Clinical Nutrition 39 (2020) 1345e1353

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Review

Dietary vs. pharmacological doses of zinc: A clinical review

Heitor O. Santos a, *, Filipe J. Teixeira b, Brad J. Schoenfeld c
a
School of Medicine, Federal University of Uberlandia (UFU), Uberlandia, Minas Gerais, Brazil
b
fona de Humanidades e Tecnologias, Campo Grande 376, 1749-024
CBIOS (Research Center for Biosciences & Health Technologies), Universidade Luso
Lisboa, Portugal
c
Health Sciences Department, CUNY Lehman College, Bronx, NY, USA

a r t i c l e i n f o s u m m a r y

Article history: Zinc deficiency has a global impact on health in both developing and developed countries, especially
Received 18 May 2019 among children and the elderly. By modulating anti-inflammatory and antioxidant pathways, zinc
Accepted 27 June 2019 supplementation is recommended for the treatment of several ailments, such as liver disease, male
hypogonadism, cancers, heart disease (e.g. dyslipidemia) and central nervous system disorders; however,
Keywords: the topic of dietary vs. pharmacological doses of zinc remains controversial. This paper provides a
Antioxidant supplements
detailed critical review of the effects of zinc supplementation in medicinal doses (i.e. >40 mg/d of
Immunonutrition
elemental zinc) on human health. We further highlight the difficulty in achieving a therapeutic dose of
Hypogonadism
Zinc supplementation
zinc from foodstuffs.
ZMA © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction
Epidemiologically, zinc status is a subject of health concern in
both developing and developed countries, particularly among
young children and elderly individuals [1e3]. Zinc is present in over
300 enzymes and numerous transcription factors [4]. As a signaling
molecule and being involved in biological processes of metal-
loenzymes, zinc is a master regulator of gene expression and bio-
logical homeostasis by virtue of its actions on DNA, RNA and protein
synthesis during cell division [5].
Zinc is an essential mineral for preventing the formation and
reactive response of free radicals, which are unstable atoms that can
damage cells and have been proposed to be associated with the
progression of chronic and degenerative diseases [6,7]. Thus, zinc
administration has been used to treat several diseases, mainly due to
its potential ability to attenuate free radical accumulation, a phe-
nomenon generally described as oxidative stress [8]. As explained in
our recent literature review [9], medical doses of oral zinc (i.e. > 40 mg
of elemental zinc) are beneficial in the treatment of male hypo-
gonadism, via improving the production and action of testosterone (T)
and sperm cells. In addition to its role in alleviating hypogonadism,
zinc has shown promise as a remedy for several other diseases using
* Corresponding author. Av. Para, nº1720, 2U Block, Umuarama Campus 38400-
902, Uberlandia, MG, Brazil.
E-mail address: heitoroliveirasantos@gmail.com (H.O. Santos).
both medical doses and foodstuffs [10e13]. However, critical insight
regarding the effects of dietary vs. medicinal doses of zinc is lacking.
Therefore, this review aims to provide an overview regarding the
posology of zinc and its variability from both foodstuffs and supple-
ments, and attempts to draw inferences for practical application.
2. Free and bound zinc
The tissue distribution of zinc varies in both free and bound
forms, thus conferring different effects on enzymes, i.e. zinc fingers
and metallothionein [14]. The free (bioavailable, rapidly
exchangeable or labile) zinc ion represents a weak-binding fraction
capable of rapidly inducing ligand exchanges [15]. Magnetic reso-
nance imaging and optical techniques have been reported to detect
free zinc in cells and tissues but are seldomly used in medical
practice for this purpose [14].
Zinc ions have a structural role across 10% of all mammalian
proteins [16]. Zinc-finger proteins are one of the most abundant
groups of proteins and have a wide range of molecular roles in
health and disease states [17]. Zinc-finger proteins are capable of
modulating DNA, RNA, and other proteins [17]. More specifically,
zinc-finger proteins regulate signal transduction, cell differentia-
tion or proliferation, cell adhesion, and transcription [17,18].
Moreover, zinc maintains the enzymatic structure at the active site
of CuZn superoxide dismutase [18].
In mammalian blood plasma, zinc is bound to albumin to be
distributed systemically [19]. However, the structure of the binding

https://doi.org/10.1016/j.clnu.2019.06.024
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1346 H.O. Santos et al. / Clinical Nutrition 39 (2020) 1345e1353
site has not been fully elucidated other than the large albumin
binding capacity for zinc [19]. Additionally, given that there is a
relationship between the zinc binding capacity and drugs, metab-
olites, and xenobiotics, this would be a useful area of further
research in order to deal with a target control of zinc balance [19].
3. Zinc biomarkers
Among zinc assessments from clinical samples, Flame Atomic
Absorption (FAAS) and Inductively Coupled Plasma Atomic Emis-
sion Spectrometry (ICP-AES) are validated methods to measure zinc
in serum or urine [20,21]. Colorimetric assays may also be used,
however they require larger volume samples and are more prone to
matrix interference [20]. ICP-AES or Inductively Coupled Plasma
Mass Spectromet (ICP-MS) are the most efficient techniques for
multielement analysis of biological samples [20]. Regarding small
samples or those with lower zinc concentrations, ETAAS is the
recommended analytical method [20].
Clinically, the BOND (Biomarkers of Nutrition for Development)
Zinc Expert Panel recommends plasma zinc concentration as the
main biomarker [18]. Although plasma zinc concentration seems to
be a modest biomarker, it has satisfactory supporting global cutoffs.
Plasma zinc concentration is a useful biomarker to assess delivery
and absorption of zinc supplements in children [22]. This is
concluded from daily administration of up to 10 mg of additional
zinc during infancy, which leads to increases in plasma zinc con-
centration and reduces zinc deficiency risk [23]. Moreover, plasma
zinc is deemed a relevant biomarker for adult diseases related to
altered zinc status [10,13].
Furthermore, different classes of leukocytes are dependent on
zinc pertaining ubiquitous defense mechanisms of innate immu-
nity [24]. Prasad et al. observed that zinc gluconate supplementa-
tion increased leukocyte and granulocyte zinc stores, but did not
increase serum zinc concentrations [25]. Thus, it may be speculated
that analyzing zinc in leukocytes is of further interest with respect
to biochemical surveillance. To the best of our knowledge, the
analysis of zinc concentration in leukocytes is of little relevance in
clinical practice, albeit being reported with higher sensitivity. In
addition to the analysis in leukocytes, zinc status in erythrocytes
has gained attention for screening iron deficiency through zinc
protoporphyrin [26]. Intriguingly, the BOND Zinc Expert Panel does
not propose erythrocyte and leukocyte zinc as biomarkers to assess
zinc intake or its status [18]. Moreover, measurements from urinary
and hair zinc are deemed as promising biomarkers to screen zinc
balance [18,27]. Nail zinc assessments, in turn, are emerging as a
zinc biomarker but there is a paucity of research to support its
association with zinc intake [18].
Taken together, blood count, serum copper, and iron status
should be considered when prescribing safe supplemental doses of
zinc, although the current body of evidence seems to suggest that
zinc administration may be benign in this regard due to its good
safety margin and profile [28e30].
4. Children
The current research emphasizes oral zinc supplementation to
improve growth in young children and as a public health strategy in
areas of endemic deficiencies [1,2]. Zinc supplementation may be
useful for treating acute gastroenteritis and diarrhea in malnour-
ished children, particularly in developing countries [31]. In these
regions, elevated rates of zinc deficiency are prevalent, leading to
underweight and/or stunted growth [22,32]. Furthermore, zinc
supplementation has been proposed as a remedy to reduce the
frequency and severity of diarrhea, with some studies also sug-
gesting a positive effect on childhood respiratory illnesses [33].
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Taken together, low dose zinc supplementation (up to 10 mg/d)
may be advantageous in children from 6 to 23 months [23,32].
5. Adults
Next to iron, zinc is the second most abundant major trace
mineral in the human body, with the typical 70 kg adult male
storing 2.3 g of zinc [34]. These stores are contained in numerous
body compartments, including important organs (Fig. 1); however,
irrespective of the body distribution, zinc displays important
physiological actions even in organs and tissues where stores are
low. For instance, the majority of zinc stores are located within
skeletal muscle [35]; however, zinc supplementation is not deemed
of primary importance to support musculoskeletal function. On the
other hand, seminal zinc contributes minimally to the total body
zinc stores; for each milliliter of human seminal plasma, the mean
zinc concentration ranges from only 0.08e0.27 mg. That said, these
relatively small amounts are fundamental for sperm cell function
[36]. In fact, medical dosages of zinc are deemed useful to improve
sperm parameters and to maintain normal physiological T con-
centration status [9].
The antioxidant actions of zinc occur in an indirect fashion, since
free radicals are molecules that contain one or more unpaired
electrons, and zinc does not hinder the free radical reaction [6]. Zinc
modulates the anti-inflammatory and antioxidant status in several
bodily organs (Fig. 2). As outlined in the following sections, zinc
plays a crucial role in positively mediating physiopathological
pathways in heart disease, cancer, diabetes and immune system
disorders. Thus, a medicinal dosage of zinc may be a valid clinical
approach.
5.1. Liver diseases
Individuals with liver disease commonly suffer from zinc defi-
ciency and an altered metabolism of this mineral [41]. Those
afflicted often have impaired nitrogen metabolism in which zinc is
paramount for the hepatic synthesis of proteins [40]. Additionally,
blood zinc concentrations may be a surrogate biomarker of protein
balance in disease states [42]. Zinc may modulate short and long
half-life circulatory proteins, such as C-reactive protein (CRP) and
albumin, whose serum half-life are estimated to be 19 h and 3
weeks, respectively [43,44].
Serum levels of zinc in chronic liver disease patients correlate
with elevated concentrations of CRP, malondialdehyde and nitric
oxide, as well as being frequently used as an indicator of the in-
flammatory status and destruction of the liver parenchyma cells
[45]. Furthermore, zinc deficiency is strongly associated with
hypoalbuminemia in cirrhosis patients [46], who display substan-
tial zinc excretion in urine due to severe musculoskeletal catabo-
lism and diuretic therapy [47]. Additionally, zinc deficiency has
been well documented in liver disease patients with a history of
alcohol abuse, whose endotoxemia induced by ethanol intake
hinders zinc absorption [48,49].
5.2. Dyslipidemia
High doses of zinc are postulated to have a detrimental effect on
high density lipoprotein (HDL) concentrations. A meta-analysis by
Foster et al. [50] found that a mean dose of elemental zinc (58 mg/
d) caused HDL concentrations to decrease by 3.9 mg/dl (equivalent
to a 7% decrease from baseline). Conversely, another meta-analysis
reported that 15e240 mg/day of elemental zinc did not signifi-
cantly affect HDL concentrations when all studies were pooled;
however, subanalyses revealed that zinc significantly improved
HDL status in non-healthy participants while reducing HDL
 H.O. Santos et al. / Clinical Nutrition 39 (2020) 1345e1353 1347

Fig. 1. Zinc distribution in the main body compartments of this mineral. Adapted from King et al., 2000 [35].

Fig. 2. Brief description of the anti-inflammatory and antioxidant roles of zinc in several organs. Overall, the cellular zinc status is important to decrease ROS and NF-kB activation
[37]. Subsequently, expression and production of pro-inflammatory cytokines and enzymes that mediate inflammatory process are also decreased [37]. Inflammatory responses are
hindered, as well. For instance, this basic pathway is important for a proper function of the liver, heart, testis and brain. Hepatocyte, cardiomyocyte, endothelial cells, spermatozoon
and neuron are cells quite sensible to redox state changes and inflammatory aspects by which this pathway may further contribute to ensue physiopathological processes [37e40].
Legend: A20, A20 zinc finger protein; COX-2, ciclo-oxigenase-2; IKK, I kappa B kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; MT, metallothionein; NADPH, nico-
tinamide adenine dinucleotide phosphate; NF-kB, factor nuclear kappa B; NIK, NF-kB-inducing kinase; PPAR-a, Peroxisome proliferator-activated receptor alpha; ROS, reactive
oxygen species; SOD, superoxide dismutase; TNF-a, tumor necrosis factor alpha.

concentrations in healthy individuals. Intriguingly, the analysis also
found that zinc supplementation reduced total cholesterol by
10.7 mg/dl and low density lipoprotein (LDL) by 4.8 mg/dl, as well
as decreasing circulating triacyclglycerols by 8.7 mg/dl [11]. A more
recent meta-analysis by Wang et al. failed to observe significant
differences in lipid profile between zinc supplementation versus
control in hemodialysis patients [10]; the elemental zinc doses
ranged from 11 to 100 mg/d and the follow-up ranged from 40 to
360 days within the studies covered in this meta-analysis. As a
whole, the current body of evidence seems equivocal at this point
regarding the effects of zinc on blood lipids. From a cardiovascular
standpoint, it should be noted that mechanistically zinc might exert
its action by inhibiting several pro-inflammatory pathways asso-
ciated with atherosclerosis [37]; the practical implications of these
effects warrant further study.
5.3. Diabetes
In addition to its role in antioxidant defense in diabetic patients,
zinc stimulates the phosphorylation of insulin receptors, thus

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enhancing glucose uptake into the cells [51]. With this regard, zinc
administration may counteract chronic hyperglycemia [52]. In 2012
Jayawardena et al. performed a meta-analysis to investigate the
effect of varying doses of chelated zinc (7.5e660 mg/d) in in-
dividuals afflicted with diabetes mellitus [12]. Insofar as glucose
screening is concerned, the pooled mean difference between zinc
supplemented and placebo groups was:
18 mg/dl for fasting blood
glucose,
35 mg/dl for 2-h post-prandial blood glucose,
0.54% for
HbA1c; regarding lipid screening:
32 mg/dl for total
cholesterol,
11 mg/dl for low-density lipoprotein cholesterol.
Additionally, the authors also reported a significant reduction in
systolic (2.4%e6.1%) and diastolic (1.3%e7.1%) blood pressure after
zinc supplementation.
In 2019, Wang et al. carried out a meta-analysis in which 32 ran-
domized controlled interventions (n ¼ 1700 subjects) were analyzed,
with 19 and 2 trials being composed of patients with type 2 diabetes
and prediabetes, respectively [53]. Compared with control groups,
zinc-supplementation groups decreased the concentrations of fasting
glucose (
14.15 mg/dl), 2-h postprandial glucose (
36.85 mg/dl),
fasting insulin (
1.82 mU/l), homeostasis model assessment for in-
sulin resistance (
0.73), glycated hemoglobin (
0.55%), and high-
sensitivity C-reactive protein (
1.31 mg/l). Overall, the mean dose
of elemental zinc was 35 mg/d (from 4 to 240 mg/d), with the duration
of zinc administration ranging from 1 to 12 months.
5.4. Hypogonadism
Evidence indicates that 220 mg of zinc sulfate (equivalent to
50 mg of elemental zinc) taken twice daily between 1 and 4 months
is an efficient and safe posology for the treatment of male hypo-
gonadism, with effects purportedly mediated by increasing serum T
concentrations and improving seminal parameters [9]. Both me-
dicinal dosages of zinc as well as dietary zinc play a crucial role in T
status. Prasad et al. observed that zinc deficiency was associated
with a significant decrease in T concentration in healthy men [25].
The researchers submitted four eugonadal young men to a diet with
low zinc (z5 mg/d of zinc) for 20 weeks, which led to a dramatic
decrease in total T from 1150 to 320 ng/dL [25]. After just 8 weeks of
induced dietary zinc deficiency, the total T levels had already
decreased to 720 ng/dL. Although derived from a small sample,
these data provide clinically relevant insights pertaining to the
impact of zinc deficiency on T function.
5.5. Immune system
Zinc has been shown to play an important role in the regulation of
the immune system, particularly T cell-mediated functions [54].
Recent meta-analytic data shows a strong correlation between
decreased levels of zinc (especially in serum and plasma) and auto-
immune diseases [13]. Notwithstanding, aging is associated with
impaired regulation of the immune system [55]. Low zinc status is
commonly reported in elderly people (immunosenescence), which
may hinder resistance to pathogens [56]. Inadequate stores of zinc
might therefore be a risk factor for pneumonia and mortality among
elderly individuals [54]. In a larger (N ¼ 725), randomized, double-
blinded, placebo-controlled intervention study, a supplemental
dose of zinc and selenium (20 mg as zinc sulfate and 100 mg as se-
lenium sulfide) increased the humoral response in institutionalized
elderly patients (aged 65e103 years) after vaccination, which may be
important to reduce morbidity from respiratory tract infections [57].
After, Prasad et al. found that oral zinc gluconate supplementation
(45 mg elemental Zn/d) resulted in a lower incidence of infections,
release of tumor necrosis factor alpha (TNF-a) and oxidative stress
markers in elderly subjects compared to placebo over a 12-month
study period [58].
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Regarding zinc support in immunosuppression scenarios and
gastroenteritis, its supplementation could be beneficial to HIV-
infected patients, since this population is commonly afflicted by
these conditions. In a long-term (18-month) study, zinc supple-
mentation (12 mg of elemental zinc for women and 15 mg for men)
delayed immunological suppression and decreased diarrhea over
time in HIV-positive adults with poor viral control [59]. Alterna-
tively, a medicinal zinc sulfate dosage (50 mg of elemental zinc
twice daily) for 14 days had no significant effect on the duration or
remission of diarrhea in HIV-infected adults [60].
5.6. Cancer and tumor
Of note, Prasad et al. proposed zinc supplementation as an
efficacious chemopreventive agent for some cancers [61]. Since
several cancers are preceded by chronic inflammation and oxida-
tive stress, zinc conceivably could act upon these pathways,
mediating immune cells and attenuating the tumorigenesis
response from nuclear factor kappa B (NF-kB) activation [61].
Indeed, mechanistically there is a link between cancer and
deficiency, excess and imbalances of zinc and its transporters [62].
So much so that, decreased serum zinc ion levels have been found
in subjects with lung, head and neck, breast, liver, lung and prostate
tumors [62]. However, uncertainty still exists regarding the best
approach of zinc administration in cancer treatments. For instance,
although reduced intracellular status is a pivotal process in prostate
carcinogenesis, Kratochvilova et al. showed that reestablishing
intracellular zinc concentrations in prostatic tumors may lead to
higher level of aggressiveness and resistance by virtue of pluripo-
tency activation- and stemness-associated with some regulatory
molecules [63]. On the other hand, Milosavljevic et al. proposed the
use of a novel anticancer drug based on a zinc-Schiff base-Novicidin
complex to deliver zinc to prostate cells [64]. Hence further
research and larger clinical trials with zinc supplementation are
required to further clarify the zinc-oncology relationship.
5.7. Depression
There is evidence that healthy dietary patterns versus con-
sumption of a western-style diet is associated with a decreased and
increased risk for depression, respectively [65,66]. Antioxidant
defense plays a crucial role in attenuating pathways of
biochemically-based disorders thought to be involved in depres-
sion [67]. Accordingly, zinc supplementation may be beneficial
when used as an adjunct to conventional antidepressant drug
therapy for depressive symptoms [68]. In a double-blinded, ran-
domized, placebo-controlled trial, 12 weeks of zinc monotherapy
(30 mg/d elemental zinc) improved mood in overweight or obese
individuals, most likely by increasing serum brain-derived neuro-
trophic factor (BDNF) levels [69]. Moreover, zinc inhibits inflam-
matory responses mediated by microglia cells via upregulation of
zinc-finger A20, which biochemically confers important anti-
depressive effects [70,71].
6. Zinc Magnesium Aspartate (ZMA): the debatable
supplement
Zinc Magnesium Aspartate (ZMA) is a supplement comprised of
zinc, magnesium and vitamin B6. The combination of these com-
pounds are not a matter of concern regarding possible micro-
nutrient imbalances, since the amounts are well within current
Dietary Reference Intakes (DRIs) and below the UL for men and
women [72].
ZMA is commonly promoted as a T booster, mainly due to its
zinc and magnesium content. Some studies have shown that ZMA is
 H.O. Santos et al. / Clinical Nutrition 39 (2020) 1345e1353 1349

ineffective when employed to increase muscle mass and physical
performance [73,74], although pharmacological doses of zinc and
magnesium have not been investigated in this regard. Viewed
collectively, however, even medical doses of these elements appear
unwarranted for musculoskeletal hypertrophy. Morton et al.
showed that regardless of circulating hormone concentrations,
such as T and dihydrotestosterone (DHT), the intramuscular
androgen receptor (AR) content is a major determinant in skeletal
muscle hypertrophy [75]. Thus, the putative effect of medical zinc
or magnesium dosages as a T booster remains unsubstantiated for
hypertrophic benefits, at least in healthy men.
Despite the lack of compelling evidence for increasing muscle
mass, it should be noted that both zinc and magnesium are ele-
ments that play important roles in T activity via decreased systemic
inflammation and sperm motility [76]. Taking into account the
favorable effects of magnesium in this regard, an improved sperm
motility is triggered by the magnesium link with energy meta-
bolism due to adenosine triphosphate (ATP) production. This is a
pathway by which many magnesium-dependent reactions assist
cellular energy production processes, especially motile sperm cell,
where mitochondrial expression is substantial [77].
As a biomarker, magnesium status appears to be an intriguing
tool to assess bone integrity, central nervous system disorders, and
male hypogonadism [78,79]. With respect to health in older men,
serum magnesium concentrations are strongly and independently
associated with total T values [80]. In male subjects with inflam-
matory prostatic fluid, seminal zinc and magnesium are lower than
in men with normal prostatic fluid [81]. A considerable amount of
supplemented magnesium (10 mg/kg/d) increased both free T and
total T levels in sedentary and active men [82]. On the other hand, a
three month placebo-controlled, randomized, clinical pilot trial
involving idiopathic infertile men patients found that magnesium
treatment (3000 mg/day) did not lead to significant improvements
on sperm markers when compared to control [83].
Vitamin B6, or pyridoxine, is a ZMA component deemed impor-
tant for general cell metabolism and physiology, mediating
biochemical reactions (e.g. neurotransmitters) and the endocrino-
logical system [84,85]. Taken together, the three elements
comprising ZMA (zinc, magnesium and vitamin B6) are used alone in
medical dosages and have applicability among diverse populations,
albeit failing to enhance muscle mass and physical performance in
young, healthy individuals [73,74]. Thus, any therapeutic benefits of
ZMA are dependent upon the dose and clinical context.
7. Pharmacological doses vs. dietary sources of zinc
It should be noted that, although fish and yogurt are often rec-
ommended as high-quality sources of zinc, these foodstuffs
represent a small contribution to the total amount of ingested zinc
in elderly populations. A cohort study [88] estimated average zinc
intake among 1545 elderly men to be only 11.5 mg/d, with red
meat, vegetables and cereals reported as the primary dietary
sources of zinc. Also, the average intake of dietary fiber was 17.3 g/d.
Hence, to attain the pharmacological doses of zinc (i.e. zinc amount
greater than UL) through dietary intake alone would require a fiber
intake of z60 g/d in elderly men [72,88], which in turn would likely
cause bowel discomfort [89]. Notwithstanding, appetite decline
and masticatory problems are also frequently reported among
elderly patients, which would make the intake of zinc from food
even more difficult [90].
8. Zinc posology
Although zinc sulfate is a commonly used zinc form, zinc citrate,
gluconate and picolinate may be valid options as well. For instance,
these forms are typically better absorbed than zinc oxide [91,92].
Above all, there is no consensus about the prescription ratio for zinc
when used with anions, thus it should be calculated from the
compounds with known molecular mass [93]. In conjunction with
zinc administration, the intake of protein may positively improve
zinc absorption. The concomitant consumption of whey protein
with zinc is an intriguing strategy [94]. Interestingly, whey protein
supplementation is suitable for complementing daily protein con-
sumption in several conditions for which medicinal doses of zinc
are prescribed, such as in cachexia, sarcopenia, cancer, bone dis-
orders and in wound healing process [95e97].
Zinc is easily found in many pharmaceutical brands added to
other vitamins and minerals [98]. The addition of other vitamins
and minerals to zinc formulas may be harmful due to possible
excessive intakes. For example, supplementing with vitamin C and
E may impair skeletal muscle adaptations in patients undertaking
regimented strength training [99e101]. Thus, caution should be
exerted when prescribing zinc.
9. Side effects
The main side effect associated with high doses of zinc is min-
eral absorption disturbances. Zinc interacts with the absorption of
Table 1
Example of a meal plan based on dietary zinc sources that would exceed the
Tolerable Upper Intake Level (UL).

Pharmacological doses of zinc are equivalent to >40 mg/d of Meal Food source in zinc Serving
elemental zinc for both male and female subjects 19 þ years, Breakfast Whole Chicken Eggs 3 Large
because the Tolerable Upper Intake Level (UL) of zinc for adults is Cheddar Cheese 1 slice
40 mg/d [72]. Overall, pharmacological doses adopted across Oatmeal 1 cup
Cow's Milk 1 cup
studies generally range from 220 mg/d to 660 mg/d of chelated
Lunch Beef, Chuck Eye Roast 1 Large Steak
zinc, having approximately 50 mge150 mg of elemental zinc Rice, Brown, Cooked 1 Cup
[10,11]. As previously mentioned, pharmacological doses of zinc Snack Yogurt, Greek, Plain, Nonfat 1 Container
may vary according to the treatment, and thus should be personally Chia Seeds 2 Tablespoon
Almonds 1 Cup
administered taking into account the specific physiopathology.
Dinner Liver, Castle, Roast 2 Slices
Oral use of pharmacological zinc doses is useful to avoid nutrient Rice, Brown, Cooked 1 Cup
imbalances in the common diet, wherein the Recommended Dietary
Nutrients of concern and overnutrition
Allowance (RDA) for adult men is 11 mg/d and 8 mg/d for women
[72]. For instance, to attain the reported medical doses of zinc from Meal Zinc Fibers Lipids Carbohydrates Protein Calories
(mg) (g) (g) (g) (g) (kcal)
foodstuffs, an excessive intake of total fat, proteins and dietary fiber
would likely occur (see examples in the Tables 1e3). This is true since Breakfast 6.53 14.5 31.84 77.1 50.25 795.96
the main food sources of zinc are meat, oilseeds, seafood and whole Lunch 11.16 3.2 9.15 51.67 32.18 417.75
Snack 6.64 27.7 80.11 48.88 52.25 1125.51
foods. Such an outcome would not only result in a caloric surplus, but Dinner 19.39 3.2 11.98 57.71 51.01 542.7
also an increase in bowel movements due to the high concentration Snack 5.30 17.6 85.01 34.1 31.26 1026.53
of lipids and dietary fiber [86]. Total 49.02 66.2 218.09 269.46 216.95 3908.45

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1350 H.O. Santos et al. / Clinical Nutrition 39 (2020) 1345e1353

Table 2
Amount of zinc per 100 g of foods known to yield a high concentration of zinc and commonly consumed among the American population. Adapted from USDA [87].

Food Zinc (mg) per 100 g in foods Dietary total fiber (g) Total Lipids (g) Carbohydrates Protein (g) Calories (kcal)

Rice, Brown, Cooked 0.71 1.6 0.97 25.58 2.74 123

Oat Bran, Raw 3.11 15.4 7.03 66.22 17.30 246
Peanuts, Raw 2.11 9.5 49.60 15.83 26.15 570
Almonds 3.12 12.5 49.93 21.55 21.15 579
Walnuts 2.61 6.7 65.21 13.71 15.23 654
Chicken, Roosted, Skinless 1.23 0 4.51 0 30.91 173
Beef, Chuck Eye, Roast 9.73 0 8.46 0 26.65 183
Liver, Cattle, Braised 11.23 0 6.26 3.77 28.42 196
Fish, Tilapia, Cooked 0.41 0 2.65 0 26.15 128
Egg, Chicken, Whole, Cooked 1.05 0 10.61 1.12 12.58 155
Milk, Cow, Liquid, Nonfat 0.41 0 0 5.02 3.37 37
Cheese, Cheddar 3.64 0 33.31 3.09 22.87 404
Yogurt, Greek, Plain, Nonfat 0.52 0 0 3.60 10.19 59
Chia, Seeds 4.58 34.4 30.74 42.12 16.54 486

Table 3
Amount of zinc obtained through food intake and resulting in an increase of macronutrients, fiber and calories. Adapted from USDA [87].

Food Serving Zinc (mg) per serving Dietary total fiber (g) Total Lipids (g) Carbohydrates Protein (g) Calories (kcal)

Rice, Brown, Cooked 1 cup, 202 g 1.43 3.2 1.96 51.67 5.53 248
Oat Bran, Raw 1 cup, 94 g 2.92 14.5 6.61 62.25 16.26 231
Peanuts, Raw 1 cup, 146 g 3.10 13.9 72.42 23.11 38.18 832
Almonds 1 cup, 143 g 4.46 17.9 71.40 30.82 30.24 828
Walnuts 1 cup, 117 g 3.05 7.8 76.30 16.04 17.82 765
Chicken, Roosted, Skinless 1 cup, 140 g 1.72 0 6.31 0 43.27 242
Beef, Chuck Eye, Roast 1 large steak, 100 g 9.73 0 8.46 0 26.65 183
Liver, Cattle, Braised 2 slices, 160 g 17.96 0 10.02 6.04 45.48 196
Fish, Tilapia, Cooked 2 fillets, 174 g 0.72 0 4.62 0 45.5 222
Egg, Chicken, Whole, Cooked 1 large, 50 g 0.53 0 5.30 0.56 6.29 78
Milk, Cow, Liquid, Nonfat 1 cup, 245 g 1 0 0 12.30 8.75 91
Cheese, Cheddar 1 slice, 28 g 1.02 0 9.33 0.87 8.75 91
Yogurt, Greek, Plain, Nonfat 1 container, 170 g 0.88 0 0 6.12 17.32 94
Chia, Seeds ~2 tablespoon, 28 g 1.30 34.4 30.74 42.12 16.54 486

calcium, manganese, copper, selenium and iron (mainly heme
iron). Among these minerals, the most serious interactions are with
copper and iron [102e104]. Iron supplementation should be avoi-
ded during zinc therapy [105] although dietary iron has little
interference with zinc absorption [106]. Copper deficiency, sec-
ondary to the oral use of high doses of zinc, may arise from over-
abundance conditions, e.g. >50 mg/d of elemental zinc for >10
months [107e109]. However, shorter periods (6 weeks) using
50 mg of elemental zinc per day were not found to cause hypo-
cupremia in healthy individuals [110].
Symptoms such as nausea, vomiting, epigastric pain, lethargy
and fatigue may occur by virtue of extremely high zinc intake,
especially with supplementation of 100e300 mg/d of elemental
zinc [111]. In a six-week randomized, placebo controlled study, the
provision of 50 mg of elemental zinc (220 mg zinc sulphate) thrice
daily induced symptoms (headache, abdominal cramps, nausea,
loss of appetite and vomiting) in 18% of healthy male patients [110].
Female patients were more susceptible to side effects, with 84% of
the group affected. Plasma zinc levels increased 36% in men and
57% in women, whereas plasma copper levels did not change
significantly. Another randomized, controlled trial allocated 40
diabetic patients to receive either 660 mg zinc sulfate or placebo for
six weeks [112]. Two cases of mild abdominal pain were reported
when receiving zinc; however, a cause and effect relationship
cannot be established from these data.
Hypocupremia is frequently reported by diseased patients
consuming chronic, high doses of zinc, suggesting that excessive zinc
supplementation may be associated with anemia [107,108]. In two
earlier studies, the use of 150 mg of elemental zinc per day in
nonresponsive celiac and sickle cell anemia patients led to severe
hypocupremia [107,108]. In one study, the treatment lasted 13 months
[107], while the other lasted 23 months [108]. After zinc adminis-
tration was interrupted in both studies, copper status normalized.
In another case report, a woman who administered 110e165 mg
of elemental zinc daily for 10 months developed a copper defi-
ciency with an associated onset of anemia and neutropenia [109].
However, it seems likely that zinc was not the major culprit, since
interrupting zinc provision while supplementing orally with copper
for two months was unable to normalize serum copper levels. In
fact, intravenous administration of a copper solution over five days
was required to normalize serum levels. This may indicate that the
patient exhibited slow zinc excretion in conjunction with impaired
intestinal absorption. Moreover, it should be noted that the patient
had a history of three gastrointestinal surgical interventions.
Additionally, a case report in a young man with sideroblastic
anemia and leukopenia reported copper deficiency with con-
sumption of a supplemental dose of zinc over two years. Inter-
rupting zinc administration was sufficient to normalize copper
serum levels [105]. To the best of our knowledge, 12 g of elemental
zinc is the highest reported intake of this mineral, which was mixed
with peanut butter [113]. This occurred in a 16-y-old male, who
experienced nausea, epigastric pain, abdominal cramps, vomiting
and diarrhea from the supplementation protocol. All symptoms
were terminated after chelation therapy.
Pharmacological zinc administration is well studied in patients
undergoing dialysis, and is associated with an improved serum
antioxidant status and a decrease in excess plasma copper and
aluminum levels [114,115]. Given that individuals with kidney
disease are prone to severe mineral disturbances [116], a medicinal
zinc dose may be appropriate in this population.

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 H.O. Santos et al. / Clinical Nutrition 39 (2020) 1345e1353
10. Conclusion
Regardless of dietary zinc intake, medical dosages of this trace
mineral may be useful for a wide spectrum of clinical situations.
Attempting to achieve medical dosages through dietary zinc intake
is associated with overnutrition and can result in excessive con-
sumption of energy, protein and fiber. Therefore, medical dosages
of zinc are potentially beneficial for managing the nutritional status
and supporting optimal levels of zinc across the lifespan.
Thus far, a medical dose of zinc (i.e. >40 mg/d of elemental zinc)
is considered safe and, due to its role in anti-inflammatory and
antioxidant status, may confer additional benefits in the manage-
ment of several illnesses, such as liver diseases, hypogonadism,
cancers, heart diseases (e.g. dyslipidemia) and central nervous
system disorders. However, zinc posology may depend on the
specific physiopathology, and long periods of a high zinc intake
may inhibit its absorption. Guidelines in the clinical nutrition field
should expand the recommendation for zinc administration,
thereby providing a more established insight into management of
diseases, in which zinc may be used as an adjunct therapy.
Author's contributions
H.O.S. and F.J.T. conducted the literature search and drafted and
revised the manuscript. B.J.S. critically reviewed and revised the
manuscript.
Funding/sponsorship
None.
Conflict of interest
H.O.S. and F.J.T. have no interests to declare. BJS serves on the
advisory board to Dymatize Nutrition.
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