The oldest evidence of Cannabis sativa use dates back to ∼4000 BCE in China and is also within some of the earliest written pharmacopeias across cultures (Touw, 1981) (Fig. 1). Today, cannabis is used by nearly 200 million people worldwide (https://www.unodc.org/unodc/en/data-and-analysis/world-drug-report-2023.html). Despite millennia of use medicinally and recreationally, many cannabinoids were not structurally identified until the latter half of the 20th century (Mechoulam and Gaoni, 1965). This breakthrough led to the discovery of the endocannabinoid system, one of the largest receptor systems and a master regulator of homeostasis within the human body. The endocannabinoid system comprises the canonical cannabinoid G protein–coupled receptors (GPCRs) CB1 and CB2; the noncanonical cannabinoid-responsive GPCRs GPR55, GPR18, and GPR119; the transient receptor potential (TRP) cation channel subfamily members V1, V2, and M8; and the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor proteins (Mangal et al., 2021). Even though research on cannabis and chronic pain is limited, nearly 50% of all people using cannabis within the United States do so to treat chronic pain (Boehnke et al., 2024).
An ancient plant for modern therapeutics. Illustration of Cannabis sativa from the antique scientific text De Materia Medica by Dioscorides (circa CE 512) pictured with minor cannabinoids (clockwise from bottom left) cannabinol, cannabidivarin, cannabigerol, Δ8-tetrahydrocannabinol, and Δ9-tetrahydrocannabivarin. Adapted from Wikimedia Commons.
Importantly, modulating the endocannabinoid system through phytocannabinoids may have therapeutic potential in treating chronic pain. To date, more than 550 compounds have been identified in the cannabis plant, with over 100 recognized cannabinoids, although the pharmacology and therapeutic potential of the minor cannabinoids and other phytochemicals are incompletely described (Rock and Parker, 2021). Despite the increased use and accessibility of cannabis over the past decade, research on cannabis use and chronic pain has mainly focused on the analgesic properties of the major cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), often neglecting these minor cannabinoids. For this issue of The Journal of Pharmacology and Experimental Therapeutics, Schwarz et al. (2024) determined whether cannabinoids found in lower quantities within Cannabis sativa (cannabinol, cannabidivarin, cannabigerol, Δ8-tetrahydrocannabinol, and Δ9-tetrahydrocannabivarin) produced cannabimimetic and pain-relieving behaviors in male and female CD-1 mice.
The work presented by Schwarz and colleagues (2024) addresses the impact of five minor cannabinoids on behavior and physiology by utilizing a cannabinoid tetrad assay alongside a paclitaxel-induced peripheral neuropathy pain model in mice. The tetrad assay evaluates cannabimimetic effects of compounds on behavioral and physiologic endpoints, including locomotion, catalepsy, nociception, and core body temperature. The study revealed that minor cannabinoid cannabinol (100 mg/kg) induces cannabimimetic effects such as hypothermia and reduced locomotion in male and female mice. Similarly, cannabigerol (100 mg/kg) induced hypothermia and tail-flick antinociception in both sexes. Furthermore, Δ8-tetrahydrocannabinol (32 mg/kg) stimulated antinociception, hypothermia, and catalepsy in both male and female mice. Conversely, low-dose Δ8-tetrahydrocannabinol (10 mg/kg) affected only female mice, increasing cataleptic behavior and decreasing temperature. In addition, Δ9-tetrahydrocannabivarin (32 mg/kg) induced three of the four tetrad endpoints, excluding locomotion, exclusively in female mice. In the paclitaxel-induced peripheral neuropathy pain model, cannabinol was the sole minor cannabinoid efficacious in reducing mechanical pain hypersensitivity for both male and female mice. Interestingly, cannabidivarin (100 mg/kg) displayed a minor but statistically significant antinociceptive effect in female but not male mice. These findings underscore the diverse effects of minor cannabinoids, illuminate potential sex-specific differences, and propose innovative avenues for the development of therapies for chronic pain.
As there is an increased interest in the retail market to provide minor cannabinoids to consumers (Moore et al., 2023), work such as that by Schwarz and colleagues (2024) grows increasingly important. This is to avoid medical claims about minor cannabinoids that may be incompletely understood and to potentially find new minor cannabinoids that can be useful to treat pain. Although the affinity of some minor cannabinoids to cannabinoid receptors are reported (Pertwee et al., 2010), systematic evaluations in neuropathic pain will enhance the translational potential of these minor cannabinoids and guide best practices for their use. Additionally, a more comprehensive understanding of the cannabimimetic effects of minor cannabinoids can be achieved by investigating their interactions with major cannabinoids. Importantly, this work addresses the understudied sex-specific differences in the responsiveness to cannabinoids and the endocannabinoid system, as the majority of completed studies relied on male animals (Soliman et al., 2021). The sex-specific differences in the effects of minor cannabinoids are akin to findings reported with THC and CBD in rats (Moore and Weerts, 2022). Further research is necessary to elucidate the molecular mechanisms underlying these observed sex differences.
The article also highlights some of the hurdles to advancing cannabis research. For example, the authors used CD-1 mice; however, there are likely variations in the effects of minor cannabinoids across different strains of mice. This may or may not be similar to prior studies identifying strain differences in the response to analgesics (Wilson et al., 2003a, 2003b). This underscores the necessity of using different experimental models for preclinical testing to facilitate the translation of these findings into clinical applications. Additionally, possibly unknown metabolites of minor cannabinoids may drive analgesia, which requires more investigation. Comparing cannabinol with other cannabinoids (Xiong et al., 2012) known for their analgesic effects or with other neuropathic pain treatments like antidepressants and gabapentinoids would also be important. Moreover, future studies should consider the effects of repeated administration of minor cannabinoids, as chronic treatment may yield different outcomes compared with acute exposure, thereby providing a more comprehensive understanding of their therapeutic efficacy over time.
Uncovering the therapeutic properties for minor cannabinoids to treat pain is necessary, as Cannabis sativa carries a risk of dependency, addiction, and, with chronic use, a possible impact on mental health. Although some of these risks may be mitigated by synthetic analogs, there requires careful consideration of dosing and delivery methods for cannabinoids. Finding a minor cannabinoid that has limited effects on tolerance and dependence can lead to developing safer opioid-free alternatives to treat chronic pain.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Ippolito, Gross, Abd-Elrahman.
Footnotes
- Received June 20, 2024.
- Accepted July 15, 2024.
This work was supported by National Institutes of Health National Institute of General Medical Sciences (NIGMS) [Grant GM119522] (to E.R.G.). K.S.A.-E. is a Michael Smith Health Research BC–funded Health Professional-Investigator and is funded by a New Investigator grant from the Alzheimer’s Society of Canada.
The authors have declared a conflict of interest. E.R.G. is an Associate Editor of The Journal of Pharmacology and Experimental Therapeutics (JPET), and M.J.I. and K.S.A.-E. are editorial fellows of JPET.
- Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics
