Cannabis-based products are commonly used by the public to self-manage symptoms of anxiety; however,
people are making decisions about what type of product to use (e.g., CBD, THC), and in what doses, in the
absence of rigorous empirical data. Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has shown
promise – based on animal and single dose findings in humans – as a natural therapeutic for anxiety and
stress-related disorders. These conditions are common, disabling, and for which first-line pharmacological and
psychosocial treatments fail 50% of patients. Although initial evidence suggests that CBD has anxiolytic
properties, the dose-dependent biological and behavioral effects have not been characterized in clinically
anxious samples. No studies, to our knowledge, have compared different CBD doses within the same clinical
sample, nor have putative biological targets (e.g., endocannabinoid function) been measured alongside anxiety
reactivity or symptom measures. This limited knowledge has impeded the translation of single dose findings to
chronic dosing randomized clinical trials in anxiety populations. The proposed two-phase, milestone-driven
project intends to address this gap by advancing knowledge about the mechanisms and therapeutic potential
of CBD for anxiety. We will test the causal role of endocannabinoid-mediated anxiety reactivity in reducing
clinical symptoms and impairment in patients diagnosed with social anxiety disorder (SAD). The R61 phase
project will evaluate the dose-dependent effects of CBD on blood plasma levels of anandamide (an
endogenous cannabinoid that has been shown to regulate stress responses; primary biological signature) and
anxiety reactivity to a social stress task (secondary target) in a sub-acute (4-day) dosing study (i.e., when
steady state CBD levels have been reached). Aim 1 will test the hypothesis that CBD increases anandamide
levels and decreases anxiety reactivity compared to placebo. Aim 2 will determine which dose (300 or 900
mg/d) of CBD produces a greater effect on anandamide and anxiety reactivity. If CBD is found to be superior to
placebo in elevating plasma anandamide levels and reducing anxiety reactivity, the R33 phase project will
attempt to replicate the R61 project findings (Aim 1; sub-acute dosing study) and examine whether changes in
anandamide and anxiety responses are associated with clinical improvement (i.e., reduction in anxiety
symptoms and impairment; Aim 2) following an 8-week double-blind, randomized, placebo-controlled trial of
CBD (dose informed by the R61 project) in subjects diagnosed with SAD. Secondary clinical outcomes will be
change in functional interference, and co-occurring symptoms of depression and general anxiety. Positive
findings will support a larger confirmatory efficacy trial to further evaluate the therapeutic potential of CBD for
anxiety disorders. Regardless of study outcomes, important information will be gained about the role of CBD in
modulating endocannabinoid-mediated anxiety outcomes, which will pave the way for future research on
cannabinoids and anxiety.
