Cannabinoid Control of Fear Extinction Neural Circuits in Humans
Condition: Healthy Participants
Study type: Interventional
Phase: Phase 4

Summary: 
      The goal of the current proposal is to investigate the effects of a cannabinoid drug on the
      memory of extinguished fear in humans and the brain circuitry important for the recall of
      extinction learning. The investigators findings will translate previous discoveries from
      animal studies to humans and increase their understanding of the neurobiological mechanisms
      supporting retention of extinction memory. This proof-of-concept study is a critical
      translational first step towards the development of cannabinoid modulators as an adjunctive
      strategy to exposure-based therapies to augment extinction learning and prevent the return of
      fear memories in patients with post-traumatic stress and other anxiety disorders.
    

Detailed description: 
      The inability to suppress inappropriate fear responses is the hallmark of anxiety disorders,
      such as posttraumatic stress disorder (PTSD), panic, and phobia disorders. Extinction of fear
      occurs during exposure therapy; however, this is temporary and fear often re-emerges with the
      passage of time (spontaneous recovery), undermining the maintenance of therapeutic gains.
      Enhancing the neural and neurochemical substrates involved in retention of extinction memory
      will be critical to solving this challenge. Animal studies have shown that activation of the
      cannabinoid system within the amgydala, hippocampus, and ventromedial prefrontal cortex
      (AMYG, HPC, vmPFC, respectively), brain structures critical to fear expression and extinction
      learning, enhances fear extinction and its retention. Specifically, CB1 receptor agonists,
      such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing
      recovery of extinguished fear in rats. However, this phenomenon has not been, but should be,
      investigated in humans. This proof-of-concept project specifically aims to assess the effects
      of THC on the recall of extinction learning and underlying neural circuit activation (HPC,
      vmPFC) when tested 24 hours and 1 week after extinction training, and to determine if the
      maintenance of extinction retention (1 week later) is mediated by the enhancement of
      vmPFC-HPC activation by THC observed during a recall test 24 hours after extinction learning.
      In a randomized, double-blind, placebo-controlled, between-subjects design, the investigators
      will couple a standard Pavlovian fear extinction paradigm in fMRI and simultaneous skin
      conductance recordings with an acute pharmacological challenge with oral, synthetic THC prior
      to extinction learning in healthy adult volunteers (n=80) and test extinction retention and
      maintenance of extinction learning at 24 hours and 1 week later, as well as fear renewal.
      This proof-of-concept study provides the most translational, impactful, informative, and
      critical test and first step towards the development of cannabinoid modulators as an
      adjunctive strategy to exposure-based therapies to augment extinction retention and prevent
      the return of fear memories in patients with PTSD and other anxiety disorders.
    

Intervention name(s): Dronabinol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Dronabinol (7.5mg) is administered only once by the oral route and is placed in opaque capsules with dextrose filler. Half of the participants will receive dronabinol.; Placebo is administered only once by the oral route and contains only dextrose in opaque capsules. Half of the participants will receive placebo.
Other intervention name(s): Marinol; Sugar Pill
Intervention MeSH terms: Dronabinol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Marinol; Dronabinol; Fear extinction; Healthy volunteers