
11. Wargent ET, Zaibi MS, Silvestri C, et al. The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;3(5):e68.
12. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215.
13. Linciano P, Citti C, Luongo L, et al. Isolation of a high-affinity cannabinoid for the human CB1 receptor from a medicinal Cannabis sativa variety: Δ9-tetrahydrocannabutol, the butyl homologue of Δ9-tetrahydrocannabinol. J Nat Prod. 2020;83(1):88-98.
14. Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci. 2016;7:19.