What Is Histapenia?

Histapenia is a term used in functional medicine to describe low histamine levels. It is not recognized as a medical diagnosis, and there is no peer-reviewed clinical evidence to show that low histamine causes specific symptoms.

The term was created in the 1970s by Dr Carl Pfeiffer, a physician and biochemist who researched mental health disorders, particularly schizophrenia. After studying more than 20,000 schizophrenia patients, he proposed that their mental health symptoms aligned with three major biochemical groups: histadelia, histapenia and pyroluria.

• Histadelia: high blood histamine levels due to undermethylation
• Histapenia: low blood histamine levels due to overmethylation
• Pyroluria: a disorder in vitamin B6 metabolism

Although Pfeiffer’s treatment system has not been validated in controlled clinical trials, the Pfeiffer Treatment Center in Illinois has treated more than 1,000 people with a diagnosis of schizophrenia. However, these terms are not recognized as standard medical diagnoses in mainstream medicine.

According to Pfeiffer, 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

Pfeiffer believed these symptoms were caused by low histamine. Histamine is a signaling chemical that affects the immune system, the gut and the brain (as a neurotransmitter). 

Pfeiffer explained that a high proportion of patients diagnosed with schizophrenia have low histamine levels in the blood, and also high levels of copper, which he believed reduces histamine.¹ He also suggested that low histamine and high copper led to symptoms such as ideas of grandeur, racing thoughts, abnormal visions, ringing in the ears and more. 

Recent research has noted that some patients with schizophrenia have high blood levels of copper, and that excess copper is linked with psychosis.²

Some functional medicine sources suggest that because it is a cofactor for enzymes such as diamine oxidase (DAO), excess copper may increase the breakdown of histamine. 

Excess copper is shown to accumulate in the brain and cause oxidative stress and neuroinflammation, which can damage neural tissues. It has been linked to psychiatric and neurological symptoms, including mood disturbances, emotional lability, irritability and even psychosis.³

However, there is no clinical evidence that high levels of copper in the body accelerate histamine breakdown or lead to low histamine.

There is no clinically validated test for histapenia as it is not recognized as a medical condition. While it is possible to test histamine levels and related pathways, it may be difficult to identify a low histamine state.

Like histapenia, overmethylation is not a recognised medical condition. There is no clinical definition, diagnostic criteria or validated biomarker for being overmethylated. 

Histamine is metabolized by the enzyme histamine N-methyltransferase (HNMT), which requires methyl groups from SAM-e. Some functional medicine sources have suggested that “overmethylation” may accelerate the breakdown of histamine. According to Pfeffier, low histamine can then cause cognitive symptoms such as depression, anxiety, poor focus and paranoia.⁴ However, there is a lack of clinical evidence to back this theory or whether overmethylation has an effect on histamine.

If you are experiencing the symptoms of histapenia (as described above), it’s important to talk to your healthcare professional about possible causes. Many of these symptoms may result from micronutrient imbalances or other health conditions. 

Histamine is synthesized in the body from the amino acid histidine, which requires vitamin B6 as a cofactor. Supporting your body’s B6 levels and your histidine intake may help support healthy histamine balance. 

Enzymes such as DAO and HNMT involved in histamine breakdown also require specific cofactors, including copper and S-adenosylmethionine (SAM-e). However, it’s important to note that there is currently no clinical evidence showing that supplementation reliably increases histamine levels or treats ‘histapenia’.

As mentioned, histapenia is not a recognized medical diagnosis. There is no established medical evidence that treatment should focus on raising histamine levels. While vitamins B6, B12 and methylfolate play roles in histamine synthesis and methylation pathways, their use to intentionally increase histamine levels is not supported by mainstream clinical evidence.

Nutrients that help to reduce copper (if necessary) include zinc, manganese and high doses of vitamin C. Molybdenum has also been shown to reduce copper levels by increasing the amount excreted in urine and interfering with its absorption in the gut.

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

There are some approaches for individuals believed to have “histapenia”, including support for methylation pathways and histamine synthesis:

• 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 docosahexaenoic acid (DHA) should be taken at least twice a day to support cognition, reduce inflammation and maintain cellular health.

Active B12 is also recommended for supporting healthy cognitive function and mood. Active forms of B12 such as methylcobalamin, hydroxocobalamin and adenosylcobalamin are already available for use in the body without further conversion. These forms are suitable for people who have methionine synthase (MTR), methionine synthase reductase (MTRR), Catechol-O-methyltransferase (COMT) or other gene mutations that may be affecting B12 absorption.