At Rasa, we are often asked: So how do adaptogens work? The easy answer is that they help us adapt to stress. The harder answer of how exactly they help us adapt to stress is an ongoing conversation in the scientific community and among herbalists worldwide. This blog is a summary of what we think we know. While herbs affect us on many levels— physical, emotional, spiritual—this is an exploration of the physical: the phytochemistry of plants.
In this review, I'll cover the use of these herbs in the energetic models of traditional medicines, the plant compounds involved (triterpenoid saponins), the main mechanism of action (cortisol regulation), and some secondary mechanisms. This is far from comprehensive! Oversimplification for the sake of brevity and losing ourselves in overwhelming technicalities are the two banks this river of words will attempt to navigate.
Energetics in traditional medicine systems have many layers. Perhaps the simplest expression of energetics is the two pairs hot/cold and moist/dry found in Traditional Greek Medicine (TGM). Ayurveda’s tridosha theory of pitta, kapha, and vata is another example. Traditional Chinese Medicine (TCM) could provide many more. While these systems are all very different, there is one core energetic concept that they all share to a degree—that of vital energy. TGM defines this vital energy as pneuma—the true energy that flows from the heart. Similarly, TCM holds Qi as the expression of a person’s vital spirit.
In many traditional medicine systems around the world, this Qi or vitality can be compromised by sudden exertion, acute shock, intense emotions, or chronic physical/mental overstimulation and work. This results in conditions of low energy, depression, lack of mental clarity, low immune function, and general weakness. Where did these traditions turn in cases of depressed vitality? To their revered herbs. These systems all hold in high regard herbs that act as restoratives or tonics for this vital life force. This includes the Qi tonics of TCM as well as the Rasayanas of India’s Ayurveda.
Qi deficiency and other expressions of this depressed vitality closely resemble the modern symptom picture of burnout and HPA-axis dysregulation (aka adrenal fatigue). So could these traditional herbs be used to counteract our modern malaise? Indeed, research is showing us that these herbs, now grouped together under the term *adaptogens*, all act as neuroendocrine restoratives. This means that they help rebalance our stress response, our hormone levels, and bring back a healthy equilibrium to our body.
While the tonics of these traditions have only recently been grouped together under the modern scientific classification of *adaptogen*, what is striking is that most of these herbs, found across the world, share a similarity in phytochemistry; there are certain compounds, namely triterpenoid saponins, that are found in almost all adaptogenic plants. And so, it is with these shared compounds and how they interact with our physiology that we will start to unravel the mystery of how these traditional restoratives are powerful regulators of our neuroendocrine system and our stress response.
Triterpenoids & Cortisol
Triterpenoid saponins and related derivatives are ubiquitous in adaptogenic plants. Examples of this classification of compounds include eleutheroside A, found in eleuthero, tangshenosides, found in codonopsis, withanolides, found in ashwagandha, and ginsenosides, found in ginseng. What's remarkable is that these compounds closely resemble our endogenous glucocorticoids. Cortisol, the “stress hormone”, is the predominant glucocorticoid actor in the stress response.
Why might adaptogenic plants have chemicals almost structurally identical to cortisol? They likely produced these compounds as a defense mechanism intended to disrupt and disable insect hormone levels. Our human hormone receptors are similar enough to the insect hormone system (the ecdysteroid system) due to shared ancestry, that these modified plant triterpenes act in some similar ways. Due to our size and more recent evolutionary differences though, these compounds are often beneficial for us while potentially deadly to insects.
Research suggests that these phytochemicals modulate our stress response through their ability to bind to cortisol receptors. This is important because chronic stress leads to chronically elevated levels of cortisol which in turn leads to a host of negative effects, including impaired digestion, immunity, sleep, mood, and cognition. But how do adaptogens famously balance our cortisol levels? First, I need to explain the cortisol negative feedback loop.
Cortisol Negative Feedback Loop
Cortisol levels are regulated through a negative feedback loop, a common regulatory system found everywhere in nature. When under stress, the brain through the HPA-axis tells the adrenals to release cortisol. Once the adrenals release cortisol into the bloodstream, receptors back in the brain, particularly in the cerebral cortex, hypothalamus, and pituitary, monitor cortisol levels in the blood. When enough cortisol activates these receptors, the brain turns off the stress alarm and the adrenals get the message to stop secreting more cortisol. This is a healthy functioning stress response.
With chronically high stress levels, this system starts to break down. What many people call adrenal fatigue is actually a dysregulation of the HPA-axis where cortisol is either way too high or way too low— the healthy negative feedback loop is broken. This happens through a variety of mechanisms. One, for instance, is the result of a stress-activated protein called Jun N-terminal kinase (JNK), which desensitizes our cortisol receptors leading to glucocorticoid receptor resistance. Think insulin resistance, but for stress…
Partial Agonism at Receptor Sites
We know through several studies that triterpenoid saponin aglycones bind to the same glucocorticoid receptors that cortisol binds to, but it appears they may act as partial agonists— activating the receptor but not fully and not in the same way that cortisol would. Receptor activation isn’t a simple on or off switch and the research shows us that adaptogens may modulate these receptors in ways that promote balance in the system. This partial agonism would explain the bi-directionality of adaptogens.
On one hand, if our stress response is elevated and trigger-happy, adaptogens may activate certain receptor sites to potentiate the cortisol negative feedback loop while also blocking cortisol from binding to some receptor sites throughout the body. This has the effect of putting a ceiling on both the levels of cortisol our stress response initiates and the degree to which this hormone affects us. Overall, this process lowers elevated cortisol levels, something research on adaptogens consistently shows. In daily life, this translates to no longer ****overreacting ****every time rush hour traffic makes us late for work. Instead, we conserve the hormones we would have wasted on road rage, giving us steadier, sustained energy for the long haul.
On the other hand, if we are in the burnout stage and have absolutely no energy and perhaps lower than normal cortisol, adaptogens can act like cortisol ****would**** and give us the extra juice we need to find our groove again. These compounds also have the effect of rehabilitating our cortisol balance. Research with ginseng shows that when these phytochemicals bind to receptor sites they also re-sensitize them. In addition, adaptogenic compounds may up-regulate the number of receptors, bringing them back to healthy levels.
Heat Shock Proteins
What do saunas, exercise, and adaptogenic herbs all have in common? They all increase concentrations of molecular chaperones called heat shock proteins. Heat shock proteins were first discovered with heat shock— aka saunas— and they play important roles in the human stress response.
HSPs are powerful stress-protective proteins that mitigate the damage high stress can inflict on our bodies. They can reduce the inflammatory and immunological pressure that accompanies chronic overload. Some are also intricately involved with our glucocorticoid receptors (cortisol binds to these, remember) and manage their signaling, half-life, and sensitivity, making our stress response more effective and efficient. For example, Hsp72 inhibits JNK, the stress-induced protein mentioned earlier. The ability to inhibit this protein influences cortisol levels in a lowering and balancing way.
Why are adaptogens able to do this? Because of their ability to activate our stress response, adaptogens act as stress mimetics. They mimic stress in a similar way that sitting in a sauna would and help us build a tolerance to more insidious types of stress.
Beyond heat shock proteins, adaptogens regulate many other mediators of the cellular stress response, including forkhead box O (FOXO), beta-endorphin, nitric oxide (NO), and ATP.
Discovering the exact mechanisms of action of these traditional tonics and modern adaptogens proves to be complex. The concept of network pharmacology, where plants act through multiple pathways on multiple targets with multiple variations in outcomes, is clearly at work here, with partial agonism, receptor up-regulation, and cellular processes all playing a role in the story of these revered herbs.
What we do know is that our bodies are constantly learning and plants act like system-critical software updates showing us how to best navigate the world. As we work to develop a relationship with these plants we also work for the benefit of a culture that is struggling to rediscover the energy that flows from the heart.
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