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Rutaecarpine Explained

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Rutaecarpine is an up-and-coming nootropic that is becoming more common in pre-workout or post-workout mixes.  Its' followers use it because of it's anti-caffeine effects, making it possible to enjoy caffeine in a late night workout mix with little repercussions on sleep.  Find out what this supplement is, the other benefits it has, and its side effects and safety.

What is Rutaecarpine?

Rutaecaprine is an alkaloid isolated from the Evodia rutaecarpa tree.  Evodia is known in Traditional Chinese Medicine as “Wu-Chu-Yu”, a multi-purpose herb which has been used for a  wide variety of ailments in traditional oriental medicine. (1)

Though Rutaecarpine is linked primarily to the Evodia tree, other plants within the Rutaceae family produce Rutaecarpine.  Other species including the Hortia, Phellodendron, Zanthoxylum, Vepris, Tetradium, Metrodorea, Spiranthera, Bouchardatia, and Fagara are known to contain the alkaloid.  (1)

Native to China and Korea, Evodia rutaecarpa’s fruit is the part of the tree most commonly used. The bitter-tasting fruit and the bark of the roots are used commonly for relief from pain caused by headaches, stomach afflictions, and some bleeding disorders.  The active pain-relieving constituents of the plant are derived from its primary alkaloids, evodiamine and rutaecarpine.  (2)

Rutaecarpine History

Rutaecarpine (C18H13N3O) was isolated by Asahina and Kashiwaki in 1915.  Additional chemical analysis of Rutaecarpine determined that it is an indolopyridoquinazolinone alkaloid which exists in two forms, differentiated by two coplanar rings which can flip their orientations within the molecular structure.  The molecular structure was confirmed by x-ray crystallography by Fujii, Kobayashi, and Hirayama in 2008.  (1)(2)

Rutaecarpine can be synthesized.  In 1927, a three-step synthesis was outlined, and several other methods for synthesizing both Rutaecarpine and its derivatives have since been discovered. (1)

Rutaecarpine Benefits

Rutaecarpine’s isolation has shown promise in preliminary animal research, but it is important to note that it cannot be cross-linked to the benefits which are derived from the use of the whole Evodia plant.  Ruteacarpine and Evodia should not be confused with one another, and the evidence for Evodia’s use in traditional oriental medicine cannot be extended to this single constituent.  Rutaecarpine is an alkaloid extract which is in its infancy in the medical and scientific realms.  Information and any human clinical data is very scarce at this time.  (3)

Safety and Side Effects of Rutaecarpine

  • Rutaecarpine is toxic to the human liver

Supplements containing Rutaecarpine have caused liver toxicity in humans resulting in severe damage and changes to the function of the human liver, including its size and weight and ratio to body weight.  Toxicity in the liver can manifest on a spectrum from mild to severe, from nonspecific and mild changes to acute or chronic hepatitis, liver cirrhosis, cholestasis, and mitochondrial dysfunction (10)( 11)(12)

In-vitro and animal research has shown that Rutaecarprine is toxic to the liver for several reasons.  Most notably, it causes oxidative damage to the mitochondria in the liver and causes the mitochondria to swell, develop vacuoles (holes), and increase pore size leading to mitochondrial permeability.  The mitochondrial permeability transition (MPT) process results in depletion of the ATP molecules which are the building units for energy.  The oxidative damage to the mitochondria causes a release of cytochrome C which triggers the pathways to induce cell death, resulting in liver toxicity.  (12)

Rutaecarpine specifically interacts with the cytochrome P450 (CYP 450) enzymes genes which are responsible for breaking down and clearing compounds from the body.  These cells are located primarily in the liver but can be found elsewhere throughout the body as well.  Drug/medication metabolism relies on these cytochrome pathways for processing.  Not all drugs/medications use the same pathway, but if many substances are present and share the same pathway for metabolism, the incidence of drug-drug interactions becomes more likely.

Ruteacarpine has significant effects on the liver’s drug processing enzymes, specifically through the CYP isoforms CYP1A2 and CYP2EI. (6)(8)(13)(14)(12)

  • Ruteacarpine is mildly toxic, even when consumed in the traditional Oriental medicine form of Evodia rutaecarpa

Though Evodia rutaecarpa has been included in many ancient traditional Chinese medical texts for thousands of years, the mild toxic effects of the plant have always been known.

There is an entry in the oldest herbal medicine book in China (Shen Nong’s Herbal Classic) describing the Evodia plant and its fruit causing mild toxic symptoms.  In present day research, symptoms such as blurred vision, stomachache, and vomiting have occurred with its use.  Long-term use causes an accumulation within the body and leads to liver toxicity.  (12)

  • Rutaecarpine can cause ischemic colitis

A supplement containing Rutaecarpine caused ischemic colitis, a condition where blood flow to the intestine is reduced or blocked, resulting in a lack of blood flow and therefore oxygen to the intestinal system.  (15)

Final Thoughts

Rutaecarpine is making its way into many supplements and post-workout mixes, and it is becoming a sought-after supplement because of its ability to counteract the effects of caffeine. 

Since the research and data is so limited at this point in time, Rutaecarpine is on the frontier of supplements that haven’t been thoroughly researched in humans.  Despite its long history of being used as a Traditional Chinese herb, there are some important safety considerations that should be made before embarking on supplementing with Rutaecarpine.  It’s difficult for people to understand why something that was used in folkloric or traditional oriental medicine should be regarded with any caution—if it was used for so long, so long ago, how can it be bad?

Most of the answer to this question is in the dose.  It is very unlikely that traditional oriental herbalists used dosages that would mimic the dosages that modern man is using.  It’s important to remember that Rutaecarpine is an extract of the whole Evodia plant, and ancient herbalists were not using this singular extract.  It is due to this reason that we can’t take benefits from the whole plant and apply them to the single alkaloid extract of Rutaecarpine.

We know that Rutaecarpine has shown some promise in some areas of medicine, but we also know that it can cause severe liver damage.  It was regarded as mildly toxic even by the practitioners of Traditional Chinese Medicine.  These ancient physicians used empiric evidence and noted the reactions, but they did not know why they were occurring.  They likely prescribed it in appropriate doses and used it sparingly.

In our modern-day quest to stay caffeinated and use something to bring us back down after taking excessive amounts of caffeine, we aren’t likely to be as calculating in our usage of Rutaecarpine.  Until it’s more thoroughly researched in humans, taking Rutaecarpine will be a personal choice.   You may decide it seems more like roulette at this point in time.


  1. Lee, Seung Ho et al. “Progress in the studies on rutaecarpine.” Molecules (Basel, Switzerland) vol. 13,2 272-300. 6 Feb. 2008, doi:10.3390/molecules13020272
  2. “Rutecarpine.” NIH National Center for Advancing Translational Sciencies, doi:https://drugs.ncats.io/drug/8XZV289PRY.
  3. Examine.com. “Evodia Rutaecarpa Supplement – Health Benefits, Dosage, Side Effects.” Examine.com, 12 Oct. 2018, examine.com/supplements/evodia-rutaecarpa.
  4. “COX-2 Inhibitor.” Wikipedia, Wikimedia Foundation, 5 June 2020, en.wikipedia.org/wiki/COX-2_inhibitor.
  5. Moon TC;Murakami M;Kudo I;Son KH;Kim HP;Kang SS;Chang HW; “A New Class of COX-2 Inhibitor, Rutaecarpine from Evodia Rutaecarpa.” Inflammation Research : Official Journal of the European Histamine Research Society … [Et Al.], U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/10669112.
  6. Neergheen-Bhujun, Vidushi S. “Underestimating the Toxicological Challenges Associated with the Use of Herbal Medicinal Products in Developing Countries.” BioMed Research International, Hindawi, 19 Sept. 2013, www.hindawi.com/journals/bmri/2013/804086.
  7. Noh, Keumhan, et al. “Effects of Rutaecarpine on the Metabolism and Urinary Excretion of Caffeine in Rats.” Archives of Pharmacal Research, 34(1): 119-25 Apr 2011, 2011, www.researchgate.net/publication/51021350_Effects_of_Rutaecarpine_on_the_Metabolism_and_Urinary_Excretion_of_Caffeine_in_Rats.
  8. Rutaecarpine. www.caymanchem.com/product/22897/rutaecarpine.
  9. Sheu, Joen-Rong. “Pharmacological Effects of Rutaecarpine, an Alkaloid Isolated from Evodia Rutaecarpa.” Cardiovascular Drug Reviews, vol. 17, no. 3, 1999, pp. 237–245., doi:http://www.nevapress.com/cdr/full/17/3/237.pdf.
  10. Cohen, S. M., Heywood, E., Pillai, A., & Ahn, J. (2012). Hepatotoxicity associated with the use of white flood, a nutritional supplement. Practical Gastroenterology, 36(10), 45-47.
  11. Teschke R. Traditional Chinese Medicine Induced Liver Injury. J Clin Transl Hepatol. 2014;2(2):80-94. doi:10.14218/JCTH.2014.00003
  12. (PDF) Toxicity of Evodiae Fructus on Rat Liver … www.researchgate.net/publication/273956506_Toxicity_of_Evodiae_fructus_on_Rat_Liver_Mitochondria_The_Role_of_Oxidative_Stress_and_Mitochondrial_Permeability_Transition.
  13. McDonnell, Anne M, and Cathyyen H Dang. “Basic review of the cytochrome p450 system.” Journal of the advanced practitioner in oncologyvol. 4,4 (2013): 263-8. doi:10.6004/jadpro.2013.4.4.7
  14. Zhu, Qiong-Ni, et al. “Rutaecarpine Effects on Expression of Hepatic Phase-1, Phase-2 Metabolism and Transporter Genes as a Basis of Herb–Drug Interactions.” Journal of Ethnopharmacology, Elsevier, 16 Mar. 2013, www.sciencedirect.com/science/article/abs/pii/S0378874113001487.
  15. Magee, Charles, and Fouad J Moawad. NO-Xplode: A Case of Supplement-Associated Ischemic Colitis. www.researchgate.net/publication/42831942_NO-Xplode_A_Case_of_Supplement-Associated_Ischemic_Colitis.


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