1521-0103/376/2/204–212$35.00 https://doi.org/10.1124/jpet.120.000340 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 376:204–212, February 2021 Copyright ª 2021 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Minireview The Pharmacological Case for Cannabigerol Rahul Nachnani, Wesley M. Raup-Konsavage, and Kent E. Vrana Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania Received September 15, 2020; accepted November 4, 2020 ABSTRACT Downloaded from Medical cannabis and individual cannabinoids, such as D9- antibacterial activity. There is growing interest in the commercial tetrahydrocannabinol (D9-THC) and cannabidiol (CBD), are re- use of this unregulated phytocannabinoid. This review focuses ceiving growing attention in both the media and the scientific on the unique pharmacology of CBG, our current knowledge literature. The Cannabis plant, however, produces over 100 of its possible therapeutic utility, and its potential toxicolog- different cannabinoids, and cannabigerol (CBG) serves as the ical hazards. precursor molecule for the most abundant phytocannabinoids. jpet.aspetjournals.org CBG exhibits affinity and activity characteristics between SIGNIFICANCE STATEMENT D9-THC and CBD at the cannabinoid receptors but appears Cannabigerol is currently being marketed as a dietary supple- to be unique in its interactions with a-2 adrenoceptors and ment and, as with cannabidiol (CBD) before, many claims are 5-hydroxytryptamine (5-HT1A). Studies indicate that CBG may being made about its benefits. Unlike CBD, however, little have therapeutic potential in treating neurologic disorders research has been performed on this unregulated molecule, (e.g., Huntington disease, Parkinson disease, and multiple and much of what is known warrants further investigation to sclerosis) and inflammatory bowel disease, as well as having identify potential areas of therapeutic uses and hazards. at ASPET Journals on October 1, 2021 Introduction Europe) in 2010, and Epidiolex in 2018. A growing number of countries have also approved the use of medical marijuana for Cannabinoids as Medicine. The use of Cannabis sat- treating a variety of medical conditions; however, the data iva as a medicine dates back millennia. In ancient China, that support the use of marijuana for treatment are often marijuana was used to treat gout, malaria, digestive disor- anecdotal or from small studies. ders, and menstrual pain (Bostwick, 2012; Russo, 2016; Cannabigerol and Cannabinoid Synthesis. Cannabi- Kinghorn et al., 2017; Ryz et al., 2017; Baron, 2018; Ambrose noid synthesis begins with the precursor molecules olivetolic and Simmons, 2019). Cannabis was introduced to Western acid and geranyl-pyrophosphate, which combine to form ’ medicine by William O Shaugnessy, who proposed its use for cannabigerolic acid (CBGA) (Shoyama et al., 1975; Fellerme- the treatment of rheumatism and seizures (Bostwick, 2012; ier and Zenk, 1998; Fellermeier et al., 2001; Gülck and Møller, Russo, 2016; Kinghorn et al., 2017; Baron, 2018). However, the 2020). CBGA serves as the precursor to most other cannabi- use of medicinal marijuana fell out of favor toward the end of noids and is converted to D9-tetrahydrocannabinolic acid the 19th century and continued to decline until it was banned (D9-THCA), cannabidiolic acid (CBDA), and cannabichromenic by the Controlled Substances Act of 1970 (Bostwick, 2012; acid (Fig. 1). Because CBGA serves as the precursory molecule Sacco, 2014; Kinghorn et al., 2017). Since that time, few to the other cannabinoids, it is normally found in very low cannabinoid drugs have been approved for human use. These quantities in Cannabis; however, strains with reduced activity drugs include nabilone in 1985, dronabinol in 1986, rimona- of the three major synthesis enzymes can accumulate higher bant in 2006 (in Europe; withdrawn in 2008), Sativex (in levels of CBGA (Fellermeier and Zenk, 1998; Fellermeier et al., 2001). All enzymatically produced cannabinoids (in- This work was supported by a sponsored research agreement from cluding CBG) are produced as their acidic form and are then Pennsylvania Options for Wellness (to K.E.V.). decarboxylated by heat to create the “active” form. No author has an actual or perceived conflict of interest with the contents of this article. With the recent deregulation of cannabidiol (CBD) and other https://doi.org/10.1124/jpet.120.000340. hemp-derived cannabinoids, such as CBG, cannabichromene ABBREVIATIONS: ADHD, attention-deficit hyperactivity disorder; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBC, cannabichromene; CBD, cannabidiol; CBDA, cannabidiolic acid; CBG, cannabigerol; CBGA, cannabigerolic acid; GPCR, G protein–coupled receptor; GPR55, G protein–coupled receptor 55; HD, Huntington disease; 5-HT, 5-hydroxytryptamine; IL, interleukin; PFC, prefrontal cortex; PPAR, peroxisome proliferator–activated receptor; D9-THC, D9-tetrahydrocannabidiol; D9-THCA, D9-tetrahydrocannabidiolic acid; TRPM, transient receptor potential cation channel subfamily M; TRPV, transient receptor potential cation channel subfamily V. 204 Potential Clinical Uses of CBG 205 Fig. 1. Biosynthesis pathway of the pri- mary cannabinoids. Cannabinoid biosyn- thesis begins with the combination of Downloaded from geranyl pyrophosphate and olivetolic acid to form CBGA. CBGA serves as the substrate for the synthesis of D9-THCA and CBDA. Decarboxylation of CBGA, D9-THCA, and CBDA by heat results in CBG, D9-THC, and CBD, respectively. Because CBGA serves as the substrate for the synthesis of the major cannabi- jpet.aspetjournals.org noids, very little is typically found in material from Cannabis sp. at ASPET Journals on October 1, 2021 (CBC), and cannabinol (2018 Farm Bill), there is growing interest cannabinoids, terpenoids, and flavonoids acting in concert. in cannabinoid pharmacology (https://www.usda.gov/farmbill). Although there is little evidence to document this, it does For instance, in spite of having CBG as a common precursor, D9- support the notion that the entire plant material needs to be THC, CBD, and CBC have dramatically different physiologic consumed. Then, with the explosion in sales of CBD products, effects. In the case of the two most widely studied compounds, D9- entrepreneurs are searching for the next economic market, THC is known to produce euphoria and appetite stimulation and it appears that CBG oil may prove to be that market. (Volkow et al., 2014), and CBD is noneuphorigenic and is thought Indeed, several commercial outlets are advertising CBG as the to be antiepileptic (Jones et al., 2010) and anti-inflammatory “mother of all cannabinoids”—presumably because in Canna- (Carrier et al., 2006). Much less is known about CBG and CBC, bis it is a common precursor. However, CBG will not give rise but since there are differences in ring structure, it is not to the myriad other cannabinoids when taken into the human surprising that they have differing pharmacological properties; body because of the lack of necessary conversion pathways. however, cannabinoids other than D9-THC and CBD have had Work in recent years has garnered interest in other little exploration and characterization. cannabinoids, such as CBC and D9-tetrahydrocannabivarin, Interest in Alternative Cannabinoids. Recent events but more studies are needed. D9-Tetrahydrocannabivarin is are prompting increased interest in the pharmacotherapeutic suggested to induce similar effects as D9-THC without potential of the 100+ cannabinoid compounds. First, there excessive appetite stimulation (Tudge et al., 2014), and exists growing belief that the beneficial effects of Cannabis studies of CBC show it can improve inflammation-related derive from the entourage effect: all of the Cannabis-derived pain (Wirth et al., 1980). 206 Nachnani et al. In the present review, we explore potential therapeutic the 5-HT1A receptor, in which the former is reported to be an benefits and adverse side effects of CBG. Recent literature on antagonist, whereas the latter is an indirect agonist (with an CBG has revealed that its pharmacology addresses therapeu- unreported affinity) (Russo et al., 2005; Cascio et al., 2010; tic targets distinct from those of D9-THC and CBD. We Rock et al., 2011, 2012). There are currently no data in this summarize previous investigations into therapeutic applica- regard for D9-THC. tions and propose new areas of interest for CBG’s medical use. Table 2 provides a more detailed analysis of the physiologic In vitro and in vivo studies suggest a potential future for CBG activities that are exhibited by CBG (whether in intact to address unmet needs in medical therapy, including its animals, whole cells, or subcellular preparations). CBG actions on adrenergic, serotonergic, peroxisome proliferator– appears to act as an agonist at the a-2 receptor (with varying activated receptor (PPAR), and cannabinoid receptor families EC50 values reported) and all of the Transient Receptor (Cascio et al., 2010; Rock et al., 2011; O’Sullivan, 2016; Potential Cation Channel (TRP) family channels (except Navarro et al., 2018). TRPM8, at which it is reported to act as an antagonist). Together, these data suggest that the physiologic effects of CBG tend toward Gi-mediated inhibition, autoregulatory ac- Discussion tivity, and calcium-based signaling by both ion channels and protein kinase C (PKC). Given the differential pharmacological The Unique Pharmacologic Properties