Histamine

Histamine is a neurotransmitter and hormone.
It has no primary significance in ADHD, but may play a role in the day-night rhythm disturbances common in ADHD.

• 1. Histamine formation
  • 1.1. Histamine pathway
  • 1.2. Site of origin of histamine in the brain
• 2. Histamine storage
• 3. Histamine release
• 4. Histamine degradation
  • 4.1. Degradation in the brain (CNS)
  • 4.2. Degradation in the body
• 5. Histamine receptors
  • 5.1. H1 histamine receptor
  • 5.2. H2 histamine receptor
  • 5.3. H3 histamine receptor
  • 5.4. H4 histamine receptor
• 6. Disorders of the histamine system
  • 6.1. Histamine deficiency
  • 6.2. Histamine excess / histamine intolerance
    • 6.2.1. Development of histamine intolerance
    • 6.2.2. Frequency of histamine intolerance
    • 6.2.3. Possible symptoms of histamine intolerance
    • 6.2.4. Foods that increase histamine
      • 6.2.4.1. Modes of action of histamine elevation
        • 6.2.4.1.1. Containing histamine
        • 6.2.4.1.2. Histamine Liberators
        • 6.2.4.1.3. DAO Inhibition
        • 6.2.4.1.4. DAO mining competitors
        • 6.2.4.1.5. Increase of intestinal permeability for histamine
      • 6.2.4.2. List of triggers in histamine intolerance and MCAD
    • 6.2.5. Histamine intolerance treatment
• 7. Histamine and ADHD
  • 7.1. Dopamine and ADHD
  • 7.2. Hebanula, ADHD and histamine
• 8. ADHD drugs increase histamine

1. Histamine formation¶

1.1. Histamine pathway¶

Conversion of the amino acid histidine to histamine by

• Pyridoxal phosphate-dependent decarboxylation using the enzyme histidine decarboxylase or
• Non-specific aromatic L-amino acid decarboxylase

Production in

• Mast cells
• Platelets
• Epidermis cells
• Gastric mucosa
• Nerve cells

α-fluoromethyl histidine suppresses histamine synthesis.¹

1.2. Site of origin of histamine in the brain¶

Only a few cells in the brain produce histamine:²

• Nucleus tuberomammillaris (tuberomamillary nuclei, TMN), a larger nucleus of the posterior hypothalamus.
  These cells also produce GABA. They project to the cerebral cortex and significantly regulate arousal and wakefulness. There seem to be 5 groups of TMN cells, which differ, among other things, in the expression of the H3 receptor and in the co-emission of GABA.
  Deactivation of the TMN by the GABA agonist muscimol results in prolonged REM-free sleep, and optogenetic activation of a subpopulation of TMN neurons induces wakefulness.³
  The activity of TMN neurons varies according to the waking state: it is low in the quiet waking state, moderate in the active waking state, and highest in the alert waking state.⁴
  Histamine maintains alertness through direct projections of TMN cells to the thalamus and cortex and indirectly through activation of cholinergic (via H1 and H2 receptors),⁵ GABAergic⁶⁷ and noradrenergic cells (in the locus coeruleus).⁸
• Mastocytes (mast cells)
• Microglia
• Microvascular endothelial cells

2. Histamine storage¶

Storage bound to heparin in vesicles, primarily in

• Mast cells
• Basophilic granulocytes
• Mucous membranes
• Bronchi
• Gastrointestinal tract

3. Histamine release¶

Release from vesicles by

• IgE-mediated allergic reactions of the “immediate type” (type I)
• Complement factors (e.g., in endotoxin-induced shock)

4. Histamine degradation¶

4.1. Degradation in the brain (CNS)¶

Degradation by histamine methylation:
Histamine is inactivated by the enzyme histamine N-methyltransferase (intracellular) to inactive Nτ-methylhistamine.
Nτ-methylhistamine is oxidatively degraded via monoaminooxidases, diamine oxidases (extracellular), and aldehyde oxidases (intracellular) to Nτ-methylimidazolylacetic acid.⁹

4.2. Degradation in the body¶

Degradation by diamine oxidases (DOA, extracellular) and aldehyde oxidases (intracellular) to imidazolylacetic acid.
After ribosylation, excretion by kidney.

Only minor degradation due to histamine methylation.

5. Histamine receptors¶

Histamine can further influence

• Learning and memory processes¹⁰
• Thermoregulation¹⁰
• Satiety (due to histamine in the brain)¹¹
• Energy consumption is increased by histamine in the hypothalamus¹⁰
• Glucose uptake and insulin function in the body¹⁰
• Feeding behavior is decreased by histamine in the hypothalamus¹⁰ while histamine generally increases arousal for feeding¹¹
• Improvement of motor balance and motor coordination via H2 receptors in the cerebellum¹²
• Increases motor activity/exploratory behavior via H2 receptors, not via H1 receptors¹
• Increases anxiety primarily via H2 and concomitantly via H1 receptors¹

5.1. H1 histamine receptor¶

• Regulatory area
  • Systemic vasodilation (vasodilatation)
  • Skin redness
  • Day-night rhythm
    • Mice lacking H1 receptor have a disturbed day-night rhythm and are not awakened by H3 antagonists.²
    • Sleep¹³
  • Vomiting
  • Bronchoconstriction
  • Neurotransmission
  • Possibly antidepressant
  • Possibly anticonvulsive
  • Possibly appetite suppressant
• Agonists
  • Histamine
  • Histaprodifen
• Antagonists
  • Loratadine
  • Cetirizine
  • Fexofenadine
  • Doxylamine
  • Diphenhydramine

5.2. H2 histamine receptor¶

• Regulatory area
  • Gastric acid secretion
  • Reflex tachycardia
• Agonists
  • Histamine
  • Betazol
• Antagonists
  • Cimetidine
  • Famotidine
  • Ranitidine
  • Roxatidine

5.3. H3 histamine receptor¶

• Regulatory area
  • Neurotransmission
    Regulation of the release of
    • Histamine (autoregulation)
      • H3 antagonists increase the release of histamine¹
    • Acetylcholine
    • Norepinephrine
    • Serotonin
    • Dopamine
    • Glutamate
  • Regulation of circadian rhythmicity
• Agonists
  • Histamine
  • Α-Methylhistamine
  • Immepip
  • Imetit
• Antagonists
  • Ciproxifan
  • Thioperamide
    • Increases motor activity / exploration behavior¹
    • Increases anxiety¹
  • Clobenpropit

5.4. H4 histamine receptor¶

• Regulatory area
  • Mast cell chemotaxis
• Agonists
  • Histamine
  • 4-Methylhistamine
• Antagonists
  • Thioperamide
  • JNJ 7777120

6. Disorders of the histamine system¶

Histamine influences

• Arousal (excitement)
• Awakening
• Maintaining vigilance¹³

Dysfunction is associated with neuropathological disorders, e.g..⁹

• Narcolepsy
  • Hallucinations
  • Schizophrenia-like conditions
    An influence of histamine on schizophrenia itself has not yet been demonstrated.¹⁴
• Sleep problems
  • H1 receptor antagonists may help with insomnia¹⁴
• Tourette’s (rare)
• Alzheimer and Parkinson
  • High histamine levels in the substantia nigra correlate with a reduced number of dopaminergic cells
  • The H1 receptor seems to be affected¹⁴
• Huntington
• Depression
  • Reduced H1 receptor binding

6.1. Histamine deficiency¶

• Tourette’s Syndrome¹⁵¹⁶
  Histidine decarboxylase knockout (HDC-KO) mice exhibit stereotyped locomotor behaviors that reflect the core phenomenology of Tourette’s.¹⁷
• Rare gene variants of the histamine receptor gene appear to be involved in Tourette’s and autism spectrum disorders.¹⁸¹⁹

6.2. Histamine excess / histamine intolerance¶

6.2.1. Development of histamine intolerance¶

Very good presentation on histamine intolerance at www.histaminintoleranz.ch²⁰

Histamine overweight can have various causes:

• Excessive histamine intake (food, fish poisoning)
• Too little histamine degradation (mostly diamine oxidase deficiency)
• Smoking seems to increase histamine levels^2122232425
  Histamine moderates reactions to cigarette smoke.²⁶ In contrast, reports that smoking reduces histamine levels²⁷ or leaves them unchanged²⁸ are the exception. It is conceivable, however, that smoking increases the response to histamine.^29303132
• The cause may further be a systemic mast cell activation disease (MCAD)
  In this process, pathologically altered mast cells (mastocytes, a type of immune cell for foreign body defense) produce histamine and other messenger substances (mediators). The incidence of MCAD is estimated between 1 and 17 %.³³
  Very good presentation on MCAD at https://www.mastzellaktivierung.info/³⁴
  MCAD acts primarily, but not exclusively, by means of histamine.
  • Types of MCAD:
    • Mast cell activation syndrome (MCAS)
    • Systemic mastocytosis (SM) (rare)
    • Mast cell leukemia (MCL) (rare)
  • Mechanisms of action of an MCAD:³⁵
    Percentages indicate consensus that the above mediators play a role in MCAD.
    • Histamine
      • Headache
      • Low blood pressure
      • Hives (red wheals, urticaria)
        • With or without angioedema (rapidly developing painless swellings)
      • Itching (pruritus)
      • Diarrhea
    • Prostaglandin-D2 (PGD2) (95%)
      • Mucus secretion
      • Narrowed airways (bronchoconstriction)
        • In interaction with thromboxane and PGF2α
      • Vascular instability (dilation of blood vessels)
      • Sleep inducing
      • Body temperature lowering
      • Possible cause of hereditary hair loss in men together with the steroid hormone dihydrotestosterone (DHT)³⁶
    • PAF2 (platelet-activating factor) (90%)
      • Abdominal cramps
      • Pulmonary edema
      • Urticaria
      • Bronchoconstriction
      • Hypotension
      • Cardiac arrhythmias
    • Proinflammatory cytokines (80 %)
      • Local inflammation
      • Edema formation
      • Leukocyte migration 80
    • LTC4 and LTD4 (80%)
      • Mucus secretion
      • Edema formation
      • Vascular instability
    • Chemokines (70%)
      • Acute inflammation
      • Leukocyte recruitment
      • Leukocyte migration
    • Tryptase (65 %)
      • Endothelial activation with subsequent inflammatory reactions
    • Leukotrienes³⁷
      • Allergic reactions
      • Inflammatory reactions

An excessive histamine level causes pseudoallergic symptoms. These vary greatly from individual to individual, so that a diagnosis based on a list of symptoms is very difficult.

6.2.2. Frequency of histamine intolerance¶

The prevalence is 1% of the population. 80% of those affected are women, 20% are men.
More recent studies have arrived at higher prevalence values.

6.2.3. Possible symptoms of histamine intolerance¶

• Skin
  • Skin redness
  • Hives
  • Eczema
  • Itching[7]
• Head
  • Headache
  • Heat sensation
  • Migraine
  • Dizziness
• Airways
  • Narrowed or runny nose
  • Breathing difficulties
  • Bronchial asthma
  • Sore throat
• Digestive system
  • Flatulence (bloating)
  • Diarrhea
  • Constipation
  • Nausea/vomiting
  • Abdominal pain
  • Stomach Stitch
  • Heartburn
• Cardiovascular system
  • Blood pressure changes
    • High blood pressure (hypertension)
    • Low blood pressure (hypotension)
  • Palpitations (tachycardia)
  • Cardiac arrhythmias
• Urology
  • Menstrual cramps (dysmenorrhea)
  • Cystitis
  • Urethritis
  • Irritation of the mucous membrane of the female genitals
• Fabric
  • Water retention (edema)
  • Bone marrow edema (BMO)
  • Joint pain
• Energy balance
  • Exhaustion states
  • Seasickness
  • Fatigue
  • Sleep disorders
• Mental symptoms
  • Confusion
  • Nervousness
  • Depressive moods

6.2.4. Foods that increase histamine¶

Foods can increase histamine in several ways.

6.2.4.1. Modes of action of histamine elevation¶

6.2.4.1.1. Containing histamine¶

Foods that contain histamine increase histamine levels.

6.2.4.1.2. Histamine Liberators¶

Some foods cause an increased release of histamine from the salivary vesicles.

6.2.4.1.3. DAO Inhibition¶

Certain substances inhibit the breakdown of histamine by diamine oxidase (DAO).

6.2.4.1.4. DAO mining competitors¶

Some foods contain substances that also require diamine oxidase (DAO) for degradation, so it is correspondingly less available to break down histamine.

6.2.4.1.5. Increase of intestinal permeability for histamine¶

Substances that increase the permeability of the intestinal wall thereby simultaneously increase the absorption of histamine.

6.2.4.2. List of triggers in histamine intolerance and MCAD¶

A very good compilation of triggers of MCAD can be found at https://www.mastzellaktivierung.info/³⁸

Foods with high histamine levels (1) lists Quade, Bailly, Bartling, Bliesener, Springer: Histamine intolerance.³⁹ This presentation concerns only the foods with high histamine content, not e.g. histamine liberators or DAO degradation competitors.

6.2.5. Histamine intolerance treatment¶

The first-line treatment is a low-histamine diet.

Often, a one-month strictly low-histamine diet that completely empties the histamine stores already helps. After that, limited consumption of individual histamine-increasing foods is usually possible. Smoking significantly increases histamine levels and thus undermines the histamine diet.²²

In addition, the missing DAO enzyme can be taken 15 to 30 minutes before meals. DAO intake can only compensate for individual “sins”, but cannot fundamentally avoid a diet.

7. Histamine and ADHD¶

There is no positive knowledge about a correlation between histamine intolerance and ADHD. NCBI / Pubmed did not find a single article under “histamine intolerance adhd”.⁴⁰

A large cohort study found that taking antihistamines (especially first-generation antihistamines) in the first years of life significantly increased the risk of later ADHD. A disturbance of REM sleep, which secondarily impaired brain maturation, was cited as a possible cause.⁴¹
According to another study, previous (former) use of antihistamines increased ADHD symptoms in atopic dermatitis sufferers.⁴²

Certain polymorphisms of genes controlling histamine degradation may moderate the correlation of ADHD and food additive intolerance.⁴³

A report of 4 individual cases of learning disabled children with ADHD describes a very large improvement in ADHD symptoms with antihistamines.⁴⁴

The H3 histamine receptor is thought to be involved in arousal, control of pituitary hormone release, cognitive function, motivation, goal-directed behavior, memory, and sleep-wake rhythm. However, clinical trials of H3 receptor drugs for ADHD (MK-0249, Bavisant, PF-03654746) have been unsuccessful in phase 2 trials or have been discontinued in phase 2 trials (betahistine).⁴⁵

7.1. Dopamine and ADHD¶

Animal studies found a correlation between high histamine levels in the substantia nigra and a breakdown of dopaminergic cells, causing decreased dopamine levels.⁹ To date, no therapeutic benefit of H3 antagonists (which increase histamine levels and dopamine levels) on Alzheimer’s disease or ADHD has been found.¹⁴

7.2. Hebanula, ADHD and histamine¶

Early childhood lesions of the habula cause behavioral and brain changes similar to those seen in ADHD.⁴⁶

The Habenula

• Transmits limbic information to the midbrain monoamine system
  • Is thereby involved in the regulation of monoamine release in target brain areas such as the striatum, where some of the biological substrates process time perception.
• Is part of the circadian rhythm network and involved in sleep regulation

Histamine H3 receptor antagonists resolve these symptoms.⁴⁷

ADHD often shows changes in circadian rhythms, sleep disturbances, and time perception.

8. ADHD drugs increase histamine¶

ADHD medications appear to increase histamine:

• Atomoxetine⁴⁸⁴⁹
• Methylphenidate⁴⁹
• Amphetamine⁵⁰⁵¹
• Modafinil⁵²
• Nicotine
• Caffeine

One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses.