Introduction

Since the stress response pathway is so critical to our health, it’s important to know what increases our stress response and what decreases it.

The problem comes when it’s activated too little, too much or it doesn’t have a good rhythm to it.  In other words, HPA ‘dysregulation’ is bad.

This has nothing to do with the capacity or your adrenal glands themselves but is related to a bunch of other factors as you will see. (See the myth of adrenal fatigue).

The HPA axis controls such vital functions as heart rate, blood pressure, and digestion. (R)

The HPA axis also communicates with several regions of the brain, including the limbic system, which controls motivation and mood, with the amygdala, which generates fear in response to danger, and with the hippocampus, which plays an important part in memory formation as well as in mood and motivation. In addition, the HPA axis is also connected with brain regions that control body temperature, suppress appetite, and control pain. (R)

Once activated, the stress response decreases growth, reproduction, metabolism, and immunity. (R)

Similarly, the HPA axis also interacts with various other glandular systems, among them those producing reproductive hormones, growth hormones, and thyroid hormones. (R)

Prolonged HPA activation will hinder the release of growth hormone and IGF-1, both of which are essential for normal growth. Cortisol also causes tissues to be more resistant to IGF-1. (R)

Most of these patients share psychological symptoms of too much HPA activation include sleep disturbances, loss of libido, and loss of appetite as well as physical problems such as an increased risk for accumulating abdominal fat. (R)

It’s a good idea to read my post on why stress is bad for a more detailed look.

Note that the HPA axis is not the only system that is part of the stress response.  Your sympathetic nervous system (SNS) is a different arm of the stress response, and it can be slowed by beta 2-adrenoreceptor blockers like propranolol. (R)

Psychological Stress and HPA Dysregulation

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Stressors that are uncontrollable, threaten physical integrity or involve trauma tend to have a high, flat cortisol release, with lower-than-normal levels of cortisol in the morning and higher-than-normal levels in the evening. This results in a high overall level of daily cortisol release. (R)

On the other hand, controllable stressors tend to produce higher-than-normal morning cortisol. (R)

HPA Axis and Disease

People with too low or too high cortisol are at risk for various diseases, especially cognitive related.

Chronic stress response activation (HPA) is believed to be a causal factor of:

Lack of the hormone CRH also results in the feelings of extreme tiredness common to people suffering from chronic fatigue syndrome. Lack of CRH is also central to seasonal affective disorder (SAD), the feelings of fatigue and depression that plague some patients during winter months. (R)

Frequent insomnia is more than just having difficulty falling asleep. Researchers found that, when compared to a group of people who did not have difficulty falling asleep, the insomniacs had higher ACTH and cortisol levels, both in the evening and in the first half of the night. Moreover, the insomniacs with the highest cortisol levels tended to have the greatest difficulty falling asleep. (R)

Common diseases like diabetes are associated with too much HPA activation and high levels of CRH (R). People with Alzheimer’s have high levels of cortisol, but it’s believed to be a result and not a cause of the disease (R).

In PTSD, there’s a lower-than-normal cortisol release, and it is thought that a blunted hormonal response to stress may predispose a person to develop PTSD (R).

Circadian Rhythms and the HPA axis:

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Alterations in the circadian rhythm of the HPA axis has been linked to the severity of autoimmune diseases (R).

Many conditions such as Autism have a dysregulated cortisol rhythm (R).

Most breast and ovarian cancer patients have alterations in their cortisol rhythm (R).

Studies in humans and animal models have revealed that cancer development is closely associated with the loss of a circadian rhythm.  This is because this rhythm controls energy balance, immune function and other important functions – much of which is controlled by the HPA axis.   These functions are involved in tumor suppression (including cell proliferation, apoptosis, and DNA damage response) (R).

This is why shift workers are at increased risk for so many chronic diseases (R).

Factors That Trigger Your Stress Response

Don’t be scared about everything that activates your stress pathway.  It’s natural and healthy for it to be activated moderately.

Psychological/Social stress (R)  Includes incomes insecurity and other occupational stress (R). Chronic stress increases CRH receptors in the PVN, which makes you even more susceptible to the harmful effects of stress (R). Everyone is affected differently by stress.  In many conditions such as Autism psychological stress over-activates the stress response pathway and results in too much cortisol (R).  In IBS, CRH causes significantly more ACTH when compared to people without IBS (R).  So we see that with a given amount of HPA activation, some people are affected more.

The following will increase your stress response:

  • Try to control an outcome
  • Try to change yourself
  • Try to exert your willpower
  • Try increase your motivation 
  • Do something you don’t want to
  • Make goals 
  • Have ambitions or try to get somewhere
  • Have a strong attachment – to an idea, object, person, etc…
  • Think about the past or future
  • Take life too seriously
  • Feel fear
  • Feel anxiety
  • Feel anger
  • Feel frustrated
  • Feel guilt
  • Feel jealousy
  • Feel hate
  • Feel embarrassed
  • Feel rejected 

Reduced Sleep (RR2)

Bad quality sleep (R)

Staying up late (R) – cortisol is increased when we are awake during our normal sleep times.

Stimulants (Caffeine (R),  Nicotine (via Acetylcholine…Increases ADH, ACTH, Cortisol) (R), Yohimbine (R), etc..),

Circadian Disruption see how to keep to a circadian rhythm.

Inflammation – Prostaglandins (R), IL-1b, TNF, IL-6 and Histamine (R)  (Food allergies, etc..), Arachidonic Acid (R) Eicosanoids (R), Platelet Activating Factor (R),

ROS/Oxidative Stress (R) –ROS inhibits negative feedback to POMC, which increases cortisol. 

Hypoglycemia/Low blood sugar (R) – from a bad diet, insulin resistance or a hypothalamic problem.

Intense prolonged exercise (R), Strenuous Breathing (IL-6, IL-1) (R)

Bacterial, Viral or other infections (from inflammation) (R, R2)

Physical trauma/Injuries/Surgery (R),

Hypoxia, High altitudes (R)

Pain (R),

Dietary: Eating (esp men) (R) – mostly caused by VIP (R) Lectins (subjective), Protein restriction/Leucine deprivation (R), Excess sodium (R),  Severe calorie restriction (R), Excess omega-6 (R), Intermittent Fasting or regular Fasting  (R) – Modern Ramadan practices in Saudi Arabia are associated with excess evening cortisol (and increased insulin resistance.) Other kinds of fasting might decrease CRH (R)

Body fat/Obesity (fat tissue produces cortisol from cortisone) (R),

Gut permeability (R) – when your gut is permeable, bacteria/endotoxins are capable of passing through your gut lymph node, liver and spleen, which causes inflammation.

Sun/UVB (locally, on skin) (R)

Light (R, R2) and Smells such as pheromones (R)

Cold (R) or Hot (R) temperatures.  Chronic cold increases CRH receptors, caused by dopamine. (R)

EMFs

Nutritional: Vitamin A inadequacy (R, R2), Zinc inadequacy (R), Magnesium inadequacy (R, R2R3).  Chromium (in-vitro) decreases cortisol at high doses. (R)  Potassium loading (R) – increases ACTH and cortisol in humans…This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol. This may also have a role in rheumatoid arthritis pain; cell potassium is always low in RA. (R)

Lifestyle: Smoking (R) (even just a 2 cigarettes), Long commutes (R), Noise (R), ‘Low Power Postures’ (R)

Excess Alcohol consumption (R).  Continuous consumption of alcohol over an extended period of time has been shown to raise cortisol levels in the body. (RMarijuana/Pot/THC (R) – dose-dependently raises cortisol. Opioid withdrawal. (R)

Toxins such as heavy metals like cadmium (R), but likely many others.  Fish with elevated mercury, PAH, PCBs had a decreased cortisol response (R), so other toxins can impair cortisol.

Hormones: CCK (R, R2), NPY (R), Estrogen (alpha, beta – CRH) (R), Pregnenolone, DHEA (R), GLP-1 (R), Leptin (R), VIP (raises CRH) (R)Sex hormones (R), Thyroid hormones (R), Vasopressin (releases CRH (R) and ACTH (R)), Ghrelin (R), AngiotensinII/ACE (R, R2), Insulin (R), Substance P (CRHR1) (R, R2), Low estrogen   and melatonin supplementation increase cortisol levels in postmenopausal women. (R) MSH (prevents fasting-induced decrease in CRH) (R)….Insulin can cause the release of vasopressin, which stimulates ACTH/cortisol. (R)

Peptides: Orexins (R), NGF (R), BDNF (R)

Neurotransmitters: Noradrenaline (R), Glutamate (R), Dopamine (D1/D2) (CRH in PVN) (R) – contradictory (R), Serotonin (specifically 5-HT2CRs): Serotonin increased CRH and its neuronal activity and CRH (and corticosterone release). (RR2)  Acetylcholine (R). Chronic SSRI usage increases CRH, but decreases ACTH and therefore cortisol (R), but fluoxetine decreases CRH (R).

Drugs/Supplements/Devices: LLLT (probably) (R), Potassium Chloride (R), 5-HTP (R), Finasteride (R), Naloxone (R) – Aspirin augments (R), Rehmannia, Lj100, Resveratrol (cortisol) (R), Forskolin (R, R2), Luteolin/PDE4 inhibitors (R), Curcumin (in goldfish, but my experience does not support this) (R), Valproate/Depakote (R)

Lithium increases vasopressin, which stimulates ACTH and cortisol (R).

Sexual stimuli increase cortisol in some women, while it’s decreased in most women (R).

Factors That Counteract Your Stress Response

Lifestyle: Positive social encounters (R), Laughing/being happy (R),

Meditation (R), Yoga (R), Being physically active (lowers cortisol in longer term) (R), Massage therapy (R), Regular dancing (R), Music therapy (R), Glucose restriction/fasting (careful) (R), Chewing (CRH) (R), ‘High Power Postures’ (R)

Supplements/Drugs: Oxytocin (R), Endorphins (R), Probiotics  (R), Phosphatidylserine (R), Magnesium (decreases CRH, ACTH response to CRH, Cortisol response ACTH) (R, R2, R3R4),  Selenium (R), Lysine (R), Vitamin C (R), Fish Oil/DHA (CRH) (R, R2), Curcumin (R), Aromatherapy (orange) (R), Bile (maybe – CRH) (R), Black Cumin Seed Oil (R), Rhodiola/Salidroside (CRH, enhances GR) (R), NSAIDs (R), Methylcobalamin (ACTH, CRH?) (R), SAM-e/Hydrogen Sulfide (in response to stressor, CRH) (R), NAC/Hydrogen Sulfide (in response to stressor, CRH) (R), P5P/Hydrogen Sulfide (in response to stressor, CRH)  (R), Lipoic Acid (CRH) (R) – contradictory (R), St John’s (R), Fluoxetine (R), Imipramine (R)

Vagus Nerve Stimulation (R)

Hormones: GHRH (in men, but not women) (R), NPY – antagonizes CRH, even though it increases its release (Y1 receptor, lateral septum)(R, R2), Growth Hormone? (R?), Prolactin? (R?), Progesterone (lowers CRH), Allopregnanolone (progesterone metabolite) (R), Testosterone (R) – In people, testosterone increases ACTH and lowers cortisol in response to CRH (R).  In male animals, DHT reduces corticosterone response to stressors.  So finasteride can increase the stress response by reducing DHT. (RCortisol inhibits CRH but not neuronal excitation (R).  a-MSH lessens the stimulatory effects of IL-1b on the HPA axis. (R)

GABAergics inhibit the HPA axis.  This includes GABAb (R, R2) or GABAa (RR2).  Note that in normal situations, GABA inhibits CRH.  But after stress, GABA can actually stimulate CRH. (R)

GABAergics supplements include Progesterone (R)Hi-Maize/Butyrate, Ketogenic dietsHonokiol (R), Theanine (R), Hops (R), Chinese Skullcap (R), Kava (R), Valerian (R), Ginkgo (R), Taurine (high dosage), Ashwagandha (weak), Bacopa (weak), Astragalus (weak), etc..

GABAerbic drugs: Benzos (mostly GABAa), Baclofen (GABAb), GHB (GABAb), Phenibut, Picamilon,

Others:

My favorite way to decrease the stress response is by putting a device called ICES on my head, which also decreases inflammation.

PEMF (higher AM, lower PM) – depends on device used (R), tDCS (R), TMS (CRH production and release) (R, R2), Electroacupuncture (R), Schisandra (Cortisol)(R), Anti-depressants (‘regulate’) (R), Aspirin (ACTH/cortisol levels after awakening, increased WM) (R, R2), Nrf2 (R),  Mucuna, CES, Uridine, Chayawanprash, Ursolic acid, Tribulus, Ginseng, Cordyceps, Ginkgo,

Decreases Cortisol: Rooibos (11β-HSD1(-) (R), EGCG (11β-HSD1(-)) (R),

NPY Stimulators: Eleuthero (NPY) (R), Schisandra (NPY) (R),

Adrenal glandular has cortisol and Licorice and Grapefruit Juice increase cortisol, which inhibits CRH, the first part of the stress response.  So the effects are variable.

Separation of monkeys from their mother causes long-lasting changes in the HPA axis, resulting in lower cortisol levels overall and a lack of a circadian cortisol rhythm (all bad) (R).

Cortisol Circadian Rhythm

Here’s a simple way to think about the circadian rhythm.  The body has thousands of processes going on at any given moment.  Many of these processes function better in concert with other processes – just like in a symphony, where different sounds work better with other sounds.

These processes have a certain rhythm or flow. The body conducts this orchestra with ‘clock genes’.  When they get expressed, it happens all over the body, in a synchronous way.

When I disrupt my circadian rhythm, I notice increased inflammation, oxidative stress and my cognitive function goes down.  This happens in people whose circadian rhythm isn’t functioning well (R).

Since our HPA axis (includes CRH, ACTH, Cortisol) is involved in so many bodily functions, it’s important that it has a good rhythm to it.

In humans, cortisol levels peak in the early morning (approximately 8 a.m.) and reaches its lowest level at about midnight-4 a.m., or three to five hours after the onset of sleep.  Information about the light/dark cycle is transmitted from the retina to the suprachiasmatic nuclei in the hypothalamus (R).

While people differ in their cortisol rhythms, a given person tends to have consistent rhythms (R).

It’s also important to realize that the ratio of cortisol to DHEA has various effects.

23andMe Genes

SelfDecode is the best gene analyzer around and helps you interpret your genetics from 23andme and ancestry

  • Higher levels of BDNF (See BDNF genes) increases the stress response by increasing CRH.
  • Low levels of COMT (see COMT genes) increases the stress response by increasing dopamine.
  • Lower levels of MAOA (see MAOA genes) can increase the stress response by increasing some catecholamines like noradrenaline, adrenaline, and dopamine.
  • Having certain Oxytocin genes can counteract the stress response.

Prenatal/Childhood Stress and the HPA Axis

Stress Before Birth

There is evidence that prenatal stress can influence HPA regulation.

In animal experiments, exposure to prenatal stress has been shown to cause a hyper-reactive HPA stress response (R).

Rats that have been prenatally stressed have elevated baseline levels and abnormal circadian rhythm of corticosterone as adults (R).

Several studies have found an association between maternal depression during pregnancy and childhood cortisol levels (R).

Additionally, they require a longer time for their stress hormone levels to return to baseline following exposure to both acute and prolonged stressors (R).

In humans, prolonged maternal stress during gestation is associated with mild impairment of intellectual activity and language development in their children, and with behavior disorders such as attention deficits, schizophrenia, anxiety, and depression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems (R).

Prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood (R).

Early Childhood

Exposure to mild or moderate stressors early in life has been shown to enhance HPA regulation and promote a lifelong resilience to stress. In contrast, early-life exposure to extreme or prolonged stress can induce a hyper-reactive HPA Axis and may contribute to lifelong vulnerability to stress (R).

Mothering may enhance HPA functioning in at least two ways.

First, maternal care is crucial in maintaining the normal stress in a period where the HPA doesn’t activate much in childhood. Extreme stress of maternal separation may lead to permanent HPA dysregulation (R).

Second, increased maternal handling (hugging, kissing) has been shown to alter expression of the glucocorticoid receptor gene implicated in adaptive stress response (in animals) (R).

Adult victims of childhood abuse show increased ACTH concentrations in response to CRH/stress, compared to healthy controls and people with depression but not childhood abuse (R).

Early life stress causes heightened neuronal activity in response to stress-induced CRH release.   With repeated exposure to stress, you’ll continue to hyper-secrete CRH. Over time, CRH receptors in the anterior pituitary will become down-regulated, producing depression and anxiety symptoms (R).

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24 COMMENTS

  • alice1128

    Hi so is GABA to be avoided? Is seems like its been helping me?

  • Martin

    What lifestyle factor could be changed or supplements introduced for someone with cortisol too low? I do not want to start to smoke, drink alcohol and coffe and stay up late. (Although it may look like attractive lifestyle to many 🙂 )

    1. Martin

      Specifically if caused by long term topical steroids usage, now discontinued.

  • Geoff

    JOSEPH M. COHEN,

    What are your thoughts on NSI 189 and it’s effects on stress response. Do you think NSI 189 could be therapeutic for someone with HPA dysfunction.

    I have low cortisol apparently. It actually feels like high/low bouts. I’d taken NSI 189 and got some fatigue but it sure as hell cleared the depression which is so nice because I could finally enjoy life! I have stopped taking it due to the concerns stated above but my mental health has got worse 4 weeks after use. Depression, anger all that has come back. What are your thoughts on this substance and it’s a effect on someone with low cortisol?

    Great article!

    Thanks for your response in advance.

  • daniel

    where exactly do you put the ices device on your head to reduce stress?

    1. Joseph M. Cohen

      For stress, ICES is not my top recommendation.

      I recommend it for

      Injuries, especially bone injuries
      Pain,
      Fatigue (on head)
      Food sensitivities when put by the gut.
      Stimulating the thyroid (when placed on thyroid)
      Increasing testosterone (experimental, when placed on testes). One person said their testosterone doubled after they put it on their testes.

  • Remy

    I wonder if you meant high dose chromium *inhibits* cortisol production, not increases?

    “This study suggests that at high concentrations, CrPic inhibits aspects of steroidogenesis in agonist-stimulated adrenocortical cells.”

    1. Joseph M. Cohen

      Yes, I did mean that. I changed it.

  • Dave

    You missed the MOST important factor about COMT and stress response, its not dopamine, its the fact the people can’t break down adrenaline and noradrenaline, this is a huge problem.

    1. Dave

      Huge problem I mean for these people (like me), many people who seen their result and dug deeper into it have proclaimed similar to this person, “2 homozygous COMT snps and one homozygous MAO snp plus countless heterozygous ones. THOSE COMT’s put everyone of my (first) 58 years in focus. No ability to shut off my adrenaline.”

  • Ole

    5g of taurine with 3g ish of glycine produced a really potent effect in me. 1g taurine and up to 10g of glycine in isolation does not do this so im thinking its either just the 5g of taurine or maaaaybe the combination.

    Results were:

    – The heart palpitations that ive had for a year are gone, (Heart beating really hard/increased awareness of it in upper body, neck and head)
    – Slowing of heart rate
    – Extreme reduction in anxiety similar to Valium and or Phenibut. (More similar to phenibut without the stimulated feeling pheni has)
    – Euphoria (pronounced, not like a drug but my depression is gone and i cant force myself to think negative at all)
    – General well being and reduction in fatigue (I have diagnosed CFS/ME)

    Probably a one time thing but this effect is more potent than any other natural substance on this list (tried all of them in high doses)

    Only thing more powerful is benzos and pheni. But low dose pheni is weaker.

    Ive taken 1-2g taurine for a long time so i was not deficient.

    1. Ole

      Also did this:
      – Eliminated caffeine side effects (severe anxiety, panic, and heart palpitations/arrhythmia)

    2. Joseph M. Cohen

      Let me know if that’s consistent

  • Andrew

    Discovered this blog today and I am hooked. Thank you Joe for pioneering (test-driving) many of the techniques covered.

    An interesting note, is that the enzyme (5a-reductase) which is inhibited by finasteride/dutasteride is the enzyme which catalyzes the reaction of progesterone into 5α-dihydroprogesterone, in addition to reducing testosterone to DHT. 5a-dihydroprogesterone is then reduced, via 3α-hydroxysteroid dehydrogenase, into allopregnanolone.

    Administration of 5a-reductase inhibitors has been associated with heightened levels of anxiety in animal studies and anecdotally in humans.

    I personally have experienced this anxiety provoking effect, when using dutasteride to prevent alopecia.

  • jules

    “…a 43% significant reduction in density of glutamic acid decarboxylase (GAD)” A reduction in the enzyme density? 😛

  • Smurfed

    Is it possible for Methyl folate to activate a stress reaponse?

    1. Joseph M. Cohen

      I can’t see how

    2. Steve C.

      I definitely have a stress response to activated folate. I have to take separate B vitamins to avoid the folate and B12.

      1. Alba

        I agree. I don’t do well with high amounts of methyl donors.

  • Dylan

    Nice write up. I really believe HPA-axis dysregulation and or high cortisol is an epidemic. One doctor I spoke to mentioned that so many people had high cortisol but the difference was how they felt. Many people with high cortisol levels aren’t bothered by them, but some are extremely sensitive. I wonder if this has to do with the cortisol receptor density.

  • lolipop

    this is unrelated but i remember how you wrote about your grandmother and i had the same exprience yesterday,she died at 91 years old. she was practically unMOBILE, almost none eating and dialysis patient before death.
    for 3 years she had dialysis. maybe the excessive medicine she took messed up her kidneys.

  • Jiri

    Joe, I have rs6265 CT genotype on 23andme. You are talking about GG or GA. How to understand that please? I’m lost…thank you!

  • mike

    I am not sure why but whenever I have a important work related event (meeting, presentation…) I feel very tired and very sleepy. This is a pain, because the performance degrades big time… recently, I was in a meeting with a client and i really felt like sleeping in the chair during the meeting. I felt like i had to make a huge effort to speak…

    The day before the meeting/presentation I am OK but on the day i feel very very tired. It is strange because I don’t sleep bad the night before the event and I don’t experience the typical nervosity or anxiety that comes with stress
    I also have a healthy lifestyle,

    Is this common? I cannot find info in the internet about such case

    Thanks!!!

    1. William D B

      The term for that is Ideopathic Hypersomnia.
      I don’t know much else.
      But I think following Joe’s tips on sleep and health generally might help a lot with it. Or not. I don’t know.
      The BHMT-08 gene has a similar but different effect.
      The treatment for BHMT is, avoid PUFAs.

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