The Unique Pharmacologic Properties of CBG

CBG is distinct from Δ9-THC and CBD in its pharmacological profile (as summarized in Tables 1 and 2). In a variety of different ways, CBG seems to reside, pharmacologically, in between Δ9-THC and CBD. From the receptor binding data presented in Table 1, CBG is more like Δ9-THC at the CB1/CB2 receptors than CBD, but with a lower affinity (by a factor of between 5-fold and 27-fold) (Pertwee, 2008; Cascio et al., 2010; Pollastro et al., 2011; Rosenthaler et al., 2014; Navarro et al., 2018, 2020). However, a 2012 study of CBG in human cell culture demonstrated negligible binding affinities for CBG at CB1 and CB2 receptors (Granja et al., 2012). More research is required to better understand the effects of CBG in vivo on cannabinoid receptor function and activity. In addition, CBD and CBG are very comparable at six transient receptor potential cation channels (TRPA1, TRPV1, TRPV2. TRPV3, TRPV4, and TRPM8) with relatively minor differences in affinity (generally less than 5-fold differences) (De Petrocellis et al., 2011, 2012; Pollastro et al., 2011; Muller et al., 2019). Important differences or gaps in our knowledge, however, exist for three key players. First, for GPR55 (the potential nonhomologous CB3 receptor), there is no information on CBG binding (Ryberg et al., 2007). Second, CBG appears to be a very potent (nanomolar to sub-nanomolar affinity) agonist at the α-2 adrenoceptor (Cascio et al., 2010). Physiologically, this is so potentially important that it is the subject of extensive discussion below. At the present time, there are no data on this receptor for CBD and Δ9-THC. Finally, there is a clear differentiation of CBG and CBD at the 5-HT_1A receptor, in which the former is reported to be an antagonist, whereas the latter is an indirect agonist (with an unreported affinity) (Russo et al., 2005; Cascio et al., 2010; Rock et al., 2011, 2012). There are currently no data in this regard for Δ9-THC.

Table 2 provides a more detailed analysis of the physiologic activities that are exhibited by CBG (whether in intact animals, whole cells, or subcellular preparations). CBG appears to act as an agonist at the α-2 receptor (with varying EC₅₀ values reported) and all of the Transient Receptor Potential Cation Channel (TRP) family channels (except 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 activity, and calcium-based signaling by both ion channels and protein kinase C (PKC). Given the differential pharmacological profiles, there are a number of important concerns to consider concerning the therapeutic potentials and potential adverse outcomes for the widespread and unregulated use of CBG.

The α-2 Adrenergic Receptor (the α-2 Adrenoceptor)

The observation that CBG is a potent agonist at the α-2 receptor has significant implications for potential therapeutic uses and adverse side effects (Cascio et al., 2010). Catecholamines (dopamine, norepinephrine, and epinephrine), produced by the nervous system, use a variety of methods to exert different physiologic effects. The main receptor families that mediate these functions are the adrenergic receptors [alpha (α-1 and α-2) and beta (β-1, β-2, and β-3) families] and the dopamine receptors (D1 through D5 receptors) (Molinoff, 1984). Using the norepinephrine system as an exemplar, these receptors almost all act in the following way: vesicles containing norepinephrine are released from the presynaptic neuron, and synaptic norepinephrine activates postsynaptic G protein–coupled receptors (GPCRs) to create a unique downstream effect. Although the catecholamine receptor families are all GPCRs of varying functions, the α-2 receptor class is best known as a presynaptic receptor (Saunders and Limbird, 1999); however, it also functions in peripheral tissues and cells. Extensive study of this autoregulatory receptor has shown its ability to dampen sympathetic nervous system activity through its Gi (inhibitory) activity that is triggered when synaptic norepinephrine binds to the presynaptic receptor. Additionally, α-2 receptor activation demonstrates other mechanisms of reduced sympathetic activity such as opening receptor operated K+ channels and inhibiting voltage-gated calcium channels (Cotecchia et al., 1990; Saunders and Limbird, 1999). The family of α-2 receptors has its own further classification into three receptor subtypes—α-2A, α-2B, and α-2C—the genes for which are found on chromosomes 10, 2, and 4, respectively (Saunders and Limbird, 1999).

Although highly related, the different subtypes of the α-2 receptor are distinct in their sequence, structure, and receptor distribution in the body (Saunders and Limbird, 1999). Structural differences between subtypes arise from the intra- and extracellular regions of the receptor structure, as well as differential post-translational modifications. Anatomic differences are well characterized for the three subtypes in the brain and in the periphery through in situ hybridization of receptor mRNA and through immunochemical analysis of rodent receptor locations (Saunders and Limbird, 1999). In the brain, 2A receptors are widely distributed and abundant in the locus coeruleus and in brainstem regions with homeostatic functions. The α-2B receptors are found in the thalamic nuclei, whereas 2C is found in the basal ganglia, olfactory tubercle, hippocampus, and cerebral cortex (Molinoff, 1984; Arnsten et al., 1988; Saunders and Limbird, 1999). The 2A and 2C receptors are the primary contributors of α-2 receptor function in the central nervous system. Although all three subtypes are found in the nervous system, each subtype has a unique peripheral tissue distribution. In the periphery, 2A is found in platelets, beta cells of the pancreas, adrenal glands, intestinal epithelia, vascular endothelium, and smooth muscle cells (Molinoff, 1984; Saunders and Limbird, 1999); α-2B is found in rat neonatal lung and liver, the adult kidney, vascular endothelium, and smooth muscle cells, whereas 2C is only found in the adult kidney (Molinoff, 1984; Saunders and Limbird, 1999).

Many of the discoveries involving α-2 receptor function were derived from experimental administration of known α-2 agonists, such as clonidine, and measuring local and systemic effects. Current therapeutic interest in peripheral α-2 agonism effects center around their antihypertensive, sedative, and analgesic functions. Clonidine and dexmedetomidine (a newer and more selective α-2 full agonist) are often used in anesthesia settings (Hunter et al., 1997; Gertler et al., 2001). Clonidine was originally popular as an antihypertensive agent but is now considered second-line or third-line in an antihypertensive regimen because of its effects at other nonadrenergic receptors. The vasodilatory and hypotensive effects of clonidine are multifactorial, owing to clonidine’s actions at not only the α-2 receptors but also imidazoline receptors, both of which reduce vascular tone when activated (Ernsberger et al., 1990). Another α-2 agonist, guanfacine, has higher selectivity at the α-2A receptor and less activity at imidazoline receptors. When compared with clonidine administration, guanfacine administration reduces blood pressure less than clonidine (Arnsten et al., 1988). Although α-2 agonists are not indicated in most antihypertensive regimens today because of efficacy of other drugs, clonidine and guanfacine are commonly prescribed for neuropsychiatric diseases because of their effects on α-2 receptors in the prefrontal cortex. The role of α-2 agonists in neuropsychiatric disease depends on their ability to modulate and improve impaired prefrontal cortex (PFC) functioning (Arnsten et al., 1988; Arnsten, 2010). PFC impairment is a common finding during normal aging, as well as conditions like attention-deficit hyperactivity disorder (ADHD), tic disorders, post-traumatic stress disorder, dementia, and others (Arnsten, 2010). The α-2 receptors, specifically 2A, are heavily involved in norepinephrine signaling in the PFC, and α-2 agonists are used to improve working memory and planning ability in ADHD in children and adults, along with tic disorders and reduction of opiate withdrawal symptom severity (Arnsten, 2010). In the treatment of ADHD, α-2 agonists have the additional benefit of being effective alternatives or adjuncts to the first-line treatment: stimulant medications. Use of α-2 agonists in conjunction with stimulant medications can reduce stimulant-induced tics and hypertension, along with reducing the necessary dosing to achieve symptom management for stimulant-sensitive patients (Arnsten et al., 1988; Arnsten, 2010). Clonidine and guanfacine, both α-2 agonists, have gained popularity in treatment of psychiatric disorders and are another example of α-2 subtype specificity determining functionality; guanfacine has less intense hypotensive and sedative side effects than clonidine while boasting increased activity at the PFC (Arnsten, 2010). Researchers believe that this is due to its specificity at α-2A. Interestingly, whereas agonism of α-2A receptors has shown benefits in selected psychiatric disorders, antagonism of α-2C receptors may be beneficial in other psychiatric disorders, such as psychosis and schizophrenia (Uys et al., 2017). This diversity in receptor distribution and potential function indicates a major need for further research into subtype-specific actions and functions of the α-2 adrenergic receptors.

Although α-2 agonists have considerable therapeutic applications, the current knowledge of CBG activity at α-2 receptor subtype and location is lacking. From the potency of CBG at this adrenergic receptor, ingestion may unpredictably change blood pressure, induce sedation, and interact with other cardiovascular medications. Later in this review, we discuss the imperatives for further research into these physiologic effects of CBG administration.

The Serotonin 5-HT_1A Receptor

Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter produced throughout the body for a variety of physiologic and neurologic functions. It plays a central role in maintaining homeostatic functions (e.g., in the enteric gastrointestinal nervous system) (Coates et al., 2017). In the central nervous system, it is a target of antidepression medications. Serotonin binds to different receptor families (Nichols and Nichols, 2008); here, we will focus on the 5-HT_1A receptor, which has previously been shown to interact with endogenous and exogenous cannabinoid ligands. The 5-HT_1A receptor is a Gi/o GPCR that inhibits adenylate cyclase, but the receptor has also been shown to interact with other growth factor pathways (Rojas and Fiedler, 2016). The receptor is located both pre- and postsynaptically, and the downstream functions of receptor activation vary based on neuronal identity and location. Inhibition of 5-HT_1A autoreceptor (presynaptic) activity is suggested to significantly affect the speed and efficacy of other serotonin-modulating drugs, such as selective serotonin reuptake inhibitors (Artigas et al., 1996). A selective 5-HT_1A antagonist, WAY100635, has potentiated the effects of fluoxetine, a selective serotonin reuptake inhibitor, in vivo. Additionally, the β-adrenergic/5-HT_1A antagonist pindolol was found to enhance the effects of several different classes of serotoninergic antidepressants in patients with major depressive disorder (Artigas et al., 1994). One possible mechanism for these effects is that 5-HT_1A antagonists reduce the increase in 5-HT_1A autoreceptor activity created by antidepressants, which increases synaptic serotonin availability.

In the present context, we note that CBG has been reported to be a potent (50 nM) 5-HT_1A antagonist. Given this pharmacological characteristic, it may have unpredictable potentiating effects on concurrently administered psychiatric medications and serotonin-modulating substances. Recently, Echeverry et al. (2020) reported that CBG and CBD have neuroprotective effects against oxidative neurotoxicity through a 5-HT_1A receptor–mediated mechanism. The effects of CBG on serotonin signaling or availability have not yet been thoroughly studied, and more research is needed to understand the impact of CBG-mediated 5-HT_1A antagonism before it is made widely available in an unregulated commercial environment.

The Peroxisome Proliferator–Activated Receptors

The PPAR family is a collection of nuclear receptor transcription factors; there are three isoforms: PPARα, PPARβ, and PPARγ. PPAR nuclear activation induces conformational changes and binding to PPAR response elements of DNA to modulate gene transcription (O’Sullivan and Kendall, 2010; O’Sullivan, 2016). These receptors transcriptionally regulate lipid metabolism, hepatic metabolic functions, and inflammation. PPARs accept a wide variety of ligands because of their large binding domains, and many cannabinoids and their metabolites are reported to interact with the various isoforms (O’Sullivan and Kendall, 2010; O’Sullivan, 2016). In the reviewed studies, CBG exhibits stronger affinity to the PPARγ receptor than Δ9-THC and CBD.

PPARγ will regulate adipocyte differentiation, insulin sensitivity, and inflammatory states. This is the therapeutic mechanism of thiazolidinediones, like rosiglitazone, commonly used in patients with type 2 diabetes to improve adipocyte functioning and increase insulin sensitivity (O’Sullivan and Kendall, 2010; O’Sullivan, 2016). Cannabinoid compounds display varying affinities at PPAR isoforms, and the effects of CBG on these receptors are being studied in the regulation of inflammation and metabolic functioning; these potential therapeutic effects are reviewed in the next section.

Potential Therapeutic Potentials for CBG

Based on the receptor signaling of the α-2, 5-HT_1A, and PPARγ receptors and the reported affinities of CBG at these receptors (in the tens of nanomolars to sub-nanomolar range), there are many reasons to believe that CBG will have therapeutic potential (Cascio et al., 2010; Rock et al., 2011; Granja et al., 2012). Similarly, however, there are reasons to monitor high-dose CBG for untoward side effects beyond drug-drug interactions.

Potential Arguments against CBG as a Therapeutic

We have highlighted the potential of cannabigerol as a therapeutic and in medical research; however, for it to be seriously considered as a potential therapeutic, it must be rigorously tested for safety and unintended effects.

CBG has potent activity at the α-2 receptor, and this unique property could also induce unintended cardiovascular consequences such as hypotension, bradycardia, and xerostomia. Additionally, some investigators have reported hypertension as a counterintuitive adverse effect in high doses of α-2 agonists, which appears to be mediated by the α-2B receptor subtype (Philipp et al., 2002). The potential for this adverse effect is unclear in the case of CBG, since its activity at different α-2 receptor subtypes has yet to be studied. Although we surmise that CBG may have therapeutic potential among neurologic, gastrointestinal, and metabolic disorders, there must be more research to ensure that unintended cardiovascular effects do not reduce the utility of CBG. In addition, in this era of unregulated CBD preparations, companies are making unsubstantiated claims and overselling the benefits and underselling the risks. Indeed, companies are already touting CBG as the “mother of all cannabinoids,” presumably because it is the immediate precursor of CBD and Δ9-THC. What they fail to point out, however, is that only the Cannabis plant goes on to convert CBG to the other molecules—the human body does not. This is problematic because very few Cannabis strains actually harbor large concentrations of CBG, so there is not much prior reporting (and virtually no documentation) of human side effects of CBG.

Several recent cautionary situations come to mind. In a couple of recent reports on CBD oil, it has been reported that not all CBD oil preparations had concentrations of CBD close to what the manufacturer claims (Bonn-Miller et al., 2017; Pavlovic et al., 2018; Raup-Konsavage et al., 2020; Urasaki et al., 2020). Moreover, the U.S. Food and Drug Administration had to prompt recalls for CBD preparations that contained unacceptable concentrations of lead (https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/inhe-manufacturing-llc-and-mhr-brands-issues-voluntary-nationwide-recall-several-products-due?utm_campaign=FDA%20MedWatch%20-%20Several%20Hemp%20Oil%20Products%20from%20InHe%20Manufacturing%20and%20MHR%20Brands%3A%20Recall&utm_medium=email&utm_source=Eloqua; https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/summitt-labs-issues-voluntary-nationwide-recall-kore-organic-watermelon-cbd-oil-due-high-lead). We have reported that, even when the different CBD oil preparations contain the reported levels of this phytocannabinoid, they had very different activities in suppressing cancer cell growth in vitro, and only one approximated the activity of pure CBD (Raup-Konsavage et al., 2020). Finally, there is also the very real risk of inducing drug-drug interactions when over-the-counter preparations like CBD oil or CBG oil are taken by a patient on other (prescription) medications (Kocis and Vrana, 2020). This may lead to unintended adverse consequences when not appropriately monitored.

Future Imperatives

Research into cannabigerol is in its infancy but has shown promise for addressing a diverse array of therapeutic needs. Based on its pharmacodynamics, here we highlight potential indications for CBG and its derivatives to improve available drug treatment regimens for selected diseases and medical conditions. However, these applications will rely on additional research studies to further understand how CBG can be used safely and effectively.

First, there is potential for CBG as a major player in the treatment of metabolic disease as described by its action on the PPAR family of receptors to improve insulin sensitivity and adipogenesis. A supplementary effect is its antihypertensive properties at α-2 receptors. Patients with diabetes frequently have hypertension, hyperlipidemia, and insulin resistance stemming from glucose dysregulation and vascular endothelial dysfunction. CBG may improve this profile as an adjunct to the mainstay of treatment, metformin, or potentially serve as its own regimen. In current practice, α-2 agonists such as clonidine are infrequently used as antihypertensive agents, largely because these effects of clonidine are enhanced with imidazoline receptor activity; this rendered clonidine too powerful as an antihypertensive drug and unreliable in practice. To our knowledge, the sympatholytic effect of CBG is limited to α-2 activity, which makes it more useful for this indication than clonidine, but more studies are needed.

Second, several studies have described the neuroprotective effects of CBG through action on the PPAR family of receptors. Other sources have reported reduction in age-related cognitive decline in patients with neurodegenerative disease with the addition of α-2 agonists to their treatment regimens. Although CBG’s effect on cognition has yet to be studied, it may play a role for improving quality of life in these vulnerable populations, as the few drugs currently available for neurodegenerative diseases also carry uncomfortable and disabling side effects.

Third, similar to other phytocannabinoid derivatives, CBG may play an important role for improving the drug cocktails of patients who struggle with disorders of executive function, such as schizophrenia and ADHD. Two current α-2 agonists, clonidine and guanfacine, are indicated for their α-2–mediated action on the human prefrontal cortex to improve executive function and self-regulation; however, clonidine is less safely prescribed because of its potent antihypertensive properties and generalized action on α-2 receptor subtypes. Guanfacine is well studied as an adjunct therapy with stimulants in ADHD because of its α-2A receptor subtype specificity. The subtype specificity of CBG has yet to be elucidated; therefore, it cannot be predicted how CBG will improve executive dysfunction compared with guanfacine. Finally, researchers have studied the effects of CBG as a safe appetite stimulant in chemotherapy-related appetite suppression in vivo and as an agent that reduces in vitro signs of pathology in colitis and colorectal cancer.

In closing, although there is much to suggest that CBG may provide alternative therapeutics for a number of disorders, much is left to learn. In particular, given the potent bioactivity CBG displays in a number of settings, we should be very cautious about releasing it in an unregulated retail environment. There is simply insufficient experience with this relatively rare phytocannabinoid, and the potential for adverse effects is high. Given the dramatic increase in unregulated CBD oil use following deregulation of hemp, it behooves the pharmacology community to undertake CBG research before its use explodes as well.