Zinc in Attention-Deficit/Hyperactivity Disorder

Abstract

The aim of this study was to review the published evidence for a role of zinc nutrition in attention-deficit/hyperactivity disorder (ADHD).
A computer literature search was supplemented by the authors' knowledge.
Numerous controlled studies report cross-sectional evidence of lower zinc tissue levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal controls and population norms. A few studies show correlations of zinc level with either clinical severity or a change thereof in response to stimulant or chemical challenge. Two placebo-controlled trials--one of zinc monotherapy, the other of zinc supplementation of methylphenidate--reported significant benefit. However, diagnostic procedures and sample representativeness were often not clear, and most such reports have come from countries and cultures with different diets and/or socioeconomic realities than are found in the United States (only one American sample in nine published reports). In particular, both positive clinical trials of zinc supplementation came from the Mid-East (Turkey and Iran), an area with suspected endemic zinc deficiency. The largest of these trials used zinc doses above the recommended upper tolerable limit and had a 2 in 3 dropout rate.
It is not clear how well the accumulating evidence for a possible role of zinc in ADHD applies to middle-class American children. However, the evidence appears strong enough to warrant further controlled study in well-diagnosed samples representative of the socioeconomic spectrum. Hypothesis-testing clinical trials are needed of this potential treatment that, if found effective, might become a relatively safe, cheap substitute for, or adjunct to, current treatments in some patients. At present, it should remain an investigational treatment.

Full text

619
Zinc in Attention-Deficit/Hyperactivity Disorder
L. Eugene Arnold, M.D.,
1
and Robert A. DiSilvestro, Ph.D.
2
ABSTRACT
Objective: The aim of this study was to review the published evidence for a role of zinc nutri-
tion in attention-deficit/hyperactivity disorder (ADHD).
Method: A computer literature search was supplemented by the authors’ knowledge.
Results: Numerous controlled studies report cross-sectional evidence of lower zinc tissue
levels (serum, red cells, hair, urine, nails) in children who have ADHD, compared to normal
controls and population norms. A few studies show correlations of zinc level with either
clinical severity or a change thereof in response to stimulant or chemical challenge. Two
placebo-controlled trials—one of zinc monotherapy, the other of zinc supplementation of
methylphenidate—reported significant benefit. However, diagnostic procedures and sample
representativeness were often not clear, and most such reports have come from countries and
cultures with different diets and/or socioeconomic realities than are found in the United
States (only one American sample in nine published reports). In particular, both positive
clinical trials of zinc supplementation came from the Mid-East (Turkey and Iran), an area
with suspected endemic zinc deficiency. The largest of these trials used zinc doses above the
recommended upper tolerable limit and had a 2 in 3 dropout rate.
Conclusion: It is not clear how well the accumulating evidence for a possible role of zinc in
ADHD applies to middle-class American children. However, the evidence appears strong
enough to warrant further controlled study in well-diagnosed samples representative of the
socioeconomic spectrum. Hypothesis-testing clinical trials are needed of this potential treat-
ment that, if found effective, might become a relatively safe, cheap substitute for, or adjunct to,
current treatments in some patients. At present, it should remain an investigational treatment.
JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 15, Number 4, 2005
Mary Ann Liebert, Inc.
Pp. 619–627
INTRODUCTION
A
TTENTION-DEFICIT/HYPERACTIVITY DISORDER
(ADHD) and its treatment is one of the most
controversial areas in psychiatry. The disorder
itself is well known to include inattention, dis-
tractibility, overactivity, and impulsivity exces-
sive for developmental age, beginning by age 7,
causing impairment in more than one setting,
and not better explained by another disorder,
according to Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV) criteria
(APA 1994). Debate begins with etiology and ap-
propriate diagnosis and extends to outcome and
treatment. Dozens of treatments have been
advocated, from well-documented (such as
U.S. Food and Drug Administration (FDA)-
approved medication and behavioral treatment)
1
Department of Psychiatry and
2
Department of Human Nutrition, Ohio State University, Columbus, OH.
The lead author (L.E.A.) has received research funding from Sigma Tau, Noven, Lilly, Novartis, Shire, and Targa-
cept, receives speaker’s honoraria from Novartis, Shire, and McNeil, and is a consultant for Sigma Tau, Dore, Noven,
and Shire.
14104C11.pgs 9/16/05 1:31 PM Page 619

620 ARNOLD AND DISILVESTRO
at one pole to questionable or possibly danger-
ous at the other pole (Arnold 1999, 2004).
The more popular nonestablished etiologi-
cal and treatment hypotheses include various
nutritional foci. One of the more promising
threads among these is a possible role of zinc
in ADHD for some patients. This paper reviews
the available published evidence relevant to
such a possibility.
The authors’ personal acquaintance with the
zinc and ADHD literature was supplemented
by a computer literature search. The peer-
reviewed evidence falls into the categories of:
Basic role in brain function, possible deficiency
states, zinc measures in ADHD, association of
ADHD symptoms with zinc levels, and two
placebo-controlled trials of supplementation.
Zinc and brain function
Zinc is an important cofactor for metabolism
relevant to neurotransmitters, prostaglandins,
and melatonin and indirectly affects dopamine
metabolism. It is necessary for 100 different
metalloenzymes and metal-enzyme complexes
(Toren et al. 1996). It contributes to the struc-
ture and function of the brain (Black 1998). For
example, it is a coenzyme with delta-6-desat-
urase, which is necessary for anabolism from
dietary linolenic and linoleic acid of the long-
chain polyunsaturated fatty acids that make up
neuronal membranes (e.g., Bettger et al. 1979).
Much of the research has focused on fetal brain
development (Wauben et al. 1999), but zinc also
has a number of roles in the functioning of the
postnatal developing, and developed, brain.
One biochemical and physiological role re-
ceiving increasing attention is zinc ion release
during neuronal activity (Li et al, 2003). Ap-
proximately 15% of the brain’s zinc can be
found in synaptic vesicles (Lopez-Garcia et al.
2001). Because these ions exhibit numerous ef-
fects on ligand-gated, voltage-dependent ion
channels in vitro, zinc ions likely modulate
synaptic transmission, though this is not di-
rectly confirmed (Li et al, 2003). Work in rats
demonstrates that zinc is an important regula-
tor of gamma-aminobutyric acid (GABA(A))
receptor function in the cortex (Schmid et al.
1999), restricts excitability of hippocampal glu-
tamatergic neurons (Takeda et al 2003b), and is
needed for brain tubulin growth and phospho-
rylation (Prasad 1993). Zinc deficiency in rats
also affects protein synthesis (Prasad 1993),
which is reflected in the brain by the altered
expression of the P2X6 purinergic receptor
(Chu et al 2003). Zinc can also affect the brain
indirectly, because it is needed for cell mem-
brane stabilization, indirect antioxidant func-
tions, proper hormonal metabolism, and
cellular energy release (Prasad 1993; Powell
2000). These functions have been shown to be
affected by somewhat moderate zinc deficien-
cies in humans and/or experimental animals
(Prasad 1993; Powell 2000; Devine et al. 1998;
Licastro et al 1992). Zinc is necessary for the
conversion of dietary pyridoxine (vitamin B
6
)
to its active form, pyridoxal phosphate. In this
form, vitamin B
6
is necessary for the conver-
sion of tryptophan to serotonin. Zinc is also
necessary for the production and modulation
of melatonin, which helps regulate dopamine
function (Sandyk 1990; Chen et al. 1999), which
is widely believed to be a key factor in atten-
tion-deficit/hyperactivity disorder (ADHD) and
its treatment. In fact, Sandyk (1990) hypothe-
sized that parasympathomimetic stimulants,
at least amphetamine, work in ADHD partly
through their effects on melatonin.
Although cellular mechanisms of zinc efflux
and influx into brain cells are largely unknown, a
zinc transporter has been identified in plasma
membrane vesicles isolated from rat brain
(Colvin 1998). Most of the zinc in the brain, ex-
cept for the ionic zinc in synaptic vesicles, is
bound tightly to proteins. As with other body tis-
sues, much of the zinc in the brain is bound to
metallothionein (Prasad 1993). Metallothionein I
and II are structurally similar, low-weight pro-
teins that seem important in drawing zinc into
the cells and in free-radical scavenging (Prasad
1993; Disilvestro and Cousins 1984). Both the
synthesis and degradation of metallothionein
are very sensitive to zinc status (Prasad 1993,
DiSilvestro and Carlson 1994; DiSilvestro and
Cousins 1984; Thomas et al. 1992). The Brain con-
tains not only metallothionein I and II, but also
has a brain-specific metallothionein III (Zheng
1998). Although there is much more to be
learned, it seems certain that brain function is in-
14104C11.pgs 9/16/05 1:31 PM Page 620

fluenced by this protein. For example, transgenic
knock-out mice that lack the metallothionein III
gene are highly sensitive to kainate-induced
seizures (Zheng 1998; Takeda et al. 2003).
The relation to brain and other central ner-
vous system (CNS) functions is also suggested
by the effects of zinc deficiency. Some evidence
from both animal and human studies suggests
that zinc deficiency may affect cognitive devel-
opment, though the mechanisms remain un-
clear (Bhatnagar and Taneja 2001). Postnatal
moderate zinc deficiency in rats has demon-
strated a number of brain effects, including
impaired learned behavior and impaired cell
maturation (Takeda et al. 2000; Yeiser et al.
2002). Chinese children with marginally defi-
cient serum zinc levels improved neuropsy-
chologic performance and growth upon zinc
repletion, especially when accompanied by
other micronutrients (Sandstead et al. 1998).
There are also sensory and behavioral re-
sponses to dietary zinc alterations. For exam-
ple, low food intake is a common finding in
even marginally deficient rats (DiSilvestro et
al. 1994). Low taste and smell sensitivity in
zinc deficiency is well established in humans,
though the degree of zinc deficiency needed to
impair taste and smell is unclear (Alpers,
1994). Thus, zinc can influence brain and other
CNS functions through a variety of mecha-
nisms, and zinc deficiency can have detrimen-
tal effects on brain function.
Zinc deficiency has been identified in children
from many parts of the world, especially in
newly developing countries (Hambidge 2000;
Prasad 1996). In the United States, severe zinc
deficiency does not seem common among
healthy children. However, a more subtle defi-
ciency state may be. This state, sometimes
called marginal zinc deficiency, has been identi-
fied by a number of studies, including studies
of children from middle-income families
(Hambidge 2000; Prasad 1996). Marginal zinc
deficiency is also generally noted in nutritional
texts (e.g., Wardlaw et al. 2004). Although its
prevalence has not yet been studied, it is be-
lieved to be widespread. Diagnosis, so far, has
been based on slow growth, low serum zinc
values, and low hair-zinc values. All of these
are reversed by increased zinc intake.
ZINC IN ADHD 621
Frank zinc deficiency shows obvious physi-
cal signs of slowed growth, which might be
considered analogous to scurvy from vitamin
C deficiency. With increased knowledge, we
now realize that somewhat higher levels of vit-
amin C may be optimal for more subtle func-
tions, such as antioxidant effects. Analogously,
marginal levels of zinc nutrition that do not re-
sult in frank physical signs might be subopti-
mal for brain physiology (e.g., Golub et al.
1996). A reverse analogy is lead toxicity, which
formerly was diagnosed at levels above
50 mcg/dL, then to 20 mcg/dL, but with in-
creased knowledge of more subtle cognitive
symptoms, the threshold was lowered to
10 mcg/dL by the Centers for Disease Control
and Prevention (CDC) in 1991, and some ex-
perts now recommend single digits as the
threshold (David et al. 1977; Kahn et al. 1995). A
large-scale comparison of dietary data to rec-
ommended zinc intake suggests a pattern of
marginally low intake in many people in the
United States, including children (Briefel et al.
2000). Other, smaller dietary surveys also
show such a pattern (Prasad 1993). This situa-
tion is likely not much improved by the intake
of most multivitamin and mineral supple-
ments, which typically use zinc oxide, which is
not a well-absorbed form of zinc (Prasad et al.
1993; Anonymous 1994).
Although moderately low zinc intake can be
one factor in marginal zinc deficiency in U.S.
children, other poorly identified factors could
also play a role (Hambidge 2000). One such
factor could be poor absorption. Acrodermati-
tis enteropathica is a recessive genetic disorder,
in which zinc is poorly absorbed because of a
defective transporter and which can be success-
fully treated by zinc supplementation (e.g.,
Perafan-Riveros 2002). It is not known whether
the heterozygous condition might have mild
impairment of zinc absorption, but the defec-
tive allele is believed rare and seems unlikely
to contribute significantly to widespread mar-
ginal zinc deficiency or to a disorder as com-
mon as ADHD. A potentially more common
cause of poor absorption could be a defect in
the production of prostaglandins E
2
and F
2
,
which are necessary for zinc absorption (Song
and Adham 1980). Yet another factor could be
14104C11.pgs 9/16/05 1:31 PM Page 621

zinc-wasting metabolism, possibly precipitated
by food additives or other ingested or environ-
mental chemicals (Ward et al. 1990). Another
possibility could be drug-induced effects on
zinc; zinc intake could be just adequate enough
for usual needs but not high enough for in-
creased needs induced by drug action.
State of art in measuring zinc deficiency
One difficulty in pinpointing the scope of
marginal zinc deficiency in the United States,
as well as identifying negative effects of drugs
on zinc status, has been the difficulty of assess-
ing bodily stores of zinc. Plasma or serum zinc
has been the traditional means of assessing
zinc status (Sandstead and Alcock 1997;
Thompson 1991; Prasad 1993). Values from
serum and plasma are virtually identical
(within the limits of lab error) and are consid-
ered interchangeable (e.g., English and Ham-
bidge 1988). Low values can occur with severe
or even marginal zinc deficiency and have di-
agnostic value. Nonetheless, this approach has
two major limitations: (1) plasma zinc is not al-
ways sensitive to small changes in chronic zinc
status (Thompson 1991; Bales et al. 1994); and
(2) plasma/serum zinc values are affected by
inflammation, other physiologic stress, and
even by recent meals (Sandstead and Alcock
1997; Thompson 1991; Prasad 1993). Therefore,
zinc investigators often measure zinc in sev-
eral different types of specimen to get a more
complete picture, such as serum, cells, hair,
urine, and even nails. Rates of marginal defi-
ciency, based on a single tissue assay, might be
considered a lower-bound estimate.
Two other measures of zinc status have re-
cently been found to be useful. One such mea-
sure is serum activity of zinc metalloenzyme
plasma 5-nucleotidase, which has the advan-
tage of being sensitive to very small changes in
zinc status. For example, Bales et al. (1994)
have found that these activities respond to rel-
atively small changes in zinc intake, over just
2 weeks or less, in human subjects, even in the
absence of a change in plasma zinc. In addi-
tion, 5-nucleotidase activities are low in
mildly zinc-deficient rats (DiSilvestro RA, un-
published results), and extremely low in Type
II diabetic subjects (Blostein-Fujii et al. 1997), a
group prone to zinc deficiency (Moutschen et
al. 1992). Activities rise in Type II diabetic
women after zinc supplementation (Blostein-
Fujii et al. 1997).
Another good measure for the assessment of
marginal zinc status is erythrocyte metallo-
thionein. Values have been depressed by exper-
imental moderately low zinc diets in human
volunteers (Grider et al. 1990; Thomas et al,
1992). A previous study showed that this pa-
rameter does not respond as quickly to mild
zinc deficiency and repletion as does plasma
5-nucleotidase activities (Bales et al. 1994).
However, this actually offers one advantage
over the use of plasma 5-nucleotidase activi-
ties alone to assess zinc status. Metallothionein
values are especially useful for assessing long-
term zinc status (Thompson 1991; Grider et al.
1990; Thomas et al. 1992). This is because val-
ues are not subject to short-term fluxes; a high
zinc meal the day before blood sampling will
not change the values.
Zinc in ADHD
Several data suggest that the marginal zinc
deficiency described above may be more con-
centrated in the ADHD population—or, stated
conversely, that the ADHD population may
have a higher prevalence of marginal zinc defi-
ciency. Both animal data (e.g., Halas and Sand-
stead 1975; Sandstead et al. 1977; Golub et al.
1996) and human findings suggest the involve-
ment of zinc deficiency in ADHD symptoms.
Studying moderately zinc-deprived monkeys,
Golub et al. (1996) reported attentional impair-
ment at levels that did not cause growth re-
tardation. They concluded that activity and
attention can be affected during the early stages
of zinc deprivation before growth retardation
results. Human zinc deficiency syndrome in-
cludes concentration impairment and jitters
(Aggett and Harries 1979), and zinc deficiency
can delay cognitive development (Black 1998).
In diagnosed ADHD, Kozielec et al. (1994) in
Poland reported serum zinc significantly (p <
0.001) deficient, compared to controls. Bekaroglu
et al. (1996) in Turkey reported mean serum
zinc of 60.6 ± 9.9 mcg/dL in 33 boys and 15
622 ARNOLD AND DISILVESTRO
14104C11.pgs 9/16/05 1:31 PM Page 622

girls with ADHD, compared to 105.8 ± 13.2
mcg/dL in healthy volunteers (30 boys and 15
girls). Toren et al. (1996), in Israel, reported sig-
nificantly lower serum zinc levels and more
variance in 39 boys and 4 girls 6–16 years of
age with ADHD than in a control group of 28
age-matched healthy controls; 30% of ADHD
subjects were below the control range. In an-
other Polish study, Starobrat-Hermelin (1998)
found a high rate of magnesium, zinc, iron,
copper, and calcium deficiencies in 116 chil-
dren with ADHD on the basis of serum, red
cell, and hair analyses. Hair zinc was lower in
ADHD with comorbid oppositional-defiant or
conduct disorder than in ADHD alone or with
anxiety. Arnold et al. (1990) reported that 18
children with Diagnostic and Statistical Manual
of Mental Disorders, 3rd edition, revised (DSM-
III-R) ADHD had 30% lower 24-hour urine
zinc than 7 normal controls, suggesting either
lower dietary intake or poorer absorption rather
than zinc-wasting metabolism. In a companion
paper (Arnold et al., 2005), we report on a nega-
tive correlation of serum zinc with parent- and
teacher-rated inattentive symptoms (r = 45,
p = 0.004). Bekaroglu et al. (1996) concluded,
“ . . . zinc deficiency may play a role in ae-
tiopathogenesis of ADHD.” Sandyk (1990)
suggests that the biochemical mechanism may
be via effects on melatonin, which, he says,
regulates dopamine function, which is known
to be implicated in ADHD. Another possibility
is that it may depend on the ionic zinc normally
in the synaptic cleft (15% of brain zinc). Rates
of marginal deficiency, based on a single tissue
assay, might be considered a lower-bound esti-
mate; additional assays using plasma 5-
nucleotidase (Bales et al. 1994) and erythrocyte
metallothionein (Thompson 1991; Grider et al.
1990; Thomas et al. 1992) should discover more
subtle marginal deficiency states.
Interaction of zinc with synthetic chemicals
There is a possibility of the exacerbation of
marginal zinc deficiency by drug or other
chemical interactions. Ward et al. (1990) in the
United Kingdom found significantly lower
zinc in 20 hyperactive boys, compared to 20
age-matched controls in urine (p < 0.001, hair
(p < 0.001), serum (p < 0.01), 24-hour urine (p <
0.01), and nails (p < 0.01). When 10 hyperactive
boys and 10 age-matched controls from that
sample were challenged with tartrazine-con-
taining commercial beverages, serum and saliva
zinc decreased while urine zinc increased in
the hyperactive but not in the control boys,
suggesting zinc wasting from the food-dye
challenge. In a larger study, Ward (1997) found
low zinc and iron in a sample of 486 hyperac-
tive children, compared to 172 normal controls.
When 47 of these subjects, with a parent-re-
ported behavioral reaction to food dye, were
challenged with 50 mg of dye, their serum lev-
els of zinc went down and urine levels went
up, compared to age- and gender-matched
normal controls. In both studies, the changes
in zinc levels were associated with behavioral
deterioration. Thus, the 5%–10% of children
with ADHD who seem sensitive to dye or other
food components may metabolically waste
some of their zinc under chemical stress, exac-
erbating their already marginal status. These
could constitute one subgroup with ADHD
and marginal zinc.
Possible effects on drug response
Some evidence suggests that optimal stimu-
lant response may depend on adequate zinc
nutrition. Arnold et al. (1990) reported a signif-
icant correlation of baseline hair zinc with
placebo-controlled d-amphetamine response on
parent- and teacher-rated Conners hyperactiv-
ity index and hyperactivity factor (r = 0.52 to
0.61; p = 0.02 to 0.047, two-tailed) in 18 boys
6–12 years of age with ADHD. The same out-
come variables also correlated nonsignificantly
at r = 0.30 to 0.45 with 24-hour urine zinc. In a
reanalysis of the same data (Arnold et al. 2000),
a pediatrician familiar with zinc assessments
blindly categorized the 18 subjects as having
good zinc nutrition (n = 5), borderline zinc (n =
5), or mild or marginal zinc deficiency (n = 8)
on the basis of hair, urine, and red-cell zinc
levels. The deficiency was mild and not clini-
cally evident and was picked up only by the
tissue tests. The placebo-controlled ampheta-
mine effects in the three zinc-nutrition groups
on teacher ratings seemed associated linearly
ZINC IN ADHD 623
14104C11.pgs 9/16/05 1:31 PM Page 623

or asymptotically with the level of zinc nutri-
tion. The placebo-controlled effect size (Cohen’s
d, difference between active-drug and placebo
means divided by SD) of amphetamine on the
Conners 10-item Hyperactivity Index was 1.37
in the presence of adequate zinc nutrition but
only 0.55 in the presence of mild or marginal
zinc deficiency, a difference of 0.82 (large) in
the effect size with and without mild zinc defi-
ciency. The “mildly zinc-deficient group” con-
stituted 44% of that sample (8 of 18).
Akhondzadeh et al. (2004) examined zinc
supplementation of methylphenidate response
in Iranian children with ADHD. Forty-four
children, 5–11 years of age, treated with
methylphenidate 1 mg/kg/day in two divided
doses, were randomly assigned to zinc sulfate
60 mg/day (22 children) versus placebo (22
children) for 6 weeks. On the DuPaul ADHD
rating scale, those assigned to MPH plus sup-
plemental zinc improved significantly more
than those assigned to MPH plus placebo by
parent (p < 0.05) and teacher (p = 0.04) ratings.
Because of differences in endemic diet, it is not
clear how applicable such Mid-Eastern find-
ings are to American children with ADHD.
Randomized clinical
trial of zinc monotherapy
Bilici et al. (2004) reported the only published
trial of zinc supplementation alone as a treatment
for ADHD, in a Turkish sample. It was flawed
by a very high dropout rate (207 of 400) after
randomization, as well as during a lead-in
phase: Only 193 of the 618 consented eligible
subjects completed the trial. Those random-
ized to zinc supplementation received 150 mg
of zinc sulfate/day for 12 weeks, a rather high
dose, above the recommended upper tolerable
limit. Instruments were either developed by the
investigators (52-item clinician-rated ADHD
scale on a 0–2 metric) or translated or adapted
from English (Conners 28-item teacher and
DuPaul 14-item parent rating). Thus, the out-
come variables may not be comparable to other
ADHD trials, thereby complicating an interpre-
tation. The unusual quasiepidemiologic sam-
ple recruitment was both a strength and a
weakness, raising questions about clinical rep-
resentativeness, which was further compro-
mized by excluding any child with comorbid-
ity (even learning disorder and enuresis) or
who was taking medicine. Nevertheless, after
12 weeks of treatment, the 46-item clinician-
rated ADHD scale showed that the supple-
mented group (n = 95 completers, 202 total)
improved by 25.4 ± 9.7 (an approximate 1/3
decrease in score) compared to the placebo
group (n = 98 completers, 198 total), which
improved by only 12.7 ± 5.4 (p = 0.002). The
significant difference was a result of the hyper-
activity, impulsivity, and impaired-socialization
subscales, with no effect on the attention-deficit
subscale. Those who were older and had higher
body mass index and lower zinc and essential
fatty-acid levels were most likely to benefit.
Not all outcome measures were significant, and,
unfortunately, it is not clear whether the cited
data are for completers or totals. The report
states, in one place, that the completers were
used for the analysis, but in another place, it
states that it was an intention-to-treat analysis
with last observation carried forward. Thus,
this study is promising but inconclusive.
Cautions and limitations
The literature reviewed in this paper do not
prove that zinc deficiency is “the cause of
ADHD” nor that zinc supplementation would
be an effective treatment for ADHD. A number
of alternative explanations for the findings
could be postulated. Zinc levels could just be
markers for some other cause of ADHD, in-
cluding poor general nutrition, rather than
having a direct causative role. For example,
they could be markers of essential fatty-acid
deficiency or imbalance because series 2
prostaglandins, derived from polyunsaturated
fatty acids, are believed to be necessary for
zinc absorption (Song and Adham 1980). They
could even be markers of general malnutrition
Wesnes et al (2003) reported that a whole-grain
cereal breakfast prevented the deterioration of
schoolchild attention and memory over the
morning that was found in no-breakfast and
glucose-drink conditions. Furthermore, zinc
levels could be markers of a gene that results
in deficient zinc absorption or metabolism and
624 ARNOLD AND DISILVESTRO
14104C11.pgs 9/16/05 1:31 PM Page 624

also affects attention but not necessarily through
the zinc deficiency. Finally, they could be mark-
ers for inflammation—either infection, trauma,
or allergy. Zinc is reduced in acute inflamma-
tion (Shenkin 1995). Hagerman and Falken-
stein (1987) reported twice the rate of otitis
media in hyperactive children compared to con-
trols, suggesting either immune problems or
greater exposure to infectious agents. Infectious
toxins, allergies or sensitivities, and repeated
trauma from the increased accident rate in
ADHD could all contribute to an association of
low zinc levels with ADHD without making low
zinc the cause of ADHD. In other words, the
low zinc could be an effect rather than a cause.
Yet another caution for American clinicians is
that most of the published reports regarding
zinc in ADHD involved samples other than
American, raising questions about dietary dif-
ferences and endemic regional deficiencies. Spe-
cifically, of nine published samples, two were
Polish, two Turkish, one Iranian, one Israeli, two
English, and only one American, with an addi-
tional American sample being published in a
companion article (Arnold et al, 2005). This also
raises questions about how similar the diagnos-
tic procedures were to U.S. practice.
As a final caution, we should note that, al-
though reasonably safe in RDA amounts, high
doses can be toxic or at least cause side effects.
At 50–150 mg/day, zinc can cause gastroin-
testinal upset and headache, and doses of
300 mg/day can suppress immune function.
Doses of 60 mg/day may be enough to impair
copper status in some adults (Prasad 1993;
Wardlaw et al 2004); presumably, lower doses
may cause this problem in children. The Turk-
ish RCT (Bilici et al, 2004) used approximately
40 mg of zinc per day (150 mg ZnSO
4
), and it is
possible that gastrointestinal side effects may
have accounted for some of the high dropout
rate (but the dropout rates were about the
same for ZnSO
4
and placebo).
CONCLUSION
The literature reviewed in this paper sug-
gests the following: In addition to the animal
data suggesting a link between zinc and
ADHD-like symptoms, there are preliminary
human data suggesting that: (1) many children
with ADHD have lower-than-average zinc lev-
els compared to both lab reference range and
to normal control children; (2) zinc nutritional
state may interact with ingested chemicals
(drug or other), and (3) two Mid-Eastern trials
showed greater improvement with zinc than
with placebo.
These findings lead naturally to hypotheses
that improving zinc nutritional status might
improve the response to stimulants or might
even have a beneficial effect independent of
stimulants, or at least might lower the stimulant
dose needed for benefit. These remain largely
untested hypotheses at present (with the excep-
tion of the Turkish and Iranian trials) but de-
serve research attention because of the obvious
potential public health importance. The data
available at this time do not prove that low zinc
causes ADHD nor make zinc supplementation
an established treatment.
Possible foci for future research should in-
clude randomized clinical trials of zinc in
well-diagnosed, broadly representative ADHD
samples, both as monotherapy and as adjunct
to open stimulant treatment; relative effect on
attentional, hyperactive, and impulsive symp-
toms; effect on comorbid disorders, especially
depression, for which there is also evidence of
zinc involvement; relationship of zinc to other
nutrients in ADHD; and effect on zinc tissue
levels of food additives and drugs, including
stimulant drugs.
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Address reprint requests to:
L. Eugene Arnold, M.D.
Department of Psychiatry
Ohio State University
479 S. Galena Road
Sunbury, OH 43074
E-mail: arnold6@osu.edu
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