Cannabigerol (CBG) Research Summary




E.M. Rock, L.A. Parker, in Handbook of Cannabis and Related Pathologies, 2017

CBG Blocks CBD-Induced Antinausea Effects in Animal Models

CBG (5 or 10 mg/kg, i.p.) blocked the CBD- (5 mg/kg, i.p.) and 8-OH-DPAT- (0.01 mg/kg, s.c.) induced suppression of acute nausea (Rock et al., 2011), again suggesting that CBG is acting on the 5-HT1A receptor to block the 5-HT1A mediated effects of CBD and 8-OH-DPAT. Also of interest is the finding that CBG (1 mg/kg, i.p.) actually suppressed acute nausea on its own (Rock et al., 2011). This result is in line with the in vitro concentration specific effects of CBG, such that low concentrations of CBG stimulate GTPγS binding to mouse brain membranes, but this effect disappears at higher concentrations where CBG acts as a 5-HT1A receptor antagonist (Cascio et al., 2010).

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Arno Hazekamp, ... Renee L. Ruhaak, in Comprehensive Natural Products II, 20103.24.4.4 Cannabigerol

CBG is one of the major cannabinoids found in most Cannabis varieties. It has shown relevant antibiotic effects,206 and could decrease intraocular pressure.207 CBG has been called ‘inactive’ when compared to THC, but it has slight affinity for CB1 receptors, approximately equal to that of CBD.90 Like CBD, it has analgesic and anti-inflammatory properties, indicating that there is scope for developing cannabinoid drugs that do not have the psychoactive properties of THC.208 In one study,209 CBG was evaluated for antitumor efficacy against mouse skin melanoma cells and showed a significant in vivo activity using an methylthiazoltetrazolium (MTT)-based cell viability assay.

Of several cannabinoids tested, CBG had the strongest potency to inhibit platelet aggregation.210 However, in recent years no further studies have been reported on the biological activities of CBG.

Potential Medical Uses of Cannabigerol: A Brief OverviewS. Deiana, in Handbook of Cannabis and Related Pathologies, 2017

Conclusions

CBG owns a broad pharmacological profile stimulating interest on this nonpsychotropic phytocannabinoid as a potential polydrug or as a starting molecular structure for chemical engineering aimed at developing more selective/potent drugs.

The expanding knowledge on its multifaceted pharmacology allowed intercepting numerous possible medical uses inspiring several attempts to patent its pharmaceutical use for a number of conditions. Among all, its anti-inflammatory and anticancer properties stimulated tremendous interest pointing CBG as a possible candidate in the development of novel drugs to prevent, control, and treat conditions where pathological inflammatory responses and abnormal cell proliferation represent a threat.

While the recent research finding summarized in this chapter highlighted the vast potentials of CBG, it is clear that extensive work is needed before its clinical benefits can be definitively stated. Decisive is the fact that, currently, there is no material on CBG pharmacokinetics/pharmacodynamics in humans, and clinicians should remain cautious until more definite studies demonstrate the safety and efficacy of CBG. Further pharmacological and preclinical experiments, together with human toxicological and proof of concept studies, should be performed to confirm the number of reports suggesting CBG value in medical practice.


Cannabinoid Regulation of Intraocular Pressure: Human and Animal Studies, Cellular and Molecular Targets

A. Aloway, ... Z.H. Song, in Handbook of Cannabis and Related Pathologies, 2017

Cannabigerol

Cannabigerol (CBG) binds CB1 and CB2, but functions as a competitive antagonist for the CB1. This compound also functions as an agonist for the α2 adrenoceptor (Cascio, Gauson, Stevenson, Ross, & Pertwee, 2010). Green et al. (1982) showed that i.v. administration of CBG to normotensive rabbits or monkeys does not lower IOP. However, in a later study, topical administration of CBG to normotensive cats showed a reduction in IOP by 7 mmHg. This effect was sustained with chronic use, and with minor systemic side effects (Colasanti, Craig, & Allara, 1984b). The CBG-induced reduction of IOP was enhanced when given with Δ9-THC, with little CNS side effects (Colasanti, 1990).

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Cannabis sativa and Hemp

Joshua A. Hartsel, ... Alexandros Makriyannis, in Nutraceuticals, 2016

Cannabigerol (CBG)

CBG is the principal precursor of phytocannabinoids in its acid form. This compound is nonpsychoactive and is a relatively weak partial agonist for both CB1 and CB2. Because of its low cannabinoid receptor potency, it can functionally antagonize the CB1 effects of THC. It has been shown to relieve intraocular pressure, which is potentially useful in the treatment of glaucoma. Additionally, its antioxidant and anti-inflammatory properties make it a potential candidate for inflammatory bowel disease. Recent evidence identifies CBG as a potential candidate for treatment of colon cancer (Ligresti et al., 2006).

An Overview of Major and Minor Phytocannabinoids

Jahan P. Marcu, in Neuropathology of Drug Addictions and Substance Misuse, 2016

Δ9-Tetrahydrocannabinol

THC is the degradation product of nonpsychotropic THCA, which is synthesized from CBGA by THCA synthase. THC is a partial agonist at CB1 and CB2 receptors with a high affinity for both receptors. Stimulation of CB1 receptors by THC can lead to a tetrad of effects in assays with laboratory animals; these effects are documented as suppression of locomotor activity, hypothermia, catalepsy (ring test), and antinociceptive effects in tail flick test (Martin et al., 1991). THC can stimulate CB2 receptors, which may decrease the growth of some cancers and reduce arthritic pain and edema in models of arthritis. Perhaps most surprising is that direct stimulation of CB2 receptors can result in significantly reducing cocaine self-administration in animals (Gardner, 2013). Stimulation of CB2 receptors is not associated with the psychotropic effects of Cannabis use.

THC also has several non-CB receptor mechanisms that have been reported; these include inhibiting the 5-HT3A receptor, enhancing glycine receptor activation by allosteric modification, elevating calcium levels via TRPA1 or TRPV2, reducing elevated intracellular calcium levels from TRPM8 activity, stimulating nuclear receptors, and stimulating G Protein Receptor 18 (Barann et al., 2002; De Petrocellis et al., 2012, 2008; Hejazi et al., 2006; McHugh, Page, Dunn, & Bradshaw, 2012; O’Sullivan, Tarling, Bennett, Kendall, & Randall, 2005).

Oral THC administration can have significant effects on anxiety, depression, and mood. The effects of THC in humans can vary depending on the experience of the subject. The oral administration of pure THC to naïve subjects can induce anxiety but this is not reported with experienced users, and use of the drug is not significantly associated with developing anxiety and depressive disorders later in life (Bahi et al., 2014; Ballard, Bedi, & de Wit, 2012; Campos et al., 2013; Crippa et al., 2009). Oral administration of THC results in its metabolism to 11-hydroxy-THC, which possesses up to10 times greater potency. This metabolism can explain some discrepancies between the observed effects in groups administered oral or inhaled forms of THC.

THC-predominant Cannabis is reported to be a commonly abused or misused substance. Street Cannabis can be contaminated or adulterated and this may underlie the negative health aspects of lifelong use. THC can cause temporary impairments to neuropsychomotor performance. All observable negative effects of THC administration on neurocognitive tasks disappear within 30 days regardless of the amount or length of use (Pope, Gruber, Hudson, Huestis, & Yurgelun-Todd, 2001). The proposed treatment for so-called Cannabis addiction or withdrawal is oral THC (Lichtman & Martin, 2005). CBD may also be considered an antidote for THC, as CBD and compounds in the plant tame or inhibit the psychotropic effects of THC (Russo, 2011). Excellent reviews are available covering numerous clinical trials with oral and inhaled THC for the treatment of over 10 pathologies (Ben Amar, 2006; Hazekamp & Grotenhermen, 2010; Pacher et al., 2006).

THC, the ECS, and the endorphin/opiate system can interact in remarkable ways (Table 1). Animal research has demonstrated a potential prophylactic effect on developing opiate dependence, as adolescent exposure to chronic THC blocks opiate dependence in maternally deprived rats (Morel, Giros, & Daugé, 2009). The ECS is proposed to interact with endorphins, through the release of opioid peptides from CB receptor activation and the synthesis of endocannabinoids induced by opiate receptor stimulation (Abrams, Couey, Shade, Kelly, & Benowitz, 2011; Russo et al., 2008). Clinically, THC may enhance the pain-relieving effects of opiates, lowering the amount of an opiate necessary for relief. Surveys suggest Cannabis is used to decrease the use of other drugs (alcohol, nicotine, and opiates) (Reiman, 2009). In the United States, the state governments that have passed commercial Cannabis/marijuana laws report lower opiate overdose and related death statistics; these populations may reflect what has been observed in surveys and clinical studies of THC and opiates (Bachhuber, Saloner, Cunningham, & Barry, 2014).

Morel et al. (2009)

Adolescent exposure to THC may impart resistance to opiate dependence in maternally deprived animals.

Abrams et al. (2011) and Russo et al. (2008)

CB receptor stimulation can result in endorphin release, and opioid receptor stimulation may increase synthesis of endogenous cannabinoids.

Abrams et al. (2011)

Clinical research demonstrates that THC can enhance the pain-relieving effects of suboptimal doses of opiates.

Bachhuber et al. (2014)

The state of Colorado has experienced a significant decrease in opiate-related deaths since the implementation of medical and commercial Cannabis laws.

The release of opioid peptides by CBs and the release of endocannabinoids by opioids may be one mechanism (Abrams et al., 2011; Russo, 2008). Clinically, THC may enhance the pain-relieving effects of opiates, lowering the amount of an opiate necessary for relief. Drug abuse studies demonstrate that adolescent exposure to chronic THC blocks opiate dependence in maternally deprived rats. There is evidence of the existence of a direct receptor–receptor interaction and cellular pathways, such as via allosteric modification of heterodimers.

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Cannabinoid Pharmacology

Ethan B. Russo, Jahan Marcu, in Advances in Pharmacology, 2017

2.3 Cannabigerol

This compound was purified from cannabis the same year as THC (Gaoni & Mechoulam, 1964), but cannabigerol (CBG) lacks its psychotropic effects (Grunfeld & Gresty, 1998; Grunfeld & Edery, 1969). Normally, CBG appears as a relatively low concentration intermediate in the plant, but recent breeding work has yielded cannabis chemotypes lacking in downstream enzymes that express 100% of their phytocannabinoid content as CBG (de Meijer & Hammond, 2005; de Meijer, Hammond, & Micheler, 2009). CBG, the parent phytocannabinoid compound, has a relatively weak partial agonistic effect at CB1 (Ki 440 nM) and CB2 (Ki 337 nM) (Gauson et al., 2007).

CBG may stimulate a range of receptors important for pain, inflammation, and heat sensitization. This compound can antagonize TRPV8 receptors and stimulates TRPV1, TRPV2, TRPA1, TRPV3, TRPV4, and α2-adrenoceptor activity (Cascio, Gauson, Stevenson, Ross, & Pertwee, 2010; De Petrocellis & Di Marzo, 2010; De Petrocellis et al., 2011). It is a relatively potent TRPM8 antagonist for possible application in prostate cancer and detrusor overactivity and bladder pain (De Petrocellis & Di Marzo, 2010; Mukerji et al., 2006). CBG can also antagonize the stimulation of serotonin 5-HT1A and CB1 receptors with significant efficiency. Older work supports gamma aminobutyric acid (GABA) uptake inhibition greater than THC or CBD that could suggest muscle relaxant properties (Banerjee, Snyder, & Mechoulam, 1975).

Analgesic and antierythemic effects and the ability to block lipooxygenase were said to surpass those of THC (Evans, 1991). CBG demonstrated modest antifungal effects (ElSohly, Turner, Clark, & Eisohly, 1982). CBG has remarkable anticancer properties in basic research models, it has proved to be an effective cytotoxic in high dosage on human epithelioid carcinoma and is one of the more effective phytocannabinoids against breast cancer (Baek et al., 1998; Ligresti et al., 2006). CBG has significant antidepressant effects in the rodent tail suspension model and is a mildly antihypertensive agent (Maor, Gallily, & Mechoulam, 2006; Musty & Deyo, 2006). Additionally, CBG inhibits keratinocyte proliferation suggesting utility in psoriasis (Wilkinson & Williamson, 2007).

CBG is a strong AEA uptake inhibitor and a powerful agent against MRSA (methicillin-resistant Staphylococcus aureus) (Appendino et al., 2008; De Petrocellis et al., 2011). Finally, CBG behaves as a potent α2-adrenoreceptor agonist, supporting analgesic effects previously noted, and moderate 5-HT1A antagonist suggesting antidepressant properties (Cascio et al., 2010; Formukong, Evans, & Evans, 1988).

International Aspects of Cannabis Use and Misuse: the Australian Perspective

D.J. Allsop, W.D. Hall, in Handbook of Cannabis and Related Pathologies, 2017

Abstract

This chapter presents an overview of cannabis use and policy evolution in Australia. It describes cultural aspects of cannabis use in a historical context, beginning with the arrival of US servicemen in Sydney during the Vietnam War, and dissemination into the community. The chapter synthesizes some of the latest research on cannabis in Australia, describing what is currently known about its availability, price, and potency, and the relationship between cannabis and other substances of abuse in the Australian context. A chronological history of the development of Australia’s policy landscape is presented in the constituent states and territories of Australia. The effects of cannabis misuse on Australian communities is briefly discussed, including what is known about treatment seeking for cannabis dependence, the effects of cannabis on educational achievement, and its impact on psychotic symptoms. We end with an overview of Australia’s public information activities about cannabis, including school based educational programs.

https://www.sciencedirect.com/science/article/pii/B9780128007563000120

List of abbreviations

ACT

Australian Capital Territory

AIC

Australian Institute of Criminology

AIDS

Acquired immunodeficiency syndrome

AIHW

Australian Institute of Health and Welfare

ATSI

Aboriginal and Torres Strait Islanders

CBC

Cannabichromene

CBD

Cannabidiol

CBG

Cannabigerol

CBN

Cannabinol

CEN

Cannabis Expiation Notice

CRT

Cannabinoid replacement therapy

GHB

Gamma-hydroxybutyric acid

IDRS

Illicit Drug Reporting System

LSD

Lysergic acid diethylamide

MDMA

3,4-methylenedioxy-N-methylamphetamine

MS

Multiple sclerosis

NCADA

National Campaign against Drug Abuse

NCP

National Cannabis Policy

NCPIC

National Cannabis Prevention and Information Centre

NDARC

National Drug and Alcohol Research Centre

NDC

National Drugs Campaign

NDSH

National Drug Strategy Household Survey

NSW

New South Wales

PWID

People who inject drugs

TGA

Therapeutic Goods Administration

THC

Tetrahydrocannabinol

THC-V

Tetrahydrocannabivarian

UNODC

United Nations Office on Drugs and Crime

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Abstract

This chapter deals with the pathway leading to the biosynthesis of cannabinoids, focusing on the corresponding enzymes and their biochemical properties. The huge diversity of more than 60 cannabinoids is mainly achieved by nonenzymatic modification reactions like decarboxylation, isomerization, and oxidation. Apart from the enzymes responsible for cannabinoid precursor biosynthesis, only three enzymes are known to be involved in the biosynthesis of cannabinoids. The enzymes cannabidiolic acid synthase, cannabichromenic acid synthase, and tetrahydrocannabinolic acid synthase convert the central precursor of cannabinoid biosynthesis, cannabigerolic acid, to the acidic forms of cannabidiol, cannabichromene, and the main pharmacologically active compound tetrahydrocannabinol, respectively.

The present chapter aims to summarize the current knowledge about the enzymes involved in cannabinoid synthesis in Cannabis sativa L. starting from primary metabolism building blocks.


List of abbreviations

AAE

Acyl-activating enzyme

BBE

Berberine bridge enzyme

CBC

Cannabichromene

CBCA

Cannabichromenic acid

CBCAS

Cannabichromenic acid synthase

CBCVA

Cannabichrovarinic acid

CBD

Cannabidiol

CBDA

Cannabidiolic acid

CBDAS

Cannabidiolic acid synthase

CBDV

Cannabidivarin

CBDVA

Cannabidivarinic acid

CBG

Cannabigerol

CBGA

Cannabigerolic acid (3-geranyl olivetolate)

CBGAS

Cannabigerolic acid synthase

CBGVA

Cannabigerovarinic acid

CBN

Cannabinol

CBNRA

Cannabinerolic acid (cis-CBGA)

CHS

Chalcone synthase

CsAAE1

C. sativa hexanoyl-CoA synthetase 1

CsAAE3

C. sativa hexanoyl-CoA synthetase 2

CsHCS1

C. sativa hexanoyl-CoA synthetase 1

CsHCS2

C. sativa hexanoyl-CoA synthetase 2

DA

Divarinic acid

DABB

Dimeric α + β barrel

DMAPP

Dimethylallyl diphosphate

DOXP

1-Deoxy-d-xylulose-5-phosphate

GOT

Geranylpyrophosphate:olivetolate geranyltransferase

GPP

Geranyl diphosphate

HTAL

Hexanoyltriacetic acid lactone

IPP

Isopentenyl diphosphate

MEP

2C-methyl-d-erythritol-4-phosphate

MVA

Mevalonate

NPP

Neryl diphosphate

OA

Olivetolic acid

OAC

Olivetolic acid cyclase

OLS

Olivetol synthase

PKS

Polyketide synthase

SNP

Single nucleotide polymorphism

STS

Stilbene synthase

THC

Tetrahydrocannabinol

THCA

Tetrahydrocannabinolic acid

THCAS

Tetrahydrocannabinolic acid synthase

THCV

Tetrahydrocannabivarin

THCVA

Tetrahydrocannabivarinic acid

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