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Commentary on Nutritional Treatment
of Mental Disorders 

from Willam Walsh, Ph.D., Senior Scientist, Walsh Research Institute

(The following information is taken from Dr. William Walsh's discussion on Safe Harbor's "Integrative Psychiatry" email list for professionals. To preserve Dr. Walsh's wealth of information, we have posted his comments here, with the notation of added commentary [with the date] as discussion goes on.)  




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Metabolic Types

About 7 years ago, I developed a classification system which subdivides the entire population into 26 metabolic types (Types A through Z). A small company in Illinois carried out a pilot study of this system (which they called "Bio-Logic") and provided compounded nutrients to more than 1,000 clients who paid for this service. The use of this system was limited to "wellness" clients who were free of serious mental problems. The company found that the results were generally very positive, with many loyal users. At least 26 types are needed to enable consideration of key factors including methylation, metal metabolism, glucose control, absorption, neurotransmitter synthesis, etc. For example, I am a Type L..... which means my genetic metabolic makeup results in a need for supplements emphasing methoinine, calcium, magnesium, zinc, and vitamins B-6, C and E...... and a need to completely AVOID supplements of folic acid, DMAE, choline, copper, etc. Proper typing requires identification of nutrients in overload (because of genetics) as well as nutrients in deficiency.


The average amount of mercury we get from breathing is 1 mcg/day. The typical American diet provides another 15-20 mcg/day. If one eats tuna or other large ocean fish daily.... an intake of 60-80 mcg/day is possible.

For persons with normal metal metabolism (metallothionein, glutathione, etc), only 5% of ingested mercury gets into the bloodstream and less than 1% into the brain. Also, there are natural neuroprotective chemical factors in the brain which can sequester mercury & prevent damage.

All bets are off if a person has a serious metal-metabolism disorder......such persons may be hypersensitive to Hg. (Oct 30, 2003)


The metallothionein (MT) theory seems more likely to be at the center of ASD. Children having a genetic weakness in MT activity would perforce have yeast overgrowth. MT kills candida, and helps regulate bacterial levels in the mucosa.

A genetic MT weakness is consistent with (1) casein/gluten intolerance, (2) presence of dense, undeveloped brain cells evident in autopsy studies, (3) hypersensitivity to mercury & other toxic metals, (4) high autism incidence after thalidomide, (5) hypersensitivity to vaccines, (6) poor immune function, (7) low stomach acid, (8) higher incidence in males, (9) taste/texture sensitivities, (10) tendency for yeast overgrowth, (11) leaky gut, (12) behavior problems.  (July 24, 2003)


Effective "markers" for methylation are (1) whole blood histamine (ref. levels 40-70 mcg/dL), available from Quest and LabCorp; (2) Absolute Basophils (ref. levels 30-50), available from Direct Healthcare, Inc in the Chicago area.

Elevated histamine and/or elevated basophils indicate undermethylation. Review of symptoms and medical history can bolster the diagnosis. For example, most undermethylated persons exhibit seasonal allergies,
perfectionism, strong wills, slenderness, OCD tendencies, high libido, etc. Overmethylated persons generally exhibit anxiety, absence of seasonal allergies, presence of food/chemical sensitivities, dry eyes, low perspiration, artistic/music interests/abilities, intolerance to Prozac and other SSRI's, etc.

Conditions associated with undermethylation: Anorexia, Bulemia, shopping/gambling disorders, depression, schizo-affective disorder, delusions, oppositional-defiant disorder, OCD.

Conditions associated with overmethylation: Anxiety/Panic disorders, anxious depression, hyperactivity, learning disabilities, low motivation, "space cadet" syndrome, paranoid schizophrenia, hallucinations. (Oct 3, 2003)

One-carbon (methyl) groups are involved in numerous important biochemical reactions in the body, including genetic expression, neurotransmitter synthesis and metabolism, etc. Methylation (more properly, the methyl/folate ratio) is a major factor in the rate-limiting step (the tetrahydrobiopterin reaction) in the synthesis of serotonin, dopamine, and norepinephrine in the brain. Undermethylated persons tend to be depleted in these 3 neurotransmitters, and the opposite is true for overmethylation.

The SAM cycle in which dietary methionine is converted to SAMe (the primary CH3 donor in the body), and then to homocysteine, is a dominant cascade of reactions in methylation and also is very important in production of glutathione, cysteine, and other aspects of sulfur chemistry.

Most persons with depression, oppositional defiant disorder, OCD, bipolar disorder, or schizophrenia exhibit a genetic abnormality in methylation..... which appears to be central to their illness. Carl Pfeiffer, MD, PhD of Princeton, NJ was a pioneer in this field. (Oct 3, 2003)

About 25 years ago, Dr. Carl Pfeiffer (Princeton, NJ) identified the condition he called "histapenia" or histamine deficiency. After studying the metabolism of more than 20,000 schizophrenics he learned that this 
"low histamine" syndrome was common in anxiety, panic disorders, and classical paranoid schizophrenia. His enormous biochemistry database revealed that most histapenics suffered from (1) copper overload and (2) 
deficiency of folic acid and/or B-12. More importantly, he found that aggressive therapy using folic acid, B-12, and B-3 usually produced dramatic improvements in these persons. Pfeiffer thought the improvements were largely due to elevating histamine levels in the body & brain.

Subsequent research has indicated that the improvements are due to normalizing the methyl/folate ratio. This ratio is important in the BH4 rate-controlling step in catecholamine synthesis (dopamine & norepinephrine). Also, methyl/folate abnormalities can impact genetic expression of many biochemicals. At any rate, too much methyl results in overproduction of DA and NE, and vice versa.

Also, a serious overload of homocysteine (homocysteinuria) can result in symptoms quite identical to paranoid schizophrenia. Folic Acid & B-12 serve to lower HCy levels.

One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)..... but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping.

I guess the bottom line is that undermethylated persons generally exhibit very elevated folate levels.... and these persons get worse if additional folate is given.

This is a fairly complex subject, and some of my medical staff are still struggling with the concept. However, they have the solace of knowing the clinical impact of methylation or folate therapy on persons with specific methylation/histamine disorders.

It's certainly true that whole blood histamine is compromised by AH treatments (including antigens and many psychiatric medications). We've gotten quite proficient in taking these factors into account. Fortunately, the ABC test doesn't suffer from this disadvantage. Also, the syndromes of over-methylation and under-methylation are well defined.... and a medical history & review of symptoms greatly aids the diagnosis. (Oct 6, 2003)

The generalization that perfume and other chemical sensitivities are associated with overmethylation, low blood histamine, and elevated norepinephaine... is exactly that...a general rule with many exceptions.  However, the correlation seems to be above 90 percent in the case of perfume sensitivity.  Whenever a patient enters our clinic wearing a mask to filter out inhalant chemicals, we immediately suspect the overmethylation syndrome.  The chemical testing usually confirms this diagnosis, but there definitely are a few persons who have severe perfume sensitivity for other reasons.  We've evaluated about 19,000 persons, including about 1500 with anxiety disorder or panic disorder.  Hundreds of these patients reported sensitivity to perfumes.  Nearly 90 percent of the perfume-sensitive group were overmethylated, and reported multiple chemical and food sensitivities. usually in the absence of seasonal inhalant allergies.  Perfume sensitivity is a classic symptom of these high nonepinephaine persons, who usually respond beautifully to folate/B-12 therapy [1 Dec -03]

Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it's surprising is isn't more commonly used. It's especially useful in reducing anxiety and enhancing sleep.

To enhance sleep for a 160 lb person, we usually recommend 650 mg tablets, 1-3 as needed for sleep. Persons who have difficulty falling asleep should take it 30-60 minutes before sleep. Persons whose main problem is waking up in the middle of the night should take it at bedtime.

We've often given as much as 3-4 grams/day to undermethylated persons who respond beautifully to Inositol, and these persons take it morning, noon, and evening.

I once gave an invited presentation at a symposium at an APS annual meeting... in which data on megadoses (15-30 g) of Inositol were reported by another speaker. The volume of Inositol used seemed extreme to me, and would present daunting compliance problems. I believe such huge doses of Inositol are unnecessary, if methionine, calcium, B-6, and other nutrients to combat undermethylation are used. However, massive doses of Inositol might be needed if one tries to combat OCD with Inositol alone.  

Regardless of the form of inositol, its use should be started as a trial, with close monitoring of patient. We've found that persons who achieve improved sleep after inositol are excellent candidates for taking it throughout the day also. I recommend you be alery for adverse side effects, especially with persons with severe anxiety or panic symptoms

Trichotillomania has been associated with OCD and undermethylation. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements

Aggressive methylation therapy can be very successful, but usually involves a very slow response. Typically, treatment with methionine, calcium, magnesium, B-6, etc requires about 2 months before the patient before any progress is evident --- and 6-12 months are required for all of the benefits to be attained. Please note that whole blood histamine is a marker for innate methylation tendency, but is not an indicator of wellness or the degree to which undermethylation has been overcome. Undermethylated patients can become quite well without their histamine lab results changing at all.

One way to speed up the process of recovery is to use SAMe supplements in the beginning. Undermethylated patients usually report nice progress after the first week or two. SAMe is quite expensive, and can be gradually
replaced by methionine after a couple of months.

Nearly all severely undermethylated persons have low serotonin levels and present with a history of depression, internal anxiety, and OCD. Many have a history of perfectionism and high accomplishment in the early years.
Unfortunately this population also has a tendency for non-compliance with any treatment. 

The late and great Carl Pfeiffer would occasionally resort to use of the anti-histamines Benedryl or Dilantin in high-histamine persons who were slow to respond. Avoidance of folate supplements is essential for most undermethylated persons, an exception being autism

Some practitioners like to tinker with the SAM cycle to promote conversion of homocysteine to methionine, but this can deplete the cystathione pathway and result in deficiencies of glutathione, cysteine, etc. Some persons have
a genetic enzyme weakness which can disrupt the SAM cycle

Undermethylated adults typically require 2,000 - 3,000 mg/day of methionine for several months to see good results. Also, augmenting nutrients such as calcium, magnesium, B-6, and zinc are essential.

TMG generally provides some benefits to undermethylated persons, but tends to make oxidative stress protections worse by diminishing the amount of homocysteine which converts via the cystathione pathway of the SAM cycle.
TMG certainly is a promising nutrient for such persons, and adding some cysteine or glutathione can overcome the cystathione pathway deficit.

Personally, I believe the use of SAMe is the quickest way to help an undermethylated, high-histamine person.


There are many possible causes of serotonin deficiency including severe B-6 deficiency, folate overload, undermethylation, malabsorption, tryptophan deficiency, weak activity of tetrahydrobiopterin, etc. It would help a lot if the underlying reason for the low serotonin activity could be identified. The rate-limiting BH4 step in serotonin synthesis deserves special attention.

Oxidative stress can also increase serotonin requirements. However, I believe that chelation for serotonin enhancement is a very bad idea. The patient might be better served by supplements of glutathione, selenium, metallothionein-promotion nutrients, etc, to reduce oxidative stresses.

Nutrient Therapy

Most mentally ill patients have a lousy diet, and aren't functional enough to achieve a major life-style change, such as fixing their diet. We've learned that the recipe for success is to first correct the primary chemical imbalance, and then fix the diet.

We've also learned to never attempt to take away their cigarettes, until AFTER they begin to respond to treatment..... for the same reason. Sometimes medical care (like politics) is the art of the possible.

We have major compliance problems with mentally-ill patients who hate medications. They become revulsed with swallowing capsules of all kinds, and it's hard to convince a paranoid patient that there really are nutrients inside.

Very few of our SZ or bipolar patients have any money or any insurance other than medicare. At present, about 65% of patients with private insurance receive coverage for our fees. PPO's pay about 20% of the time, but HMO's almost never cover our services. As a public charity, we provide financial assistance for most of our seriously mentally ill clients.

Compliance with nutrient therapy is a big problem even in cases of 100% recovery. Eventually a patient will wonder if they really need to continue swallowing those capsules daily, and may stop for a few days. They don't realize that it may take several weeks/months for their brain chemistry to revert to the original condition..... Often they are ok for about a month and then relapse. Nutrient therapy is much slower in response than medications.

We learned that best results are achieved if the patient continues their medication(s), if any, during the first few months of treatment. After the patient is significantly improved, we suggest that the medication be slowly reduced "to determine the optimum dosage of the medication". Many psychiatrists will agree to this..... but often are astonished to discover that the patient is just fine with zero medication.

Medications can usually take away a patient's psychosis, but the resulting over-sedation and "zombie-like" condition is repulsive to many. (March 18, 2003)


Obsessive Compulsive Disorder (OCD)

Most OCD patients (both obsessive thoughts AND compulsive actions) exhibit undermethylation and associated low levels of serotonin, dopamine, and norepinephrine. Choline is anti-dopaminergic and often makes OCD patients worse. Generally OCD patients respond nicely to methionine, SAMe, calcium, magnesium, B-6, inositol, TMG, and zinc. Most OCD patients get worse if given supplements of DMAE, choline, copper, or folic acid. 500 to 1000 mg/day of inositol will probably be needed to provide good response. (9 Jan, 2003)

We have corrected the disordered chemistry of hundreds of conduct disorder & ODD children & teens. We've learned that the older patients have a rotten self-image and terrible social habits, even if the original cause of the behavior disorder is eliminated. They usually profit greatly from quality counseling, once the chemistry is fixed. (1 Jan, 2003)

In my experience, counseling is often unsuccessful until the "edge" of the OCD tendency is overcome with methylation therapy..... but thereafter quality counseling can be helpful. (21 Dec, 2002)

My clinic has used inositol with thousands of patients & learned the following:

A) Inositol is usually very helpful for UNDERMETHYLATED, HIGH HISTAMINE patients. This includes nearly every OCD patient we have seen. Inositol usually provides calming throughout the day and ability to settle down to sleep at night, for these patients.

B) On the other hand, OVERMETHYLATED patients usually derive little or no benefit from Inositol, and may experience very nasty side effects from it.

C) Although a couple thousand milligrams may be needed to do the job & the tablets are often quite large, Inositol has the great advantage of being palatable..... Many of our patients chew it before swallowing, and report it "doesn't taste bad at all".

I'm quite surprised that Inositol isn't more popular due to its effectiveness and its role as a major "second messinger" in neurotransmission.

Anorexia and bulimia

We have found that nearly all anorexic and/or bulemic patients are very undermethylated, low serotonin persons. Most of then respond very well, albeit slowly, to aggressive doses of methionine, Vitamin B-6, and calcium. A positive response can usually be achieved more rapidly with SAMe. In severe cases we often start with SAMe to get a quick improvement, and than gradually convery to methionine/B-6/calcium.

I certainly agree that a lousy food choices can aggravate an eating disorder, and might even trigger it in a person with a tendency for OCD and delusional thinking. An excellent dietary & nutritional program is an important component of success for these persons. (7 Jan, 2003)

In my experience, most anorexics are perfectionistic, obsessive-compulsive, high-histamine, low serotonin persons. Most have a history of high accomplishment in school and were never discipline problems. Most anorexics also have a history of being overweight, at least in their eyes. When they begin to diet, their OCD takes over and they go to great extremes. Also, when these emaciated skeletons of people look in the mirror, they tell me that all they see is FAT. It seems to involve a nasty combination of obsessive/compulsive disorder plus delusional thinking. I've never noticed a correlation with lousy diets. The anorexic I know best at present is a dedicated nutritionist/dietician..... who eats only the finest nutrient-dense whole foods. Her condition is still serious. (Jan, 2003) 

I've observed that most anorexic and bulemic patients benefit greatly from a combination of biochemical therapy and counseling/psychotherapy. (30 Dec, 2002)

I've researched the biochemistry of hundreds of OCD patients, many of whom had comorbidity for schizo-affective disorder or delusional disorder. Typical characteristics for this patient population include undermethylation, weak functioning of the BH4 rate-limiting steps in synthesis of serotonin, and dopamine, low calcium levels, excessive folate levels, and high oxidative stress.  (Aug 4, 2003)

Other helpful nutrients for OCD are methionine, calcium and magnesium...... since virtually all OCD patients are undermethylated, low-serotonin persons. (Aug 8, 2003)

Inositol is especially helpful for undermethylated persons (for example most persons with OCD), but can cause negative side effects in those who are overmethylated. Since Inositol is one of the primary second messengers in neurotransmission, it's surprising is isn't more commonly used. It's especially useful in reducing anxiety and enhancing sleep.

To enhance sleep for a 160 lb person, we usually recommend 650 mg tablets, 1-3 as needed for sleep. Persons who have difficulty falling asleep should take it 30-60 minutes before sleep. Persons whose main problem is waking up in the middle of the night should take it at bedtime.

We've often given as much as 3-4 grams/day to undermethylated persons who respond beautifully to Inositol, and these persons take it morning, noon, and evening.

I once gave an invited presentation at a symposium at an APS annual meeting... in which data on megadoses (15-30 g) of Inositol were reported by another speaker. The volume of Inositol used seemed extreme to me, and would present daunting compliance problems. I believe such huge doses of Inositol are unnecessary, if methionine, calcium, B-6, and other nutrients to combat undermethylation are used. However, massive doses of Inositol might be needed if one tries to combat OCD with Inositol alone.

A word of caution --- Manganese supplements tend to aggravate Tourette's Syndrome, and can also worsen the symptoms of OCD.

Trichotillomania has been associated with OCD and undermethylation. If you can confirm the presence of undermethylation, the patient should benefit from (1) aggressive doses of l-methionine, calcium, magnesium, along with augmenting nutrients zinc, B-6, Inositol, Vitamin A & C and (2) strict avoidance of folic acid, choline, DMAE, and copper supplements


Oxidative Stress

It's essential of course for digestive exzyme preparations (such as AbsorbAid) to survive stomach acid. However, this won't help if there is too much oxidative stress in the gut, as this can wipe out many of the key enzymes (such as DPP-IV). Oxidative stresses often are the cause of the malabsorption or maldigestion problems..... Sending in more enzymes can have limited effect in this case. It's a little bit like Pickett's charge in the Civil War: The new soldiers are killed off as soon as they enter the fray.

We find that zinc therapy and metallothionein-promotion therapy can be effective in easing oxidative stress in the G.I. tract and overcoming these problems.

Tests for plasma zinc, serum copper and serum ceruloplasmin can give a good indication of "metal" oxidative stress. A Cu/Zn ratio greater than 1.20 or an excessive amount of "unbound" copper..... that is, copper not bound to ceruloplasmin..... are indicators of excessive free radical metal ions which can suppress or destroy many digestive enzymes, cause diarrhea, digestive pain, maldigestion, malabsorption and multiple food sensitivities. The levels will be abnormal in the presence of toxic overloads of mercury, cadmium, lead, antimony, etc. A hair analysis for the metals can provide some information also.(March 6, 2003)

Biochemical individuality is the key since there are many different biochemical abnormalities which may be at the root of the disorder....and each requires different clinical intervention.

However, one common thread which is present in most cases of SZ, ODD, ADHD, etc...... is excessive oxidative stress. As a result most of these patients exhibit high-normal (or worse) levels of toxic elements. The toxic metals are not the cause of the condition, but rather a consequence of genetic abnormality in metal-metabolism. Use of oral chelation is a short-term solution since DMSA, DMPS, etc do nothing to prevent lead, cadmium, mercury, etc from accumulating in the body again due to natural environmental exposures. Personally, I greatly favor metallothionein promotion therapy which can provide enduring benefits.

Many patients report a very nice improvement within a few days after oral chelation..... the improved symptoms usually last about 3 weeks, after which most patients return to the original state. Most  practitioners who supervise chelation focus on driving toxic metals out of the body. However, I'm convinced that the improved symptoms are really due to the fact that the patients had severe oxidative stress, and DMSA, DMPS, etc are terrific antioxidants. I've known of many cases of autistic children who improve dramatically after DMSA, but lose the benefits in a very short time...... The same scenario may occur after more than 1.5 years of chelation. This clearly indicates that the improvements achieved were due to antioxidative benefits, rather than exit of toxic metals.

Occasionally we encounter a patient who has actually been severely poisoned by a toxic metal, and chelation is the first option. However, this is really quite rare.  (Aug 4, 2003)

Another factor to consider is the high incidence of oxidative stress in the G.I. tract. This environment can destroy key digestive enzymes such as DPP-IV (needed to break down casein & gluten)..... This condition is especially common in autism-spectrum disorders.

Failure to correct the oxidative stress would doom supplemented enzymes to an early death. The result can be similar to Pickett's Charge at the battle of Gettysburg.... The digestive enzymes are mowed down as soon as they enter the G.I. tract.

On the other hand, amino acid supplements can be quite helpful, even if digestive enzymes are absent. The reason is that the enzymes act to cleave (break down) proteins into the individual amino acids before the AA's can be absorbed. "Free-form" amino acids need no further digestion or conversion..... They are already completely broken down to the form needed for efficient absorption.

Of course, proper enzymatic action is needed for effective processing of dietary protein and other foods, a requisite for good G.I. tract health.   (Aug 20, 2003)

The casein-free, gluten-free diet often results in rapid striking improvements. However, nutritional supplements which overcome G.I. tract oxidative stress can make the CF/GF diet unnecessary.

Normalization of zinc, metallothionein, and glutathione in the G.I. tract isn't difficult to accomplish. It's a lot easier to take a couple of capsules daily than this difficult diet. It takes about 6-8 weeks for the G.I. tract to get "fixed" using this therapy.

We've had many patients who were extremely sensitive to dairy and wheat.... and did marvelously after the CF/GF diet. Many of these same patients completely lost their sensitivity to casein and gluten after the antioxidant supplementation..... and now can eat a normal diet without a problem. (Aug 21, 2003)

It's becoming increasingly clear that oxidative stress has an important role in mental illness. Since psychic stress increases oxidative stress in the brain, sudden easing of emotional traumae would be expected to have a direct and beneficial chemical effect on the brain.

It's true that mercury can be devastating to the brain and chelation cleans up peripheral mercury. However, most of us have a very effective system to protect us from mercury, namely glutathione & metallothionein in intestinal barriers, liver, blood/brain barrier, and the brain itself. Chelation to remove metals should be helpful only (a) in cases involving massive poisoning by heavy metals, or (b) in cases in which the normal protective systems fail to function properly. However, chelation can provide 2-3 weeks of benefits just from the antioxidant effect, whether or not there are nasty metals present.

Did you know that nearly all psychiatric medications are powerful anti-oxidants? I don't think this is a coincidence.


Paranoia is a symptom rather than a specific disease condition, and is associated with a number of biochemical imbalances. First of all, it is clear that paranoia generally involves a genetic predisposition. In my experience paranoia usually involves either highly elevated norepinephrine or diminished GABA levels. The recipe for paranoid schizophrenia is (1) overproduction of dopamine due to an innate tendency for overmethylation, (2) excessive conversion of dopamine to norepinephrine due to high copper levels, and (3) depressed levels of GABA (which tends to quench the paranoia & anxiety associated with elevated norepinaphrine. The patients are usually afflicted with multiple medications which can provide some relief, albeit with very unpleasant side effects. Complementary medicine techniques to balance body/brain chemistry may involve therapies using folates, zinc, manganese, and vitamins B-3, B-6, C, and E and can be very successful This treatment should be individualized to reflect the individual's array of chemical imbalances.... for best results. In many cases paranoia is exacerbated by estrogen therapy, environmental sources of copper, well-intentioned (but wrong) vitamin/mineral supplements, and/or chelation therapy. For females, paranoia tends to flare up during hormonal events including puberty, childbirth, and menopause. (Feb 10, 2003)

Placebo effect

I believe there are 4 major factors at work here: (1) improvements resulting from environmental changes, (2) true placebo effects in which a caring practitioner supplies hope, encouragement, and a positive attitude to the patient, (3) a Hawthorne effect in which the family and medical practitioners are giving attention & are monitoring the patient, and (4) cycles of improvement and relapse which are so strong that they overwhelm the therapies. (30 Dec, 2002)

Post Partum Depression

We have seen more than 3,500 persons with clinical depression including several hundred with a history of post-partum depression. Most PPD females exhibit a copper overload and zinc deficiency.  Most PPD females report major improvement after nutrient therapy aimed at balancing Cu & Zn levels. Most normals have Cu/Zn ratios in the 0.75 to 1.15 range, whereas most PPD females exhibit a Cu/Zn ratio in the 1.5 to 2.0 range. The cause appears to be a genetic weakness in regulation of Cu & Zn which may involve weak functioning of the metallothionein/glutathione system.


Depression, anxiety, panic episodes, and paranoia in pregnancy are often caused by an inborn inability to regulate copper and zinc in the body. During pregnancy, a woman's blood copper level more than doubles..... in order to provide sufficient copper to the fetus to support angiogenesis.  Persons who have a genetic tendency for copper overload get into real trouble during and immediately after pregnancy since elevated Cu levels in blood result in diminished dopamine and elevated norepinephrine in the brain. This is a recipe for panic attacks, depression, etc.

I suggest a blood serum test for copper and a plasma test for zinc. If the levels are severely abnormal, there are natural treatments which can decisively correct the problem. The first step is to discontinue  pre-natal vitamin supplements that contain copper. We've guided dozens of anxiety/panic/depression prone women through pregnancies, but one must be careful to avoid aggressive therapies (including natural ones) which might adversely affect the fetus. (Sep 8, 2003)

Psychiatric Medications

Individual psychiatric medications can impact methylation, histamine levels, oxidative stress, and can result in depletion or accumulation of specific proteins, enzymes, neurotransmitters, vitamins, and minerals. (Aug 1, 2003)

A published article of interest is one by John Crayton (research psychiatrist, then at U. of Chicago). Crayton measured dendrite populations with and without psychiatric medication. He found that psychiatric medication (I think he focused on Prolixin) caused a proliferation of dendrites on peripheral neurons. This, of course, is a 
permanent change..... and possibly the cause of Tardive Dyskinesia. This article received very little attention, despite its striking finding..... namely, permanent damage caused by psychiatric medication. 
(Sep 2, 2003)

Pyrrole Disorder

Omega 3s can worsen mental symptoms in bipolar or schizophrenic patients.... if they have a pyrrole disorder. This phenotype is dramatically short of arachidonic acid & giving omega 3 oils aggravates the situation since omega 3 and omega 6 EFA's are in competition for delta 5,6 desaturases. We use red blood cell membrane analysis for EFA's
if we suspect this problem.

Pyroluric mental patients will usually get worse if given fish oils, DHA, EPA, etc. They thrive on Primrose Oil, a good source of AA and other omega 6s. (June 23, 2003)

Most persons with pyroluria respond very quickly to the B-6, Zn, C, E therapy..... Major improvements are often seen by the 2nd day, and almost always by the end of the first week. The exceptions are: (1) persons with severe mental illness (schizophrenia or bipolar), (2) persons with other significant chemical imbalances, and (3) patients with a major malabsorptive condition. When pyroluria is diagnosed along with another chemical imbalance, I like to track a patient during the first 6-8 weeks to determine which is the dominant imbalance. If major improvement occurs immediately, it's because pyroluria has been corrected. Some patients report a nice early improvement followed by a plateau, and then another advance.

Schizophrenic and bipolar pyrolurics usually report some progress after a few weeks, but it may take 3-6 months to get to steady state. The biggest problem with the Kp analysis is getting a proper sample to the lab. The kryptopyrrole molecule is unstable and will disappear rapidly at room temperature or if exposed to bright light. The urine sample must be placed in a freezer immediately after acquisition. Kp can be lost in the freezer if the temperature isn't well below 32 degrees F. We've also learned that exposure to bright light results in breakdown of the Kp molecule. Finally, the sample must be maintained in a frozen condition during shipment. I would greatly suspect any Kp value below 3.0. Usually this means the sample didn't get to the lab in proper condition.

With respect to reference levels: We consider a healthy level to be between 4-8 mcg/dL. We consider persons between 10 and 20 to have mild pyroluria, and a good response to treatment is usually reported. Persons exhibiting 20 to 50 mcg/dL have moderate pyroluria, which can be a devastating condition. Persons above 50 mcg/dL have severe pyroluria.

Longitudinal testing of pyrolurics has shown that major variations can occur during a day. For example, Arthur Shawcross (famous NY serial killer) had levels ranging from 35 to 203, with higher levels observed during stressful periods in prison. However, he always tested as pyroluric in multiple tests. Stresses, illnesses, injury, etc can be expected to elevate Kp levels. Medical history and review of symptoms are vital to this diagnosis.

The major challenge in differential diagnosis of pyroluria is the similarity in symptoms between pyroluria and overmethylation (low blood histamine). Another problem is that symptoms of pyroluria are greatly muted in undermethylated, obsessive/compulsive persons. These persons may be high achievers, with great internal tension..... Persons with pyroluria alone tend to underachieve, partly because of a poor short term memory and associated reading problems. (Nov 10, 2003)

We've obtained hair Zn and plasma Zn levels (simultaneously) about 40,000 times.  Low hair zinc correlates beautifully with low plasma levels.  However, very elevated Zn in hair nearly always means Zn deficiency and loss plasma Zn levels.  Most of the time this involves a Pyrrole disorder which results in very high Zn excretion in urine (and hair).  In a healthy person without metal-metabolism problem, only about 4 percent of excreted Zn leaves through the kidneys. [28 Nov 03]

Symptoms of pyroluria include (1) stunting of growth, (2) unpleasant body odor, (3) delayed puberty, and (4) skin stretch marks. This family's symptoms are certainly consistent with pyroluria.

Pyroluria definitely runs in families. We have a mother in Kane County, IL who has 15 children & all of them tested pyroluric. The mother had a Kp level of over 150 herself

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