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ADHD as a chronic stress regulation disorder

ADHD as a chronic stress regulation disorder

Our thoughts on stress and ADHD in no way question the accuracy of the current literature on ADHD. We do not see our thoughts in contradiction to the standard works, but as a supplementary illumination of a single aspect. A fortiori, no derivation of any “alternative healing methods” results from it.
We ask ourselves what part the stress systems, in particular the HPA axis, play in the development of ADHD symptoms and whether conclusions can be drawn from this for the understanding of ADHD.

“It is of great importance to understand the extent to which the HPA axis plays a role in the pathogenesis of ADHD-HI, as it affects pathways in the body that are often aberrant in ADHD-HI patients, such as: circadian rhythm, sleep, and emotions.”1

“Both animal and human studies found that prenatal maternal stress affects the brain and behavior of offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk that the child will have a range of emotional, behavioral, and/or cognitive problems later in life. These include depression, anxiety, attention deficit hyperactivity disorder (ADHD-HI), and/or conduct disorder. … Studies of the biological correlates and mediators of these findings suggest that the HPA axis plays a role in mediating the effects of maternal stress on the fetal brain.”2

According to our hypothesis, in ADHD there is - also - a disturbance of the stress regulation systems and here in particular of the HPA axis. There should be little reasonable doubt that the stress systems, especially the HPA axis, are closely linked to the central dopaminergic and noradrenergic neurotransmitter systems affected in ADHD.

“The [stress] system also activates (acutely and transiently) the mesolimbic dopaminergic reward system (connecting the VTA to the nucleus accumbens) and the mesocortical dopaminergic system (connecting the ventral tegmentum to the frontal-prefrontal lobe), while receiving inhibitory input from the latter.”34567

“Activation of the stress system stimulates arousal and suppresses sleep; conversely, sleep loss is associated with inhibition of the stress system.”3

ADHD symptoms, as we understand it, are caused in the same way as (the corresponding) symptoms of severe chronic stress: by an (action) deficiency of dopamine and norepinephrine in certain brain regions, primarily the dlPFC and the striatum.8 Nevertheless, ADHD is different from chronic stress, because ADHD remains even if the stressor leaves.

ADHD can result from several interacting factors:

  • Purely genetic due to a coincidence of gene variants that cause certain influences in the brain (in particular, a reduction in dopamine levels or dopamine action in the PFC and striatum) These factors are innate and unchangeable.
  • Epigenetic through inherited characteristics of genes, which influences their activity in such a way that they exert similar influences in the brain. For example, nicotine use by fathers or mothers before conception causes such epigenetic changes, which are inherited by the children over 2 to 4 generations. Nicotine consumption by the father before conception
  • Environmental influences (especially early childhood stress = first hit, as well as possibly further added stress in adolescence = second hit), which epigenetically change the own genes, so that they permanently change the dopamine level in the same direction.
  • Environmental influences that reversibly cause the same influences in the brain directly itself (e.g., lead, food intolerances, sleep disorders, etc.)

Of course, shortening to decreased levels of dopamine and norepinephrine in PFC and striatum is a simplification. Nevertheless, these are likely to be the most important factors.

So how does disruption of stress regulatory systems fit into this picture?
The following further arguments move us to suspect a close relationship between stress regulation and ADHD.

  • The relationship between genetic factors and environmental influences as an influence on an existing ADHD can already change within a few years.9 We are considering whether this does not indicate a significantly higher influence of environmental influences than previously assumed.
  • Chronic stress, depending on the stressor and the age of the individual, can have persistent influences on the brain that support the development of ADHD, e.g., dopamine and norepinephrine may be decreased in the PFC and striatum, which naturally produces identical resulting symptoms.
    • Acute stress tends to counteract the ADHD-typical influencing factors, since acute stress typically increases dopamine and noradrenaline in the PFC. This could explain why some affected persons can also experience acute stress, e.g. at work, as something positive, since they then “function better”.10
  • Purely genetically (i.e. not epigenetically) inherited gene variants can permanently alter the activity of the HPA axis. This is the case, for example, in the Spontaneous(ly) hypertensive rat (SHR), which serves, among other things, as a model animal for ADHD with hyperactivity. In this one, ADHD symptoms can be improved by dexamethasone, which acts directly on the HPA axis similar to cortisol. This proves that even gene variants not modifiable by environmental influences (i.e. epigenetic), which may be involved in ADHD, can affect the stress systems. In this case, stress is neither the cause nor the trigger of ADHD, but the stress systems are mediators of ADHD symptoms.
  • Neurofeedback, mindfulness training and psychotherapy are able to bring about lasting improvements in ADHD symptoms, although not a complete cure. We still know too little about what neurophysiological changes are mediated by this, but we suspect that this also occurs via changes in the stress systems of those affected. Research is needed here to confirm or refute this assumption.
  • ADHD often shows an increased sensitivity to stress. See 1.5 below.
  • Depending on the subtype, there are different changes in the stress systems.
    • ADHD-I (without hyperactivity) is (like melancholic depression) very often characterized by an exaggerated endocrine stress response. The excessive increase of noradrenaline during stress leads to a shutdown of the PFC (blackouts, inability to make decisions) while the excessive cortisol stress response leads to a too frequent shutdown of the HPA axis and to a TH1/TH2 shift of the immune system: less inflammation, more foreign body fighting (allergies).
    • ADHD-HI and ADHD-C (like atypical and bipolar depression) are often characterized by an insufficiently elevated (flattened) endocrine stress response, in which slightly elevated norepinephrine causes only activation but not shutdown of the PFC. Because cortisol down-regulates stress systems again at the end of its action, an insufficiently elevated cortisol stress response does not trigger sufficient re-shutdown of the HPA axis, leaving it trapped in the stress endurance state and causing permanent internal agitation and inability to recover.
    • In our view, the different subtypes represent different stress phenotypes, i.e. typical patterns of commonly occurring stress symptoms that most closely match the respective personality profile of the affected person. ADHD-HI tends to externalize stress, while ADHD-I tends to internalize it.
    • In a completely stimulus-poor environment (2 weeks in a mountain hut without internet and electronic devices) many (but probably not all) symptoms of ADHD disappear, but return immediately unchanged already with quite normal stress in quite normal everyday life.
    • There are likely to be other patterns of different stress system imbalances, but these have not yet been explored.
      For more on this (including sources), see The subtypes of ADHD: ADHD-HI, ADHD-I, SCT, et al as well as ⇒ The HPA axis / stress regulation axis
  • ADHD shows peculiarities in attention characterized by hyperfocus (task switching problems) on the one hand and distractibility (stimulus openness) on the other hand. This profile of altered attention is not dysfunctional under other circumstances, but is conducive to survival: under severe (survival) threatening stress. Severe (survival) threatening stress alters attention toward those things that are personally important. Motivability is lowered overall. Weaker motivability for things that are not personally interesting subsequently impairs attentional control and attentional performance. With high personal motivation or high extrinsic rewards, attention (also sustained attention!) and attention control function so well in ADHD sufferers that they can no longer be reliably distinguished from those of non-affected persons in tests.
    ADHD is pathological not because attention is altered in this way, but because it is so altered without an adequate stressor.
  • In our view, all ADHD symptoms are symptoms of stress. ADHD symptoms are stress symptoms Conversely, not all stress symptoms are ADHD symptoms.
    This does not mean that ADHD symptoms have to be triggered by acute stress. Especially in ADHD, they typically are not. As explained earlier, acute stress causes an increase in phasic DA and NE in the PFC and striatum, whereas ADHD and certain chronic stresses cause a decrease in phasic and tonic DA and NE in the PFC and striatum. Nevertheless, the symptoms caused by these are almost the same. This is because both too high and too low neurotransmitter levels in these brain regions cause almost identical, or at least very similar, symptoms: the signals that these neurotransmitters should mediate are altered. This alteration occurs when neurotransmitter levels are not optimal, i.e., when they are too high as well as when they are too low. If the symptoms are mediated by the neurotransmitter changes in PFC and striatum that are typical in stress, it would be conceivable that there is an entity that initiates these changes in stress. In the absence of an adequate acute stressor in ADHD, it would be conceivable that this instance mediates stress in ADHD without being appropriate.
    We have mentioned the Spontaneous(ly) hypertensive rat (SHR). Their genes (clearly defined and not epigenetically altered toward stress sensitivity by environmental influences) cause changes in the HPA axis that mediate ADHD symptoms, and ADHD symptoms (but also hypertension) are remediable in them by dexamethasone.
    Further, stress symptoms are not an end in themselves. They have a benefit. We call this the stress benefit. Stress benefit is the advantage an individual has in an actual life-threatening situation if he or she responds as conveyed by the stress symptom.
    • For example, the DRD4-7R gene variant commonly involved in ADHD is only 40000 to 50000 years old, which results in a much less sensitive D4 dopamine receptor (which is inhibitory, so in DRD4-7R the inhibition of the brain region is reduced). Now DRD4-7R is much more common today than a normal hereditary distribution would suggest. From this, evolutionary biology concludes that it must be an unusually successful gene. From this, one might conclude that the traits conferred by DRD4-7R are advantageous. However, these advantages could depend on the circumstances: in acute stress (much DA), the inhibition of the brain region in question is increased due to a higher inhibitory effect of D4 receptors. In chronic stress (little DA), inhibition is reduced. Over the last 50,000 years, individuals with this change appear to have survived more successfully. Whether this is still true for the last 5,000 to 10,000 years since sedentarization and especially for the last hundreds of years since industrialization and office work is an open question.
  • A study of 2,307 subjects found correlations between ADHD and neurophysiological biomarkers of stress.11
  • Meta-analyses on childhood biochemical studies found a significant correlation of ADHD with peripheral biomarkers associated with monoaminergic pathways and the HPA axis.12

While ADHD could (according to our hypothesis - also) be a stress regulation disorder, not every stress regulation disorder is ADHD. Stress systems are also overreactive in other mental disorders, e.g., depression or PTSD. For example, PTSD is characterized by increased levels of norepinephrine in the PFC, whereas norepinephrine is decreased in the PFC in ADHD. In epilepsy, stress increases the likelihood of seizures.1314
ADHD shows a very general activation / deactivation of the stress systems, whereby all ADHD symptoms would still be functional stress symptoms if they were the reaction to an adequate stressor (which, however, does not exist in ADHD). In contrast, in the case of e.g. depression, anxiety or compulsion, the respective stress symptoms have become dysfunctional.

To illustrate that all ADHD symptoms are stress symptoms:
ADHD symptoms are stress symptoms

The connection becomes comprehensible when one considers the benefits of stress symptoms. Stress is a very old control instrument of the human organism. In the development of Homo sapiens15 - which is 100,000 to 300,000 years old, depending on the account - as in the hominids, which have existed for several million years, a wide variety of mechanisms have evolved to protect the respective individual from situations that threaten survival: the stress systems we are talking about.
At least 97% of his time, until 10,000 years ago, Homo sapiens lived as a nomad. The urban way of life began only 2000 to 3000 years ago. Our stress systems have not yet been able to adapt optimally to the recent developments of big city life and office jobs, and still act today by causing symptoms that were optimized for living conditions when Homo sapiens was not yet sedentary.
In terms of hominid time, our stress systems could have used just 1/500 of their time to adapt to sedentariness. Converted to 24 hours (1440 minutes), that would be about 2 minutes and 50 seconds.

Our stress systems are tasked with helping us fight for survival.
When considering the benefits of each stress response,
Stress utility-the survival-enhancing purpose of stress symptoms It becomes easy to understand that all ADHD symptoms are functional (useful) stress symptoms.
ADHD symptoms are stress symptoms

For the diagnosis of ADHD it would be helpful if at least individual ADHD symptoms were not at the same time symptoms of (massive) stress. Then ADHD could be distinguished from a “mere” acute stress situation without chronified misreaction of the stress regulation systems on the basis of these specific symptoms. Unfortunately, no such ADHD symptoms have yet been identified, which is why ADHD in children is so difficult to distinguish from acute stress. In adults this is easier, because it is easier to find out whether there is an acute stress situation (children usually do not know any other life circumstances and therefore cannot put even severely stressful circumstances into perspective) and whether the symptoms have existed since childhood or adolescence.
Especially the core symptoms typical of ADHD, hyperactivity/impulsivity and attention problems, are classic symptoms of severe stress and, on closer inspection, very useful and helpful in combating an actual threat.
ADHD is characterized by stress symptoms occurring without an adequate stressor.

1. ADHD symptoms as chronic misregulation of the stress systems

ADHD usually results from a confluence of several components:

  • Strong genetic imprinting and/or
  • Genetic disposition plus early childhood stress experience.

1.1. Gene disposition

ADHD has a strong genetic component of 70 to 80 %. The heritability of ADHD is thus greater than that of intelligence. Nevertheless, so far only 5 % of the genetic heritability can be attributed to specific gene variants.
Genetic and epigenetic causes of ADHD.
This could also be due to the fact that only some of those affected have a purely genetic cause, while others only have a genetic disposition that only needs to be manifested by additional environmental influences.

1.2. Early childhood stress experience

If an early childhood stress experience is added to an existing gene disposition, the ADHD gene candidates can change epigenetically in such a way that ADHD now manifests itself.
How ADHD develops: genes or genes + environment.
Epigenetics means that (intense) experiences in life cause changes in gene expressions: the genes then have a stronger or weaker effect on the mechanisms they control. These acquired changes can in turn be passed on. How ADHD develops: genes + environment - chapter epigenetics

Early childhood stress can cause permanent damage to neurotransmitter systems (e.g., the dopaminergic system) and the physiological stress systems (HPA axis, vegetative nervous system). Prolonged or particularly intense short-term (traumatizing) stress also causes serious damage to the stress systems. For ADHD, early childhood stress experiences are more significant because this is the time when the stress systems are just emerging. Stress damage - effects of early childhood and/or prolonged stress

Since during the development of all neurotransmitter- and hormone-controlled systems a “calibration” always takes place at the same time in the form of an adaptation to the living conditions, unfavorable living conditions from conception to approx. 6 years are basically extremely harmful and lead to permanent maladaptations of the neurotransmitter or hormone systems.

Once the setting has been found, it remains almost unchanged after the development of the brain region in question has been completed. Figuratively, this can be compared to an engine that is installed in a car. If the car is crooked during installation, the dipstick will not measure correctly and the engine will be installed with too much or too little oil. One can also imagine wax that is filled into a glass and that cools down at the end of the developmental spurt of the brain region. If the glass was crooked until then, the wax will represent the crooked position of the glass in the development phase for a lifetime.

Finally, prolonged cortisolergic stress leads to neurological damage to stress regulatory systems, such as the hypothalamic-pituitary-adrenocortical (HPA) axis, also called the stress axis.
The HPA axis / stress regulation axis
Cortisol is activating in the short term, but neurotoxic in the long term. If cortisol stress lasts too long, various neurological maladaptations result.
Stress damage - effects of early childhood and/or prolonged stress

The etiology (gene disposition plus an early childhood stress experience that activates it) is not peculiar to ADHD but is reported in almost all mental disorders. Gene disposition and early childhood stress as a cause of other mental disorders Specific to ADHD, however, is the general overreactivity of stress regulatory systems.

ADHD symptoms such as hyperactivity and aggressiveness are also described as a Moro reflex persisting from infancy as a consequence of early childhood disorders of central nervous system development.16 The different name should not change the etiology.

These maladaptations lead to the specific consequences in ADHD-HI and ADHD-C, on the one hand, and ADHD-I subtype, on the other hand, as outlined at the beginning and in more detail in the articles mentioned there.

1.3. Maladjustments of neurotransmitter and hormonal systems; downregulation, upregulation

Stress symptoms are mediated by stress hormones, primarily CRH, ACTH, and cortisol. The HPA axis, which releases these stress hormones, is activated by a massive increase in neurotransmitters in the brain, primarily dopamine and norepinephrine, mediated by the limbic system.
The causes of individual symptoms must be distinguished from the activation of the HPA axis.
Stress symptoms can be mediated by any deviation of a neurotransmitter or hormone level from the optimal level for signal transmission - i.e., by an upward deviation as well as a downward one (Yerkes-Dodson law).171819

1.3.1. How stress usually occurs

The mechanisms by which acute stress is mediated in the unaffected are:

  • The phasic norepinephrine level and dopamine level2021 in the PFC increase.
    This causes
    • The dopamine level in the striatum decreases22
    • The HPA stress axis is activated,
    • Which causes the stress hormones CRH, ACTH and cortisol to rise,
    • Which then together trigger the stress symptoms.
  • Cortisol - as the last hormone to be released - terminates the stress response of the HPA axis again. Cortisol decreases dopamine levels and increases norepinephrine levels in the locus coreuleus, the PFC, and the striatum.23 The widely known reduction of dopamine levels in the striatum in ADHD is thus also a consequence of stress.

1.3.2. What distinguishes ADHD from general stress

ADHD is not a result of acute stress, but of chronic stress. ADHD is characterized by

  • Dysregulated stress regulation systems that have impaired dopaminergic and noradrenergic neurotransmitter systems due to too early and prolonged stress, among other things, by means of downregulation or upregulation of the receptor systems.
    See more at Mechanisms of damage from prolonged stress: downregulation/upregulation (in: Stress damage from early childhood and/or prolonged stress)
    • In ADHD, too many dopamine transporters (especially in the striatum) are probably formed. This can either be a consequence of genetic imprinting (the gene variant DAT1 10/10 associated with ADHD forms more dopamine transporters)24 or could possibly be a consequence of upregulation due to long-lasting reduced tonic dopamine levels in the striatum: dopamine deficiency correlates with an increase in the number of dopamine transporters.25
      The stress hormone cortisol triggers a reduced dopamine level in the striatum.23 Prolonged stress can lead to permanently reduced dopamine levels in the striatum and subsequently to the presented upregulation of the DAT.
    • In ADHD-HI (with hyperactivity), dopamine receptors appear to be downregulated in the cingulate cortex.26 Downregulation could indicate an oversupply of dopamine in the cingulate cortex. ADHD, however, is characterized by permanently reduced dopamine levels in the PFC. At most, it would be conceivable that receptor downregulation was already triggered by earlier chronic stress that was still associated with elevated dopamine levels. Similar changes occur in tonic (basal) cortisol levels during chronic stress.
  • A general, non-specific overexcitability

As a result, the stress systems in ADHD are dysregulated even in the absence of a specific stressor - whether they kick in too quickly and react too intensely (ADHD-I) or fail to shut down (ADHD-HI), see above.

Short-term stress (here: of the last month) has no effect on ADHD.27

1.4. The stress systems of humans

The different stress systems in humans (amygdala, central nervous system, vegetative nervous system, HPA axis) are presented in detail at The stress systems of humans.

1.5. Subjective stress response increased in ADHD

In addition to the biological / neurological changes in the various human stress systems in ADHD, the subjective perceptual intensity of the stress response differs significantly and reproducibly. The same increase in cortisol leads to a stronger perception of stress in ADHD sufferers than in non-affected individuals.2829
ADHD sufferers have a stronger psychophysiological response to the same stress as non-affected individuals, e.g., greater test anxiety.3031
This is particularly interesting in light of the fact that in healthy individuals, the cortisol and ACTH stress response correlates only moderately with subjective stress perception - a meta-analysis found a correlation of 0.3 to 0.5 in only 25% of 49 studies. Still, two-thirds of the studies found a correlation between cortisol stress response or ACTH stress response and subjective stress perception.32
The subjective experience of stress seems to correlate more with the physiological (cortisol) stress response during the acute stressful situation itself than with that before or after the acute stress.33

ADHD sufferers show a maladaptive response to stress. ADHD severity correlates with stronger stress transfer and higher negative affect. Stress transfer and mean negative affect scores mediate the association between ADHD-HI traits and internalizing problems.34

2. Stress biomarkers of ADHD

In a study, different immune system biomarkers of unmedicated ADHD sufferers and non-affected persons were compared.35 The evidence of changes found in various biomarkers compared to unaffected individuals is shown below in each case in parentheses. Regrettably, the study does not differentiate by subtype. We suspect that the results are likely to differ greatly between subtypes.

  • Erythrocyte glutathione (GSH) (INCREASED)
  • Plasma lipid soluble antioxidants
    • Retinol
    • Α-Tocopherol
    • Γ-Tocopherol
    • Retinyl palmitate (INCREASED)
    • Β-Carotene
    • Coenzyme Q10
  • Plasma malondialdehyde (MDA) (INCREASED in plasma)
  • Cytokines in blood
    • IL-
    • IL-5 (REDUCED)
    • IL-6
    • IL-8
    • IL-10
    • Tumor necrosis factor (TNF)
    • Interferon (INF) -γ
  • Immunoglobulins
    • IgM
  • 8-Hydroxy-2′-deoxyguanosine (8-OHdG) in urine (INCREASED)

Another study found in adult ADHD sufferers:36

  • Total thiol value reduced
  • Native thiol value reduced
  • Disulfide levels increased
  • 8-OHdG- values increased
    • 8-OHdG is considered a marker for DNA damage

3. ADHD symptoms are stress symptoms

If we compare the list of common stress symptoms with the typical symptoms of ADHD, we find that almost all typical symptoms of ADHD are also typical stress reactions. In contrast, not all stress symptoms that exist are also ADHD symptoms. ADHD symptoms are stress symptoms While ADHD has a very wide range of symptoms, the focus is on emotional, cognitive, and motor stress symptoms. ADHD manifests remarkably few somatic (physical) stress symptoms.
The other way around can be said as well: uncontrollable (cortisol tolerant) stress triggers symptoms identical to ADHD symptoms.

This explains, for example, why children who are bullied (e.g., unrecognized gifted children who cannot compensate for their “being different” due to poor social skills) are initially hardly distinguishable from ADHD sufferers: it is precisely this self-esteem-threatening stress that causes almost identical symptoms via the HPA axis. A misunderstood “not belonging” and “being different” threatens the self-worth much more than the boredom that is actually frequent for unrecognized gifted people, on the one hand due to underchallenge and on the other hand because gifted people (just like ADHD patients) are much more difficult to motivate extrinsically.

This leads to the question: if all ADHD symptoms are also triggered by stress - what is ADHD then? Does ADHD exist at all or do those affected “only” have too much stress?

The answer is:

  • Stress symptoms are triggered by deviations of neurotransmitter levels from the optimal moderate mean. In acute stress, for example, the phasic dopamine and norepinephrine levels in the PFC are elevated. This causes dysfunction of, for example, working memory in the dlPFC.
    In chronic stress, there is a long-term dysregulation of the tonic Neurotransmitter systems, which - depending on the stressor and the person affected - may be permanently increased or permanently decreased. Depending on which brain region experiences long-term up- or downregulation of which neurotransmitters, different risks for different mental disorder patterns result. ADHD is the result of a permanent reduction of dopamine and norepinephrine in the PFC and striatum. Genes that are unchanged by environmental influences have a compensatory or reinforcing character here (such as DRD4-7R, which makes dopamine D4 receptors less sensitive, so that they require 3 times as much dopamine as in other DRD4 gene variants). If a person with DRD4-7R were to suffer upregulation of dopamine and norepinephrine in the PFC, this would not be as severe as someone suffering downregulation because of DRD4-7R.
    The symptoms of dysfunctional working memory (disorganization, impaired executive functions) are neurophysiologically caused by decreased dopamine and norepinephrine levels in the dlPFC in ADHD, and by excessive dopamine and norepinephrine levels in acute stress. With excessive norepinephrine levels, a shutdown of the PFC occurs, whereas with flattened dopamine levels it does not - the PFC remains in steady state even during stress. This explains the difference in symptoms between ADHD-HI and ADHD-I. SCT, which might be particularly affected by PFC shutdown according to its symptomatology, should correlate with particularly high norepinephrine levels in the PFC if our hypothesis is correct. This could explain why stimulants work worse in SCT - these increase dopamine and norepinephrine in the PFC.
  • People who develop symptoms that seem like ADHD symptoms due to acute or chronic stress therefore do not have to have ADHD yet. If the symptoms disappear again after the overload is gone, there is no ADHD. In the case of ADHD, quite “normal” life circumstances without any particular stress are already sufficient to cause massive stress symptoms.37
    The former are purely stress symptoms due to acute overload, the latter are a chronic overreaction of the stress regulatory system - that is ADHD.
    Stress goes with the stressor - ADHD stays, even without an adequate stressor.
    In order to distinguish ADHD from acute stress, the diagnosis of ADHD is based on the occurrence of symptoms in various areas of life and their persistence since childhood or adolescence. A small percentage of affected persons (approx. 1 %) develop symptoms for the first time after the age of 16 (late onset).38

In early childhood, prolonged stress exposure subjects the body to prolonged elevated levels of CRH and cortisol. Stress hormones such as cortisol are neurotoxic, meaning that too much and too long stress damages the nervous system. One of the consequences of damage to the HPA axis from early stress is an alteration in cortisol receptors (downregulation/upregulation) Mechanisms of damage from prolonged stress: downregulation/upregulation (in: Stress damage from early and/or prolonged stress)

CRH and cortisol are designed to trigger fight/flight/freeze responses and, unlike adrenaline, are only released in response to highly aversive or novel stimuli. While epinephrine cannot cross the blood-brain barrier, cortisol is able to do so. Adrenaline is released more quickly and broken down again more quickly than cortisol.39

The consequence of this is that the body already reacts to smaller amounts of stress hormones (e.g. CRH or cortisol) with stress. This is likely to be the central cause of ADHD.

As mentioned earlier, the fact that all ADHD symptoms are symptoms of stress becomes vividly tangible when one considers the benefits of stress symptoms.
Stress utility-the survival-promoting purpose of stress symptoms

ADHD has - very generalized - the following interactions with stress:

  • Massive stress in childhood (cause of origin)
    • Activates a possibly existing genetic disposition for ADHD
    • Leads to undesirable developments in the stress systems such as
      • Reduced stress threshold
      • Downregulation of the receptors (cortisol, CRH)
      • Non-specific excitation (noradrenaline)
      • Downregulation of dopamine receptors in the striatum
  • This manifests a chronic misreactivity of the stress systems
  • As a result, ADHD sufferers are under constant stress even without an acute stressor
  • ADHD sufferers perceive stress more intensely than non-affected people at the same cortisol level (see above 1.5.)
  • Consequence of stress are stress symptoms
  • ADHD symptoms are general (functional) stress symptoms

4. High confusability of ADHD

The fact that all ADHD symptoms are stress symptoms also explains why ADHD is so easily misdiagnosed and occasionally even doubted. Sometimes acute stress is mistaken for ADHD, sometimes vice versa. Alleged ADHD sufferers who suddenly lose their symptoms because external circumstances change and acute stress is eliminated did not have ADHD. This does not mean that all other people with the same symptoms only had acute stress and no ADHD. There are people who suffer from acute stress and there are people who suffer from ADHD.
Whereas in non-affected persons the stress symptoms disappear again when the acute stress trigger is eliminated, whereby a healthy resilience returns in these persons, in ADHD affected persons the stress regulation system is permanently damaged. They develop the ADHD-typical (and possibly other) stress symptoms even when there is no situation that could justify such stress symptomatology, i.e. when there is no adequate stressor.

Therefore, a careful diagnosis is extremely important and must not be exhausted in the query of (currently existing) symptoms, but must carefully illuminate the current life circumstances and the development before their occurrence.
These correlations further make it clear that all psychological test diagnostics will never be able to prove the existence of ADHD, because by their very nature, tests can only determine the existence of symptoms as a snapshot, but this still does not prove a difference between acute stress and ADHD.
It is possible that ADHD could be distinguished subtype-specifically from acute stress using the dexamethasone/ACTH/CRH test or other measurable endocrine stress responses.

ADHD thus has a special position within the mental disorders.

  • Difficult diagnosis. ADHD is particularly often confused and (under- as well as over-) misdiagnosed due to its rather general stress symptomatology - precisely because ADHD has no particularly peculiar and specific symptom that facilitates an unambiguous diagnosis.
  • Easy treatment. No other mental disorder is so well treatable (acutely with medication and therapeutically in the long term).

5. ADHD and stress: a self-reinforcing system

We see in the high correlation between ADHD symptoms and low self-esteem or depressive symptoms an indication that dysfunctional stress regulation systems, once manifested in ADHD due to genetic predisposition and triggering unfavorable circumstances, subsequently form a self-reinforcing system. The unpleasant symptoms of ADHD reinforce the stress, which produces additional stress symptoms that may be congruent with ADHD symptoms. This results in a downward spiral of stress and ADHD symptoms responding to this as a resonance, causing further stress. This mechanism has been described several times, for mental disorders in general40 as well as for ADHD in particular,41 among others in a large cohort study in Sweden.42

Furthermore, especially in ADHD-HI and ADHD-C, the symptom of inability to recover is strongly represented. Inability to recover is a functional stress symptom: It is beneficial for survival not to indulge in pleasure and relaxation as long as there is a survival-threatening danger. It is equally an original ADHD symptom of the ADHD-HI and mixed types.
This is the reason why mindfulness techniques (e.g. yoga, meditation, ChiGong, etc.) are perceived as extremely aversive, especially by ADHD-HI sufferers. Thus, stress deprives sufferers of the opportunity to reduce stress through relaxation and mindfulness techniques.
The same applies to the symptom of dysphoria when inactive. This symptom, too, aims to keep the person active in order to combat the stressor. However, as in ADHD, if there is no adequate stressor, the stress symptom is meaningless.

There is a bidirectional relationship between negative life events and mental illness.
Pronounced ADHD causes other negative life events.

Most strongly correlated with negative life events are

  • Severity of ADHD-HI expression
  • Female sex
  • Low socioeconomic status and
  • Comorbid emotional disorders

The severity of ADHD-HI expression correlates more strongly with recent negative life events than with the expression of other comorbid disorders.4344
A study of stress levels in children with ADHD found that severe stress levels in childhood and adolescence were associated with severe ADHD-HI or ADHD-I progression into adulthood, whereas children with low stress levels often showed remitting ADHD (ADHD-HI as ADHD-I).45 A Swedish cohort study confirms this.42
Stressors in youth that predicted persistent ADHD were cited as:46

  • Chronic diseases
  • Disabilities of the child
  • Disabilities of another immediate family member
  • High work pressure at school
  • Problems at home
  • Neighborhood problems
  • Unemployment
  • Financial difficulties
  • Fewer friends than the child would like to have
  • Bullying
  • Ongoing conflicts with family members
  • Ongoing conflicts with a person outside the family
  • Family members with ongoing conflicts

6. The difference: stress goes with the stressor, ADHD stays

Compared to ADHD, stress has the “advantage” that it can also end one day. With the end of the stress load, the stress symptoms disappear in healthy people at the same time.
ADHD can also apparently be “gotten rid of” by retreating to a completely stimulus-free environment. ADHD sufferers lose their symptoms after spending several weeks in a secluded mountain hut (without cell phones or the Internet).
The difference becomes apparent when both return to a normal living environment that does not include any particular stress triggers. The non-affected person will continue to do well, while the ADHD sufferer will immediately develop the old symptom picture.

7. ADHD comorbidities as dysfunctional stress symptoms

The most common comorbidities of ADHD are

  • Anxiety / panic states
  • Depression
  • Constraints
  • Addiction

All these phenomena in their basic forms are also typical stress symptoms.
But here it already becomes clear: even if dysphoria in inactivity is a helpful stress response (in case of actual threat), it is obvious that depression, obsessive-compulsive disorder and anxiety are based on much more than a momentary, acute stress state. In such disorders, individual, specific stress symptoms are out of control (have become dysfunctional), whereas in ADHD the balance between stress symptoms (in the sense of a “healthy” stress response under the assumption of an existing threat) is still largely maintained. In ADHD, the state is disturbed (that stress exists even though there is no corresponding stressor), while the stress response itself is physiologically functioning largely correctly.
Acute cortisol tolerant stress may cause the stress symptoms equivalent to those of ADHD, but not readily symptoms of major depression or severe obsessive-compulsive behavior.
However, it has been proven that, on the one hand, depression can be caused by prolonged stress - and, on the other hand, that depressives are in a state of increased permanent stress.47 Early childhood stress in combination with the genetic disposition relevant for depression leads to a high susceptibility to depression.
How ADHD develops: genes + environment

Up to this point, the triggering cause and continuing mode of action of depression and ADHD coincide. In depression, a deficiency of serotonin, a hormone that serves to reduce stress, maintains the increased state of permanent stress.47 In ADHD, it is primarily the dopamine balance that is altered, and secondarily the norepinephrine balance, as well as, albeit more slightly, the acetylcholine balance and the serotonin balance (keyword: dysphoria during inactivity).
Stress also inhibits the melatonin balance, which normally counteracts stress states.

8. Correlation of stress sensitivity and ADHD in animal models

The Spontaneous(ly) hypertensive rat (SHR) is a genetically selected rat that is an animal model for ADHD-HI and hypertension.
The animals possess genes by which they develop hypertension (without early childhood stress experience) at the age of 15 months. At the same time, they are considered a scientific animal model for ADHD-HI (with hyperactivity) in ADHD research.48
With increasing age and in parallel with increasing hypertension, an increasing sensitivity of the HPA axis to stress is observed in animals.49
ADHD symptoms, as well as hypertension, are remediable in SHR by targeting the HPA axis with dexamethasone.

Unfortunately, it can be assumed that the mechanisms for remedying ADHD in SHR only work reliably in the (fixed) genetic constellation as it exists in SHR. This treatment method is therefore not transferable 1:1 - even from a scientific point of view - to the treatment of other genetic constellations or to all ADHD sufferers. However, it could be applicable to those whose ADHD symptoms are caused by exactly this neurophysiological pathway.

Spontaneous hypertensive rat (SHR)

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