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Journal of Clinical and
Basic Psychosomatics The endocannabinoid system

These endocannabinoids serve as retrograde pain, inflammatory disorders, neurodegenerative diseases,
messengers, transmitting signals from postsynaptic metabolic disorders, mood disorders, and addiction [108,109] .
neurons back to presynaptic terminals, effectively curbing
the release of neurotransmitters. This feedback mechanism 3.1. Endocannabinoid system and the regulation of
plays a crucial role in the regulation of synaptic functions, stress
synaptic plasticity, and an array of behavioral aspects, The ECS asserts its influence over the HPA axis through the
including learning, memory, reward, addiction, pain activation of cannabinoid receptors, particularly CB1Rs.
perception, and anxiety [101] . The HPA axis’s core responsibility is to coordinate the
Endogenous cannabinoids engage with and activate body’s response to stress, mainly by regulating the release of
cannabinoid receptors, primarily CB1Rs and CB2Rs, cortisol and other stress hormones. On activation, CB1Rs
which are distributed widely throughout the body. can modulate the HPA axis’s stress response, thereby
These receptors belong to the family of G protein- contributing to a mitigation of the release of cortisol and
[110-114]
coupled receptors (GPCRs), characterized by their seven other stress-related mediators .
transmembrane domains and comprising extracellular Endocannabinoids, such as AEA and 2-AG, are
aminoterminal and intracellular carbonyl terminal synthesized and released in response to stress. These
segments. On binding to a ligand, these activated compounds can bind to CB1Rs in various brain regions,
cannabinoid receptors interface with specific G proteins including the hypothalamus, the central regulator of HPA
within the cell. CB1Rs, in particular, initiate the activation axis activity. The activation of these receptors leads to a
of Gαi/o proteins, while CB2Rs may additionally interact reduction in the release of CRH and ACTH, ultimately
with Gαs proteins, initiating a chain of events that trigger restraining the release of cortisol (Figure 1B) [115-117] .
the disintegration of G proteins into their subunits, thereby Preclinical research involving animal models has
influencing intracellular signaling pathways [102-106] . CB1Rs demonstrated that the activation of CB1Rs can ameliorate
are abundantly found within the brain, predominantly on the physiological and behavioral effects of stress. These
neurons within the central nervous system (CNS). They effects encompass a reduction in the secretion of stress
are particularly prominent in brain regions associated with hormones, a blunting of the stress-induced activation of the
motor coordination, cognitive functions such as decision- HPA axis, and mitigation of anxiety-like behaviors [118,119] .
making, learning, memory, and the intricacies of human
emotions. Furthermore, CB1Rs are also found, although Human studies have provided valuable insights into
in more modest densities, in certain organs and peripheral the therapeutic potential of ECS modulation in conditions
tissues, including endocrine glands, salivary glands, linked to stress. Several trials have explored the use of
leukocytes, the spleen, the heart, and components of the cannabinoids, such as cannabidiol (CBD), in alleviating
reproductive, urinary, and gastrointestinal systems [107] . symptoms of anxiety and post-traumatic stress disorder
In contrast, CB2Rs primarily reside in immune cells and (PTSD). These studies indicate that cannabinoids may help
tissues, with a limited presence in the pancreas. Recent regulate the HPA axis’s response to stress and ameliorate
research has even identified the presence of CB2Rs within the psychological symptoms associated with stress-related
the CNS, specifically on glial and microglial cells, though disorders [120] .
in diminished quantities [106] . Chronic stress can induce the dysregulation of the ECS,
The ECS emerges as an indispensable player in a setting the stage for a vicious cycle of heightened stress
spectrum of physiological processes, spanning the response and emotional turmoil. Restoring equilibrium
modulation of pain, the regulation of immune function, within the ECS through modulation may offer a promising
the control of inflammation, the management of approach to mitigating the deleterious effects of chronic
appetite, the maintenance of metabolic homeostasis, the stress [121] .
orchestration of neuronal plasticity, and the handling of PSDs, characterized by the intricate interplay between
stress responses. It operates as a sentinel of homeostasis, psychological distress and somatic symptoms, frequently
diligently guarding the body’s equilibrium. The ECS involve an amplified stress response and emotional
contributes to the perception of pain, immunomodulation, turbulence. The capacity of ECS modulation to attenuate
and the regulation of appetite and energy balance. the HPA axis’s stress response and alleviate anxiety and
Furthermore, it plays a pivotal role in memory, the mood-related symptoms holds particular relevance in the
processes of learning, neuroprotection, and the regulation management of PSD. By tempering the physiological and
of emotions. Dysregulation of the ECS has been implicated psychological aspects of chronic stress, ECS modulation
in a multitude of health conditions, encompassing chronic may contribute to the amelioration of psychosomatic

Volume 2 Issue 1 (2024) 8 https://doi.org/10.36922/jcbp.2288