The vanilla plant, Vanilla planifolia or Vanilla fragrans (family Orchidaceae), is native to Mexico and is cultivated in numerous sites worldwide, with Indonesia and Madagascar being major sources of production. Vanilla tahitensis and Vanilla pompona are other key species contributing to commercial vanilla production. The green vanilla 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 reactions 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 fragrances. 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 Administration (FDA) standard of identity. Imitation or synthetic vanilla 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 extract could cost several dollars per ounce depending on market 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 limited culinary purposes, natural extracts from V. planifolia may be used. However, for a preponderance of food applications, less expensive imitation extract is used to produce a desired vanilla flavor. In many baked products, for example, imitation and natural vanilla flavors are essentially indistinguishable, especially in those products where vanilla is not intended to be the prominent flavor. As a sweet noncaloric flavoring, vanilla can contribute to strategies to decrease consumer intake of sugars. Extract chemicals also are used for perfumes and pharmaceuticals. The distinctive flavor of vanilla is due to the collective orosensory contribution 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 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 general lack of research data on this area of nutrition. In light of preliminary findings to date, there is a need for a more systematic approach to exposing any health benefits by examining vanilla's possible biological actions in animal models and humans. This narrative review outlines the emerging research on vanilla, providing direction for systematic research building the evidence base for potential human health benefits.
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 specifically address animal and human studies were the primary sources of information. Although the quality of studies varied 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 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.
There is limited information about the systemic bioavailability of vanilla's constituents following ingestion. In a recent 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 parent compound, despite other suggestions4 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 (Cmax) for vanillic acid was 2.74 μg/mL, and the half-life (T½) 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 determined 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 conjugates 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 oxidation 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 becomes 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 Cmax 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 (AUClast) values were 17.4 and 565.8, respectively. The bioavailability of vanillin delivered 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 decreased, although it is worth noting that biological responses were observed both at lower and higher doses. After administration, vanillic acid distributes mainly to liver and kidney, with trace amounts in the brain.23 It was determined in another rat study24 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 of vanillin and vanillic acid in the human GI tract and subsequent tissue distribution of metabolites are needed, especially as an important complement to future clinical studies.
Emerging Research in Humans
Few clinical studies 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 infants, exposure to the odor of vanillin prior to and during routine blood draws contributed to a significant soothing effect on the subsequent expressions of distress30–34 without affecting heart rate and blood oxygen saturation.35,36 Similarly, this calming response to vanillin was also observed 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 stimulating the olfactory nerve and enhancing orbitofrontal blood flow.41 In healthy adults, it was reported that vanillin odor influenced respiratory patterns during sleep, suggesting 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 induced 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 examining 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).
Sickle cell disease (SCD) is an inherited disorder in humans leading to hemolytic anemias. This is a consequence of a point mutation in the β-globin gene, which causes the resultant 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 polymerization of these molecules into a tangle of fibers that yield the distinctive sickle or disk shape of these aberrant erythrocytes. This process impairs erythrocyte permeability and leads to erythrocyte aggregation with neutrophils and platelets and their subsequent adhesion to vessel endothelium. This causes hemolysis, impedes blood flow, and ultimately 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 vanillin 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 toxicity66,86–88 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 study50 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 administration 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 investigated. Such products along with a number of other potential 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
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 inflammatory 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 produce 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 proinflammatory cytokines and reactive oxygen species, and activating the protein complex nuclear factor κ light-chain enhancer of activated B cells. Similarly, when compared with controls, injection of vanillic acid (10–100 mg/kg, i.p.) exhibited antinociceptive properties in rodent pain models.22,57 Yrbas et al22 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 subtype (TPRV1, TRPA1, and TRPM8). They also noticed that this analgesic action was not accompanied by nonspecific muscle relaxant or sedative effects as assessed by 3 behavioral tests. Others58 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 administered 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. administered the drug diazepam (1 mg/kg per day). The authors speculated that the mechanism of action might involve antioxidant 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 antianxiety action of vanillic acid also was evaluated in a rat cerebral hypoperfusion model.61 Compared with controls, oral administration 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 antidepressant action of vanillin.62–65 In the forced swim and tail suspension tests, the behavior of mice p.o. administered vanillin (10 mg, 100 mg/kg per day, 10 days) was compared with those 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 vanillin 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. administered saline, venlafaxine (40 mg/kg per day), or vanillin (100 mg/kg per day) for 9 weeks. As assessed in 3 behavioral tests, both venlafaxine and vanillin exhibited significant antidepressive actions in response to CMS, compared with stressed controls, and even produced behaviors comparable to those of unstressed rats. In subsequent analyses of the brain homogenates, vanillin and venlafaxine significantly corrected stress-induced changes in brain levels of glutathione, nitric oxide, and serotonin, essentially to levels comparable to unstressed rats. Another study in rats64 using a similar CMS model showed that, compared with controls, animals exposed to the odor of vanillin exhibited a significant 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 impulse to olfactory projection centers. These authors in a later study reported in this model of depression that vanillin aromatherapy 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 chemically induced brain toxicity due to exposure to such agents as ethanol, carbon tetrachloride, and potassium bromate (KBrO3).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 α gene, and generation of inflammatory cytokines. In the brain, it reduced histopathological injury and oxidative damage and preserved the integrity of the blood-brain barrier.
The capacity of vanillin and vanillic acid to influence neurodegenerative processes such as Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease was evaluated 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 impairments 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 lipopolysaccharide (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 vanillin 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) improved 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 striatum lipid peroxidation; on activities of CAT, SOD, and acetylcholinesterase; and on the impairment of several striatal mitochondrial enzyme complexes. Similarly, in animal models of Alzheimer's disease and vascular dementia, vanillic acid treatment (25–100 mg/kg, p.o.; 14–28 days) produced significant cognitive/behavioral improvements and amelioration of neurodegenerative processes, compared with controls.74,75 In another experiment, mice were treated with KBrO3 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 KBrO3 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 administered vanillin (12.5–50 mg/kg, p.o.; 15 days), a significant decrease in blood glucose, triglyceride (TG), and total cholesterol levels and an increase in blood levels of high-density lipoprotein cholesterol were observed, compared with controls.77 Mice fed a high-fat diet supplemented with 0.1% vanillin78 for 14 weeks exhibited significantly decreased blood levels of low-density lipoprotein cholesterol and TG along with increased 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 α were also lowered in vanillin-fed mice. Of interest, the data also suggest that vanillin may modify populations of obesity-related gut microbiota. Specifically, vanillin suppressed the abundance of representatives of the Firmicutes phylum, increased populations from the phyla Bacteroidetes and Verrucomicrobia, and decreased the levels of the LPS-producing bacteria of the Bilophila genus and the H2S-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 detected in brown adipose tissue, compared with controls, which was accompanied by higher levels of uncoupling protein 1 and peroxisome proliferator-activated receptor γ coactivator 1a.82
Mechanisms of Action Related to Cardiovascular Disease
Vanillic acid was evaluated in various animal models of chemically induced hypertension, chemically induced cardiotoxicity, 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 Nω-nitro-l-arginine methyl ester hydrochloride. 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 ventricular function and aortic nitric oxide metabolism. Histopathological 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 thiobarbituric acid–reactive substances and LOOH, compared with controls. Additionally, in rats treated with vanillic acid, infarct size was smaller, cardiac ionic homeostasis was normalized, 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 improved ventricular function, compared with controls. Of interest, 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 inducible nitric oxide synthase and endothelial NOS mRNAs; and lowered left ventricular end-diastolic pressure. Also, cardiac lactate dehydrogenase and xanthine oxidase activities were lower in vanillic acid–treated rats, compared with controls. In a separate study102 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, compared with controls. Bile duct–ligated cirrhotic rats exhibit cardiac distress, as well.104 When these rats were administered 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 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 homeostasis 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 alleviate neurological, cardiovascular, and metabolic conditions.
Vanillin and vanillic acid demonstrate a variety of other potential disease-modifying properties in animal models. Beneficial actions were reported toward cancer development,121–129 periodontal disease,130 and bone deterioration.131–133
Through the centuries, cultural uses of vanilla were numerous including as a flavoring constituent, fragrance ingredient, and medicinal agent. Vanilla extract, oil, seed powder, and vanillin are considered generally recognized as safe 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 Additives, number 959.134 Rats provided dietary vanillin at levels of 20 and 50 g/kg diet for 1 and 2 years, respectively, exhibited no effects on growth, hematology, and tissue pathologies.135 Similarly, Ho et al66 dosed rats p.o. and i.g. with vanillin (150 and 300 mg/kg) for 14 weeks without detecting 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 bronchoconstriction 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 following 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 transporter 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 organic ion transporter 1,143 which is a member of a transporter family that participates in the distribution and kidney clearance 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 CYP1A2144 and to reverse multidrug resistance via inhibition of P-glycoprotein.145 Also, it was reported to have no effect on the metabolism of phenylephrine, a hypotensive drug metabolized by the enzyme monoamine oxidase, which removes certain neurotransmitters from the brain.146 In 2 other in vitro studies, vanillin was determined not to be an endocrine disruptor.147,148 Of related interest, vanillin was observed in vitro to inhibit nonenzymatic glycation of albumin, suggesting it has the potential to block the formation of advanced glycation end products.149
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 distressed infants and diminish sleep apnea in infants and adults. Use of this mode of vanillin exposure to accrue human benefits, however, requires clarification of practical aspects of implementation and needs more research to characterize the complex emotional and physiological responses involved. In animal models, preliminary findings suggest vanillin 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 establishing 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 unlikely at this point.
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