**6. Anxiety and post-traumatic stress disorder (PSTD)**

Anxiety can be described as an inner emotion that can create a state of unease, usually correlated with future events. Biologically, anxiety is a response to a perceived danger or threat (i.e., hypervigilance) in the future using past key memories as validation (i.e., learned trauma) as opposed to an immediate threat (i.e., fear). Anxiety has many disorders that manifest in different forms such as Generalized Anxiety Disorder, Panic Attack Disorder, COPD, and asthma [58–61].

PTSD can be understood as a form of anxiety but its onset from specific traumatic events, which then the patient eventually experiences the constant state of the same symptoms. Like those mentioned above for anxiety with obvious commonalities such as panic attack and generalized anxiety disorder depending on the nature of the trauma and the psychological makeup of the patient. PTSD patients will display higher affinity of CB1 receptors but lower peripheral concentrations of anandamide or N -arachidonoylethanolamine (AEA), the endogenous ligand of CB1 [60–62].

In a study using THC and Cognitive Brain Therapy, it was demonstrated that THC prevented the recovery of learned fear. This was a randomized double-blind placebocontrolled study [63]. With the guidance of a psychiatrist/therapist, tetrahydrocannabinol moreover, cannabis could be used as a viable therapy additive for cognitive brain therapy, PTSD, and other psychological and sociological disadvantages. In an anxiety study using Nabilone, a synthetic THC, patients showed a dramatic improvement when compared with placebo. Side effects reported were dry mouth, dry eyes, and drowsiness. Patients did not report any psychotropic effects of Nabilone since it was synthesized to act like the non-intoxicating cannabinoid of cannabis [64]. Refer to Terpenes and Flavanoids chapter, Pinene section, and Unraveling Cannabis for potential paradox.

### **7. Multiple sclerosis/Parkinson's disease**

MS is a disease where the myelin, a protectant surrounding nerves, is attacked by the immune system. This is a progressive disease and many patients have trouble walking, muscle weakness and spasms, pain, depression, problems focusing or remembering. Parkinson's disease (PD) is a neurodegenerative disease wherein the substantia nigra (i.e., a basal ganglia structure located in the midbrain) begins to deteriorate due to dopamine deficiency. Post synaptic results of this disease involve the extrapyramidal system (i.e., denoting parts of the nervous system dealing with motor function) wherein the central nervous system that mainly affects the motor system begins to cause stiffness, bradykinesia, resting tremor, speech in pediment, and postural instability. Symptoms will not appear until approximately 50% of the nigral dopamine (DA) neurons are lost in the substantia nigra and striatal dopamine deficiency.

Numerous studies have shown that Sativex, an oromucosal spray of cannabisbased medicinal extract (CBME), significantly reduced spasms and pain [65, 66] showing great promise for cannabis as a medication for calming and protecting the auto immune system even in damaged systems.

In a 2016 Survey conducted through the Michael J Fox Foundation and National Multiple Sclerosis Society, both PD and MS volunteers of both cannabis users and non-cannabis users participated. A total 85% reported cannabis effectiveness as moderate or above in relieving their symptoms. In this study MS participants found more relief than PD patients. Additional findings showed that people that suffer from MS reduced the use of prescription medications since beginning cannabis use. Both

MS and PD participants that medicated with cannabis reported lower levels of their disability, mostly in regions of memory, mood, and fatigue [67].

Once again, the paradoxical effect is found in the human and not the medicine, i.e., cannabis, it is important to shine light on the areas in which the ASR or ATD has functions. The disruption from PD (dopamine deficiency) and MS (nerve protectants attacked by the immune system) in the CNS could be considered as focal points to the cascading effects where the paradoxical effect may have a hand in. As to say, it would be a progressive move to avoid extreme dopamine actuation in PD and suppress over responsive immune responses for MS that attack the nervous system through the blood-brain barrier (BBB). Though cannabis shows promising therapeutic responses via CBD < study>, those therapeutic responses depend on resources. This then opens the field to dietary supplementation for the symptom and the medicine. Once again, to shine a light on phytochemical entourages that could lead to a paradoxical effect, which are: Limonene being an antagonist via A2A actuating dopamine via D2 and serotonin agonist via 5HT1A as explained in "The Paradoxical Location." To counter the paradox in a lack there of, memory mood and fight fatigue, a high tryptophan diet, DOPA-L supplimentation, and proper cannabis dosing all play a part in supplementing homeostasis.

Tryptophan and DOPA-L supplementation work in replenishing and regulating serotonin and dopamine as an additive to any ongoing pharmaceutical regiment and both have a higher chance of efficacy with patients prescribed cannabis and in theory could combat the likelihood of a paradoxical effect happening at the Serotoninergic/ HPA axis level and dopaminergic transmission. As dopamine is produced in the body, Tryptophan is a precursor to the neurotransmitter serotonin, a non-polar aromatic amino acid and is something humans cannot biologically make it and must get the essential tryptophan via diet.

### **8. Asperger's syndrome**

Asperger's syndrome is classified as a subtype of the autism spectrum disorder that encompasses a spectrum of psychological conditions that are characterized by abnormalities in social interaction and communication that provide the individuals functioning and by restricted and repetitive interests and behavior as defined by World Health Organization (WHO). In 2015, an estimated 37.2 million people around the world suffer from this entourage of a disorder [68, 69].

The syndrome is lifelong and usually begins around the second year from birth and the effectiveness of interventions is supported by only limited data. Most treatments are geared toward improving communication skills, unhealthy and life hindering OCD or repetitive routines, and physical coordination. The methods that have proven they are worth include cognitive behavioral therapy (CBT), physical therapy, speech therapy, parental training, and medications for the associated problems, i.e., mood and/or anxiety. Medication for Asperger's includes but is not limited to Catapres Lamictal, Guanfacine, Oxcarbazepine, Zoloft, Buspar, CeleXA, Prozac, Lexapro, Klonopin, Strattera, Risperdal, Ritalin, Paxil from a 2019 national survey for psychiatric and seizure medications. Most, if not all, of these medications mentioned treat conditions ranging from anti-seizure, SSRI anti-psychotic, anti-seizure, and stimulants and are riddled with common and frequent side effects such as fatigue/drowsiness, depression, aggression, appetite loss, sleep problems, and general worsening [46, 70, 71].

*Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical Effect… DOI: http://dx.doi.org/10.5772/intechopen.101555*

When biochemically and neuropathically compared to cannabis (i.e., a specific cultivar that has been cultivated for specific cannabinoids, terpenoids, and flavonoids in the efforts for a higher chance at treating specific symptoms) for the purpose of alleviating Asperger's syndrome, the low side effects that can be avoided in cannabis and the vast medicinal properties of cannabis are unmatched and should be considered a dietary additive in some medical regimens. Since cannabis has infinite possible genetic outcomes, cloning and hybridizing and marijuana extraction methods would be the best means to find and maintain a specific cultivar/chemovar for any one person and their symptoms on the spectrum per harvest [70].

### **9. The entourage effect**

The Entourage effect can be explained as a specific group of cannabinoids, terpenes, and flavonoids that have the ability to synergistically create specific effects on the endocannabinoid system. Some of these effects can magnify/desensitize the nervous system, force more CB1 and CB2 receptors on and/or off, reduce unwanted effects while amplifying wanted effects/vice versa. Through reviewing numerous studies, I have come to find that in every sub-specie of cannabis lies a unique terpene bouquet and a general entourage of cannabinoids specific to the cultivar and genetics).

Terpenoids and cannabinoids are present throughout the plant's flowering stage. Terpenes can also have the potential to determine what the most likely outcome of the plant's impact on the ECS and CNS will be. Another way to describe it is a gestalt, the whole plant being larger than the sum of its parts.

Not all terpenes contribute to the entourage affect [72]. As for as the ones that do, and that will be gone over, they do exist in cannabis. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant [73]. In a more recent study, "Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors," it is thoroughly explained that terpenes have modes of operation elsewhere outside of CB one and CB two signaling via 5HTs, A2A, TRP GPR, and many more [74].

The inter-entourage effect suggests that enhanced biological activity may be attributed to secondary metabolites—mainly terpenes—produced by cannabis strains. Terpenes are known for their medicinal properties including anti-inflammatory and anticancer activities [75–77], but here, in the general gist of the interentourage effect, they are considered as promoters and instigators of therapeutic phytocannabinoid activity.

Moreover, mixing co-related terpenes and phytocannabinoids (i.e., THCA. related terpenes with THC or CBDA related terpenes with CBD) at ratios close to the natural plants showed the strongest effect. This could then encourage research studies to look into multiple cultivars for treatment of an indicator.

### **10. The paradox**

Once again to understand the paradoxical effect whether it is the cannabis itself or the person who is being treated, a closer look to what makes marijuana's entourage will display pathology and functionality in the ECS and CNS in the efforts of reaching homeostasis.

#### **10.1 Unraveling cannibis (cannabinoids sub)**

This section will educate the reader on the various bioavailable cannabinoids that reside in the five sub-species of cannabis, excluding Hemp/Sativa/NLH, i.e., industrial hemp. There are over 150 identified cannabinoids in in legal Medical Cannabis from past to recent study.

CBD, CBC, CBG, CBDA, CBD-V, CBN, THC-V, THC-A, THC, CBL, which are the most bioavailable cannabinoids that have beneficial health impacts ranging from antiinflammatory, pain relief, anti-anxiety, neuroprotectant, anti-spasmodic, anti-cancer/ tumor, analgesic that all have a place in the mammalian ECS. Henceforth each cannabinoid will be evaluated for its affinity to a possible biphasic ASR/ATD.

#### **10.2 Cannabidiol**

#### *10.2.1 (CBD)N-PA*

CBD, being one of the main cannabinoids in cannabis, possesses no intoxicating effects and works frequently with the CB-2 receptor, which interacts directly with the immune system via 5-HTA1 and combats inflammatory diseases [65, 73]. Other areas affected are not limited to Gastrointestinal via transient receptor potential (TRP) channels, specifically the TRP cation channel, subfamily V, member (TRPV3) treating IG inflammation. CBD can also act like an antagonist, blocking THC from binding to the CB2 receptor. This affect has the tendency to also reduce the anxiety associated with THC [45, 78]. This binding shows promise by lowering the rate of psychotic episodes of those individuals by using cannabis with higher levels of CBD [79]. A 1:1 ratio of CBD to THC and their respective constitutes would suffice depending on the metabolism of a patient.

Does CBD contribute to the paradoxical effect? Yes and no.

No. It helps alleviate side effects of the indication, therefore canceling out a possible ASR/ATD.

Yes. If serotonin levels are below a healthy level, it would be fair to assume nothing will most likely be felt since CBD is 5Htp-dependent.

Moreover, if THC is more abundant causing more serotonin depletion while tryptophan is already low in the body or below a healthy level, the use of CBD may be futile in the efforts of analgesia but may only have the ability in this state to counteract side effects of THC via CB1 and CB2 binding unless receptors have been exhausted.

Conclusion: More study must be done to understand tryptophan depletion in the body, metabolism of cannabinoids, and the medication needed to help it.

#### **10.3 Cannabichromene**

#### *10.3.1 (CBC)N-PA*

CBC is an abundant non-intoxicating cannabinoid due to a recessive gene [80] that modulates the vanilloid type-1 (TRPV1) and ankyrin type-1 (TRPA1) receptors and TRPV2,3,4 [45, 81]. Briefly, TRP channels and the ECS are involved in inflammation and have a role in pain [81, 82]. Modulation of these receptors can cause elevated endocannabinoid levels, thereby amplifying total cannabinoid availability via turning on more docile CB1 and CB2 receptors with more respectable affinity to the CB2 receptor. Health benefits range from anti-inflammatory and pharmacokinetics of

#### *Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical Effect… DOI: http://dx.doi.org/10.5772/intechopen.101555*

other available cannabinoids [83]. CBC also has the ability to potentiate the analgesic effects of THC [45, 84, 85]. In one study CBC shows promise in positively affecting the viability of mammalian adult neural stem cell progenitor cells, i.e., an essential component of brain function in health and disease [82]. This particular cannabinoid could then be what allows a patient's "high" to then proverbially stack or amplify if given more of the same medication. This then opens the door for a possible addition to the paradox in question being an "agonist" via TRPV1 and possibly, marginally mediating CB1, thus amplifying GABA sensory inhibiting or prohibiting 5-HT.

One study indirectly shows CBCs' synergistic affinity with limonene [86], this could then mean if both are present in the ECS; limonene has a valid chance at having a synergistic paradoxical effect via "CBC modulating TRPV1" [81, 87, 88]. In another synergy with TRPV1, the synergistic manner of (the known receptor affinity to the monoterpene Limonene) adenosine A2A receptor modulating TRPV1 as documented by [89] raises a curiosity to the possible multitude of concurrently dependent inceptions of synergies and the affiliated synergies in between. Henceforth, these two synergies between CBC and TRPV1, and A2A and TRPV1 should definitely be researched to further understand the cannabis entourage and its effects in the human body.

Does CBC contribute to the paradoxical effect? May have amplifying properties when combined with THC and limonene and/or linalool.

#### **10.4 Cannabidiolic acid**

#### *10.4.1 (CBDA)N-PA*

CBDA (Cannabidiolic Acid) transforms into CBD through a process called decarboxylation. Baking, lighting, or heating cannabis removes the acid group from CBDA and transforms it into CBD [90]. Prolonged oxidation via sunlight (infrared/ultraviolet light) can also slowly change CBDA to CBD. The majority of cannabis research has focused on THC or CBD, not CBDA. Though one study shows that CBDA is a Cox-1 and Cox-2 inhibitor; an anti-inflammatory and analgesic, similar to ibuprofen [91]. The study shows CBD and its constituents to be a more effective analgesic than Ibuprofen with nonexistent to minimal side effects. CBDA, in a toxicology study, showed strong dependence on particular sesquiterpenoids, namely guiaolstol, γ-eudesmolstol, trans-α- bergamotenest, γ-elemenest, α-bisabololstol, and α-farnesenest.

Does CBDA contribute to the paradoxical effect? No, unlikely based on the current research, however, nothing is definitive at this time since minimal research is done.

#### **10.5 Cannabinol (CBN)**

CBN can be considered a time stamp and uses the same logic as carbon dating. This process is due to a degradation byproduct of various cannabinoids via oxidation. CBN can also cause drowsy-like effects like an analgesic, but at high doses [90], CBN is the cannabinoid that has been used to treat glaucoma; its anti-inflammatory properties reduce intraocular eye pressure (IOP). A reduction of 16–45% of IOP was initially documented in a 1971 study [92]. CBN is considered the natural decomposition byproduct of the three main phytocannabinoids (i.e., CBDA, THCA, and CBCA), the strongest correlation between two phytocannabinoids is between THC and CBN [53].

Does CBN contribute to the paradoxical effect? No evidence so far for ASR or ATD pathological indicator.

#### **10.6 Tetrahydrocannabinol (**Δ**<sup>9</sup> -THC)PA**

THC is a Phytocannabinoid chiefly from the Cannabis Indica ssp. cultivar that actuates endogenous signaling in the ECS and CNS, predominantly known for its psychotomimetic effects. Receptors affected in the ECS and CNS are the CB1, CB2, GPR55, GPR18 receptors. From these cannabinoid receptors, extracellular signals trigger intracellular cascades. These cascades can represent behavior from cannabis with therapeutic effects. THC is an agonist of the CB1 receptors (Psychotomimetic effect) and CB2 receptors (Possible immunologic, anti-inflammatory effects) [93]. Numerous studies and current education show THC is also an agonist at GPR18 (most efficacious at), GPR55, and TRP ligands TRPA1,TRPV2, TRPV4 and TRPV3 while being an antagonist at TRPM8 and 5HT-3A known for treating long-term depression (LTD). The agonistic effects range from: GRP55 responsible for neuroimmunological regulation; GPR18 has been associated with numerous physiopathological processes, such as cellular migration, immunomodulation, sperm physiology, cardiac physiology, obesity, intraocular pressure, pain, and cancer, among others.

Does THC contribute to the paradoxical effect?

Yes, only via CB1 Signaling, especially when CBD is absent.

No, when a balanced amount/or more of CBD is present, but is a terpene carrier of limonene through the BBB when vaporized, smoked, taken as a tincture or orally ingested.

No. If THC is lower than CBD allowing the agonist ability of CBD to calm the usage with seritonin i.e., 5-HT, while only needing little for itself (CBD) to operate, then THC will most likely operate within a healthy ratio, aside from the metabolic breakdown within the endocannabinoid system. Also if limonene is not present.

#### **10.7 Tetrahydrocannabivarin (THC-V)PA**

THC-V Is an intoxicating cannabinoid mostly found in NLM (narrow leaf marijuana) (stimulating); small traces have been found in BLMD (sedating) strains as well. In a 2013 mouse pilot study, the purpose was to investigate the clinical effect and tolerability of THCV and CBD alone and in combination with patients with Type 2 diabetes [94]. THCV decreased plasma glucose and increased B-cell function (B-cells identify pathogens and produce antibodies). In the conclusion section of the study, it states "based on these data, it can be suggested that THCV may be useful for the treatment of the metabolic syndrome and/or type 2 diabetes, either alone or in combination with existing treatments. Given the reported benefits of another non-THC cannabinoid, CBD in type 1 diabetes, a CBD/THCV combination may be beneficial for different types of diabetes." Later in 2016, a human study was conducted, the same results were reported "compared with placebo, THCV significantly decreased fasting plasma glucose." The study concluded that THCV could be a new therapy for patients with type 2 diabetes [95, 96].

Does THC-V contribute to the paradoxical effect? Yes.

Conclusion: Plausible, if in combination with certain cannabinoids terpenes and depending on the indicator to the ECS.

#### **10.8 Tetrahydrocannabinolic acid (THCA)***N-PA*

THC-A is a highly plentiful non-intoxicating cannabinoid lacking affinity to the CB1 receptor. Lacking affinity to the CB1receptor could imply that vaporization

*Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical Effect… DOI: http://dx.doi.org/10.5772/intechopen.101555*

(heating and/or any processes of combustion) would be a non-effective delivery method for THC-A [44, 45]. Like CBD, THC-A can relieve inflammation being a viable neuroprotectant, therefore providing treatment for various neurological diseases such as MS, ALZ, Parkinson's, and has even shown to slow the expansion/ multiplication/proliferation of cancer cells [87]. Given the cannabinoid life cycle, developing a stable version may be difficult because by its very nature THCA converts to THC easily. "Studies suggest that THCA may be more stable in herbal cannabis, where it is 'hermetically sealed' within glandular trichomes, along with terpenoids which serve as protective antioxidants. The same studies showed that THCA decarboxylated within minutes at temperatures above 80°C. At room temperature in glass bottles with limited exposure to light, THCA dropped to 80% of initial levels after 25 months. At refrigeration (4°C) temperatures, 94.7% of THCA was still present" [44].

The correlation plot in the study shows that while nerolidol has relative affinity to THCA, the other terpenoids described in their paper range from having no affinity to THCA to having minor affinity to CBDA, see also [7, 97]. This may explain the lack of activity observed when those specific terpenoids were added to THC. According to results, THC activity is enhanced only by its co-related terpenoids, while other terpenoids inhibit its biological activity [44, 45, 53].

Does THCA contribute to the paradoxical effect? No.

Conclusion: non-intoxicating and no synergistic entourage to Paradox.

#### **10.9 Cannabivarin**

#### **10.10 (CBD-V)N-PA**

CBDV has the affinity to inhibit the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (diacylglycerol lipase/DAGL) [50% inhibitory concentration (IC50) 16.6 μM] and may decrease activity of its product, the endocannabinoid, 2-AG [81, 98]. An experiment on GABA receptors in the production of use-dependent GABA, a current after prolonged exposure to CBDV has shown great efficacy in the efforts as an anticonvulsant, especially for epilepsy, via GABAergic action. Therefore, a solid DAGL regulator to the endo cannabinoid system [99].

Does CBDV contribute to the paradoxical effect? No. Conclusion: may show great promise to alleviate ATD.

#### *10.10.1 Cannabicyclol (CBL)N-PA*

Most cannabinoids are the chemical breakdown of CBG, whereas CBL starts its oxidizing life cycle from CBC. As observed by Shoyama, much larger amounts of CBLA can be harvested early in the vegetative phase and stored as opposed to harvesting in the reproductive phase. This prompted a quick conclusion that CBLA is a natural breakdown via ultraviolet light of CBCA [100–102]. Clearly more study must be done on this world-renowned medicinal herb to understand its true potential.

#### **10.11 Cannabigerol (CBG) cannabigerolic acid (CBGA) N-PA**

#### *10.11.1 The mother cannabinoid*

CBGA is of the first cannabinoids produced for the cannabis plant and births once geranyl pyrophosphate biosynthesizes with olivetolic acid through a prenyltransferase catalyst conversion, thus creating CBGA. From this momentary precursor begins several different syntheses, i.e., CBG, THC, CBD, and CBC wherein the number of biosynthesized and oxidized (aged) cannabinoids reaches the hundreds and from these will eventually create the cannabinoid side of the entourage effect [103].

Not much study has gone into CBGA but in numerous studies it has been noted as an analgesic and anti-inflammatory. Once CBGA loses its acid group via heat or oxidation, Cannabigerolic acid becomes Cannabigerolic (CBG).

CBG affects cannabinoid, serotoninergic, peroxisome proliferator-activated receptors ((PPARs), i.e., nuclear receptor proteins that act as a transcription factor of the expression of genes regulating cellular differentiation, development, and metabolism, and tumorigenesis; α2-adrenoceptors (norepinephrine (noradrenaline) and epinephrine (adrenaline) signaling); TRP, vanilloid, melastatin, and ankyrin channels. CBG inhibits dopamine norepinephrine, GABA, and serotonin reuptake [103]. Thus, utilizing 5HT as an anti-depressant [104]. So to say, CBG does take part in serotonin release and reuptake especially alongside THC more so in the instance where THC is higher creating a synergistic 5-hydroxytryptamine release/uptake/ reuptake. For CBG, potential medicinal uses can range from analgesia/inflammation, feeding disorders, cancer, glaucoma, inflammatory bowel disease (IBD), psoriasis, Neuroinflammation (MS), bone healing, antibacterial; helping with testosterone balance and mood disorders [103]. In the case of mood disorders and the bidirectional influence at CB1, and an anxiogenic at TRPV1, other synergies along this pathology should be acknowledged.

In light of synergies, specifically terpenoid synergies, "CBGA was related to δ-selinenest, cis-α- bisabolenest, and α-famesenest, moreover, mixing co-related terpenoids and phytocannabinoids (i.e., THCA-related terpenoids with THC or CBDArelated terpenoids with CBD) at ratios close to the natural plants showed the strongest effect. This increased activity may be the result of some preferential pathway in which the given terpenoids enhance the absorbance or activity of phytocannabinoids in the cells" [53]. This proves that specific synergies from/between cannabinoids and terpenes can take place at different stages of biosynthesis and/or oxidation either via UV, heat, human influence, or natural degradation but still hold relative synergistic terpene relation. To further understand decarboxalation synergies, Cannabigerolic acid (CBGA) was related to δ-selinenest, cis-α- bisabolenest, and α-famesenest (subscript abbreviations: mt—monoterpene; st—sesquiterpenes; stol—sesquiterpenes; dt—diterpene), Ergo, guaiol and eudesmol derivatives showed strong positive correlation with CBD [53].

Though dependence on different terpenes and cannabinoids may vary from cultivar, it is only due to the bioavailability and genotype. Thus, more study must be done to fully understand synergistic properties between cannabinoids and terpenes at the various growth stages in cannabis.

In medicating with medical cannabis, specifically MLM sub-species, if multiple cannabinoid synergies are co-related with one terpene, i.e., B- Myrcene, a hypothesis could then be made; if multiple synergies to one terpene might cause a faster metabolization depleting that specific synergy resource for synthesis and if paired with D-Limonene, a known A2A antagonist, would then be the remainder, possibly giving a delayed agitation wherein the goal of this type of homeostasis (MLM) (a 1:1 of stimulating and sedating terpenes) balance/homeostasis would be lost toward the middle or end of the bell curve depending on the metabolization mediation of any one patient. So as to understand, CBG has a synergy with limonene, it is fair to assume between the oxidative life cycle and biosynthesis of CBG that is later counterparts may have synergies much like the

*Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical Effect… DOI: http://dx.doi.org/10.5772/intechopen.101555*

one between CBG and limonene and that more study should go into this volatile mono terpenoid and its many possible synergistic effects throughout the human body. Does CBG contribute to the paradoxical effect? Isolated, No.
