Curcumin Inhibits Virus-Induced Cytokine Storm

Curcumin, the active ingredient in the spice turmeric, has a solid foundation in science with numerous studies vouching for its anti-inflammatory effects.¹ As noted in a 2017 review in the journal Foods:²

"[Curcumin] aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia … Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects."

Along with several other supplements, curcumin has also been identified as having particular benefit against COVID-19.

According to the paper,³ "Potential Inhibitor of COVID-19 Main Protease (M^pro) From Several Medicinal Plant Compounds by Molecular Docking Study," posted March 13, 2020, on preprints.org, curcumin and demethoxycurcumin were two compounds among several that were found to inhibit COVID-19 M^pro.

As noted in "Designing of Improved Drugs for COVID-19,"⁴ COVID-19 M^pro is a potential drug target because "the crystal structure of M^pro provides a basis for designing of a potent inhibitor to the protease with a marked tropism to the lung."

Studies have also shown curcumin has an inhibitory effect on virus-induced cytokine storms, which occur as a result of an overproduction of immune cells and pro-inflammatory cytokines. This too suggests it may be of particular use against COVID-19, considering the cytokine storm triggered in severe and critical COVID-19 infection is what ends up killing these patients.

Curcumin Is a Potential Therapeutic Against COVID-19

Most recently, a scientific review⁵ in Frontiers in Cell and Developmental Biology, published June 12, 2020, reports curcumin might be useful in cases of severe viral pneumonia such as COVID-19. According to the authors:

"Coronavirus infection, including SARS-CoV, MERS-CoV, and SARS-CoV2, causes daunting diseases that can be fatal because of lung failure and systemic cytokine storm.

The development of coronavirus-evoked pneumonia is associated with excessive inflammatory responses in the lung, known as 'cytokine storms,' which results in pulmonary edema, atelectasis, and acute lung injury (ALI) or fatal acute respiratory distress syndrome (ARDS).

No drugs are available to suppress overly immune response-mediated lung injury effectively. In light of the low toxicity and its antioxidant, anti-inflammatory, and antiviral activity, it is plausible to speculate that curcumin could be used as a therapeutic drug for viral pneumonia and ALI/ARDS.

Therefore, in this review, we summarize the mounting evidence obtained from preclinical studies using animal models of lethal pneumonia where curcumin exerts protective effects by regulating the expression of both pro- and anti-inflammatory factors … promoting the apoptosis of PMN cells, and scavenging the reactive oxygen species (ROS), which exacerbates the inflammatory response.

These studies provide a rationale that curcumin can be used as a therapeutic agent against pneumonia and ALI/ARDS in humans resulting from coronaviral infection."

Curcumin Inhibits Cytokine Storm

As discussed in that Frontiers in Cell and Developmental Biology review,⁶ curcumin has a long history of medicinal use, without overt side effects. Studies have demonstrated it has potent antioxidant, anti-inflammatory, anticancer and antidiabetic activity, and clinical trials have shown efficacy in the treatment of cardiovascular diseases, metabolic syndrome, Type 2 diabetes and infectious diseases — especially viral infections.

In light of and its preventative and therapeutic role in viral infection and cytokine storms common to all viral infections, curcumin could conceivably be considered as an attractive agent for the management of coronavirus infections.

One important mechanism behind curcumin's beneficial effects is its ability to modulate immune responses, meaning it can both upregulate and downregulate immune responses as needed. According to the authors, at least four studies, published between 2018 and 2020, suggest curcumin inhibits virus-induced cytokine storms. These include:

• A 2018 study⁷ in the International Immunopharmacology journal, which showed curcumin inhibits influenza A virus replication and influenza-induced pneumonia. It also activates the Nrf2 signaling pathway, inhibits oxidative stress and improves influenza-induced ALI in vivo.
• A 2018 study⁸ in the Journal of Food and Drug Analysis, which found curcumin effectively inhibits influenza A infection.
• A 2019 study⁹ in Frontiers in Microbiology, which highlighted curcumin's antiviral activity against the influenza virus, hepatitis C virus and HIV.
• A 2020 study¹⁰ in the International Journal of Molecular Sciences that reported curcumin has the ability to block herpes simplex virus Type 2 (HSV-2) infection and inhibit production of inflammatory cytokines and chemokines in vitro.

Curcumin's Mechanisms of Action

As for how curcumin inhibits the cytokine storm and modulates immune function, the Frontiers in Cell and Developmental Biology review explains:¹¹

"There is clear evidence from coronavirus infected patients with both high cytokine levels and pathological changes in the lung. For example, in plasma of COVID-19 patients, high concentrations of IL-2, IL-6, and IL-7 have been observed.

In particular, IL-6 was significantly elevated in critically ill patients with ARDS compared to patients without ARDS and was statistically significantly correlated with death …

Numerous in vivo and in vitro studies have been shown that curcumin and its analogs markedly inhibit the production and release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, TNF-α …

Curcumin also decreases expression of many other inflammatory mediators … which regulate the activity of immune cells and inflammatory responses and promote fibrosis in the lung after infection.

The mechanism underlying curcumin modulation of inflammation has been extensively investigated and engages diverse signaling pathways, among which NF-κB plays an essential role. It was reported that curcumin effectively regulates NF-κB signaling through multiple mechanisms (Figure 2):

First, curcumin inhibits activation of IKKβ … Second, curcumin enhances the expression or stability of IκBα … Third, curcumin activates AMPK. It has been documented that curcumin blocks NF-κB signaling upon infection with Influenza A virus (IAV) as a consequence of AMPK activation. Fourth, curcumin acts on p65 to disturb the NF-κB pathway.

Infection with IAV led to a decrease of p65 in the cytosol of macrophages and a corresponding increase in the nucleus, where it forms a functional complex with NF-κB, ultimately upregulating transcription of pro-inflammatory cytokines. In contrast, the use of curcumin blocks the nuclear translocation of NF-κB and p65, downregulating transcription of the cytokine genes …

In contrast to its negative effect on pro-inflammatory molecules, curcumin has been shown to regulate anti-inflammatory cytokines positively, in particular IL-10. The latter is an essential negative regulator for inflammatory responses …

IL-10 acts on inflammatory monocytes to reduce the release of TNF-α, IL-6, and ROS, thereby alleviating tissue damage caused by the continuous inflammatory response … Curcumin noticeably attenuates lung injury by inducing the differentiation of regulatory T cells (Tregs) and upregulating IL-10 production."

Figure 2.

Curcumin Has Antiviral Activity

Curcumin also has direct antiviral activity — including against SARS-CoV (the coronavirus responsible for SARS), as demonstrated in a 2007 study.¹² Several studies have elaborated on its antiviral mechanisms, which Frontiers in Cell and Developmental Biology lists as:¹³

• Directly targeting viral proteins
• Inhibiting particle production and gene expression
• Blocking viral attachment to cells (possibly by disrupting the fluidity of the viral envelope)
• Blocking viral entry into the cell
• Blocking viral replication

Curcumin binds strongly to hemagglutinin (HA), a glycoprotein that allows the influenza virus to attach to the cell. Research has shown curcumin interacts with HA, thus disturbing the integrity of the viral membrane. This is what blocks viral binding to the host cell and prevents the virus from entering the cell. Curcumin has also been shown to directly inactivate certain strains of influenza virus.

Other Pulmonary Benefits of Curcumin

Other beneficial effects that suggest curcumin may be suitable in the treatment of COVID-19 include:¹⁴

Alleviating exudation of proteins to alveoli spaces	Alleviating lung edema triggered by inflammation
Attenuating lung injury	Reducing the degree of airway inflammation
Disrupting airway remodeling by inhibiting the proliferation of bronchial epithelial cells	Improving pneumonia and preventing development of severe pneumonia
Alleviating ALI-induced pulmonary fibrosis	Improving lung index

According to the Frontiers in Cell and Developmental Biology review,¹⁵ the available research "suggest that curcumin administration could have both prophylactic and therapeutic effects on virus-induced pneumonia and mortality." Furthermore, while human trials on curcumin for coronaviruses are still lacking:

"… in light of and its preventative and therapeutic role in viral infection and cytokine storms common to all viral infections, curcumin could conceivably be considered as an attractive agent for the management of coronavirus infections."

Research published in 2015 further supports the conclusions in the Cell and Developmental Biology review. That study,¹⁶ "Curcumin Suppression of Cytokine Release and Cytokine Storm," found curcumin could be a potential therapy for patients infected with Ebola and other dangerous viruses. According to the authors:¹⁷

"The activity of curcumin in suppressing multiple cytokines, and its activity in experimental models of diseases and conditions associated with cytokine storm, suggest it may be useful in the treatment of patients with Ebola and cytokine storm.

Curcumin is poorly absorbed from the intestinal tract; however, intravenous formulations may allow therapeutic blood levels of curcumin to be achieved in patients diagnosed with cytokine storm."

How to Get the Most Out of Your Curcumin Supplement

If you want to use curcumin, be aware that its poor absorption rate is one of its greatest drawbacks. While IV formulations may solve the problem in clinical settings, that would be rather impractical for home use.

Researchers have investigated a variety of different delivery methods, including oral, intravenous, subcutaneous and intraperitoneal delivery, as well as a variety of formulations, to optimize bioavailability. The following methods were all found to improve the absorption rate of curcumin:¹⁸

• When delivered as a nanoparticle
• Combined with polylactic-co-glycolic acid
• Liposomal encapsulation

Since curcumin is fat-soluble, you might be able to further increase absorption by making a microemulsion. To do that, combine 1 tablespoon of curcumin powder with one or two egg yolks and 1 to 2 teaspoons of melted coconut oil, then use a hand blender on high speed to emulsify the powder.

Timing is another important variable. One of the ways curcumin works is to activate AMPK and autophagy. Both of these occur during the fasted state. So, it would best to take curcumin at least three hours after a meal and/or right before you go to bed. This would be similar for another powerful anti-COVID supplement, quercetin, which should also be taken while fasting and preferably with zinc.

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