Vanillin Found in Jugs in Ancient Tomb Leads to Questions on Its Use for Inflammation

By Jacob Schor, ND, FABNO

December 31, 2018

I’ve recently chanced upon an exciting bit of medical hypothesis that I want to share. It started with news reports about Vanessa Linares who made a presentation at a conference in Denver last November. Linares is an archaeologist who is working on her PhD at Tel Aviv University in Israel. She has been investigating a tomb discovered in 2016 in the ancient city of Megiddo. You may have heard of the city by its biblical name, Armageddon. The tomb is old; carbon dating suggests 3,600 years old. At that time Megiddo was a busy metropolis, located on the major trade routes.1

Three bodies were found in the tomb, “… an adult female, an adult male and an 8- to 12-year-old boy. Elaborate types of bronze, gold and silver jewelry were found on and around the three skeletons. Exact replicas of several pieces of jewelry appeared on each individual.”2 Three ancient earthen jugs were found along with the body remains. Linares conducted a careful chemical analysis of the jugs and found that they had once contained olive oil and the chemical 4-hydroxybenzaldehyde, what we know as vanilla.3

Up until Linares’s research was presented, the earliest traces of vanilla had been found in Mexico, about 1,000 years ago. Linares’ discovery pushed the origins of vanilla back several millennia. The other thing that stood out is how far that vanilla must have been carried to reach Megiddo. Vanilla is not grown anywhere in the Middle East. Linares narrowed down the vanilla source to 3 of the 110 species of vanilla orchards growing in the world; the vanilla in the Megiddo jugs came from either central east Africa, India or from southeast Asia.4

Linares’s research prompted me to read other research on vanilla, some of which proved to be fascinating. In order to explain why it is so exciting, I must detour and describe the recent history of another medicinal spice, turmeric and its concentrate curcumin. Back in the mid 1990s we were excited about the potential medicinal uses of curcumin based on epidemiological and animal research. Animal studies suggested that curcumin was a potent antioxidant, anticancer agent and was protective against Alzheimer’s and other neurodegenerative diseases.5-7

However human clinical trials generated disappointing results. Researchers from UCLA eventually developed technology to measure blood levels of curcumin and reported that there was next to no curcumin in the blood of people taking it. Tricks were developed to increase curcumin absorption and bioavailability.5 We now choose between several competing curcumin products that all seem to have greatly enhanced absorption. These new products do much better in human trials than the original products producing significant benefits. Yet when blood of study participants is tested, there is only a small amount of curcumin found.6 Curcumin is rapidly degraded in the body through hydrolysis. Curcumin seems to be helpful but clearly the curcumin doesn’t last in the body long enough to deserve much credit for any benefits seen. It has been suggested that degradation products are responsible for curcumin’s beneficial actions.7

In a 2012 study, Shen and Ji posed the question asking how curcumin does what it does? The low bioavailability was the obvious problem but that seemed to have been solved. They took their query a step further examining the enzymes curcumin appears to inhibit and pointed out that the recognized binding pockets on these enzymes do not accommodate curcumin.8

In a series of papers these two researchers analyzed the degradation products of curcumin and suggested that the credit for benefits should be attributed to one or more of these other chemicals.9,10

Curcumin in the body is broken down to two main products, vanillin and ferulic acid.11 Vanillin is the primary flavor chemical found both in natural vanilla extracts and in synthesized ‘artificial vanilla flavoring.’ It is basically what Linares found buried in Megiddo. Research attention has turned toward vanillin and how it acts in comparison to curcumin.

What I consider a landmark study by Clara Iannuzzi and colleagues from Naples, was published in November 2017. Curcumin interferes with amyloid aggregation making it an attractive potential drug to use for treating Alzheimer’s disease. In a surprising twist, Iannuzzi also tested vanillin comparing its action with curcumin’s action. The authors suggested that vanillin may “… be responsible for mediating its [curcumin’s] beneficial effects.” In their research, both curcumin and vanillin acted similarly protecting against advanced glycation end products (AGEs) and they wrote that their “ … novel findings not only suggest that the main health benefits observed for curcumin can be ascribed to its degradation product vanillin, but also open new avenues for developing therapeutic applications of curcumin degradation products.”

We potentially might see the same or even better health effects from vanillin as we do from curcumin. A search of the medical literature yields a short but tantalizing list of studies that have reported similar actions of vanillin to what we previously have seen from curcumin.

A paper published in August 2018, used lipopolysaccharides (LPS) to trigger inflammation in microglia cells, the resident macrophages of the central nervous system. Microglia cells regulate the nerve inflammation that is currently blamed for diseases such as Alzheimer’s and Parkinson’s. Vanillin significantly decreased the production of nitric oxide and inflammatory cytokines including interleukin-1β, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). “Vanillin also reduced the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as the mRNA expression levels of IL-1β, TNF-α, and IL-6. Moreover, vanillin inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB.”12

Vanillin has anticancer effects on liver cancer and neuroblastoma. That puts vanillin on a short list of potential anti-cancer agents that have minimal side effects.13 Other studies suggest that vanillin decreases the ability of cancer cells to spread.14 Yet another study reports that vanillin enhanced apoptosis in cancer cells by inhibiting NF-KappaB activation, an action that is often associated with how curcumin triggers cancer cell death.15 It is via apoptosis, cell suicide, that vanillin stops colon cancer cell growth.16 As already mentioned vanillin prevents formation of AGEs.17 It was reported in 1977 that vanilla could potentially fight sickle cell anemia at least in in vitro experiments.18,19

We should note that ferulic acid, the other primary degradation product of curcumin, also possesses a wide variety of desirable biological activities such as antioxidant, antiinflammatory, antimicrobial, antiallergic, hepatoprotective, anticarcinogenic, antithrombotic, increased sperm viability, antiviral and vasodilatory actions, metal chelation, modulation of enzyme activity, activation of transcriptional factors, gene expression and signal transduction.20

At this point there is little research on using vanilla in animals and even less on using it medicinally in humans, though obviously there are countless food recipes that incorporate vanilla as flavoring. In several trials vanilla was given to pre-term babies to assess its calming effects. “Breast milk odor can decrease the variability of premature infants' heart rate and blood oxygen saturation during and after venipuncture.”21 [It should be mentioned though before anyone gets too excited, that the odor of breast milk itself has a greater calming effect than vanilla does.22]

What is fascinating about all this is that no one seems to be using vanillin therapeutically the way we use curcumin. OK, lots of protein powders contain vanilla flavoring, but that’s to cover up the taste of other ingredients. There is no reason for us to worry about toxicity or side effects from vanilla; it’s been on the FDA GRAS list forever. One big problem with vanilla though is that the human stomach breaks down vanilla prior to absorption. Neither large quantities of Breyer’s vanilla ice-cream nor Vanilla Hagen Daz will act as anti-inflammatories the way curcumin seems to.

There is an experimental drug called MX-1520 that attempts to sneak vanilla past all that digestion business and get it into the body. It seems to work, at least in mice.23 Though it’s still in early stages of development and is not yet available.

A 2013 paper reported that vanillin could be micro encapsulated with phosphatidylcholine in much the same way curcumin is to increase absorption.24 One must wonder whether curcumin and vanillin might be combined together into one liposomal product? It might also be possible to make a transdermal vanillin product.

One has to assume that someone will figure out a way to efficiently get vanillin into the body sometime soon. Then it will only be a matter of time to see if vanilla lives up to its promise. In the meantime it won’t hurt to add a bit of vanilla to your morning smoothie.

About the Author

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor.

References

  1. https://www.sciencemag.org/news/2018/11/biblical-city-armageddon-signs-early-vanilla-and-elaborate-medical-care Lawler A. In biblical city of Armageddon, signs of early vanilla and elaborate medical care. Science. Nov. 28, 2018.
  2. Bower B. A Bronze Age tomb in Israel reveals the earliest known use of vanilla. Science News. Vol. 194, No. 12, December 22, 2018, p. 10
  3. V. Linares. Long distance trade: Vanillin as a mortuary offering in Middle Bronze Age Megiddo. American Schools of Oriental Research annual meeting, Denver, November 16, 2018.
  4. V. Linares. Long distance trade: Vanillin as a mortuary offering in Middle Bronze Age Megiddo. American Schools of Oriental Research annual meeting, Denver, November 16, 2018.
  5. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol. Pharm. 2007;4:807–18. doi: 10.1021/mp700113r
  6. Ji HF, Shen L. Can improving bioavailability improve the bioactivity of curcumin? Trends Pharmacol. Sci. 2014;35:265–6. doi: 10.1016/j.tips.2014.04.001.
  7. Shen L, Ji HF. Contribution of degradation products to the anticancer activity of curcumin. Clin. Cancer Res. 2009;15:7108. doi: 10.1158/1078-0432.CCR-09-1749
  8. Shen L1, Ji HF. The pharmacology of curcumin: is it the degradation products? Trends Mol Med. 2012 Mar;18(3):138-44.
  9. ibid
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  11. Wang YJ, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal. 1997;15:1867–76.
  12. Kim ME, Na JY, Park YD, Lee JS. Anti-Neuroinflammatory Effects of Vanillin Through the Regulation of Inflammatory Factors and NF-κB Signaling in LPS-Stimulated Microglia. Appl Biochem Biotechnol. 2018 Aug 10.
  13. Naz H, Tarique M, Khan P, et al. Evidence of vanillin binding to CAMKIV explains the anti-cancer mechanism in human hepatic carcinoma and neuroblastoma cells. Mol Cell Biochem. 2018 Jan;438(1-2):35-45. d
  14. Jantaree P, Lirdprapamongkol K, Kaewsri W, et al. Homodimers of Vanillin and Apocynin Decrease the Metastatic Potential of Human Cancer Cells by Inhibiting the FAK/PI3K/Akt Signaling Pathway. J Agric Food Chem. 2017 Mar 22;65(11):2299-2306.
  15. Lirdprapamongkol K, Sakurai H, Suzuki S, et al. Vanillin enhances TRAIL-induced apoptosis in cancer cells through inhibition of NF-kappaB activation. In Vivo. 2010 Jul-Aug;24(4):501-6.
  16. Ho K, Yazan LS, Ismail N, Ismail M. Apoptosis and cell cycle arrest of human colorectal cancer cell line HT-29 induced by vanillin. Cancer Epidemiol. 2009 Aug;33(2):155-60.
  17. Awasthi S, Saraswathi NT. Vanillin restrains non-enzymatic glycation and aggregation of albumin by chemical chaperone like function. Int. J. Biol. Macromol. 2016;87:1–6.
  18. Zaugg, R.H., Walder, J.A. & Klotz, I.M.(1977) Schiff base adducts of hemoglobin. Modifications that inhibit erythrocyte sickling. Journal of Biological Chemistry, 252, 8542–8548
  19. Abraham DJ, Mehanna AS, Wireko FC, Whitney J, Thomas RP, Orringer EP. Vanillin, a potential agent for the treatment of sickle cell anemia. Blood. 1991 Mar 15;77(6):1334-41.
  20. Kumar N, Pruthi V. Potential applications of ferulic acid from natural sources. Biotechnol Rep (Amst). 2014 Sep 16;4:86-93.
  21. Neshat H, Jebreili M, Seyyedrasouli A, et al. Effects of Breast Milk and Vanilla Odors on Premature Neonate's Heart Rate and Blood Oxygen Saturation During and After Venipuncture. Pediatr Neonatol. 2016 Jun;57(3):225-31.
  22. Jebreili M, Neshat H, Seyyedrasouli A, et al. Comparison of Breastmilk Odor and Vanilla Odor on Mitigating Premature Infants' Response to Pain During and After Venipuncture. Breastfeed Med. 2015 Sep;10(7):362-5.
  23. Zhang C1, Li X, Lian L, et al. Anti-sickling effect of MX-1520, a prodrug of vanillin: an in vivo study using rodents. Br J Haematol. 2004 Jun;125(6):788-95.
  24. Castan L1, Del Toro G, Fernández AA, González M, Ortíz E, Lobo D. Biological activity of liposomal vanillin.J Med Food. 2013 Jun;16(6):551-7.