Cannabinoid facilitation of fear extinction memory recall in humans

Abstract

A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during 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 investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing.

Endocannabinoid concentrations in hair are associated with PTSD symptom severity

“…By contrast, Rabinak et al (2013) observed enhanced extinction memory retention when THC was administered, but no immediate effects on extinction learning. This effect might be mediated by increased activity in the basolateral part of the amygdala, the prefrontal cortex and hippocampus during extinction memory recall, brain structures centrally involved in extinction learning (Rabinak et al, 2014).…”

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“…The compound disrupts the reconsolidation of a contextual fear memory in a manner dependent on activation of CB1 located in prelimbic subregions of the medial prefrontal cortex and on memory retrieval/reactivation (823). In humans, oral dronabinol prevents the recovery of fear (706).…”

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“…The next day, participants were treated with placebo or dronabinol 2 h prior to an extinction session. Those treated with dronabinol had less reinstatement of fear responding 24 h later relative to the placebo group (Rabinek et al, 2013). Given that exposure therapy to treat PTSD is often associated with poor extinction retention (eg, Milad et al, 2009), these data suggest that cannabinoid administration during extinction training might reduce the reinstatement of fear responding.…”