Histamine and Adrenal Fatigue Syndrome – Full Version

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

Histamine is a compound 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.

Histamine 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. Histamine binds 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 histamine 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, histamine is 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 histamine in a process known as mast cell degranulation, can eventually result in chronic inflammation and inflammatory disorders such as allergies or asthma.

Knowing where histamine is and what it does is half the battle. How do these chemical reactions translate to the real world though? Histamine is a toxic molecule. It has a long list of negative effects on the body if left unchecked.

Elevated Histamine

While 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 histamine such as fatigue, anxiety, brain fog, and palpitations will be felt as the body is continuously overloaded with histamine.

Histamine in Food

Another way that inadvertently increases histamine levels is by eating foods high in histamine. Histamine is usually metabolized in the intestines and liver. However, some individuals may have low levels of the required enzymes to metabolize histamine and thus have increased circulating histamine. Histamine is typically found in foods that have been fermented or highly processed. Fermented cheeses such as cheddar and Gouda are high in histamine. Other dairy products such as yogurt and buttermilk also contain elevated histamine amounts. Salami, pepperoni, sausage, and other processed meats are also high in histamine. Vegetables such as tomatoes, spinach, and eggplant contain increased histamine compared to other vegetables. Berries have been shown to be high in benzoates, which release histamine. Spices such as cinnamon, cloves, and nutmeg also contain benzoate and release histamine when ingested. These are usually not an issue because the body metabolizes them automatically without a problem.

Harmful Effects of Histamine

Excessive histamine can wreck havoc in the body. Starting with the brain, histamine has the ability to inhibit almost every neurotransmitter and is a neurotransmitter in itself. Any unbalance in the chemical makeup of your brain is bound to cause unwanted effects such as brain fog, fatigue, and anxiety. It is also why histamine has been implicated in several major psychiatric disorders. Along with psychiatric disorders, histamine is also involved in the sleeping cycle, mainly stimulating the body to stay awake. This can only worsen the symptoms manifesting in the brain. At the cardiovascular system, with histamine being a vasodilator and opening up the vessels in the body, the heart will have to pump harder and faster to maintain the same blood flow. This can lead to tachycardia, heart palpitations and low blood pressure. Heart palpitations combined with increased anxiety can often lead to panic attacks too. Unchecked histamine can also lead to increased gastric acid secretions in the gut, contributing to irritable bowel syndrome and gastric ulcers.

On top of all these conditions, histamine actively plays a role in inflammation and the allergic reaction, having high histamine levels in your body is similar to being in a chronic inflammatory or allergic state. One can experience itching, nasal congestion, asthma, red eyes, hives, and even angioedema. These symptoms are largely modulated by the adrenal glands. We will go into these in more detail later.

Histamine and Adrenal Glands

Elevated histamine levels do not bode well for the adrenal glands. Histamine is an inflammatory molecule. Cortisol, released by the adrenal glands, is an anti-inflammatory compound. One can imagine the contrasting battle these two molecules go through on a daily basis. Any unnecessary rise in histamine levels only serves to burden the adrenal glands. Most sufferers of Adrenal Fatigue Syndrome (AFS), especially those in advanced stages, invariably are overloaded with histamine internally without sufficient cortisol to counter its effect. It comes as no surprise that many are in a generalized inflammatory state with many nonspecific but bothersome symptoms of discomfort.

As a result of inflammation, many suffer from migrating pain of unknown origin, especially in the muscles and joints. There is no deformity in the joints, and the discomfort can come and go at will without a set pattern. Doctors are usually at a loss after a normal blood test without significant signs of autoimmune disease. Pain medications are usually prescribed but seldom necessary as the discomfort is generally nagging in nature and not very severe.

Sometimes pain can be in the lower back area surrounding the kidneys. There is no significant physical finding. Visits to family doctors are made and bladder and urinary track infection workups are usually negative. Abdominal CT scans are normal. Many will report a dull ache or a sensation of feeling heat in the adrenal glands area that is worsened under stress or when energy levels are low, or when certain type of food are consumed. There is no specific point of tenderness on palpation. The sufferer is usually told that it is all in their head.

Food sensitivity is common when histamine levels rise beyond what the body can handle. Intake of watermelon, for example, can lead to skin itchiness in distant parts of the body such as the ear lobes. Dairy products can lead to excessive nasal drip that can be postnasal in nature. Sufferers generally report a sense of congestion during the day, and wake up in the morning with a cough. Headaches of unknown origin, excessive bloating, and stomach pain are all common presentations.

Increased sensitivity to seasonal allergens is also a common finding. Due to intrinsic high histamine levels within, the threshold for external allergens to trigger inflammation is reduced, especially from pollen and grass during the spring. Most sufferers of AFS will find themselves highly sensitive to such external allergens in addition to heat intolerance when outdoors. Runny nose, sense of itchiness at the throat, and sniffling are common presenting complaints. Steroidal nasal sprays and anti-histamine medications are prescribed frequently for what appears to be classic signs of allergic rhinitis. Without understanding the root cause and trigger, this medication only acts to reduce symptoms and bring temporary relief. With prolonged use, tolerance and dependency develop. Those with marginal or mild adrenal fatigue will find their condition worsens over time, as the adrenals will slow down production of steroids due to the ample external supply as the feedback loop is disrupted. Withdrawal and rebound symptoms may arise if the medications are stopped abruptly.

Natural Antihistamine Food and Compounds

Fortunately, there are natural compounds and food that can reduce histamine load. We will now look at these in more detail.

Mangosteen, a tropical fruit, has been shown to have potent antihistamine properties. It is uncertain what compound in the fruit causes such action. Mangosteen also has anti-inflammatory properties. Mangosteen is available as a fruit, juice, or extract.

Holy Basil is a superstar as a natural antihistamine. Not to be confused with regular basil, holy basil, otherwise known as Thai Holy basil or Ocimum tenuiflorum or Ocimum sanctum, inhibits H2 receptors, and works great against gastric ulcers. Research has even shown it to be equally effective as over-the-counter medications such as Zantac. On top of that, Holy basil also exhibits its antihistamine effects in anaphylactic and asthmatic situations by inhibiting mast cell degranulation. It has even been used to treat hives on skin. Butterbur and Echinacea, although not antihistamines, have anti-inflammatory and decongestant properties that make them effective against seasonal allergies. Holy basil also increases cortisol production in the adrenal glands.


The most impressive research has been done on a special extract of milk thistle (Silybum marianum) known as silymarin, a group of flavonoid compounds. These compounds protect the liver from histamine damage and enhance the detoxification process.

Silymarin prevents damage to the liver by acting as an antioxidant. It is much more effective than vitamin E and vitamin C. Numerous research studies have demonstrated its protective effect on the liver. Experimental liver damage in animals is produced by extremely toxic chemicals such as carbon tetrachloride, amanita toxin, galactosamine, and praseodymium nitrate. Silymarin has been shown to protect the liver against these toxins.

Silymarin also works by preventing the depletion of glutathione. The higher the glutathione content the greater the liver’s capacity to detoxify harmful chemicals. Moreover, silymarin has been shown to increase the level of glutathione by up to thirty-five percent. In human studies, silymarin has been shown to exhibit positive effects in treating liver diseases of various kinds including cirrhosis, chronic hepatitis, fatty infiltration of the liver, and inflammation of the bile duct. The best delivery of silymarin is in the fermented form. Clinical effectiveness is greatly exaggerated as compared to the normal form because fermentation is a living process. Only take the fermentation form in pure liquid non-pasteurized and manufactured under strict standards.

Flora Supplementation

A healthy intestine is of paramount importance to reduce inflammation caused by histamine. Optimal gastrointestinal health depends on the balance of microscopic interplay between billions of beneficial (good) and pathogenic (bad) bacteria. Both are needed for normal bowel function. A well-maintained balance between these opposing microorganisms is essential for a properly functioning digestive tract.

About 400 species of these good bugs inhabit the intestines. Their total population is about one hundred times the number of cells in your body. Remarkably, these microorganisms coexist peacefully in a carefully balanced internal ecosystem. As long as they flourish, they prevent pathogenic (disease-causing) bacteria and fungi from colonizing. In this way, beneficial bacteria help keep you healthy. If the delicate intestinal environment is disrupted, pathogenic bacteria, parasites and fungi such as clostridia, salmonella, staphylococcus, Blastocystis hominis and Candida albicans often move in, multiply and attack the beneficial bacteria.

Research has shown that the good bacteria otherwise known as probiotics, helps defend our bodies from the pathogenic species of bacteria and detoxify toxic chemicals. They also produce valuable vitamins including biotin, folic acid, niacin, pantothenic acid, riboflavin, thiamin, vitamin B6, vitamin B12 and vitamin K. The bacteria assists in breaking down dietary proteins into amino acids, which are then reconfigured into new proteins that are useful for the body. Good bacteria also ensure that toxins are excreted from the bowels (via the stool) rather than absorbed into the bloodstream.

One such good bacterium is acidophilus. They stimulate activity in the thymus and spleen (both are key immune system glands). They prompt your body to manufacture natural antibodies. Certain acidophilus strains even protect against the formation of tumors and promote production of interferon, a hormone that protects against cancer. When probiotics are present, they secrete mediators in which the pathogenic forms cannot grow. However, when the micro-organic forms take over, they will exclude the probiotics with their toxins. Replacing our natural flora is vital to prevent any disease and to keep our bowels healthy.

Numerous studies have been conducted to understand the mechanism of how probiotics work. Many amazing facts have been established concerning the beneficial and therapeutic aspects of probiotics including:

1. Increased enzyme production such as proteases that digest proteins and lipases that digest fats.
2. Improved bowel transit time and texture of the fecal matter.
3. Increases synthesis of immune antibodies and augmentation of gamma-interferon production.
4. Reduction of lactose intolerance caused by a deficiency of the enzyme lactase which leads to reduced bloating, gas formation and stomach discomfort after milk consumption.
5. Acts as an antitoxin with anticarcinogenic and antitumor agent.
6. Relief of dermatitis and other skin disorders by improving gastrointestinal bacteria balance.
Many scientists at the forefront of probiotics research believe that the toxins secreted from the pathogens, rather than the pathogens, are responsible for disease. One mechanism of such assault is by raising histamine levels. Although this is not a widely recognized fact among the traditional medical establishment, this statement has been proven without a doubt.

Regular supplementation with probiotics such as acidophilus repopulates your intestinal tract with benevolent bugs. These microorganisms restore and maintain balance within your internal ecosystem while displacing noxious bacteria and fungi at the same time. Histamine level is reduced.

Acidophilus supplements are widely available in health food stores and drugstores. Selecting from among the numerous something-dophilus products may appear a daunting task. Examine the labels and you will discover a variety of useful bugs including Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus bulgaricus and Streptococcus faecium. Some products may contain fructo-oligosaccharides, which are sugars that nourish beneficial bacteria to make them colonize faster. All of these ingredients are acceptable and any combination of them works well.


Quercetin can be considered the king of flavonoids. It is an excellent natural antihistamine. It also interferes with the pain promoting inflammatory histamine that is generated in the body in many autoimmune diseases including rheumatoid arthritis and colitis. In addition to its antihistaminic effect, studies have shown that it is also able to fight off an enzyme that neutralizes cortisol, a natural anti-inflammatory chemical produced by the body. You can get quercetin by drinking more unfermented green tea as well as red wine. Apples, onions, tomatoes, green peppers, as well as broccoli are all excellent sources of quercetin. However, as a large amount of it is required to produce a positive effect, it is better to take a quercetin supplement.


Bromelain is an enzyme that is found in pineapple stems. Its primary activity is to reduce inflammation and promote healing, especially in muscles and joints. As such, it is popular and is used widely in sports medicine and trauma management. Bromelain’s anti-inflammatory property also plays a significant role in the management of asthma, arthritis, colitis, and other allergy responses. It should be noted that only high potency and high quality supplements should be used in a therapeutic setting. It should be taken on an empty stomach along with quercetin.

Vitamin C

Vitamin C is a fundamental nutrient to good health. In particular, in asthma and allergy settings, vitamin C has been proven to effectively combat allergies. A dosage of 1000 mg or more has some antihistaminic effect, but the vitamin C does much more than that. Because vitamin C is water soluble, its action is slower. A few weeks may be needed to achieve the adequate blood level. In the case of asthma, many studies have shown that a daily vitamin C dosage of 1000-2000 mg can improve lung function and reduce the chances of asthmatic attacks. In one study, a daily dose of 2 grams has been shown to reduce asthma. Always try to include bioflavonoids when taking vitamin C, especially in high doses. While there is a fair amount of vitamin C in fresh fruit, there is a trade off in the sense that fruits high in vitamin C are high in sugar and carbohydrates. If you prefer to take vitamin C from natural sources, dark green vegetables, red peppers, and lemon juice are smart selections. Cabbage, broccoli, strawberry, and citrus fruits are also acceptable. Try to stay away from the melon family, as melons are high in sugar. Taking large amounts of vitamin C is remarkably safe. It is also good to add some digestive enzymes, which contribute to a better blood concentration of vitamin C. The body uses vitamin C quickly after it has been injected. It is good to take vitamin C in divided doses, with no more that 2 grams at any one point in time. Taking vitamin C together with bioflavonoids such as quercetin will potentiate the effects of vitamin C. In the case of allergic response, always take vitamin C in conjunction with some quercetin. Therapeutic dosage is anywhere between 2-10 grams of a complex cocktail consisting of vitamin C, L-lysine, L-proline, bioflavonoids, grape seed extracts, and ascorbyl palmitate. Vitamin C comes in different forms and delivery systems, each with its advantages. The liposomal form is best for potency, the fat-soluble form for slow delivery, while plain ascorbic acid is fast acting. The best cocktails incorporate different forms for maximum bioavailability.


Pantethine is a derivative of pantothenic acid (vitamin B5). When inside the body, it is converted into Coenzyme A. Coenzyme A is one of the few substances that the body needs in the metabolism of protein, fat, and carbohydrates. It is also the basis for the production for adrenal steroidal hormones, which have an anti-inflammatory effect. The use of Pantethine is therefore an excellent choice when it comes to conditions such as allergies, asthma, lupus, or psoriasis. Because it helps in the production of cortisol, the body’s natural steroid, anybody who is taking prednisone or other steroidal medicine stands to benefit. While it may not be able to replace drugs, there is often a synergistic effect and the amount of drugs required may be reduced. Pantethine also allows the adrenal glands to generate more omega-3 fatty acid in the body. Omega-3 fatty acid is well known to have anti-inflammatory properties. Reducing inflammation and inflammatory response is a key recovery pathway in an allergic therapeutic setting.

Essential fatty acids

Essential fatty acids are indispensable as they provide building blocks for the body’s numerous eicosanoids and therefore reduce the damaging effect of inflammation caused by histamine. Many of these hormone-like compounds are also called prostaglandins and have tremendous anti-inflammatory power. Omega-3 fatty acid in particular is very strong in generating eicosanoids. Most of us living in the modern world already have a high intake of omega-6 fatty acid from a variety of processed foods. Accordingly, we are low in omega-3. Inflammatory conditions such as arthritis, plaque, blood clots, and immune system weakness are related to a lack of omega-3 fatty acid intake.

Essential fatty acids found in omega 3 fats and oil are alpha-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA). The anti-inflammatory properties of omega-3 fatty acid have been well established. In high doses of 3-5 grams or more a day of the active ingredient EPA and DHA, it has been shown that there is a tremendous beneficial effect in inflammatory bowel diseases such as colitis and Crohn’s disease, autoimmune diseases such as rheumatoid arthritis, and a variety of skin disorders such as eczema. Because there is a strong inflammatory component in asthma, the use of fish oil in a pulmonary disorder such as asthmatic conditions is an excellent choice.

As a natural compound, the anti-inflammatory properties of omega-3 fatty acid are excellent. However, doses of up to 10-20 grams may be necessary. It also takes anywhere from three to six months for the omega-3 fatty acid blood level to be built up. One note of caution: Most low potency capsules contain approximately 300 mg of DHA and EPA combined. In contrast, high quality fish oil capsules have up to 600 mg of combined DHA and EPA. If one were to take in 5 grams of DHA and EPA, then up to 18 capsules of fish oil, depending on potency, may be required. When a high dose is contemplated, use only the liquid bottled form. Insist on the purest product that is molecularly distilled and contains less than 5 ppb of mercury. When not in use, and this is one test of purity, such fish oil liquid should be stored in an amber glass bottle and placed in the freezer. Pure fish oil of high quality will not freeze when put in the freezer. The freezing cold will stop the oxidative process from reducing the effectiveness of the oil. Fish oil should also be dispensed in silverware, and not onto plastic or Styrofoam utensils. Because pure fish oil may melt Styrofoam and plastic, fish oil should be stored in a glass container only.

Enzyme Supplementation

Enzymes are molecule catalysts located in abundance in the body. In fact, there are over 1,300 different types. Enzymes are considered as the construction workers that facilitate all the bodily functions.

There are several forms of enzymes. Raw fruits and vegetables contain a plentiful supply of enzymes. Cooking and processing of food can destroy enzymes. When enzymes are destroyed, the body’s ability to digest food, delivery of nutrients and optimum functions are affected. Toxins thus build up and accumulate in the body.

Digestive enzymes are especially important, as exhaustion is one of the main reasons of accelerated aging. Plant enzymes assist in the digestion of food directly through the intestinal tract. Supplemental enzymes help prevent feelings of bloating and exhaustion after a big meal. We consume an average of two pounds of food per day or twenty tons over a lifetime. A smooth passage of food through the gastrointestinal tract is critical to avoid stasis of feces, which releases toxins. Digestive enzymes help in this respect together with a high soluble fiber diet.

Digestive enzymes also help other vitamins and minerals. For example, the fat-soluble vitamins A, D, E, and K require fat for absorption. Fat has to be broken down by an enzyme known as lipase. If lipase is not present in sufficient quantities, the fat will not be broken down. If the fat is not broken down, the vitamins will not be released. Therefore, you can spend a fortune on vitamin pills but if there is an absence of the proper enzymes to release the vitamins into the body’s system, the vitamins will still be flushed out.


Reducing internal histamine load should be part of a total recovery program in AFS. The key is to first recognize that histamine does play an important role in worsening adrenal fatigue. The astute clinician should be on alert for symptoms mentioned above as clues for further investigation. Normal laboratory finds are actually supportive of the investigative process. The key rests with a detailed history conducted carefully by an experienced clinician. Nature has provided us with a battery of compounds with antihistamine effects. They are best used in a nutritional cocktail for optimal results.

If you think that you are have symptoms of high histamine levels and suffer from Adrenal Fatigue Syndrome, recovery needs to be personalized. An improper approach to recovery can complicate, deter, or even exacerbate your current state.

If you have questions please write to us below for free or call us for a free initial consultation.


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