Reviewed: Wieland LS, Piechotta V, Feinberg T, et al. Elderberry for prevention and treatment of viral respiratory illnesses: A systematic review. BMC Complement Med Ther. April 7, 2021;21(1):112. doi: 10.1186/s12906-021-03283-5.

The COVID-19 pandemic has brought renewed attention to the potential of complementary and alternative medicine (CAM) to help prevent or treat viral upper respiratory tract infections (URTIs). Elder berry (Sambucus spp., Viburnaceae) flowers and fruit have been used traditionally for respiratory symptoms, including those caused by colds and influenza. Mainstream sales of elder berry dietary supplements in the United States grew by more than 150% from 2019 to 2020. Elder berry products may be legally marketed as being able to support immune health, but the US Food and Drug Administration has issued warnings to manufacturers that claim elder berry products can prevent, treat, or cure COVID-19. There is currently no known evidence for or against these claims. Several human clinical trials of elder berry and COVID-19 are underway,^1,2 but no results have been published as of October 2021.

Elder berry’s anthocyanins have demonstrated immunomodulating, antiviral, and anti-inflammatory effects in vitro. They attach to viral glycoproteins, which limits viral ingress into cells and thus inhibits infection. While some evidence suggests that anthocyanins increase levels of pro-inflammatory cytokines, other evidence shows decreases. While an increase in pro-inflammatory mediators might help prevent some conditions and is a natural part of the immune response to infection, one concern with using elder berry is that the deadly “cytokine storms” afflicting some COVID-19 patients might be made worse by pro-inflammatory agents. The authors of a previous meta-analysis on elder berry, which predated COVID-19, did not include elder berry’s effects on cytokine-related outcomes.³

The authors conducted a systematic review (SR) of randomized, controlled trials (RCTs) and ex vivo studies (i.e., cytokine-related studies) that investigated the potential benefits and risks of elder berry alone or compared with placebo or active interventions in preventing or treating viral respiratory ailments. They also assessed the relationship between elder berry supplements and any negative health consequences associated with excessive cytokine production.

Inclusion Criteria

Studies of elder berry’s preventive effects were included even if participants had not yet been diagnosed with the common cold, flu, or any novel coronavirus infection. The authors excluded unpublished studies, as well as studies on bacterial respiratory infections and virally triggered respiratory conditions (e.g., rhinosinusitis) that were not related to the common cold, flu, or novel coronaviruses. To assess elder berry’s effects on cytokines, the authors also included studies with participants who received elder berry for other reasons.

While European elder berry (S. nigra) was the most-used species, studies that used other elder berry species, preparation types (e.g., syrup, lozenge, capsule), and doses were included. Studies of elder berry combined with other herbs were included but grouped separately from elder berry-only studies in all analyses. One studied product, Echinaforce^® Hot Drink (A. Vogel AG; Roggwil, Switzerland), combined elder berry and echinacea (Echinacea purpurea, Asteraceae).

Study Details

Eight studies were included in this SR: five RCTs on prevention and/or treatment and three ex vivo studies that assessed cytokine production. One RCT (n = 312) reported on elder berry vs. placebo in preventing common cold symptoms. Three RCTs (n = 151) assessed elder berry vs. placebo in treating influenza. One RCT (n = 420) reported on Echinaforce Hot Drink vs. oseltamivir in treating influenza.⁴

The three ex vivo studies that evaluated cytokine production included an RCT (n = 52), a single-arm cohort study (n = 22), and an evaluation of cytokine production before and after single doses of elder berry vs. diclofenac (n = unknown).

Unclear and/or high risks of bias marred most reports. Levels of certainty for evidence of elder berry’s ability to prevent or treat viral respiratory infections were moderate to very low. Study heterogeneity appeared high. Insufficient data prevented subgroup analyses based on cohort demographics, clinical characteristics, or dose/type of elder berry formulation.

Results

The five prevention and treatment RCTs showed slight advantages of elder berry, but limited data and poor study quality prevented the authors from making any firm conclusions. The RCT of elder berry’s preventive effects on the common cold showed no clear evidence of reduced risks but suggested that elder berry may decrease duration and severity of symptoms. In the three RCTs of elder berry treatment in influenza, reduced symptom duration and severity also were suggested. The RCT of Echinaforce Hot Drink vs. oseltamivir found a slightly higher recovery rate with oseltamivir after one day of treatment but little or no difference between treatments at five or 10 days. There may be less risk of adverse effects and complications with the herbal product than with oseltamivir.

In healthy adults, elder berry significantly reduced some cytokines, indicating a possible anti-inflammatory effect, but evidence was “underwhelming” in studies with longer durations, suggesting that the effect may abate with repeated use. Elder berry was as effective or slightly less effective as diclofenac in reducing interleukin-1 (a key signaling molecule involved in regulating inflammation) concentrations over time. No evidence indicated that elder berry causes excessive cytokine production.

Conclusion

According to the authors, elder berry is a promising intervention for preventing and treating viral respiratory infections, and it does not appear to be associated with serious adverse effects, but scientific evidence is limited in amount and quality. Unpublished and ongoing trials may help clarify elder berry’s potential role in viral respiratory infections, but more studies of sufficient size and quality are needed.

References

1. A comparison of elderberry (Sambucus nigra) extract syrup and placebo against COVID-19 symptoms in outpatients and home quarantined patients: A randomized double-blind clinical trial. Iranian Registry of Clinical Trials website. Available at: https://en.irct.ir/trial/46958. Accessed July 25, 2021.
2. Help research treatments into Covid-19. June 24, 2021. East Kent Hospitals University/National Health Service Foundation Trust website. Available at: www.ekhuft.nhs.uk/patients-and-visitors/news-centre/latest-news/help-research-treatments-into-covid-19/. Accessed July 25, 2021.
3. Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019;42:361-3655. https://doi.org/10.1016/j.ctim.2018.12.004.
4. Gafner S. Echinaforce^® Hotdrink is as effective as Tamiflu^® in early treatment of influenza. HerbalGram. 2015;107:30-31.