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Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial
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  • Published: 06 February 2026

Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial

  • Ryann Tansey  ORCID: orcid.org/0000-0002-6865-58931,2,3,
  • Irene Perini  ORCID: orcid.org/0000-0002-5972-09134,5,
  • Gavin N. Petrie  ORCID: orcid.org/0000-0003-3391-67471,2,3,
  • Connor J. Haggarty  ORCID: orcid.org/0000-0001-6678-05704,
  • Raegan Mazurka  ORCID: orcid.org/0000-0002-4974-48154,
  • Adam Yngve  ORCID: orcid.org/0000-0003-1012-72864,5,
  • Sarah Mina1,2,3,
  • Madeleine R. Jones4,
  • Hilda Engelbrektsson4,
  • Andrea J. Capusan  ORCID: orcid.org/0000-0003-1758-22064,
  • Matthew N. Hill1,2,6,
  • Markus Heilig  ORCID: orcid.org/0000-0003-2706-24824,5 &
  • …
  • Leah M. Mayo  ORCID: orcid.org/0000-0002-0645-48691,2,3,4 

Translational Psychiatry , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Neuroscience
  • Psychiatric disorders

Abstract

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.

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Code availability

Code used in the generation of the results can be found at https://github.com/PaCT-Lab/Open/tree/main/MRI/PTSD-FAAHi.

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Acknowledgements

Authors gratefully acknowledge contributions of research nurses Åsa Axén, Sandra Boda, Lisbet Severin, Sara Gustavson, and psychologist Daniella Dahmén.

Funding

This study was funded by the Swedish Research Council grants to LMM (2019-01887) and MH (2013-07434), the Swedish Medical Association to LMM (SLS-939751), and the Mental Health Initiative in Stress and Trauma Chair at the University of Calgary to MNH and LMM. RT received salary support from Alberta Innovates and the CANTRAIN Canadian Clinical Trials Training Platform. GNP received salary support from the Canadian Institutes of Health Research and the Hotchkiss Brain Institute. Open access funding provided by Linköping University.

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Authors and Affiliations

  1. Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Ryann Tansey, Gavin N. Petrie, Sarah Mina, Matthew N. Hill & Leah M. Mayo

  2. Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Ryann Tansey, Gavin N. Petrie, Sarah Mina, Matthew N. Hill & Leah M. Mayo

  3. Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB, Canada

    Ryann Tansey, Gavin N. Petrie, Sarah Mina & Leah M. Mayo

  4. Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

    Irene Perini, Connor J. Haggarty, Raegan Mazurka, Adam Yngve, Madeleine R. Jones, Hilda Engelbrektsson, Andrea J. Capusan, Markus Heilig & Leah M. Mayo

  5. Center for Medical Image Science and Visualization (CMIV), Linköping, Sweden

    Irene Perini, Adam Yngve & Markus Heilig

  6. Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada

    Matthew N. Hill

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  1. Ryann Tansey
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  2. Irene Perini
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Contributions

Ryann Tansey: Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Visualization; Irene Perini: Methodology, Writing – review & editing; Gavin N. Petrie: Investigation, Writing – review & editing; Adam Yngve: Investigation, Writing – review & editing; Connor J. Haggarty: Investigation, Writing – review & editing; Raegan Mazurka: Investigation, Writing – review & editing; Sarah Mina: Formal analysis, Writing – review & editing; Madeleine R. Jones: Investigation, Writing – review & editing; Hilda Engelbrektsson: Investigation, Writing – review & editing; Andrea J. Capusan: Writing – review & editing; Matthew N. Hill: Investigation, Resources, Writing – review & editing; Markus Heilig: Resources, Writing – review & editing; Leah M. Mayo: Conceptualization, Methodology, Resources, Writing – original draft, Writing – review & editing, Supervision, Funding acquisition

Corresponding author

Correspondence to Leah M. Mayo.

Ethics declarations

Competing interests

MH received clinical trial materials and funding from Janssen Pharmaceutica NV for work related to this trial. MH has also received consulting fees, research support or other compensation from Indivior, Camurus, Molteni, BrainsWay, Aelis Farma, and Lundbeck. AJC has received consulting fees from Indivior, Camurus, Lundbeck, and DNEPharma. LMM has received consulting fees from Synendos Therapeutics. All other authors report no other disclosures or conflicts of interest.

Ethics declarations

This clinical trial (EudraCT 2020-001965-36) was approved by and conducted according to the regulations of the Swedish Ethical Review Authority (Dnr 2020-57043) and the Swedish Medical Products Agency.

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Tansey, R., Perini, I., Petrie, G.N. et al. Functional neuroimaging of fatty acid amide hydrolase inhibition in posttraumatic stress disorder: a randomized clinical trial. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03864-3

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  • Received: 03 June 2025

  • Revised: 13 December 2025

  • Accepted: 28 January 2026

  • Published: 06 February 2026

  • DOI: https://doi.org/10.1038/s41398-026-03864-3

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