How Does Ecdysterone Work? Mechanism and Pharmacology of Ecdysteroids

Introduction 

Ecdysterone is a plant-based supplement which is known to have anabolic properties and can be found at low concentrations in spinach, quinoa, and others. As more ecdysterone and turkesterone containing supplements become available on the market, many are asking "how do these compounds actually work?" In this article, we will discuss the complex mechanisms of ecdysterone and bridge the gap between discussions about ecdysteroids from the academic, pharmaceutical, and fitness industry perspectives, in order to provide the highest quality and easily accessible information to all.

Despite evidence showing both in vivo (in living organisms) and in vitro (in cell models) anabolic effects of ecdysteroids, their cellular mode of action has not been fully elucidated. While not knowing the precise mechanism of a compound may imply that it is not well studied, this logic is inherently flawed. For example, acetaminophen (Tylenol®) is one of the oldest and most widely used medications to treat pain, yet its mode of action is still debated and unknown.¹ Couple this with the fact that ecdysterone is considered a nutraceutical (plant based or traditional herbal medicine) which are often known to be "dirty compounds" (i.e., they work on multiple biological pathways and cause numerous effects on the body). Due to this, a complex and unknown mechanism is to be expected for ecdysterone. In fact, research in mammals has revealed ecdysterone possesses a wide array of effects including anabolic, anti-inflammatory, hypolipidemic, anti-diabetic, and hepatoprotective effects.² For this discussion we will focus only on the mechanism of anabolic effects, since that is what the fitness industry is concerned with. 

(Read more about misconceptions regarding ecdysteroids here)

Pharmaceutical Industry Perspective

Unbeknownst to many, 20-hydroxyecdysone (aka beta-ecdysterone, aka ecdysterone) has been extremely well researched in humans. To date roughly 500 patients have been enrolled to randomized clinical trials lasting several months where ecdysterone is the study intervention. These trials have revealed ecdysterone to be a very well tolerated with most side effects occurring at a similar rate to the placebo group. Ecdysterone is also being studied to treat various human disease due to its anti-inflammatory and anabolic properties. These trials are sponsored by the pharmaceutical company Biophytis®, who are attempting to bring to their drug candidate BIO101 (an ecdysterone containing medication) for various treatment indications, including sarcopenia, a debilitating muscle wasting disease. It is important to note that while many supplements have little to no concrete evidence to prove their safety or efficacy, ecdysterone does not fall into that camp. This is because unlike other supplements, it is being studied as a medication to treat human disease. Furthermore, pharmaceutical companies have significantly more incentive and funding to conduct better controlled studies, with more participants, for longer durations of time.

Pharmacology 

There are several different theories that attempt to explain how ecdysteroids work in humans. Based on the clinical and preclinical data from academic and pharmaceutical sources, ecdysterone has been shown to activate the MAS receptor in cardiac and skeletal muscle cells via the Renin-Angiotensin-Aldosterone System (RAAS). This activation triggers two important downstream signaling-pathways in myocytes, which are impaired in many muscle wasting conditions:

1. P13K/AKT/mTOR pathway – Increases protein synthesis, preserving muscle mass and increasing muscle strength
2. AMPK/ACC pathway – Stimulates energy production, increasing muscle strength and mobility

Credit: Biophytis®

(https://www.biophytis.com/wp-content/uploads/2021/07/Sarconeos_BIO101_MAS_Receptor.png.webp)

Now let's step back and breakdown what this all means. The RAAS pathway is a fundamental endocrine pathway that various medication classes target to modulate fluid/electrolyte balance, leading to improvements in blood pressure and cardiovascular outcomes. The RAAS pathway is also involved in the regulation of smooth, cardiac and skeletal muscle metabolism, playing a crucial role in muscle function and mobility in muscle wasting disease states. MAS activation in skeletal and smooth muscles stimulates muscle metabolism and strength.^3,4,5 The mTOR pathway is responsible for anabolic and catabolic signaling of skeletal muscle mass, resulting in the modulation of muscle hypertrophy and muscle wastage.⁶ The mTOR pathway has also been well studied in the development of new anti-cancer agents. The AMPK pathway is stimulated when AMP and ADP levels in the cells rise due to variety of physiological stresses.⁷ Essentially, they are a form of energy production when our cells under under stress. The full breakdown of these biological signaling mechanisms are out of the scope of this article, this is only meant to be a brief overview and simplification.

Another mechanism which is frequently cited is that ecdysterone activates estrogen receptor (ER) beta. The theory is that ecdysteroids can increase muscle protein synthesis by binding to these ER which then increase transcription and translation of proteins from the nucleus of a cell. There are two ER subtypes, ER alpha and ER beta.^8,9 ER alpha is predominantly responsible for the sex characteristics one might expect from estrogen compounds and is expressed in reproductive tissues such as the uterus and mammary gland, as well as in the heart, liver, and kidney. On the other hand, ER beta is mainly expressed in the gastrointestinal tract, vascular endothelial cells, and the prostate.^8,9 Both ER and ER are expressed in skeletal muscle of humans. The question of whether ecdysterone can interact with ERs is actually controversial as studies have found conflicting results.

Interestingly, in multiple studies conducted using receptor-binding assays, no significant binding affinity of ecdysterone to the androgen receptor (AR) could be detected.⁹ Meaning these compounds do not carry the risk of virializing side effect one would expect from anabolic androgenic steroids, such as testosterone. These in vitro finding are confirmed by the lack of the presence of these side effects in clinical trials. 

Conclusion

Overall, we have seen that the literature describing the the mechanism of action for ecdysterone is complex and sometimes even conflicting. Knowing the effects that a compound can have on the body does not necessarily mean that mechanism is related to how it treats disease or causes a certain response (i.e., hypertrophy). Further research is required to determine the precise mechanism by which this class of compounds is able to enhance muscle protein synthesis. For now we can summarize by saying that ecdysterone increases muscle protein synthesis and via numerous pathways, however it is not clear which is predominantly responsible for this effect.

References 

1. Ohashi N, Kohno T. Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action. Front Pharmacol. 2020;11:580289. Published 2020 Nov 30. doi:10.3389/fphar.2020.580289
2. Dinan L, Dioh W, Veillet S, Lafont R. 20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases. Biomedicines. 2021; 9(5):492. https://doi.org/10.3390/biomedicines9050492
3. Gorelick-Feldman J, Cohick W, Raskin I. Ecdysteroids elicit a rapid Ca2+ flux leading to Akt activation and increased protein synthesis in skeletal muscle cells. Steroids. 2010;75:632–637.
4. Gorelick-Feldman J, Maclean D, Ilic N, Poulev A, Lila MA, Cheng D, Raskin I. Phytoecdysteroids increase protein synthesis in skeletal muscle cells. J Agric Food Chem. 2008;56:3532–3537.
5. Syrov VN. Comparative experimental investigation of the anabolic activity of phytoecdysteroids and steranabols. Pharm Chem J. 2000;34:193–197.
6. Yoon MS. mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass. Front Physiol. 2017;8:788. Published 2017 Oct 17. doi:10.3389/fphys.2017.00788
7. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016-1023. Published 2011 Sep 2. doi:10.1038/ncb2329
8. Bathori, M., Toth, N., Hunyadi, A., Marki, A. et al., Phytoecdysteroids and anabolic-androgenic steroids—structure and effects on humans. Curr. Med. Chem. 2008, 15, 75–91.
9. Parr MK, Zhao P, Haupt O, et al. Estrogen receptor beta is involved in skeletal muscle hypertrophy induced by the phytoecdysteroid ecdysterone. Mol Nutr Food Res. 2014;58(9):1861-1872. doi:10.1002/mnfr.201300806