Chronic Stress

Chronic Stress

If you have ever received bad news and felt a cold feeling in the pit of your stomach, that feeling might have been adrenaline being released into your bloodstream. That is one of the most notable signs that your body has triggered the stress response, or the fight-or-flight response.

This response is supposed to be a life-saving measure. Your body releases extra sugar into your bloodstream, shunts resources from the digestive tract to the brain, stops repairing bone and cartilage and gets amino acids flowing in the blood to be ready to repair damage, heightens your ability to remember dangerous situations, and triggers your brain’s alarm system and moods.

In our daily lives, the stress response is more likely to be triggered by deadlines at work or some other non-life-threatening event. Deadlines are not life-threatening, but try explaining that to your adrenal glands. Your body will sacrifice a little health tomorrow in order to ensure that you make it to the end of the day today.

When the body’s alarm system is triggered over and over, the stress response becomes less helpful and more harmful. The body’s primary stress hormone is cortisol, which is one of the glucocorticoid hormones, and its job is to make you instantly ready to meet stress with a full mobilization of the body’s resources.

The stress response involves the Hypothalamic-Pituitary-Adrenal axis. This system is triggered by the amygdala, which is the alarm system of the brain. The amygdala recognizes danger and signals the hypothalamus to begin the hormonal cascade that will make you ready for the fight.

The Hypothalamus, the first part of the HPA axis, secretes corticotropic releasing hormone (CRH). Corticotropic releasing hormone stimulates the Pituitary (which is the second part of the HPA axis) to release adrenocorticotropic hormone (ACTH), which causes the Adrenal glands (the third part of the HPA axis) to release glucocorticoid hormones, including cortisol.

In the brain, cortisol affects the memory. It works in conjunction with epinephrine (adrenaline) in the hippocampus of the brain to form sharp memories of things that are perceived as dangerous. Long term hippocampal exposure to cortisol damages cells in the hippocampus, which causes reduced memory recall and impaired learning. Damage to hippocampal cells can actually cause the hippocampus to shrink! This can make a person more prone to PTSD as well as affecting memory and learning. “Indeed, impaired glucocorticoid receptor function has been suggested to be causal for HPA (Hypothalamic-Pituitary-Adrenal) axis hyperactivity in depression, as glucocorticoids usually regulate the HPA axis through negative feedback inhibition and thereby reduce the production of glucocorticoids themselves. This effect is thought to be mediated in part by the [Glucocorticoid Receptors]. Therefore, hyperactivity of the HPA axis has been explained by an impaired feedback inhibition of glucocorticoids, possibly due to an impaired or dysfunctional glucocorticoid receptor (so-called “glucocorticoid resistance”) (Anacker, Zunszain, Carvalho, & Pariante, 2011).

Sometimes people get so used to being stressed that it seems normal to them.  How would you know whether you are chronically stressed? One way is to check your blood cortisol level. Draw a lab sample at 8AM and a second sample at 4PM. Cortisol should vary in its blood level through the day. The 8AM draw should be the high level of the day, and the 4PM should be the low level. If the levels are similar, then further investigation of the matter is warranted.

Another option is to measure stress with an EEG. Different brain areas will show increased and decreased electrical activity in response to chronic stress.  Other imaging techniques such as PET scans and fMRI can also be helpful in confirming chronic stress, but those tests have more serious risks and contraindications than EEG or lab work. By assessing the client for biomarkers that do not rely on self-report, a clinician can compare biomarker results with the client’s verbal report of stress. If the client reports less stress than the biomarkers indicate, this might mean that the client is experiencing the placebo effect or has sufficient hope that the future will improve.

What can help calm the HPA axis?

Ginseng is a plant that has been part of traditional Chinese medicine for thousands of years, and its use has spread globally. Since the 1960s, it has been studied by Western allopathic medical practitioners, and quite a bit of what it does is now known.

The medicinally active components of ginseng are called “ginsenosides.” There are more than 90 ginsenosides, with some that are more abundant and active in the human body than others.

Two ginsenosides, Rg1 and Re, interact with glucocorticoid receptors. The action they take on the receptor is a “partial agonist.” Agonists help a mechanism to work to its greatest potential, partial agonists help a mechanism of action work, but at a weaker level. These ginsenosides have a strong attraction to the glucocorticoid receptor, so they bind very well, but only weakly stimulate the receptor. If a person had too much glucocorticoid in the receptor space and their HPA axis was causing an excessive release of stress hormones, the application of these ginsenosides would crowd the stress hormones out of the receptor sites and weakly stimulate (Mukherjee, Knisely, & Jacobson, 2004).

Note:  This part is too technical, there is a translation from jargon to English below!

Stimulating that receptor causes the HPA axis to stop secreting ACTH, which interferes with adrenal production of glucocorticoids and cortisol. The antidepressant Imipramine uses this mechanism of action to treat psychotic depression (Mukherjee, Knisely, & Jacobson, 2004). There is some evidence that the HPA axis is stimulated by glucocorticoid receptors in parts of the brain that are newly implicated in the presentation of psychosis and depression, such as the amygdala. The amygdala is the warning bell of the brain (Vincent et al., 2013).

In order for these ginsenosides to have that mechanism of action, the ginsenosides have to be absorbed and transported into the blood. Han and Fang (2006) explain that, “Elimination in the stomach, large intestine and liver contributed to the low oral bioavailability of Rg1 but low membrane permeability might be a more important factor in determining the extent of absorption.” However, an emerging method of ginseng fermentation demonstrates a way to increase the absorption and bioavailability of ginsenosides. Fermented red ginseng has an increased amount of polyphenols (antioxidants), ginsenosides, and ginsenoside metabolites. Non-fermented red ginseng is absorbed at a rate of about 0.1-3.7% (Ryu et al., 2013). “The sum of Rb1 and Rg1 (this is the ginsenoside that is a partial agonist in glucocorticoid receptors) in the NFRG (10.25±0.51 mg/g) was significantly higher (p<0.05) than that of the FRG (2.33±0.07 mg/g). However, the level of ginsenoside metabolites (Rg2, Rg3, Rg5, Rk1, CK, Rh1, Rh2, and F2) was significantly higher (p<0.05) in the FRG (33.90±0.97 mg/g) compared to that of NFRG (14.75±0.46 mg/g).”

Let’s go over that last paragraph again and translate it from statistics into English. The ginsenosides have to make it into the bloodstream in order to work on glucocorticoid receptors. The stomach, large intestine, and liver remove ginsenosides from the GI tract and the blood, which decreases their bioavailability. However, it is probably the inability of ginsenosides to move from inside the intestine into the bloodstream that blocks most of the ginsenosides, leaving only 0.1-3.7% of the ginsenosides biologically active in the blood. A fermentation process can improve the total amount of ginsenosides available, and is absorbed by the small intestine as much as fifteen times more than non-fermented ginseng.

The fermentation process breaks down the large molecules of ginsenosides to smaller molecules, which more easily pass through the GI tract and are absorbed better into the blood.

In this discussion, we considered stress and how it negatively affects the brain and body. We considered one possible mechanism of action for stress, and two possible pharmacologic approaches to address stress. We went over two biomarkers that can help a clinician accurately diagnose chronic stress, and two diagnostic tests that have elevated risks to the client. In later articles, I will cover some lifestyle changes a person can use to successfully cope with stress with or without pharmacological support.

If you think chronic stress is negatively affecting your life, call Mid-Valley Counseling at (503) 364-6093. As of 10/2/2015, I am accepting new clients.  Salem, OR is located between Portland, OR and Eugene/Corvallis, OR.


Anacker, C., Zunszain, P. A., Carvalho, L. A., & Pariante, C. M. (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment? Psychoneuroendocrinology, 36(3), 415-425. doi:10.1016/j.psyneuen.2010.03.007

Electro-Physiological Data Fusion for Stress Detection (PDF Download Available). (n.d.). Retrieved from

In Fischbach, F. T., & In Dunning, M. B. (2015). A manual of laboratory and diagnostic tests (11th ed.). Philadelphia, PA: Lipincott Williams & Wilkins.

Han, M., & Fang, X. (2006). Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models. Acta Pharmacologica Sinica, 27, 499-505. doi:10.1111/j.1745-7254.2006.00303.x

Leung, K. W., & Wong, A. S. (2010). Pharmacology of ginsenosides: a literature review. Chinese Medicine, 5(20). doi:10.1186/1749-8546-5-20

Mayo Clinic. (2013, July 11). Chronic stress puts your health at risk – Mayo Clinic. Retrieved September 7, 2015, from

Mukherjee, K., Knisely, A., & Jacobson, L. (2004). Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice. Endocrinology. doi:10.1210/en.2004-0147

Ryu, J. S., Lee, H. J., Bae, S. H., Kim, S. Y., Park, Y., Suh, H. J., . . . Jay, Y. H. (2013). The bioavailability of red ginseng extract fermented by Phellinus linteus. Journal of Ginseng Research, 37(1), 108-113. doi:10.5142/jgr.2013.37.108

Vincent, M. Y., Hussain, R. J., Zampi, M. E., Sheeran, K., Solomon, M. B., Herman, J. P., . . . Khan, A. (2013). Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. Brain Research. doi:10.1016/j.brainres.2013.05.031

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