Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Laviolette, Steven

Abstract

While cannabidiol (CBD) has been documented to elicit anxiolytic effects, only recently have studies been conducted demonstrating the anxiolytic efficacy of the aromatic monoterpene, linalool. Pa

While cannabidiol (CBD) has been documented to elicit anxiolytic effects, only recently have studies demonstrated the anxiolytic efficacy of the aromatic monoterpene, linalool. Past research involving phytocannabinoid-phytocannabinoid formulations has shown that CBD may yield superior anxiolytic efficacy when administered alongside other cannabis compounds, with this phenomenon termed the “Entourage Effect” (EE); however, this EE has not been investigated in phytocannabinoid-terpene formulations. Furthermore, investigations involving intra-cranial CBD administration have shown the nucleus accumbens shell, known for affective processing, to be a therapeutic target of interest. Thus, using treatment interventions in behavioral and molecular assays, this thesis investigated the possibility of EE-potentiated anxiolysis within linalool-CBD formulations through olfactory and intra-NAcSh routes of concurrent acute administration, focusing on GABAAR and ERK signaling mech

While cannabidiol (CBD) has been documented to elicit anxiolytic effects, only recently have studies demonstrated the anxiolytic efficacy of the aromatic monoterpene, linalool. Past research involving phytocannabinoid-phytocannabinoid formulations has shown that CBD may yield superior anxiolytic efficacy when administered alongside other cannabis compounds, with this phenomenon termed the “Entourage Effect” (EE); however, this EE has not been investigated in phytocannabinoid-terpene formulations. Furthermore, investigations involving intra-cranial CBD administration have shown the nucleus accumbens shell, known for affective processing, to be a therapeutic target of interest. Thus, using treatment interventions in behavioral and molecular assays, this thesis investigated the possibility of EE-potentiated anxiolysis within linalool-CBD formulations through olfactory and intra-NAcSh routes of concurrent acute administration, focusing on GABAAR and ERK signaling mechanisms previously shown to be mediated by linalool and CBD. Altogether, findings ultimately suggest that linalool-CBD formulations elicit EE-potentiated anxiolysis through GABA

ttAR- and ERK-dependent mechanisms capable of reversing chronic stress-induced anxiety.

anisms previously shown to be mediated by linalool and CBD. Altogether, findings ultimately suggest that linalool-CBD formulations elicit EE-potentiated anxiolysis through GABAAR- and ERK-dependent mechanisms capable of reversing chronic stress-induced anxiety.

st research involving phytocannabinoid-phytocannabinoid formulations has shown that CBD may yield superior anxiolytic efficacy when administered alongside other cannabis compounds, with this phenomenon termed the “Entourage Effect” (EE); however, this EE has yet to be investigated in phytocannabinoid-terpene formulations. Furthermore, investigations involving intra-cranial CBD administration have shown the shell region of the nucleus accumbens (NAcSh), located within the mesocorticolimbic pathway and known for affective processing, to be a therapeutic target of interest. Thus, using treatment interventions in behavioral and molecular assays, this thesis investigated the possibility of EE-potentiated anxiolysis between linalool and CBD formulations through olfactory and intra-NAcSh routes of concurrent acute administration. Altogether, the findings ultimately suggest that linalool-CBD formulations elicit EE-potentiated anxiolysis through GABAAR- and ERK-dependent mechanisms capable of reversing chronic stress-induced anxiety.

Summary for Lay Audience

Commonly referred to as cannabis, the plant species Cannabis sativa contains two major substances, cannabidiol and tetrahydrocannabinol (THC), both of which modulate emotional processing. Although these substances are collectively termed “phytocannabinoids”, they yield contrasting psycho-modulatory effects. While THC has been shown to yield psychoactive symptoms, CBD has been demonstrated to reverse these symptoms when co- or post-administered, and also elicit anti-anxiety effects. Interestingly, developments in cannabis research have documented that when administered in conjunction, THC and CBD may yield greater anti-anxiety effects than those achieved alone with CBD plant extracts. This phenomenon of increased anti-anxiety effects following the combination of cannabis compounds has been termed the “Entourage Effect” (EE). Furthermore, studies demonstrated that administrations of these compounds into specific brain structures within a circuit known as the mesolimbocortical (MCL) pathway are especially effective in generating mood-altering effects. Within this MCL pathway, the nucleus accumbens brain structure—in particular its “shell” sub-region (NAcSh)—has shown to be a therapeutic target of interest, given that past studies employing intra-NAcSh administrations of these cannabis compounds reported significant mood-altering results. Importantly however, combinations involving terpenes (aromatic substances) found in cannabis have yet to be explored despite their anxiolytic potential, highlighting an area of interest in the investigation of the Entourage Effect.

Thus, this thesis sought to determine whether an EE existed in combined linalool (anxiolytic terpene) and CBD treatments, using olfactory and intra-NAcSh routes to respectively administer these compounds in rat models. Utilizing behavioral tests followed by molecular analyses of biomarkers of interest, the findings of this thesis demonstrated that there exists EE-potentiated anti-anxiety effects following concurrent administration of odorous linalool and intra-NAcSh CBD. In addition, through incorporation of protein modulators and models of chronic stress, the observed EE was found to successfully reverse chronic stress-induced anxiety and elicit anti-anxiety effects through specific protein modulations. Ultimately, these findings highlight the therapeutic potential of cannabis as a natural alternative to conventional medications used to treat anxiety symptoms and disorders. With safe use profiles, CBD and linalool may serve as an adjunct—or even replacement—for these conventional medications riddled with unwanted and potentially dangerous, side-effects.

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