Zizyphus

The drug is suan zao ren, the seed from inside the stone of the sour jujube fruit. It is not the sweet edible date, and not the fruit.

Shen Nong’s Herbal Classic, the earliest Chinese materia medica, ranked it a top-grade medicine for regulating the five organs and for long life ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}. Its use as a medicine for sleep dates to the Eastern Han dynasty, when the spine-date seed decoction was recorded ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}.

The Chinese Pharmacopoeia classes it as sweet, sour and neutral, entering the Liver, Gallbladder and Heart channels. It nourishes the heart and tonifies the liver, calms the mind, restrains sweating and generates fluids. The pharmacopoeia gives it for restlessness and insomnia from deficiency, palpitations with vivid dreams, heavy sweating from weakness, and thirst ^{36Reference 36Chinese Pharmacopoeia Commission · 2015ReviewChinese Pharmacopoeia Commission (2015). 酸枣仁 Suanzaoren (Ziziphi Spinosae Semen) — monograph: source, identification, assay limits for jujuboside A and spinosin, taste, channels, actions and dose. Pharmacopoeia of the People’s Republic of China, 2015 ed., Vol. I, pp. 365–366. https://www.drugfuture.com/Pharmacopoeia/CP2015-1/365-366.pdfView study →}.

It is used to nourish the heart and liver and to calm the mind ^{31Reference 31Liu et al. · 2025ReviewPhytochemical, pharmacological, pharmacokinetic and toxicological characteristics of Ziziphi Spinosae Semen: a review — [review]View study →}. Its main indications are insomnia and palpitations, along with dizziness, headache and anxiety. More than 30 formulas containing it are listed in the Chinese Pharmacopoeia ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}.

Older texts separate the raw and the fried seed. The fried seed was given for insomnia from deficiency, and the raw seed for drowsiness from heat ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}. The Bie Lu also records it for cold sweats and thirst ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}.

Today the seed is dry-fried before decoction, especially for sleep ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}.

The only trial of the seed on its own was a randomised, double-blind, placebo-controlled crossover feasibility study in Melbourne. Twelve adults with insomnia took encapsulated granules, 2 g a day, for four weeks ^{1Reference 1Shergis et al. · 2021RCTMedicinal seeds Ziziphus spinosa for insomnia: A randomized, placebo-controlled, cross-over, feasibility clinical trial — [randomised, double-blind, placebo-controlled crossover RCT]View study →}.

Sleep quality on the Pittsburgh Sleep Quality Index improved more on the seed than on placebo (t = −2.276, df = 10, 95% CI −3.3 to −0.04, p = 0.046). Sleep diaries showed gains in total sleep time, sleep efficiency and time to fall asleep. The other outcomes did not differ between treatments, and the authors present it as a feasibility study ^{1Reference 1Shergis et al. · 2021RCTMedicinal seeds Ziziphus spinosa for insomnia: A randomized, placebo-controlled, cross-over, feasibility clinical trial — [randomised, double-blind, placebo-controlled crossover RCT]View study →}.

The larger human evidence tests the seed inside formulas. A meta-analysis of nine Suanzaoren trials found better subjective sleep quality than placebo (standardised mean difference −0.58). Against benzodiazepines or cognitive behavioural therapy, insomnia severity fell by a further 2.68 points at four weeks ^{2Reference 2Yang et al. · 2023Meta-analysisThe Herbal Medicine Suanzaoren (Ziziphi Spinosae Semen) for Sleep Quality Improvements: A Systematic Review and Meta-analysis — [systematic review and meta-analysis]View study →}.

Other systematic reviews of Suanzaoren decoction and related formulas report benefit similar to benzodiazepines with fewer adverse events. They also report low study quality and a high risk of bias ^{3,4,6,7,8Reference 3Birling et al. · 2020Meta-analysisZao Ren An Shen for insomnia: a systematic review with meta-analysis — [systematic review with meta-analysis]View study →Reference 4Liu et al. · 2022Meta-analysisSuanzaoren Decoction for the treatment of chronic insomnia: a systematic review and meta-analysis — [systematic review and meta-analysis]View study →Reference 6Xie et al. · 2013Systematic reviewEfficacy and safety of Suanzaoren decoction for primary insomnia: a systematic review of randomized controlled trials — [systematic review of randomised controlled trials]View study →Reference 7Yeung et al. · 2012Systematic reviewChinese herbal medicine for insomnia: a systematic review of randomized controlled trials — [systematic review of randomised controlled trials]View study →Reference 8Zhou et al. · 2018Meta-analysisSuanzaoren Formulae for Insomnia: Updated Clinical Evidence and Possible Mechanisms — [systematic review and meta-analysis of RCTs, with animal-model mechanisms]View study →}. A 2025 network meta-analysis of 186 trials of Chinese herbal medicines ranked suanzaoren among the five best for sleep-quality scores ^{5Reference 5Li et al. · 2025Meta-analysisChinese herbal medicine for insomnia: A systematic review and network meta-analysis — [systematic review and network meta-analysis]View study →}.

In animals, spinosin shortens the time to sleep and lengthens NREM and slow-wave sleep in pentobarbital-treated rodents, through serotonin 5-HT1A signalling ^{11,12,13Reference 11Wang et al. · 2008AnimalSpinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system — [mouse in vivo study]View study →Reference 12Wang et al. · 2010AnimalPotentiating effect of spinosin, a C-glycoside flavonoid of Semen Ziziphi spinosae, on pentobarbital-induced sleep may be related to postsynaptic 5-HT(1A) receptors — [rat in vivo study]View study →Reference 13Wang et al. · 2012AnimalAugmentative effect of spinosin on pentobarbital-induced loss of righting reflex in mice associated with presynaptic 5-HT1A receptor — [mouse in vivo study]View study →}. Jujuboside A restores GABA balance in sleep-deprived mice and supports mitochondrial function in the prefrontal cortex ^{9,17Reference 9Wang et al. · 2025AnimalJujuboside A in ameliorating insomnia in mice via GABAergic modulation of the PVT — [mouse in vivo study]View study →Reference 17Zhang et al. · 2025AnimalJujuboside A improves insomnia by maintaining mitochondrial homeostasis in prefrontal neurons — [mouse in vivo study]View study →}. Sanjoinine A does not cause sleep on its own, but it prolongs pentobarbital sleep by increasing GABA-A-mediated chloride influx ^{14Reference 14Ma et al. · 2007AnimalSanjoinine A isolated from Zizyphi Spinosi Semen augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems — [mouse in vivo study]View study →}.

EEG and EMG recording in mice shows that injected spinosin raises NREM sleep and changes activity in sleep-regulating brain regions ^{10Reference 10Zhao et al. · 2025AnimalSpinosin enhances non-rapid eye movement sleep and alters c-Fos expression in sleep-wake regulatory brain regions in mice — [mouse in vivo (EEG/EMG) study]View study →}.

Gap: only one small single-herb RCT exists; every larger positive result is a multi-herb decoction, and no trial standardizes the seed to its marker compounds or its dry-fried whole-seed form.

The anxiety evidence is preclinical. Oral spinosin at 2.5–5 mg/kg increased time on the open arms of the elevated plus maze and in the light compartment of the light/dark box, and increased central entries in the open field, without changing activity levels ^{15Reference 15Liu et al. · 2015AnimalGABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice — [mouse in vivo study]View study →}.

Both effects were blocked by the GABA-A antagonist flumazenil and the 5-HT1A antagonist WAY-100635 ^{15Reference 15Liu et al. · 2015AnimalGABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice — [mouse in vivo study]View study →}.

Sanjoinine A at 2 mg/kg produced the same pattern in mice. In cultured neurons it increased chloride influx and the expression of GABA-A receptor subunits. Unlike diazepam, it did not reduce movement ^{16Reference 16Han et al. · 2009AnimalAnxiolytic-like effects of sanjoinine A isolated from Zizyphi Spinosi Semen: possible involvement of GABAergic transmission — [mouse in vivo study]View study →}.

Jujuboside A also reduces anxiety-like behaviour in mice given an insomnia model ^{17Reference 17Zhang et al. · 2025AnimalJujuboside A improves insomnia by maintaining mitochondrial homeostasis in prefrontal neurons — [mouse in vivo study]View study →}.

In traditional use, the seed is given for restlessness and irritability rather than as a standalone remedy for anxiety.

Gap: all direct evidence is rodent behavioral pharmacology on isolated compounds; there is no human anxiety trial and no data on whether an oral whole-seed preparation reaches anxiolytic exposures.

Several animal studies suggest the seed’s compounds support memory and resist neurodegeneration. This is not a traditional use of the seed ^{22Reference 22Liu et al. · 2026AnimalMetabolomic insights into the neuroprotective actions of Ziziphi spinosae semen and jujuboside B against Aβ-induced toxicity — [C. elegans in vivo study]View study →}.

Oral spinosin reversed scopolamine-induced memory deficits in mice through 5-HT1A-linked ERK/CREB signalling ^{18Reference 18Jung et al. · 2014AnimalAmeliorating effect of spinosin, a C-glycoside flavonoid, on scopolamine-induced memory impairment in mice — [mouse in vivo study]View study →}. Injected into the brain in an amyloid-β model of Alzheimer’s disease, it reduced hippocampal malondialdehyde and amyloid accumulation and restored BDNF ^{19Reference 19Xu et al. · 2019AnimalNeuroprotective Effects of Spinosin on Recovery of Learning and Memory in a Mouse Model of Alzheimer’s Disease — [mouse in vivo study]View study →}.

Jujuboside A promoted amyloid-β clearance and improved cognition in APP/PS1 mice through an Axl/HSP90/PPARγ pathway ^{20Reference 20Zhang et al. · 2018AnimalJujuboside A promotes Aβ clearance and ameliorates cognitive deficiency in Alzheimer’s disease through activating Axl/HSP90/PPARγ pathway — [mouse in vivo (APP/PS1) study]View study →}.

The whole seed and jujuboside B protected against amyloid-β toxicity in the nematode C. elegans, through the daf-16 and sir-2.1 longevity pathways ^{22Reference 22Liu et al. · 2026AnimalMetabolomic insights into the neuroprotective actions of Ziziphi spinosae semen and jujuboside B against Aβ-induced toxicity — [C. elegans in vivo study]View study →}.

Suanzaoren decoction reduced ferroptosis and synaptic damage in Alzheimer’s-model mice through DJ-1/Nrf2 signalling ^{21Reference 21Long et al. · 2024AnimalSuanZaoRen decoction alleviates neuronal loss, synaptic damage and ferroptosis of AD via activating DJ-1/Nrf2 signaling pathway — [mouse in vivo (APP/PS1) study]View study →}.

All of this is preclinical, spread across several models and compounds, and some of it uses injection into the brain.

The antidepressant evidence rests on one compound in rodents. Jujuboside A, at 10–30 mg/kg for three weeks, reduced immobility in the tail-suspension and open-field tests in mice with corticosterone-induced depression, and raised hippocampal BDNF, TrkB and CREB ^{23Reference 23Li et al. · 2022AnimalAntidepressant effect of Jujuboside A on corticosterone-induced depression in mice — [mouse in vivo study]View study →}.

In a rat model of visceral pain with depression, jujuboside A relieved depressive-like behaviour and reduced P2X7 receptor expression in the spinal cord and hippocampus ^{24Reference 24Liu et al. · 2026AnimalJujuboside A alleviates visceral pain and depression comorbidity and modulates the P2X7R-BDNF signaling axis — [rat in vivo study]View study →}.

These are two rodent studies of a single isolated saponin, with no evidence on whether an oral seed preparation reaches these levels.

Liver protection is documented only for isolated saponins in animal disease models. Jujuboside B reduced liver injury in septic mice, lowering ALT, AST and necrosis. It dampened TNF-α, IL-1β and nitric oxide and raised the liver’s own antioxidant capacity ^{27Reference 27Kim et al. · 2023AnimalHepatoprotective functions of jujuboside B — [mouse/rat in vivo study]View study →}.

Jujuboside A reduced diabetes-associated fatty liver in db/db mice and in cultured liver cells, by restraining YY1/CYP2E1 signalling. It cut liver fat, inflammation and oxidative stress ^{28Reference 28Zhang et al. · 2024In vitroJujuboside A through YY1/CYP2E1 signaling alleviated type 2 diabetes-associated fatty liver disease by ameliorating hepatic lipid accumulation, inflammation, and oxidative stress — [mouse in vivo and in vitro study]View study →}.

This is isolated-compound work in animal and cell disease models.

The heart evidence is preclinical and compound-level. Spinosin and 6‴-feruloylspinosin, injected at 5 mg/kg before a coronary artery was tied off, reduced heart-muscle injury, enzyme release and cell death in rats ^{25Reference 25Gu et al. · 2020AnimalSpinosin and 6‴‑Feruloylspinosin protect the heart against acute myocardial ischemia and reperfusion in rats — [rat in vivo study]View study →}.

Jujuboside A given before a septic challenge improved survival and heart function in mice by reducing inflammation and supporting autophagy ^{26Reference 26Wang et al. · 2023AnimalJujuboside A attenuates sepsis-induced cardiomyopathy by inhibiting inflammation and regulating autophagy — [mouse in vivo study]View study →}.

These are single-compound rodent studies, and the rat study used injection.

One study underpins this. In db/db diabetic mice and in liver cells exposed to high glucose and fatty acids, jujuboside A improved high blood sugar and reduced liver fat, inflammation and oxidative stress, through the same YY1/CYP2E1 pathway as its fatty-liver effect ^{28Reference 28Zhang et al. · 2024In vitroJujuboside A through YY1/CYP2E1 signaling alleviated type 2 diabetes-associated fatty liver disease by ameliorating hepatic lipid accumulation, inflammation, and oxidative stress — [mouse in vivo and in vitro study]View study →}.

The metabolic effect has not been tested for the whole seed.

The anticancer evidence is a single cell study. Jujuboside A killed bladder-cancer cells by blocking ATP1A2 and disrupting their mitochondrial energy supply ^{29Reference 29Zhu et al. · 2026In vitroJujuboside A induces bladder cancer cell apoptosis by inhibiting ATP1A2-mediated mitochondrial energy metabolism regulation — [in vitro cell-line study]View study →}. A review lists cytotoxic effects of spinosin in other cell lines ^{30Reference 30Kuang et al. · 2022ReviewThe pharmacology, pharmacokinetics, and toxicity of spinosin: A mini review — [review]View study →}.

Gap: cell-line data only, one tumor type, no animal or human evidence.

Toxicity. Mice given 150 g/kg of the seed by mouth showed no toxic signs, and long-term feeding in rats also showed very low toxicity ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}.

Adverse events in people. A systematic review of medicinal seeds found adverse-event reports for sour jujube seed, but none it classed as serious ^{33Reference 33Yuan et al. · 2025Systematic reviewSafety of medicinal and edible herbs from seed sources for human consumption: A systematic review — [systematic review]View study →}. In the single-herb trial the seed was well tolerated over four weeks at 2 g a day, with only minor adverse events ^{1Reference 1Shergis et al. · 2021RCTMedicinal seeds Ziziphus spinosa for insomnia: A randomized, placebo-controlled, cross-over, feasibility clinical trial — [randomised, double-blind, placebo-controlled crossover RCT]View study →}. Formula meta-analyses report fewer adverse events than benzodiazepines ^{2,3Reference 2Yang et al. · 2023Meta-analysisThe Herbal Medicine Suanzaoren (Ziziphi Spinosae Semen) for Sleep Quality Improvements: A Systematic Review and Meta-analysis — [systematic review and meta-analysis]View study →Reference 3Birling et al. · 2020Meta-analysisZao Ren An Shen for insomnia: a systematic review with meta-analysis — [systematic review with meta-analysis]View study →}.

Sedatives and alcohol. Its compounds act on GABA-A and serotonin pathways ^{11,14,15Reference 11Wang et al. · 2008AnimalSpinosin, a C-glycoside flavonoid from semen Zizhiphi Spinozae, potentiated pentobarbital-induced sleep via the serotonergic system — [mouse in vivo study]View study →Reference 14Ma et al. · 2007AnimalSanjoinine A isolated from Zizyphi Spinosi Semen augments pentobarbital-induced sleeping behaviors through the modification of GABA-ergic systems — [mouse in vivo study]View study →Reference 15Liu et al. · 2015AnimalGABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice — [mouse in vivo study]View study →}, so it may add to the effect of sedatives, sleep medicines, benzodiazepines, alcohol and other central nervous system depressants.

Drug transport. In intestinal-cell tests, spinosin and the other seed flavonoids were pumped back out by P-glycoprotein, which limits how much is absorbed ^{37Reference 37Song et al. · 2020In vitroMechanism of the Intestinal Absorption of Six Flavonoids from Zizyphi Spinosi Semen Across Caco-2 Cell Monolayer Model — [in vitro study]View study →}. No CYP450 or human interaction study has been done.

Regulatory status. The seed is listed in the Chinese Pharmacopoeia ^{32Reference 32He et al. · 2020ReviewBotanical and Traditional Uses and Phytochemical, Pharmacological, Pharmacokinetic, and Toxicological Characteristics of Ziziphi Spinosae Semen: A Review — [review]View study →}. The European Pharmacopoeia Commission was unable to complete a monograph for it, and the EMA has not issued a recommendation ^{34Reference 34Rodríguez Villanueva et al. · 2017ReviewExperimental and Clinical Pharmacology of Ziziphus jujuba Mills — [review]View study →}.