Descriptions and specific supplement prescriptions for pyroluria, histadelia and histapenia.

Do Pyroluria Histadelia & Histapenia Really Exist?

©Peter Smith 2011 Updated April 2013
I’ve decided to provide information on pyroluria, histadelia and histapenia because people looking for alternative non-drug help with mental health problems may come across these syndromes and want advice as to whether or not to invest time and money seeing if these syndromes may provide the solution for their mental health problems. 
Below you’ll find the prescriptions that you would use to treat these conditions however before you jump to the prescriptions please read this page because promising as these hypothetical medical conditions may appear to be their existence is as yet unsubstantiated. I have been in practice since 1988 and have specialised in using none-drug therapies especially nutritional remedies for mental health but have yet to see any benefit from testing for pyroluria, histadelia or histapenia. Don’t get me wrong there are very effective non-drug options for depression, bipolar syndrome (including my own bipolar), anxiety and OCD using nutritional and alternative therapies. As we learn more we need to keep up to date and the earlier hope that diagnosing and treating pyroluria, histapenia and histadelia would add to our ability to treat mental health problems just did not pan out. Please read this page and if you are looking for non-drug solutions to mental health problems invest your time, energy and money wisely. Despite my reservations about the existence of these syndromes you can simply test them for yourself by following the prescriptions below for a month or so and then you’ll be able to see for real if they help you or not.  

(Obviously be safe and don’t come of your pharmaceutical meds unless you can do so safely). If you do find these prescriptions give you better results than other options please let me know…

I learnt about the potential existence of these syndromes, the role they could play in mental health problems and how to treat them a couple of decades ago. Researching these syndromes online today can be very confusing, and for this reason I've decided to provide a clear and concise explanation as to what they are and how you would treat them. However I personally no longer give these ideas any credibility. They held up the possibility of being able to significantly help at least some people with mental health problems. Also the possibility of making firm diagnoses and prescriptions based on blood and urine tests as opposed to just symptoms was (and still is) so appealing. Sadly however these ideas turned out to be a false hope and failed to deliver useful treatments, with perhaps one exception. The one possible benefit that I gained from these ideas came from the concept of pyroluria (see below). My understanding of pyroluria led me to experiment with high doses of zinc and B6 supplements in people with long-term, dysthymia type, depression combined with social withdrawal. My anecdotal clinical observation is that this combination of remedies (see pyroluria prescription below) can help both depression and lessen the avoidance of social interaction in this type of person.

If you've never heard of, or been confused by the syndromes before you can simply skip the rest of this chapter. The potentially useful prescription I just mentioned will be repeated elsewhere, so you will miss out on anything mentioned below. 
Carl Pfeiffer an American psychiatrist (see Wikipedia for his bio) gave some of his patients with depression and schizophrenia different prescriptions of nutritional supplements based on whether they had high or low levels of serum (blood) histamine. He treated and purportedly helped thousands of patients with mental health problems with his methods. Pfeiffer was a pioneer that developed the nutritional biochemical approach to treating mental health problems. Personally I am indebted to him, in 1986 his book Mental and Elemental Nutrients helped and inspired me to start treating my own mental health problems with nutrition medicine which at the time were quite severe and untreated. 
What I gained from Pfeiffer’s work and literature was that pharmaceutical drugs are not the only compounds that can effectively change the levels of neurotransmitters in the brain. You can increase the production of neurotransmitters and treat mental health by supplementing the body with the building blocks of neurotransmitters, with fish oils, vitamins, minerals and herbal compounds. It turns out you can even therapeutically increase serotonin levels by exposing oneself to bright light (see chapter Bright Light and Total Darkness Treatments). For some of these remedies there is only a limited amount of scientific evidence, for others there is a substantial body of high quality evidence. The important point being that there is at least some proper published research confirming that each these remedies are capable of producing therapeutic effects on mental health problems (see appendix Does it Work, Proof & Evidence). Unfortunately however, I cannot find any published evidence of properly done experiments or even basic trials that basing prescriptions on these syndromes (pyroluria, histadelia and histapenia) is effective. This lack of evidence does not automatically rule out the possibility that these syndromes exist and could occasionally be useful. It’s possible that they are just extremely rare and haven’t received sufficient funding for proper research yet. 

Practicing so called alternative medicine I have had to get used to using methods that have little or even no double-blind placebo-controlled research to prove they work. In herbal medicine for example some of the herbs have had their chemical composition and therapeutic effects scientifically validated and some of them haven't, however we use these remedies because they consistently produce good results. For example I have been routinely curing people from IBS and lower blood pressure for over two decades using diets (along with herbs and supplements) that until recently were not proven and published in medical journals. Today these diets are published and have names like the DASH and FODMAP diets. What I knew was my blood pressure metre didn't lie and my patients would tell me their IBS was gone. With depression, bipolar, anxiety and addiction improvements are assessed by the patients’ subjective experience and judgements rather than some objective scientific measurement.  With these conditions patients are perfectly able to tell when the treatment is working or not. 
In clinical practice one often prescribe several remedies at the same time and I’m well aware that often I cannot be certain precisely which part of the several things I’ve used to treat a particular condition produced the improvements including the placebo effect (see the placebo effect). This problem would have been even worse for Pfeiffer, as a pioneer he did not have the benefit prior research and the vast body of shared anecdotal experiences I have today. 

The point I want to make here is that it’s possible that Pfeiffer and Hoffer- with the best of intensions- thought they had identified subtypes of depression and schizophrenia and misinterpreted what part of the treatments they tried produced the improvements and this may have misled them down a false path that these patients’ conditions were caused by abnormalities in metabolism.  Science and medicine are lettered with examples of failed hypotheses.  
I’ve held the concept of these metabolic disorders in my mind for over twenty years of clinical observation, but in all that time I’ve never found it necessary to test for them.  Nor have I seen the worsening of symptoms predicted by the theory of these syndromes if you take the “wrong” vitamins. You can find lots of websites describing these syndromes but no examples of people claiming that treating these syndromes was the definitive cure for the problem. This is in marked contrast to searching the web for the effects of supplements and herbs on mental health in general, such a search reveals numerous examples of people saying they experienced great benefits in their mental health using natural remedies.

For these reasons I don’t see the point to the expense of laboratory tests for these (probably mistaken) diagnoses, anyone interested in seeing if they have these syndromes can test the hypothesis simply and safely by taking the prescription and seeing how they feel. Take pyroluria described below for example, the urine tests to determine you have it would cost about $100, a few weeks’ worth of the prescription you would use to treat it would cost about half that and be completely safe to try. So why not just try the high-dose zinc, B6 and B complex and see if it in fact improves your depression or not. It has been my personal experience that these remedies can have life changing benefits in some individuals with depression and no doubt Pfeiffer will have also observed this. I believe the mistake he made was to associate the people who benefit from B6 and zinc supplementation with the presence of kryptopyrrole chemicals in their urine. Let me reiterate my position I’ve lots of personal and professional experience that some people with depression and other mental health problems benefit from very specific combinations of vitamins and minerals but never encountered any evidence to verify the existence of metabolic conditions pyroluria, histadelia and histapenia.

My advice is rather than spending your money on testing these hypothetical syndromes  directly experiment by trying the actual therapeutic remedies in various combinations and protocols and see what they do for you in the real world. Don’t get hooked up on only these conditions, try them if you want but be repaired to let go of the idea if it doesn’t help and move on to experimenting with another protocol.

I suggest you:-
  • Eliminate hypoglycaemia and fatty acid deficiencies.
  • Rule out hypothyroidism and brain allergies.
  • Rule out heavy metal toxicity.
  • Have psychotherapy when you have obvious emotional causes relating to your mental health problem.
Then test the effectiveness of adjusting the levels of individual neurotransmitter imbalances:-
  • Serotonin dependent depression.
  • Dopamine dependent depression and bipolar syndrome.
  • PEA dependent depression.
  • GABA and serotonin dependent anxiety.
In addition experiment with therapeutic usefulness of exercise, bright light therapy, total darkness therapy, relaxation training and meditation.

All the remedies in this book including the prescriptions for pyroluria, histapenia and histadelia can be safely tried as long as you avoid contraindicated drug interactions and take precautions where there is risk of bipolar mania. 
You can experiment with the remedy protocols given below for these metabolic conditions or the protocols suggested elsewhere for problems involving of serotonin, dopamine PEA etc. You will be able to tell quite quickly when a particular combination is right for you by the way you feel; if not the worst that happens is you go without treatment for a little while and as long as you can cope with that there is no harm done. According to the theories of histapenia and histadelia (see later) it is suggested that if you take the wrong thing you can actually make your symptoms worse, however as I said above I’ve never seen this happen, I’ve seen combinations of natural remedies fail to help people but never actually make them worse. 
In what I’ve just said above I absolutely don’t mean to put you off trying any supplement combination to see if it genuinely helps your mental health problem, far from it I encourage you to look for effective solutions, to experiment and learn how to self-medicate. What I’m suggesting is you save your money for remedies and real-world experimentation rather than blood and urine tests for hypothetical metabolic conditions.

It is claimed although no evidence is cited that the prevalence of these metabolic disorders is several times higher in people with mental health problems than in the general population. 
Pyroluria (severe B6 and zinc deficiency).
Pyroluria is said to cause long term depression with significant social withdrawal. 
In psychiatry continuous unrelenting depression lasting more than two years is called dysthymia. Although dysthymia could be caused from purely psychological causes, the long-term and relentless nature often involves a chemical imbalance in the brain. 
Relentless (dysthymic type) depression coupled with social isolation can put the sufferer at high risk of suicide, so take this situation seriously and consider chemical treatments along with talking therapies . 
People with dysthymia would benefit from talking therapies, learning to see the half full part of the glass, improving self-esteem, developing a new positive sense of self identity and new upbeat cognitive self appraisal etc etc. These concepts may be practically none-existent in someone with long-term depression.
The reclusive poet Emily Dickinson would typify the type of depression described by pyroluria, she wrote:
“The Soul selects her own society, then closes the door.”
Also think of Howard Hughes. 
The test for pyroluria is a simple urine test for excess kryptopyrroles.  If pyroluria was a useful diagnosis the simple nature of the test would I think have proven its worth.

Despite questioning the relevance of kryptopyrrole levels in the blood I have observed in myself and in several patients that dysthymia with social withdrawal/avoidance can respond very well and quickly to high the high zinc and B6 supplements recommended for pyroluria. Try increasing serotonin with tryptophan and the following supplements for this mental condition.

Treatment is to supplement B6 and zinc. 
  • B6 up to 250 mg or enough to produce strong dream recall. 
  • P5P 40-60 mg. I recommend combining some P5P with your B6. Vitamin B6 is converted (metabolised) into P5P, taking the P5P metabolite can have a stronger effect than B6 and avoids the risk of B6 overdose. 
  • Zinc (chelated or Food State with copper) 30-50 mg.
  • Also add manganese or a multi-mineral containing manganese, it is needed for preventing depression and it‘s levels can become depleted by the high zinc.
Caution: manganese can raise blood pressure so monitor.


Okay let's begin with a little biochemistry. You'll be familiar with the existence of histamine and how when your body makes a lot of histamine, say because of hay-fever or other allergies, parts of your body become inflamed. They become itchy, irritable, red, swollen, runny etc. this is one of the body’s responses to the threat of invading pathogens.  Histamine serves vital functions in our immune responses and without it we would be under defended against pathogens, however prolonged excessive histamine causes health problems. Histamine causes inflammation a, necessary body process, but imagine the swelling you get in the nose with hay-fever happening inside your brain or the arteries of your heart, over time it can lead to long-term damage. Prolonged excessive levels of inflammation causing chemicals such as histamine and homocysteine accelerate the progression of almost all degenerative diseases including heart disease and the ageing process in general. In 2010 elevated levels of the inflammation causing chemical homocysteine were implicated in causing or at least accelerating the ageing and degeneration of the brain that occurs in Alzheimer’s. There is mounting evidence that the reducing and preventing unnecessary inflammation in the body is one of the cornerstones of healthy living and disease prevention. 
According to the theory of histadelia and histapenia developed by Carl Pfeiffer histamine levels can be responsible for some types of depression and schizophrenia.
These two syndromes were considered to be diagnosed identifying abnormal levels of histamine in the blood. When histamine is too high it was said to cause histadelia, and when histamine is too low it was said to cause histapenia. They are considered to require opposite treatments strategies. 

It's suggested that although one uses histamine levels to determine the presence of either histadelia or histapenia, the high or low level of histamine is not what actuallycaused mental health problems. This would explain why antihistamines, whilst lowering histamine effects would not act as antidepressants for people with histadelia i.e. high serum histamine levels. 
We now know the body uses chemicals called methyl groups to quench excessive histamine and other inflammatory processes and that some people have do indeed have under-methylated body’s that are more prone to more long-term damage from inflammation than people who are adequately methylated.  Under-methylation may be due to deficiencies of B6, methylfolate (not folic acid see MTHFR Mutation) and B12, also over the last few year’s genetics has identified a genetic mutation (MTHFR), that can cause people to have a poor ability to metabolise methylafolate and manufacture enough methyl groups to control inflammation. This would cause a tendency towards high histamine, high homocysteine, an increased risk of heart disease and accelerate the ageing process. 
The enzyme the MTHFR gene makes is also indirectly involved in the production of serotonin and dopamine and this genetic mutation may be involved in depression and schizophrenia, but as of 2012 the usefulness of testing for this genetic mutation for people with mental health problems is unknown. I will post updated information on this subject on my website as it becomes available.
Contemporary advocates of the theory of histadelia and histapenia now use the new updated understanding of methylation to explain the underlying cause of these syndromes, despite updating the theoretical cause they have still not proven it has any clinical usefulness.

The theory goes:
People with histadelia have too much histamine because they have too little methylation, or too few methyl groups breaking down excess histamine.
People with histapenia have too little histamine because they over methylate producing too many methyl groups and excessively lowering normal histamine levels.
Although it is true that histamine plays a role in stimulating the release of serotonin, dopamine and norepinephrine from the hypothalamus, there is no evidence that antihistamines influence mood disorders. What is interesting however is that the converse can be true, some old type antidepressants (the tricyclic antidepressants) can lower histamine. 
Histadelia (high serum histamine, more than 70 mcg/dl).
Today histadelia is often called under-methylation.
The psychological symptoms were said to be a mixed bag, people that were said to be suffering from histadelia were said to display high energy, lots of drive, the typical type “A” personality. This may not appear to sound like typical depression, however on the inside type A personalities can suffer with perfectionism, inner tension and depressed feelings. They may also be compulsive and hyper, manic, prone to phobias, insomnia alcohol and all sex addiction. Today this collection of symptoms would be classified as bipolar, probably type II. See About Bipolar Syndrome and Bipolar Treatment without Drugs 

Alcohol or other drugs used was said to be a characteristic primarily to dull themselves down and obtain temporary relief from their symptoms. 
With low serotonin they would be prone to insomnia or survive on little sleep. 
Frequent bouts of depression, coupled with impulsiveness and decisiveness would put them at a high risk of suicide and with high libido sex addiction may be a problem. Again just like bipolar Type II. 
With high histamine their mucous membranes may produce excessive secretions, they may even have saliva leaking out the sides of their mouth. On the plus side because of the protective qualities of saliva they should get less dental cavities. 
They would have a high metabolic rate, so typically wouldn't have any weight problems, unless it was because of food allergies, which the high histamine would make them prone to. 
The American presidents the Kennedys would typify histadelia. 
People with histadelia were said to be prone to compulsive behaviour and it was claimed to be involved in most if not all cases of OCD, if you search online you can find no experimental or anecdotal evidence to back this up. There is some evidence and anecdotal stories however that boosting serotonin and supplementing inositol helps want to manage the symptoms of OCD.
Like I said above the description of histadelia characterises what we would call bipolar Type II today and I would recommend trying the remedies and light/darkness treatments first before you try and anti-histadelia program.
Just for information the classic Histadelia Treatment protocol is as follows:
  • methionine 500 mg half an hour before each meal and 500 mg on an empty stomach before bed. You could substitute or even add SAM-e 400-1600 mg on top of the methionine in the beginning to get quicker results. You could give up the SAM-e once you get the desired results off. With methionine and SAM-e always include B6 to control homocysteine. 
  • B6 250 mg in the morning. 
  • Calcium 500 mg twice per day. 
  • Add magnesium 400 mg as it as it is calming, and balances the calcium.
  • Vitamins C 1000-2000 mg twice per day.  
  • Inositol 1000 mg twice per day. 
It was claimed that with histadelia you must avoid high levels of methylfolate and B12, which increase histamine levels and would worsen the symptoms. As I said earlier in this chapter I've never seen patients with bipolar type to get worse by having methylfolate and B12 included in their prescriptions. I actually routinely prescribe B12 to people with bipolar for improved sleep management, see the chapter. I would also be very careful with SAM-e because of its high propensity to induce manic and hypomanic symptoms. 
The amino acid histadine in protein foods will synthesise more histamine so to treat histadelia one would avoid a high protein diet. Going vegetarian/vegan for a month or so in the beginning was claimed to speed up results, after that one was recommended to only have small portions of animal protein, substituting beans and lentils for protein needs. 
Treatment of histapenia was claimed to be slow, taking 2-3 months to see results and 6-12 months for full benefits of treatment to be achieved. 
Unfortunately the treatment targets under-methylation and not histamine directly, so you could only use histamine levels as a guide in the beginning to tell you to try the treatment, you could not use follow up histamine levels to measure your progress. Results were measured by improvement in mental health symptoms. 


(high blood serum copper/low histamine, less than 40 mcg/dl).
(Today histadelia is often called over-methylation)
People with histapenia were said to be paranoid and suspicious. 
Their paranoid and suspicious nature would cause their minds to imagine things that are not there, and that people are against them. In hypnotherapy terms they would be said to be highly prone to and struggle to control the trance phenomena known as positive hallucination. 
In addition to positive hallucination histapenics would be prone to grandiose fantasies and ideas, however because of their low-energy state there are not likely to manifest any of their ideas. 
They would be very prone to a low energy, irritable, depressed state. Even with severe depression, like their grand ideas, they are unlikely to see through any suicidal desires  
They may have anxious and racing thoughts. 
With histapenia imagine an inactive person with worrying, antsy, racing thoughts, lots of ideas but no energy to carry them out; frustrated, dissatisfied, irritable.
They would have low libido and generally low energy. 
They would have a dry mouth and a tendency towards an above average amount of dental cavities. 
Histapenia was said to be the cause of some cases of postpartum depression, which is interesting because high serum copper has been linked to postpartum depression, demonstrating that the theories of histadelia and histapenia had some basis in fact and that they were just early interpretations of observable phenomenon. 
Histapenics were said to be unlikely to develop allergies, because of the low histamine, but with a lethargic system they were prone to weight gain. Unfortunately long term high copper levels can lead to premature hearing loss. 
It was claimed that 50% of schizophrenics are histapenic and may be helped by this treatment. As I said elsewhere schizophrenia is not my area of expertise. 

I found it difficult to interpret the concept of histapenia with more up-to-date understanding concepts the lack of energy would look like dopamine dependent depression or misdiagnosed hypothyroidism both of which may be treated with the amino acid tyrosine and relevant cofactors, however elevating dopamine levels with the amino acid tyrosine not only energises the system but also increases the brains propensity to make connections and can in some circumstances increase the connections a person’s mind makes that lead to the feelings of paranoia and therefore make in theory make a person feel worse. My recommendation in such a situation would be to try elevating the levels of the sedating neurotransmitters GABA and serotonin at the same time, this may counteract racing paranoid thoughts should they arise there are also some excellent NLP and psychological techniques that one can use to control a paranoid condition. 
Just for information the classic Histapenia Treatment protocol is as follows:
Histapenia treatment involved raising histamine with the amino acid histadine plus B3, B12 and methylfolate
and also lowering copper with zinc, manganese and C. The amino acid histadine actually reduces zinc availability, so you must use very high doses of zinc to combat the high copper and overcome the binding effect of histadine.
  • Histadine 500 mg half an hour before each meal and one before bed, to elevate histamine.
  • Niacin B3 (not if you have liver damage) 500 mg twice a day with meals.
  • Methylfolate (not folic acid just in case you have the MTHFR gene mutatio) 800 µg twice a day.
  • B 12 500 µg twice a day.
  • Zinc 25 mg twice a day.
  • B6 50 mg
  • Vitamins C 500-1000 mg twice a day.
  • Manganese 10 mg once a day.
  • For the above combination to work you also need adequate levels of essential fatty acids at 1 to 2 teaspoons of quality fish oil per day.
  • Optional quercetin 300 mg one with each meal.
With histapenia it is claimed you must avoid SAM-e, methionine and copper supplements, which would worsen the symptoms. 
Summary: The Dos and Don’ts Of Histamine Disorders
It is claimed:
  • SAM-e, methionine and copper may make histapenia worse. 
  • Methylfolate and B12 may make histadelia worse. 
And that the reverse would be true, SAM-e is exactly what is needed for histadelia and methylfolate/B12 are exactly what you need for histapenia. 
However in over 20 years of practice I've never seen people have a worsening of their mental health by any of the above remedies. If you believe in histadelia and histapenia and are concerned that any of these remedies may actually make you worse you could either have your blood histamine levels tested or simply introduce a remedies once a time and monitor your symptoms. Any worsening would quickly stop once you have discontinued the problem remedy. 
(Version: 2/13)
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