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Is cortisol good or bad? Implications for adrenal support in ME/CFS, stress-related and inflammatory conditions

Cortisol is associated with neurotoxicity and subsequent depression, with papers showing that sustained high cortisol is associated with reduced neuroplasticity. Studies that supply animals with Prednisolone, a synthetic cortisol analog and therefore a member of the glucocorticoid family, reliably show depressive behaviours (see Gonzalez-Perez et al, Hill et al, and Kajiyama et al).

This, perhaps unsurprisingly, as has led many to consider cortisol a ‘bad’ hormone and proclaim that therapy should focus on reducing its output. However, this cortisol-neurotoxicity link stands out as another example of how misunderstandings occur when we fail to separate correlation from causation. The above papers show a strong association between higher glucocorticoid levels and reduced neuroplasticity, yet papers that actually look into the mechanisms involved paint a very different picture. So let’s get a little bit technical.


Cortisol: mechanisms

Cortisol impacts on neuroplasticity via several mechanisms. The key connection is mediated by the hormone’s effect on serotonin metabolism, specifically because it is needed to maintain healthy serotonin levels in the brain. When serotonin binds with its 5HT1a receptors, it then drives neural remodelling in concert with BDNF, a central player in stimulating a central player stimulating both the survival of stressed cells and the proliferation of new ones. It’s relevant that inflammatory cytokines, specifically IL-1b, can supress BDNF; cortisol’s anti-inflammatory role therefore comes to the fore in limiting the cytokine-induced suppression of BDNF. It also plays a further role in promoting the formation of pro-BDNF into its mature/active form. This explains glucocorticoids increase spine density of dendrites (an effect measured in vitro and in vivo). Rises in cortisol are vital to repair and remodelling of the brain.

This makes sense from an evolutionary perspective. Evolution has selected for energy production and immune activity that is sustainable, that is to say a setup that produces sufficient energy to satisfy baseline demands and provides adequate systemic defence, but does not destabilize the system (through excessive oxidative stress / inflammatory damage to cells / etc). However, it has also selected for a stress response that makes permits extra energy availability and increased defensive activity in times of increased need (ie. when subject to threats). This stress response is multifaceted and comes with costs. For examples, it involves:


  • Increased energy production at mitochondrial level through adrenaline-induced increases in glucose uptake at cell membranes and SDH activity in the mitochondria, the cost being increased oxidative stress
  • Increased alertness/vigilance and resilience to emotional overwhelm via adrenaline’s effect on regional brain activation, the cost being a deactivation of brain structures that permit introspection, sensory processing and social engagement
  • increasing the availability of sugars and salts through the opening of the gut lining, the cost being increased endotoxin movement and subsequent increases in inflammation
  • increased readiness against slash wounds and other injuries that may be sustained through conflict, achieved through removing the vagus nerve ‘brake’ on macrophage activation and through CRH-mediated activation of mast cells, the cost again being increases in inflammation

It therefore figures that there would be an evolutionary advantage in the stress response being accompanied by a response that, upon cessation of threat, switches off adrenaline and reduces inflammation. Such a response would be particularly advantageous if it was accompanied by changes that promote introspection and learning (neuroplasticity), so that the individual can make sense of the events, reducing future risk through internalizing the strategies that were successful/unsuccessful in fending off the threat and forming associations between circumstances prior to the threat and the threat itself (to better avoid it in future). And cortisol does all of this. It is anti-adrenaline, anti-CRH, anti-inflammatory, pro-neuroplasticity and pro-serotonin (which aids in sensory processing and introspection, as well as further contributing to neuroplasticity). Cortisol powerfully supports brain health following stress.

So, if cortisol actually helps brain health, how can the above papers make such robust links between high cortisol levels and neural pathology? It comes down to their failure to recognize the difference between cortisol’s acute effects and what happens to this pathway over sustained exposure to high cortisol levels. The difference here is all due to downregulation of cortisol receptors (aka the glucocorticoid receptor/GR). GRs are fairly inactive at baseline, becoming active only at high levels of cortisol, demonstrating that these receptors have evolved for transient activation to restabilize the system. They are not evolved for perpetual activation we see in chronic stress.

When the receptor is bound repeatedly/continuously, it becomes downregulated and stops responding the way it should. It stops protecting the organism the way it was designed. This is why activation of the glucocorticoid receptor should reliably show a neuroprotective effect, while anything that reduces activity here should show depression and related metabolic problems. And this is indeed what we see; ats bred for lower mRNA expression of the glucocorticoid receptor develop depression-like behaviours. Animals who are subject to adrenalectomy develop fatigue. Humans with low cortisol levels are more vulnerable to mental health disorders.

Experiments that induce in models of sustained stress (which translates to sustained elevations in glucocorticoids, sufficient to downregulate the receptor), show similar changes in behaviours (see Huynh et al and Regenthal et al). Of particular interest is that, in the one model with reduced length of stress exposure (two hours of restraint stress per day instead of four most commonly used in other models, and a two weeks study period instead of the month-long affair employed elsewhere), these changes did not occur. This indicates that output of adrenal hormones like cortisol can help maintain resilience to stress but the receptor will downregulate over time. Importantly, it tells us that, as soon as the receptor begins to downregulate, such resilience falters. This explains why most studies show a link between high cortisol and neurotoxicity whereas others do not. As with insulin, cortisol is not the enemy; it is cortisol resistance that is our primary concern.

The above studies make it very clear that cortisol resistance can be induced simply by sustaining high levels of cortisol (or analogs) for a sustained period of time. This appeared to be several weeks when using animal stress models and as little as a week when using large doses of exogenous steroid hormone. However, endotoxins remain a powerful factor in inducing resistance at the glucocorticoid receptor. Endotoxins are little fragments of dead bacteria that can move from the gut into the bloodstream when there is increased intestinal permeability.



  • More activity at the glucocorticoid receptor = more neuroprotection
  • Cortisol increases binding at the receptor (leading to more activity, more neuroprotection), but too much cortisol binding for too long will downregulate the receptor (leading to lower activity, less neuroprotection)
  • Sustained exposure to endotoxins can downregulate the receptor
  • We must separate the effects of cortisol from the effects of cortisol resistance


What this means on the front line

Cortisol resistance has long been identified as a key factor in ME/CFS, although there are a number of conditions where cortisol resistance can be found. For example, 25% of asthmatics are cortisol-resistant and so are 40% of depressed patients. This cortisol resistance has been shown in a number of studies in mental health disorders (see Pariente 2006, Carvalho & Pariente 2008 and Anacker et al 2011), with papers highlighting how a key function of anti-depressants may be to rebalance glucocorticoid receptor activity. It’s no coincidence that Depressive patients treated with antidepressants that do not normalize their plasma glucocorticoid levels have increased risk of relapse.

This is relevant for so many reasons. If the glucocorticoid receptor is not being activated, then the body’s most powerful anti-inflammatory agent cannot do its job. Supporting the body’s anti-inflammatory response in inflammatory conditions (rheumatoid arthritis, eczema, asthma, autoimmune hypothyroidism, etc etc) are therefore destined to fail. If this receptor is not being activated, then it cannot undertake its role in serotonin-trafficking. Supporting neurotransmitter balance through additional means (via amino acid support or anti-depressants) are therefore likely to have unpredictable effects. If this receptor is not being activated, then it cannot switch off the stress response. Lifestyle changes, meditation practices, engagement in therapy and introduction of sleep hygiene are therefore likely to be limited in their effect.

Also relevant is the self-perpetuating cycle that plays out once cortisol resistance kicks in. As mentioned above, endotoxins are powerful agents in inducing cortisol resistance (doing so via activating the p38 MAPK pathway). While this cortisol resistance obviously has a number of consequences across the body any brain, the cruel irony is that this cortisol signalling is crucial to limit inflammatory cascades that activate this p38 MAPK pathway. Additionally, cortisol resistance means reduced negative feedback to the hypothalamus and excessive activation of the stress response (which further drives endoxemia). Rinse and repeat. Cortisol resistance directly causes more endotoxemia and a reduced ability to handle the inflammatory reaction to these endotoxins, which leads to more cortisol resistance.  

It’s worth touching on this circular relationship, as it demonstrates how cortisol resistance can drive endotoxemia and vice versa. Endotoxemia is synonymous with increased intestinal permeability, which can occur via separation of intestinal cells (seen in gluten intolerance, food intolerances, alcohol consumption and inflammation) or through the opening of channels in the cells themselves (seen in the stress response). The takeaway here is that we must take action at the receptor itself and also on all causes of intestinal permeability, especially stress; for reference, I don’t expect this cycle to switch off unless HRV readings are regularly hitting 60 rMMSD or higher.

Having teased apart the difference between cortisol activity (more activity at the receptor) and cortisol resistance (less activity at the receptor), there remains at least one logical question: so what? Because even if we take steps to boost cortisol, surely the benefits will be short-lived because cortisol resistance will kick in at the receptor?



  • Cortisol resistance is present in a lot of inflammatory and stress-related conditions
  • If we ignore this issue, we give the individual little chance if achieving improvements
  • Action must acknowledge both the cyclical relationship of endotoxemia and cortisol resistance and provide support from both directions


Taking action at the receptor: nutritional approaches

No pharmaceuticals currently exist to modify receptor activity. However, there are a number of nutritional options that can help in these circumstances. These include:


  • Licorice Root. Licorice inhibits 11-b-HSD2, an enzyme that would otherwise break down cortisol. In doing so, it increases availability at cellular level. it is particularly relevant that, despite its reliable effects in increasing cortisol availability, does not show the neurotoxic effects that are seen with direct cortisol replacement (eg. prednisolone, hydrocortisone, etc) and instead shows a reliably positive effect on brain health (Dhingra & Sharma, 2006; Wang et al, 2008; Lai et al, 2020). This may because the mechanism involved (inhibition of 11b-HSD2) does not downregulate the receptor (this has not yet been studied) or may be due to concurrent effects the herb has on antioxidant response, BDNF production and mitochondrial output. Licorice exerts several other useful effects, including inhibition of endotoxin-induced inflammation.
  • Rhodiola Rosea. A famous adaptogen that enhances sensitivity at the cortisol receptor by inhibiting production of cellular stress signal JNK (a signal that would normally downregulate the receptor). It also demonstrates a variety of other properties, including a pro-serotonin and pro-dopamine effect (via MAO inhibition), antioxidant effects and upregulating the production of red blood cells.
  • Korean Ginseng. Ginsenoside RG1 enhances the glucocorticoid receptor, which restores the negative feedback at the hypothalamus (and subsequently reduces serum glucocorticoids). Through its effects at the glucocorticoid receptor, we see restored neuroprotection and neurogenesis. In cell studies, ginsenosides show protective effects on the receptor even when exposed to huge doses of steroids. They also upregulate downstream actors in neuroplasticity pathways, upregulating PI3K/Akt and inhibiting ERK. The Ginsenosides also reverses superoxide-induced suppression of ACTH release, which boosts cortisol levels in those with low production (thus explaining its famed ‘adaptogen’ effect in fatigue disorders)
  • Phosphatidyl Serine. This is a nutritional supplement that has long been used as an ‘anti-cortisol’ agent, based on a reduced cortisol output following the physical stress of exercise. It too works by restoring the negative feedback loop at the hypothalamus (which again means reduced activation of the HPA axis and reduced serum cortisol as a consequence). It reduces the expression of a secondary signal known as p38 MAPK, which is induced by exposure to lipopolysaccharides and causes a downregulation in the glucocorticoid receptor. Its integration into the cell membrane also permits a variety of secondary messengers in the cell, which accounts for many of its cognitive-enhancing effects.



I have lost count of the number of practitioners and individuals I have spoken to over the years who have expressed concern and resistance over the use of the above items. These concerns centre on the idea that cortisol is an undesirable side-effect of stress and that ‘lower is better’.

Cortisol signalling is central to the body’s resilience to stress. If it is disturbed, we can expect to see a myriad of problems and major obstacles in responding to therapeutic interventions. It is therefore vital to make this a central focus in any nutritional plan, with the understanding of the important benefits it offers and the options open to us to improve cortisol signalling. But perhaps this starts with the most basic step of all, which is by recognizing that cortisol is less ‘the stress hormone’ and more ‘the hormone that helps us cope with stress’.


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