Early-life stress, the endocannabinoid system, and fear memory extinction

Rationale: Early life stress (ELS) constitutes a major risk factor for the development and persistence of mental disorders, increasing rates of posttraumatic stress disorder (PTSD). A first-line and empirically validated approach to treat this disorder is Prolonged Exposure Therapy (PE), one component of which involves repeated exposure to fear-linked cues to produce ¡¥¡¥extinction¡¦¡¦ of fear and to prevent avoidance responses to these cues. However, a significant number of patients have incomplete responses or fail to sustain improvements over time, mainly due to the fact that extinction learning, which is the core mechanism underlying exposure-based therapy, is vulnerable to the return of pathological fear. A promising novel strategy is adding drug treatment to exposure therapy in a timed manner to improve the long-term outcome of exposure therapy. Recent findings indicate that hydrocortisone, a synthetic form of the endogenous stress hormone cortisol, may improve stress adaptation and enhance the extinction of fear memories. Critically, recent data from rodent models demonstrate that glucocorticoids exert their actions via recruitment of the endogenous cannabinoid (endocannabinoid) system. Pre-clinical studies moreover suggest that ELS causes disturbances in the endocannabinoid system which might render hydrocortisone ineffective as adjuvant treatment to exposure therapy. A striking and recurrent clinical observation is that a large percentage of PTSD patients, in particular those with a chronic course associated with ELS, uses cannabis as ¡§self-medication¡¨ to alleviate their symptoms. Also, initial results from studies in healthy volunteers show that exogenous cannabinoids may strengthen extinction learning.
We will therefore compare the efficacy of £G9-tetrahydrocannabinol (THC; dronabinol), one of the active components of natural cannabis, and hydrocortisone in enhancing extinction learning in healthy volunteers with and without ELS.

Objective: We hypothesize that in healthy individuals with ELS, THC, which directly targets the endocannabinoid system, is more effective than hydrocortisone in improving stress adaptation and extinction learning in an experimental model of exposure therapy compared to healthy individuals without ELS.



Study design: 2*3 mixed factorial double-blind, placebo-controlled, cross-over interventional study with Drug (THC, hydrocortisone or placebo) as within-subject factor and Group (ELS vs. Non-ELS) as between-subject factor.



Study population: Two groups of healthy individuals (n=25 each) with either a history of ELS or without a history of ELS.



Intervention: To investigate the role of the endocannabinoid system in fear memory extinction and stress adaption, we will use established behavioral and neuroimaging paradigms. We will test the different effectiveness of two different pharmacological interventions: THC (7.5mg), hydrocortisone (20mg) in fear memory recall test. The control condition will use a double placebo procedure.

We hypothesize that in healthy individuals with Early-life stress (ELS), THC, which directly targets the endocannabinoid system, is more effective than hydrocortisone in improving stress adaptation and extinction learning in an experimental model of exposure therapy compared to healthy individuals without ELS.

One day after drug administration

To investigate the role of the endocannabinoid system in fear memory extinction and stress adaption, we will use established behavioral and neuroimaging paradigms including (1) a classical fear conditioning, extinction and recall task, (2) an autobiographical memory recall task and (3) dynamic facial expression task. We will test the different effectiveness of two different pharmacological interventions: THC (7.5mg), hydrocortisone (20mg) in fear memory recall test. The control condition will use a double placebo procedure.