Research study · Translational Psychiatry · 2026
Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial
Verified on PubMed Oxford CEBM Level 1B: Randomized Controlled Trial
A 2026 randomized controlled trial in Translational Psychiatry tested amidohydrolases in post-traumatic stress disorders. It made no measurable difference to the brain scans. This trial shows that a medicine that boosts a natural calming chemical in the body does not visibly change brain activity in people with this condition, at least after four weeks and.
In plain language
Study overview
This study looked at adults with post-traumatic stress disorder, a condition that can follow frightening events. Participants took either a experimental medicine or a dummy pill for four weeks, then had brain scans while doing a task involving emotional images and words.
Findings
It made no measurable difference to the brain scans. The medicine did raise a natural calming chemical in the blood, but the brain activity patterns looked the same in both groups.
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The deeper readScientific analysis
The endocannabinoid ligand anandamide (AEA) plays a role in fear extinction, the conceptual foundation of the gold standard treatment for posttraumatic stress disorder (PTSD), exposure-based psychotherapy. Converging evidence from animal models and non-clinical human studies highlights the potential to enhance fear extinction pharmacologically by inhibiting the AEA catabolic enzyme, fatty acid amide hydrolase (FAAH). However, in our randomized clinical trial (n = 100), a FAAH inhibitor did no better than placebo at enhancing the response to exposure-based therapy in PTSD. Here, we used functional magnetic resonance imaging to investigate the neurobiological effects of FAAH inhibitor treatment on resting-state functional connectivity and the neural correlates of emotional processing (n = 76 scanned). We found that greater symptom improvement was significantly related to lower functional connectivity between ventromedial prefrontal cortex (vmPFC) and right dorsolateral prefrontal cortex (dlPFC), as well as lower task activation of the right dlPFC. Further, we found that self-reported symptoms at the time of scan were associated with increased functional connectivity of the vmPFC and the amygdala across the cortex (mainly in the ventral attention network and sensorimotor network, respectively). However, while we confirmed that 4 weeks of FAAH inhibition significantly increased AEA, there were no significant differences in functional connectivity or task activation between treatment groups. These findings suggest that FAAH inhibition does not affect intrinsic functional connectivity or emotional task response in PTSD, and that the dlPFC may play an important role in the response to exposure-based psychotherapy.
The paper
Citation
Tansey R, Perini I, Petrie GN, Haggarty CJ, Mazurka R, Yngve A, et al. Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial. Translational Psychiatry (2026). PubMed 41651806 · DOI
Limitations the authors noted
Only one MRI scan collected, at 4 weeks on drug and before psychotherapy; no longitudinal imaging. Sample predominantly female (about 85%), limiting generalizability to male and military veteran PTSD populations. Excluded complex PTSD and ongoing trauma; findings may not generalize to these groups. Symptom burden in sample was not severe, which may have limited detection of group differences. The emotional conflict task has low replicability per recent meta-analysis, possibly limiting sensitivity. Small effect size estimates for PCL and CAPS on BOLD activation limit clinical translatability. Several reported associations were exploratory and only trending after multiple comparisons correction. Per-protocol analysis designation and attrition details are limited in the main text.
In practice
Why this matters
This trial shows that a medicine that boosts a natural calming chemical in the body does not visibly change brain activity in people with this condition, at least after four weeks and before therapy began. It does not show that the chemical is useless, since other doses, longer use, other groups of people or other brain measures were not tested. The study mainly points to the right dorsolateral prefrontal region as a possible area to study further, and its findings are preliminary.
Frequently asked questions
Clinical Questions & Answers
What were the primary clinical findings regarding Amidohydrolases and Fear?
It made no measurable difference to the brain scans. The medicine did raise a natural calming chemical in the blood, but the brain activity patterns looked the same in both groups.
What study limitations or clinical safeguards should patients keep in mind?
Only one MRI scan collected, at 4 weeks on drug and before psychotherapy; no longitudinal imaging. Sample predominantly female (about 85%), limiting generalizability to male and military veteran PTSD populations. Excluded complex PTSD and ongoing trauma; findings may not generalize to these groups.
Browse related research
Condition: Fear Condition: Post-traumatic stress disorders Topic: Amidohydrolases Topic: Endocannabinoids
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Reviewed by Dr. Caplan on October 19, 2026.
This page is general education about a published study. It is not medical advice and does not create a doctor-patient relationship. For care specific to you, book a consultation.
