Histamines and Adrenal Fatigue Syndrome – Part 1

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM

Histamines and Adrenal FatigueHistamines are compounds found in various parts of the body. From the brain to the gut, histamine has a variety of actions. It is both a neurotransmitter as well as an immunomodulator. Depending on where it is found in the body, and what receptor it interacts with, histamine can elicit a multitude of reactions. There are four types of receptors, numbered H1 to H4. Each are found in different parts of the body and have distinctly different effects on the body when activated.

Histamines 101

H1 receptors are found in the central nervous system (CNS) as well as the peripheral nervous system (PNS). When activated in the CNS they produce a number of effects. One such effect is the firing of hypothalamic neurons that are active when we are awake. This is why anti-histamine drugs such as Benadryl can cause drowsiness by blocking this receptor. Histamine’s effect on the PNS H1 receptor is completely different. These receptors are found on smooth muscles and on inside blood vessels. This is the receptor that gets activated when you have an allergic reaction. Histamines bind to the H1 receptor in the blood vessels to cause vasodilation and increase permeability. This is what causes hives as well as the redness and swelling seen in inflammation. It also causes smooth muscle contraction in your bronchial muscles, leading to difficulty breathing, asthma, and potentially life threatening anaphylaxis.

H2 receptors are mainly found in the gut. They are located on parietal cells, which are responsible for the secretion of gastric acid. An increase in histamines will subsequently lead to an increase in gastric acid secretion. This is why H2-antagonist drugs such as Zantac were developed. These drugs are used to decrease the release of gastric acid and help with conditions such as peptic ulcer disease and gastro-esophageal reflux disease (GERD) as well as the prevention of stress ulcers.

H3 receptors are unique in that they are inhibitory receptors. Mostly found in the CNS, they are part of a negative feedback loop that inhibits histamine synthesis and release. They have also been shown to inhibit other neurotransmitters such as dopamine, acetylcholine, GABA and serotonin. Blocking the H3 receptor in animals has been shown to increase anxiety. When the H3 receptor is blocked, histamine synthesis and release are no longer inhibited, causing an increase in histamine. Thus, histamines are thought to be related to anxiety. Although no drug has been developed and approved specifically to target the H3 receptor, many drugs still act on the receptor secondarily and produce anxiety or depression as a side effect. Due to the H3 receptor’s effect on other neurotransmitters, it has also been implicated in other mental disorders such as attention deficit hyperactivity disorder, Alzheimer’s disease, and even schizophrenia.

The fourth and final histamine receptor, H4, is found primarily in the bone marrow and on basophils. It is responsible for releasing neutrophils into the bloodstream from the bone marrow as well as mast cell chemotaxis. Mast cells are immune cells that are loaded with heparin and histamine. They play a major role in allergies and anaphylaxis. So in a chain reaction, H4 receptor modulation and chemotaxis leads to Mast cell aggregation, which upon releasing amplified amounts of histamines in a process known as mast cell degranulation, can eventually result in chronic inflammation and inflammatory disorders such as allergies or asthma.

Knowing where histamines are and what they do is half the battle. How do these chemical reactions translate to the real world though? Histamines are toxic molecules. It has a long list of negative effects on the body if left unchecked.

Elevated Histamines

Elevated HistaminesWhile histamine is a natural compound that is produced by your body and manifested at normal levels automatically elevated levels can occur. Antihistamines are common drugs prescribed by doctors and even available over the counter. Antihistamines have common side effects such as drowsiness, upset stomach, difficulty urinating, nervousness, dry mouth, and dry nose. They are typically used in an acute setting when requiring immediate symptom release such as allergic reactions and hay fever. This is fine as the receptor gets blocked for a short duration, but everything goes back to baseline soon enough. However, when taking antihistamines chronically, the body never gets back to baseline. Antihistamine drugs do not stop the production of histamine. They occupy the receptor so that histamine cannot act on it. Histamine continues to be produced in increasing amounts as the body recognizes that histamine is not functioning, as it should be. The body slowly builds a tolerance to antihistamine medication until the medicine no longer works. When antihistamines are discontinued, a rebound effect occurs and the body is flooded with histamine. The body will continue to release high levels of histamine because that is what it is used to doing. All the negative effects of histamines such as fatigue, anxiety, brain fog, and palpitations will be felt as the body is continuously overloaded with histamine.

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© Copyright 2015 Michael Lam, M.D. All Rights Reserved.

Dr. Lam’s Key Questions

Hives can be due to many reasons, the most common of which is some form of sensitivity that leads to excessive histamine release. This can be associated with AFS.

You could have allergies from the environment, chemical or food. Keep a journal and find out what is causing your allergies. Allerdim has quercetin that is a natural antihistamine. Allergic (food or chemicals or sensitivities) and asthma reactions usually have strong adrenal components. Many allergies involve the release of histamine and other pro-inflammatory substances. The body’s response is to produce cortisol, a strong anti-inflammatory hormone. The weaker the adrenals, the higher the frequency of allergies. This is because the more histamine is released, the more cortisol it takes to control the inflammatory response and the harder the adrenals have to work to produce more cortisol. When the adrenals are eventually exhausted, cortisol output is compromised, allowing unopposed histamine to inflame the bodily tissues more. This vicious circle can lead to progressively deepening adrenal exhaustion and producing more severe allergic reactions.


5 stars –Hi,Hi,

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Histamines and Adrenal Fatigue

5 - "My rushed pace to find"
My rushed pace to find definitive answers and solutions I forgot to thank you for your website and your personal reply to my questions. My friend's symptoms are grossly improving? Thank you.