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letter
. 2021 Feb;20(1):8–9.

Letters

Emine Karatas 1
PMCID: PMC8352416  PMID: 34393670

Dear Editor,

The article named “The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents” does not coherent with references. The author misunderstands the studies about elderberries.

The author has emphasized that ‘One in-vitro study reported an increase in TNF-alpha levels related to a specific commercial preparation of elderberry,1 leading some to caution that its use could initiate a “cytokine storm.” However, these data were not confirmed when the same group performed similar studies, which were published in 2002.2’

But first study (105) show that “Production of inflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8) was significantly increased, mostly by the Sambucol Black Elderberry Extract (2-45 fold), as compared to LPS, a known monocyte activator (3.6-10.7 fold).’’

The other study shows that ‘’The Sambucol preparations increased the production of five cytokines (1.3-6.2 fold) compared to the control. Protec induced only a moderate production of IL-8 (1.6 fold) and IL-10 (2.3 fold) while Chizukit N caused only a moderate increase in IL-10 production (1.4 fold). Both Protec and Chizukit N caused moderate decreases in IL-1 beta, TNF-α and IL-6 production. Lipopolysaccharide, a known activator of monocytes, induced the highest levels of cytokine production (3.6-10.7 fold).’’

Protec and Chizukit N contain propolis and Echinacea, claimed to be immune enhancers, do not contain elderberries

I am looking forward to your answers. Best regards.

References

  • 1.Evans JM, Luby R, Lukaczer D, et al. The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents. Integr Med (Encinitas). 2020;19(Suppl 1):34-42. [PMC free article] [PubMed] [Google Scholar]
  • 2.Evans JM, Luby R, Lukaczer D, et al. The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents. Integr Med (Encinitas). 2020;19(Suppl 1):34-42. [PMC free article] [PubMed] [Google Scholar]
Integr Med (Encinitas). 2021 Feb;20(1):8–9.

Response

The IFM Covid-19 Task Force

The scope of our review did not allow for a complete discussion of elderberry’s potential antiviral benefits, and related to this comment, the likelihood that consumption of elderberry preparations could initiate or exacerbate a cytokine storm subsequent to an infection by SARS-C0V-2. The in vitro study performed by Barak et al. in 2001 is often cited by those cautioning against the use of elderberry for this very reason.1 As Dr. Karatas correctly points out, the follow-up in vitro study published by Barak et al. in 2002 indeed showed a higher increase in cytokine production when various commercial elderberry products were added to patient monocytes (when compared to other non-elderberry preparations).2 However, unlike the first study, the magnitude of increase with elderberry preparations was significantly lower than when LPS was used. Similarly, using a pure elderberry extract, researchers recently showed a dose-dependent decrease in TNF-alpha, IL-6, COX-2, and PGE2 when added to LPS-stimulated mouse monocytes.3 Nevertheless, it is notoriously challenging to translate in vitro studies, where commercial preparations are directly placed upon isolated immune cells, to their potential positive (or negative) outcomes in human subjects. When using botanical compounds that are known to have low absorption, and/or are modified after ingestion, it becomes even more challenging.4

Only a few published studies appear to have evaluated the levels of various cytokines after the ingestion of elderberry preparations in animals or humans. While these data are limited, none of them show an increase in pro-inflammatory cytokines after ingestion of elderberry extract, and the animal studies suggest the potential to lower some of these cytokines. A study in obese mice showed that oral consumption of elderberry extracts (berry-13% anthocyanins) for 16 weeks reduced markers of insulin resistance and inflammation (specifically TNF-α).5 Elderberry and Aronia berry extracts given separately to rats (diabetes model) for 16 weeks also showed decreased inflammatory markers (including TNF-a).6 Finally, a human clinical study which gave elderberry extract in capsules (500 mg/day of anthocyanins, comparable to 25 grams of elderberries) to postmenopausal women for 12 weeks found, disappointingly to the researchers, no changes in any inflammatory biomarker measured (CRP, TNF-α, IL-6, TNF RI and RII, and RANTES).7 These women did not have particularly elevated inflammatory markers prior to consuming the elderberry extract (CRP was 1.3 mg/L at baseline). Again, while these data are limited, they are more consistent with the larger data set showing anti-inflammatory (or no effect) related to the consumption of anthocyanin-rich diets or products.8,9

Whether the consumption of elderberry preparations proves to be an effective adjunct therapy for preventing or treating COVID-19, in a manner similar to the published results with other respiratory viral infections, is still to be determined.10 Nonetheless, the notion that consumption of elderberry preparations is likely to contribute to a cytokine-induced negative outcome in subject with COVID-19 is highly implausible. We are not aware of any reports published in 2020, during a time when elderberry consumption has depleted most of the global supply, of such an adverse outcome; in keeping with the long-term safety of such preparations.

References

  • 1.Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw. 2001Apr-Jun;12(2):290-6. [PubMed] [Google Scholar]
  • 2.Barak V, Birkenfeld S, Halperin T, Kalickman I. The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines. Isr Med Assoc J. 2002November;4(11 Suppl):919-22. [PubMed] [Google Scholar]
  • 3.Zielińska-Wasielica J, Olejnik A, Kowalska K, et al. Elderberry (Sambucus nigra L.) Fruit Extract Alleviates Oxidative Stress, Insulin Resistance, and Inflammation in Hypertrophied 3T3-L1 Adipocytes and Activated RAW 264.7 Macrophages. Foods. 2019August8;8(8). pii: E326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Frank T, Janssen M, Netzet G, et al. Absorption and excretion of elderberry (Sambucus nigra L.) anthocyanins in healthy humans. Methods Find Exp Clin Pharmacol. 2007October;29(8):525-33. [DOI] [PubMed] [Google Scholar]
  • 5.Farrell NJ, Norris GH, Ryan J, et al. Black elderberry extract attenuates inflammation and metabolic dysfunction in diet-induced obese mice. Br J Nutr. 2015October28;114(8):1123-31. [DOI] [PubMed] [Google Scholar]
  • 6.Badescu M, Badulescu O, Badescu L, Ciocoiu M. Effects of Sambucus nigra and Aronia melanocarpa extracts on immune system disorders within diabetes mellitus. Pharm Biol. 2015April;53(4):533-9. [DOI] [PubMed] [Google Scholar]
  • 7.Curtis PJ, Kroon PA, Hollands WJ, et al. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12 weeks. J Nutr. 2009December;139(12):2266-71. [DOI] [PubMed] [Google Scholar]
  • 8.Fallah AA, Sarmast E, Fatehi P, Jafari T. Impact of dietary anthocyanins on systemic and vascular inflammation: Systematic review and meta-analysis on randomised clinical trials. Food Chem Toxicol. 2020January;135:110922. [DOI] [PubMed] [Google Scholar]
  • 9.Li S, Wu B, Fu W, Reddivari L. The Anti-inflammatory Effects of Dietary Anthocyanins against Ulcerative Colitis. Int J Mol Sci. 2019May27;20(10). pii: E2588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Harnett J, Oakes K, Carè J, Leach M, Brown D, Cramer H, Pinder TA, Steel A, Anheyer D. The effects of Sambucus nigra berry on acute respiratory viral infections: A rapid review of clinical studies. Adv Integr Med. 2020December;7(4):240-246. [DOI] [PMC free article] [PubMed] [Google Scholar]
Integr Med (Encinitas). 2021 Feb;20(1):9.

Response

Samuel F Yanuck 1

One of the challenges we have in the evaluation of natural medicine tools is that our traditional views of how they work are often rooted in ideas like “immune support” that don’t have specific enough meanings to match the complexity of their actual mechanisms of action, which are almost always multiple, weblike, and dependent on the context of individual patient biology. In immunology in particular, the explosion of new knowledge has rendered old explanations and ideas obsolete, while giving us newer and deeper ways to understand what we’re seeing in our patients. Despite these new and more textured levels of understanding, the tendency toward simplification extends into discussions of what cytokines like TNF-α or IL-6 do. Measuring specific cytokines in narrow contexts in a research setting has limited application to the much more complex biological environment of a human. An herb, for example, may contain fifty different bioactive substances, each of which may act on multiple targets in different body compartments, yielding a web of effects.

In a clinical setting, we track patient responses to specific interventions and compare them with what the research suggests would be the expected responses, all in the context of thinking about the underlying biology. When our observations don’t match the research, we have to sort out what that might or might not mean. That process is informed by thoughts from our colleagues in the clinical epidemiology world and don’t need to be reviewed here. But what’s clear is that the observations need to be taken at face value.

What concerns me about elderberry is that, in my own clinical experience, it’s pretty clear that my use of elderberry unwittingly instigated new autoimmunity in several patients, back in the 1990’s when I thought that elderberry was an “immune support.” And, since observing this, when I then began to carefully examine the timelines of new patients at intake, for whom autoimmunity had already developed, I’ve often identified the same pattern in their history of elderberry use.

What’s most important in any scientific endeavor is that direct observations need to be given a high level of evidentiary consideration. Doing good research is essential and we need to keep doing it. We also need to keep making clinical observations and integrating them into the ongoing research process. There are ways in which both the research process and the clinical observation process have inherent limitations. And each may have useful ways of informing the other. I don’t know whether my observations reflect a causal connection between autoimmune instigation and elderberry. But it is clear to me that, from an immunological point of view, the currently available research does not exclude that possibility.

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