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Vanilla
Potential Health Benefits
Keith W. Singletary, PhD
The vanilla bean, obtained from Vanilla planifolia and Vanilla
tahitensis, members of the Orchidaceae family, is the source
of vanilla extract, one of the most desired and widely used
food flavorings worldwide. Besides uses of vanilla in foods,
perfumes, and pharmaceuticals, it has complementary me-
dicinal applications including alleviation of fever, spasms,
and gastrointestinal irritations, to name a few. However, sup-
port from the scientific literature for human health benefits of
vanilla and its chemical constituents vanillin and vanillic acid
is limited and preliminary. This narrative review provides a
summary of findings from human and animal studies ad-
dressing potential health benefits of the extract of this bean
and select extract components. Nutr Today 2020;55(4):186–196.
The vanilla plant, Vanilla planifolia or Vanilla fragrans
(family Orchidaceae), is native to Mexico and is cul-
tivated in numerous sites worldwide, with Indonesia
and Madagascar being major sources of production. Vanilla
tahitensis and Vanilla pompona are other key species con-
tributing to commercial vanilla production. The green va-
nilla beans harvested from the plants are essentially odorless
and lacking flavor. It is during the curing process of ripening,
drying, and conditioning that chemical and enzymatic re-
actions produce the distinctive flavor and aroma profiles
of the different end products.These species provide vanilla
products differing in quality and use. For example, V. pompona
bean is of lesser quality and used more in the production of fra-
grances. On the other hand, V. planifolia and V. tahitensis
exhibit stronger, more desirable aroma profiles. Vanilla extract
is prepared by further macerating cured vanilla pods with a
solution of ethanol and water to produce a finished flavoring
product that must meet a specific Food and Drug Administra-
tion (FDA) standard of identity. Imitation or synthetic va-
nilla extract is a cheaper food flavoring synthesized from
starting chemicals originating from less expensive entities,
such as clove oil, spruce tree lignin, and a petrochemical-
derived precursor. The price of natural vanilla extract can
vary considerably. Practically speaking, retail real vanilla ex-
tract could cost several dollars per ounce depending on mar-
ket forces, whereas imitation vanilla extract could cost several
cents per ounce.
Extracts of the dried bean (Figure 1) are used for a wide
assortment of food products. The largest use of vanilla is for
ice cream preparations. It has widespread use in enhancing
consumer acceptance of yogurt products, and it is added
to both alcoholic beverages and soft drinks. Baked goods,
such as cookies, brownies, and cakes, contain vanilla, which
also flavors syrups, custards, and puddings. For certain lim-
ited culinary purposes, natural extracts from V. planifolia
may be used. However, for a preponderance of food appli-
cations, less expensive imitation extract is used to produce a
desired vanilla flavor. In many baked products, for exam-
ple, imitation and natural vanilla flavors are essentially in-
distinguishable, especially in those products where vanilla
is not intended to be the prominent flavor. As a sweet non-
caloric flavoring, vanilla can contribute to strategies to de-
crease consumer intake of sugars. Extract chemicals also are
used for perfumes and pharmaceuticals. The distinctive
flavor of vanilla is due to the collective orosensory contri-
bution of a multitude of aromatic volatiles created during
processing of the bean. Hundreds of chemicals in the extract
have been identified that together participate in crafting
this unique flavor profile, although vanillin (4-hydroxy-3-
methoxybenzaldehyde) is the main contributor (Figure 2),
achieving levels of 1% to 2% wt/wt in cured pods. Additional
important flavor components include p-hydroxybenzoic acid,
p-hydroxybenzaldehyde, vanillic acid (4-hydroxy-3-methylbenzoic
acid), p-hydroxybenzyl alcohol, anise alcohol, and vanillyl
alcohol, as well as tannins, resins, free amino acids, and other
nonvolatiles. Both vanillin and vanillic acid are approved
Keith W. Singletary, PhD, is professor emeritus of nutrition in the De-
partment of Food Science and Human Nutrition at the University of
Illinois. From 2001 to 2004, he was the director of the Functional Foods
for Health Program at the Chicago and Urbana-Champaign campuses of
the University of Illinois. Dr Singletary received bachelor's and master's de-
grees in microbiology from Michigan State University and his PhD in nutri-
tional sciences from the University of Illinois. Dr Singletary's primary
research interests include molecular carcinogenesis and the potential use
of natural products in cancer chemoprevention. He has been recognized
with the Senior Faculty Award for Excellence in Research by the College
of Agricultural, Consumer and Environmental Sciences at the University
of Illinois. Dr Singletary currently resides in Florida.
The author has no conflicts of interest to disclose.
Funding for the preparation of this article was provided by McCormick
and Co.
Correspondence: Keith W. Singletary, PhD, Department of Food Science
and Human Nutrition, University of Illinois, 905 South Goodwin Ave,
Urbana, IL 61801 (kws@illinois.edu).
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided
it is properly cited. The work cannot be changed in any way or used com-
mercially without permission from the journal.
Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc.
DOI: 10.1097/NT.0000000000000412
Food Science
186 Nutrition Today
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Volume 55, Number 4, July/August 2020
food-flavoring agents. Some traditional medicinal uses of
vanilla include treatment for fever, spasms, dysmenorrhea,
blood clotting, and gastrointestinal (GI) distress.
1–7
In the
18th century BCE, vanillin was even used as an Old World
mortuary offering.
8
More recently, the antioxidant, anti-
inflammatory, antisickling, antimicrobial, and hypolipidemic
properties of vanilla extract have drawn the attention of the
food and nutraceutical industries.
9–15
Currently, there is a gen-
eral lack of research data on this area of nutrition. In light of
preliminary findings to date, there is a need for a more sys-
tematic approach to exposing any health benefits by examin-
ing vanilla's possible biological actions in animal models and
humans. This narrative review outlines the emerging re-
search on vanilla, providing direction for systematic re-
search building the evidence base for potential human
health benefits.
METHODS
A search of the PubMed and Science Direct databases was
conducted using terms that included Vanilla planifolia,
Vanilla tahitensis,Vanilla pompona, vanilla, vanillin, vanillic
acid, 4-hydroxy-3-methoxybenzaldehyde, and 4-hydroxy-
3-methylbenzoic acid. Full reports of English-language
publications and English-language abstracts of foreign-
language articles from peer-reviewed journals that specifi-
cally address animal and human studies were the primary
sources of information. Although the quality of studies var-
ied considerably, all published investigations identified were
included in this overview so that the totality and diversity
of information can be described, and issues for future
FIGURE 1. Vanilla beans and vanilla extract.
FIGURE 2. Structures of vanillin, vanillic acid, and p-hydroxybenzaldehyde.
Volume 55, Number 4, July/August 2020 Nutrition Today
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187
research can be identified. Additional information was
gleaned from bibliographies within these sources. Studies
examining vanilla within multi-ingredient preparations
were not included in this overview.
RESULTS
Bioavailability
There is limited information about the systemic bioavail-
ability of vanilla's constituents following ingestion. In a re-
cent human study, volunteers were given a 600-mg oral
dose of vanillin.
16
As early as 5 minutes after dosing, vanillin
was essentially undetectable in plasma, whereas vanillic acid
was readily detectable, suggesting rapid metabolism of the
administered compound. The authors thus speculated that
the potential biological activities of vanillin might be due
more to its oxidation metabolite vanillic acid than to the par-
ent compound, despite other suggestions
4
that vanillin may
be biologically active only in its unoxidized state. In light of
this, the biological actions of both vanillin and vanillic acid
are described in this overview. Pharmacokinetic data from
these volunteers indicated that the vanillic acid formed from
vanillin is rapidly absorbed and eliminated, a process that
appears to be similar for rats and humans. The maximum
plasma concentration (C
max
) for vanillic acid was 2.74 μg/mL,
and the half-life (T
½
) was 0.95 hour.
The metabolism of vanillin also was studied in several
animal models. In a study, rats were administered vanillin
orally (p.o.) at 100 mg/kg, and bioavailability was deter-
mined to be only 7.6%.
17
Administration (intraperitoneally
[i.p.] and p.o.) of vanillin (100 mg/kg) to rodents resulted
in the presence predominantly of vanillic acid and its con-
jugates in the urine.
18,19
Similar results were observed from
urine obtained from rabbits fed 2 g vanillin.
20
In rodents,
this vanillic acid presumably is a consequence of rapid ox-
idation of vanillin in the upper GI tract. To overcome the
poor oral bioavailability, vanillin was modified to be part
of a prodrug, a biologically inactive compound that be-
comes biologically active when metabolized by the body.
In this case, the synthetic prodrug of vanillin (MX-150) was
designed to release vanillin after ingestion and absorption
into the body.
21
After oral administration of equimolar amounts
of vanillin (100 mg/kg) or the prodrug (186 mg/kg), the C
max
of vanillin and prodrug-derived vanillin were 2.45 and
9.51 μg/mL, respectively, and the area under the curve
from zero to last time point (AUC
last
) values were 17.4
and 565.8, respectively. The bioavailability of vanillin de-
livered by this prodrug was approximately 30-fold greater
than vanillin given alone.
The bioavailability of vanillic acid was determined to be
30% in an experiment in which mice were given i.p. doses
of 10 to 100 mg/kg.
22
Peak blood levels of vanillic acid following
this i.p. dosing occurred at 5 minutes and then rapidly de-
creased, although it is worth noting that biological responses
were observed both at lower and higher doses. After admin-
istration, vanillic acid distributes mainly to liver and kidney,
with trace amounts in the brain.
23
It was determined in an-
other rat study
24
that the absorption and elimination of vanillic
acid can be affected by the health condition of the rat. In light
of these reports, a detailed characterization of the metabolism
ofvanillinandvanillicacidinthehumanGItractandsubse-
quent tissue distribution of metabolites are needed, especially
as an important complement to future clinical studies.
Emerging Research in Humans
Few clinicalstudies evaluated the human health benefits of
vanilla. Flavor perception and food acceptance in humans
have been examined using olfactory stimulation by vanillin
in order to characterize the process of sensory maturation
of humans as early as in utero through childhood.
25–29
A
small number of clinical investigations also examined the
impact of olfactory stimulation by vanillin on the well-being
and behavior of neonates, specifically on how chemosensory
stimuli may affect pain responses and prevention of apnea
in newborns. In both premature and full-term human in-
fants, exposure to the odor of vanillin prior to and during
routine blood draws contributed to a significant soothing
effect on the subsequent expressions of distress
30–34
with-
out affecting heart rate and blood oxygen saturation.
35,36
Similarly, this calming response to vanillin was also ob-
served to modify newborn crying time and discomfort.
37
Of interest are several trials that evaluated the impact
of olfactory stimulation by vanillin on apnea, a common
problem in premature newborns. Exposure to vanillin as
a sweet, familiar olfactory stimulant decreased frequency
of apnea and prevented bradycardia,
38–40
possibly by stim-
ulating the olfactory nerve and enhancing orbitofrontal
blood flow.
41
In healthy adults, it was reported that vanillin
odor influenced respiratory patterns during sleep, suggest-
ing that olfactory stimulation may be an approach for relief
of apnea in adults as well.
42
In adults, the odor of vanillin
acts as a positive stimulus that can subdue or calm an in-
duced startle reflex.
43
This olfactory capacity of vanillin to
affect mood and emotions in adults may be gender-
dependent.
44
Taken together, these data on the effects of
vanilla in humans are essentially limited to clinical trials ex-
amining responses to vanilla olfactory stimulation on mood,
emotions, and distress.
Animal Model Research on Potential
Mechanisms of Action
Multiple physiological actions of vanillin and vanillic acid
in animals have been identified (Table).
Antisickling Action
Sickle cell disease (SCD) is an inherited disorder in humans
leading to hemolytic anemias. This is a consequence of a
188 Nutrition Today
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Volume 55, Number 4, July/August 2020
point mutation in the β-globin gene, which causes the re-
sultant hemoglobin (Hb) molecule within red blood cells
(RBCs) to have sharply reduced solubility. Under conditions
of low oxygen tension or after repeated deoxygenation,
this Hb deforms to a configuration that produces polymer-
ization of these molecules into a tangle of fibers that yield
the distinctive sickle or disk shape of these aberrant eryth-
rocytes. This process impairs erythrocyte permeability and
leads to erythrocyte aggregation with neutrophils and
platelets and their subsequent adhesion to vessel endothe-
lium.This causes hemolysis, impedes blood flow, and ulti-
mately initiates vaso-occlusion. Acute pain, organ damage,
and decreased life expectancy are the likely outcomes.
83–85
Identification of agents that allosterically modify the
sickled Hb and stabilize its conformation is one avenue
of research toward a treatment. The flavoring agent van-
illin was identified as a candidate molecule capable of
covalently binding to and suppressing the propensity of sickle
Hb to polymerize, thus improving oxygen affinity and aberrant
RBC permeability.
45–49
Because it exhibits very low toxicity
66,86–88
and is considered generally recognized as safe by the US
FDA, it was initially considered a promising antisickling
agent.
46
The efficacy of vanillin was confirmed in a human
study
50
in which vanillin was p.o. administered (1 g/d; 40 days)
to adult homozygous patients. Compared with placebo, those
given vanillin showed a significant decrease in percentage
of sickled RBC and a significant delay in the progress of
polymerization. However, in light of the apparent rapid
breakdown of vanillin in the GI tract and the need for ad-
ministration of larger doses, its potential oral efficacy for
general treatment of SCD was considered problematic.
21
Subsequently, strategies to encapsulate and derivatize
vanillin so as to improve bioavailability have been investi-
gated. Such products along with a number of other poten-
tial therapeutic agents are being evaluated to replace
hydroxyurea for treatment of SCD patients because of the
poor response rate, poor tolerance, and undesirable side
effects of hydroxyurea.
89–93
Neurological Actions
Vanillin and vanillic acid were investigated in preclinical
studies as potential antinociceptive therapeutic agents, that
is, capable of inhibiting the sensation of pain. In rat and mouse
pain models, compared with controls, vanillin at oral doses
of 1 to 12.5 mg/kg selectively decreased visceral inflamma-
tory pain.
51–53
This antinociceptive action was mediated by
its action on α2-adrenergic and opioid receptors as well as
with suppression of reactive oxygen species. Also, in rats,
vanillin dosing suppressed mechanical allodynia (painful
sensation from harmless stimulus, eg, light touch) produced
by sciatic nerve restriction,
17
a response that apparently was
not a result of central motor or general depressive effects.
Similarly, inhalation of vanillin by mice was shown to pro-
duce antinociceptive and muscle relaxant effects without
inducing anxious or aggressive behavior.
54
Oral vanillic acid
(12.5–50 mg/kg) alleviated pain in several rodent pain models
and did not induce liver or stomach lesions.
51,55,56
These
responses, in part, were determined to be due to vanillic acid
affecting the opioid system, suppressing production of proin-
flammatory cytokines and reactive oxygen species, and acti-
vating the protein complex nuclear factor κlight-chain
enhancer of activated B cells. Similarly, when compared with
controls, injection of vanillic acid (10–100 mg/kg, i.p.) exhib-
ited antinociceptive properties in rodent pain models.
22,57
Yrbas et al
22
determined that vanillic acid's analgesic action
was associated with modulation of the serotoninergic and
adrenergic systems, of acid-sensing ion channels, and of
transient receptor potential channels of the vanilloid sub-
type (TPRV1, TRPA1, and TRPM8). They also noticed that
this analgesic action was not accompanied by nonspecific
TABLE Summary of Biological Effects of Vanilla in Animal Models
Biological Action
Responsible
Agent Possible Mechanism References
Antisickling Vanillin Bind to and allosterically modify sickled hemoglobin 45–50
Pain relief Vanillin, vanillic
acid
Modify opioid, serotonergic, adrenergic, and transient
receptor potential channel systems; suppress inflammation
and oxidative stress
17,22,51–58
Antianxiety Vanillin, vanillic
acid
Modulate neurotransmitters, decrease oxidative stress 59–61
Antidepressant Vanillin Correct stress-induced brain levels of glutathione, nitric
oxide, and serotonin
62–65
Protect against nerve damage
and neurodegeneration
Vanillin, vanillic
acid
Suppress oxidative stress and inflammation in the brain 66–76
Correct blood glucose and lipid
dysregulation
Vanillin, vanillic
acid
Suppress oxidative stress and inflammation, lower insulin
resistance, alter gut microbe populations
77–82
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189
muscle relaxant or sedative effects as assessed by 3 behav-
ioral tests. Others
58
observed that inhibition of voltage-gated
sodium channels contributed to the antinociceptive action
of injected vanillic acid.
Three studies in rats examined the anxiolytic activity of
vanillin and its metabolite vanillic acid. Vanillin was admin-
istered p.o. to the rats (10, 100, 200 mg/kg per day) for 10 days
prior to performance of 2 behavioral assessment tests.
59
Compared with controls, all doses administered to the rats
produced a decrease in fear responses, with the 100-mg/kg
dose yielding comparable efficacy to that of rats p.o. admin-
istered the drug diazepam (1 mg/kg per day). The authors
speculated that the mechanism of action might involve anti-
oxidant and neurotransmitter-modulating actions of vanillin.
Compared with controls, mice given vanillin (2.5–10 mg/kg,
p.o.) in a similar study exhibited less anxiety.
60
The antianx-
iety action of vanillic acid also was evaluated in a rat cerebral
hypoperfusion model.
61
Compared with controls, oral admin-
istration of vanillic acid (100 mg/kg per day, 14 days) resulted
in a significant decrease in anxiety-like behavior following
transient carotid artery occlusion.
Four animal experiments suggest a potential antidepres-
sant action of vanillin.
62–65
In the forced swim and tail sus-
pension tests, the behavior of mice p.o. administered vanillin
(10mg,100mg/kgperday,10days)wascomparedwiththose
p.o. dosed with the antidepressants imipramine (15 mg/kg per
day, 10 days) or fluoxetine (20 mg/kg per day, 10 days).
62
In the tail suspension test but not the forced swim test, both
doses of vanillin showed significant antidepressant effects,
compared with controls, and the 100-mg/kg dose of vanil-
lin was significantly more effective than mice administered
fluoxetine. It is important to keep in mind that the doses of
vanillin provided to the mice in the latter study are orders
of magnitude greater, on a body weight basis, than what
a human might typically ingest. In a rat study, animals were
subjected to chronic mild stress (CMS) caused by random
exposure to 10 external stimuli.
63
Four separate groups of
animals either received no treatment or were p.o. adminis-
tered saline, venlafaxine (40 mg/kg per day), or vanillin
(100 mg/kg per day) for 9 weeks. As assessed in 3 behav-
ioraltests,bothvenlafaxineandvanillinexhibitedsignif-
icant antidepressive actions in response to CMS, compared
with stressed controls, and even produced behaviors com-
parable to those of unstressed rats. In subsequent analyses
of the brain homogenates, vanillin and venlafaxine signifi-
cantly corrected stress-induced changes in brain levels of
glutathione, nitric oxide, and serotonin, essentially to levels
comparable to unstressed rats. Another study in rats
64
using
a similar CMS model showed that, compared with controls,
animals exposed to the odor of vanillin exhibited a signifi-
cant decrease in symptoms of depression, apparently acting
through an effect on an olfactory pathway. Additionally,
vanillin elevated serotonin and dopamine levels in brain
homogenates. The authors speculated that vanillin's
effects were due to its binding to an olfactory sensory neuron
receptor that then invoked transmission of a nerve impul se to
olfactory projection centers. These authors in a later study
reported in this model of depression that vanillin aroma-
therapy improved serum magnesium and brain-derived
nerve growth factor levels,
65
compared with controls.
The ability of vanillin to protect against a variety of neural
toxicities was investigated in rodent models. Vanillin
(300 mg/kg, p.o.; 100–150 mg/kg, i.p.) counteracted chem-
ically induced brain toxicity due to exposure to such agents
as ethanol, carbon tetrachloride, and potassium bromate
(KBrO
3
).
66–68
Compared with controls, vanillin dosing was
associated with decreased lipid peroxidation, oxidative stress,
and generation of inflammatory cytokines in the brain. Two
studies reported that vanillin (286 mg/kg, i.p.) decreased
neurological destruction in the spinal cord and subsequent
motor dysfunction following ischemia-induced spinal cord
injury and, at 20 to 80 mg/kg (i.p.), suppressed hypoxic-
ischemia–induced brain damage,
69,70
compared with
controls. In the spinal cord, vanillin treatment decreased
injury-induced spinal apoptosis, oxidative stress, expression
of the hypoxia inducible factor 1 subunit αgene, and gener-
ation of inflammatory cytokines. In the brain, it reduced
histopathological injury and oxidative damage and pre-
served the integrity of the blood-brain barrier.
The capacity of vanillin and vanillic acid to influence neu-
rodegenerative processes such as Parkinson's disease (PD),
Alzheimer's disease, and Huntington's disease was evalu-
ated in several animal models. In a model, rats were induced
with rotenone to produce PD-like symptoms and treated
with vanillin (5, 10, 20 mg/kg, p.o.; 40 days). Compared with
controls, vanillin diminished behavioral and cognitive im-
pairments and counteracted the rotenone-induced striatal
depletion of dopamine.
71
In a rat model in which symptoms
of PD were produced by intranigral injection of lipopolysac-
charide (LPS), vanillin administration (5, 10, 20 mg/kg, i.p.;
24 days) improved motor dysfunction, enhanced the survival
rate of dopaminergic neurons in the substantia nigra (SN),
and suppressed LPS-induced activation of microglia in the
SN.
72
In the PD model, the beneficial actions of vanillin were
associated with increases in glutathione peroxidase (GPx),
superoxide dismutase (SOD), and catalase (CAT) activities
in brain tissue and in the level of glutathione (GSH) in
the SN. Furthermore, vanillin counteracted the rotenone-
induced changes in expression of B-cell lymphoma 2 and
in caspases 3, 8, and 9 in the SN and striatum. Benefits of van-
illin were also observed in a rat model of Huntington's disease
produced by 3-nitropropionic acid (3-NPA). Compared with
controls, vanillin dosing (75, 150 mg/kg, p.o.; 18 days) im-
proved locomotion and motor function and counteracted
learning and memory deficits elicited by 3-NPA.
73
In this
model, vanillin attenuated 3-NPA–induced effects on stria-
tum lipid peroxidation; on activities of CAT, SOD, and ace-
tylcholinesterase; and on the impairment of several striatal
190 Nutrition Today
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Volume 55, Number 4, July/August 2020
mitochondrialenzymecomplexes.Similarly,inanimalmodels
of Alzheimer's disease and vascular dementia, vanillic acid
treatment (25–100 mg/kg, p.o.; 14–28 days) produced sig-
nificant cognitive/behavioral improvements and ameliora-
tion of neurodegenerative processes, compared with
controls.
74,75
In another experiment, mice were treated with
KBrO
3
to increase oxidative damage and degenerative
changes in the brain. Compared with controls, decreased
oxidative stress in the cerebellum and improved cognitive
performance were observed for mice first treated with
KBrO
3
and subsequently administered vanillin (100 mg/kg, i.
p.; 15 days).
76
Considered collectively, these effects on the
nervous system suggest the capacity of vanilla to impact
perception of pain, anxiety, mood, and brain pathologies
warrants further scrutiny.
Blood Glucose and Lipid Regulation
Vanillin and vanillic acid were investigated for their impact
on hyperglycemia, high blood lipids, and obesity. When mice
with diabetes type 2 fed a high-glucose/lipid diet were ad-
ministered vanillin (12.5–50mg/kg,p.o.;15days),asignificant
decrease in blood glucose, triglyceride (TG), and total choles-
terol levels and an increase in blood levels of high-density lipo-
protein cholesterol were observed, compared with controls.
77
Mice fed a high-fat diet supplemented with 0.1% vanillin
78
for
14 weeks exhibited significantly decreased blood levels of
low-density lipoprotein cholesterol and TG along with in-
creased blood levels of high-density lipoprotein cholesterol,
compared with controls. In these animals, consumption of
vanillin resulted in enhanced insulin sensitivity and glucose
tolerance, and additionally, these animals had significantly
lower body and adipose tissue weights. Plasma and liver
concentrations of the inflammatory cytokines interleukin
6 and tumor necrosis factor αwere also lowered in vanillin-
fed mice. Of interest, the data also suggest that vanillin may
modify populations of obesity-related gut microbiota. Spe-
cifically, vanillin suppressed the abundance of representa-
tives of the Firmicutes phylum, increased populations
from the phyla Bacteroidetes and Verrucomicrobia, and de-
creased the levels of the LPS-producing bacteria of the
Bilophila genus and the H
2
S-producing bacteria of the
genus Desulfovibrio. In 2 experiments,
79,80
rats fed high-
fat diet were administered vanillic acid (30–50 mg/kg, p.
o.) for 4 to 8 weeks. Compared with controls, those given
vanillic acid exhibited decreased blood glucose, serum
insulin, TGs, and free fatty acids, as well as lower insulin
resistance and blood pressure (BP). One of the studies
detected less liver damage and measured a reduction in
plasma, liver, kidney, and heart thiobarbituric acid reactive
substances and lipid peroxides (LOOH). Also, CAT, SOD,
and GPx were elevated in the tissues.
80
For a mouse study,
vanillic acid was provided either as part of a high-fat diet
(0.5% wt/wt; 15 weeks) (A53) or at 10 to 1000 mg/kg per
day (p.o.) for 4 weeks.
81
Compared with controls, mice
given vanillic acid had less white adipose tissue and lower
body weights and decreased liver steatosis. Increased
mitochondria- and thermogenesis-related activity was de-
tected in brown adipose tissue, compared with controls,
which was accompanied by higher levels of uncoupling
protein 1 and peroxisome proliferator-activated receptor
γcoactivator 1a.
82
Mechanisms of Action Related to
Cardiovascular Disease
Vanillic acid was evaluated in various animal models of
chemically induced hypertension, chemically induced cardio-
toxicity, and ischemia-reperfusion (IR)–induced cardiac distress.
In 3 reports,
94–96
vanillic acid was administered (25–100 mg/kg
per day, intragastric (i.g.); 4 weeks) to rats with hypertension
induced by N
ω
-nitro-L-arginine methyl ester hydrochlo-
ride. Compared with controls, vanillic acid–treated animals
exhibited lower BP, decreased markers of oxidative stress,
elevated antioxidant enzyme activities in multiple organs,
improved blood lipid profiles, and improved left ventricu-
lar function and aortic nitric oxide metabolism. Histopath-
ological evidence of cardiac damage also was diminished.
For isoproterenol-treated myocardial-infarcted rats,
97–99
vanillic acid administration (5, 10 mg/kg per day, i.g.;
10 days) decreased the activity of the cardiac damage
markers creatine kinase, creatine kinase-MB, and lactate
dehydrogenase and suppressed plasma levels of thiobarbi-
turic acid–reactive substances and LOOH, compared with
controls. Additionally, in rats treated with vanillic acid, in-
farct size was smaller, cardiac ionic homeostasis was nor-
malized, and the expressions of oxidative stress–induced
apoptotic enzymes in the heart were decreased.
In the IR model,
100–102
vanillic acid dosing (5–20 mg/kg
per day, i.g.; 10 days) led to smaller infarct size and im-
proved ventricular function, compared with controls. Of in-
terest, in a study, IR-exposed rats were also subjected to
inhalation of particles with an aerodynamic diameter of less
than 10 μm (PM10), exposure to which also can contribute to
cardiac dysfunction.
103
Compared with controls, vanillic acid
treatment increased cardiac activities of SOD, CAT, and
GPx; corrected the aberrant cardiac expression of induc-
ible nitric oxide synthase and endothelial NOS mRNAs;
and lowered left ventricular end-diastolic pressure. Also, car-
diac lactate dehydrogenase and xanthine oxidase activities
were lower in vanillic acid–treated rats, compared with
controls. In a separate study
102
when healthy rats inhaled
PM10, vanillic acid dosing (10 mg/kg per day, i.g.; 10 days)
corrected cardiac irregularities, lowered BP, and enhanced
plasma activities of several antioxidant enzymes, com-
pared with controls. Bile duct–ligated cirrhotic rats exhibit
cardiac distress, as well.
104
When these rats were adminis-
tered vanillic acid (10 mg/kg per day, i.g.; 4 weeks), they
showed an increase in P-R intervals in electrocardiography,
compared with the P-R interval suppression observed in control
Volume 55, Number 4, July/August 2020 Nutrition Today
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191
animals. Taken together, these findings suggest that vanilla
constituents should be examined in more detail to better
understand how they may influence blood and lipid homeo-
stasis and affect contributors to cardiovascular disease risk.
Amelioration of Tissue Damage
Both vanillin and vanillic acid were shown to counteract
chemically and mechanically induced tissue injury in mouse
and rat models. Compared with controls, administration of
vanillin (1–150 mg/kg, p.o., i.p.; 1–21 days) or vanillic acid
(25–200 mg/kg, p.o.; 1–6 weeks) mitigated damage to the
kidney,
105–108
lung,
109,110
skin,
111
muscle,
112
liver,
113–115
GI
tract,
116–118
erythrocytes,
119
and breast.
120
Taken together,
these preclinical studies suggest that vanillin and vanillic acid
warrant additional scrutiny for possible use in strategies to al-
leviate neurological, cardiovascular, and metabolic conditions.
Miscellaneous Actions
Vanillin and vanillic acid demonstrate a variety of other po-
tential disease-modifying properties in animal models. Ben-
eficial actions were reported toward cancer development,
121–129
periodontal disease,
130
and bone deterioration.
131–133
SAFETY
Through the centuries, cultural uses of vanilla were numer-
ous including as a flavoring constituent, fragrance ingredi-
ent, and medicinal agent. Vanilla extract, oil, seed powder,
and vanillinare considered generally recognized assafe by
the US FDA for use as spices and other natural seasonings
and flavorings in food (section 409 of the Federal Food,
Drug, and Cosmetic Act [21 CFR 182.10; 21 CFR 182.60;
CFR582.10]). Vanillic acid is approved as a food flavoring
by the Joint FAO/WHO Expert Committee on Food Addi-
tives, number 959.
134
Rats provided dietary vanillin at levels
of 20 and 50 g/kg diet for 1 and 2 years, respectively, exhib-
ited no effects on growth, hematology, and tissue patholo-
gies.
135
Similarly, Ho et al
66
dosed rats p.o. and i.g. with
vanillin (150 and 300 mg/kg) for 14 weeks without detect-
ing toxicities. These results are consistent with others,
86–88
indicating a lack of toxicity of vanilla components at approved
levels of intake in foods. In contrast, rats fed vanillin (1.25 g/kg
diet, 42 days) in a study showed decreased growth and lower
blood and liver activities of glutathione-S-transferase and SOD,
compared with controls.
136
The reason for this latter response
to vanillin compared with the other reports is not known.
In humans, isolated adverse events include broncho-
constriction in an asthmatic patient following oral doses of
either 0.24 mg or 1 mg vanillin.
137
Occupational contact
dermatitis to vanilla was reported for producers of baked
goods, and contact dermatitis resulted from use of a vanilla
lip salve. Dermatitis due to mechanical irritation of vanillin
dust also was observed.
138,139
Anaphylaxis was noted fol-
lowing ingestion of vanilla ice cream, the specific cause of
which, however, was determined to be due to lupine added
to the ice cream.
140
Variable responses to skin sensitization
tests have been reported in several case reports.
141
The capacity of vanillin and vanillic acid to interact with
drugs and hormones was examined in vitro. In a rat muscle
L6 myotube assay, a model system to study glucose trans-
porter type 4 glucose uptake, vanillic acid showed additive
enhancement of 2-deoxyglucose uptake stimulated by 2,4-
thiozoladinedione, compared with controls, whereas it did
not demonstrate synergy with metformin dosing.
142
In cell
culture, vanillic acid also inhibited the activity of human or-
ganic ion transporter 1,
143
which is a member of a transporter
family that participates in the distribution and kidney clear-
ance of many endogenous and exogenous organic ions. The
clinical relevance of this is unclear. In microsomal assays and
cell culture, vanillin was reported to interact with drug-
metabolizing enzymes CYP2E1 and CYP1A2
144
and to reverse
multidrug resistance via inhibition of P-glycoprotein.
145
Also, it
wasreportedtohavenoeffectonthemetabolismofphenyl-
ephrine, a hypotensive drug metabolized by the enzyme
monoamine oxidase, which removes certain neurotransmit-
ters from the brain.
146
In 2 other in vitro studies, vanillin was
determined not to be an endocrine disruptor.
147,148
Of re-
lated interest, vanillin was observed in vitro to inhibit non-
enzymatic glycation of albumin, suggesting it has the potential
to block the formation of advanced glycation end products.
149
CONCLUSION
Although support from the scientific literature for use of
vanilla to impart human health benefits is preliminary and
limited, there is emerging research suggesting that specific
vanilla constituents may potentially help improve symptoms
of several chronic conditions. Small clinical studies suggest
that olfactory exposure to vanillin may sooth and calm dis-
tressed infants and diminish sleep apnea in infants and
adults. Use of this mode of vanillin exposure to accrue hu-
man benefits, however, requires clarification of practical
aspects of implementation and needs more research to char-
acterize the complex emotional and physiological responses
involved. In animal models, preliminary findings suggest van-
illin and vanillic acid have potential to alleviate neurological
disorders, dysregulation of glucose and lipid homeostasis,
and cardiac distress, in particular. Considerable additional
characterization of these physiological actions is needed
and includes clarifying their mechanisms of action and estab-
lishing an oral dose-response relationship. The small amounts
of vanilla currently consumed as a flavoring in foods make
any practical human health benefits from culinary uses un-
likely at this point.
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TOO MUCH OR TOO LITTLE SLEEP SPIKES CONSTIPATION
Individuals who sleep more or less than average report significantly more constipation, compared with normal sleepers, based on
data from a large study of adults based on data from the NHANES during 2005-2010. To examine the association between sleep duration
and bowel function, the researchers identified 14 590 adults 20 years or older who completed questionnaires on sleep and bowel health
as part of the NHANES. The amount of sleep was divided into 3 categories based on standards from the National Sleep Foundation: short
(<7 hours), normal (7-8 hours), and long (>8 hours).
Overall, constipation rates were significantly lower among normal sleepers (8%) compared with both short and long sleepers
(11% and 13%, respectively).
Bowel function was defined based on stool form and bowel movements per week as normal, constipation, or diarrhea. After
controlling for demographic, lifestyle, and dietary factors, long sleepers were 61%, and short sleepers 38%, more likely to report
constipation, compared with normal sleepers.
However, sleep duration was not related to diarrhea, the researchers noted.
The results suggest that decreased sleep is associated with constipation among adults in the United States. However, re-
searchers warn that “further studies are needed to evaluate the physiologic mechanisms driving the impact of sleep duration
on bowel function to determine whether sleep disorders or their underlying causes affect constipation.”Clinicians should be aware
of the impact of both short and long sleep on constipation. Individuals who are unable to have adequate periods of sleep because
of other diseases, including insomnia, disrupted job schedules, or conditions with extremely long sleep, or sleep at inappro-
priate times, such as narcolepsy, may all additionally suffer from constipation. Such patients may need regular evaluation
and treatment for constipation to improve their discomfort.
Source: Digestive Disease Week (DDW) 2020:abstract Sa1711.
DOI: 10.1097/NT.0000000000000429
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