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Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic–pituitary–adrenal (HPA) axis responsivity in female and male mice.

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Title: Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic–pituitary–adrenal (HPA) axis responsivity in female and male mice.
Authors: Jenkins, Bryan W. (AUTHOR), Spina, Hayley A. (AUTHOR), Nicholson, Kate (AUTHOR), Newman, Amy E. M. (AUTHOR), Khokhar, Jibran Y. (AUTHOR)
Source: Psychopharmacology. Feb2026, Vol. 243 Issue 2, p287-299. 13p.
Subjects: Hypothalamic-pituitary-adrenal axis, Cannabidiol, Psychological stress, Anxiety, Neuropsychology, Emotional conditioning, Corticosterone, Gender differences (Psychology)
Abstract: Rationale: Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus–pituitary–adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior. Objectives: We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice. Methods: C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol. Results: Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC. Conclusions: CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology. [ABSTRACT FROM AUTHOR]
Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Cannabidiol (CBD) potentiates physiological and behavioral markers of hypothalamic–pituitary–adrenal (HPA) axis responsivity in female and male mice.
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  Data: <searchLink fieldCode="AR" term="%22Jenkins%2C+Bryan+W%2E%22">Jenkins, Bryan W.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Spina%2C+Hayley+A%2E%22">Spina, Hayley A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nicholson%2C+Kate%22">Nicholson, Kate</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Newman%2C+Amy+E%2E+M%2E%22">Newman, Amy E. M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Khokhar%2C+Jibran+Y%2E%22">Khokhar, Jibran Y.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Psychopharmacology%22">Psychopharmacology</searchLink>. Feb2026, Vol. 243 Issue 2, p287-299. 13p.
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  Data: Rationale: Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus–pituitary–adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior. Objectives: We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice. Methods: C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol. Results: Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC. Conclusions: CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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              Text: Feb2026
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