Given the central role of HPA axis dysregulation in chronic stress and stress-related diseases, restoration of neuroendocrine homeostasis represents a critical therapeutic objective. Conventional pharmacological interventions, including glucocorticoid receptor antagonists, selective serotonin reuptake inhibitors (SSRIs), and benzodiazepines, are effective for symptom management but are frequently limited by adverse effects such as immunosuppression, metabolic disturbances, sedation, tolerance, and incomplete normalization of HPA axis function [15].

In recent years, natural bioactive compounds, particularly terpenes, have gained attention as potential complementary modulators of stress-related pathophysiology [16]. Terpenes exhibit pleiotropic biological effects, including attenuation of neuroinflammation, antioxidant effects, immune modulation, and neuroprotection, all of which are closely linked to chronic HPA axis activation and stress-associated neuroendocrine perturbations [17]. Preclinical studies demonstrate that specific monoterpenes, such as α-pinene and β-pinene, exert neuroprotective effects in cellular models of neurodegeneration, including reduction in amyloid-β-induced toxicity and inhibition of amyloid fibril formation, processes relevant to Alzheimer’s disease pathology [17].

In experimental models, isolated terpenes and selected compounds belonging to the modified class of terpenes known as terpenoids have been reported to modulate inflammatory and redox-sensitive pathways by suppressing pro-inflammatory cytokines, inhibiting NF-κB signaling, and reducing oxidative stress biomarkers. These mechanisms may be relevant to chronic stress-associated neuroinflammation and immune dysregulation [18,19]. These findings support mechanistic relevance to chronic stress-associated neuroinflammation and immune dysregulation, but should not be interpreted as direct evidence of endocrine regulation in humans [18,19]. Broad mechanistic and clinical evidence for terpenes directly altering HPA axis hormones, such as ACTH or cortisol, remains limited. Most of the available data come from studies of essential oils, complex mixtures of aromatic volatile compounds in which terpenes are the predominant constituents, and from preclinical models, rather than from controlled human trials using isolated compounds [20,21]. Nevertheless, reviews of individual terpenes, such as α-pinene, and terpenoids, such as linalool, report neuroactive and stress-relevant effects and highlight the need for further investigation into their potential endocrine actions [17,22,23].

In oncology-related models, the anti-inflammatory and antioxidant properties of terpenes/terpenoids intersect with key aspects of tumor biology by modulating immune surveillance, apoptotic pathways, and pro-tumorigenic inflammatory signaling within the tumor microenvironment [24]. Terpenoids have been shown to induce cell-cycle arrest and apoptosis via regulation of p53, Bax/Bcl-2 family proteins, caspase activation, and ROS-mediated signaling, while concurrently downregulating survival pathways such as PI3K/Akt/mTOR and JAK/STAT. Moreover, these compounds can enhance antitumor immune responses and improve the efficacy of conventional therapies by modulating immune effector mechanisms and reducing tumor-associated inflammation [24].

Taken together, this heterogeneous evidence supports the hypothesis that terpene-related exposures may act as potential multi-target modulators of stress-responsive neuroimmune and redox pathways, although the strength and specificity of the evidence vary substantially across isolated compounds, essential oils, phytoncide exposure, and experimental models. Beyond experimental and clinical models, these mechanistic insights are reflected in real-world interventions such as forest bathing (Shinrin-yoku), a structured form of nature-based therapy shown to promote physical and psychological well-being [25]. The benefits of forest exposure have been attributed in part to inhalation of terpenes and terpenoids, and other biogenic volatile compounds emitted by trees, providing a biologically plausible link between environmental exposure and molecular pathways involved in stress regulation. However, forest-bathing studies involve complex environmental exposures that include physical activity, visual and sensory stimulation, psychological relaxation, and social or contextual factors, in addition to inhalation of biogenic volatile organic compounds. Therefore, these studies were interpreted separately from interventions using isolated terpenes or defined essential oil preparations. Historically, the health-promoting effects of natural environments were recognized by Hippocrates and later conceptualized as Vis Medicatrix Naturae. Contemporary research increasingly substantiates these early observations by identifying specific plant-derived compounds capable of modulating stress-related biological pathways. Figure 2 illustrates the potential systemic effects of inhaled forest-derived terpenes on the brain, immune system, oxidative balance, and overall homeostasis.

Within this framework, terpenes emerge as chemically defined compounds with potentially tractable mechanisms that may bridge empirical observations of nature-based therapies with modern neuroendocrine and immunopharmacology, highlighting their potential relevance to strategies aimed at mitigating chronic stress and HPA axis dysfunction. The following sections summarize the impact of chronic stress and HPA axis dysregulation on endocrine, immune, and nervous systems, followed by a critical overview of current mechanistic and translational evidence supporting terpenes as modulators of stress-associated pathophysiology.