DISCERNING THE MAUVE FACTOR, PART 2

Woody R. McGinnis, MD; Tapan Audhya, P ~ DWilliam

; J. Walsh, P ~ DJames
; A. Jackson, P ~ DJohn
; McLaren-Howard, DSC, FACN;
Allen Lewis, MD;Peter H. Lauda, MD;Douglas M. Bibus, P ~ DFrances
; Jurnak, P ~ DRoman
; Lietha, MD;Abram Hoffer, MD, P ~ D

mwmyF3; K ~ % g p r ' ~=m ~ . n S ' ~ I ~ J w ~ ~ , ~ ~ ~ . y l b ~ l i ~ : ~ ~ & ~ ~ r

i r o li~
'X.lauv$ Factor" was ~ n c e " m i s ~ a k e r i ' ~ o r 4 ~ t o p yhut c I ~ P nittir dxide (P<.O(rOlI.Thus, besides implying propodonate
' kydrvxylautam OF hernnpyrrule, hyrlroqhemupyrrdin-2-011e nerds fur r i l a r n u ~BGand zinc, T V Z . is a promising biornark~rfor
WK). Treatment with nr~trienls-parkubrly r r i r ~ ~3nd nxlriative stress. HI'L i s known to cause non-erythroid I I P ~ I P
zinc--reducr?s urinary !rxccrrho rrt' HPL and i m p r o v ~di whicl1 low CWascs i c oxide, arid increas-
netlmhh&oml sympto~nsin wljn'k with rlevat~du r i n q stress.
Hc$htencd 13%euetinn rlassiually awaciatcs with rrnol listration one reporl ~ k e dKPL
$cress, which in tunis knc lciate wit11 uxidxtive s Tiire adrenoco~tirnid(and cat~cholamine)
k r thi~ retitw, markers f~1 a1 SSIA~IIS ;il~ 3 fur; mid Ite inteslinal prrn~eability,urinary HTI. was
stress were examined in reh PL. lip lo rrtinary irdcans, pltwmptke marker
In ccohorts,withmix& diqposes. 24-lour urmaq - m,l
. m T
or ~nresrmz~ pemcaoility. Lrinary I-1Pi2ar~ociataclwith higher
related neprivdgrvith vitamin R6activity and zinc concc~~tr ~veFsof u~dicanc(k.Ol)Ol). ihtibiotics rrporttdl>~ W~UCP WI. ill
in red cclls 1P<.0001).hbcnlc-normal JtR ~ x c r tir~n e corrc.spn ~rinr,suggesting an enrcrrd~icrole in pmdutmon. PotwtiaDy, pr
Lo stthnormal vitamin IZ, activity and suhnurmal zinc **.lib IS x~s~rvnir tor HPT.nr its TlrcJcilrsos,ahd stress-related changes in
. b b l ~con:3istency. N <I urinary (
and red-ceI1 ratalase. tly rc-ith pli .sz.>

Study, Auckland, New Zealand. Tapan Audhya, P ~ Dis, a

research professor of Endocrinologyat New York University Health and Medicine. (2008;14(2):40-50.)
School of Medicine, New York. WilliamJ. Walsh, P ~ D is , director
of research at H e a r Treatment Center, Warrenville, Illinois.
James A. Jackson, P ~ Dis, a retired professor of medical technol-
ogy, Wichita, Kansas.John McLaren-Howard,DSC,FACN, is
director of BioLab Medical Unit, London. Allen Lewis, MD, is
medical director, lJfeiEer Treatment Center. Peter H. Lauda, MD,
is medical director, Diagnostic and Therapy Center, Vienna,
Austria. Douglas M. Bibus, phD,is director of Lipid
Technologies, Austin, Minnesota, and a faculty member at the
Center for Spirituality and Healing, University of Minnesota,
Minneapolis. FrancesJurnak, P ~ Dis, a professor ofphysiology an enterobial role in production of HPL.

Applied Biology, Rapperswil, Switzerland.Abram Hoffer, MD,

P~D,is president emeritus of the International Schizophrenia
Foundation and founder and editor in chief of theJournal of D-lysergic diethylamide (LSD), did increase HPL excretion in
Orthomoledr Medicine, Victoria, British Columbia. 20%of subjects."
Pfeiffer suggested that HPL results from breakdown
heme,"6 and Irvine identified a distinctive triad of urobilinoids

that perform HPL assay: Audhya (VitaminDiagnostics,Inc, Cliffwood with derivation of HPL from microbial degradation of bile p
Beach, New Jersey); Jackson (Bio-Center Laboratory, Wichita, ment.78Irvine was unable to produce HPL from heme, bilirub
Kansas); and McLaren-Howard (Biolab Medical Unit, London). or bile pigments under mild laboratory conditionsg and foun

56 ALTERNATIVE THERAPIES, MAY/JUN 2008, VOL. 14, NO. 3 D~scernlngthe Mauve Factor, P
 that a large dose of hemoglobin (1.6 kg of blood sausage over 48 HPL might be expected to associate with intestinal permeability.
hours) produced no effect on HPL excretion." Suppression of urinary HPL with zinc (admittedly, in combina-
Irvine hypothesized that HPL is a metabolite of PBG or por- tion with B6; there is no record of attempts to suppress HPL with
phyrins from the heme biosynthetic pathway, citing the structural zinc alone)6comports with evidence that zinc lessens bowel per-
similarity of these compounds to HPL, the porphyrinogenicityof meability in animals3133 and in humans3c37and reduces bacterial
HPL, and very high levels of HPL in acute intermittent porphyria adherence to enterocyte~.~~
(AIP).9The side-chains of PBG correspond exactly to HPL once Irvine observed that laxatives and enemas increase urinary
they are decarboxylated and deaminated, and an endogenous HPL.' The types of enemas and laxatives were not specified, but
enzyme is known to convert PBG to the corresponding hydroxy- the range of possibilities would appear to increase intestinal per-
lactam. Irvine included as precursor candidates all porphyrins meability. Magnesium sulfate3' and biscody140significantly
with a methyl, vinyl, or ethyl group found in hemo-configuration increase intestinal pemeability. Soap-suds or tap-water enemas
on ring I."esponse to a large oral dose of aminolevulinic acid result in epithelial loss,41which would be expected to increase
(ALA) (1.5 g) did double urinary HPL over baseline in one subject intestinal permeability. The effect of laxatives and enemas sug-
for several days." Irvine failed to produce HPL from porphyrins gests that intestinal permeability affects urinary HPL.
ynder mild laboratory condition^.^ To explain the clinical observation that HPL excretion and
Of all the porphyrins, isocoproporphyrin is most homolo- stress are associated, Sohler specifically proposed that urinary
gous to HPL.912Isocoproporphyrins are an abnormal series of excretion of HPL relates to a "stress-induced anomaly of intestinal
porphyrins from altered human heme bio~ynthesis.'~'~ A poly- permeability which permits these pyrroles to get into the systemic
morphism for CPOX increases isocoproporphyrins, as do toxins c i r ~ u l a t i o n . It
" ~is~well
~ ~ ~established that stress increases intesti-
such as mercury,15 diazinon,16 and hexachl~robenzene.'~ nal permeability. One hour of water-avoidance stress" or 4 hours
Suggestively,urinary coproporphryin concentrations were great- of restraint stress43significantly increased intestinal permeability
er in high-Mauve schizophrenics than other schizophrenics," in rats. Psychosocial stress results in intestinal inflammation and
and intraperitoneal injection of rats with 0.65 pmol/kg of HPL greater intestinal permeability in humans.M46 More specifically,
(Cutler's low dose, as discussed in part 1of this article) quintu- emotional stress increases urinary excretion of compounds nor-
pled urinary coproporphyrins.18 mally retained in the bowel, including bilirubin metabolites4748
The formation of isocoproporphyrin from altered human and in dole^^^ 51 from bacterial degradation of tryptophan.
heme biosynthesis requires participation of gut flora. Altered The permeabilized intestinal epithelium of stressed rodents is
host CPOX produces dehydroisocoproporphyrinogen, which is characterized by greater numbers of bacteria adhering to or pene-
degraded by gut flora to produce isocoproporphyrin in stool.13"I6 trating bowel epithelium,Mtration by mononuclear cells,5253 mast
If, as Irvine suggested, isocoproporphyrin is a precursor to HPL, cell activation, and depletion of r n u c ~ u sCatecholamines
.~~~~ and glu-
then either host or microbelg could effect the final conversion cocorticoids--the so-called "stress hormones"-increase many-fold
from isocoproporphyrin. But the preceding step-dehyrodroiso- during stress. Experimentally, administration of stress hormones
coproporphyrinogen to isocoproporphyrin-is microbial. duplicates the effects of experimental stress on intestine.
Preliminary evidence does suggest bacterial involvement in Application of norepinephrine to sheets of large bowel
the formation of Mauve. Oral tetracycline reversibly abolished increased bacterial adherence within 30 minutess5Intestinal epi-
urinary HPL excretion in 4 previously Mauve-positive subjects. thelial permeability is increased by glucocorticoid injection and
Oral dosing with kanamycin, a non-absorbable antibiotic, revers- mediated by glucocorticoid receptor^.^^ Central or peripheral
ibly abolished or sharply reduced urinary HPL in 9 subjects.120 injection of corticotropin releasing factor (CRF) mimics stress-
induced degranulation of mast cells and increased permeability
MAUVE AND THE GUT in ~ o l o n .Dexamethasone
~~.~~ injections of rats decreased IgA and
There has been no quantification of HPL in stool or direct increased bacterial adherence to epithelium within 24 hours.58
measurement of intestinal permeability of high-Mauve subjects, Irvine's attempts to provoke HPL in animals with a number
but multiple observations suggest that intestinal permeability of treatments were futile, with one notable exception: urinary
modulates HPL excretion in urine. As these facts are considered, HPL increased significantly in Sprague-Dawley rats and female
it should be kept in mind that Mauve not only is associated with hyperprolinemic (PRO/Re) mice treated with p r e d n i s ~ n e . ~ ~ ~ ~
neurobehavioral symptoms, but abdominal signs and symptoms Other mechanisms-including porphyrinogenic-are possible,
exist in many high-Mauve subjects. Abdominal tenderness was but the response to prednisone is consistent with a permeability
reported in a large percentage of high-Mauve subject^,^' and effect on HPL excretion.
Pfeiffer associated Mauve with sharp abdominal pains, as "stitch- Roman Lietha presented data that suggested an association
i n - ~ i d e . "Schizophrenics*
~~.~~ and a u t i s t i c ~ ~
have
~ " ~more abdomi- between urinary HPL and indicans in 154 patients at a Princeton
nal symptoms, and abdominal pain is characteristic of AIP. BioCenter conference in 1988. The indicans test is a qualitative
It is known that zinc deficiency results in intestinal epitheli- assay for urinary indoles, which result from enterobial degradation
al damage and increased permeability mediated by greater intes- of tryptophan. It is known that intestinal permeability associates
tinal NO.30Since urinary HPL associates with zinc deficiency, with increased accumulation of tryptophan in intestinal

Discerning the Mauve Factor, Part 2 ALTERNATIVE T.MERAPIES, MAY/JUN 2008, VOL. 14, NO. 3 s7
Indicans correlate poorly with dietary protein and small bowel flora MISLEADING LITERATURE AND OTHER OBSTACLES
but do associate with enteric protein loss? which in turn associates After a period of initial activity, no basic research on Mauve
with intestinal ~ermeability.~~Urinary indicans, while lacking speci- has graced the peer-reviewed literature for many years. This inac-
ficity, would be expected to associate with intestinal permeabity. tivity contrasts rather sharply with ongoing enthusiasm for
Data from a mixed cohort of 2726 subjects from the Biocenter Mauve among a subgroup of nutritional practitioners and fami-
Laboratory in Wichita, Kansas, were examined to determine if a lies. The disparity probably stems in part from continuing mis-
relationship exists between indicans and HPL in urine. Indicans identification of the compound as KP. Also, HPL is a highly
positively correlated with HPL by colorimetric assay (Pc .0001) labile, technically challenging compound to study. What's more,
(Figure 1). Mauve appears to relate to gut (Figure 2). only recently did the prevailing psychoanalytic paradigm open to
underlying physical causation of "psychiatric" disease and the
HPL and Indicans facilitative concept of oxidative stress. Finally, unwarranted nega-
35
tive conclusions about Mauve in the peer-reviewed literature dis-
courage potential investigators.
30 - An article in the AmericanJournal flsychiatry disparagingly
entitled "Pyroluria: a Poor Marker in Chronic S~hizophrenia"~~
25 - found no relationship between qualitative urinary Mauve and a
presumptive list of signs and symptoms for zinc and vitamin B6
20 deficiency. Remarkably, the cohort had only 2 subjects with posi-
tive urine.
15 - An article in Clinical Science stated unequivocally in title and
abstract that Mauve, "is not causally related to s~hipohrenia.""(p~~~)
The text of the article softened the conclusion by stating that
10 -
Mauve was "unlikely" to be causal, because no difference was
found between schizophrenics and controls. The technical han-
5- dling of specimens is suspect because Mauve was undetected in
I
half of samples, at a purported detection limit of 0.25 pgfdL. The
0 use of subjects with active somatic illness as controls was unfortu-
0 1+ 2+ 3+ 4+
nate, because Mauve is elevated in somatic i l l r ~ e s s . ~ ~ ~ ~ ~ ~ ~
lndicans
As discussed in part 1 of this article, Cutler minimized
FIGURE 1Median Values for ColorimetricHPL Equivalents*Correlated
With Indicans in Singe-voidUrine From Mixed Cohort of 2726 Subjects potential neurotoxicity of HPL in humans in Pharmacology and
Toxicology on the basis of hypothetical estimates of HPL in
*Normal <20pg/dL. human blood contradicted by prior published values.71In addi-
HPL values for the 4+ indicans group were skewed, necessitatinguse of median
values for siphcance testing. tion, the article indicated that thesis work by Graham failed to
P<.0001for difference in medians of all groups. demonstrate a positive correlation between HPL levels and
symptom severity in schizophrenia. It fact, only 1of 7 schizo-
phrenics in the thesis data had above-normal urinary HPL."
Kershner reported in Journal @Nutritionn the results of a ran-
domized trial that sought to evaluate HPL as a screening test for
response to nutrients. Twenty children with learning disability/
hyperactivity received a low carbohydrate diet for 6 months, and
Emotional Stress 18 of 20 improved. Then the cohort was divided into groups of 10.
One group received daily vitamin C, nicacinamide, vitamin B,, and
vitamin B6(500-750mg); the other group received placebo. After 6
months, neither group showed additional improvement. Kershner
1' Gut Permeability concluded that "Kryptopyrrole [colorimetric HPL] proved invalid
as a screening test for vitamin-dependent learning disorder^"^^(@^^)
because pre-treatment levels did not demonstrate statistical rela-
tionship with improvement on vitamins.
The mean HPL values for the 2 groups were well within nor-
Cp450 mal limits, and only 6 subjects (presumably 3 in either cohort,
I'HPL
.1Regulatory Heme but not specified) had elevated HPL prior to nutrients. To com-
FIGURE2 Proposed RelationshipsAmong HPL, Emotional Stress, pensate for the inadequate number of subjects with abnormal
Oxidative Stress,Zinc,Heme, and Intestinal Permeability HPL, Kershner arbitrarily adjusted the normal range for HPL
prior to statistical analysis. The choice of nutrients for the

58 ALTERNATIVE THERAPIES, MAY/JUN 2008, VOL. 14, NO. 3 Discerning the Mauve Factor, Part 2
Kershner study would be considered suboptimal by current stan- FUTURE RESEARCH
dards and at the time of the study. Hoffer embraced vitamin B6 As a high priority, randomized clinical trials are needed to
and zinc as superior to multi-gram doses of B3 years earlier, yet examine symptom improvement in high-Mauve subjects after
Kershner used no zinc. Pfeiffer4,."and McCabe" reported that treatment with B6 and zinc. There are many corollary questions
without zinc, as much as 3 g of B6 were required to suppress to answer: Does P5P, which protects intestinal GSHPX,~~ warrant
HPL, but Kershner used far less. an expanded role, and if so, in which patients? Would zinc,
From the Kerschner study is extracted a useful clinical point. which blocks intestinal lipoxidation and permeability,'%e useful
Behavioral deterioration in some subjects after vitamins was in high boluses or perhaps in poorly absorbable forms? If the
relieved by the addition of magnesium. The late Bernard relationship to oxidative stress is fundamental, would antioxi-
Rimland, P ~ D founder
, and former Director of Autism Research dants such as GSH or coenzyme Qlobe useful treatments?
Institute, San Diego, California, affirmedin oral communications Suggested novel applications of Mauve in behavioral disor-
from 1997 to 2006 that optimal response to higher doses of B6 ders include prevention of suicide," prevention of psychiatric ill-
often is achieved with concurrent magnesium. n e s ~ ,and
~ ] treatment and prevention of criminal behavior.7879
Hoffer found that sudden, unexpected deviant behavior in previ-
CONTEMPORARY THERAPEUTICAPPROACHES ously well-adapted adults associated with Mauve.80
Vitamin B6 (200-800 mg daily) in combination with zinc The status and use of fatty acids in high-Mauve subjects
(25-100 mg daily) usually is sufficient to suppress HPL and needs elucidation. Owing to the vulnerability of double bonds to
achieve optimal symptomatic response. Generally, higher uri- oxidative stress, both omega3 and omega-6 fatty acid depletion
nary HPL suggests the need for proportionately higher dosing of might be expected in high-Mauve subjects. Preliminary data on
zinc and B6, and repeated measurements of HPL influence dos- 23 schizophrenics suggests this is the case, at least in schizophre-
ing decisions. nia. Plasma from the schizophrenics contained significantly less
Clinical symptoms and HPL suppression are the primary docosahexanoic acid (DHA, omega-3), as a percentage of total
determinants of B6 dosing. Poor dream recall or morning nau- lipids, than controls. Only the 6 high-Mauve subjects from this
sea/anorexia reportedly are useful signs of insufficient B6.=Blood cohort also had lower arachidonic acid (AA, omega-6) (P<.01).8I
tests for EGOTT4or P5PUmay be used to confirm functional sta- A number of studies have found lower concentrations of
tus of B6, but pyridoxine blood levels are not considered useful. omega3 and omega-6 fatty acids in blood from schizophren-
Long-term treatment of 3000 high-Mauve patients with high- i c ~ including
, ~ ~ lower
~ ~ red-cell membrane DHA and AA.83
dose vitamin B6 resulted in no cases of peripheral ne~ropathy,'~ Multiple trials report improvement in groups of schizophrenics
but reversible median nerve paresthesis has been reported.23P5P receiving omega3 s~pplementation.~~ It is possible that Mauve
is unassociated with n e u r ~ p a t h y .As
~ ~orally
, ~ ~ communicated by identifies a subgroup which would benefit from omega-6 supple-
William Walsh, P ~ D in, 2005, P5P may be effective in combina- mentation in combination with omega3 or as a higher priority.
tion with B6 or instead of B6 in some high-Mauve subjects, Evening primrose oil (EPO), a rich source of gamma linolen-
including "slender malabsorbers." ic acid (GLA), is a precursor for both AA and dihomo-gamma-
Zinc requirement may be quite high in subjects with elevat- linolenic acid (DGLA), immediate precursor for prostaglandin
ed HPL. Subnormal and low-normal levels of cellular or plasma El (PGE-1). PGE-1 rapidly lowers intestinal permeability, includ-
zinc indicate the need for,more zinc. For assessment with plasma ing stress-induced intestinal ~ermeability.8~~~ EPO also improves
zinc, avoidance of zinc supplementation for 24 hours excludes zinc absorption.9092 EPO and misoprostol, a commercial PGE-1
artifact. Long-term zinc requirements may be less than optimal analogue, are logical possibilities for Mauve research.
doses in initial months of treatment, during accelerated growth, HPL is a potentially useful screen for other biochemical
or during extended periods of psychosocial stress. Recurrence of abnormalities, including dysregulation of homocysteine, a neu-
leukonychia or striae is a relatively sure sign of lagging zinc. rotoxicg3metabolite. Cystathionine beta-synthase,which metabo-
Excessive zinc supplementation, which results in copper lizes homocysteine, is uniquely dependent on both vitamin B6
depression and depressed immunity, can be avoided with periodic and heme as c o f a c t o r ~ In . ~written
~ ~ ~ communication, Allen
blood testing. Especially in adults receiving more than 50 mg of Lewis, MD, Medical Director of Pfeiffer Treatment Center,
elemental zinc daily, cellular or plasma zinc should not exceed Warrenville, Illinois, reported in 2005 that serum HCY and colo-
upper limits of normal, and cellular or serum copper should not rimetric HPL (single-void, unadjusted) from unsupplemented
be below the normal range. Supplemental copper is rarely indi- autistic children seen at the PfeifTer Treatment Center correlated
cated in high-Mauve subjects and can aggravate symptoms. significantly (N=ll4; P=.002). Plasma HCY associates with great-
Suppression of manganese may result from aggressive zinc er risk of cardiovascular and neurodegenerativeg6disease.
supplementation. Small dosages (approximately 5 mg manga- Mauve assay may be useful in the care of subjects with strictly
nese for each 30 mg of supplemental zinc) reportedly improve somatic diagnoses or in the optimization of health in subjects with-
symptoms in some high-Mauve subjects. Serum or red-cell levels out diagnoses. Mauve elevation in somatic illness2'6&6870 presum-
may be monitored during supplementation with manganese, ably reflects unrecognized nutritional deficits and greater oxidative
which in excess is pro-oxidant. stress. In allergy, which is associated with zinc defi~iency,~~ Mauve

Discerning the Mauve Factor, Part 2 ALTERNATIVE THERAPIES. MAY/JUN 2008, VOL. 14, NO. 3 S9
 testing might enhance nutritional awareness. (PfeiEer suggested ate with HPL. Downstream effects of heme suppression by HPL
allergic diathesis in association with mauve, citing the zinc require- may be detectable in animals and high-Mauve subjects. HPL may
ment for histamine storage in mast cells.u)Similarly,cancer associ- exert significant effects on gut or brain, including hallucinosis.
ates with zinc deficiency98and B6 deficien~y.~~.~~~ Associated EEG abnormalityUgmay normalize with Mauve sup-
Corroboration of HPL as marker for biotin deficiency should pression, but modern brain scans have eluded Mauve.
be a high priority. The finding is plausible. Biotinidase, necessary
for maintenance of biotin levels, is sensitive to oxidative modifi- CONCLUSION
cation, and oxidative stress is suspected to lower biotinidase in At the very least, this review should clarify the identity and
Biotin deficiency causes brain dysfunction, and sub- history of Mauve (HPL). Hopefully, it will strengthen commit-
jects with partial biotinidase deficiency remain asymptomatic ment to careful handling and refined laboratory approaches to
until stressed.lo3 urinary assay of HPL, including normalization to specific gravity
HPL testing is potentially useful in pregnancy, when nutri- or creatinine. And for the first time, herein were presented orga-
tional demands are enormous and when nutritional deficits can nized data that examined-and confirmed-urinary HPL as a
result in fetal disease or malformation. Biotin deficiency, for yardstick for functional B6 and zinc deficiency. The findings are
example, is relatively common in pregnancy," and marginal bio- congruous with clinical observationsover the decades and should
tin deficiency is teratogenic in mice.lMDeficiencies of stimulate independent corroboration and further research.
zinc,lo7and B p independently result in cleft palate in animals. In its search for clinically relevant biomarkers for oxidative
Presumably, combined deficiency of these nutrients increases stress, modern medicine wbuld do well to consider urinary
teratogenic risk. Hyperhomocysteinuria associates with fetal dis- Mauve as a means to quantify oxidative stress and to guide the
ease and malformation," and heme modulates neur~genesis."~ use of specific antioxidant therapies. Besides practical potential,
Pfeiffer associated Mauve with mi~carriage.~~ Mauve provides an exquisite conceptual model for the interplay
Predisposition to Mauve may be heritable. Some clinicians of oxidative stress, emotional stress, nutrients, and gut as they
consider elevated Mauve in one family member an indication for pertain to disease of brain and body.
family-wide testing. Polymorphisms favoring HPL production are
considered most likely in genes for altered expression of CPOX, por- REFERENCES
1. Irvine DG. Kryptopyrrole in molecular psychiatry. In: Hawkins D, Pauling L, eds.
phyrins, metabolism of stress hormone^,"^."^ or production of OrthomolecularPychiatry: TreatmentofSchizophrenia.San Francisco: WH Freeman and
endogenous antioxidants such as metall~thionein.~~ Defective Company; 1973:146-178.
2. Hoffer A. D-lysergic acid diethylamide (LSD): a review of its present status. Clin
enzymes may associate with HPL, especially those that are sensitive Pharmacol Tker 1965 Mar-Apr;6:183-255.
to oxidative impairment" and also are either B6-dependent(eg, glu- 3. Denson R. Lysergide therapy and the mauve factor. Acta Psychiatr Scand.
1968;44(3):280-288.
tamic acid decarboxylase)or zinc-dependent(eg, pyridoxal kinase). 4. PfeifFer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schiuo-
Porphyrin profiles in high-Mauve subjects might confirm phrenias. JAppl Nutr. 1975;27:9-39.
5. Sohler A, Holsztynska MS, PfeifFer CC. A rapid screening test for pyroluria; useful in
origin in the heme biosynthetic pathway, any defect of which can distinguishing a schiuophrenic population. JOrfhomolecPsychiatr. 1974;3(4).273-279.
be magnified by factors that increase activity of ALA synthase 6. Ward JL. Relationship of kryptopyrrole, zinc and pyridoxine in schizophrenics.
JOrthomolecPsychiatr.1975;4:27-31.
(ALA-S). Treatment of animals with HPL significantly increased 7. IMne DG. Preliminary characterization of a fecal pigment associated with hydroxyhe-
ALA-S activity,l2.'" presenting the intriguing possibility that an mopyrrolenone excretion. Proceedings of the 23rd Annual Psychiatric Research Meeting.
April 1978; Saskachewan:26-28.
aberrant product of porphyrin metabolism may exert positive 8. IMne DG. The region of the molecule yielding hydroxyhemopyrrolenone in the oxi-
feedback on its own production. A number of toxins-especially doreduction of bide pigments. Proceedings ofthe 23rd Annual Psychiatric Research
Meeting. April 1978; Saskachewan:23-24.
heavy metals and alcohol-increase ALA-S activity." 9. Irvine DG. Clinical, EEG and biochemical correlates of hydroxyhemopyrrolenone
Research is needed to confirm the relationship between HPL excretion. Proceedings of the 22nd Annual Psychiatric Research Meeting, Saskatoon
Psychiatric Research Division. Saskatoon, Saskatchewan;May 1977: 59-60.
excretion and stress, and to more completely characterize HPL as 10. MiyashitaH, K i n e DG. Source of kryptopyrrole: quantitative loading studies with cer-
a biomarker for oxidative stress. H202 should be measured in tain unlabelled substrates. Report to the Research Meeting ofthe Saskatchewan Pychiab.ic
Association. 1972: 242-248.
high-Mauve subjects. Besides catalase, depression of other heme- ll. Hoffer A. The presence of malvaria in some mentally retarded children.Am JMent Def:
dependent enzymes could potentiate greater oxidative stress in 1963;67:730-732.
12. Irvine DG, W i o n DL. Oxidized monopyrroles in porphyric disorders and related con-
high-Mauve subjects. For instance, lower cytochrome p450 ditions. In: Doss M, ed. Porphyrins in Human Diseases: Proceedings ofthe International
might confer greater sensitivity to medications or toxins. Porphyrin Meeting, 1st. Freiburg, Germany, May, 1975. Basel, Switzerland: Karger
Publishers; 1976. pp 217-224.
Association of HPL excretion with stress hormones and oxida- 13. Elder GH. The metabolism of porphyrins of the isocoproporphyrin series. Enzyme.
tively modified biomolecules such as 8-OHdG and isoprostane 1974;17(1):61-68.
14. Cooper CL, Stoh CM, Jones MA, Lash TD. Metabolism of pentacarboxylate porphy-
seems likely. The perspective for research in this area is provided by rinogens by highly purified human coproporphyrinogen oxidase: further evidence for
the understanding that emotional stress causes increased oxidation the existence of an abnormal pathway for heme biosynthesis. Bioorg Med Chem.
2005;13(22):6244-6251.
of biomolecules, including brain, as surely as do toxins or deficiency 15. Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction
of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme bio-
of antioxidant nutrients (as reviewed by McGinnis in 2007).m synthetic pathways and porphyrin production. ToxicolLeR. 2006;161(2):159-166.
The biological effects of HPL are mostly unexplored, and 16. Bleakley P,Nichol AW, Collins AG. Diazinon and porphyria cutanea tarda. Med JAust.
1979;1(8):314-315.
interpretation of such studies will be abetted by accurate quanti- 17. Pfeiier CC, Sohler A, Jenney EH, et aL Treatment ofpy~oluricschiiphrenia (malvaria)with
fication of HPL in blood and stool. Specific microbes may associ- large doses ofpyridoxineand a dietary supplementofzinc.JApplNm. 1974;26:21-28.

60 ALTERNATIVE THERAPIES. MAY/JUN 2008, VOL. 14, NO. 3 Discerning the Mauve Factor, Part 2
I
18. Graham DJM, Thompson GG, Moore MR, Goldberg AA. The effects of selected 51. Mandell AJ, Sabbot IM, Mandell MP, Kollar EJ. The stress responsive indole substance
monopyrroles on various aspects of heme biosynthesis and degradation in the rat. Arch in sleep deprivation. Arch Gen Psychiatry. 1964 Mar;10:299-305.
Biochem Biophys. 1979;65(1):132-138. 52. Cameron HL, Perdue MH. Stress impaics murine intestinal barrier function: improve-
19. Hatch T,Lascelles J. Accumulation of porphobinogen and other pyrroles by mutant ment by glucagon-like peptide-2.JPharmacolExp Ther. 2005;314(1):214-220.
and wild type Rhodopseudomonas speroides: regulation by heme. Arch Biochem 53. Velin AK, Ericson AC, Braaf Y, Wallon C, Soderholm JD. Increased antigen and bacteri-
Biophys. 1972;150(1):147-153. al uptake in follicle associated epithelium induced by chronic psychological stress in
20. Irvine DG. Mauve factor and 6-sulfatoxy skatole: two biochemical abnormalities asso rats. Gut. 2004;53(4):494-500.
ciated with specific measures ofpsychiatric disease. Clin Chem. 1963;9:444-445. 54. Soderholm ID, Yang PC, Ceponis P, et al. Chronic stress induces mast cell-dependent
21. McCabe DL. Kryptopyrroles.JOrthomolec Psychiatr. 1983:12:2-18. bacterial adherence and initiates mucosal inflammation in rat intestine.
22. Pfeiffer CC. Mentaland Elwental Nutrients. New Canaan, CT:Keats Publishiing;l976. Gastroenterology. 2002;123(4):1099-1108.
23. Pfeiffer CC, Maillous R, Forsythe L. f i e Schizophrenias: Ours to Conquer. Wichita, 55. Chen C, Lyte M, Stevens MP,Vulchanova L, Brown DR. Mucosally-directedadrenergic
Kansas: BioCommunications Press; 1988. nerves and sympathomimetic drugs enhance non-iitimate adherence of Escherichia
24. Hoffer A. Mechanism of action of nicotinic acid and nicotinamide in the treatment of coli 0157:H7 to porcine cecum and colon. EurJPharmacol. 2006;539(1-2):U6-124.
schizophrenia. In: Hawkins D, Pauling L, eds. Orthomolecular Psychiaty Treatment of 56. Meddiigs JB, Swain MG. Environmental stress-induced gastrointestinal permeabity
Schizophrenia.San Francisco: WH Freeman and Company; 1973:202-262. is mediated by endogenous glucocorticoids in the rat. Gastroenterology.
25. White JF. Intestinal pathophysiology in autism. Exp Biol Med (Maywood). 2000;U9(4):1019-1028.
2003;228(6):639-649. 57. Tache Y, Martinez V, M i o n M, Maillot C. Role of corticotropin releasing factor recep-
26. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr GastroentprolRep. tor subtype 1in stress-related functional colonic alteration: implications in irritable
2002;4(3):251-258. bowel syndrome. EurJSurg Suppl. 2002;(587):16-22.
27. Jyonouchi H, Geng L, Ruby, Zimmerman-Bier B. Dysregulated innate immune 58. Alverdy JC, Aoys E. The effect of dexamethasone and endotoxin administration on bil-
responses in young children with autism spectrum disorders: their relationship to gas- iary IgA and bacterial adherence.J S u x Res. 1992;53(5):450-454.
*
trointestinal symptoms and dietary intervention. Neuropsychobiology.2005;51(2):77-85. 59. Irvine DG. Kryptopyrrole and other monopyrroles in molecular neurobiology. Int Re,
' 28. Parracho HM, Biigham MO, Gibson GR, McCartney AL. Differences between the gut Neurobiol. 1974;16(0):145-182.
microflora of children with autistic spectrum disorders and that of healthy children. J 60. Irvine DG. Pyrrolooxygenasesand psychiatric disorders: a new hypothesis. Report to the
MedMicrobiol. 2005;54(Pt 10):987-991. PsychiatricResearchMeeting ofthe Saskatchewan PsychiatricAssociation. 1973: 74-78.
29. MacFabe DF, Cain DP, Rodriguez-CapoteK, et al. Neurobiological effects of intraven- 61. Basova NA, Markov IuG, Berzin' NI. Effects of natuml (zinc, vitamin E) and synthetic
tricular propionic acid in rats: possible role of short chain fatty acids on the pathogene- (diludin) antioxidants on the intestinal permeability in chicks with vitamin A deficien-
sis and characteristics of autism spectrum disorders. Behav Brain Res. cy [in Russian]. Ross FiziolZh Im I M Sechenova. 2002;88(5):650-657.
2007;176(1):149-169. 62. Mayer PJ, Beeken WL. The role of urinary indican as a predictor of bacterial coloniza-
30. Cui L, Takagi Y, Wasa M, Sando K, Khan J, Okada A. Nitric oxide synthase inhibitor tion in the human jejunum. AmJDigDis. 1975;20(ll):1003-1009.
attenuates intestinal damage induced by zinc deficiency in rats. J Nutr. 63. Keller KM, Knobel R, Ewe K. Fecal alpha 1-antitrypsin in newborn infants. JPediatr
1999;129(4):792-798. GastroenterolNu& 1997:24(4):271-275.
31. Rohweder J, Runkel N, Fromm M, SchulzkeJD, Buhr HJ. Zinc acts a protective agent on 64. Cruz R, Vogel WH. Pyroluria: a poor marker in chronic schizophrenia. Am /Psychiatry.
the mucosal barrier in experimental TNBS colitis [in German]. Langenbecks Arch Chir 1978;135(10):1239-1240.
SupplKongressbd. 1998;U5(Suppll):223-227. 65. Gorchein A. Urine concentration of 3-ethyl-5-bydroxy-4.5-dimethl-delta 3-pyrrolin-2-
32. Rodriguez P, Darmon N, Chappuis P, et al. Intestinal paracellular permeability during one ("mauve factor")is not causally related to schizophrenia or to acute intermittent
malnutrition in guinea pigs: effect of high dietary zinc. Gut. 1996;39(3):416-422. porphyria. Clin Sci (Lond). 1980;58(6):469-476.
33. Sturniolo GC, Fries W, Mazzon E, Di Leo V, Barollo M, D i c a R. Effect of zinc snpple- 66. Hoffer A, Osmond H. The association between schizophrenia and two objective tests.
mentation on intestinal permeability in experimental colitis. J Lab Clin Med. Can Med AssocJ 1962;87(12):641-646.
2002;139(5):3U-315. 67. O'Reilly PO, Ernest M, Hughes G. The incidence of malvaria. BrJPsychiatry. 1965
34. Mahmood A, Fitzgerald AJ, Marchbank T, et al. Zinc carnosine, a health food supple- Aug;lll:741-744.
ment that stabilizes small bowel integrity and stimulates gut repair processes. Gut. 68. Hoffer A. The psychophysiology of cancer./Asthma Res. 1970;8(2):61-76.
2007;56(2):168-175. Epub 2006 Jun 15. 69. Jackson JA, Riordan HD, Neathery S, Riordan NH. Urinary pyrrole in health and dis-
35. Bates CJ, Evans PH, Dardenne M, et al. A trial of zinc supplementation in young rural ease.JOrthomolec Med. 1997 First Quarter;12:96-98.
Gambian children. BrJNutr. 1993;69(1):243-255. 70. Jackson JA, Rordan HD, Bramhall N, et al. Urine pyrroles in patients with cancer. J
36. Chen P, Soares AM, Lima AA, et al. Association of vitamin A and zinc status with OrthomolecMed. 2003;1:41-42.
altered intestinal permeability: analyses of cohort data from northeastern Brazil. J 71. Cutler MG, Graham DJ, Moore MR. The mauve factor of porphyria, 3-ethyl-5-hydroxy-
Health Popul Nutr. 20003;1(4):309-315. 4,5-dimethyl-delta-3pyrroline-2-one: effects on behavior of rats and mice. Pharmacol
37. Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Inci R. Zinc supplementation Toxicol. 1990;66(1):66-68.
tightens "leaky gut" in Crohn's disease. Injamm BowelDis. 2001;7(2):94-98. 72. Graham DJM. Monopyrroles in Porphyria and Related Disorders [doctoral thesis].
38. Roselli M, Finamore A, Garaguso I, Britti MS, Mengheri E. Zinc oxide protects cultured University of Glasgow; 1978.
enterocytes from t h e damage induced by Escherichia coli. J Nutr. 73. Kershner J, Hawke W. Megavitamins and learning disorders: a controlled double-blid
2003;133(12):4077-4082. experiment.JNuh: 1979;109(5):819-826.
39. Saknrai E, Fukuse G, UedaM, Murata R, Hikichi N, Niwa H. Alteration of biogenic 74. Jaffee R, Kruesi OR. The biochemical-immunologywindow: a molecular view of psychi-
amines, serotonin, histamine and polyamines, in cases of diarrhea induced by various atric case management. JAppl Nutr. 1992;44:26-42.
cathartics li Japanese]. Nippon YakurigakuZasshi. 1980;76(5):293-299. 75. Das D, BandyopadhyayD, Banerjee RK. Oxidative inactivation of gastric peroxidase by
40. Farack UM, Nell G. Mechanism of action of diphenolic laxatives: the role of adenylate site-specific generation of hydroxyl radical and its role in stress-induced gastric ulcer-
cyclase and mucosal permeability.Digestion. 1984;30(3):191-194. ation. Free RadicBiolMed. 1998;24(3):460-469.
41. Schmelzer M, Schiller LR, Meyer R, Rugari SM, Case P. Safety and effectiveness of 76. Joseph RM,Varela V, Kanji VK, Subramony C, Mihas AA. Protective effects of zinc in
large-volumeenema solutions. Appl Nurs Res. 2004;17(4):265-274. indomethacin-induced gastric mucosal injury: evidence for a dual mechanism involv-
42. Saunders PR, Santos J, Hanssen NP, Yates D, Groot JA, Perdue MH. Physical and psy- ing lipid peroxidation and nitric oxide. Aliment Pharmacol Ther. 1999;13(2):203-208.
chological stress in rats enhances colonic epithelial permeabiity via peripheral CRH. 77. PfeifFer CC, Holford P. Mental Illness and Schizophrenia: The Nutritional Connection.
DigDis Sci. 2002;47(1):209-215. Great Britain: Harper Collins Publishers; 1987.
43. Saunders PR, Kosecka U, McKay DM, Perdue MH. Acute stressors stimulate ion secre- 78. Walsh WJ, Glab LB, Haakenson ML. Reduced violent behavior following biochemical
tion and increase epithelial permeability in rat intestine. Am JPhysiol. 1994;267(5 Pt therapy. PhysiolBehav. 2004;82(5):835-839.
1):G794-G799. 79. Kraus RT. An enigmatic personality: case report of a serial killer. J OrthomolecMed.
44. Hart A, Kamm MA. Review article: mechanisms of initiation and perpetuation of gut 1995 Fist Quarter;lO:U-24.
inflammation by stress. Ailment Pharmacol Ther. 2002;16(12):2017-2028. 80. Hoffer A. Malvaria and the law. Psychosomatics.1966;7(5):303-310.
45. Martinez-Augustin0 , SQnchezde Medina F Jr, SPncbez de Medina F. Effect of psycho- 81. Bibus DM. Holman RT, Walsh WJ. Fatty acid profiles of schizophrenic phenotypes.
genic stress on gastrointestinal function.JPhysiolBiochem.2000;56(3):259-274. Paper presented at: American Oil Chemists' Society 91st Annual Meeting and Expo;
46. Bhatia V, Tandon RK. Stress and the gastrointestinal tract. J GastroenterolHepatol. April25.2000; San Diego, California.
2005;20(3):332-339. 82. Arvindakshan M, Ghate M, Ranjekar PK, Evans DR. Mahadii SP. Supplementation
47. Yamaguchi T, Shioji I, Sugimoto A, Yamaoka M. Psychological stress increases b i i u - with a combination of omega-3 fatty acids and antioxidants (vitamins E and C)
bin metabolites in human urine. Biochem Biophys Res Commun. 2002;293(1):517-520. improves the outcome of schizophrenia. Schizophr Res. 2003;62(3):195-204.
48. Miyaoka T, Yasukawa R, Yasuda H, et al. Urinary excretion of biopyrrins, oxidative 83. Khan MM, Evans DR. Gunna V, Scheffer RE, Parikh W, Mahadik SP. Reduced erythro-
metabolites of bilirubin, increased in patients with psychiatric disorders. Eur cyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at
Neuropsychophannacol.2005;15(3):249-252. the never-medicated fist-episode of psychosis and after years of treatment with antip-
49. Mandell AJ, Slater GG, Mersol I. Indole-like urinary stress reactant in man. Science. sychotics. Schuophr Res. 2002;58(1):1-10.
1961June 9;133:1832-1833. 84. Arvindakshan M, Sitasawad S, Debsikdar V, et al. Essentail polyunsaturated fatty acid
50. Mandell AJ, Kollar EJ, Sabbot IM. Starvation, sleep deprivation and the stress respon- and lipid peroxide levels in never-medicated schizophrenia patients. Biol Psychiatry
sive indole substance. Recent AdvBiolPsychiahy. 1963:84:96-104. 2032:53(1):56-64.

Discerning the Mauve Factor, Part 2 ALTERNATIVE THERAPIES, MAY/JUN 2008, VOL. 14, NO. 3 61
 85. Kemperman RF, V e u ~ M, k van der Wal T, et al. Low essential fatty acid and B-vitamin
status in a subgroup ofpatients with schizophrenia and its response to dietary supple-
mentation. Prostaglandins LeukotEssent Faty Acids. 2006;74(2):75-85.
86. Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs.
2005;65(8):1051-1059.
87. Empey LR, Fedorak RN. Effect of misoprostol in preventing stress-induced intestinal
fluid secretion in rats. Prostaglandins Leukot Essent Fatty Acids. 1989;38(1):43-48.
88. Gao F, Hone T. Protective effect of prostaglandins on the methotrexate induced dam-
age of small intestine in rats. In Kvo. 2000;14(3):453-456.
89. Bjarnason I, Smethurst P, Fenn CG, Lee CE, Menzies IS, Levi AJ. Misoprostol reduces
indomethacin-induced changes in human small intestinal permeability. Dig Dis Sci.
1989;34(3):407-411.
90. Cunnane SC. Maternal essential fatty acid supplementation increases zinc absorption
in neonatal rats: relevance to the defect in zinc absorption in acrodermatitis entero-
pathica. Pediatr Res. 1982;16(8):599-603,
91. Rosenthal MI, Hwang M,Song MK. Effects of archidonic acid and cyclo (his-pro) on
zinc transport across small intestine and muscle tissues. L@ Sci 2001;70(3):337-348.
92. Song MK, Adham NF. Relationship between zinc and prostaglandin metabolisms in
plasma and small intestine of rats. Am JClin N u 8 1985;41(6):1201-1209.
93. Bleich S, Degner D, Sperling W, Bonsch D, ThiiraufN, KornhuberJ. Homocysteine as a
neurotoxin in chronic alcoholism. Prog Neuropsychopharmacol Biol Psychiatry.
2004;28(3):453-464.
94. Taoka S, Ohja S, Shan X, Kruger WD, Banejee R. Evidence for heme-mediated redox
regulation of human cystathionine beta-synthase activity. / Biol Chem.
1998:273(39):25179-25184.
95. Jhee KH, Kruger WD. The role of cystathione beta-synthase in homocysteine metabo-
lism. AntioxidRedox Signal. 2005;7:813-822.
96. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases.
Altern MedRev. 2003;8(1):7-19.
97. Di Toro R, Galdo Capotorti G, Gialanella G, et al. Zinc and copper status of allergic
children. Acta Pediatr Scand. 1987:76:612-617.
98. Fong LY, Zhang L, Jiang Y, FarberJL. Dietary zinc modulation ofCOX-2 expression and
lingual and esophageal carcinogenesis in rats.JNat Cancer Inst. 2005;97(1):40-50.
99. Key TJ, Silcocks PB, Davey GK, Appleby PN, Bishop DT. A case-control study of diet
and prostate cancer. BrJCancer. 199776(5):678-687.
100. Alberg AJ, Selhub J, Shah KV, Vicidi RP, Comstock GW, Helzsouer KJ. The risk of cer-
vical cancer in relation to serum concentrations of folate, vitamin Biz, and homo-
cysteine. CancerEpidemiolBiomarkers Prevent. 2000;9(7):761-764.
101. Hartman TJ, Woodson K, Stolzenberg-Solomon R, et al. Assocation of the B-vitamins
pyridoxal5'-phsophate(B(G)),B(12), and folate with lung cancer risk in older men. Am
JEpidemiol. 2001;153(7):688-694.
102. Mayne ST, Risch HA, Dubrow R, et al. Nutrient intake and risk of subtypes of esopha-
geal and gastric cancer. CancerEpidemiol Biomarkers Prev. 2001;10(10):1055-1062.
103. Zaffanello M, Zamboni G, Fontana E, Zoccante L. Tat6 L. A case of partial biotinidase
deficiency associated with autism. Child Neuropsychol.2003;9(3):184-188.
104. Mock DM. Marginal biotin deficiency is teratogenic in mice and perhaps humans: a
review of biotin deficiencyduring human pregnancy and effects of biotin deficiency on
gene expression and enzyme activities in mouse dam and fetus. J Nutr Biochem.
h
2005:16(7):435-437. , C ~ I
105. Watanabe T,Dakshiiamurti K, Persaud TV. Biotin influences palatal development of
mouse embryos in organ culture.JNuutr. 1995;125(8):2114-2121.
1 Fib
106. Mock DM, Mock NI, Stewart CW, LaBorde JB, Hansen DK. Marginal biotin deficiency li LY~
is teratogenic in ICR mice.JNu& 2003:133(8):2519-2525. 2ND
107. Shah D, Sachdev HP. Zinc deficiency in pregnancy and fetal outcome. Nutr Rev. 464
2006:64(1):15-30. Review. $18
108. M i e r TJ. Cleft palate formation: a role for pyridoxine in the closure of the secondary 1-51
palate in mice. Teratology. 1972;6(3):351-356. 1
109. Davis SD, Nelson T, Shepard TH. Teratogenicity of vitamin B6 deficiency: omphalo-
cele, skeletal a n d n e u r a l defects, a n d splenic hypoplasia. Science.
1970;169(3952):1329-1330.
ll0. Jacobsson C, Granstrom G. Effectsofvitamin B6 on beta-aminoproprionitrile-induced
palatal cleft formation in the rat. Cleft Palate CraniofacJ 1997:34(2):95-100, Fur mc
lll. Rugolo S, Mirabella D, Cantone SM, Giueida A. Hyperhomocysteinemia: associated nix,,
obstetric diabetes and fetal malformations [in Italian]. Minerva Ginecol. -1,1,.c.
2005:57(6):619-625.
l12. Ishii DN, Maniatis GM. Haemin promotes rapid neurite outgrowth in cultured mouse
and N-1
neuroblastoma cells.Nature. 1978;274(5669):372-374. (QCCt
l13. James SJ, Melnyk S. Jernigan S, et al. M e t a b o w e s L t Y L I7
are associated with oxidative stress in children with autism. Am J Med Genet B 131 L U r
Neuropsychiatr Genet. 2006:141(8):947-956. Suite 61
ll4. Herken H, Erdal ME. Catechol-0-methyltransferase gene polymorphism in schizophre-
nia: evidence for association between symptomatology and prognosis. Psychiah. Genet. Herhat
2001;ll(2):105-109. T I 1
ll5. Serajee FJ, Nabi R, Zhong H, et al. Polymorphiims in xenobiotic metabolism genes and mane:
autism.JChildNeuro1 2004;19(6):413-417. Fax: 30
ll6. McGinnis W. Oxidative stress in autism. Altem Ther Health Med. 2004;10(6):22-36.
118. McGinnis,WR. Could oxidative stress from psychosocial stress affect neurodevelop- Email:
ment in autismlJAutism Dev Disord. 2007;37(5):993-994.
ll9. Feldman DS, Levere RD, Liberman JS, Cardinal RA, Watson CJ. Presynaptic neuromus-
cular inhibition by porphobilinogen and porphobilin. Proc Nat Acad Sci, U S A.
1971;68(2):383-386.