Bupleurum: Xiao Yao San and Mood Research

Table of Contents

1. The Formulas
2. The 2020 Meta-Analysis
3. How to Read Those Numbers
4. Why the Reviewers Called It Low Quality
5. The Laboratory Research
6. The Inflammation Idea
7. Antidepressants, Interactions and Safety
8. How It Compares With Other Herbs Studied for Mood
9. Where the Mood Evidence Stands
10. What Would Settle the Question
11. Terms Used on This Page
12. Key Research Papers
13. Connections

The Formulas

Xiao yao san was first recorded in the Taiping Huimin Heji Jufang (Pharmacopeia of the Welfare Dispensary Bureau) of the Song dynasty, according to a 2022 review in Frontiers in Pharmacology. It is made from eight herbs: chai hu (bupleurum), dang gui (Angelica sinensis root), bai shao (white peony root), bai zhu (Atractylodes rhizome), fu ling (Poria mushroom), bo he (mint), sheng jiang (ginger) and gan cao (licorice) (Chen et al., Front Pharmacol 2022). That review describes it as the most commonly prescribed Chinese formula for anxiety and depression attributed to "liver qi stagnation, blood deficiency, and spleen deficiency."

Chai hu shu gan san and si ni san are two other bupleurum formulas named in a 2024 review of bupleurum for depression. A 2018 review notes that bupleurum is sold in China in chai hu shu gan tablets and xiao yao wan tablets, a pill form of the same family of formulas.

Every one of these combines bupleurum with several other active herbs. White peony and dong quai, for example, have their own research literatures; the site covers White Peony, Dong Quai, Atractylodes and Poria separately.

The 2020 Meta-Analysis

The key human paper is a systematic review and meta-analysis published in the Journal of Alternative and Complementary Medicine by researchers from Guangzhou and RMIT University in Australia. They searched English and Chinese databases up to March 2019 for randomized trials of "Bupleurum chinense herbal formula" in major depressive disorder.

• Who was included: adults aged 18 to 65 with major depression. People with depression after stroke, bipolar disorder, or other mental or physical illnesses were excluded.
• Comparisons: 30 trials compared a bupleurum formula with antidepressants (SSRIs); 25 compared a formula plus SSRIs with SSRIs alone.
• Formula vs antidepressant: the formula groups improved more on the Hamilton Rating Scale for Depression, with a standardized mean difference of −0.35 (95% CI −0.52 to −0.18).
• Formula plus SSRI vs SSRI alone: a larger difference, −1.03 (95% CI −1.43 to −0.62).
• Side effects: the total number and severity of adverse events were lower in the formula groups than in the antidepressant groups.
• Quality: assessed with the GRADE system. "Heterogeneity of the included studies was high and quality was low."

The authors' conclusion carried both halves: the formulas "reduced depression severity," but "the evidence is low quality and at risk of bias," and well-designed studies "are needed to validate the results."

How to Read Those Numbers

A standardized mean difference (SMD) expresses the gap between groups in units of the spread of scores, so trials using slightly different scales can be pooled. By common convention, about 0.2 is small, 0.5 moderate and 0.8 large. On that scale, −0.35 is a small-to-moderate difference and −1.03 a large one.

The I² figure measures how much the trials disagree beyond chance. The review reported 81.2% for the first comparison and 94.2% for the second. Values that high mean the individual trials gave very different answers, so a single pooled number summarizes them poorly.

The comparisons are also against active drugs, not placebo. A formula "beating" an SSRI in an open, unblinded trial, where patients and assessors know who got what, is a different finding from beating a dummy pill under blinding.

Why the Reviewers Called It Low Quality

The abstract gives the reviewers' verdict rather than every reason. GRADE, the system they used, rates a body of evidence down for risk of bias within trials (for example, no blinding or unclear randomization), inconsistency between trials, indirectness, imprecision and suspected publication bias; the abstract names high heterogeneity, low quality and risk of bias. The 2010 review of xiao chai hu tang in hepatitis B, discussed on the Saikosaponins and the Liver page, found the same divide, with one good-quality English-language trial and poor-quality Chinese-language trials.

None of this means the formulas do nothing. It means the trials so far cannot tell a real effect apart from the effects of expectation, unblinded assessment and selective publication. The 2024 review reached a similar place from the laboratory side, writing that further research is needed to "evaluate its effectiveness in human subjects."

The Laboratory Research

A 2024 review in Pharmaceuticals lists the compounds from bupleurum studied for antidepressant activity: saikosaponin a, saikosaponin d, rutin, puerarin and quercetin. In laboratory models, these act on several systems linked to depression:

• Neurotransmitters such as serotonin (5-HT) and dopamine.
• The NMDA system, the glutamate receptor targeted by the drug ketamine.
• BDNF (brain-derived neurotrophic factor), a growth factor for nerve cells.
• Other cell-signalling pathways inside neurons.

One detailed experiment shows the style of evidence. In 2023, researchers gave saikosaponin b2 to mice subjected to chronic unpredictable mild stress, a standard way of producing depression-like behaviour in rodents. The treated mice did better on tests such as sugar-water preference, open-field exploration, tail suspension and forced swimming. In the brain, saikosaponin b2 calmed microglia (the brain's resident immune cells), reduced a form of iron-dependent cell death called ferroptosis, and eased stress inside cells; silencing the gene GPX4 cancelled the protection.

These are tests of mouse behaviour and cell chemistry. They suggest mechanisms worth testing, not proof of benefit in people.

The Inflammation Idea

A popular modern theory holds that low-grade inflammation, including inflammation in the brain, contributes to some cases of depression. Saikosaponins fit that theory well in the laboratory: a 2025 review of herbal saponins lists them among anti-inflammatory compounds, and a 2018 review describes them as anti-inflammatory and antioxidant. The saikosaponin b2 mouse study tied its antidepressant-like effect to calming inflammatory signalling (the TLR4/NF-κB pathway) in microglia.

The gap is the same as elsewhere on this site: none of the research reviewed here includes a trial that measured inflammation markers in depressed people taking bupleurum and linked them to mood. The theory connects plausibly; it has not been tested in the way that would settle it.

Antidepressants, Interactions and Safety

Half the trials in the meta-analysis gave bupleurum formulas together with SSRI antidepressants, and reported fewer side effects in formula groups. That is reassuring but limited: small, short trials are not designed to detect uncommon harms.

Other sources bear on combined use:

• A 2021 review reported that saikosaponin d can influence drug-metabolizing liver enzymes (CYPs) and the P-glycoprotein drug pump, which handle many medicines, including many psychiatric drugs.
• A 2000 Lancet review of herb–drug interactions reports lower blood levels of prednisolone with xiao chai hu tang, and, among other herbs, mild serotonin syndrome when St John's wort is mixed with SSRIs. It notes that "many reports of herb-drug interactions are sketchy."
• A 2014 review of liver injury from herbal Chinese medicine products lists the Japanese-named formula Kamishoyosan, as well as chai hu, among products with potential hepatotoxicity.
• Reviews of saikosaponins report overdose and accumulation liver toxicity, and a 2021 review lists nerve toxicity among saikosaponin d's toxic effects in research.

The 2024 review itself advises that "it is essential to consider the potential adverse effects and clinical restrictions of Bupleurum." Decisions about combining herbal formulas with antidepressants belong with the prescribing clinician.

How It Compares With Other Herbs Studied for Mood

For perspective, other herbs on this site have been studied for mood as single herbs rather than as parts of formulas, and their pages report their own trial records. Bupleurum's evidence differs in kind: it is a formula literature, tested against or alongside antidepressants rather than against placebo, so it cannot be compared head-to-head with single-herb results. See St John's Wort and Saffron: Mood and Depression for those records.

Where the Mood Evidence Stands

• Human: 55 randomized comparisons of bupleurum formulas in major depression, pooled positive, rated low quality with very high heterogeneity, and not placebo-controlled.
• Animal and cell: several saikosaponins and flavonoids act on serotonin, dopamine, NMDA receptors, BDNF and brain inflammation in models.
• Bupleurum alone: not tested in people in any study reviewed here.
• Safety: fewer reported side effects than SSRIs in the trials; interaction and liver questions remain from other sources.

The site's Depression page covers the condition and its established treatments. Depression with thoughts of self-harm is treated as urgent in medical care.

What Would Settle the Question

The reviewers asked for "well-designed studies." In practical terms, a trial able to show whether a bupleurum formula helps depression would typically include:

• A placebo arm with a matching dummy formula, so expectation is balanced.
• Blinding of patients and of the people scoring depression.
• Pre-registration of the outcomes before the trial begins, so results cannot be selected afterwards.
• Enough people and enough time to measure relapse and side effects, not only a few weeks of symptom scores.
• A defined, quality-controlled preparation, with saikosaponin content reported, so others can repeat it.
• Separate testing of bupleurum alone, if the question is about the herb rather than the formula.

The 2020 abstract does not describe the included trials as meeting that standard, and its low quality rating indicates that, as a group, they did not.

Terms Used on This Page

• Major depressive disorder: the clinical diagnosis of depression used in trials.
• SSRI: selective serotonin reuptake inhibitor, the most common class of antidepressant.
• Hamilton Rating Scale for Depression (HRSD): a clinician-scored questionnaire of depression severity.
• Standardized mean difference: the gap between groups expressed in units of score spread.
• I²: the percentage of variation between trials that is beyond chance.
• GRADE: the international system for rating the certainty of a body of evidence.
• Microglia: the immune cells resident in the brain.
• Ferroptosis: a form of cell death driven by iron and fat oxidation.
• Liver qi stagnation: a traditional Chinese medicine pattern to which xiao yao san's use for anxiety and depression is attributed.

Key Research Papers

1. 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. Journal of alternative and complementary medicine (New York, N.Y.). 2020;26(1):8-24. PubMed PMID: 31328996
2. Ran S, Peng R, Guo Q, et al. Bupleurum in Treatment of Depression Disorder: A Comprehensive Review. Pharmaceuticals (Basel, Switzerland). 2024;17(4). PubMed PMID: 38675471
3. Wang X, Li S, Yu J, et al. Saikosaponin B2 ameliorates depression-induced microglia activation by inhibiting ferroptosis-mediated neuroinflammation and ER stress. Journal of ethnopharmacology. 2023;316:116729. PubMed PMID: 37277081
4. Li X, Li X, Huang N, et al. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2018;50:73-87. PubMed PMID: 30466994
5. Zheng Q, Wang T, Wang S, et al. The anti-inflammatory effects of saponins from natural herbs. Pharmacology & therapeutics. 2025;269:108827. PubMed PMID: 40015518
6. Zhou P, Shi W, He XY, et al. Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics. Pharmaceutical biology. 2021;59(1):1480-1489. PubMed PMID: 34714209
7. Fugh-Berman A. Herb-drug interactions. Lancet (London, England). 2000;355(9198):134-8. PubMed PMID: 10675182
8. Teschke R. Traditional Chinese Medicine Induced Liver Injury. Journal of clinical and translational hepatology. 2014;2(2):80-94. PubMed PMID: 26357619
9. Tian Y, Guo J, Jiang X, et al. Exploring the Therapeutic Potential of Bupleurum in Medical Treatment: A Comprehensive Overview. Pharmaceuticals (Basel, Switzerland). 2025;18(9). PubMed PMID: 41011202
10. Teng L, Guo X, Ma Y, et al. A comprehensive review on traditional and modern research of the genus Bupleurum (Bupleurum L., Apiaceae) in recent 10 years. Journal of ethnopharmacology. 2023;306:116129. PubMed PMID: 36638855
11. Ashour ML, Wink M. Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action. The Journal of pharmacy and pharmacology. 2011;63(3):305-21. PubMed PMID: 21749378
12. Qin XK, Li P, Han M, et al. [Xiaochaihu Tang for treatment of chronic hepatitis B: a systematic review of randomized trials]. Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2010;8(4):312-20. PubMed PMID: 20388470

PubMed Topic Searches

1. PubMed: Xiaoyaosan and depression
2. PubMed: Chaihu shugan san and depression
3. PubMed: Saikosaponin and depression
4. PubMed: Bupleurum depression meta-analyses

Connections

• Heart, Liver and Metabolic Herbs — the parent category
• Bupleurum (Chai Hu) — the main topic page
• Bupleurum Benefits Deep Dive — the hub
• Sho-Saiko-To and Interstitial Pneumonia
• Saikosaponins and the Liver
• Chai Hu in Traditional Chinese Medicine
• Depression
• St John's Wort — the most-trialled single herb for depression
• Saffron: Mood and Depression
• White Peony — bai shao, in xiao yao san
• Dong Quai — dang gui, in xiao yao san
• Atractylodes — bai zhu, in xiao yao san
• Poria — fu ling, in xiao yao san
• Peppermint — bo he is a mint