What Is Histapenia?

Most of us have heard about histamine, and how it’s related to symptoms such as sneezing, itching, and watery eyes. You may have even heard about people who have consistently high histamine levels, and end up suffering prolonged inflammatory reactions. 

In fact, most information about histamine is related to histamine intolerance and how to block or reduce histamine levels in the body. 

So, if high levels of histamine are a problem, then surely low levels are ideal? 

Well, not quite. Too little histamine - known as histapenia - can be just as catastrophic as too much. As a major brain neurotransmitter, histamine plays a major role in stimulating the release of serotonin, dopamine, and norepinephrine from the hypothalamus. Low levels can therefore manifest as psychological and behavioral disorders. 

Let’s examine why healthy, balanced histamine levels are so crucial for the proper functioning of the body and mind. 

What is histamine?

Histamine is a chemical produced by your body. It’s actually known as an autacoid, which means it acts like a local hormone near where it is synthesized in the body. The highest concentrations of histamine are found in your intestinal mucosa, skin, and bronchial tissues. Histamine is also present in many foods. 

As one of the most versatile molecules in your body, histamine can cause a huge range of effects depending on where it’s released. 

Histamine is most commonly known for its role in allergic and inflammatory processes, including immediate and delayed hypersensitivity immune reactions. When produced during a local immune response, its main role is to cause inflammation. The release of histamine causes your capillaries to become more permeable to white blood cells and other proteins. This allows your white blood cells to target and attack foreign bodies in the affected tissue. 

Histamine and your brain

Histamine isn’t just about inflammation. It also serves as a neurotransmitter like serotonin and dopamine, which means it’s involved in alertness, arousal, learning, memory, regulation of appetite, and pain perception. 

Aside from stimulating the release of neurotransmitters, another role of histamine in the brain is to counteract the effects of dopamine and filter sensory data going to the brain.

American psychiatrist Carl Pfeiffer made some breakthrough discoveries regarding the influence of nutrients on mental illness. Pfeiffer believed that an imbalance of histamine was at the core of schizophrenia, and that deficiency in histamine (histapenia) was linked to excess copper in the body. Both of these conditions were related to the development of classic paranoid schizophrenia. 

What happens when histamine is out of balance?

Too much or too little histamine in the body can cause severe health conditions. 

According to the Pfeiffer protocol, the “normal” blood histamine range is 33-65 ng/ml. 

  • High blood histamine levels (70+ng/ml) are referred to as histadelia
  • Low blood histamine levels are considered 27.6ng/ml for females and 20.2ng/ml for males.
  • Other sources suggest histapenia is histamine levels below 40ng/ml (0.35umol/L), low basophils, and elevated copper by measuring either 24-hour urine copper or serum ceruloplasmin .

Histadelia: too much histamine

Excess histamine is often referred to as histadelia, and usually involves the central nervous system (CNS), gastrointestinal tract, cardiovascular system, respiratory tract, skin, and reproductive system. It can occur due to metabolic imbalances such as a lack of DAO enzyme, which is required to break down histamine in food.

Signs of excess histamine include: 

  • CNS symptoms: headaches, insomnia, anxiety, dizziness, depression, panic disorders.
  • Gastrointestinal symptoms: bloating, pain, diarrhea, and gastroesophageal reflux.
  • Cardiovascular symptoms: increases in blood pressure, palpitations, and other heart rhythm disorders.
  • Respiratory symptoms: cough, respiratory distress, asthmatic symptoms, sneezing, and phlegm.
  • Skin and mucosal symptoms: hives, itching, redness, and swelling of the skin, lips and tongue.
  • Reproductive symptoms: Women may experience dysmenorrhea and headaches associated with the menstrual cycle.

Histapenia: too little histamine

Histapenia is the term used to describe a deficiency in histamine or chronically low levels of histamine. Because histamine is a major brain neurotransmitter, low levels usually manifest as psychological and behavioral disorders. This is due to elevated levels of serotonin, dopamine, and norepinephrine, along with low basophils. 

People with histapenia are also often found to have high copper levels. Copper toxicity decreases blood histamine and is linked with psychosis. 

According to Pfieffer, signs of histapenia or low histamine can include:

  • Canker sores
  • Heavy growth of body hair
  • Ideas of grandeur
  • Undue suspicion of people
  • Racing thoughts 
  • Feeling that someone is controlling your mind
  • Seeing or hearing things abnormally
  • Ringing in the ears
  • High anxiety
  • Food sensitivities
  • Depressed metabolism 

The lack of histamine typically means an absence of seasonal or respiratory allergies. However, histapenia may instead cause a range of chemical or food sensitivities, low libido, obsessions, tendency for paranoia and auditory hallucinations, hyperactivity, and “nervous” legs .
People are often frustrated, dissatisfied, and irritable, with low energy levels. There are also reports of a dry mouth and a tendency towards an above-average number of dental cavities.

What causes histapenia?

Many of the above symptoms are associated with excess copper levels. Copper contains the enzymes that regulate histamine, and excess copper in the brain allows histamine to be degraded much more quickly. 

In turn, lowered histamine levels allow more copper to accumulate, creating a cycle that’s generating negative symptoms and responses in the body. Because histamine also acts as a neurotransmitter, imbalances can affect brain chemistry. High levels of copper in the brain are known to cause:

  • Restlessness
  • Insomnia
  • Violence
  • Depression
  • Irritability
  • Paranoia
  • High blood pressure

Histamine and methylation

Histamine levels correlate with the efficiency of methylation processes in the body. Histamine and methyl are inversely related to one another, which means that if someone’s whole blood histamine is low, they will be overmethylated. If their blood histamine is high, they will be undermethylated. 

It’s also been found that excess copper in the brain may be due to a genetic metabolic condition that causes histamine levels to be reduced by too many methyl groups. This has led researchers to suggest that histapenia may be a result of over-methylation .

Methylation is a process by which things happen in your body. Methylation adds a methyl group to your DNA, which means it’s responsible for many biochemical activities in the body. These activities affect everything from energy levels, immune system, mood, detoxification processes, and more. Methyl groups also break down excess histamine and other inflammatory processes. Proper methylation is essential for daily function. 

When the blood contains high amounts of histamine, some of the excess gets stored in the brain. This is primarily due to the action of the histamine receptors, especially histamine receptor 3. In the brain, histamine can interrupt the release of important neurotransmitters which include serotonin, dopamine, and norepinephrine.

The theory is that people with histapenia have too little histamine because they over methylate, producing too many methyl groups and excessively lowering normal histamine levels.

In simple terms, overmethylation is “too much of a good thing”. Too little histamine means dopamine levels will be elevated and this may result in anxiety, paranoia, being suspicious, and hallucinations. It can also mean high serotonin levels, which in turn causes dopamine to stay in the brain for longer periods of time. Although these chemicals make us feel good, excess can lead to emotional problems, confusion, and poor motivation.

People who are overmethylated also tend to have an adverse reaction to serotonin-boosting medications such as Prozac, Paxil, Zoloft, and St. John’s Wort. They may also experience sleep disorders, have an adverse reaction to estrogen therapy, have sensitivities to certain foods and chemicals, and a tendency to overreact to life experiences. Clinical studies have suggested that a significant proportion of people diagnosed with schizophrenia are also severely overmethylated .

Treatment options for overmethylation

Overmethylators tend to have high copper levels, low zinc, high estrogen, and high homocysteine levels. In this case, they may benefit from supplementation with folate, zinc, vitamin C, and B vitamins.

Histapenia treatment should, therefore, begin by increasing histamine levels. This is usually done by supplementing with the amino acid histidine, as well as vitamins B3, B12, and methylfolate. At the same time, efforts must be made to reduce copper levels using zinc, manganese, and vitamin C. Histidine actually reduces zinc availability, so it’s important to use very high doses of zinc to combat the high copper and overcome the binding effect of histidine.

Pfeiffer developed a nutritional biochemical approach to treating mental health problems. He treated thousands of patients with depression and schizophrenia using nutritional supplements based on whether they had high or low levels of serum (blood) histamine. He found a range of different body chemistries and symptoms and was able to devise individualized therapies for each biotype.

One of his most interesting discoveries was that 90 percent of patients with schizophrenia could be categorized into three major biochemical types: histapenia, histadelia, and pyroluria.
Pfeiffer treated his patients with folic acid, vitamin B12, niacin, zinc, and a range of other supplements designed to augment the effects of these nutrients.

Some of the recommended nutrients for treating histapenia / overmethylation include: 

  • High doses of zinc, manganese, Vit C, niacinamide, Vit B12 and folic acid (though methylated folate will be preferred, especially if you have an MTHFR mutation, which is a large portion of the population)
  • Tryptophan: Converts to serotonin, a calming neurotransmitter that corrects sleep disturbances and lowers agitation.
  • Zinc: Inhibits absorption of copper and permits the storage of histamine.
  • Buffered Vitamin C: Excretes copper, protects against copper oxidizing brain tissue.
  • Niacin (B-3): Raises histamine levels
  • Folate: Produces histamine
  • Vitamin B12: Produces histamine
  • Manganese: Inhibits absorption of copper
  • Histidine: Raises histamine levels
  • Quercetin: Helps to modulate histamine release by stabilizing mast cell membranes that store it.

Diet for those with histapenia

Overmethylated people tend to benefit from a diet rich in folate and other B vitamins. They are also advised to increase their intake of zinc, manganese, vitamin C, niacin, vitamin B12, and folate. These nutrients help to reduce high blood copper levels and relieve symptoms over several months.

Food and supplements containing copper should be avoided. Copper contains the enzymes that regulate histamine, and high amounts of copper allow histamine degradation to occur. Excess copper decreases histamine in the brain, and the lowered histamine levels allow more copper to accumulate. Copper-rich foods include organ meats (such as liver), oysters, spirulina, and shiitake mushrooms. 

Response to treatment is usually good but can take some time in patients who have been suffering from histapenia-related symptoms for months or years. Some people may initially experience a worsening of symptoms due to body stores of copper being recirculated.

Recommended supplements

As mentioned, treating histapenia should involve raising levels of histamine, along with vitamins B3, B12, and methylfolate. Nutrients that lower copper should be taken, such as zinc, manganese, and Vitamin C. 

N-acetylcysteine (NAC) has also been shown to improve symptoms in patients with schizophrenia and bipolar disorder who suffer psychosis. 

Copper levels can be reduced through supplementation with zinc, which absorbs copper in the diet. Molybdenum has also been shown to reduce copper levels by increasing the amount excreted in urine and interfering with its absorption in the gut. 

A basic histapenia treatment protocol might include: 

  • Histidine before meals and before bed to elevate histamine
  • Niacin (Vitamin B3) twice daily with meals
  • Methylfolate twice a day (not folic acid) in case of MTHFR gene mutation
  • Vitamin B12 twice a day
  • Zinc twice a day
  • Vitamin B6
  • Vitamins C twice a day
  • Manganese once a day
  • NAC 1000-2000mg twice a day

Essential fatty acids are also highly recommended. Purified liquid fish oil containing a high dose of DHA should be taken at least twice a day to support cognition, reduce inflammation, and maintain cellular health. 

Methyl-Life’s™B12 Complete is an excellent option for those with low levels of histamine. It contains the 5,000 mcg of vitamin B12 as Methylcobalamin (2,500 mcg), Hydroxocobalamin (1,250 mcg) and Adenosylcobalamin (1,250 mcg). 

B12 Complete contains a combination of the most bioactive forms of B12 for maximum delivery and absorption. Bioactive simply means that the B12 has already been converted into a form that can be absorbed and used by the body’s cells immediately. This makes it suitable for people who have MTR, MTRR, COMT, or other gene mutations that may be affecting B12 absorption). 

Methylcobalamin is an active form of vitamin B12 that helps in the synthesis of methionine and S-adenosylmethionine (SAMe). It is also required to maintain the integrity of myelin, neuronal function, proper red blood cell formation, and DNA synthesis. It may also help in lowering homocysteine levels and reducing the risk of anemia.

Hydroxocobalamin is a precursor to methylcobalamin and Vitamin B12 and often recommended in conditions where B12 cannot be properly absorbed in the gut. Hydroxocobalamin is essential for DNA replication and synthesis, the proper function of the nervous system, cellular energy, as well as the conversion of homocysteine into methionine. It’s known to help with brain fog, pernicious anemia, and mopping up excess peroxynitrites. It’s also known to be the most well-tolerated form of active B12.

Adenosylcobalamin is the form of B12 stored in the mitochondria and selected when your body requires a biologically active form of vitamin B12 to support the Krebs cycle and cellular energy production. Adenosylcobalamin helps in muscle recovery, myelin sheath integrity, and reduces the risk of anemia. 



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