Yokukan-san: a review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions

Figures & data

Table 1 Components of Yokukan-san

Constituent herbs	Weight (g)
Japanese Angelica root (当帰)	3.0
Atractylodes lancea rhizome (蒼朮)	4.0
Bupleurum root (柴胡)	2.0
Poria sclerotium (茯苓)	4.0
Glycyrrhiza root (甘草)	1.5
Cnidium rhizome (川芎)	3.0
Uncaria hook (釣藤鈎)	3.0

Table 2 Case reports

Patient (age [years]/sex)	Diagnosis	Symptoms	Daily dose	Results	Adverse effects	Author, year of publication
44/F	Somatoform disorder	Tinnitus, headache, insomnia	7.5 g	Complete remission	None	Okamoto et al, 2005^Citation26
81/M	DLB	Psychosis, sleep disturbance	7.5 g	Markedly improved	None	Shinno et al, 2007^Citation1
60/M 74/F 87/F	REM sleep behavior disorder	Dream-enacting behaviors	2.5–7.5 g	Complete remission	None	Shinno et al, 2008^Citation15
73/F	Charles Bonnet syndrome	Visual hallucinations	7.5 g	Complete remission	None	Miyaoka et al, 2009^Citation28
85/M	Traumatic brain injury	Impulsive and aggressive behaviors	7.5 g	Markedly improved	None	Saito et al, 2010^Citation27
62/F 80/F 75/M	Restless legs syndrome	Unpleasant sensations in the legs	5 g	Complete remission	None	Shinno et al, 2010^Citation16
74/M 78/F	Poststroke emotional incontinence	Uncontrollable episodes of crying or laughing	7.5 g	Complete remission	None	Kajitani and Kanba, 2012^Citation29
50/M	Nocturnal eating/drinking syndrome, restless legs syndrome, schizophrenia	Uncontrollable consumption of food and pain and discomfort in legs at night	2.5 g	Complete remission	None	Kawabe et al, 2012^Citation30
85/M 44/M 29/M	AD Tardive dystonia IED	Aggressive behaviors Muscle contractions Aggressive impulses	5 g 7.5 g 7.5 g	Partially improved (markedly improved after Orengedoku-to augmentation)	None	Okamoto et al, 2013^Citation31

Abbreviations: AD, Alzheimer-type dementia; DLB, dementia with Lewy bodies; F, female; IED, intermittent explosive disorder; M, male; REM, rapid eye movement.

Table 3 Controlled studies of dementia

Design	Diagnosis	Study size	Dose, duration	Results	Adverse effects	Author, year of publication
Prospective, randomized, observer-blind, multicenter, open-label	Mild-to-severe dementia	N=52 (YKS group n=27; control n=25)	7.5 g/day, 4 wks	Significant improvement in NPI and BI scores. No significant change in MMSE	EPS were not observed. Two participants became oversedated after trial (well tolerated with 3–4.5 g/day of YKS)	Iwasaki et al, 2005^Citation2
Prospective, single-arm, open-label	Mild-to-severe DLB	N=14	7.5 g/day, 4 wks	Significant improvement in NPI and BI scores. No significant change in MMSE. Visual hallucinations disappeared within 2 weeks in 12 of 15 patients	One dropout due to drowsiness	Iwasaki et al, 2005^Citation3
Prospective, single-arm, open-label	Mild-to-severe dementia	N=5 (DLB n=3; AD n=2)	7.5 g/day, 4 wks	Significant improvement in total sleep time, number of awakenings, PLMs index in PSG as well as NPI scores. Significant increase of Stage II sleep. No significant change in MMSE	None	Shinno et al, 2008^Citation4
Prospective, randomized, cross-over, multicenter, open-label	Mild-to-severe AD (including mixed-type dementia), DLB	N=103 (YKS administration for first 4 wks and non-treatment for next 4 wks n=53; non-treatment for first 4 wks and YKS administration for next 4 wks n=50)	7.5 g/day, 4 wks	NPI scores significantly improved in first 4 wks in both groups and also markedly improved in the YKS treatment period in both groups. No significant change in MMSE, BI, or IADL	Gastrointestinal symptoms (vomiting/diarrhea, nausea, epigastric distress) in three patients, hypokalemia in two patients (3.8→3.4, 4.1→2.2 mEq/L) and one of two also showed sedation, leg edema in one patient	Mizukami et al, 2009^Citation5
Prospective, randomized, open-label	Mild-to-severe AD	N=15 (YKS group n=10; control n=5)	7.5 g/day, 12 wks	Decrease of the sulpiride dose (continuation therapy for BPSD), significant improvement in NPI, unchanged MMSE scores	Hypokalemia in two patients (one of them was supplemented with potassium until the end of the study)	Monji et al, 2009^Citation6
Prospective, single-arm, multicenter, open-label	Mild-to-severe AD (including mixed-type dementia)	N=26	7.5 g/day, 4 wks	Significant improvement in NPI scores. No significant change in MMSE or DAD	Hypokalemia in one patient and oversedation in one patient	Hayashi et al, 2010^Citation7
Prospective, randomized, multicenter, open-label	Mild-to-severe AD (including mixed-type dementia)	N=63 (YKS group n=30; control n=33)	7.5 g/day, 4 wks	Significant improvement in NPI scores. No significant change in MMSE, DAD, ZBI, or SDS	None	Okahara et al, 2010^Citation8
Prospective, single-arm, open-label	Parkinsonian dementia	N=14 (PDD n=7; PD n=7)	7.5 g/day, 4 wks	Significant improvement in NPI scores after 1–2 weeks of YKS administration. Recurrences of hallucinations in five PD and three PDD patients after cessation of YKS treatment (no recurrence in the remaining patients during the 4-week follow-up period)	Sialorrhea in one PDD patient and mild elevation of blood liver enzymes in one PD patient	Kawanabe et al, 2010^Citation9
Prospective, single-arm, open-label	Mild-to-severe FTD	N=20	7.5 g/day, 4 wks	Significant improvement in NPI and SRI scores	Hypokalemia in two patients	Kimura et al, 2010^Citation10
Prospective, single-arm, multicenter, open-label	Mild-to-severe DLB	N=54	7.5 g/day, 4 wks	Significant improvement in NPI and ZBI scores. No significant change in MMSE or DAD	Hypokalemia in four patients and worsening hypotension in one patient. Three patients discontinued YKS due to spasticity and exacerbation of BPSD, edema, and nausea	Iwasaki et al, 2012^Citation11
Prospective, single-arm, open-label	Mild-to-severe VaD	N=13	7.5 g/day, 4 wks	Significant improvement in NPI scores. No significant change in MMSE, BI, DAD, or UPDRS	None	Nagata et al, 2012^Citation12
Prospective, single-arm, open-label	CRF patients with mild-to-severe dementia receiving hemodialysis three times per week	N=11 (AD n=8; VaD n=3)	7.5 g/day, 4 wks	Significant improvement in NPI. No significant change in BI. Blood potassium remained within the normal range during YKS administration although 6.5%–41.2% of CRF patients receiving hemodialysis were supposed to be hyperkalemic	Mild and transient (nausea in one patient and tiredness in one patient)	Sumiyoshi et al, 2013^Citation13
Prospective, randomized, rater-blinded, flexible-dosed, triple group trial	Mild-to-severe dementia (dementia subtypes were diagnosed into AD, VaD, or DLB)	N=76 (YKS n=26; risperidone n=25; fluvoxamine n=25; patients were randomized to a flexible oral dosing regimen of either YKS, risperidone, or fluvoxamine by the trial investigator to preserve rater blinding)	YKS (2.5–7.5 g/day), risperidone (0.5–2.0 mg/day), or fluvoxamine (25–200 mg/day), 8 wks	NPI scores were improved in all 3 drug groups with no significant between-group differences. No significant change in MMSE or FIM. DIEPSS scores did not change in the YKS and fluvoxamine groups, but increased significantly in the risperidone group	No severe side effect possibly related to YKS. Constipation and muscle rigidity were significantly increased in the risperidone group compared with the YKS and fluvoxamine groups	Teranishi et al, 2013^Citation14

Abbreviations: AD, Alzheimer-type dementia; BI, Barthel Index; CRF, chronic renal failure; DAD, Disability Assessment for Dementia; DIEPSS, Drug-Induced Extrapyramidal Symptoms Scale; DLB, dementia with Lewy bodies; EPS, extrapyramidal symptoms; FIM, Functional Independence Measure; FTD, frontotemporal dementia; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; PD, Parkinson’s disease; PDD, Parkinson’s disease with dementia; PLMs, periodic limb movement during sleep; PSG, polysomnography; SDS, Self-rating Depression Scale; SRI, Stereotypy Rating Inventory; UPDRS, Unified Parkinson’s Disease Rating Scale; VaD, vascular dementia; wks, weeks; YKS, Yokukan-san; ZBI, Zarit Burden interview.

Table 4 Controlled studies on other diseases

Design	Diagnosis	Study size	Dose, duration	Results	Adverse effects	Author, year of publication
Prospective, single-arm, open-label	Schizophrenia and neuroleptic-induced tardive dyskinesia	N=22	7.5 g/day, 12 wks	Significant improvement in AIMS, both positive and negative symptoms in PANSS, and CGI scores	Mild and transient (nausea in one patient and constipation in one patient)	Miyaoka et al, 2008^Citation17
Prospective, single-arm, open-label	Borderline personality disorder	N=20	2.5–7.5 g/day, 12 wks	Highly significant improvement in BPRS, HAM-D, AQ, GAF, and CGI scores	Mild and transient (headache and nausea in two patients and tiredness in one patient)	Miyaoka et al, 2008^Citation18
Prospective, randomized, open-label	Treatment-resistant schizophrenia	YKS group (N=34) versus control (N=25)	2.5–7.5 g/day, 4 wks	Significant improvement in both positive and negative symptoms in PANSS scores. No significant change in DIEPSS	Mild and transient (nausea in two patients and tiredness in one patient)	Miyaoka et al, 2009^Citation19
Prospective, cross-over, open-label	Huntington’s disease	N=4 (two patients took YKS for 8 wks first, and after 4 wks of washing out, they took SRBT for 8 wks. Two other patients took those medicines in reverse order)	Doses not shown, 8 wks	Significant improvement in UHDRS-m scores by not SRBT but YKS treatment without extrapyramidal symptoms or changes of cognition or ADL scores	None	Satoh et al, 2009^Citation36
Prospective, single-arm, open-label	Charles Bonnet syndrome	N=20	2.5–7.5 g/day, 4 wks	Significant improvement in NPI, hallucination subscale of the PANSS, and CGI scores	Mild and transient (nausea in three patients)	Miyaoka et al, 2011^Citation33
Prospective, single-arm, open-label	Pervasive developmental disorder not otherwise specified (PDD-NOS) or Asperger disorder	N=40	2.5–7.5 g/day, 12 wks	Significant improvement in CGI and ABC-I scores	Mild and transient (nausea in five patients)	Miyaoka et al, 2012^Citation34
Prospective, single-arm, open-label	Very late-onset schizophrenia-like psychosis	N=40	2.5–7.5 g/day, 4 wks	Significant improvement in both positive and negative symptoms, general psychopathology, and total scores in PANSS. No significant change in MMSE, Simpson–Angus score, Barnes Akathisia Scale index, or AIMS	None	Miyaoka et al, 2013^Citation20
Prospective, single-arm, open-label	Pervasive developmental disorder in children and adolescents (6–17 years old)	N=20	2.5–7.5 g/day, 12 wks	Significant improvement in CGI, CGAS, and ABC-I scores	Mild and transient (drowsiness in two patients)	Wake et al, 2013^Citation35

Abbreviations: ABC-I, Aberrant Behavior Checklist-Irritability subscale; ADL, activities of daily living; AIMS, Abnormal Involuntary Movement Scale; AQ, Aggression Questionnaire; BPRS, Brief Psychiatric Rating Scale; CGAS, Children’s Global Assessment Score; CGI, Clinical Global Impression; DIEPSS, Drug-Induced Extrapyramidal Symptom Scale; GAF, Global Assessment of Functioning; HAM-D, Hamilton Rating Scales for Depression; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; PANSS, Positive and Negative Syndrome Scale; SRBT, Saiko-ka-ryukotsu-borei-to; UHDRS-m, Unified Huntington’s Disease Rating Scale-motor assessment; wks, weeks; YKS, Yokukan-san.

Table 5 Animal studies

Antidepressant-like effects

YKS increased the number of wheel rotations in a water tank, counted as escape attempts, at lower doses (60 and 150 mg/kg/day) and decreased the number at the highest dose (300 mg/kg/day)^Citation37

Pain-relieving effects

• YKS reduced the number of acetic acid-induced writhing responses^Citation37

• YKS inhibited mechanical and cold allodynia in the von Frey hair or acetone test, respectively^Citation38

Anti-aggressive properties

YKS ameliorated aggressiveness induced by:

• Social isolation^Citation39

• Zinc deficiency^Citation40

• Social isolation in zinc-deficient and pair-fed mice^Citation41

• The intravenous injection of para-Chloroamphetamine^Citation42

• Intracerebroventricular injection of amyloid beta protein^Citation43

Anxiolytic effects

• Repeated administration of YKS decreased anxiety-like behavior in an open-field test and an elevated plus-maze test in a dose-dependent manner^Citation45

• YKS’s anxiolytic effect was inhibited by flumazenil, a benzodiazepine receptor antagonist^Citation46

• Three months of YKS administration improved age-related anxiety in F344/N aged rats^Citation47

• Repeated administration of YKS suppressed rats’ freezing behavior on re-exposure to the box where they had experienced footshock in a contextual fear conditioning test and increased the time spent in open arms in rats subjected to footshock stress compared to control rats^Citation48

Efficacy of YKS in dementia models of Alzheimer’s disease

• Treatment with YKS for 2 months reduced the increased number of entries and the time spent in open arms in the elevated plus-maze test, treatment for 5 months shortened the time until reaching the platform in the Morris water maze test, and treatment for 9 months suppressed the increase in locomotion in the open-field test in the Tg2576 mice expressing the human form of the APP695SWE^Citation49

• YKS ameliorated spatial memory impairment in an early-phase Alzheimer’s disease rat model^Citation51

• YKS improved learning and memory impairments in olfactory bulbectomized mice^Citation52

Studies using animal models of other dementia types

YKS ameliorated:

• Memory disturbance as well as BPSD-like behavior such as anxiety-like behavior, increases in aggressive behaviors, and decreases in social behaviors in thiamine-deficient rats^Citation53

• Age-related impairments of working memory and reversal learning in aged (24-month-old) rats^Citation55

• Anxiety-like behaviors in rats subjected to repeated cerebral ischemia^Citation56

Studies on other clinical efficacies of YKS

• YKS ameliorated vacuous chewing movement in rats, an index for tardive dyskinesia, caused by haloperidol decanoate^Citation57

• YKS had a reversal effect on the decrease in pentobarbital sleep by social isolation without affecting pentobarbital sleep in group-housed mice^Citation58

Abbreviations: BPSD, behavioral and psychological symptoms of dementia; YKS, Yokukan-san.

OkamotoHOkamiTIkedaMTakeuchiTEffects of Yokukan-san on undifferentiated somatoform disorder with tinnitusEur Psychiatry2005201747515642449

 PubMed Web of Science ®Google Scholar

ShinnoHUtaniEOkazakiSSuccessful treatment with Yi-Gan San for psychosis and sleep disturbance in a patient with dementia with Lewy bodiesProg Neuropsychopharmacol Biol Psychiatry20073171543154517688986

 PubMed Web of Science ®Google Scholar

ShinnoHKameiMNakamuraYInamiYHoriguchiJSuccessful treatment with Yi-Gan San for rapid eye movement sleep behavior disorderProg Neuropsychopharmacol Biol Psychiatry20083271749175118656519

 PubMed Web of Science ®Google Scholar

MiyaokaTNagahamaMTsuchieKCharles Bonnet syndrome: successful treatment of visual hallucinations due to vision loss with Yi-Gan SanProg Neuropsychopharmacol Biol Psychiatry200933238238319141308

 PubMed Web of Science ®Google Scholar

SaitoSKobayashiTOsawaTKatoSEffectiveness of Japanese herbal medicine Yokukan-san for alleviating psychiatric symptoms after traumatic brain injuryPsychogeriatrics2010101454820594286

 PubMed Web of Science ®Google Scholar

ShinnoHYamanakaMIshikawaISuccessful treatment of restless legs syndrome with the herbal prescription Yokukan-sanProg Neuropsychopharmacol Biol Psychiatry201034125225319913591

 PubMed Web of Science ®Google Scholar

KajitaniKKanbaSSuccessful treatment of poststroke emotional incontinence with Yokukan-san, an Asian herbal medicine: report of two casesJ Am Geriatr Soc201260237938122332687

 PubMed Web of Science ®Google Scholar

KawabeKUenoSHosodaYHoriguchiJNocturnal eating/drinking syndrome with restless legs syndrome caused by neuroleptics improved by Yi-Gan San add-on treatment: a case reportClin Neuropharmacol201235629029123151467

 PubMed Web of Science ®Google Scholar

OkamotoHChinoAHirasakiYUedaKIyoMNamikiTOrengedoku-to augmentation in cases showing partial response to Yokukan-san treatment: a case report and literature review of the evidence for use of these Kampo herbal formulaeNeuropsychiatr Dis Treat2013915115523378767

 PubMed Web of Science ®Google Scholar

IwasakiKSatoh-NakagawaTMaruyamaMA randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patientsJ Clin Psychiatry200566224825215705012

 PubMed Web of Science ®Google Scholar

IwasakiKMaruyamaMTomitaNEffects of the traditional Chinese herbal medicine Yi-Gan San for cholinesterase inhibitor-resistant visual hallucinations and neuropsychiatric symptoms in patients with dementia with Lewy bodiesJ Clin Psychiatry200566121612161316401166

 PubMed Web of Science ®Google Scholar

ShinnoHInamiYInagakiTNakamuraYHoriguchiJEffect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementiaProg Neuropsychopharmacol Biol Psychiatry200832388188518243460

 PubMed Web of Science ®Google Scholar

MizukamiKAsadaTKinoshitaTA randomized cross-over study of a traditional Japanese medicine (Kampo), Yokukan-san, in the treatment of the behavioural and psychological symptoms of dementiaInt J Neuropsychopharmacol200912219119919079814

 PubMed Web of Science ®Google Scholar

MonjiATakitaMSamejimaTEffect of Yokukan-san on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer’s diseaseProg Neuropsychopharmacol Biol Psychiatry200933230831119138715

 PubMed Web of Science ®Google Scholar

HayashiYIshidaYInoueTTreatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukan-san in clinical practiceProg Neuropsychopharmacol Biol Psychiatry201034354154520184936

 PubMed Web of Science ®Google Scholar

OkaharaKIshidaYHayashiYEffects of Yokukan-san on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer’s diseaseProg Neuropsychopharmacol Biol Psychiatry201034353253620170698

 PubMed Web of Science ®Google Scholar

KawanabeTYoritakaAShimuraHOizumiHTanakaSHattoriNSuccessful treatment with Yokukan-san for behavioral and psychological symptoms of Parkinsonian dementiaProg Neuropsychopharmacol Biol Psychiatry201034228428719948198

 PubMed Web of Science ®Google Scholar

KimuraTHayashidaHFurukawaHTakamatsuJPilot study of pharmacological treatment for frontotemporal dementia: effect of Yokukan-san on behavioral symptomsPsychiatry Clin Neurosci201064220721020447015

 PubMed Web of Science ®Google Scholar

IwasakiKKosakaKMoriHImprovement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of Yokukan-san, a traditional Japanese medicinePsychogeriatrics201212423524123279145

 PubMed Web of Science ®Google Scholar

NagataKYokoyamaEYamazakiTEffects of Yokukan-san on behavioral and psychological symptoms of vascular dementia: an open-label trialPhytomedicine201219652452822421528

 PubMed Web of Science ®Google Scholar

SumiyoshiHMantaniANishiyamaSYokukan-san treatment of chronic renal failure patients receiving hemodialysis, with behavioral and psychological symptoms of dementia: an open-label studyAm J Geriatr Psychiatry201321111082108523567442

 PubMed Web of Science ®Google Scholar

TeranishiMKuritaMNishinoSEfficacy and tolerability of risperidone, Yokukan-san, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia: a blinded, randomized trialJ Clin Psychopharmacol201333560060723948783

 PubMed Web of Science ®Google Scholar

MiyaokaTFuruyaMYasudaHYi-Gan San for the treatment of neuroleptic-induced tardive dyskinesia: an open-label studyProg Neuropsychopharmacol Biol Psychiatry200832376176418201810

 PubMed Web of Science ®Google Scholar

MiyaokaTFuruyaMYasudaHYi-Gan San for the treatment of borderline personality disorder: an open-label studyProg Neuropsychopharmacol Biol Psychiatry200832115015417765378

 PubMed Web of Science ®Google Scholar

MiyaokaTFuruyaMYasudaHYi-Gan San as adjunctive therapy for treatment-resistant schizophrenia: an open-label studyClin Neuropharmacol20093216919471183

 PubMed Web of Science ®Google Scholar

SatohTTakahashiTIwasakiKTraditional Chinese medicine on four patients with Huntington’s diseaseMov Disord200924345345519133663

 PubMed Web of Science ®Google Scholar

MiyaokaTFuruyaMKristianLYi-Gan San for treatment of Charles Bonnet syndrome (visual hallucination due to vision loss): an open-label studyClin Neuropharmacol2011341242721164340

 PubMed Web of Science ®Google Scholar

MiyaokaTWakeRFuruyaMYokukan-san (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger’s disorder: a 12-week prospective, open-label studyBMC Psychiatry20121221523194148

 PubMed Web of Science ®Google Scholar

MiyaokaTWakeRFuruyaMYokukan-san (TJ-54) for treatment of very-late-onset schizophrenia-like psychosis: an open-label studyPhytomedicine201320765465823453830

 PubMed Web of Science ®Google Scholar

WakeRMiyaokaTInagakiTYokukan-san (TJ-54) for irritability associated with pervasive developmental disorder in children and adolescents: a 12-week prospective, open-label studyJ Child Adolesc Psychopharmacol201323532933623782127

 PubMed Web of Science ®Google Scholar

KoshikawaNImaiTTakahashiIYamauchiMSawadaSKansakuAEffects of Hochu-ekki-to, Yokukan-san and Saiko-ka-ryukotsu-borei-to on behavioral despair and acetic acid-induced writhing in miceMethods Find Exp Clin Pharmacol199820147519575482

 PubMedGoogle Scholar

SuzukiYMitsuhataHYuzuriharaMKaseYAntiallodynic effect of herbal medicine Yokukan-san on peripheral neuropathy in rats with chronic constriction injuryEvid Based Complement Alternat Med2012201295345922454692

 PubMed Web of Science ®Google Scholar

UchidaNEgashiraNIwasakiKYokukan-san inhibits social isolation-induced aggression and methamphetamine-induced hyperlocomotion in rodentsBiol Pharm Bull200932337237519252280

 PubMed Web of Science ®Google Scholar

TamanoHKanFOkuNTakedaAAmeliorative effect of Yokukan-san on social isolation-induced aggressive behavior of zinc-deficient young miceBrain Res Bull201083635135520813168

 PubMed Web of Science ®Google Scholar

TakedaAIwakiHIdeKTamanoHOkuNTherapeutic effect of Yokukan-san on social isolation-induced aggressive behavior of zinc-deficient and pair-fed miceBrain Res Bull201287655155522373913

 PubMed Web of Science ®Google Scholar

KannoHSekiguchiKYamaguchiTEffect of Yokukan-san, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected ratsJ Pharm Pharmacol20096191249125619703376

 PubMed Web of Science ®Google Scholar

SekiguchiKYamaguchiTTabuchiMIkarashiYKaseYEffects of Yokukan-san, a traditional Japanese medicine, on aggressiveness induced by intracerebroventricular injection of amyloid β protein into micePhytother Res20092381175118119165748

 PubMed Web of Science ®Google Scholar

ShojiHMizoguchiKBrain region-specific reduction in c-Fos expression associated with an anxiolytic effect of Yokukan-san in ratsJ Ethnopharmacol201314919310223770052

 PubMed Web of Science ®Google Scholar

KameiJMiyataSOhsawaMInvolvement of the benzodiazepine system in the anxiolytic-like effect of Yokukan-san (Yi-Gan San)Prog Neuropsychopharmacol Biol Psychiatry20093381431143719647028

 PubMed Web of Science ®Google Scholar

MizoguchiKTanakaYTabiraTAnxiolytic effect of a herbal medicine, Yokukan-san, in aged rats: involvement of serotonergic and dopaminergic transmissions in the prefrontal cortexJ Ethnopharmacol20101271707619799980

 PubMed Web of Science ®Google Scholar

YamaguchiTTsujimatsuAKumamotoHAnxiolytic effects of Yokukan-san, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stressJ Ethnopharmacol2012143253353922819689

 PubMed Web of Science ®Google Scholar

TabuchiMYamaguchiTIizukaSImamuraSIkarashiYKaseYAmeliorative effects of Yokukan-san, a traditional Japanese medicine, on learning and non-cognitive disturbances in the Tg2576 mouse model of Alzheimer’s diseaseJ Ethnopharmacol2009122115716219146938

 PubMed Web of Science ®Google Scholar

UchidaNTakasakiKSakataYCholinergic involvement and synaptic dynamin 1 expression in Yokukan-san-mediated improvement of spatial memory in a rat model of early Alzheimer’s diseasePhytother Res201327796697222888033

 PubMed Web of Science ®Google Scholar

YamadaMHayashidaMZhaoQAmeliorative effects of Yokukan-san on learning and memory deficits in olfactory bulbectomized miceJ Ethnopharmacol2011135373774621513784

 PubMed Web of Science ®Google Scholar

IkarashiYIizukaSImamuraSEffects of Yokukan-san, a traditional Japanese medicine, on memory disturbance and behavioral and psychological symptoms of dementia in thiamine-deficient ratsBiol Pharm Bull200932101701170919801831

 PubMed Web of Science ®Google Scholar

MizoguchiKShojiHTanakaYTabiraTAmeliorative effect of traditional Japanese medicine Yokukan-san on age-related impairments of working memory and reversal learning in ratsNeuroscience201117712713721195139

 PubMed Web of Science ®Google Scholar

NogamiASakataYUchidaNEffects of Yokukan-san on anxiety-like behavior in a rat model of cerebrovascular dementiaJ Nat Med201165227528121152992

 PubMed Web of Science ®Google Scholar

SekiguchiKKannoHYamaguchiTIkarashiYKaseYAmeliorative effect of Yokukan-san on vacuous chewing movement in haloperidol-induced rat tardive dyskinesia model and involvement of glutamatergic systemBrain Res Bull2012895–615115822982367

 PubMed Web of Science ®Google Scholar

EgashiraNNogamiAIwasakiKYokukan-san enhances pentobarbital-induced sleep in socially isolated mice: possible involvement of GABAA–benzodiazepine receptor complexJ Pharmacol Sci20111163316320

 Web of Science ®Google Scholar