The efficacy of elevating anandamide via inhibition of fatty acid amide hydrolase (FAAH) combined with internet-delivered cognitive behavioral therapy in the treatment of post-traumatic stress disorder: a randomized, placebo-controlled clinical trial

Abstract

Post-traumatic stress disorder (PTSD) is a severe mental health disorder with limited treatment options. Gold standard treatment includes cognitive behavioral therapies (CBT) that incorporate exposure to traumatic memories to facilitate extinction. CBT can be effective in PTSD, but effects are incomplete and symptoms are prone to spontaneous return. Pharmacologically facilitating fear extinction could potentiate the effects of exposure-based therapy. Here, we explored whether targeting the endocannabinoid (eCB) system, a neuromodulatory system critically involved in fear extinction, would promote the efficacy of exposure-based CBT. Specifically, we tested the effects of elevating the eCB ligand anandamide (AEA) via inhibition of its main degradative enzyme, fatty acid amide hydrolase (FAAH). In this double-blind, placebo-controlled study, patients with PTSD (N = 100; 85 women) were randomized to the FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg b.i.d.) or placebo for 12 weeks. In weeks 5-12, all participants completed an internet-delivered CBT that included exposure-based modules. The primary outcome was clinician-assessed PTSD symptom severity (CAPS-5). Secondary outcomes included self-reported symptoms of PTSD, depression, anxiety, and sleep quality. Blood samples were taken to measure levels of drug and eCBs. Overall, PTSD symptoms improved over time. While FAAHi increased AEA levels, there was no effect of FAAHi on PTSD symptoms or any secondary measure. FAAHi combined with internet-delivered CBT did not improve PTSD symptoms to a greater extent than internet-delivered CBT alone. Thus, FAAH inhibition does not appear to be a suitable adjunct treatment for enhancing CBT in PTSD. This study was registered as Eudra-CT 2020-001965-36.

Fig. 1. Study schematic and CONSORT diagram.

A Study schematic depicting study overview. Participants were randomized to FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg, twice daily) or placebo (PBO) for 12 weeks. After week 4, all participants started an 8-week internet delivered cognitive behavioral therapy (CBT) based on exposure learning. Primary outcomes were assessed at week 0 and 12, as well as a 16-week follow-up. Secondary outcomes were assessed at weeks 0, 4, 8, and 12. B CONSORT diagram of participant flow.

Fig. 2. Clinician-assessed and self-reported PTSD symptoms decreased over time but were unaffected by FAAH inhibition.

A Mean scores at week 0 (baseline), week 12 (post-treatment) and week 16 (phone follow-up) for FAAHi and PBO treatment groups. No drug effect was observed, only an effect of time. Error bars represent standard deviation. B Individual CAPS-5 scores at week 0 and 12 for the PBO group. C Individual CAPS-5 scores at week 0 and 12 for the FAAHi group. D Mean self-reported PTSD symptoms as measured by PCL-5 at week 0, 4, 8 and 12 and 16 for PBO and FAAHi treatment arms. No drug effect was observed. Error bars represent standard deviation. E The change in CAPS-5 scores between week 0 and 12 correlated strongly to the change in PCL-5 scores between week 0 and week 12, in both treatment groups.

Fig. 3. FAAH inhibition did not improve any secondary measure.

Mean scores of secondary outcome measures for the PBO and JNJ treatment groups. No effect of the drug was observed for any of these outcome measures. Error bars represent standard deviation. A Anxiety levels (CPRS-S-A) at week 0 and week 12. B Depressive symptoms (CPRS-S-A) at week 0 and week 12. C Sleep quality (PSQI) at week 0, 4, 8, 12 and 16.

Fig. 4. FAAH inhibitor JNJ-42165279 was detectable in blood and correlated with anandamide levels.

A Individual plasma concentrations of JNJ-42165279 at week 4, 8 and 12 in the JNJ treatment arm. Many participants took the study drug the same day as the blood sample was drawn, which is why results should be used as an indicator of compliance and not trough levels. B Plasma concentrations of JNJ-42165279 correlated strongly with anandamide levels.