Background: Converging lines of evidence from preclinical studies, treatment studies in animals, and anecdotal reports suggest that cannabidiol (CBD) may have a therapeutic role in chronic pain disorders. Emerging neurobiological evidence suggests that the transition from acute to chronic pain is mediated by a) the biological mechanism of increased brain microglial activation and b) the physiological mechanism of increased central pain-sensitization. However, whether CBD modulates brain microglial activation and central pain-sensitization in humans has not been examined to-date. Intradermal capsaicin-induced secondary hyperalgesia (ICSH) is a validated measure of central pain-sensitization related to activation of specific brain regions. We have demonstrated, in pilot data, that ICSH is sensitive to the effects of cannabinoids (such as THC) in a laboratory paradigm. Low-dose lipopolysaccharide (LPS) has been shown to increase brain microglial activation. The combination of LPS and intradermal capsaicin provides a unique experimental paradigm to examine the relationship between brain microglial activation and central pain-sensitization. Harnessing the high sensitivity and molecular specificity of positron emission tomography (PET) imaging, we have demonstrated in vivo evidence of increased brain microglial activation following LPS, using [11C]PBR28. Additionally, LPS has been shown to result in a 2-fold increase in capsaicin-induced secondary hyperalgesia (ICSH). The combination of LPS with intradermal capsaicin (pLPS-IC) thus provides a validated and reliable model to examine the effects of CBD on a) the biological mechanism of increased brain microglial activation and b) the physiological mechanism of increased central pain-sensitization. Hypothesis #1: CBD pretreatment will result in lower brain microglial activation (specifically in the thalamus) compared to placebo in healthy individuals.
Aim#1 : To examine the effect of CBD pretreatment on brain microglial activation in vivo in humans using a LPS-challenge paradigm and [11C]PBR28 PET imaging. Hypothesis #2: The degree of reduction in brain microglial activation with CBD pretreatment will correlate with the degree of reduction in central pain-sensitization.
Aim#2 : To examine the relationship between microglial activation and central pain-sensitization with CBD pretreatment, measured using [11C]PRB28 and ICSH in a pLPS-IC paradigm.

Public Health Relevance

Cannabidiol (CBD) is a constituent in cannabis that may have a role in the treatment of chronic pain disorders by reducing the activation of specific cells in the brain (called microglia) and reducing a sensation of exaggerated pain (called central pain-sensitization). Being able to visualize activated microglia in the brain of living individuals (i.e., in vivo) has recently become possible with the availability of [11C]PBR28, a radioligand that binds to a protein that is seen on activated microglia. Therefore, the goal of this study is to utilize Positron Emission Tomography (PET) and this radioligand to examine whether treatment with CBD can prevent activation of microglia and whether it can reduce central pain-sensitization using a laboratory paradigm in healthy individuals.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Belfer, Inna
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Yale University
Schools of Medicine
New Haven
United States
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