**2. Defining a paradoxical effect**

A paradoxical effect is an effect of a chemical substance, usually a medical drug or horticultural consumable that has the propensity to react opposite to the effect that would normally be expected. To understand why paradoxical effects happen for some and not for most calls for some examples to further understand this enigma. Specifically the paradox in question seems to act in a biphasic manner (having two phases), i.e., normal function to overabundance or a lack there of.

#### **2.1 Benzodiazepine**

A sparse example is benzodiazepine, intended to mildly sedate, wherein rare cases can cause excessive talkativeness, excitement, and increased movement. Benzodiazepine forms a pharmacological effect by actuating the γ-aminobutyric acid (GABA) receptor, this effect causes an elevated chloride channel opening with increased GABA-mediated inhibition giving the perception of sedation, anti-anxiety, and reports of amnesia [1]. In a 2004 study by Mancuso [2], it was reported that a very small percentage of patients experienced a paradoxical or biphasic reaction including acute excitement and hostility.

This could then imply any previous and/or present damage to reuptake pathology of serotonin and sedatives, systemic or invoked, could stop sedatives altogether from working via trauma, prolong depression, and/or abuse or natural tolerance of sedatives. Sedative tolerance may be due to poor uptake and reuptake including the nurtured abuse of dopamine and/or serotonin actuation; an abuse of the drug, exhausting the serotoninergic pool; i.e., a situation where there is not enough tryptophan in a diet to invoke the positive effects of medication.

#### **2.2 Methylphenidate**

A more common example would be the pronounced mediation between stimulating and sedating perceptions of psychostimulants in people who are prescribed Attention Deficit Hyperactivity Disorder (ADHD) medications. ADHD medications such as "methylphenidate" i.e., "Ritalin" are by nature stimulants and inhibit reuptake and stimulant release of dopamine in the Central Nervous System (CNS), thus giving increased temporal and spatial presence of dopamine at postsynaptic receptors [3–6]. The intent of Ritalin is to calm and focus patients in attempt to correct or alleviate cognitive dysfunction, whereas a non-ADHD person will simply experience Ritalin as a stimulant.

Use of the Spontaneously Hypertensive Rat (SHR) is widely accepted in the hypothesis of dysregulation and dopaminergic neurotransmission in line to the behavioral alterations in both ADHD patients and SHR [3]. Past reports have shown an imbalance in the pathophysiology of ADHD and SHR displaying altered functional adenosinergic neurotransmission and affinity of agonists to brain adenosine receptors [7–9]. Thus, adenosine, a neuromodulator in the CNS via cell surface receptors, may display a paradoxical effect at adenosine locations or disrupted locations. Adenosine was more recognized for the ability of caffeine as an A1 and A2 receptor antagonist

[3, 9, 10]. Extensive evidence to date states that ADHD patients have formidable disadvantages with dopamine uptake, storage, and/or metabolism, [11–14]. In addition, that most, if not all, adenosine receptors are a prime target for treatment of diverse disorders in relation with a dysregulation and dopamine neural transmission that occurs in PD, schizophrenia, and ADHD [3, 15].

The paradoxical/biphasic effect displayed in the paragraph above shows a close relation between adenosinergic and dopaminergic transmission in which A1A, A2A are modulated by dopaminergic processes and down/upregulate glutamate. Where the medication is it meant to overwhelm and suppress; instead in a non-ADHD stays open and causes anxiety or stimulant experience.

#### **2.3 Coffee**

A closer look into coffee, a common household stimulant and an adenosine A2A receptor antagonist. Caffeine specifically is responsible for "antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, A2B and, adenosine exerting effects on neurons and glial cells of all brain areas" [16]. In coffee, the natural psychoactive stimulant, caffeine, is well known for causing uplift and energy in the general population. This type of stimulant at first look would deter most in the effort for a calm and relaxed state due to being in an extended hyperactive state **Figure 1**.

However, past study results show that adenosine receptor antagonist, i.e., caffeine, might represent a very important therapeutic role for the treatment of ADHD [18–21] but would not be a substantial replacement for the current medications. This would then imply coffee moreover, caffeine, an A2A adenosine receptor antagonist has the propensity in humans and SHR to act in a biphasic manner much like Methylphenidate, in the efforts of either stimulating or sedating a specific patient indication.

#### **Figure 1.**

*Safer and Krager [6] Model of intrastriatal network during cocaine and A2A-R antagonists' exposure [17].*

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

#### **2.4 Cocaine hydrochloride**

One not so common household stimulant is cocaine hydrochloride. Technically, a cocaine alkaloid collection is also an A2A receptor antagonist. As an A2A antagonist, cocaine is known for its increased alertness, elevated body temperature, euphoria, excessive talkativeness, restlessness, irritability, pupil dilation, and decreased appetite [22].

A closer look in a more recent study will show that D2/A2A in its activation of cholinergic interneurons influences the excitatory synaptic transmission MSNs of direct and indirect pathways via a retrograde release of endocannabinoids, which in turn interacts with striatal glutamatergic (GABA) and dopaminergic transmission (Dopamine) [23, 24]. This implies that A2A antagonists affect retrograde cannabinoid release in the ECS allowing tryptophan use and serotonin release along with dopamine transmission, showing similar receptor affinity and excitatory properties much like methylphenidate and caffeine.

#### **2.5 Cannabis**

Another well-known plant across the globe is cannabis. The use of cannabis is known throughout history and in one study dates medicinal use back to 4000 BC via Carbon-14 dating [25]. More archeological research could be done to discover if cannabis or other mind-expanding drugs (with respective similarity) were implemented at even earlier dates. This could then give even stronger precedents for cannabis as evidence for a viable medication and/or diet additive toward a true non-synthetic homeostasis. Presently cannabis is understood as a medicine to be used in treatment for various indications ranging from cancer to neurodegenerative disorders. Vast studies show cannabis acting on the ECS, which is "comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids" [26].

Notorious and major parts that make up the female inflorescence of cannabis are cannabinoids, terpenoids, flavonoids, bracts (flower), pistils, styles and stigmas, trichomes, fan, and sugar leaves. Of these parts, their biochemistry is psychoactive, i.e., (the ability to pass through the blood-brain barrier and modulate brain chemistry) and non-psychoactive, synergistic and non-synergistic, and do so through the efficacy of specific synergies between bio-available phytochemicals such as cannabinoids and terpenes; thus, creating an entourage effect transmitting throughout the ECS and CNS that almost works in a harmonic and chaotic matrix of possible synapses.

New discoveries are constantly unfolding about this herbal Rubik's Cube as cannabis becomes accepted into society medically or recreationally. The paradoxical effect in question that cannabis is suspected to give has not gone through any pathological nor clinical study to present date, but has been said to have effects much like coffee commonly existing in the cultivar ranges of BLMD-NLM, where caffeine may stimulate or sedate some but still has been solely based out of hearsay and grapevine knowledge or "Stoner Mythology." Given the far-reaching medicinal properties of cannabis, one would be fair to assume that any medication acting on ECS and CNS would have the affinity to act like cannabis with the respective nature of cannabis and its ongoing discoveries. Therefore, receptors are going to respond no differently if cannabis, cocaine, or coffee triggers the receptor. Importantly, what separates cocaine and cannabis is what makes cannabis unique.

A published doctor of osteopathic medicine, Joseph Cohen of Holo Health explains that "what allows cannabis to be separated from most pharmaceuticals, especially

opioids, is due to the natural scarcity of endocannabinoid in the brain stem, avoiding cardiac and respiratory centers entirely. Whereas narcotic analgesics (opioids), or any medicine affecting opioid receptors have a chance to manipulate dopamine and opioid receptors in the brain stem with a fair risk of overdosing." Thus, cannabis only affects a specific area of the body leaving alone parts that are crucial in the sustainability of continuing life and is probably one of the safest means of medication for the human mind and body than any pharmaceutical on the market when paired with a healthy diet and wholesome mindful coexistence or simply a perspective of livity.

Briefly, all the above would imply that many substances in the world can plausibly be medicine and even act in the same mannerisms as others. Undoubtedly more scientific study must be done in order for those things acting like medications, like pharmaceuticals, or possible medicine occurring naturally in the environment to be a safe viable and fundamental means for consumption and the longevity of the consumer. Furthermore, through the thousands of years of evolution engaging with intoxicants, many other herbs aside from cannabis have therapeutic involvement with the human body such as clary sage, mushrooms containing psilocybin, as to say that it may be a natural part of life and evolution for humans having the sentiments that they do.

In the study of cannabis and its pharmacokinetics, it should not be limited to just chemical properties but understood as a paradigm of physical-anthropology, nutrition, neurology, horticulture, taxonomy, chromatography, and herbalism. Unfortunately in 2019, cannabis is still illegal on a federal level and is described as a Schedule 1 drug, i.e., determined by the abuse/addiction rate factor of the drug, which results in a scheduling of five subcategories; Schedule 1 being the most restrictive; 21 U.S.C. §802, prevents any Schedule 1 or 2 to be a medication or used for clinical study. 21 USC § 813 (2011) states any substance pharmacologically substantially similar (a proper example would be Sativex, Nabilone, or any synthetic acting like cannabis in the United States) to a Schedule 1 or Schedule 2 substance will be carried out under the same extent of the law as said above in 21 U.S.C. §8029 (Pub. L. 91–513, title II, §203, as added Pub. L. 99–570, title I, §1202, Oct. 27, 1986, 100 Stat. 3207–13; amended Pub. L. 100–690, title VI, §6470), Nov. 18, 1988, 102 Stat. 4378).
