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Cortisol and other stress hormones in ADHD

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Cortisol and other stress hormones in ADHD

1. Stress hormones in ADHD

In ADHD, various stress hormones are altered.
The stress hormones discussed below, cortisol, ACTH, and CRH, are the 3rd, 2nd, and 1st stage stress hormones of the HPA axis. Alpha-amylase is a biomarker of autonomic nervous system activity.

In summary, it must be assumed that although the cortisol response to acute stressors, which is often flattened in ADHD-HI and very often exaggerated in ADHD-I, is a biomarker for a pathological alteration of the HPA axis, the alteration of the cortisol response does not represent the cause of ADHD. Comparable experiences are made in the treatment of depression.1

However, too many studies suffer from the fact that in ADHD, as in depression, the externalizing subtypes (ADHD-HI, atypical depression) and the internalizing subtypes (ADHD-I, melancholic depression) are not recorded separately.

2. Cortisol responses to stress and personality traits

2.1. High cortisol response: internalizing, low cortisol response: externalizing

We have collected quite a few sources showing that high or low cortisol stress responses in healthy individuals correlate with gender and with various general personality traits.
For more, see Cortisol stress responses and personality traits in healthy individuals In the section Stress response patterns in healthy people of the article Stress theories and stress phenotypes: a possible explanation of ADHD subtypes.

2.2. Cortisol responses as an expression of stress phenotype

The available research strongly suggests that externalizing or disruptive behaviors, such as aggression, with or without a presence of (comorbid) Oppositional Defiant Disorder (ODD) or a symptomatically more severe Conduct Disorder (CD), are associated with lower basal cortisol levels and a flattened cortisol response to acute stress.

Elevated basal blood cortisol levels in 15-year-old ADHD sufferers (decreasing in the late afternoon) correlated with aggression in boys but not in girls.2 Another study found a correlation of aggression with flattened cortisol responses to acute stress, while basal cortisol levels remained unchanged.3

In contrast, depression or depressive personality traits45 6 as well as anxiety78 correlate with elevated morning (CAR) or serum cortisol levels.
Cortisol in other disorders

If - as we assume - not only ADHD but also the other mental disorders mentioned here are understood as dimensional disorders and further ADHD-HI as externalizing stress phenotype and ADHD-I as internalizing stress phenotype, the thesis suggests that primarily the stress phenotype could determine the cortisol response to acute stress (or the cortisol response to acute stress could predict the stress phenotype).
This view further leads to the conclusion that dexamethasone testing of the HPA axis for cortisol reactivity could only determine whether an HPA axis disorder is present and whether it results in an externalizing or an internalizing stress phenotype, but not which mental disorder is present within each spectrum.

It is argued that cortisol stress responses are more predictive of comorbidities than ADHD. According to this view, blunted cortisol responses to stress are said to be associated with comorbid DBD (disruptive behavioral disorder), whereas high cortisol responses are associated with comorbid anxiety disorders.910 This is consistent with our view of correlating blunted cortisol stress responses with externalizing and exaggerated cortisol stress responses with internalizing disorders.

Reduced exchange between brain hemispheres appears to be a cause of reduced cortisol stress response (especially in PTSD), as well as alexithymia.11 Further, a coincidence of decreased basal cortisol levels (despite normal cortisol response to ACTH) and alexithymia is reported in some sufferers of chronic stress, from which the authors inferred ACTH-independent mechanisms that decrease cortisol levels.12

2.3. Cortisol responses by time course

It is problematic that the individual stress cortisol response maximum differs by up to 20 minutes. In a group of 54 healthy adults, the cortisol maximum in the early group occurred immediately at the end of the 15-minute TSST stressor (cortisol increase from 0.04 to 0.21 ng/ml), whereas in the late group it occurred 20 minutes later (from 0.05 to 0.22 ng/ml). If both groups had been examined immediately after the end of TSST, the late group would have been incorrectly categorized as responding predominantly to stress with a flattened cortisol rise from 0.05 to 0.07.13 In most studies, a cortisol measurement 20 minutes after the end of the TSST is common. The question arises as to whether the early group’s cortisol rise lasts long enough to be cleanly detected when measured after 20 minutes.
Many studies do not take enough cortisol samples at the end of the stress test to account for this.

According to one source, the cortisol levels of ADHD sufferers only deviate (upward) from those of non-affected persons even under stressful conditions if relationship-relevant topics were the subject of the stress test (increased sensitivity to relationship topics), but not in the case of purely cognitive stressors.14 This is not confirmed by most research. To clarify this, a distinction is made below between cognitive and emotional stressors.

2.4. Cortisol responses by gender

Cortisol responses to stress also differ by sex.15

2.5. Cortisol responses to stress in the unaffected

  • Among 102 non ADHD-diagnosed five-year-old children, HPA activity was significantly higher in girls than in boys. Emotional stress (story telling away) caused a significant increase in cortisol in all children, and this was even higher in girls than in boys. Increased HPA system activity (basal and stress reactive) correlated significantly with hyperactivity/impulsivity and emotional problems in boys and with positive emotions in girls.16
  • Chronic stress decreases the morning cortisol maximum (CAR, typically 30 to 60 min after waking) in healthy young men (mean 22.5 years).17 Even low levels of stress increased baseline levels upon awakening and significantly decreased the CAR maximum (30 min after awakening). Severe stress led to an even significantly higher baseline value with a likewise flattened CAR, which moreover already occurred 16 min after waking.
  • The cortisol response to physical stress is dependent on
    • The individual cortisol resting concentration and the preload1819
    • Of muscle mass. The cortisol response to physical stress is relatively lower with larger muscle mass than with smaller muscle mass.20 According to our assumption, this could simply be due to the lower relative load when one and the same work is performed by more muscle mass.
    • The current blood glucose concentration and insulin availability before the start of the load 21
      • The rise in cortisol during physical exertion is predominantly triggered by a probably adrenergically mediated rise in ACTH22
      • In addition, glucose-sensitive receptors in the liver and brain modulate load-induced
        Cortisol response through activation of the pituitary-adrenocortical axis22
    • A metastudy of 29 studies on 2601 subjects found no correlation between externalizing behavior and a (flattened) cortisol stress response, as should exist according to the hypothesis we advocate.23

2.6. Interplay between cortisol and dopamine

Glucocorticoid receptors are located on numerous dopaminergic cells of the midbrain and hypothalamus.24 Cortisol is thought to influence dopamine release in the basal ganglia and in nigrostriatal and mesolimbic pathways.25
Cortisol inhibits tyrosine hydroxylase, an enzyme that limits catecholamine synthesis by serving as a catalyst for the conversion of tyrosine to DOPA. Tyrosine hydroxylase is inhibited by cortisol (as well as by dopamine and norepinephrine themselves (negative feedback).26
This suggests a reciprocal interplay between dopamine and cortisol release.

A retrospective analysis found a correlation between inhaled corticosteroid use in younger children with moderate to severe asthma. This correlation was not found in older children.27

2.7. Interplay between CRH and norepinephrine

The hypothalamus, which releases CRH, is closely connected to the nucleus coeruleus, which produces noradrenaline. CRH activates norepinephrine release, while conversely, at the same time, norepinephrine stimulates CRH production.26

3. Changes of cortisol levels in ADHD

A large number of studies have been devoted to the question whether and how the HPA axis reacts deviantly in AD(HHD). There is now massive evidence that there are sustained changes in the HPA axis in ADHD.

Epidemiological and preclinical studies have shown that HPA axis dysfunction in ADHD may result from excessive cortisol exposure in the fetal and early postnatal period (early childhood stress). Glucocorticoid administration at this stage of life may permanently alter glucocorticoid receptors in the brain, causing dysregulation of HPA axis activity, disturbances in the biosynthesis of neurotransmitters and their receptors, and alterations in intracellular pathways. Glucocorticoids (cortisol) enhance the activity of the dopaminergic system. Decreased expression of glucocorticoids could thereby cause the underactivity of the dopaminergic system.28

A fundamental distinction must be made between basal cortisol levels and cortisol responses (reactions) to acute stress. While the subtypes of ADHD differ by reduced basal cortisol values compared to non-affected persons, but not by deviations among each other, the cortisol response to acute stress of ADHD-HI/ADHD-C on the one hand and ADHD-I subtype on the other hand differs considerably and systematically from each other and deviates in different directions from the values of non-affected persons.
Basal cortisol levels thus distinguish ADHD sufferers from non-affected individuals, and cortisol responses further distinguish subtypes.

Furthermore, it is striking that in ADHD-I (without hyperactivity/impulsivity) the stress-induced cortisol increase is significantly higher than in non-affected persons, whereas in ADHD-HI (with hyperactivity) as well as in ADHD-C acute stress triggers a significantly lower cortisol response than in non-affected persons.

This may be relevant to treatment because cortisol not only mediates the stress response of the HPA axis but also acts as a feedback loop to calm and deactivate the stress systems (the HPA axis and central nervous system).

We hypothesize that a one-time higher cortisol administration in ADHD-HI could shut down the stress systems again. If the cortisol response that signals the shutdown of stress systems is absent, it would at least be worth considering compensating for this with a one-time cortisol substitution. Since a high cortisol stress response is a healthy response to shut down the HPA axis again, no disadvantages should necessarily result from a one-time intermittent administration. For ADHD-I sufferers, on the other hand, this is unlikely to be useful by its very nature.

Dexamethasone could be recommended for this purpose, as it addresses GR 30 times more strongly than MR. If necessary, a combination with an MR antagonist such as eplerenone could be considered, as it was used in a study for the treatment of back pain.29

Cortisol administration could not only downregulate the HPA axis but also support downregulation of the PFC.
Stress-induced highly elevated norepinephrine inhibits PFC and working memory function via norepinephrine-α1 receptors to shift action control from slow analytic control by the PFC to rapid instinctive control by older brain regions because this is advantageous during fight or flight.
Stress-induced high cortisol release leads to stimulation of these same norepinephrine-α1 receptors in the PFC. The simultaneous addressing of these receptors enhances the effect caused by high norepinephrine levels.30
In healthy individuals, the endocrine stress responses of norepinephrine and cortisol correlate, so that a coincidence of high norepinephrine and high cortisol levels can trigger PFC deactivation.

Cortisol plays a role in ADHD,31 but not in inhibition.32

3.1. Cortisol responses to stress in ADHD altered in a subtype-specific manner

Quite a few studies have looked at the cortisol response of ADHD sufferers to stress by measuring cortisol levels before and after stress exposure.

However, a distinction must be made between ADHD-HI (with hyperactivity) and ADHD-I (without hyperactivity). If this differentiation is omitted, even meta-studies find no difference in the cortisol stress response of ADHD to non-affected individuals.33

Chronic stress exposure decreases the expression of the glucocorticoid receptor (GR), which shuts down the HPA axis after a stress response. A slower decline in cortisol levels to baseline after an acute stressor, i.e., a prolonged time to recovery, was observed.34

3.1.1. Responses to cognitive stress in ADHD

  • 51 of 68 ADHD-affected children (mean age 8.8 years) showed no increase in cortisol on an unspecified “psychological test as stressor”. It is possible that the Hamburg-Wechsler Intelligence Test (WISC-III) was also used as a stressor. The 17 subjects with cortisol increase under stress had higher IQ, although the report is not clear whether this is the IQ value measured after stress or the IQ value without stress. The pretest cortisol level correlated with IQ. The lower the cortisol level after the test, the lower the IQ of the subjects.35
  • 20 Children with ADHD and comorbid Oppositional Defiant Disorder (ODD) and Social Behavior Disorder (CD), thus with high levels of aggression, showed no cortisol increase to a cognitive stressor at age 4 to 6 years as 2 years later at age 6 to 8 years. ADHD sufferers whose problem persisted showed a flattened cortisol response.36 This is consistent with the other studies in that ODD and social behavior disorder are typical comorbidities of the hyperactive/impulsive ADHD-HI subtype, for which a decreased/absent cortisol rise is commonly reported.
  • Of 48 children exposed to the Korean Hamburg-Wechsler Intelligence Test (KEDI-WISC) as a stressor, 28 showed a drop in cortisol and 15 showed an increase in cortisol levels.37 Children with a cortisol drop made more omission errors and incorrect responses, which is thought to demonstrate impulsivity problems. This suggests the hyperactive-impulsive ADHD-HI subtype. The children with an elevated cortisol stress response made more false responses in the attention test, suggesting attention problems. Non-affected individuals were not compared.
  • Of 49 children with ADHD without other comorbidities between 6 and 17 years of age, 33 showed no cortisol increase on the Korean Hamburg-Wechsler Intelligence Test (KEDI-WISC) and the TOVA test as (cognitive) stressors, and 16 showed a cortisol increase.3 The 33 children with a cortisol decrease had an IQ greater than 110, and the 16 children with an increase had an IQ less than 110 (IQ mean: 92.3). A cortisol decrease also correlated with higher aggression scores and lower attention scores in the K-CBCL. Children with cortisol increases tended to have more withdrawn characters and fewer social problems. This also fits the picture of a decreased/absent cortisol response in the hyperactive-impulsive ADHD-HI subtype. Non-affected individuals were not compared.
  • 68 of 90 ADHD-affected children did not show increased cortisol responses to stress by the Korean-Wechsler Intelligence Scale for Children-Third Edition (K-WISC-III). Increased cortisol responses to a stressor correlated with increased variance in response time.38 Nonresponders were not compared.
    Increased variance in response times could be explained by an impairment in the performance of the PFC, as is particularly pronounced in the ADHD-I subtype.
    Prolonged reaction times correlated with ADHD-I.39
  • 38 ADHD-affected children showed a significantly higher cortisol increase to the Continuous Performance Test (CPT) as a stressor than 38 non-affected children, regardless of subtype.40 A follow-up study of the same subjects 4 years later showed that the cortisol stress responses of the ADHD-affected subjects had decreased and were now similar to those of the nonaffected subjects.41

Rating:

We consider stress testing by means of an intelligence test to be of little use. That people with a higher IQ are less stressed by an IQ test than people with a lower IQ should be the intrinsic purpose of an IQ test. We further assume that children with reduced intelligence are more stressed by cognitive tests and intelligence tests because they expect a negative evaluation, which ultimately means that only the expected social evaluation would trigger stress. On the question of which circumstances trigger cortisolergic stress in the first place, see above.

Further, the ADHD-HI (hyperactive/impulsive) and ADHD-I (non-hyperactive) subtypes are likely to respond differently to different stressors due to their different stress phenotypes. We hypothesize that the more extroverted ADHD-HI type will be less stressed and possibly even more stimulated by social exposure (finishing storytelling and doing mental arithmetic aloud while observing/judging others) than the more introverted ADHD-I type, whose stress response is an inward escape.
This is consistent with van West’s findings.42

3.1.2. Reactions to emotional stress in ADHD

  • A study of 9 ADHD-HI, 10 ADHD-I, and 14 ADHD-C affected and 33 unaffected (6 to 8 years, mean 6.3 years) using TSST-C also found a significantly decreased cortisol response in ADHD-HI affected and a comparatively higher cortisol response in ADHD-I affected. All subtypes showed lower baseline cortisol levels than unaffecteds. Unaffected individuals did not show a strong cortisol response.43 The latter could indicate test arrangement problems. In addition, the number of subjects per subtype was too small for reliable conclusions.
  • A study of 18 ADHD-affected adults and 18 non-affected adults did not come to a clear conclusion. Only a general tendency towards a reduced cortisol response to acute stress and an increased subjective stress perception in ADHD sufferers was reported.44 This may have been due to the small number of subjects, as well as the lack of separation by subtype.
  • A study of young adults without differentiation between ADHD-HI and ADHD-I generally found increased cortisol stress responses in ADHD.45
  • A study that used simple sensory items rather than the TSST as stressors to examine high sensitivity in ADHD found no significant differences in cortisol stress response between nonaffected, ADHD affected without, and ADHD affected with high sensitivity.46 It would have been interesting to see if the responses to the TSST would have differed.
3.1.2.1. ADHD-HI, ADHD-C, and comorbid externalizing disorders
  • A study of 96 adults with ADHD and 25 unaffected individuals revealed a flattened cortisol response in ADHD-C compared with unaffected individuals, and an increased stress-induced cortisol response in the ADHD-I subtype.47
  • Children (6 to 12 years, mean 8.6 years) with the ADHD-HI-ADHD-C were significantly less likely to have the cortisol increase (expected in healthy individuals) to emotional stress (Public Speaking Task, PST and Trier Social Stress Test, TSST) than unaffected individuals, whereas the predominantly inattentive ADHD-I subtype showed a significantly stronger cortisol response than unaffected individuals.48 Only 35% of ADHD-C sufferers showed stress-related elevated cortisol levels, compared with 92% of ADHD-I sufferers and 88% of nonaffected individuals. This study also confirmed a relationship between aggression, externalizing problems, and decreased cortisol stress response.
  • ADHD sufferers with high hyperactivity/impulsivity symptoms showed decreased cortisol suppression after dexamethasone testing.49 This may result from a flattened cortisol stress response or from lower addressable glucocorticoid receptors.
  • When alpha-amylase release (marker of the sympathetic stress system) is low in response to acute stress by the TSST, a concomitant low cortisol response correlates with high levels of aggression; when alpha-amylase release is high in response to acute stress, the cortisol response has no correlation with aggression.50
  • Of 202 male adolescents (10 to 17 years, mean 14 years), the 107 who had comorbid social behavior disorder (CD) responded to a psychosocial stressor with significantly greater reduced cortisol stress reactivity compared with the 97 ADHD-HI-only subjects.
    The more severe the ADHD symptoms were, the lower the basal cortisol level was. In contrast, social behavior disorder was associated with increased basal cortisol levels and decreased cortisol stress response. Impaired cortisol reactivity might reflect fearlessness and be associated with poor emotion regulation and inhibition of aggressive and antisocial behavior.51 Regrettably, no nonaffected individuals were included as controls.
  • 7-12 years (mean: 10 years) old children with oppositional defiant disorder (ODD) have decreased patterns of activity of the autonomic nervous system or HPA axis. fifteen children with ODD, 31 children with ODD and AD, and 23 ADHD-only children were compared with 26 unaffected children. Cortisol response to competition-induced stress (nonrelational stress) was significantly decreased in ODD children with or without ADHD-HI and was equally normal in ADHD-only and unaffected children. Pulse rate was significantly decreased in ODD affected with and without stress. ODD, ODD/ADHD-HI, and ADHD-HI sufferers all equally had significantly lower skin conductance values under stress.52 Because MPH medication was not suspended for the study, the results are likely to be biased. That 17 of the 23 ADHD-HI-only children received MPH may explain the normalization of the stress-induced cortisol response.
  • Oppositional defiant behavior in ADHD correlated with aberrant cortisol responses to acute stress.53
  • ADHD-affected children showed a flattened cortisol response to the TSST, the more they showed psychopathic traits (callous unemotional traits = CU-traits) such as lack of empathy, coldness of feeling, etc..54
  • 22 Children with DBD (disruptive behavior disorder) showed both decreasing and increasing cortisol responses to stress, with those with decreasing cortisol responses exhibiting more severe symptoms than those with increasing cortisol responses.55
  • Disorder of social behavior (CD) correlates with a flattened cortisol stress response.56

Because externalizing disorders correlate with ADHD-HI (with hyperactivity), we consider a tendency toward flattened cortisol stress responses in ADHD-HI and ADHD-C a plausible possibility.

3.1.2.2. ADHD-I and comorbid internalizing disorders
  • A study of 96 adults with ADHD and 25 unaffected individuals revealed a higher stress-induced cortisol response in the ADHD-I subtype than in unaffected individuals, and a flattened cortisol response in ADHD-C.47
  • ADHD-I sufferers of the pure inattentive subtype exhibited an exaggerated cortisol response to acute stress.57
  • A study of 20 ADHD-I sufferers and 19 unaffected (8 to 13 years, mean 10.3 years) using TSST-C58 revealed that the 7 ADHD-I sufferers with severe inattention symptoms showed a significantly reduced cortisol response to the stressor, unlike the 13 ADHD-I sufferers with moderate symptoms and the 19 unaffected.
    A similar study found a greater decreased cortisol response in ADHD sufferers with severe inattention symptoms than in sufferers with less severe inattention symptoms.59
    These results contradict our analysis that ADHD-I is characterized by an exaggerated cortisol stress response.
  • One study found a severely flattened cortisol stress response to the TSST in boys with marked inattention. Girls with marked inattention also showed a flattened cortisol stress response during and after the TSST, with elevated levels before the TSST. Basal cortisol levels were unchanged.60 The study further mentions that flattened cortisol stress responses are common in chronic stress.
    The children were categorized as ADHD-I according to inattention scores alone, not according to the absence of hyperactivity/impulsivity. This could explain the results if they were subjects showing strong hyperactivity/impulsivity scores at the same time. Comorbid externalizing or internalizing disorders did not affect the results.
  • In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with increased cortisol responses to the TSST (as typically exhibited by the ADHD-I), but not with ACTH levels.61
  • This is equally true for higher risk aversion (which is also more consistent with the ADHD-I subtype).62
  • Anxiety, depression, subjective stress perception, impulsivity, and a higher ADHD symptom total score correlated with elevated cortisol responses to acute stress (which is surprising in relation to impulsivity) in a study of adults.63

3.1.3. Reactions to physical stress

  • Of 170 ADHD-affected elementary school-aged children, venipuncture as a stressor resulted in a cortisol increase in those with comorbid anxiety problems, whereas those with comorbid DBD and oppositional defiant disorder had a decreased cortisol response. ADHD-HI subtypes did not elicit different cortisol responses.64
  • Of 62 ADHD-affected children, the ADHD-HI type showed an identical cortisol level before venipuncture as nonaffected individuals, whereas the ADHD-I subtype showed an elevated cortisol level even before venipuncture compared with nonaffected individuals. Since basal cortisol levels are lower in both ADHD-I and ADHD-HI affected individuals compared with nonaffected individuals, this could be an anxiety response in anticipation of the stressor.65 The same pattern was shown with respect to alpha-amylase as a representative of the autonomic nervous system.
  • In the same 62 ADHD-affected children, the ADHD-HI subtype showed a decrease in cortisol levels 10 minutes after venipuncture, whereas it increased slightly in the 40 unaffected and increased more in the ADHD-I affected.65 The same pattern was seen with respect to alpha-amylase as a representative of the autonomic nervous system.
  • Children with ADHD tended to show increased cortisol stress responses to venipuncture when first presented in a home setting and significantly lower basal cortisol levels and significantly flattened cortisol stress responses when second presented in a clinic setting compared with unaffected individuals.66
  • In children with ADHD, a visit to the dentist as a stressor showed a lower increase in cortisol than in those not affected. The cortisol increase was particularly low in children with high hyperactivity/impulsivity scores.67

3.2. Basal cortisol levels reduced in ADHD

In ADHD, basal (constant, basic) cortisol levels are usually decreased, with the cortisol level decrease being even more pronounced in ADHD-HI and in ADHD-C than in the ADHD-I subtype.2865

Decreased basal cortisol levels are a typical reaction to stress in non-affected individuals. Decreased basal cortisol levels are the rule in ADHD sufferers.

Reduced basal hair cortisol levels in 4-year-old children over several months are a good predictor of an increase in ADHD symptoms in boys (but not girls) the following year.68 Similar findings are described by Pauli-Pott et al.69 Another study found that hair cortisol levels in children correlate between parental psychopathology and major depression and ADHD in children.70 One study found a correlation between low hair cortisol levels and low working memory scores and low intelligence performance only in boys but not in girls. In boys, hair cortisol fully explained the associations of ADHD inattention symptoms with working memory and intelligence performance.71

According to quite a few accounts, morning blood cortisol levels are decreased in ADHD.72677374
Significantly lower cortisol levels were found at 8 a.m. in 128 Chinese children between 6 and 12 years of age with AD(HHD).75

In 109 adults with ADHD(H)S, 64% were found to have a normal morning cortisol awakening response (with no significant differences between subtypes), compared with 84% in unaffected controls.76

ADHD sufferers with high inattention symptoms, on the other hand, showed an increased cortisol awakening response, and this was mainly due to comorbid anxiety or depression disorders.49

248 Adolescents with ADHD showed lower basal cortisol levels and higher perceived stress, although basal cortisol levels and perceived stress did not correlate.77

In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with elevated baseline cortisol levels but not with elevated ACTH levels.78

In ADHD-I sufferers, one study found no changes in daily cortisol levels.59

Three studies found no overall change in basal cortisol levels in ADHD compared with nonaffected individuals.795349

Low basal stress levels (basal = not stress induced) are interpreted as an adaptation reaction of the HPA axis (stress axis) to chronic stress experience. Not only ADHD-affected children, but also their mothers showed reduced cortisol levels at 9 a.m. compared to non-affected individuals.
The salivary cortisol level of 5 to 9-year-old boys immediately after waking up around 06:30 was on average 0.4 ng/ml lower than that of non-affected individuals. However, the individual range of cortisol levels in people is much wider than the statistical difference (unaffected 0.7 to 10.5 ng/ml; ADHD affected 1.3 to 8.1 ng/ml).80

Several studies show that decreased basal cortisol levels are not an exclusive feature of ADHD. They also correlate with (comorbidly present) social behavior disorders.818283
However, the measure of aggression does not yield different basal cortisol levels.3

Elevated blood cortisol levels in 15-year-old ADHD sufferers (decrease in late afternoon) correlated with aggressiveness in boys but not in girls.2

3.3. Decrease in cortisol levels without stress induction in ADHD?

A rather small study came to the conclusion that a steeper drop in cortisol levels from 06:30 to 09:00 was typical in ADHD. In 19 ADHD sufferers, the cortisol level drop of 66% was significantly steeper than that of 40 non-affected persons by 56%.84
Another study also reported abnormal cortisol level changes throughout the day that correlated with levels of hyperactivity.85

3.4. GR variant influences cortisol action and ADHD risk

See GR gene variants In the article Cortisol and other stress hormones in AD(H)S

4. ACTH in ADHD

  • No differences in basal ACTH levels were found between 128 ADHD affected and 30 unaffected children. ADHD subtypes also did not differ.72

  • In healthy adults, lower Novelty Seeking (which is more consistent with the ADHD-I subtype) correlated with increased cortisol responses to the TSST (as is very commonly exhibited by the ADHD-I subtype), but not with altered ACTH levels.78

  • This is equally true for higher risk aversion (which also correlates with ADHD-I subtype).62

  • In one study, sexually abused girls were found to have decreased basal ACTH levels and decreased ACTH responses to CRH stimulation, whereas the cortisol response was unremarkable.86

  • Early childhood stress causes permanent changes in the HPA axis, as evidenced by altered basal and stress-induced cortisol levels. Children with internalizing problems often showed elevated cortisol stress responses, whereas adults who suffered early childhood psychological stress often showed decreased basal cortisol levels and increased ACTH responses to acute stress.87

  • Early experiences of stress can cause disturbances in the ACTH receptor systems that prevent extinction of the fear experience, causing long-term stress. This could be ameliorated by ACTH administration.88 In our opinion, the alteration of ACTH receptor systems could possibly be a consequence of a downregulation/upregulation response. ⇒ Downregulation / Upregulation

  • Rats separated from their mothers early or poorly cared for showed89

    • Elevated ACTH levels basal
    • Elevated ACTH levels on acute stress
    • More than doubled CRH levels on inflammation
    • Reduced density of CRH receptors in the anterior pituitary lobe
    • Alterations in extrahypothalamic CRH systems
      • Increase of 59% in the number of CRH receptor binding sites in raphe nuclei
      • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86%
    • Behavioral problems such as90
      • Increased anxiety
      • Anhedonia
      • Increased alcohol preference
      • Sleep disorders
      • Cognitive impairments
      • Increased sensitivity to pain
  • In borderline sufferers without comorbid PTSD, the DST showed an increased ACTH response; in borderline sufferers with comorbid PTSD, the DST showed a significantly attenuated ACTH response.91

5. CRH in ADHD

  • Young monkeys raised under early attachment stress had elevated CRH and decreased epinephrine levels at 4 years of age.9293
  • Cortisol initially mediates stress symptoms after its release. Further, a high cortisol level has the effect of shutting down the HPA axis and norepinephrine again.
    However, since GR cortisol receptors are less sensitive after prolonged stress due to downregulation, they do not perceive this signal. The shutdown of the stress systems fails to occur.94 As a result, CRH levels remain permanently elevated and permanently trigger CRH-mediated symptoms. This mechanism has already been outlined for depression.9596
  • Prolonged stress caused chronic demethylation of the CRH gene in adult mice.97

6. α-Amylase in ADHD

The alpha-amylase level represents the activity of the primarily adrenergic controlled autonomic nervous system. Alpha-amylase reacts very strongly to a psychosocial stressor, but does not correlate with other so-called stress markers such as cortisol, noradrenaline or heart rate. Alpha-amylase is thus suitable for detecting physical changes caused by stress.9899100101 In contrast, concentration tasks (Stroop test) as a stressor do not increase the alpha-amylase level.102

  • In ADHD, basal alpha-amylase levels are usually decreased, with the α-amylase level decrease being even more pronounced in ADHD-HI subtype/ADHD-C than in ADHD-I subtype. This pattern is consistent with decreased basal cortisol levels (a representative of the HPA axis).65
  • Of 62 ADHD-affected children, the ADHD-HI type showed an identical α-amylase level before venipuncture as nonaffected individuals, whereas the ADHD-I subtype already showed an increased α-amylase level before venipuncture compared with nonaffected individuals. Because basal α-amylase levels are lower in both ADHD-I and ADHD-HI affected subjects than in unaffected subjects, this could be an anxiety response in anticipation of the stressor.65 The same pattern was shown with respect to cortisol as a representative of the HPA axis.
  • In the same 62 ADHD-affected children, the ADHD-HI subtype showed a decrease in α-amylase level 10 minutes after venipuncture, whereas it increased slightly in the 40 unaffected and increased more in the ADHD-I-affected.65 The same pattern was seen with respect to cortisol as a representative of the HPA axis.

Alpha-amylase is an enzyme in the intestine responsible for breaking down carbohydrates into sugars. There could be a connection here between stress and eating problems or obesity.

6.1. Correlation between alpha-amylase and cortisol

An examination of the time course of the response of alpha-amylase, representing the autonomic nervous system, and cortisol, representing the HPA axis, to a TSST as a stressor indicates mutual dependencies of the two stress hormones:103

  • An alpha-amylase rise was followed moderately frequently by a cortisol rise 14 minutes later.
  • A rise in cortisol was followed slightly frequently by a drop in alpha-amylase 14 minutes later.
  • An alpha-amylase increase was followed moderately frequently by a cortisol decrease 42 minutes later.

7. Diagnosis and treatment of ADHD by cortisol / dexamethasone?

Dexamethasone is an (artificial) glucocorticoid that binds to the glucocorticoid receptors of the pituitary gland in healthy volunteers, thereby inhibiting the ACTH precursor protein POMC. As a result, the release of ACTH from the anterior pituitary is reduced. Since ACTH normally stimulates cortisol release, a healthy response to administration of dexamethasone would be to decrease cortisol levels - called suppression.
Nonsuppression (a lack of cortisol reduction by dexamethasone) suggests a maladjustment of the HPA axis, in the form of a lack of response of the glucocorticoid receptors that mediate HPA axis shutdown. We suspect such HPA axis misalignments as a possible cause of ADHD, and we believe that the lack of HPA axis shutoff is typical of ADHD-HI.

Whether there is a problem of HPA axis shutdown in the form of cortisol nonsupression can be determined using the dexamethasone/CRH test, an evolution of the previously used dexamethasone-only test.

For procedure and evaluation of the dexamethasone test, see Dexamethasone/CRH test and Dexamethasone test in the chapter Pharmacological endocrine function tests.

In melancholic depression, which like ADHD-I is very often characterized by an exaggerated cortisol response, but probably also frequently in atypical depression, which is characterized by a flattened cortisol stress response, the dexamethasone test to dexamethasone administration shows insufficient negative feedback from the HPA axis and therefore insufficient cortisol suppression.

We hypothesize that in ADHD-I (unlike melancholic depression), the exaggerated cortisol response leads to frequent shutdown of the HPA axis. This may be a misconception, or may reveal a difference between melancholic depression and ADHD-I.

In support of the hypothesized difference between depression and ADHD-I, a large study (n = 2307) found decreased cortisol suppression to dexamethasone in hyperactivity/impulsivity (ADHD-HI), whereas inattention (ADHD-I) showed no correlation to nonsupression.104 This is consistent with the results of a smaller study that found nonsupression in only a portion of ADHD sufferers and found that nonsuppression correlated with higher levels of hyperactivity.105 Another small study, but involving only 9 ADHD-affected children, found suppression in ADHD.106 Another smaller study found nonsuppression in 22.7% of ADHD-HI-affected individuals (with hyperactivity), a 4-fold increase over the 5.7% in healthy individuals.107
However, an argument against general nonsupression is that in rats that serve as animal models of ADHD-HI (with Hperactivity) (Spontaneous hypertensive rat), dexamethasone shows a reduction in ADHD-HI symptoms.108109 SHR genetically have excessive mineralocorticoid receptor (MR) expression and normal glucocorticoid receptor (GR) expression.110

These results suggest that in ADHD-I, glucocorticoid receptors are not desensitized.

The results further suggest that in ADHD-HI, in addition to the reduced cortisol response, which by its nature results in insufficient downshift of the HPA axis, there is also (relative) overactivity of the MR or desensitization of the GR. The nonsupression of the HPA axis observed in hyperactivity when dexamethasone is administered proves that nonsuppression exists even in the presence of a short-term high cortisol level, i.e., a deficient shutdown of the HPA axis.

In summary, we interpret this as follows:

  • Melancholic / psychotic depression
    • High cortisol stress response
    • Nevertheless no shutdown of the HPA axis
    • → Desensitization of the GR or overactivity of the MR
  • ADHD-I
    • High cortisol stress response
    • Shutdown of the HPA axis
    • → no desensitization of the GR or overactivity of the MR
  • Atypical depression
    • Low cortisol stress response
    • No shutdown of the HPA axis
      • Not only for lack of sufficient cortisol stress response
      • Also with artificial glucocorticoid administration (dexamethasone)
        • → more frequent desensitization of GR (more likely) or hyperactivity of MR (less likely, as dexamethasone addresses GR 30 times more than MR and yet nonsupression occurs)
  • ADHD-HI
    • Low cortisol stress response
    • More often no shutdown of the HPA axis
      • Not only for lack of sufficient cortisol stress response
      • Also with artificial glucocorticoid administration (dexamethasone)
        • → more frequent desensitization of GR (more likely) or hyperactivity of MR (less likely, as dexamethasone addresses GR 30 times more than MR and yet nonsupression occurs)

8. Treatment of ADHD by cortisol / dexamethasone?

8.1. Dexamethasone as a drug for ADHD

Another strong indication that the HPA axis, and cortisol in particular, plays a central role in ADHD is provided by a study according to which dexamethasone (as a drug) in SHR rats (considered an animal model for ADHD-HI (with hyperactivity)) was able to significantly reduce their ADHD-HI symptoms.111
However, it must be kept in mind that ADHD-HI can be caused by a variety of different gene constellations and SHRs only represent a single gene constellation, so the result cannot be readily generalized to every ADHD-HI.

The dopamine D1 transporter in the PFC, which is damaged in schizophrenia, can be reactivated by cortisol in animal models, which restores dopamine levels to normal.112

Dexamethasone has so far only been studied for its basic efficacy in rats. With regard to ADHD, there have been no studies on its use in humans or the effects of long-term use, which may have side effects (e.g., on the immune system).

On the other hand, compensation of the too low cortisol level in ADHD and especially in ADHD-HI - as long as only the existing deficit is compensated - could show a positive influence in other ways as well.

We developed the idea of dexamethasone shock treatment as a hypothesis: Dexamethasone in ADHD

8.2. Cortisol as a drug for emotional stabilization in ADHD?

In one study, administration of 20 mg to 40 mg of cortisol significantly reduced feelings of sadness, activity, alertness to acute stress, and improved relaxation. In addition, fatigue was reduced.113

Cortisol (along with other mechanisms) influences attention, vigilance, and memory.114 The hippocampus, which is responsible for memory storage and retrieval processes, has the greatest cortisol receptor density in the brain.114

An administration of 10 mg cortisol before learning vocabulary significantly worsened memory retrieval performance. Whether this occurred only in men or also in women, who might be protected against this by their sex hormones, is an open question.115 ADHD-I sufferers respond to acute stress with increased cortisol release. In these, memory recall is also impaired after stress - but only in males.115

While existing medications for ADHD (stimulants, atomoxetine, guanfacine) primarily improve attention problems and hyperactivity problems, we do not believe they are as effective in reducing internal tension. According to our hypothesis, infrequent high-dose cortisol administration should be able to reassure the HPA axis. In contrast, prolonged or regular administration is detrimental because it may cause effects similar to chronic severe stress.

Because of the significant disadvantages of corticoids acting on mineralocorticoid receptors, only corticoids that selectively address glucocorticoid receptors should be considered (such as dexamethasone, which addresses GR to MR in a 30:1 ratio).

8.3. Mode of action of dexamethasone

Dexamethasone is a selective glucocorticoid receptor (GR) agonist and thus acts like an increase in cortisol levels.111
The cortisol receptor agonist dexamethasone promotes PACAP mRNA transcription, cell proliferation, and DA synthesis, whereas a cortisol receptor antagonist inhibits this.116

Cortisol acts on the β-adrenoceptor -cAMP/protein kinase A (PKA) signaling pathway to facilitate the synthesis and release of norepinephrine, which binds postsynaptically to ɑ1-adrenoceptor and β-adrenoceptor. A β-adrenoceptor directly coupled to adenylate cyclase (AC) can stimulate cAMP production and trigger certain responses that can be regulated by ɑ1-adrenoceptor. Glucocorticoid receptors, together with the ɑ1-adrenoceptor, have an effect on the β-adrenoceptor-cAMP system.117 and may activate the NE system by activating the NE neuronal group in the brainstem. GR may also regulate transcription.
Activated GR bound to the glucocorticoid response element (GRE) affects gene expression as well as transcription factors, such as NF-kB, AP-1, CREB, etc., which in turn affect the combination of cAMP and PKA regulatory subtypes that model DA neuron production and survival and regulate DA activity and secretion.118

8.4. Dexamethasone in ADHD-HI, GR antagonists in ADHD-I?

The studies that established efficacy of dexamethasone as an ADHD medication did so using SHR rats, which are considered a typical model of ADHD-HI (with hyperactivity).
This raises the theoretical question of whether, just as the GR agonist dexamethasone might function as an active agent in ADHD-HI, a GR antagonist might possibly be effective in ADHD-I.

This should not be the case.

A GR antagonist would prevent the HPA axis from shutting down. However, the reswitching of the HPA axis after a stress response is, first, usually a healthy response and, second, is probably not impaired in ADHD-I.

Research on dexamethasone testing in ADHD shows that problems with HPA axis shutdown correlate with measures of hyperactivity, but not with inattention.
For more, see Medications in ADHD, here Dexamethasone in ADHD.

In our opinion, the problems of ADHD-I do not arise at the level of the HPA axis but at the level of excessive PFC addressing due to too much norepinephrine, which causes a shutdown of the PFC and triggers the thought blocks and decision-making difficulties typical in ADHD-I.


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