Interplay between the HPA axis and inflammation as mechanisms therapeutic targets of Cannabis sativa in depression
Fernanda Pilatti, Marieli Philippsen, A. G. Bertollo, Cleneide Picinin Webler, Alessandra Bordignon, Z. M. Ignácio
Frontiers in Pharmacology May 19, 2026 DOI: 10.3389/fphar.2026.1801474 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Cannabis Depression |
| Key findings | Argues that MDD involves interacting chronic stress, HPA axis dysregulation, immune activation, and neuroinflammation, with epigenetic mechanisms modulating stress responsivity and inflammatory pathways. Reports that preclinical and clinical evidence suggests Cannabis sativa-derived cannabinoids may modulate the endocannabinoid system, attenuate HPA axis hyperactivity, reduce neuroinflammation, and influence monoaminergic and neuroplasticity-related pathways. |
Abstract
Major Depressive Disorder (MDD) is a highly prevalent and disabling psychiatric disorder, representing a major global health burden across all age groups. Increasing evidence indicates that its pathophysiology involves a complex interplay between chronic stress, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, immune activation, and neuroinflammation. Persistent HPA axis hyperactivity, glucocorticoid resistance, and altered expression of key regulators such as FKBP51 contribute to sustained inflammatory signaling and impaired neural plasticity in brain regions involved in mood regulation. Epigenetic mechanisms, including DNA methylation and microRNA-mediated regulation, further modulate stress responsivity, inflammatory pathways, and vulnerability to major depressive disorder. In this context, growing attention has been directed toward Cannabis sativa and its bioactive constituents as potential therapeutic agents. Preclinical and clinical evidence suggest that cannabinoids may modulate the endocannabinoid system, attenuate HPA axis hyperactivity, reduce neuroinflammation, and influence monoaminergic and neuroplasticity-related pathways. This review synthesizes the current literature on the mechanistic links among the HPA axis, inflammation, and MDD, highlighting the emerging role of Cannabis sativa-derived compounds in targeting these interconnected pathways.
Comparable studies
Other narrative reviews on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Causal association between cannabis and psychosis: examination of the evidence | 2004 | Review | |
| Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. General (historical and pharmacological review) | 2018 | Review | |
| Psychiatric effects of cannabis | 2001 | Review | |
| Beyond THC: The New Generation of Cannabinoid Designer Drugs | 2011 | Review | |
| Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug | 2006 | Review |
Citations in the library
Cites 4
- Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023 Current Psychiatry Reports April 1, 2024
- History of cannabis and the endocannabinoid system Dialogues in Clinical Neuroscience September 1, 2020
- The “Entourage Effect”: Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders Current Neuropharmacology January 23, 2020
- A naturalistic examination of the perceived effects of cannabis on negative affect. Journal of Affective Disorders August 1, 2018