**7. The paradoxical entourage**

To find, understand, or even combat the paradoxical effect, one must figure out how to counteract the symptoms so the medication or goal for homeostasis works in the way it is intended.

#### **7.1 Misconceptions and experiences: A paradoxical effect from Cannabis**

There is a common misconception about what constitutes *C. indica* and its subspecies variation. Specifically, medicinal cannabis commonly described as "calming, couch-locked, sedating," and/or claiming the original term, "Indica" (i.e., BLM) may actually fall under BLMD where the distant genetics of an NLM is still relevant among the BLM genetics when hybridized. Thus, having a chance at agitation depends on the NLM genetics. A proper example of this miscommunication would be a BLM crossed with "Green Crack," a known Sativa cultivar creating a hybrid of stimulating and sedating effects and then sold as an Indica. To further explain the *C. indica* ssp. Afghanica/BLM is of the genotype sub-specie Afghanica i.e., Indica ssp. Afghanica; the plant structure is of the shortest growing species revealing the broadest leaves accompanied with the most round and dense flower structure containing very petite pistils permeating a terpene bouquet from trichomes of deep sugary warmth, earthy spiced leather, chocolate, tobacco, and mushroom perceptive smells. *Indica* ssp. *Indica* (NLM), i.e., original term "Sativa" a misclassification by Jean Baptiste Lamarck, (1802); permeating more volatile aromas like grapefruit, tangerine, diesel, solvents, lemon, and pine equally showing polar opposite inflorescence.

What may be perceived as a paradoxical effect, is in fact a misconception of what the medicine actually contains past its genetic name and suggested effects from cannabis. Also, a common misconception when dealing with MLM "Hybrids," is the extreme ebb and flow from BLMD and NLMD sub-species variation alone, making up a galaxy of possibilities. Within the infinite genetic possibilities of hybrids, the common misconception validifies a relative vice versa, where an NLMD i.e., "sativa dominant hybrid strain," for instance, "Purple Haze" genetics from Prime Wellness of PA will pleasantly contain predominantly sedating terpenes resulting in a metabolic paradox of a stimulating cultivar and predominantly sedating terpenes. Since cannabinoids are less volatile, terpenes and their chemical makeup break down faster. Thus, resulting in a premature depletion of part of the whole medicine possibly resulting in stimulation or agitation toward the end of the medicated bell curve; to counteract this paradox the simple solution would be to add more bioavailable sedative terpenoids along with proper levels of CBD to combat any excessive psychoactive imbalance such as the 2019 "Freedom blend distillate" produced by ILERA to continue the cultivars intended medicinal entourage.

The vice versa misconception plays out similarly wherein an Indica leaning hybrid (BLMD) claiming the label indica i.e., BLM, may carry enough traces of Sativa genetics possibly causing agitation to hypersensitive patients in efforts of sedation. When dealing with a Ruderalis (AFM) specific plant speciation can be guaranteed and determined in a chromatography test to identify where the phytonutrients land on the spectrum of sedating, null, and stimulating effects. Thus, the infinite possibilities of hybridization and the cannabinoid and terpene profiles that can be created, have

*Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical… DOI: http://dx.doi.org/10.5772/intechopen.101556*

viable means of documentation. So as to understand when medicating with cannabis, separate the whole to understand how to medicate properly for any specific indicator.

To further understand, cannabis speciation (BLM-NLM) controls sedating/stimulating properties; terpenes and cannabinoids, and their synergies, carry out special tasks manipulating the physical and psychological state prolonging or exhausting a patient's balance of homeostasis depending on the accuracy of correct strain name choice to the indicator. Meaning the "engine size" of psychoactivity; the "transportation" of cannabinoids and the ebb, and flow of stimulating and sedating terpenes are what "drive" any entourage to actuate specific tasks throughout the ECS and CNS.

Thus, looking past strain names, subspecies claim, suggested effects, and acknowledging the cannabinoid and terpene profile of any medicinal cannabis would be a safer guarantee of medicating properly.

### **8. The paradoxical location**

Through the research conducted in the ECS and CNS receptors, I have found a specific entourage of cannabinoids and specific terpenes that are the likely cause of a constant fundamental reaction resulting in this easily avoidable paradoxical effect.

In this paradoxical entourage, I believe the terpenoid D-limonene to possess a prime fundamental pathology to modulate D2 respectively via adenosine A2A receptor dealing with motor behavior, emotional reward, and behavior motivation mechanisms as one of its synergistic post reactions; and an agonist at 5HT1A with effects to counteract excitation; to explain further, limonene could be stimulating and consecutively sedating but that if certain biosynthesis pools are depleted or below average to achieve homeostasis then D-limonene will most likely cause excitation, thus a paradox. With synergistic cannabinoids, not limited to, <CBC, THC, THC-V, CBG, CBD>, and possibly other terpenes to help trigger and prolong the biphasic cycle/ paradoxical effect more specifically ATD/ASR or avoid the paradox entirely. This biphasic actuation of D-limonene will have either sedating presents or stimulating presents depending on the entourage it is coupled with and the human physiology it is metabolized by. Patients with PTSD or patients under systemic or triggered anxiety/ depression-like symptoms, ongoing physical trauma, will most likely have an affinity to the paradoxical effect or the buildup to an advanced serotonin release (ASR) and should consult their doctor before consuming any unintentional stimulants [41].

In a study where patients had their tryptophan artificially suppressed, it was reported that the depletion/reduction of tryptophan caused a severe decrease in mood [42]. There are significant ethical considerations as that tryptophan depletion can have a profound negative impact on the patient. " … a recovered depressed patient from the acute tryptophan depletion study by Delgado" reported,"… she began to cry inconsolably and described her emotions as being out of control", continued explanations of feeling "as if all the gains she had made over the past few weeks had evaporated." After the tryptophan levels were restored, the patient reported feeling "back to herself."

A disrupted balance of serotonin is an important risk factor for depressive mood, also a common symptom in the later course of treatment of chronic disorders such as cancer, infections, and autoimmune syndromes [15, 37, 43] with indications like autoimmune disease depression autism, epilepsy, HD, or any indicators residing in the ECS and some parts of the CNS will have a higher risk of this happening.

I refer to this function as an ATD or ASR, which happens when specific synergistic cannabinoids and terpenes already using serotonin, uses reserves consecutively at a

more advanced rate of depletion due to the chemical nature of another synergistic action of the same source of depletion or; whilst a consecutive respectively similar (i.e., dopamine and serotonin) depletion ensues.

It is interesting to note that acute tryptophan depletion techniques (referred to by Simon N. Young, PhD (2013) as ATD studies) were first applied by Concu in 1977 and have been used for over 25 years. This technique requires that the patient have their tryptophan levels artificially and intentionally suppressed in an attempt to document the cause and effect. ATD and ASR mentioned in this chapter, describe the postreactions and neurological processes that are documented through studies discovered and cited in this chapter. The information provided is a compilation of information gathered from clinical studies, scientific papers, and the study of cannabis.

In this paradoxical entourage, I believe D-limonene to be one of the prime terpenoids with the ability to excite and release GABA and dopamine as its post-reaction with synergistic cannabinoids, but not limited to CBC, THC, THC-V, and possibly other terpenes to help trigger and prolong the biphasic cycle/paradoxical effect. More specifically aiding in an ATD/ASR. D-limonene being an A2A antagonist in the presence of THC with excitatory properties would then have a much similar reaction like caffeine, methylphenidate, and certain modes of activation of a cocaine alkaloid collection. This allows an accelerated rate of D2/5-HTA1 and serotonin release via GABA-A, which can then cause patients with PTSD or patients under systemic or triggered anxiety/depression-like symptoms, ongoing physical trauma, an affinity to the paradoxical effect, or the buildup to an ASR. [43] cb1 PTSD). Other more serious symptoms if left untreated can result in tumors, cancer, autoimmune deficiencies, often antagonizing the main purpose for medicating.

In this hypothesis, the entourage in question plays out similarly from a study by J Marcel, et al. 2010 [44], "...On the one hand, both THC and CBD were shown to decrease TNF-α production in human NK cells and peripheral blood mononuclear cells (PBMC), whereas THC was demonstrated to increase TNF-α production in human monocytes [15, 19]. Treatment of human PBMC with low doses of THC or CBD, comparable to plasma levels detectable after smoking marijuana (10–100 ng/ mL), was demonstrated to stimulate interferon (IFN)-γ production, while higher concentrations of these cannabinoids (5–20 μg/mL) efficiently suppressed formation of this cytokine [19]. These contradictory findings are suggested to be based on a biphasic response relative to the cannabinoid ligand concentration applied, since most of reports showing stimulatory capacities were reported at lower doses, in the nanomolar concentration range, whereas inhibitory activities of cannabinoids were found in the micromolar concentration range [22, 25]. These concentration dependent effects of cannabinoids could be demonstrated for Th1- as well as Th2-type cytokines [26]." Marcel continues, "The suppressive effect of THC and CBD on cytokine-induced tryptophan degradation may constitute an additional mechanism by which anti-depressant effects of cannabinoids might be linked to the serotonergic system."

Disturbed balance of serotonin levels is an important risk factor for depressive mood, which is also a common symptom in the later course of chronic disorders such as cancer, infections, and autoimmune syndromes [6, 18, 45, 46]. Many patients with chronic inflammatory diseases show accelerated depressive mood, implicating a role of cytokine-induced IDO enzyme activity in psychiatric diseases [3, 19]. Additionally, several studies showed that mood is negatively influenced by the depletion of tryptophan [39, 47]. Since tryptophan is essential for the biosynthesis of serotonin, the decreased availability of tryptophan during inflammatory conditions

*Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical… DOI: http://dx.doi.org/10.5772/intechopen.101556*

as a result of degradation by IDO may negatively affect the biosynthesis of this neurotransmitter [37].

The charts below are taken from "Endocannabinoids and Motor Disorders" by J. Fenardez-Ruiz, British Journal of Pharmacology (2009) 1561029–1040 se.mcu.dem@ rfjj or se.denrebic@ziur-zednanref.J (**Figures 1** and **2**).

The connection between cannabis and serotonin release is that cannabinoids affect GABA which releases serotonin via CB1 and CB2. To further explain this catch 22 situation with cannabinoids and synergistic terpenes as cleanly said by an article in Proof of Pot Writer [48], "Low dose THC and FAAH inhibitors can have anti-anxiety effects. A 2007 study showed that the anti-anxiety effects of THC depended on the 5-HT1A receptor [49], although a 2015 study [50] demonstrated a dependence on the 5-HT2A receptor."

"Both THC and FAAH inhibitors, which raise levels of anandamide, can improve animal models of depression. The antidepressant effects of these molecules went away when animals were depleted of serotonin (2016 study, 2018 study), indicating that they are working at least partially through increasing serotonin release" [51, 52]. In addition, the antidepressant effect of CBD in animal models depended on activation of the 5-HT1A receptor (2016 study) [48, 51].

#### **Figure 1.**

*Location of CB1 and TRPV1 receptors in specific neuronal subpopulations within basal ganglia circuits. Regulatory pathways are indicated in blue, whereas inhibitory and excitatory inputs are indicated in red and green respectively. Unknown neurons are shown in black. CB1, cannabinoid receptor type 1; GABA,*  γ*-aminobutiric acid; GLU, glutamate; TRPV1, transient receptor potential vanilloid type 1.*

#### **Figure 2.**

*On the scheme shown in Figure 1, a diagram has been superimposed to show the different targets (CB1, CB2 and TRPV1 receptors) that might mediate the ability of cannabinoid-based medicines to alleviate specific symptoms, or to delay/arrest the progression of the disease in basal ganglia disorders. CB1, cannabinoid receptor type 1; DA, dopamine; GABA,* γ*-aminobutiric acid; GLU, glutamate; HD, Huntington's disease; PD, Parkinson's disease; TRPV1, transient receptor potential vanilloid type 1.*

### **9. Fundamental and Hypothetical Solution**

A fundamental fact to keep in mind is many foods like turkey, cheese, eggs, salmon, broccoli, or over the counter 5HT/ 5–hydroxytryptophan pills, mainly things that either contain or biosynthesize tryptophan for consumption is the only way to get it as humans do not produce tryptophan. Tryptophan is converted to 5-hydroxytryptophan by the hydroxyls enzyme (i.e., the rate-limiting step of serotonin synthesis) (l-tryptophan: basic metabolic functions, behavioral research, and therapeutic indications; 2009 Dawn Richard, Michael Dawes PMID20651948). Therefore, without tryptophan, there will be no serotonin production.

In the efforts to understand, supplement, and avoid an ASR or ATD; I would like to give a hypothetical example or scenario that briefly describes the ways tryptophan is utilized in invoked or systemic trauma.

For this hypothetical scenario, your directed goal is to always keep your tryptophan tank full or commonly at a respectable balance. If you take damage via physical, mental trauma and/or develop systemic trauma, this will then create an ongoing tank

#### *Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical… DOI: http://dx.doi.org/10.5772/intechopen.101556*

depletion. Thus, more damage will equal more tryptophan depletion, plus tryptophan dependency (due to prolonged systemic or invoked damage) in efforts to reach a targeted 100% homeostasis or maintain minimal levels. Cannabis with high amounts of D-limonene, in this scenario, would be the medication that gives you one step forward and two steps back given no tryptophan has been consumed and depending on how well your character utilizes tryptophan. In this reaction to stimuli via A2A, the body may react out of survival, fear, or a mindful manner response [22].

The longer the tank is empty or struggling to maintain a minimal equilibrium or homeostasis during excitation, the faster the body and mind will suffer due to the absence of tryptophan. Due to this absence of serotonin production, the mind will go through a depressive prolonged shutdown, almost forced into a default mode. The inevitable side effects open doors such as susceptibility to autoimmune deficiencies, cancer, more depression, and eventually your life would be over before your actual intended life expectancy.

Possibly supporting the case of some medical marijuana patients/MCP's peeking, wherein the normal amounts consumed no longer have the intended medicinal effect and may be due to an ATD/ASR without recovery or healthy diet to supplement cannabis amount into the diet.

The combined knowledge indicates that the paradoxical effect does not exist in cannabis but in an individual, and how they metabolize a certain entourage with any disruption to the CNS and ECS that has the potential to exist across the BLM-NLM spectrum of cannabis. The entourage in question has an affinity to use up tryptophan/release serotonin in the efforts to achieve homeostasis via GABA-A modulation through multiple networks in a biphasic/paradoxical manner. More so in those that constantly suffer from hyperkinesia, prone to anxiety and depression, ADD/ADHD, and or in constant extreme pain or from neurological indicators that depend on the presence of tryptophan and the release of serotonin and other dopaminergic reactions.

### **10. An entourage for everyone**

In most cases, the dependability on strain availability and ebb and flow of cannabis morphology throughout each year will be tough to maintain for any cannabis industry grower or dispensary to keep consistency stocked or any cannabis patient to even have. Everyone has their own entourage that creates homeostasis in one's body whether it mediates heavily from one to another or hardly at all. A unique solution would be to compare and contrast multiple cultivars' bioavailability, synergies. In end creating a whole new cascade of newly perceived entourages that have a higher chance at meeting homeostasis directed goals for a patient and their ECS directed by their psychiatrist, cannabis physician, or therapist regardless of genetic availability.

I have created The **Multi Cultivar Entourage Effect Chart** (MCE2 C) that unravels multiple cultivars' bioavailability to then combine and create a more robust and stronger entourage being pulled from multiple cultivars with specific bioavailability of cannabinoids, terpenoids, and flavonoids necessary to treat any specific indication.

### **11. Multi-cultivar entourage effect chart**

This chart is able to track a patient's intended intake of cannabinoids and terpenes; displaying what total entourage effect the patient is actually administering when

using multiple cultivars to treat a whole indicator/or many; track over long periods of time showing conscious, subconscious, and habitual tendencies, and may even aid in the help of showing if a certain terpene or cannabinoid synergy is a causation to an adverse effect/ susceptibility through post and present perceptions with DATA to track primary, ancillary, and supplementary levels of an encourage (**Figure 3**).


Here in (**Figure 4**) every cultivar is broken down into the accompanying cannabinoids to be mixed and matched among other cultivars and their accompanying cannabinoids.

In (**Figure 5**) all terpenoids are separated to then be compared and contrasted to either amplify or avoid a specific terpene encourage.

In a MCE2C schedule, a patient can visually see the expected entourage from multiple cultivars, patients can add or remove as many strains to achieve a desired balance/homeostasis.

This schedule lasted until certain strains were no longer readily available (i.e. PHZ & AFG) but was later documented after the original multi cultivar entourage was concluded. that patient one replaced PHZ with RF and FB replaced AFG.


**Figure 3.** *Genetic cultivar key Ryan McKinley 2020.* *Marijuana, a Journey through the Endocannabinoid System: Unmasking the Paradoxical… DOI: http://dx.doi.org/10.5772/intechopen.101556*


#### **Figure 4.**

*Unraveled cannabinoids from six different chemovars to be mixed and matched for a new entourage or combined synergistic experience (Ryan McKinley 2020).*


#### **Figure 5.**

*Unraveled terpenoids from six different chemovars to be mixed and matched (Ryan McKinley, 2020).*

### **12. Conclusion and future research**

In bringing this infinitely hybridized herbal Rubik's cube full "Square," the cascade of entourages displayed from cannabis and the cannabinoids, terpenes, and flavonoids therein have potential and viable medicinal purposes. The research studies used in this chapter cover centuries of cannabis usage since 4000 BC through modern pharmaceutical research and its history in North and South American society circa 2019.

This research identified people under systemic, invoked, or prolonged mental or physical trauma will be susceptible to agitation from certain cannabis inter-entourages consisting of stimulating terpenes (specifically D-limonene and its co-related cannabinoid synergies) more so than healthy individuals, thusly experiencing a paradoxical effect.

Individuals who have a propensity to experience stimulants in a biphasic manner have formidable disadvantages with dopamine uptake, storage, and/or metabolism. Limonene affects A2A allowing a catch 22 of symptoms ranging from a general excitability/alertness via D-limonene. D-Limonene is also an anti-depressant via CBD from 5-HT1A (serotonin, for reduction in neuronal excitability and firing), unless serotonin levels are low or depleted then perceptions may shift to the more agitative especially with an A2A agitator present in the entourage.

ATD or ASR, happens when specific synergistic cannabinoids and terpenes already using serotonin and use reserves consecutively, at a more advanced rate of depletion due to the chemical nature of another synergistic action of the same source of depletion or; whilst a consecutive respectively similar (i.e., dopamine and serotonin) depletion ensues. It is fundamentally understood, that without tryptophan, most, if not all serotonin production would cease in the human body. Henceforth, studies state respectable levels of serotonin in the body inhibit dopamine production, calming down impulsive behavior and side effects of dopamine abuse either natural (i.e., habit) or foreign (i.e., drug).

The 5-HT2A dependent cannabinoid THC uniquely being a synergistic vehicle for a few terpenes and a prime dictator of the psychoactive engine size guarantees the highly lipophilic D-limonene transportation through the blood–brain barrier. These two powerhouses in their own synergistic pathological right actuate dopamine and use of the serotonergic pool. Therefore paramount to uphold a strict healthy diet to supplement basic natural dopamine use and tryptophan depletion that may happen in patients with said indications is pertinent while medicating with cannabis to ensure true beneficial homeostasis from any entourage.
