Investigating the Therapeutic Impact of Cannabinoids on Neuroinflammation and Neurobiological Underpinnings of Suicide Ideation in Veterans With PTSD

This study, referred to here as the 'Neuroimaging Study,' is a supplement (add-on) to our ongoing VMR study (Wayne State Warriors Marijuana Clinical Research Program: Investigating the Impact of Cannabinoids on Veterans' Behavioral Health", PIs: Lundahl and Ledgerwood), which will be referred to as the 'Parent Study'. The Neuroimaging Study will be the first-ever neuroimaging study of cannabis treatment in US armed forces veterans with PTSD, or in any population. The Parent Study involves randomizing 200 veterans with PTSD into one of four different THC (∆9-tetrahydrocannabinol) : CBD (cannabidiol) dose conditions (High THC:High CBD; HighTHC:Low CBD; Low THC:High CBD, and Low THC:Low CBD) for a 12-week treatment phase. For the Neuroimaging Study, half of the 200 participants from the Parent Study (up to N=100; i.e., roughly 25 of the 50 participants in each dose condition) will additionally complete two brain imaging assessments: one before (i.e., 'baseline' scan) and one after the 12-week treatment period (i.e., 'post-treatment' scan). Primary outcomes include: A) neuroinflammatory state as measured via positron emission tomography (PET) imaging with the radiotracer, 1-(2-[+F]fluoroethyl)-L-tryptophan or [18F]FETrp; B) resting or 'basal' neural network communication as measured via functional magnetic resonance imaging (fMRI); and C) brain activation during well-validated inhibitory control (Go/No-Go), emotion regulation (Emotional Stroop), and reward processing (Duke Card Guessing) tasks as measured via fMRI. We will focus on brain regions that are consistently linked to both PTSD symptom severity and suicidal ideation, and that are densely populated with cannabinoid receptors (which are modulated by acute cannabis/cannabinoid administration). Further, the collection of whole-brain, multi-modal neuroimaging data (structural MRI, functional MRI, and PET imaging data) during the same session will allow us to explore the impact of cannabis/cannabinoid administration on the relationship between neuroinflammatory state and neural network activation and interactions throughout the brain, and link these brain metrics to clinical outcomes (e.g., reduction in suicidal ideation or PTSD/depression symptoms over time). This highly innovative approach will provide unprecedented insight into the neurobiological underpinnings of PTSD and suicidal ideation and the potential therapeutic effects of cannabis (and associated brain mechanisms) on these and other critical outcomes (e.g., quality of life, depressive symptoms). Findings from this Neuroimaging Study may also identify veterans who will benefit most from cannabinoid therapeutics and specific THC:CBD dose combinations therein, and thus, may inform a personalized medicine approach for veterans with PTSD in the future.