Cannabinoid modulation of corticolimbic activation during extinction learning and fear renewal in adults with posttraumatic stress disorder.
Zabik et al.·Neurobiology of learning and memoryImpact 1.8
MixedGRADEModerate20 citations
Samplen = 71 Pat.
Durationunclear
ControlPlacebo
EndpointfMRI corticolimbic activation
Blindingdoppelblind
DesignRCT
Cannabinoidthc
Routeoral
”Key finding
THC showed effects on neural activation (vmPFC and amygdala) in PTSD patients during extinction learning and fear renewal, but no significant effects on behavioral fear indicators.
Summary
RCT with n=71 (PTSD n=19, trauma-exposed controls n=26, healthy controls n=26); randomized to low-dose oral THC (n=34) vs. placebo (n=37) before extinction learning. PTSD patients under THC showed greater vmPFC activation during early extinction learning and greater amygdala activation during fear renewal (vs. placebo). No significant effects on behavioral fear indices.
P
PopulationAdults with PTSD (n=19), trauma-exposed controls (TEC, n=26) and healthy controls (HC, n=26); total N=71
I
InterventionOral THC (low dose, acute) before extinction learning
C
ControlPlacebo (oral)
O
OutcomePTSD patients under THC showed greater vmPFC activation than TEC during early extinction learning; under renewal higher vmPFC activation in HC and PTSD vs. TEC; increased amygdala activation in PTSD under THC vs. placebo; no group effects on behavioral fear indices
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
Failure to successfully extinguish fear is a hallmark of trauma-related disorders, like posttraumatic stress disorder (PTSD). PTSD is also characterized by dysfunctional corticolimbic activation and connectivity. The endocannabinoid system is a putative system to target for rescuing these behavioral and neural deficits. In healthy adults, acute, low-dose delta-9-tetrahydrocannabinol (THC) facilitates fear extinction and increases cortico-limbic activation and connectivity in response to threat. The present study determines the effect of acute, low-dose THC on fear-related brain activation and connectivity during fear extinction in trauma-exposed adults with (PTSD = 19) and without PTSD [trauma-exposed controls (TEC) = 26] and non-trauma-exposed [healthy controls (HC) = 26]. We used a Pavlovian fear conditioning and extinction paradigm, where we measured concurrent functional magnetic resonance imaging (fMRI) and behavioral responses (i.e., skin conductance responding and expectancy ratings). Using a randomized, double-blind, placebo-controlled design, N = 71 subjects were randomized to receive placebo (PBO, n = 37) or THC (n = 34) prior to fear extinction learning. During early extinction learning, individuals with PTSD given THC had greater vmPFC activation than their TEC counterparts. During a test of the return of fear (i.e., renewal), HC and individuals with PTSD given THC had greater vmPFC activation compared to TEC. Individuals with PTSD given THC also had greater amygdala activation compared to those given PBO. We found no effects of trauma group or THC on behavioral fear indices during extinction learning, recall, and fear renewal. These data suggest that low dose, oral THC can affect neural indices of fear learning and memory in adults with trauma-exposure; this may be beneficial for future therapeutic interventions seeking to improve fear extinction learning and memory.