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Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors

Neuropsychopharmacology volume 50, pages 1606–1614 (2025)Cite this article

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Abstract

Anxiety disorders are prevalent psychiatric conditions that frequently emerge during adolescence. Among the neurobiological systems implicated in these disorders, the endocannabinoid (eCB) signaling system plays a crucial role, making it a promising target for therapeutic interventions. In addition to its direct effects on anxiety regulation, eCBs may also influence response to first-line pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs). However, little is known about developmental changes in eCB lipids—N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG)—or their relationship to anxiety symptoms and treatment response. Circulating AEA and 2-AG concentrations were measured in youth (aged 9–17, N = 199) with varying anxiety symptoms, assessed using the Screen for Child Anxiety-Related Disorders (SCARED). We evaluated how eCBs relate to developmental factors (e.g., demographics, biological variables) and anxiety symptoms (SCARED total). Additionally, we examined how eCB concentrations change in response to acute SSRI treatment in a subsample of adolescents (age 12–17, N = 41) with generalized anxiety disorder (GAD), who participated in an 8-week randomized placebo-controlled trial of escitalopram (15 mg/day, titrated to 20 mg/day). Body mass index (BMI) was positively correlated with circulating AEA, while 2-AG showed negative associations with age, female sex, and time-of-day. After adjusting for these variables, more severe anxiety symptoms were associated with higher AEA and lower 2-AG. Greater increases in 2-AG from baseline (without changes in AEA) were linked to improved treatment response in adolescents with GAD. Our study suggests that circulating eCBs may serve as biomarkers for anxiety severity and predictors of treatment response in youth.

ClinicalTrials.Gov Identifier: NCT02818751.

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Fig. 1: Anandamide (AEA; left) and 2-arachidonoylglycerol (2-AG; right) concentrations and associations with biological sex (a, b), age (in years, c, d), BMI (e, f), and time of day (in hours, g, h).
Fig. 2: Anxiety symptom severity is positively associated with circulating concentrations of anandamide (AEA, a) and negatively associated with circulating 2-arachidonoylglycerol (2-AG, b).

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Acknowledgements

The authors would like to thank the following individuals and organizations for their assistance with study design, recruitment, data collection, and/or analysis: Amanpreet Bhogal, Shelley Paulisin, Jovan Jande, Emily Crisan, Alexander Jakubiec, Shravya Chanamolu, Sneha Bhargava, Myles Davis, Zazai Owens, Carla Hannah, Iveta Kopil, Shreya Desai, Cameron Martella, Autumm Heeter, Julia Evanski, Ahmad Almaat, Dr. Christine Rabinak, Leah Gowatch, Dr. Leslie Lundahl, Dr. Krishna Rao Maddipati, Dr. Laura Benjamins, Dr. Sharon Marshall, Dr. Christopher Youngman, Wayne Pediatrics, The Children’s Center, The Wayne State University Lipidomics Core and MR Research Facility. A generative large language AI model was used to assist with copy editing the manuscript.

Funding

This study was supported by National Institutes of Health Award K01MH119241 (to HM), a Richard Barber Interdisciplinary Research Grant (to HM and JB), and a Social & Behavioral Determinants of Health Research Stimulus Program Pilot Project Grant from the Wayne State University Office of the Provost (to HM and JB). Dr. Strawn was also supported in part by the Yung Family Foundation and the National Institute of Child Health & Development (R01HD099775 and R01HD098757) and the clinical trial was funded by the National institute of Mental Health (K23MH106037). Dr. Marusak was partially supported by R01MH132830 and R21HD105882. Dr. Zundel was partially supported by F32 MH133274, and Ms. Ely was partially supported by T32GM139807 and a Merrill Palmer Skillman Institute for Child and Family Development Fellowship. This study was partly supported by grants from the National Institutes of Health S10RR027926 and S10OD032292 to the Lipidomics Core Facility of Wayne State University.

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Author notes

  1. These authors contributed equally: Jeffrey R. Strawn, Jeanne Barcelona.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA

    Hilary A. Marusak, Clara G. Zundel, Tehmina Shakir, Samantha L. Ely, Carmen Carpenter, MacKenna Shampine, Reem Tamimi, Mariya Matsko, Sarah Rogers, Jennifer Losiowski, Emilie O’Mara, Alaina M. Jaster & Kamakashi Sharma

  2. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    Hilary A. Marusak

  3. Merrill Palmer Skillman Institute for Child and Family Development, Detroit, MI, USA

    Hilary A. Marusak & Samantha L. Ely

  4. Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA

    Terri A. deRoon-Cassini

  5. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

    Cecilia J. Hillard

  6. Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Heidi K. Schroeder & Jeffrey R. Strawn

  7. Department of Pediatrics, Divisions of Child & Adolescent Psychiatry and Clinical & Translational Pharmacology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Heidi K. Schroeder & Jeffrey R. Strawn

  8. Department of Economics, University of Cincinnati, Cincinnati, OH, USA

    Jeffrey A. Mills

  9. College of Education, Wayne State University, Detroit, MI, USA

    Jeanne Barcelona

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Contributions

Hilary A. Marusak: Substantial contributions to the conception and design of the work; acquisition, analysis, and interpretation of data; drafting the manuscript and revising it critically for important intellectual content; final approval of the version to be published; accountable for all aspects of the work, ensuring the accuracy and integrity of the work. Clara G. Zundel: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Tehmina Shakir: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Samantha L. Ely: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Carmen Carpenter: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. MacKenna Shampine: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Reem Tamimi: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Mariya Matsko: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Sarah Rogers: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Jennifer Losiowski: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Emilie O’Mara: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Alaina M. Jaster: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Kamakashi Sharma: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Terri A. deRoon-Cassini: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Cecilia J. Hillard: Revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Heidi K. Schroeder: Substantial contributions to the acquisition of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Jeffrey A. Mills: Substantial contributions to the analysis and interpretation of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; agreement to be accountable for the accuracy and integrity of the work. Jeffrey R. Strawn: Substantial contributions to the conception and design of the work; acquisition and analysis of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; accountable for ensuring the accuracy and integrity of the work. Jeanne Barcelona: Substantial contributions to the conception and design of the work; acquisition and analysis of data; revising the manuscript critically for important intellectual content; final approval of the version to be published; accountable for ensuring the accuracy and integrity of the work.

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Correspondence to Hilary A. Marusak.

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Competing interests

Dr. Hillard is a member of the Scientific Advisory Board and has equity in Formulate Biosciences. Dr. Strawn has received research support from the National Institutes of Health (NIMH/NIEHS/NICHD) and material support from Myriad Genetics. He receives royalties from Springer and Cambridge University Press, honoraria from the Neuroscience Education Institute, and serves as an author for UpToDate. He has consulted to MindMed, Abbvie (Cerevel), Otsuka, Vistagen, Supernus and Genomind. Drs. Strawn and Mills receive research support from the Yung Family Foundation. All other authors report no biomedical financial interests or potential conflicts of interest.

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Marusak, H.A., Zundel, C.G., Shakir, T. et al. Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors. Neuropsychopharmacol. 50, 1606–1614 (2025). https://doi.org/10.1038/s41386-025-02155-7

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