**6. D-limonene (the energetic uplifting agitator)**

The volatile monoterpene, limonene, one of the most abundant terpenes in cannabis, and its perceived effects can be summed up as uplifting (as to correct a depressed mood) and energetic (as to cure slothfulness); having antioxidant, antiinflammatory, and neuroprotective properties [37]. These hyperactive characteristics of D-limonene indicate it to be a prime candidate for A2a receptor affinity, and thus, "It plays an important role in many biological functions, such as cardiac rhythm and

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

circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders" [38].

In an *in vitro* dose-dependent study of D- and L-limonene, effects on the pregnant rat myometrium (mid-layer of the uterine wall and the smooth muscle tissue), D- and L-limonene caused myometrial contractility (i.e., increases the contractions of a pregnant uterus); interestingly, L-limonene caused myometrial smooth muscle contraction independent of A2A receptors. Due to the subsequent findings of D- and L-limonene causing myometrial contractility via activation of the A2A receptor and opening of the voltage-gated Ca2+ channel, D- and L-limonene should be avoided during any pregnancy [39].

To indulge in the topic of the A2A receptor and its synergistic affinity with limonene, the above-mentioned study was focused on "in vitro" muscle contractility, thus would be fair to assume that any humans suffering from constant or frequent agitation from symptoms/indicators like MS, PMDD, PD, spectrum disorders, or neurodegenerative diseases may also want to avoid this terpene. In cases where this is difficult to avoid, it would then be crucial to understand how a person metabolizes both sedatives and stimulants. Curiosity in this area may open more doors into the point of agitation i.e., invoked and/or systemic and could then be regulated with the correct level of sedating to stimulating terpenes and aim for a genetic strain with a similar entourage. In the effort to stimulate without agitation, cannabis entourages with sedative terpenes could be added into the stimulating entourage via cultivation/ hybridizing and/or multi-cultivar entourage dosing.

A good rule of thumb about the terpene limonene is to understand the biphasic modes in which this part of the entourage manipulates; a handful of studies dissect the physiology of citrus fruit-bearing plants and all come to a consensus that limonene affects serotonin via 5HT1A and dopamine via D2, thus giving the cascade of both stimulating and suppressant like effects.

However, the patient should be made aware of any synergies that may use 5HT or suppress and should supplement the 5HT usage via diet to avoid accelerated tryptophan depletion (ATD).

Additionally, humans suffering from indications such as PTSD, spectrum disorders, and general anxiety should also be wary of this terpene due to its excitatory tendencies via the A2A receptor having excitatory biphasic responses. The goal for the vast genetic variety of "balanced" cannabis cultivars, i.e., hybrids (BLMD, MLM, NLMD), has been utilized from BLM's(medicinal cannabis Indica sub-species Afghanica) genetics and crossed with NLM (*Cannabis indica* sub-species Indica) or any other sub-species to then aim to produce (in this case) a vast range of sedative leaning MLM's (marijuana hybrids) i.e., BLMD. Henceforth, giving agricultural/horticultural cannabis growers the ability to hybridize and clone for a more viable chance at an endless possibility of medicinal cannabis strains. This being said, a BLMD with deviating genetics from the true "Indica," i.e., the Afghanica sub-species, has the chance to contain the volatile monoterpene limonene. In spite of the excitatory ability of limonene, this could then be a perfect supplement or addition to pharmaceutical ADHD medication.

Furthermore, "All the terpenoids discussed herein are Generally Recognized as Safe, as attested by the US Food and Drug Administration as food additives or by the Food and Extract Manufacturers Association and other world regulatory bodies." [40].

**Does limonene contribute to the paradoxical effect?** Highly plausible, but clinical study must still be done to truly understand the all working mechanisms of its cascade effects within the entourage effect.

Plausible location (A2A, D2 dopaminergic receptors), (5HT1A, serotonergic receptors).
