Cannabis has been used for thousands of years because of its many properties but only recently cannabinoids and their derivatives have starting gaining the importance that they deserve within research. Mechanisms of action were an unsolved mystery until tetrahydrocannabinol (THC) and the first cannabinoid receptor, CB1 were discovered, followed by the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG).1–3 AEA, 2-AG and the CB receptors have been regrouped and classified by physiologists as the endocannabinoid system (ECS).1–3 The ECS is a complex network of neurotransmitters and receptors that work together in signaling and transmitting information throughout the body, modulating essential neurovegetative functions and helping the maintenance of body homeostasis.4 AEA is most often the tonic signaling agent of the ECS and regulator of synaptic transmission, while 2-AG acts as a phasic signal activator in neuronal depolarization and mediator of synaptic plasticity.5 Phytocannabinoids on the other hand, are terpenophenolic compounds naturally occurring in Cannabis plants. Among them, we find not only the psychoactive tetrahydrocannabinol (THC), but also non-psychoactive molecules like cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) cannabichromene (CBC) and many others.6 CBG type of molecules are the natural precursors of cannabinoids, and they have been demonstrated in several independent studies to have many different therapeutic properties and thus to be a promising tool for the development of novel therapies for the treatment of a wide range of ailments.7,8 We aim with this div to inform the scientific community about the last developments of research on CBG properties and therapeutic effects.
CBG isolation has been reported for the first time in 1964, when Y. Gaony et al. reported the structure and the partial synthesis of many cannabinoids, among them CBG.9 However, since CBG is present in most of the Cannabis types only in relatively small amount, researchers concentrated their efforts in the more abundant cannabinoids THC and CBD.10–16 Beside the cannabinoids occurring in nature, in the last decades many synthetic cannabinoid-inspired compounds have been synthetized as lead drugs for the pharmaceutical market.17,18 Some of these chemically modified cannabinoids do not have the psychotropic effects attributed to THC but at the same time, retain some of the already known cannabinoids therapeutic properties. 17,18 However, synthetic drugs have often the downsides of containing solvent residues and by being novel compounds, to carry with them severe and sometimes life-threatening adverse effects.19,20 Cannabinoids, on the other hand, have been used for their recreational and therapeutic effects for a very long time and no life-threatening side effects have ever been reported.21
Phytocannabinoids like CBD, CBN and CBG retain most of the therapeutic effects of THC, while not being psychotropic. These cannabinoids have been showing to be effective on an increasing amount of diseases and conditions, but their use is unexplainably still limited and unavailable to the mass. Moreover, while many scientific and clinical studies are available for CBD, CBG still remain a fringe compound and its therapeutic properties are still under investigation.
As mentioned before, CBG isolation has been reported for the first time in 1964, when Y. Gaoni et al. reported the structure and the partial synthesis of many cannabinoids, among them CBG.9 CBG is a terpenophenolic compound and, like other cannabinoids, can be opportunely divided in three different parts, which not only carry different chemical and pharmaceutical properties, but also influence the bioavailability of the molecule in different ways. The hydrophilic part is represented by the phenolic ring, which is also believed to carry the antibacterial and antimicrobial properties of cannabinoids.22 The ring is then linked to two lipophilic chains on the very opposite ends. One is the n-alkyl chain, while the second one is represented by a terpenoic function, which bears therapeutic action by its own right and seems to be related to many of the medicinal properties of CBG.7 By bearing two lipophilic moieties, CBG, like other cannabinoids, is very poorly water-soluble and at the same time very well absorbed by cell membranes and tissues.
As mentioned above, CBG is the natural precursor of THC, CBD and CBN. Its phenolic moiety is probably formed via polyketide pathway whereby a triketoacid may be suggested as intermediate. Its cyclization leads to olivetoic acid, which is then C-alkylate by geranyl diphosphate by means of CBGa synthase.23 The carboxylic acid form of this phytocannabinoid, cannabigerolic acid (CBGa), is very important for the synthesis of other phytocannabinoids, and that is the chemical form in which the phytocannabinoid is present in fresh cannabis plant material.8 The correspondent cannabinoids are then obtained by decarboxylation via heat (Figure 1).24 The conversion of CBG acid into THC-, CBD-, and CBN acid is also catalyzed by specific enzymes, which are respectively called THC-, CBD- and CBN acid synthase.
Despite the relatively few investigational studies conducted on CBG, there is evidence of pharmacological actions at a number of targets. CBG has shown to have relatively weak partial agonistic effect at CB1 (Ki 440 nM) and CB2 (Ki 337 nM), which explain the non-psychotropic properties of the molecule.25 It does however affect endocannabinoid tone indirectly by inhibiting AEA uptake, thereby increasing levels of AEA.8 Older works support CBG as a gamma aminobutyric acid (GABA) uptake inhibitor, in a range of affinity comparable or superior than THC or CBD, which could explain the anti-anxiety and muscle relaxant properties.26 Evans and coworkers in 1991 showed also that CBG presents analgesic and antierythemic effects, by blocking lipooxygenase activity and therefore reducing inflammation in a range of potency that was found to be higher than common analgesics7,27 CBG has also shown to act as antidepressant in rodent models and as a mild anti-hypertensive agent.7,28 Most of the mentioned effects are mediated by its potent activity as ?-2 adrenoreceptor agonist and by its moderate antagonizing binding properties towards 5-HT1A.29,30 Additionally, CBG inhibits keratinocyte proliferation suggesting utility in psoriasis,31 and by being a relatively potent TRPM8 antagonist, it has been suggested for possible applications in prostate cancer and bladder pain.32,33 Moreover, CBG recently proved to be an effective cytotoxic molecule in human epithelioid carcinoma,34 and the next most effective phytocannabinoid against breast cancer after CBD.35 Finally, CBG demonstrated beside its well know powerful antibacterial and antimicrobial properties (including methicillin-resistant Staphylococcus aureus, MRSA), to have modest antifungal effects.22,36,37
In addition, numerous studies have been also suggested possible synergetic effects in association with terpenoids. Terpenoids are quite potent, and affect animal and even human behavior when inhaled from ambient air at serum levels in the single digits ng·mL-1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis based medicinal extracts.7 Limonene for example has shown to synergize with CBG and CBD by promoting apoptosis in breast cancer cells,38 while Myrcene, a terpenoid present in hops, synergizes with CBG and CBD by blocking hepatic carcinogenesis aflatoxin induced.39 Also linalool, a terpenoid present in lavender, seems to synergize with CBD and CBG in the treatment of anxiety.40 Moreover, CBC and CBG have been showing synergic properties in association with the terpenoid caryophyllene oxide, a natural compound present in lemon balm, as antifungal, with a potency comparable to commercial antifungal drugs like sulconazole and ciclopiroxolamine.41 Finally, also CBGa has shown synergetic properties in association with the lemon balm terpenoids as insecticidal and anti-feedant, representing a promising alternative for protecting crops and vegetable from insects and parasites.7
CBG has shown promising results in the many treatments. However, since CBG appears as a relatively low concentration intermediate in the plant, therapeutic administration of CBG oil could be limited by the low amount of compound obtained from plant extraction. Fortunately, recent breeding work has yielded cannabis chemotypes lacking in downstream enzymes that express 100% of their phytocannabinoid content as CBG.42 After 9 years of hard work and breeding programs at endoca we have created CBG oil and pure 99% CBG isolate. Albeit additional studies are needed in order to confirm and enlarge the wide variety of therapeutic applications of CBG oil.