Introduction

Humans can distinguish five basic tastes: sweet, sour, bitter, salty, and umami. The evolutionary development of these tastes has enabled the human species to discern what foods are beneficial to our health, as well as what foods are toxic or rotten. These toxic and rotten foods are often high in bitter constituents, and as such, humans have developed a sensitivity to these flavors (Andres-Barquin & Conte, 2004). This sensitivity to the bitter taste manifests in a G coupled protein receptor that is controlled by the Type 2 Receptor (T2R) gene family. These T2Rs, first thought only to be located on the tongue's taste buds, have recently been discovered in virtually every system within the body. The prevalence of T2Rs throughout the body could explain why bitters have a broad medicinal effect. Illustrative of this idea, Hoffman (2003) provides eight body system affinities of bitter herbs along with 18 secondary herbal actions.

Our ancestors understood the healing power of herbs, and to that extent, virtually every single known herbal tradition includes the use of bitters orally for a myriad of toning and digestive stimulation. It's not until fairly recently that the discovery of T2Rs on the skin opened an entire panacea of new research designed to obtain a better understanding of how exactly herbal constituents interact with the human skin. Bitter herbs are being demonstrated in clinical settings to improve conditions like dermatitis and psoriasis (Wölfle et al., 2015). While this is promising, perhaps it's the anti-aging and anti-microbial qualities bitters appear to have that could be transformative for the cosmetics and hygiene industries (You, 2015).

In a broad sense, humans evolved to have a sharp sense for detecting bitters as a protection mechanism to help keep us safe from an environment that's filled with a whole host of toxins. The primary goal of the body's reaction to bitter compounds is to eliminate or reduce their deleterious effects as quickly as possible. As such, bitter elements tend to speed up digestion, increase the production of digestive juices, and aid in toning the digestive tract. On the skin, bitters have an equally protective role. Regardless of the location of the bitter taste receptor, bitters have a pivotal role to play in the herbal medicine formulations of the future. But before understanding what the future of bitters has in store for us, it's important to understand what bitters have done to get us to where we are today.

The History and Energetics of Herbal Bitters

Virtually every culture uses bitter herbs for their cooling and drying energetics (Woods, 2004). Traditional Chinese Medicine (TCM) classifies bitters as Yin and use them to help clear and discharge heat, aid in drying damp conditions, and consolidate Qi (Chen et al., 2015). In Ayurvedic tradition, bitters are used to aid in balancing the hot and intense attributes of Pitta constitution (Purkh et al., 2008). The American eclectic understanding of bitters was equally as widespread, with over 100 herbs being cited as having bitter qualities in King's American Dispensatory (Felter & Lloyd, 1898). While the historic application of bitters looks at the energetics and constitution, a more modern approach is developing a deeper understanding of the specific interaction bitter compounds have on the body. This pharmacodynamic interaction starts when a bitter compound meets the Type 2 Receptor (T2R), most abundantly found in the taste buds throughout the tongue.

The Bitter Taste Receptors

Activated by bitter compounds, the T2Rs on the tongue ignite a chemical signaling process that ultimately leads to the firing of neurotransmitters through the gustatory nervous system to alert the brain of the bitter sensation (Andres-Barquin & Conte, 2004). The brain then directs an upregulation of digestive function. These T2Rs may also function on a more acute level. Should a bitter compound find its way into the sinus cavity, the T2Rs located there within will cause the sinonasal epithelia to increase the ciliary beat frequency allowing for the cell to more rapidly remove harmful microorganisms (Lu et al., 2017). Once the bitter compound is swallowed, the T2Rs located throughout the gut will initiate a type 2 immunity response and the enteroendocrine cells (EEC) within the gut will trigger an endocrine hormone response. Further down the digestive line, the T2R's contained within the lower gastrointestinal tract, when activated, stimulate release with the intent to rid the body of possible toxins within the stool (Lu et al., 2017).

These T2Rs aren't merely relegated to the digestive system. Take, for example, a bitter compound which finds its way into the urethral system. The T2Rs contained within brush cells, will trigger an acetylcholine response which stimulates a localized muscle contraction, essentially tightening the barriers for potentially harmful agents (Lu et al., 2017). T2Rs are found in the male and female reproductive systems, the respiratory system, and within smooth muscle tissue (Workman et al., 2015). These T2R receptors can be found throughout the human body and seem to always play a protective role.

The Skin and the Bitter Taste Receptors

The skin is the largest organ and protective barrier our bodies have which is responsible for thermoregulation, UV protection, and provides a critical role in supporting immunological functions (Egert et al., 2017). Not surprisingly, the skin also contains an abundance of T2Rs (Shaw et al., 2018) and have been demonstrated to be triggered by exposure to one of the most bitter compounds on the planet, amarogentin, which is a constituent of Gentiana lutea (Wölfle et al., 2015).

Gentiana lutea and the Skin

In addition to G. lutea's anti inflammatory qualities, G. lutea also increases the production of a specific lipid called ceramides (Wölfle et al., 2017). Ceramides are vital for skin function and health, and starting around the age of 20 ceramide production is naturally reduced by about 1 - 1.5% per year (Wölfle et al., 2017). The fact that topical application of G. lutea could slow the aging process of skin could have profound effects in the cosmetic industry. G. lutea isn't the only bitter herb that has been demonstrated to have this ceramide producing effect. Bonté et al. (1996) used an extract of Simarouba amaret to similar effect. This idea suggests that while G. lutea will certainly trigger these lipid production effects, it's possible that this lipid refueling effect could be a systemic quality of herbal bitters and not just a unique property of G. lutea root. Another powerful herb, Andrographis paniculata, has also been shown to have many beneficial effects when applied topically.

Andrographis paniculata and the Skin

In vitro, A. paniculata constituents were demonstrated to have antifungal (Sule et al., 2012), as well as antibacterial and free radical scavenging effects (Arifullah et al., 2013). While these effects haven't been specifically proven to be effective topically in vivo, based on the overwhelming interaction topical bitters have with the skin, it's certainly highly likely these effects exist. Another topical bitter plant with remarkable qualities is Achillea millefolium.

Achillea millefolium and the Skin

Taraxacum officinale and the Skin

This maintained production of GSH, a powerful antioxidant, combined with it's UV protective and restorative properties all lend credence to the speculation that an aqueous extract of T. officinale leaf and flower could be an effective natural sunscreen agent (Yang, & Li, 2015).

Artemisia vulgaris, A. asiatica, and A. annua and the Skin

It's been well demonstrated thus far that bitter herbs have a role to play as topical antimicrobials and anti-inflammatories, but some bitters, specifically A. vulgaris, for example, enhanced the expression of healthy skin bacteria while simultaneously not increasing inflammation. Broadly applied A. vulgaris across the skin could introduce the idea of microbiome management to hygiene products (Egert, Simmering, & Riedel, 2017). Another plant in the Artemisia family that has topical considerations is A. asiatica. A. asiatica is UV protective, can stimulate collagen growth, reduces photoaging, and helps remodel the skin (Jeong et al., 2018).

A. annua provides anti-inflammatory and antimicrobial benefits to the skin, has been shown to be very effective against Staphylococcus aureus bacteria (Mirbehbahani et al., 2020). Artemisinin, an antimalarial drug created from A. annua, is antiinflammatory when applied to the skin with possible therapeutic uses for inflammatory skin disorders like rosacea (Yuan et al, 2019).

The Bright Future of Bitters

Herbal bitters have been used for thousands of years. Medical traditions from all over the world have used a plethora of bitter plants to support a wide range of conditions. Classically, bitters have been used to improve and tonify digestion. Though with a greater understanding of receptor theory and the realization that the bitter receptor, T2R, is located throughout various systems within the body has expanded their medical impact. Recently with the realization that the skin contains T2Rs, a host of research has been conducted to determine the precise effect of topical bitters application. This research has started to forge a fascinating new frontier in medical use of bitters.

G. lutea, A. paniculata, A. millefolium, T. officinale, A. vulgaris, and A. asiatica all have well documented effects on the human skin when applied topically. While each herb might interact with the skin in various ways, a few common themes of the research have emerged. Topically applied bitter herbs have been clinically demonstrated to be anti-inflammatory, anti-microbial, promote skin cell regeneration, increase skin cell's collagen production and elasticity, anti-photoaging, and protective against UV light.

The results of this research could have profound effects in cosmetic and hygiene applications. Bitter soaps might help with improved hygiene. Bitter face cleansers could be used as beauty designed to reduce the appearance and effect of aging and sun exposure. Bitter sun screens can protect and heal the skin at the same time. Bitter baths could promote the maintenance of an optimal skin biome. In a more clinical setting, bitter creams and oils can be developed to possibly treat psoriasis and dermatitis. Research can be performed to see what effect topical bitters might have on skin cancer.

Additionally, there are 25 variations of the bitter receptor, and lists are being made of which bitter ligand interact with which bitter receptor variation (Meyerhof et al., 2009). Possible research could be focused around targeting specific bitter receptors with a very specific bitter compound to stimulate a specific effect in a specific human tissue.

The research presented in this report is a promising start to a better understanding of how herbal bitters can be used topically. Future research can work to develop a better understanding of specific dosing, as well as exploring possible synergies in combining multiple bitter herbs together. Regardless of where the research goes from here, one thing is clear: topical application of bitter herbs has massive clinical and self-care potential. While A. paniculata might hold the name "king of bitters," perhaps it's time to finally anoint bitters with the title so rightfully deserved: "King of Herbs."