Xiao Yao San

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Xiao Yao San

Common Names

  • Free and Easy Wanderer
  • Rambling Powder
  • Jia Wei Xiao Yao San
  • Dan Zhi Xiao Yao San
  • Augmented rambling powder
  • Kamishoyosan
  • TJ-24

For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.


What is it?

Xiao Yao San (XYS) is a traditional Chinese medicine (TCM) formula. It’s made up of 8 different herbs. A slightly modified product called Dan Zhi XYS or Jia Wei XYS is also available.  

What is it used for?

XYS is used to:

  • Treat depression (strong feelings of sadness)
  • Treat anxiety (strong feelings of worry or fear)
  • Lower stress
  • Manage symptoms around and after menopause (permanent end of menstrual cycles). These include fatigue (feeling more weak than usual), mood swings, depression, and insomnia (trouble falling asleep, staying asleep, or waking up too early)

Talk with your healthcare providers before taking herbal formulas. They can interact with some medications and affect how they work. For more information, read the “What else do I need to know?” section below.

What are the side effects?

Side effects of Xiao Yao San and its modified form may include:

  • Headache
  • Dizziness
  • Fatigue (feeling more weak than usual)
  • Mild diarrhea (loose or watery bowel movements)
What else do I need to know?
  • Talk to your healthcare provider if you have hormone-sensitive breast cancer. Some herbs in XYS and Jia Wei XYS may not be suitable for you.
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For Healthcare Professionals

Clinical Summary

Xiao Yao San (XYS) is a traditional Chinese medicine (TCM) formula documented in Tai Ping Hui Min He Ji Ju Fang, a collection of prescriptions written during the Song Dynasty around 1078-1085 AD. It consists of eight herbs: Bupleuri radix (Chai Hu), Angelicae radix (Dang Gui or Dong Quai), Paeoniae radix alba (Bai Shao), Atractylodis rhizome macrocephalae (Bai Zhu), Poria cocos (Fu Ling), Zingiberis siccatum rhizome (Sheng Jiang), Menthae haplocalycis (Bo He), and Glycyrrhizae radix (Gan Cao or Licorice). Xiao Yao San has a long history of use as a treatment for depression, anxiety and stress.

A modified version known as Dan Zhi XYS or Jia Wei XYS was developed with two additional herbs with cooling properties, Cortex Moutan (Mu Dan Pi) and Fructus Gardeniae (Zhi Zi). This formulation is used both in China and Japan to manage symptoms such as mood, anxiety, fatigue, and insomnia associated with climacteric syndrome. Jia Wei XYS is also the most prescribed product for breast cancer patients according to the Taiwan health insurance research database (1). In addition, a large retrospective study found that Jia Wei XYS was frequently utilized (nearly a third of all herbal prescriptions) by breast cancer patients treated with tamoxifen. The authors reported notable reductions in the risk of endometrial cancer along with improvements in tamoxifen-induced side effects although improvements affected by Jia Wei XYS were statistically non-significant (2).

Below are the major symptoms for which XYS and Jia Wei XYS are prescribed along with current clinical evidence.

Depression

In a systematic review conducted in 2012, 26 randomized clinical trials involving 1,837 depressive patients were assessed. The interventions employed included XYS or its modified forms, XYS plus antidepressants such as selective serotonin re-uptake inhibitors (SSRIs), tricyclics and tetracyclics, with antidepressants as controls.  Primary outcomes included the Hamilton depression rating scale (HAMD) and self-rating depression scale (SDS) scores. Data showed that XYS and its modified forms combined with antidepressants were superior to antidepressants alone. The formulae also improved the HAMD scores without increasing the number of adverse events (3).

In another review (5 XYS studies, 1,260 participants), Butler et al., concluded that despite some positive findings, the use of Chinese herbal medicine (CHM) for depression cannot be fully substantiated (4). But growing evidence since then suggests otherwise. A meta-analysis (11 XYS trials, 3,549 participants) showed that CHM led to better clinical outcomes based on HAMD scores. Furthermore, adding CHM to conventional treatments reduced the adverse effects associated with their use; CHM alone also caused fewer adverse events compared with antidepressants (5). An additional review (4 XYS trials with 1,441 gastric, lung, esophageal, breast and liver cancer patients) yielded similar findings. Compared to conventional antidepressants, CHM users experienced fewer adverse events of functional gastrointestinal disorders, sleep disturbances, blurred vision, and fatigue.  However, the authors did not perform subgroup analysis for the different cancer types or disease stage (6).

In the latest analysis, Yang et al., assessed 55 studies involving 5,572 participants. Of these, 30 trials compared CHM vs SSRIs (fluoxetine, paroxetine and sertraline) whereas 25 compared CHM + SSRIs vs SSRIs.  Although the studies were of poor quality, CHM (with or without SSRIs) was associated with statistically significant improvements in HAMD scores with fewer, less severe adverse events (7).

Anxiety

In an 8-week multi-center trial, Su et al., randomized 191 patients with mild to moderate depression and anxiety to receive Jia Wei XYS or sertraline. Primary outcomes included HAMD, Hamilton Anxiety Rating Scale (HAMA) and Clinical Global Impression Scale scores. Jia Wei XYS was comparable to sertraline in all outcomes at the 8-week assessment, with sustained benefits at the 12-week follow-up. This suggests that the anti-depressive and anti-anxiolytic effects of Jia Wei XYS are more durable than those of sertraline. Jia Wei XYS was also associated with lower adverse event rate at the 12-week follow-up (8).

Insomnia

Data show that 40-60% of patients with mood disorders develop insomnia before developing symptoms associated with mood disorders (9). In the trial described above (8), the authors reported that in addition to improving anxiety, Jia Wei XYS also affected reductions in symptoms of sleep disorder at the 12-week follow up.

Jia Wei XYS may benefit patients with psychological stress insomnia as well. In a small comparative effectiveness study, Jia Wei XYS, used alone or combined with the benzodiazepene estazolam, led to subjective improvements in sleep quality (10).

Although accumulating evidence suggests benefits of both XYS and Jia Wei XYS, majority of the above mentioned studies are limited by small sample sizes, risk of bias, variations in treatment duration and dosage, and medication compliance. Larger methodologically robust trials are needed to determine the therapeutic potential of these formulations.

Purported Uses
  • Depression
  • Anxiety
  • Stress
  • Climacteric syndrome including symptoms such as mood, fatigue, depression and insomnia
Mechanism of Action

The mechanisms underlying the biological effects of XYS have yet to be elucidated. Recent findings suggest that it exerts anti-depressant effects by regulating lactic acid, glycerol, glutamine, glutamic acid, hypoxanthine, myo-inositol and cholesterol levels, which are involved in D-glutamine and D-glutamate metabolism, arginine biosynthesis as well as alanine, aspartate and glutamate metabolism (11).

Warnings

Two components of XYS, Dang Gui (Dong quai) and Licorice, have estrogenic properties. But data are lacking to determine whether or not XYS acts as a phytoestrogen. It is advisable for patients with hormone-sensitive breast cancer to discuss with their physicians the risks and benefits of starting, or continuing XYS and its modified form. 

Contraindications

None known

Adverse Reactions

Jia Wei XYS may cause headache, dizziness, fatigue and mild diarrhea (12).

Herb-Drug Interactions
  • 5-fluorouracil (5-FU): In a murine model, low dose Jia Wei XYS did not affect the pharmacokinetic parameters in blood and brain. But a higher dose (2400 mg/kg/day) increased half-life of 5-FU in the brain, along with reducing its clearance (13).
  • Paclitaxel: In a murine model, Jia Wei XYS was found to decrease the AUC and Cmax of paclitaxel by 1.5 fold both in plasma and lymph. The half-life of paclitaxel increased from 73 min to 111 min (14).
  • Tamoxifen: In vitro and in vivo studies did not find significant changes in tumor weight or in the expression of AKT, ERK, p38, and p27 (Kip1) genes at mid-high dose of Jia Wei XYS (2.6 g/kg-3.9g/kg). But at low dose (1.3 g/kg) there was a decreased expression of the LC3-II gene (15).

It is important to note that the clinical relevance of the above interactions remains to be determined.

Dosage (OneMSK Only)
References
  1. Lai JN, Wu CT, Wang JD. Prescription pattern of chinese herbal products for breast cancer in taiwan: a population-based study. Evid Based Complement Alternat Med. 2012;2012:891893.
  2. Tsai YT, Lai JN, Wu CT. The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: a population-based study. J Ethnopharmacol. Sep 11 2014;155(2):1256-1262.
  3. Zhang Y, Han M, Liu Z, Wang J, He Q, Liu J. Chinese herbal formula xiao yao san for treatment of depression: a systematic review of randomized controlled trials. Evid Based Complement Alternat Med. 2012;2012:931636.
  4. Butler L, Pilkington K. Chinese herbal medicine and depression: the research evidence. Evid Based Complement Alternat Med. 2013;2013:739716.
  5. Wang Y, Shi YH, Xu Z, Fu H, Zeng H, Zheng GQ. Efficacy and safety of Chinese herbal medicine for depression: A systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. Oct 2019;117:74-91.
  6. Li M, Chen Z, Liu Z, et al. Twelve Chinese herbal preparations for the treatment of depression or depressive symptoms in cancer patients: a systematic review and meta-analysis of randomized controlled trials. BMC Complement Altern Med. Jan 23 2019;19(1):28.
  7. Yang L, Shergis JL, Di YM, et al. Managing Depression with Bupleurum chinense Herbal Formula: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Altern Complement Med. Jan 2020;26(1):8-24.
  8. Su R, Fan J, Li T, et al. Jiawei Xiaoyao capsule treatment for mild to moderate major depression with anxiety symptoms: a randomized, double-blind, double-dummy, controlled, multicenter, parallel-treatment trial. J Tradit Chin Med. Jun 2019;39(3):410-417.
  9. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. Jan-Feb 2003;37(1):9-15.
  10. Li Y, Xu BY, Xiao F. [Effect of modified xiaoyao powder for improving sleep in patients with psychological stress insomnia]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Mar 2009;29(3):208-211.
  11. Liu X, Wei F, Liu H, Zhao S, Du G, Qin X. Integrating hippocampal metabolomics and network pharmacology deciphers the antidepressant mechanisms of Xiaoyaosan. J Ethnopharmacol. Nov 3 2020:113549.
  12. Feng DD, Tang T, Lin XP, et al. Nine traditional Chinese herbal formulas for the treatment of depression: an ethnopharmacology, phytochemistry, and pharmacology review. Neuropsychiatr Dis Treat. 2016;12:2387-2402.
  13. Chiang MH, Chang LW, Wang JW, Lin LC, Tsai TH. Herb-drug pharmacokinetic interaction of a traditional chinese medicine jia-wei-xiao-yao-san with 5-Fluorouracil in the blood and brain of rat using microdialysis. Evid Based Complement Alternat Med. 2015;2015:729679.
  14. Hou ML, Lu CM, Tsai TH. Effects of Jia-Wei-Xiao-Yao-San on the Peripheral and Lymphatic Pharmacokinetics of Paclitaxel in Rats. Evid Based Complement Alternat Med. 2016;2016:5614747.
  15. Chen JL, Chang CJ, Wang JY, et al. In Vitro and In Vivo Effects of Jia-Wei-Xiao-Yao-San in Human Breast Cancer MCF-7 Cells Treated With Tamoxifen. Integr Cancer Ther. May 2014;13(3):226-239.
  16. Luo HC, Qian RQ, Zhao XY, et al. [Clinical observation on effect of danzhi xiaoyao powder in treating depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Mar 2006;26(3):212-214.
  17. Li YJ, Luo HC, Qian RQ. [Effect of Danzhi Xiaoyao Powder on neuro-immuno-endocrine system in patients with depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Mar 2007;27(3):197-200.
  18. Yang ZY, Zhang WB, Liu JL. [Comparative study of Modified Xiaoyao Pill combining amitriptyline on therapeutic effect and compliance in treating patients with depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Jul 2007;27(7):642-644.
  19. Yu GH, Liang SC, Sun QZ. [Study on Modified Xiaoyao Decoction combining Clomipramine treating depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Apr 2007;27(4):318-320.
  20. Zhang HW, Wang CY, Xu HN, et al. [Clinical study on effect of fluoxetine combined with Chinese medicine or tibetan drugs in treating senile depression in plateau district]. Zhongguo Zhong Xi Yi Jie He Za Zhi. Mar 2006;26(3):202-204.
  21. Zhang ZJ, Kang WH, Li Q, Tan QR. The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) for mood disorders: double-blind, placebo-controlled studies. J Psychiatr Res. Nov 2007;41(10):828-836.
  22. Liu ZH, B. X. Chinese medicine diagnosis and treatment for breast cancer clinical observation of 30 cases of depression. Guiding Journal of Traditional Chinese Medicine and Pharmacy. 2011;17:13-15.
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