Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice

Aymen H. Sadaka, Ana G. Ozuna1, Richard J. Ortiz, Praveen Kulkarni, Clare T. Johnson, Heather B. Bradshaw, Bruce S. Cushing, Ai‑Ling Li, Andrea G. Hohmann and Craig F. Ferris

Journal of Translationnal Medicine, 2021, 19, 220, 1-16.

Doi : 10.1186/s12967-021-02891-6

 

Abstract

Background : The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.

Methods : During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.

Results : CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex.

Conclusion : The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

Keywords : Tonic immobility, Behavioral arrest, Reticular activating system, Olfaction, N-acylphosphatidylethanolamines-specific phospholipase D, PTSD, Negative BOLD

Introduction

CBD has anxiolytic properties, reducing the autonomic and emotional responses to stress and interfering with the consolidation and extinction of fearful memories [1], which has been associated with anxiety disorders [2], autism spectrum disorder [3], psychosis [4] and post-traumatic stress disorder [5]. It’s potential as a therapeutic compound is emphasized by the fact that CBD is the primary active compound in the anti-epileptic drug, Epidiolex [6]. CBD has a complex pharmacology within the brain impacting multiple receptors by altering the lipidome, increasing and/or decreasing lipid mediators in specific brain areas [7], associated with dose, neurological condition and the environment. The primary targets for CBD given systemically are unknown. Non-invasive magnetic resonance imaging (MRI) using changes in BOLD (blood oxygen level dependent) signal has been used to detect the immediate increases and decreases in site-specific brain activity in response to various drugs [8–11]. The changes in BOLD signal are basically a proxy for increases and decreases in cerebral blood flow to areas of increased and decreased metabolic activity, respectively. Several studies in humans have used functional BOLD imaging to look at the neuroanatomy affected by treatment with CBD [12–19]. These studies looking at the effects of CBD have all evaluated a single oral dose given prior to scanning. While this approach establishes a baseline of resting state blood flow that changes with different task-related paradigms or differs from placebo or healthy controls in response to a preexisting condition, they do not address the effects of repeated exposure or the potential for dose-dependent changes in activity, consistent with drug target specificity.

Pharmacological MRI (phMRI) is a non-invasive method to evaluate neural circuitry involved in the behavioral effects of drugs independent of their specific biochemical mechanism [20]. To our knowledge, no published reports, in either animals or humans, have used phMRI to assess the immediate dose-dependent effects of CBD on global brain activity. Therefore, the goal of the present study was to characterize the dose-dependent
changes in brain activity induced by CBD. Given that CBD may have a narrow dose range, impact multiple targets, and show context-dependent efficacy, phMRI is an ideal method to globally assess the integrated effects of CBD across multiple neural circuits to understand how CDB may impact anxiety and fear. We predict that at a certain dose there would be a decrease in relative activity, assessed using BOLD, in neural circuitry controlling stress-related behaviors. To test our prediction, we imaged awake mice using three different doses of CBD.

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