Botanical dietary supplements related to immune function have been in high demand for the past several years, even before the COVID-19 pandemic began. For example, elderberry experienced over 100% growth in both 2018 and 2019, and in 2019 three of the top four selling botanicals in the mainstream channel were from the immune health category.

While elderberry and echinacea are two of the most popular herbs that have long been associated with immune support and are well-studied for immunity endpoints, there is increased research interest in a group of botanicals called adaptogens that show activity as immune modulators.

Awareness of the benefits of adaptogens has been galvanized by the need for efficient tools to manage stress in the everyday lives of modern humans, as these herbs are associated with resilience and are generally marketed to support mental stamina and help the body cope with stress.

The concept of adaptogens in human health has roots in a 1936 letter to the editor of Nature by Hans Selye where the classic general adaptation syndrome was first proposed, the gist being that a stressor causes a temporary decrease in function followed by an adaptation that improves function and maintains homeostasis. During the 1940s in the context of WWII, the theory that a pill could improve mental and physical performance in healthy people was proposed and various substances perceived as stimulants were tested on pilots and submarine crews. In the 1950s and 1960s scientists further developed the idea of using medicinal plants to increase stamina and survival in stressful or potentially harmful environments, and the concept of “adaptogens” was introduced by Russian toxicologist Nikolay Lazarev in 1958. Adaptogens were originally described as enhancing the state of non-specific resistance, and as leading to increased working capacity and performance in an environment of fatigue and stress, regardless of the nature of the stressor.

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The immunity connection

Humans are exposed to a variety of stressors each day, including millions of potential pathogens like viruses and bacteria. The ability to prevent infection is in part mediated by the adaptive immune system, which remembers specific pathogens and attacks them when encountered again. But adaptive immune responses require several days or more to respond effectively to pathogens upon first exposure, and a crafty pathogen that reproduces quickly can develop into a full-blown infection in a single day. So, during the first critical hours and days of exposure to a new pathogen, humans depend on the innate immune system for protection.

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Innate immune responses are not specific to a particular pathogen; they depend on a group of proteins and phagocytic cells that recognize broadly conserved features of pathogens and are quickly activated to destroy the invaders. Adaptogens have been shown to modulate these processes through a variety of mechanisms.

The term adaptogen has been defined variously, but generally refers to preparations that increase focus and endurance in fatigue, reducing stress-induced issues by mediating multiple pathways in neuroendocrine and immune function.

More than 100 plants have been reported in the literature as being adaptogenic, but only a few of those species are known to exhibit key multitarget effects on the neuroendocrine-immune system—including schisandra, eluthero, rhodiola, and Andrographis paniculata. These effects include triggering adaptive signaling pathways that promote cell survival, resilience in stress, anti-inflammatory activities, and regulating metabolism and homeostasis through a variety of stress hormones such as cortisol and melatonin.

The big four adaptogens

The early study of adaptogens was prolific in Russia, with more than 1,000 pharmacological and clinical studies published in just a few decades, most focused on Schisandra chinensis or Eleutherococcus senticosus.

Schisandra emerged with reports of Nanai hunters in far eastern Siberia and northern Manchuria using the berries and seeds as a tonic to reduce thirst, hunger, and exhaustion and to improve night‐time vision.

In the 1960s schisandra preparations became official as Russian medicines and the basis of several pharmacopeial monographs after clinical research with various ailments, including infectious diseases such as influenza and pneumonia. More recent rigorous clinical investigations on schisandra, alone or complexed with other herbs, support early observational studies and have reported positive outcomes for immune-related indications like COPD and chemotherapy-induced immunosuppression.

Eleuthero was also extensively studied in early clinical work with over 70 observational trials on more than 4,500 patients showing beneficial effects on stress-related and cardiopulmonary disorders. More recent investigations have shown promise for eleuthero’s ability to prevent infectious disease incidence; a controlled, double-blind study with more than 1,300 subjects showed beneficial effects against influenza and other respiratory infections.

Some of the existing clinical work on adaptogens has been conducted on multi-herb formulations. Five randomized, controlled trials on more than 1,000 subjects, all using a product made by the Swedish Herbal Institute containing both eleuthero and andrographis, showed beneficial effects against respiratory tract infections and symptoms of the common cold.

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Andrographis preparations have been the focus of a large body of clinical work. A meta-analysis of 33 randomized controlled trials in more than 7,000 patients showed evidence of reduced cough and sore throat and improved overall symptoms of respiratory tract infections. As revealed in this meta-analysis, randomized double-blind trials in patients with the common cold have consistently reported decreased intensity of symptoms like sinus pain and headache when compared with placebo.

Other noted beneficial effects of A. paniculata have also included less time to recovery and reduced sick leave days after infections. Preclinical work has elucidated some of the multi-target mechanisms; for example, the constituent andrographolide is highly active against influenza A viruses in vitro, including H1N1 and H5N1, and exerts its antiviral activity by directly interfering with viral particle binding to red blood cell surface receptors.

Rhodiola rosea is a revered adaptogen that was popular with the Vikings to enhance mental and physical endurance and has been used throughout history in Iceland, Sweden, France and Russia. Greek physician Dioscorides discussed the virtues of rhodiola root in the first century CE; the herb was included in the first Swedish Pharmacopeia and the 1749 Materia Medica of Carl Linnaeus. Multiple clinical trials have confirmed the adaptogenic properties of rhodiola showing improvements in physical performance and stress-related fatigue, and protective effects in respiratory conditions and ischemic heart disease. One study reported increased anti-viral activity in marathon runners, and research continues for a variety of immunity related endpoints.

A recent review analyzed hundreds of published studies detailing direct and indirect preclinical effects of adaptogens on immune response and evaluated significant clinical work on adaptogens in viral infections. The authors suggest adaptogens that exert effects through multiple molecular targets can play a potentially important role in prevention, infection, inflammation and recovery phases of viral infection. 

Stress and inflammation are closely linked to the human immune response, so it makes sense that adaptogens, which are known to be effective in mediating stress responses and inflammatory pathways, may also be useful in maintaining a healthy immune system. There will certainly be more research to come.

Holly E. Johnson, Ph.D. is a pharmacognosist and the Chief Science Officer for the American Herbal Products Association.

For more on immune-support ingredients, download the free Natural Products Insider digital magazine on all things immunity—evidence-based ingredients, innovative finished products so you can keep up on the competition, and how to market products depending on your risk tolerance.