Exposing the Therapeutic Potential of Cannabigerolic Acid
The Awful state of sleep Deprivation
Sleep deprivation is one of humankind’s biggest challenges, affecting over 60% of adults, 40% of adolescents, and 25-50% of children. Although it is not identified as a disease condition, sleep deprivation is responsible for many diseases ravaging our world. Lack of sleep is a pandemic strictly sponsored by the need to meet tight deadlines and fit into a technology-driven environment while coping with chronic diseases.
Information from the CDC shows that about 70 million Americans suffer from chronic sleep problems triggered by chronic diseases, poor mental health, injuries, increased healthcare cost, lost work productivity and poor quality of life, increased screen time, and deterioration of general well-being.
Sleep plays a vital role in our well-being as humans. It is necessary for proper growth and development. Increased exposure to sleep-related problems like insomnia, obstructive sleep apnea (OSA), restless leg syndrome, and more can create a perfect environment for chronic conditions like obesity, anxiety, and depression to thrive.
When we sleep, our body recharges itself by getting rid of toxic wastes and allow our brain to store new information. During sleep, our nerve cells communicate and reorganize to support our brain functions while our body repairs the cells, restores energy, and releases hormones and proteins that help us grow. Sleep also contributes to bodily and brain homeostasis.
Even with the recent advances in medicine, quality sleep has continued to elude us, thus driving researchers to more natural-based remedies, including cannabinoids like CBGA for sleep. Note that the cannabis plant is home to about 420 different chemicals which assist the endocannabinoid system (ECS) in carrying out its activity.
The ECS is a network of receptors and chemicals (endogenous cannabinoids) that help modulate cognitive activities such as homeostasis, hormonal balance, pain relief, hunger, and sleep.
Relationship between the Endocannabinoid System and Sleep
The ECS is responsible for maintaining the daily sleep-wake cycles. It achieves this by a series of complex cell signaling involving cannabinoids and receptors. The ECS is home to CB1 and CB2 receptors expressed in the brain and peripheral nervous system (CB1 receptors) and immune system (CB2), respectively.
In connection with other neurotransmitters, the ECS receptors can induce sleep and stimulate wakefulness depending on the time of the day and the concentration of cannabinoids supplied. The activity of the ECS on the sleep-wake cycle is generally determined by the presence of light and endocannabinoids like anandamide (AEA) and 2–Arachidonoylglycerol (2-AG). Note that AEA interacts with the CB1 receptors while 2-AG interacts with the CB2 receptors.
Research data show that a high concentration of AEA in the body will support sleepiness, while a low concentration can trigger arousal and wakeful activities. Furthermore, the expression of CB1 receptors is affected by the time of the day. This interaction between the diurnal fluctuation in the AEA and CB1 levels in the brain may be the reason behind the use of CBGA for sleep/insomnia.
Since phytocannabinoids can interact with the ECS receptors, there is a clear indication that they may play an important role in the sleep-wake cycle, thus promoting sleep. Let’s see how CBGA, the mother of cannabinoids, can promote a night of good sleep.
CBGA Removes The Obstacles To Restorative Sleep
CBGA (cannabigerolic acid) is the first phytocannabinoid formed in the cannabis plant. The compound is a non-psychoactive, bioactive component that converts to CBDA, THCA, and CBCA. While CBGA may not play a direct role in good sleep for all individuals, it has unique potential to mitigate the most common causes of disrupted sleep.
- CBGA can trigger relief from anxiety and depression
It is almost impossible for a clouded mind to enjoy a good night’s sleep. Anxiety and depression have been identified as one of the most common causes of preventable deaths. Although the mode of activity is still unknown, CBGA can trigger the release of feel-good hormones and assist users in keeping a clear mind, thus aiding sleep.
- CBGA may play an important role in diabetes treatment
Insomnia and diabetes have evolved to become an inseparable duo. Information from research shows that CBGA can inhibit the activities of aldose reductase, an important enzyme in diabetes. It is also important in combating some disease complications like cardiovascular diseases. Aldose reductase contributes to oxidative stress that leads to heart problems. The ability of CBGA to neutralize their effect also shows a possible antioxidant property.
- Energy booster
More energy of motivation during the day can give you the impulse you need to
expend that extra energy, creating the fertile grounds for restful sleep.
- Pain relief
There are also reports pointing to the possible use of CBGA as an anti-inflammatory agent for pain relief and cancer treatment. The anti-inflammatory properties of CBGA have been reported on colon cancer.
A Review of the available Peer-reviewed literature..
Cannabigerolic acid (CBGA) is the first cannabinoid synthesized in Cannabis sativa L, hence the nickname “the mother of all cannabinoids”. It plays an important role in the biosynthesis of other cannabinoids. Although CBGA comes with ubiquitous therapeutic potential, the research thus far has focused primarily on its conversion to “neutral form” cannabinoids like CBD, CBG, and THC. This review paper aims to demonstrate the possible therapeutic potential of the “acid form” of the mother molecule, CBGA, from the available peer-reviewed literature. Our review focuses on the biosynthesis of CBGA, its bioactivity and therapeutic potential, and which central and peripheral nervous system cannabinoid targets are involved in its therapeutic activity.
Keywords: Cannabigerolic acid, CBGA, CBG, biosynthesis, bioactive CBGA
The cannabis plant is home to over 554 phytochemicals identified as cannabinoids, terpenes, complex sugars, and flavonoids1,2. Out of this vast number of compounds, about 120 have been identified as cannabinoids with several therapeutic benefits 1,3. The cannabinoids share similarities with anandamide and 2-Arachidonyolglycerol (2-AG), the body’s natural bliss switches, thus allowing them to interact with the cannabinoid receptors to modulate cognitive activities.
The interaction between the cannabinoids and the cannabinoid receptors has been the bedrock of cannabis research and its legalization for recreational and medical activity since 19644. At this time approximately 70 countries have legalized the use of cannabis for medical or recreational purposes (or both). This number is expected to increase as more people become aware of the power of the “God plant” to address all forms of oxidative-stress-related diseases of mind and body.
While neutral form-or distillate-phytocannabinoids like CBD, CBC, CBN, CBG, and THC have been the subject of intense research over the past 50 years, their acidic counterparts have remained largely unexamined by most research institutions. Most research papers dealing with cannabinoid acids like Cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabichromenic acid (CBCA), and tetrahydrocannabinolic acid (THCA), have focused on their conversion to neutral cannabinoids with little focus on their therapeutic benefits when the acids are preserved not decarboxylated. However, the latest findings from recent peer-reviewed research demonstrate that cannabinoid acids may possess an excellent level of therapeutic benefits, which may even outshine their neutral forms.5–7
Cannabigerolic acid (CBGA) is a direct product of olivetolic acid and geranyl phosphate. It is a dihydroxybenzoic acid with the hydrogen at position 3 substituted by a geranyl group (see figure 1)6. The relationship between CBGA and olivetolic acid makes it the mother of cannabinoids. As a 22-carbon compound (C22H32O4), it has a ring of carbon atoms attached to long carbon chains and a carboxylic group (hence the name cannabigerolic acid). This review aims to expose the potential benefits of CBGA and how it can lead to a new medicine movement if harnessed by the cannabis industry world-wide so that its full therapeutic potential becomes the order of the day.
Biosynthesis of CBGA
CBGA and CBGVA (cannabigerovarinic acid) are the first cannabinoids to be synthesized in the cannabis plant. While CBGA serves as the mother of all neutral cannabinoids, CBGVA serves as the mother of varin cannabinoids. CBGA is a product of interaction between olivetolic acid and geranyl phosphate, as shown in figure 2.8 The enzymatic reaction involves the alkylation of olivetolic acid in the presence of geranyl pyrophosphate. Olivetolic acid is a polyketide nucleus of all cannabinoids. It serves as the framework that supports the existence of all cannabinoids.
Cannabinoids contain a terpenophenolic skeleton originating from geranyl diphosphate (GPP), a monoterpene, and olivetolic acid. These frameworks are produced by polyketide synthase (PKS) and olivetolic acid cyclase. After producing the frameworks, cannabigerolic acid synthase (CBGAS) then catalyzes the transfer of the phenol group via an electrophilic aromatic substitution that helps to form CBGA. The formed CBGA can further be cyclized by other synthases (THCA synthase, CBDA synthase, and CBCA synthase) to form other acidic cannabinoids.9
Most of the CBGA produced in the plant is sequentially converted into other acidic cannabinoids like THCA, CBDA, and CBCA helped by synthase enzymes (THCA synthase, CBDA synthase, and CBCA synthase). The synthase enzymes catalyze the oxidative cyclization of the monoterpene moiety of CBGA to form other acidic cannabinoids.
Before now, research on CBGA has been highly limited due to the minute quantities of the acidic cannabinoid in the cannabis plant. But recently, plant breeding created specialized strains that lack the enzymes for converting CBGA into other acidic cannabinoids. Note that all cannabinoids exist in their acidic forms and are produced in the trichomes as compounds of the plant’s own immunological self-defense: The mechanism created by the cannabis plant to combat insects, absorb ultraviolet radiation, and promote cell death of the plant’s own leaves to promote growth of the cannabis flower itself.2
CBGA is highly concentrated in young cannabis plants, usually within the rooting and vegetative phases. Although the concentration of CBGA varies based on chemovars and the plant parts involved, researchers discovered that CBGA exhibits the highest concentration in cannabis leaves in the root growing phase while the flowers have the highest CBGA concentration after between 150 to172 days of plant growth.10
Besides harvesting the plants early to obtain a large concentration of CBGA, there are reports on how CBGA can be synthesized from yeast and some bacterial cells, thus promoting their formation and availability for research.11–13
Therapeutic Benefits of CBGA
Although most research has focused on the conversion of CBGA to other cannabinoid acids, the therapeutic potential of CBGA cannot be overemphasized. CBGA is expected to supplant CBD as the medicine of choice for a variety of oxidative stress related disorders by 2030.14,15 Recently, the therapeutic potential of CBGA was put on display by the discovery that the mother molecule possesses a more active anticonvulsant property than CBD.17 Besides performing better at reducing seizures, CBGA was also observed to require lesser dosage and performed excellently at boosting the activities of clobazam, a choice medication for convulsion. Some of the other possible therapeutic benefits of CBGA have been summarized as follows:
CBGA and other cannabinoids acids (except Δ9-THCA) can scavenge free radicals and prevent the oxidation process and reduce metal ions. This is important for restoring internal balance to the calcium ion exchange necessary to convert food into ATP throughout all types of cellular activity and to reduce the spread of cancerous cells.6
Cannabinoids generally exhibit an excellent antioxidant activity, usually higher than α-tocopherol or vitamin C.18 The antioxidant activity is controlled by the phenolic (-OH) groups in the cannabinoids, thus showing why CBGA>CBDA>Δ9-THCA in providing antioxidant activity. This trend is also observed in the activity of neutral cannabinoids with CBG>CBD>THC>CBN. 6 The relatively low antioxidant activity of Δ9-THCA can be attributed to the presence of one OH group, which is engaged in the formation of hydrogen bond with COOH groups.
The carboxyl group plays a critical role in determining the antioxidant property of cannabinoids. Combining the acidic cannabinoids and their neutral forms increases the overall antioxidant activity of the cannabinoids with CBGA: CBG>CBDA: CBD>THCA: THC.
The anti-inflammatory roles of CBGA and other cannabinoids in calming the inflammatory storms of COVID-19 have been explored by Kovalchuk et al. (2021)19. Their research shows how cannabis extracts containing cannabinoids, including CBGA, can decrease the level of pro-inflammatory cytokines in human 3D tissues. The extracts downregulated pathways involved in inflammation and fibrosis in COVID-19 patients. However, the extracts used in the research contained only a negligible concentration of CBGA (0.32% in the extracts and 0.1% in the flowers), with THC and CBD occupying the largest percentage.
Similar research by Ruhaak et al. (2011)20 showed how CBGA exhibited better inhibitory activity than NSAIDS in preventing the activities of prostaglandins. This may be important in proffering solutions to inflammation-induced diseases like rheumatoid arthritis (RA), chronic obstructive pulmonary diseases (COPD), asthma, and multiple sclerosis. In their research, CBGA showed over 30% inhibitory potential thus, suggesting an excellent anti-inflammatory property. Kogan et al.21 also reported how novel CBG derivatives and CBGA analogs could reduce inflammation, pain, and obesity.
The anticancer activities of CBGA have been reported on colorectal cancer22, lymphocytic leukemia23, brain tumor growth, and lung cancer24. CBGA possesses some cytotoxic activity that can induce apoptosis in cancer cell lines and delay the growth of tumors. The success of CBGA in cancer control is further being explored in developing novel cancer drugs for treating colorectal cancer. The proposed drug will contain CBGVA and CBGA, the two mother cannabinoids.25
Melchoulam et al. were the first to discover the antibacterial activity of CBGA against Gram-positive bacteria in 196516. Besides this, the findings of Karas et al.26 observed the moderate activity of CBGA on Multi-Drug Resistant Staphylococcus aureus (MRSA). When compared with CBD, CBGA was 4 times more effective at inhibiting MRSA.27 CBGA may also contribute to inhibiting the growth of Bacillus subtilis.28
Apart from inhibiting the growth of bacteria, CBGA has shown a good anti-parasitic property.
Its antileishmanial activity on Leishmania donovani at a concentration of 12.0 μg/mL is also considered to be effective.29 CBGA showed no cytotoxic effect on African green monkey fibroblast, thus showing its possible safety for human populations.
Some researchers have attributed the antimicrobial activity of CBGA to the inhibition of anthranilate synthase (AS). AS is a target enzyme for the discovery of new antimicrobial compounds, and it is important for tryptophan synthesis. 28
Anticonvulsant and anti-seizure activity
CBGA possesses potent anticonvulsant and anti-seizure properties, which was more effective for seizure relief than CBD.17 It was the most potent phytocannabinoid against hyperthermia-induced seizures in test animals. CBGA also shows some positive interaction with clobazam thus, suggesting a possible new line of medication for Dravet syndrome. The interaction between CBGA and cannabinoid receptors can also come in handy in reducing pain and other symptoms associated with chronic epileptic episodes.
The antidiabetic potentials of CBGA are largely attributed to its inhibitory activities on aldose reductase (AS).30 The cannabis extract used in the research contained non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA. Aldose reductase converts glucose to sorbitol and fructose. Its activity supports the establishment of secondary complications of diabetes such as cataracts, retinopathy, nephropathy, and neuropathy controlled by insulin.
The neuroprotective properties of CBGA and its derivatives have been extensively explored for possible pain relief from arthritis and multiple sclerosis.31 The derivatives interacted with peroxisome proliferator-activated receptor-γ (PPAR-γ) to protect the cells from neuro-inflammation. This may hold a promise in reducing the severity associated with neurodegenerative diseases and may promote adult neurogenesis.
Antidepressant and anxiolytic properties
Although CBG shows little affinity for CB1 and CB2 receptors, the compound and its derivatives were observed to show a promise in serving as an antidepressant, anxiolytic, and analgesic agent. It also produces a neuromodulator function that may be useful in several other diseases. CBGA also provides an excellent entourage effect which may come in handy in promoting the activities of other cannabinoids.32–34
CBGA has been reported to improve the trans corneal penetration of eye care products by over 300%. 13 There is great promise in CBGA for glaucoma patients through improved drug delivery mechanisms.
CBGA metabolism is unique since it does not interact with CB1 and CB2 receptors. The carboxyl group improves its bioavailability, thus making it less susceptible to first-pass metabolism. Although there is limited research on the fate of ingested CBGA, Anderson et al.35 explained the pharmacokinetics of cannabinoid acids via intraperitoneal (I.P) administration. The 2019 research observed the fate of the molecules in adult mice and discovered that it takes 15-45 minutes for users to experience the effects of CBGA. The researchers observed a maximum plasma concentration after 15 minutes of administration while the maximum brain concentration was recorded in 30 minutes. CBGA absorption peaked at 45 minutes
CBGA exhibited a half-life of 120 minutes in the plasma and 62 minutes in the brain cells. The lower half-life in brain cells was attributed to rapid brain interaction between CBGA and brain cells. Overall, CBGA and other cannabinoid acids exhibited low brain penetration in an oil vehicle.
Using full-spectrum products showed a considerably higher half-life for all cannabinoid acids. In full spectrum administration, the half-life increased to 298 minutes, thus supporting entourage effects and greater bioavailability at target sites. 36
Cannabinoid Targets of CBGA
A 2020 study demonstrated how CBGA shows a little affinity for both CB1R and CB2R receptors. This ultimately limits the pharmacological activity of the compound due to CB receptors. 37,38 On this note, it is pertinent to note that CBGA produces its therapeutic benefits by interacting with other cannabinoid receptors. The cannabinoid receptors responsible for the therapeutic benefits of CBGA are discussed below (see figure 4);
G-protein coupled receptor 55:
G-protein Coupled receptors (GPCR) are the largest and most diverse receptors in animals. They function as an inbox for messages in the form of peptides, lipids, fats, and proteins. About one-third of marketed drugs are believed to exhibit their activities by binding to these receptors. 39
GPR55 has been widely reported to play critical roles in the activities of cannabinoids, with CBGA acting as a non-competitive antagonist. 40 CBGA binds to the allosteric sites of the receptors or binds to the receptor sites in an irreversible manner, thus modulating its activities. This reaction is responsible for its anticonvulsant activities.
The activities of GPCR55 are directly involved in pain sensitivity relating to inflammatory and neuropathic pain. It can initiate cellular activity and may also increase the concentration of intracellular calcium in neurons during seizures. There are also reports on how GPCR55 is associated with disease conditions like cancer, diabetes, obesity, and the proper functioning of the gastrointestinal tract, making CBGA a promising remedy for such conditions. 41,42
Transient receptor potential cation channel V1 (TRPV1)
Receptors in the Transient potential channel subfamily V member 1 (TRPV1) are also known as capsaicin receptors or vanilloid receptor 1 (VR1). They are expressed in nociceptive neurons and are responsible for the transmission of pain.43 TRPV1 is responsible for selectively activating the sensory neurons responsible for conveying information about unpleasant stimuli to the central nervous system. CBGA can function as an antagonist of the receptors, thus promoting pain relief. 44
Transient receptor potential ankyrin type 1 (TRP1A)
TRP1A responds to noxious stimuli, inflammatory cytokines, or pungent substances and plays an active role in pain signaling, taste, and inflammation. It is a member of the transient receptor potential family. 43,45 CBGA functions as an agonist of TRP1A receptors, promoting anti-inflammatory properties and analgesic effects.46
Transient receptor potential Melastatin 8 (TRPM8)
TRPM8 receptors are activated by chemical cooling agents like menthol or when temperatures drop below 260C. They detect cold stimuli and are involved in the transmission of sensitive roles in cold evoked pain stimuli. TRPM8 has been reported to play important roles in skin anti-inflammatory properties and was initially thought to be triggered by CBG. Instead, CBGA was found to play an antagonistic role on these receptors. 46 The therapeutic role of TRPM8 and the effect of CBGA have been reported in colorectal cancer.33
Peroxisome proliferator-activated receptor gamma (PPARγ)
PPARγ or PPARG is a member of the supergene family of nuclear receptors responsible for the transcription and regulation of genes like cellular intermediary metabolism and inflammation.47 They are directly involved in regulating fatty acid storage and glucose metabolism, thus indicating a good point for the antidiabetic potentials of CBGA. The activation of PPRG can inhibit the growth of cultured cell lines from the human breast, prostate, and lung cancer. Researchers have discovered that Cannabinoid acids like CBGA, CBDA, and THCA are more efficient at activating the PPARG receptors and may be super active in killing cancerous cells.48
Gamma-aminobutyric acid (GABAA) receptors:
GABA is an amino acid that functions as the primary neurotransmitter for the central nervous system. It reduces neuronal excitability via the inhibition of nerve transmission. The neurons are in the brainstem, hypothalamus, basal ganglia, thalamus, and hippocampus. They also participate in stabilizing neurological functions.49
Low GABA activity has been associated with several neurobehavioral illnesses. It is responsible for generalized anxiety, schizophrenia, autism spectrum disorder, and depressive disorder. They are also associated with seizures and epilepsy, where CBGA is examined to increase the peak currents, thus assisting people with epilepsy and seizures.17
Prospects for Future Research into CBGA and Other Cannabis Acids
Cannabinoids like CBGA, CBG, CBGVA, CBDA, THCA, and CBCA are set to supplant CBD and THC as the new kid on the block in the near future. These rare cannabinoids, especially CBGA, possess an excellent therapeutic profile that will outperform CBD when utilized. Although research in CBGA is limited, there is an increased awareness of the possible therapeutic potential of the molecule after it outperformed CBD in calming seizures.
CBGA also possesses an excellent therapeutic profile that can boost the activity of other cannabinoids while suppressing the psychoactive effects of THC and other psychoactive cannabinoids. It requires a lesser dosage and may possess a higher bioavailability. That CBGA can provide better results than CBD at a lower dosage is a breakthrough in cannabis research. Given its ubiquitous therapeutic properties, much more research regarding CBGA metabolism and interaction with other cannabinoids is needed.
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