Jujube

Metadata

Approved Indications

Commission E / ESCOP / EMA

Jujube has not been assessed by any of the three major European phytotherapy regulatory bodies:

• Commission E (Germany): No monograph exists. Jujube was never part of the European herbal tradition evaluated by Commission E.
• ESCOP: No monograph. Not within the scope of ESCOP assessment.
• EMA/HMPC: No assessment report or monograph. Jujube is not listed in the EU herbal substances inventory.

This absence reflects the herb’s origin in East Asian medical traditions rather than a negative assessment. Jujube has no history of traditional use in European phytotherapy.

Chinese Pharmacopoeia

• Suan Zao Ren (Semen Ziziphi Spinosae): Official drug in the Pharmacopoeia of the People’s Republic of China (2020 edition). Listed indications include nourishing the heart and liver, sedating the nerves (an shen), arresting sweating, and promoting salivation. Used for insomnia, palpitations, dreaminess, spontaneous sweating, night sweats, and thirst due to fluid depletion. Over 30 Suan Zao Ren-containing prescriptions are documented in the Chinese Pharmacopoeia.
• Da Zao (Fructus Jujubae): Also an official drug. Listed indications include supplementing the middle (zhong qi), nourishing blood, calming the spirit (shen), and moderating the properties of other herbs.
• Dual-use status: Jujube is among the first batch of dual-use medicinal and edible products approved by the Ministry of Health of China, reflecting its long history as both food and medicine.

Japanese Pharmacopoeia / Kampo

• Taiso (Ziziphi Fructus): Official crude drug in the Japanese Pharmacopoeia (JP) and the Japanese Herbal Medicine Codex (JHMC). The fruit appears in 90 of the 294 OTC Kampo formulations, with annual consumption in Japan exceeding 900,000 kg.
• Sansoninto (Suan Zao Ren Tang): The jujube seed-based insomnia formula is an approved prescription Kampo medicine in Japan, manufactured by Tsumura (formula No. 103) and other companies. It is covered by the Japanese national health insurance system.

Agreement/Disagreement

There is a stark regulatory divide. In East Asia, jujube (both fruit and seed) is among the most widely recognized and officially sanctioned medicinal herbs, with pharmacopoeia listings in both China and Japan. In Europe and North America, it has no regulatory recognition whatsoever. This gap reflects the herb’s exclusively East Asian traditional use history rather than any safety or efficacy concerns identified by Western regulators. The convergence between the Chinese and Japanese pharmacopoeias on sedative/calming indications for the seed lends traditional credibility.

Conditions Treated

Primary — Insomnia and Sleep Disturbance (Suan Zao Ren)

• Insomnia (difficulty falling asleep and maintaining sleep): The seed (Suan Zao Ren) is the principal herb in the classical formula Suan Zao Ren Tang, one of the most commonly prescribed insomnia treatments across China, Taiwan, and Japan. Both preclinical and limited clinical evidence support improved sleep quality and reduced sleep latency.
• Sleep disturbance in specific populations: Limited clinical trials have studied jujube seed in postmenopausal women, patients on methadone maintenance, and individuals with psychiatric comorbidities.

Secondary — Anxiety and Restlessness

• Anxiolytic effects: Preclinical studies demonstrate anxiolytic activity of spinosin and jujuboside A in elevated plus maze, light/dark box, and open field tests. Both GABAergic and serotonergic pathways are implicated in this activity. Clinical evidence for standalone anxiolytic use is minimal.
• Nervous restlessness and irritability: Traditional TCM indication for both the seed and fruit in patterns of heart blood or yin deficiency with restlessness.

Traditional (TCM and Kampo)

• TCM — Suan Zao Ren (seed): Nourish heart blood, supplement liver blood, calm the spirit (an shen), arrest sweating. Used for patterns of heart blood deficiency or liver blood deficiency with insomnia, palpitations, excessive dreaming, night sweats, and anxiety. Classical source: Jin Gui Yao Lue (Essential Prescriptions from the Golden Cabinet) by Zhang Zhongjing, circa 210 CE.
• TCM — Da Zao (fruit): Supplement the middle (spleen/stomach qi), nourish blood, calm the spirit, moderate the harsh properties of other herbs. Da Zao is one of the most frequently used harmonizing agents in multi-herb formulas. According to the Annotation of Shen Nong’s Herbal, jujube “removes poison of any substance, and is used to harmonize drugs in a prescription.”
• Kampo — Sansoninto: The Japanese adaptation of Suan Zao Ren Tang, prescribed for patients with weakness, fatigue, irritability, insomnia, palpitations, poor memory, and neurotic symptoms. Used in psychiatric settings alongside conventional treatment.
• Kampo — Taiso in formulas: The fruit (Taiso) appears as a harmonizing ingredient in major Kampo prescriptions including Kakkonto, Hochuekkito, Rikkunshito, and many others, serving the same harmonizing and spleen-supplementing function as in TCM.

Mechanism of Action

Primary Mechanisms

1. Jujuboside A — GABA-A receptor potentiation and glutamate inhibition: Jujuboside A (JuA) is the principal sedative saponin from jujube seed. In hippocampal neurons, JuA enhances GABAergic inhibition by increasing tonic GABA currents in a dose-dependent manner. Concurrently, JuA inhibits glutamate-mediated excitatory signaling: at 0.1 g/L, it significantly blocks penicillin-induced glutamate release in hippocampal tissue and inhibits glutamate-induced intracellular calcium increases. JuA also decreases the slopes of excitatory postsynaptic potentials and the amplitudes of population spikes in hippocampal granule cells and CA1 pyramidal cells. The proposed upstream mechanism involves anti-calmodulin action — JuA antagonizes calmodulin in a manner similar to the calmodulin antagonist trifluoperazine. At the transcriptional level, JuA (50 microg/mL) increases mRNA expression of GABA-A receptor subunits GABRA1, GABRA5, GABRB1, and GABRB2. The net effect is a shift in the excitation/inhibition balance toward inhibition, promoting sedation and sleep.

2. Spinosin — Serotonergic and GABAergic dual modulation: Spinosin, the major C-glycoside flavonoid, potentiates pentobarbital-induced sleep through the serotonergic system. Mechanistic studies indicate spinosin acts as an antagonist at presynaptic 5-HT1A autoreceptors (which would disinhibit serotonin release) and at postsynaptic 5-HT1A receptors, with the net pharmacological effect of modulating serotonergic tone. Separately, spinosin’s anxiolytic effects in behavioral tests (elevated plus maze, light/dark box, open field) are blocked by both the GABA-A receptor antagonist flumazenil and the 5-HT1A receptor antagonist WAY-100635, confirming dual GABAergic and serotonergic involvement. Spinosin and 6'''-feruloylspinosin also significantly enhance GABRA1 and GABRA5 mRNA expression in hippocampal neurons.

3. Sanjoinine A (frangufoline) — Cyclopeptide alkaloid sedation: Sanjoinine A is a 13-membered cyclopeptide alkaloid identified as a sedative principle of jujube seed. It augments pentobarbital-induced sleep behaviors through modification of GABAergic systems, specifically by increasing GABA synthesis via GAD65/67 (glutamic acid decarboxylase) activation. Sanjoinine A binds to calmodulin (CaM) in a calcium-dependent manner at two sets of binding sites, and its effects on Ca2+-ATPase correlate with sedative potency.

Secondary Mechanisms

4. Betulinic acid — GABAergic modulation: Betulinic acid, a pentacyclic triterpene present in jujube seed, modulates the GABAergic system via multiple subtypes of GABA-A receptors, contributing additional sedative activity.

5. Zizyphusine — Serotonergic modulation: The isoquinoline alkaloid zizyphusine modulates the serotonergic system via multiple subtypes of 5-HT receptors, providing a serotonergic complement to the predominantly GABAergic saponin and alkaloid constituents.

6. Da Zao (fruit) — Cyclic AMP and nutritive effects: The fruit is notably rich in cyclic adenosine monophosphate (cAMP), a second messenger involved in numerous cellular signaling pathways. While the clinical significance of oral cAMP from jujube fruit is debated, the fruit’s nutritive profile (vitamin C, polysaccharides, organic acids) supports the TCM concept of “nourishing blood” and supplementing qi through direct nutritional support.

Pharmacological Summary

The sedative and anxiolytic effects of jujube seed appear to result from the convergence of multiple active compound classes on two primary neurotransmitter systems: the GABAergic system (jujubosides, spinosin, sanjoinine, betulinic acid) and the serotonergic system (spinosin, zizyphusine). This multi-target pharmacology is consistent with the complex phytochemical profile and may explain why the whole seed extract performs differently from isolated compounds in preclinical models.

Clinical Evidence Summary

Clinical evidence for jujube is limited and is characterized by small sample sizes, heterogeneous preparations, and methodological limitations. Most clinical research has studied the multi-herb formula Suan Zao Ren Tang (SZRT) rather than jujube seed as a standalone agent.

Suan Zao Ren Tang (SZRT) — Formula Trials

SZRT consists of five herbs: Suan Zao Ren (jujube seed, principal), Fu Ling (Poria cocos), Chuan Xiong (Ligusticum chuanxiong), Zhi Mu (Anemarrhena asphodeloides), and Gan Cao (Glycyrrhiza uralensis). The formula was first documented in the Jin Gui Yao Lue (circa 210 CE).

Standalone Jujube Seed Trials

Sansoninto (Kampo) Studies

Systematic Reviews and Meta-Analyses

• Yi et al. (2023): A systematic review and meta-analysis of nine trials involving 905 participants supported SZRT’s short-term benefits. Subjective sleep quality improved significantly compared to placebo, and SZRT achieved notable reductions in insomnia severity when compared with benzodiazepines or cognitive behavioral therapy for insomnia (CBT-I). However, the authors noted heterogeneity across trials and generally poor methodological quality.
• Wang et al. (2020): Published protocol for a systematic review of Suan-Zao-Ren decoction for insomnia, planned to search multiple databases comprehensively.

Evidence Limitations

• No large standalone RCTs: The single standalone jujube seed RCT (Mahmoudi et al. 2020, n=106) is the only placebo-controlled study of the seed extract alone, and it used a relatively short duration (21 days).
• Formula confounding: Most evidence comes from the five-herb SZRT formula, making it impossible to attribute effects to jujube seed alone.
• Methodological quality: Many studies lack adequate blinding, allocation concealment, or intention-to-treat analysis. Several are open-label.
• Outcome measures: Reliance on subjective sleep quality measures (PSQI) without polysomnography or actigraphy limits the strength of findings.
• Publication bias: Most studies originate from China or Taiwan, and positive publication bias in traditional medicine research from these regions has been documented.
• Dosage heterogeneity: Preparations range from raw decoctions to concentrated granules to capsulated extracts, making cross-study comparison difficult.

Safety Profile

General Assessment

Jujube seed and fruit are considered to have very low toxicity and are generally well tolerated. The fruit has a long history of safe dietary consumption across East Asia. The seed has been used medicinally for nearly two millennia with few reports of adverse effects.

Contraindications

• Concurrent sedative medications: Additive sedation is a theoretical concern when combining jujube seed with benzodiazepines, barbiturates, Z-drugs, antihistamines, or other CNS depressants. The GABAergic mechanism provides a pharmacological basis for this interaction.
• TCM-specific contraindications: Not recommended in patients with excessive “fire” or “phlegm-heat” patterns, or severe diarrhea, according to traditional TCM usage guidelines.
• Pregnancy: Safety category unknown. Insufficient data for use during pregnancy. No human safety data. Avoid until safety is established.
• Lactation: Insufficient data. Avoid until safety is established.
• Children: No clinical data in pediatric populations. Not recommended without practitioner supervision.

Drug Interactions

• CNS depressants (benzodiazepines, barbiturates, opioids, alcohol): Theoretical additive sedation due to GABAergic mechanism. The Chan et al. (2015) trial combined SZRT with methadone without reported adverse interactions, but vigilance is warranted.
• CYP1A2 substrates: In vivo rat studies show that Ziziphus jujuba fruit extracts increased CYP1A2 activity, resulting in a 43.2% (water extract) and 15.5% (ethanolic extract) reduction in the AUC of the probe substrate phenacetin. This could reduce plasma concentrations of CYP1A2-metabolized drugs (theophylline, clozapine, duloxetine, melatonin). Clinical significance in humans is not established.
• Antiepileptic drugs: A preclinical study found pharmacokinetic interactions between jujube hydroalcoholic extract and phenytoin, phenobarbitone, and carbamazepine, with enhanced anticonvulsant effects. Co-administration warrants monitoring.
• Venlafaxine: An interaction with venlafaxine has been reported, though details are limited. Caution with serotonergic medications is reasonable given spinosin’s 5-HT1A activity.
• CYP3A4: Spinosin exhibited inactive effects on CYP3A4 in human liver microsomes, suggesting low risk of interaction via this pathway.

Side Effects (at recommended doses)

• Common: Generally well tolerated. No consistent adverse effects reported in clinical trials at standard doses.
• Uncommon: Mild gastrointestinal discomfort (bloating, loose stools) reported occasionally.
• Rare: No serious adverse events have been reported in published clinical trials of SZRT or standalone jujube seed preparations.

Toxicology

• Acute toxicity: Very low. In laboratory animals, a single oral dose of 50 g/kg body weight produced no toxic symptoms. Daily dosing at 20 g/kg for 30 days produced no toxic reactions.
• Genotoxicity: Compound capsule formulations containing jujube seed showed negative results in the Ames test, mouse bone marrow cell micronucleus test, and mouse sperm deformity test.
• Maximum tolerated dose: Intragastric administration of 30,000 mg/kg in mice produced no signs of poisoning or mortality.
• Overall: The toxicological profile supports classification as a very safe botanical with an exceptionally wide therapeutic index.

Clinical Dosage

Suan Zao Ren (Seed) — Decoction

• Standard TCM dose: 9-15 g of dried seed per day in decoction
• Higher doses (some sources): Up to 18-30 g daily for severe insomnia, under practitioner supervision
• Note: Seeds are typically dry-fried (chao) or crushed before decoction to improve extraction

Suan Zao Ren (Seed) — Extract/Capsule

• Capsule form: 250-500 mg of seed extract, twice daily (as in Mahmoudi et al. 2020 trial)
• Standardization: Products may be standardized to total saponins (jujuboside A content) or total flavonoids (spinosin content); no universally accepted standardization exists

Suan Zao Ren Tang / Sansoninto (Formula)

• Traditional decoction: Suan Zao Ren 15-18 g, Fu Ling 6 g, Zhi Mu 6 g, Chuan Xiong 6 g, Gan Cao 3 g — decocted and taken before bedtime
• Concentrated granules (Japan): Tsumura Sansoninto granules, 7.5 g/day in divided doses (equivalent to the raw herb decoction proportions)
• Extract tablets/capsules: Variable by manufacturer; typically 2-4 g of concentrated granules per day

Da Zao (Fruit) — Harmonizing Agent

• Standard TCM dose: 3-12 pieces (approximately 10-30 g) in decoction
• Used in formula context: Almost never used alone; serves as a harmonizing and moderating agent

Duration of Use

• Clinical trials have used durations of 3-12 weeks
• Traditional use supports ongoing use for chronic insomnia, though practitioner reassessment is recommended
• No established maximum duration

Sources

• Chinese Pharmacopoeia Commission. Pharmacopoeia of the People’s Republic of China. Vol 1. 2020 Edition
• Chan YY, Lo WY, Li TC, et al. Clinical Efficacy of Traditional Chinese Medicine, Suan Zao Ren Tang, for Sleep Disturbance during Methadone Maintenance: A Randomized, Double-Blind, Placebo-Controlled Trial. Evid Based Complement Alternat Med. 2015;2015:710895
• Yeh CH, Arnold CK, Chen YH, Hsiao SJ. Suan Zao Ren Tang as an Original Treatment for Sleep Difficulty in Climacteric Women: A Prospective Clinical Observation. Evid Based Complement Alternat Med. 2011;2011:673813
• Xie CL, Gu Y, Wang WW, et al. Suan zao ren tang in combination with zhi zi chi tang as a treatment protocol for insomniacs with anxiety: a randomized parallel-controlled trial. Evid Based Complement Alternat Med. 2013;2013:913248
• Mahmoudi R, Ansari S, Haghighizadeh MH, et al. Investigation the effect of jujube seed capsule on sleep quality of postmenopausal women: a double-blind randomized clinical trial. BioMedicine. 2020;10(4):30-38
• Yi M, Wang S, Wu T, et al. The Herbal Medicine Suanzaoren (Ziziphi Spinosae Semen) for Sleep Quality Improvements: A Systematic Review and Meta-analysis. Integr Cancer Ther. 2023;22:15347354231165229
• Wang J, Liang L, Wei S, et al. Suan-Zao-Ren decoction for insomnia: A protocol for a systematic review and meta-analysis. Medicine (Baltimore). 2020;99(34):e21728
• Aizawa R, Kanbayashi T, Saito Y, et al. Efficacy and Safety of Sansoninto in Insomnia with Psychiatric Disorder: An Open-Label Study. Altern Ther Health Med. 2002;8(3):62-69
• Zhang ZJ. Jin Gui Yao Lue (Essential Prescriptions from the Golden Cabinet). circa 210 CE
• Cao JX, Zhang QY, Cui SY, et al. Inhibitory effect of jujuboside A on glutamate-mediated excitatory signal pathway in hippocampus. Planta Med. 2003;69(8):692-695
• Shou CH, Wang J, Zheng XX, Guo DW. Inhibitory effects of jujuboside A on EEG and hippocampal glutamate in hyperactive rat. Zhongguo Zhong Yao Za Zhi. 2001;26(5):339-341
• You ZL, Xia Q, Liang FR, et al. Effects on the expression of GABAA receptor subunits by jujuboside A treatment in rat hippocampal neurons. J Ethnopharmacol. 2010;128(2):419-423
• Wang LE, Cui XY, Cui SY, et al. Potentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors. J Pharm Pharmacol. 2010;62(11):1515-1521
• Jiang JG, Huang XJ, Chen J. Separation and purification of saponins from Semen Ziziphus jujuba and their sedative and hypnotic effects. J Pharm Pharmacol. 2007;59(8):1175-1180
• Ko SY, Lee HE, Park SJ, et al. GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice. Pharmacol Biochem Behav. 2015;128:41-49
• Wang LE, Bai YJ, Shi XR, et al. Spinosin, a C-glycoside flavonoid from semen Ziziphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system. Pharmacol Biochem Behav. 2008;90(3):399-403
• Ma Y, Han H, Eun JS, et al. Sanjoinine A isolated from Zizyphi Spinosi Semen augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems. Biol Pharm Bull. 2007;30(9):1748-1753
• Peng WH, Hsieh MT, Lee YS, Lin YC, Liao J. Anxiolytic effect of seed of Ziziphus jujuba in mouse models of anxiety. J Ethnopharmacol. 2000;72(3):435-441
• Chen CJ, Liu JH. Effects of Ziziphus jujuba fruit extracts on cytochrome P450 (CYP1A2) activity in rats. Chin J Nat Med. 2015;13(8):588-594
• Shergis JL, Ni X, Sarris J, et al. Ziziphus spinosa seeds for insomnia: A review of chemistry and psychopharmacology. Phytomedicine. 2017;34:38-43
• Tsumura & Co. TSUMURA Sansoninto Extract Granules for Ethical Use (product information). Tsumura, Japan
• Takenaga M, et al. Characterization of Marker Compounds in Ziziphi Fructus. Chem Pharm Bull. 2025;74(2):c25-00717
• Memorial Sloan Kettering Cancer Center. Suan Zao Ren Tang. Integrative Medicine Herbs Database

Connections

• GABA-modulating sedative herbs: Compare with Valerian (valerenic acid — GABA-A subunit selectivity), Passionflower (chrysin and related flavonoids), Hops (2-methyl-3-buten-2-ol), Kava (kavalactones — lipid membrane GABA-A modulation), and Magnolia Bark (honokiol/magnolol — positive allosteric GABA-A modulation). Jujube seed is distinctive in combining GABAergic saponins (jujubosides) with serotonergic flavonoids (spinosin) in a single botanical source.
• TCM sedative/calming herbs (an shen): Jujube seed belongs to the TCM category of “substances that nourish the heart and calm the spirit,” alongside Bai Zi Ren (Platycladus orientalis seed), Long Yan Rou (Dimocarpus longan aril), and He Huan Pi (Albizia julibrissin bark). This category addresses insomnia from deficiency patterns, contrasting with the “heavy settling” substances (Long Gu, Mu Li) used for excess-type insomnia.
• Kampo sedative formulas: Sansoninto (Suan Zao Ren Tang) represents one of the few Kampo formulas specifically indicated for insomnia. Compare with Yokukansan (Yi Gan San), which addresses insomnia with irritability and aggression, and Kamishoyosan (Jia Wei Xiao Yao San), used for insomnia with menopausal or emotional disturbance.
• Da Zao as harmonizing agent: The fruit’s role as a formula harmonizer is functionally comparable to Glycyrrhiza (Gan Cao / licorice root) in TCM — both are among the most frequently appearing herbs in classical formulas, serving to moderate harshness and support digestion.
• Schisandra comparison: Like Schisandra, jujube bridges TCM and East Asian pharmacopoeia traditions with limited Western clinical validation. Both are multi-constituent botanicals with well-characterized preclinical pharmacology but insufficient standalone RCTs by Western evidence-based medicine standards.