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The term “vitamin D” is a collective term for several structurally related secosteroids, e.g:1
Cholecalciferol (inactive)
Ergocalciferol (inactive)
25-hydroxyvitamin D (calcidiol, active)
1,25-dihydroxyvitamin D (calcitriol, active)
Calcitrol (1,25(OH)2D3), which is active in the body and brain, is formed from 2 precursors. While vitamin D2 is obtained from food, vitamin D3 is mainly formed in the skin from 7-dehydrocholesterol (7-DHC) by means of UVB radiation in sunlight.2 Vitamin D2 and D3 are hydroxylated in the liver by CYP27A1 (sterol 27-hydroxylase) to 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] respectively (collective name: 25-hydroxyvitamin D or 25(OH)D). These are converted in the kidney by the second hydroxylation by CYP27B1 (1, α-hydroxylase) into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol, hereinafter referred to simply as D3), which is active as a hormone.
The active forms of both compounds (D2 and D3) are involved in regulating the expression of more than 900 genes.
1.1.1.1. Formation of vitamin D3 through sunlight¶
In summer, between 10,000 and 20,000 i.U. D3 are produced within 15 to 30 minutes by full-body sunbathing between 10 am and 2 pm. Longer exposure to the sun brings no further benefits. Taking individual skin sensitivity into account, half of the time from which reddening of the skin occurs in unprotected sunlight is optimal. However, this should also be observed without protection in order to ensure the supply of D3. When using sun cream from SPF 14 and in winter, no more D3 is formed due to a lack of sufficient sun intensity.3
The following times are helpful for sufficient vitamin D production without the risk of sunburn (here: adjusted to the intensity of sunlight in Switzerland):4
The daily dose of 800 i.U. recommended by the DGE can barely be absorbed through food. The following would be required (as an alternative):3
400 g mackerel
4 kg pork schnitzel
16 to 20 eggs
20 liters of whole milk
10 kg calf’s liver
10 kg Brie (with 45 percent fat content)
600 g avocado
1 kg shiitake mushrooms
In Germany, an average of 80 to 160 i.U. is absorbed daily through food. As a result, 60% of Germans have a vitamin D3 deficiency between November and April, even in summer for people with dark skin.3 60% of adult Germans have a D3 level below the standard value.5
1.1.2. Standard values and prevalence of vitamin D3 deficiency¶
1.1.2.1. Deficiency, insufficiency, normal values of D3¶
Vitamin D3 supply states are defined on the basis of the blood serum level: D3 deficiency: Less than 10 ng/mL6 / less than 12 ng/mL7 / less than 20 ng/mL89 D3 insufficiency: Between 10 and 30 ng/mL (Canadian recommendations)6 / 12 to 19 ng/mL7 / 20 to 32 ng/mL8 / below 28 ng/mL (Germany)10 D3 standard values: 20 to 49 ng/mL (Germany)7 / 30 to 90 ng/mL(Canada)6 / 32 to 64 ng/mL (Germany)10 / 33 to 80 ng/mL8 / in sunny countries: 54 to 90 ng/mL8 D3 excess: From 50 ng/mL 7 / more than 100 ng/mL8
400 iU/day (infants up to 12 months)11
400 IU/day from 2 years of age12
600 IU/day for 1- to 70-year-olds, 800 IU/day for those over 70. (USA, Canada)9
800 IU/day (from 1 year)11. Some D3 experts consider this value to be too low13, especially in times of low sunshine (Germany: October to May)
In winter: 1.000 to 2,000 IU10
Upper limit for adults: 4,000 IU/day, corresponds to an average serum 25OHD level of 50 ng/ml (USA, Canada)9
Hypo- and pseudohypoparathyroidism: 10,000 to 200,000 IU10
Serum calcium control required for dose adjustment.
Cancer (gallbladder cancer, pancreatic cancer) 3,000 to 5,000 IU/day or 50,000 to 100,000 IU every 3 months10
Deficiency / D3 deficiency prophylaxis 3,000 to 5,000 IU/day or 50,000 to 100,000 IU every 3 months18
60% of German adults have a D3 level below the standard value.5
The prevalence of insufficient vitamin D3 intake in Europe is between 33% and 100%.20 In Germany, 99.9 % (women) and 98.9 % (men) of adults (19 to 64 years) were reported to have an insufficient intake, and 99.1 % (women) and 91.4 % (men) of older people (aged 65 and over).
A study from less sunny countries showed that depression due to D3 deficiency is strongly linked to the amount of sunlight in the respective region:21
20 % of the population in Alaska, 64th parallel
12.5 % of the population in New York, 41st parallel
2.6 % of the population in Florida, 28th parallel
A dose of D3 is recommended in the fall/winter when there is little sunlight.
D3 requires fat for absorption, i.e. ingestion requires that the preparations contain fat or that food is consumed at the same time. A glass of milk should suffice for this.
Vitamin D3 has been associated with changes in dopamine levels in various studies.
1.1.3.1.1. D3 deficiency during pregnancy or early development impairs the dopamine system¶
Vitamin D3 deficiency during pregnancy and after birth causes permanent maldevelopment of the brain, particularly of the dopaminergic system. Rodents whose mothers had a vitamin D deficiency showed typical ADHD symptoms.
See in detail under D3 deficiency during pregnancy In the article Prenatal stressors as environmental causes of ADHD
1.1.3.1.2. D3 deficiency affects the dopamine system¶
Rodents that became vitamin D deficient at 4 months of adulthood also showed ADHD symptoms:14
Hyperactivity
Increased sensitivity to environmental changes
Cognitive impairment
Deficits in spatial learning
Glutamate and glutamine reduced
GABA and glycine increased
Vitamin D deficiency reduces GABA receptors, glutamate synthetase 1 and GABA transmitter synthetase (GAD65 and GAD67). GABA and glutmate regulate dopamine.14
Other studies are investigating the dopaminergic links between vitamin D3 deficiency and Parkinson’s22 or schizophrenia23, both of which are also based on disorders of the dopamine system. Low D3 levels in pregnant mothers correlated with an increased risk of schizophrenia in the offspring. Vitamin D supplementation during the first year of life in northern Finland, especially at ≥2000 IU/day, reduced the risk of schizophrenia at the age of 31 years, but only in men.24
1.1.3.1.3. D3 administration influences the dopamine system¶
Dopamine neurons in the midbrain and their target neurons in the striatum express vitamin D3 receptors27
Acute D3 administration led to transcriptional changes of dopamine-related genes in these regions in naive mice
Acute D3 administration enhanced amphetamine-induced dopamine release in both naïve mice and rats and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.)
D3 increased the differentiation of DA neurons in vitro:28
NEUROG2 decreased (a marker of immature DA neurons)
COMT gene expression increased
MAOA expression increased
DRD2 expression increased
VMAT2 expression increased
N-cadherin expression291
N-cadherin plays a role in the differentiation of dopaminergic cells
increased in VDR-expressing neuroblastomas
in the embryonic mesencephalon is reduced
Vitamin D attenuated behavioral deficits, dopamine dysmetabolism, oxidative stress and neuroinflammation induced by severe dopamine deficiency in the striatum in mice from30 and protected dopaminergic neurons from inflammation and oxidative stress in rats with severe dopamine deficiency in the striatum.31
A daily administration of 2000 UI D3 increased serum dopamine levels in people with ADHD.32 However, as dopamine in the blood cannot cross the blood-brain barrier, the increase in serum dopamine has no effect on the dopamine deficiency in the brain.
Regular vitamin D treatment can improve anhedonia-like symptoms in rats exposed to chronic mild stress causing depression symptoms, similar to the antidepressant fluoxetine. This is thought to occur by regulating the action of dopamine-related effects in the nucleus accumbens.33
In developing rat brains, the vitamin D receptor appears at E12 (embryonic day 12). This is exactly the time when the dopaminergic system begins to develop.1342835 D3 appears to trigger the differentiation of dopaminergic neurons.36
Vitamin D deficiency influences
Neurogenesis in brain development44
See the studies on the increased risk of ADHD and ADD in offspring due to reduced D3 levels in the mother during pregnancy.
D3 receptors are expressed almost ubiquitously. Almost all cells respond to D3. About 3 % of the genome of mice and humans is directly and/or indirectly regulated by the endocrine system of vitamin D.55
A loss of VDR in the intestinal epithelium leads to an increase in butyrate-producing bacteria during intestinal inflammation59
VDR-KO mice with a VDR deletion in immune cells showed a significant down-regulation of quinolinate and tocopherol metabolites and an increase in nicotinamide . Quinolinate acts as a neurotoxin, pro-inflammatory mediator and pro-oxidant molecule. These changes indicate a possible role of VDR in neurophysiology.60
An association with ADHD has been reported for one VDR gene variant (IVS8 - 10 G>A at intron8).61
The entire presentation on vitamin D3 outside of this section refers to the effect of D3 on the VDR.
Vitamin D further binds to the membrane-associated 1,25D3 steroid binding protein (1,25D3-MARRS), which also functions as protein disulfide isomerase A3 (PDIA3). Its activation causes a rapid cellular response.1
PDIA3 (1,25D3-MARRS) appears to be the most important D3 receptor in the brain of rats, especially in62
Neurons
Astrocytes
Endothelial cells
PDIA3 (1,25D3-MARRS) caused
neuroprotective effects against infections (caused by prions)63 or toxic drugs such as METH64 in humans
BDNF expression increased
phosphorylated cAMP response element-binding protein (pCREB) expression increased
Rodents without vitamin D deficiency that received additional vitamin D supplementation showed:14
Improved cognitive functions in old age
Improved learning ability in old age
Improved social behavior in NS-PTEN knockout mice
Increased late neurogenesis in the hippocampus.
Reduced level of pS6 and pAKT (downstream targets of mTOR)
consequences of reduced abnormal dendritic spines in NS-PTEN knockout mice (suggesting improvement in ASD)
D3 requires fat to be absorbed by the body. It should therefore be taken with meals. Vitamin D3 also needs vitamin K2 and magnesium in order to be optimally effective.13
On the differences between plant D2 and animal D3 (which is also formed by sunlight), in detail and with several sources: Rotter.67
When taking D3 (short-term daily doses from 2000 I.U. or weekly use of up to 20,000 I.U.), the calcium level in the blood serum should be checked every 3 to 6 months for excessive values. Vitamin D-induced hypercalcemia shows calcidiol serum levels of over 88 ng/ml.17
Studies on children with ADHD often found reduced D3 blood levels.6869 A meta-analysis of k = 8 studies with n = 11,324 children (including 2,655 with ADHD) found significantly lower serum concentrations of 25(OH)D in ADHD in all 8 studies (SMD 0.73).70
At the same time, the administration of D3 - also in addition to MPH - appears to reduce ADHD symptoms according to several studies.71727374 A D3 deficiency does not seem to cause ADHD as much as a D3 deficiency in the case of existing ADHD seems to increase its severity75
These differences in results between these studies could be due to different sample sizes and large individual differences. Therefore, the current evidence is not sufficient to conclude that vitamin D supplementation could reduce ADHD-related behavioral problems. Understanding the neural mechanisms will help to clarify this issue, and the following mechanisms have been proposed in the literature:
In the Spontaneous(ly) hypertensive rat (SHR), which is an animal model of ADHD-HI (with hyperactivity) (more specifically, a single, specific genetic variant of it), one study found, compared to WKY rats (which serve as healthy controls):
Increased systolic blood pressure
Sympathetic drive increased
Cardiac hypertrophy and cardiac remodeling
These deviations correlated in the paraventricular nucleus of the hypothalamus (PVN) with
Higher mRNA and protein expression levels of
High mobility box 1 (HMGB1)
Receptor for advanced glycation end products (RAGE)
Toll-like receptor 4 (TLR4)
Nuclear factor-kappa B (NF-κB)
Pro-inflammatory associated cytokines
NADPH oxidase subunit
Elevated levels of reactive oxygen species
Activation of microglia
and
Increased noradrenaline levels in the blood plasma
These phenomena could be eliminated in a study by an infusion of 40 ng D3.76
40 ng D3 corresponds to 0.04 micrograms of vitamin D3. At a weight of approx. 200 g / rat, this should correspond to 0.2 micrograms / kg body weight. At 70 kg, this would correspond to a dose of 14 µg (micrograms). For humans, an intake of 5-10 µg (200 - 400 IU) daily is recommended, whereby an intake of up to 50 µg (2000 IU) is not harmful for adults,178 up to 800 IU.
There is clear evidence of a benefit of D3 in ADHD.14
Randomized double-blind placebo-controlled studies in children found benefits of administering 2000 iU of vitamin D in addition to stimulants already taken in children aged 5 to 12 years with ADHD.77 or in high doses of 50,000 iU / week78 and combined with magnesium 79
In children with ADHD aged 6 to 12 years, a double-blind placebo-controlled study found that 50,000 iU of D3 per week and 6 mg/kg/day of magnesium significantly improved symptoms in the areas of conduct disorder, social behavior and anxiety, but not psychosomatic symptoms.80 A placebo-controlled study of children with ADHD found improvement in ADHD symptoms (particularly inattention) at 50,000 iU weekly, but this was only significant in the children with D3 insufficiency.81 None of the studies with an administration of 50,000 iU/week reported side effects.
One study found that treating ADHD patients with an MPH/vitamin D combination was more effective than administering MPH alone82
Higher vitamin D levels appear to reduce the negative effect of the organophosphate chlorpyrifos on the risk of ADHD.83
A meta-analysis of 4 studies with n = 256 subjects on vitamin D supplementation as an add-on therapy to methylphenidate for ADHD found small but statistically significant improvements in
ADHD total scores
Inattention
Hyperactivity
Behavior
There was no statistically significant improvement in opposition scores. No increased side effects were reported.84
A placebo-controlled study in children aged 2 to 18 years found improvements in attention in all D3 recipients with ADHD. In addition, improvements were also found in hyperactivity and ADHD total score in those people with ADHD who had previously shown reduced D3 blood levels.85
Our impression is that people with ADHD are particularly susceptible to winter depression. It is therefore advisable (based on the light conditions in Germany) to take additional D3 from mid-October to the end of April.
The vitamin D receptor (VDR) is a zinc finger protein from the nuclear receptor superfamily (nuclear receptors).36
In addition to the significantly reduced vitamin D level in the blood - regardless of subtype - VDR function appears to be significantly reduced in ADHD.86 No differences in relation to calcium, phosphorus or alkaline phosphates were found in this study. Unfortunately, there is no further study on VDR in ADHD.
Deletion of VDR in the intestinal epithelium led to an increase in kynurenine, a metabolic pathway associated with inflammatory neurological disorders, in a mouse model.60 One study reported increased kynurenine levels (+ 48 %) in ADHD87 (which could indicate a VDR functional deficiency), another study reported unchanged kynurenine levels in adults with ADHD.88
An association with ADHD has been reported for one VDR gene variant (IVS8 - 10 G>A at intron8).61
Anyone who has symptoms typical of D3 deficiency despite sufficient D3 levels should in any case have their D3 receptor tested, which can be done in the laboratory, as can the serum D3 level.
There are clear indications of a benefit of D3 in ASA.14
A meta-analysis found little evidence of a link between prenatal vitamin D deficiency and autism spectrum disorders.89
One study found no association between the VDR gene variant and ASD.90
The frequency of B12 deficiency in ADHD is controversial. Some sources assume that B12 deficiency is rarely involved in ADHD,919293 others believe that vitamin B12 deficiency often appears to be present in ADHD.94 Prevalence of a B12 deficiency9520
Young adults 5 to 10 %
Older adults 10 to 30 %
The prevalence of insufficient vitamin B12 intake in Europe is between 0% and 40%.20 In Germany, 7.7% (women) and 8% (men) of adults (19 to 64 years) were reported to have an insufficient intake, and 7.4% (women) and 3.6% (men) of older people (aged 65 and over).
A large study of 432 children found significantly lower serum levels of vitamin B12 in children with ADHD.96 This correlated with an increased intake of nutrient-poor foods such as foods high in sugar and fat and a lower intake of vegetables, fruit and protein-rich foods than in healthy children.
It remains to be seen whether the change in diet is the cause, consequence or vicious circle of ADHD.
Another study found a correlation between low B12 levels and increased hyperactivity/impulsivity in ADHD and Oppositional Defiant Disorder (ODD).9798 B12 deficiency can increase homocysteine levels in several ways.99 B12 deficiency (or the excessive homocysteine levels it triggers) can explain up to 13% of the hyperactivity/impulsivity symptoms of ADHD.97
Vitamin B6 (pyridoxal phosphate) is required for the synthesis of catecholamines (dopamine, noradrenaline, adrenaline) and the neurotransmitter PEA (phenylethylamine, a co-transmitter of noradrenaline).93
ADHD often appears to be associated with a vitamin B6 deficiency = pyridoxine deficiency.9492
A large study of 432 children found significantly lower serum levels of vitamin B6 in children with ADHD.96 This correlated with an increased intake of nutrient-poor foods such as foods high in sugar and fat and a lower intake of vegetables, fruit and protein-rich foods than in healthy children.
It remains to be seen whether the change in diet is the cause, consequence or vicious circle of ADHD.
One study found a correlation between low serum B6 levels and ADHD, including the severity of symptoms in adults.100
One report suggests that vitamin B6-related enzymes may be significantly imbalanced in ADHD. Several years of treatment with pyridoxine (vitamin B6) would correct this imbalance with no expected side effects. The same research team already considers these B6 metabolic enzyme complex imbalances to be the cause of epilepsy.101 However, given the scope of the theory presented, the number of test subjects is very limited
In the case of people with ADHD
TRP (tryptophan) tripled
KYN (kynurenine) more than doubled
3-HOKYN (3-hydroxykynurenine) more than doubled
KA (kynurenic acid) strongly increased
IND (indoxyl sulfate) reduced
4PA (4-pyridoxic acid)/TRP ratio reduced
IND/TRP ratio reduced
IND/KYN ratio reduced
3-HOKYN is toxic. The KYN / TRP ratio is an index of indoleamine 2,3-dioxygenase activity, the enzyme that limits tryptophan degradation. The 3-HOAA / 3-HOKYN ratio is an index of kynureninase activity.
MPH, the standard medication for children with ADHD, appears to increase kynurenic acid and decrease quinolinic acid in their plasma.102
B1 deficiency can cause various symptoms, some of which are similar to ADHD symptoms.92 Bieger operates a laboratory and sells food supplements. In laboratory analyses, his own products were recommended without the conflict of interest being disclosed.
1.4.1. Symptoms of B1 deficiency that can be confused with ADHD:¶
Lack of concentration
Irritability
Depression
Tiredness
Memory disorders (Korsakow syndrome), states of confusion
Reduced production of antibodies during infections
Disturbed energy production
1.4.2. Symptoms of B1 deficiency atypical for ADHD:¶
Disorders of the carbohydrate metabolism and nervous system (e.g. polyneuropathy)
Visual disturbances
Loss of appetite
Anemia
Frequent headaches
Heart problems
Heart failure
Tachycardia (rapid heartbeat)
Low blood pressure
Shortness of breath (dyspnea)
Edema
Muscle problems
Muscular atrophy
Weak muscles (especially calf muscles)
Muscle cramps (calf cramps)
Diseases:
Beriberi
Wernicke’s encephalopathy
Strachan syndrome
Alzheimer’s disease
frequently reduced glucose and oxygen utilization in the brain, which is associated with B1 deficiency. It remains to be seen whether B1 deficiency is the cause or consequence of Alzheimer’s disease.
Folate refers to the sum of the folate-active compounds (with one or more glutamate residues attached; polyglutamates), folic acid is the form with a monoglutamate residue.
Vitamin B9 is sensitive to heat and light.
The prevalence of insufficient vitamin B9 intake in Europe is between 10% and 45%.20 In Germany, 26.7 % (women) and 27.5 % (men) of adults (aged 19 to 64) were reported to have an insufficient intake, and 20.7 % (women and men) of older people (aged 65 and over).
A folate deficiency often appears to be present in ADHD.9492
A large study of 432 children found significantly lower serum levels of folate in children with ADHD.96 This correlated with an increased intake of nutrient-poor foods such as foods high in sugar and fat and a lower intake of vegetables, fruit and protein-rich foods than in healthy children.
It remains to be seen whether the change in diet is the cause, consequence or vicious circle of ADHD.
Another study also found reduced folate levels in ADHD.97
Vitamin C is required for the synthesis of noradrenaline.103 Bieger operates a laboratory and sells food supplements. Its own products were recommended in laboratory analyses without the conflict of interest being disclosed.
The prevalence of insufficient vitamin C intake in Europe is said to be between 5 and 35%.20
In Germany, 11 % (women) and 19 % (men) of adults (aged 19 to 64) and 11 % (women) and 12 % (men) of older people (aged 65 and over) were mentioned.
Vitamin E is a collective term for certain fat-soluble substances with antioxidant effects. Examples are tocopherols, tocotrienols, tocomonomoenols, marine derived tocopherols (MDT).
Source: Bieger.92 Bieger operates a laboratory and sells food supplements. Its own products were recommended in laboratory analyses without the conflict of interest being disclosed.
Source: Bieger.92 Bieger operates a laboratory and sells food supplements. Its own products were recommended in laboratory analyses without the conflict of interest being disclosed.
Source: Bieger.92 Bieger operates a laboratory and sells food supplements. Its own products were recommended in laboratory analyses without the conflict of interest being disclosed.
