# Systematic Review on the Efficacy and Safety of Herbal Medicines for Vascular Dementia

Authors: Sui Cheung Man; Kam Wa Chan; Jia-Hong Lu; Siva Sundara Kumar Durairajan; Liang-Feng Liu; Min Li
Journal: Evidence-Based Complementary and Alternative Medicine
 (2012)

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## Abstract

We present a systematic review of existing research that aims to assess the efficacy and safety of herbal medications (HM), as either monotherapy or adjunct to orthodox medications (OM), mainly comprised of cholinesterase inhibitors, for vascular dementia (VaD). We included 47 studies conducted in mainland China, each testing different HM. Of 43 HM monotherapy studies, 37 reported HM to be significantly better than OM or placebo; six reported similar efficacy between HM and OM. All four HM adjuvant studies reported significant efficacy. No major adverse events for HM were reported. Heterogeneity in diagnostic criteria, interventions and outcome measures hindered comprehensive data analysis. Studies suggested that HM can be a safe and effective treatment for VaD, either alone or in conjunction with OM. However, methodological flaws in the design of the studies limited the extent to which the results could be interpreted. Thirty most commonly used herbal constituents, including Rhizoma Chuanxiong (Chuanxiong in Chinese), Radix Polygoni Multiflori (Heshouwu in Chinese) and Radix Astragali (Huangqi in Chinese). were ranked. Further multi-center trials with large sample sizes, high methodological quality and standardized HM ingredients are necessary for clinical recommendations to be made.


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## Body

## 1. Introduction

Vascular dementia (VaD) is one of the most common forms of dementia after Alzheimer’s disease (AD) [1], and the most frequent cause of dementia in the elderly [2]. First described as arteriosclerotic dementia [3], VaD is defined as loss of cognitive function resulting from ischemic, hemorrhagic brain lesions (such as border zone infarcts and ischemic periventricular leukoencephalopathy) or hypoperfusion, due to cerebrovascular disease or cardiovascular pathology [4]. Incomplete microangiopathic infarcts due to fibrohyalinosis are regarded as the major pathophysiological manifestation [5] of VaD. While AD is characterized by memory impairment, VaD is characterized by executive dysfunction [6] and behavioral psychological symptoms such as apathy, abulia, opposition, agnosia [7], anxiety [8], depression [9], and suicidal thoughts [9]. Cognitive impairment is relatively mild as compared to AD.VaD accounts for approximately 30% of dementia in the world today [10]. In Europe, out of 3.7 million of people with clinical dementia, 800,000 have a diagnosis of VaD [11]. The prevalence rate of VaD is around 1–4% in Western developed nations [12]. Recently, in mainland China, a nationwide investigation found the prevalence of VaD to be around 0.8% [13]. The total annual cost (direct, illness related and cost arise from informal care) of dementia in developing countries is estimated to be at least USD 73 billion [10]. A study in Denmark revealed the annual cost per demented person to be DKK 77,000 (approximately USD 14,114) [14]. Thus, the total healthcare cost for VaD patients is highest among all other forms of dementia [15], and the frequency of VaD is increasing exponentially for people over the age of 65 years old [16]. If current trends continue, VaD will become an increasingly significant public health problem in the 21st century.Drugs currently used in the treatment of VaD include cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) [17] and non-cholinergics (memantine, nimodipine, hydergine, nicergoline, CDP-choline, folic acid [18], posatirelin, propentofylline, and pentoxifylline [19]). These orthodox medications (OM) have some efficacy [20]. Preventive therapeutic strategies aiming at reducing cerebrovascular risk factors [17] are also considered by patients likely to develop VaD. As yet, there is no compelling evidence that any of these strategies are effective, and no single intervention can be recommended for the prevention of VaD [21]. This creates a difficult and frustrating situation for sufferers of the disease, their caregivers, and healthcare providers [18], as well as for healthy people hoping to avoid developing VaD.Owing to the limitations of OM and therapeutic prevention, some patients resort to herbal medications (HM). Traditionally, a number of herbs have been used for cognitive disorders. For example,Artemisia  absinthium (Wormwood) was used in traditional European medicine to restore cognitive functions [22]. Melissa  officinalis (Lemon balm), also widely used in Europe, has been claimed to restore memory [23]. Since the 16th century, Europe, Salvia  lavandulaefolia (Spanish sage) and Salvia  officinalis (common sage) have been reported as being effective for improving memory [22]. Bacopa  monniera (water hyssop) has been used in Ayurvedic medicine to improve memory and intellectual functions. Centella  asiatica (Asiatic pennywort), another Ayurvedic remedy, when combined with milk, is also given to improve memory [24]. Withania  somnifera root is classed among the rejuvenative tonics in Ayurvedic medicine and is known to sharpen memory [25]. Codonopsis  pilosula root (Dangshen in Chinese), Biota  orientalis leaves (Cebaiye in Chinese), and Polygala  tenuifolia root (Yuanzhi in Chinese) have been used in traditional Chinese medicine (TCM) for amnesia [26, 27]. Some compounds with cognition-improving properties have been isolated from various plants. EGb 761, an extract from the leaves of the tree Ginkgo  biloba, originally used in Western medicine for circulatory disorders [28], shows reversal of decline in cognitive function and of cerebral insufficiency in numerous studies [29], and is now mainly used in VaD as well [30]. In another study, hyperforin, isolated from Hypericum  perforatum, a herb used in Portuguese folk medicine, appears to enhance cognitive function [31].In China, a nation with its own system of medicine that has been continuously documented over two thousand years, the incorporation of Chinese herbal medicine (CHM) with Western medicine in the treatment of dementia has become a standard in recent decades.Salvia  miltiorrhiza Bge. (Danshen in Chinese) and Pueraria  thomsonii Benth. (Gegen in Chinese), commonly used herbs in the Chinese materia medica for the treatment of cardiocerebrovascular symptoms, are well tolerated and effective in improving vascular function and structure. Thus, either one might be able to effectively intervene in the pathophysiological cascade of VaD [32]. An animal study revealed that glossy privet fruit (Ligustrum  lucidum Ait.), a kidney-tonifying Chinese herbal medicine, inhibits neural cell apoptosis following the onset of vascular dementia by reducing apoptotic signals induced by cerebral ischemia/hypoxia [33]. A number of proprietary herbal medicines may also be effective for VaD. According to a study, Chunghyul-dan, which possesses therapeutic effects for microangiopathy, could be useful to inhibit the development of VaD [34]. Huperzine A (HupA), a cholinesterase inhibitor naturally derived from the Chinese herb Lycopodium  serratum or Huperzia  serrata, has even better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action than tacrine, donepezil, and rivastigmine [35]. Its anticholinesterase activity is stronger than galantamine (a commonly used drug to treat Alzheimer’s disease and various memory impairments) [26]. Its ability to improve memory deficits in elderly people with VaD and AD has been demonstrated, with minimal peripheral cholinergic side effects and no unexpected toxicity [35]. These reports suggest that comprehensive investigation of the efficacy and safety of HM is worthwhile; the results could lead to better treatment of VaD as well as effective prevention.In a previously conducted systematic review [36], we looked for clinical trials for Alzheimer’s disease (AD), and found an even larger number of clinical trials conducted on VaD patients, mainly from mainland China. Because a large proportion of patients have both VaD and AD pathologies [37], and because the current OM treatments for both types of dementia are similar, we have systematically reviewed the clinical trials of HM conducted on VaD patients in this study.


## 2. Objective

This systematic review was conducted to assess the safety and efficacy of HM, as either monotherapy or adjunct to OM in the treatment of VaD.


## 3. Method

### 3.1. Inclusion Criteria

All published studies reporting randomized, controlled clinical trials comparing HM as monotherapy or adjuvant therapy, with placebo or OM as controls, were included. No restriction on the language of publication was imposed. As there is a lack of a single, specific criterion for the diagnosis of VaD [38], we accepted the use of the following instruments: Diagnostic and Statistical Manual of Mental Disorders (DSM-III, DSM-III-R [39], and DSM-IV [40]), the International Classification of Diseases, 10th Revision (ICD-10) [41]; the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) scale [42]; the Hachinski Ischemic Scale (HIS) [43]; the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences scale (NINDS-AIREN) [44]. Trials with participants possessing other forms of dementia (Alzheimer’s disease, Lewy body dementia, and frontotemporal dementia) were excluded. There was no restrictions on the ethnicity, gender, age, or disease duration of the participants in the trials. The HM interventions could be either (1) a single herb, (2) a preparation containing multiple herbs, (3) extracts from an herb, or (4) proprietary herbal products. They had to have been used alone or coadministered with conventional medications (OM). The control intervention had to have been either (1) a placebo, or (2) OM. Trials of all durations were included. Crossover studies were also accepted if the first phase fulfilled the above criteria. Outcome measures of interest were (1) Mini-Mental Status Examination (MMSE) [45], (2) Activities of Daily Living Scale (ADL) [46], and (3) Hasegawa Dementia Scale (HDS) [47]. The safety profile might be represented in (5) adverse effect count, (6) biochemical indications, or (7) number of withdrawals due to adverse events.


### 3.2. Search Strategy and Method of Review

We identified trials from the following electronic databases: (1) Ovid MEDLINE In-Process and Other Non-Indexed Citations and Ovid MEDLINE; (2) CINAHL; (3) EMBASE; (4) EBM Reviews; (5) AMED; (6) ACP Journal Club; (7) Cochrane Central Register of Controlled Trials; (8) Cochrane Database of Systematic Reviews; (9) Cochrane Methodology Register; (10) Database of Abstracts of Reviews of Effects; (11) Health Technology Assessment; (12) National Health Service Economic Evaluation; (13) China National Knowledge Infrastructure (CNKI); (14) Chinese Sci and Tech Journals (VIP); (15) CBM disc; (16) China Doctor Dissertations Full-Text Database; (17) China Master Theses Full-text Database. The search conducted in March 2011 followed a strategy (Table1) developed with reference to a Cochrane review on herbal medicine [48], regardless of language and publication status. Hand-search of a list of Chinese and English journals was carried out to find the latest studies. We also referred to the reference lists of relevant papers to identify potential studies.Table 1
Search strategy.
1exp Plant Extracts/or exp Drugs, Chinese Herbal/or exp Plants, Medicinal/or exp Medicine, Chinese Traditional/or exp China/or chinese medicine.mp. or exp Medicine, Oriental Traditional/or exp Phytotherapy/2drugs non prescription.mp. or exp Drugs, Non-Prescription/3medicinal herbs.mp4herbs medicinal.mp.5drugs non prescription.mp. or exp Drugs, Non-Prescription/6alternative medicine.mp. or exp Complementary Therapies/7complementary medicine.mp.8Phytotherapy/or Plants, Medicinal/or Plant Extracts/or Herb-Drug Interactions/or herbs.mp. or Drugs, Chinese Herbal/or Plant Preparations/9exp Phytotherapy/or exp Plants, Medicinal/or exp Plant Extracts/or exp Herb-Drug Interactions/or exp Alkaloids/or herbs.mp. or exp Drugs, Chinese Herbal/or exp Plant Preparations/101 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 911randomized controlled trials.mp. or exp Randomized Controlled Trials/12exp Random Allocation/or exp Clinical Trials/or exp Double-Blind Method/or double blind.mp. or exp Placebos/13single blind.mp. or exp Single-Blind Method/14clinical trials.mp.15prospective studies.mp. or exp Prospective Studies/16follow up studies.mp. or exp Follow-Up Studies/1711 or 12 or 13 or 14 or 15 or 1618exp Mental Retardation/or exp Dementia/or exp vascular dementia/or progressive brain disorder.mp. or exp Memory Disorders/19(vascular dementia).mp.2018 or 192110 and 17 and 20Two independent reviewers (K. W. Chan and S. C. Man) assessed the trials for their eligibility. The inclusion of trials was confirmed upon consensus of reviewers. Risk of bias assessment of the trials was performed according to the revised Consolidated Standards of Reporting Trials (CONSORT) statement [49]. Any disagreement was settled by discussion.


## 3.1. Inclusion Criteria

All published studies reporting randomized, controlled clinical trials comparing HM as monotherapy or adjuvant therapy, with placebo or OM as controls, were included. No restriction on the language of publication was imposed. As there is a lack of a single, specific criterion for the diagnosis of VaD [38], we accepted the use of the following instruments: Diagnostic and Statistical Manual of Mental Disorders (DSM-III, DSM-III-R [39], and DSM-IV [40]), the International Classification of Diseases, 10th Revision (ICD-10) [41]; the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) scale [42]; the Hachinski Ischemic Scale (HIS) [43]; the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences scale (NINDS-AIREN) [44]. Trials with participants possessing other forms of dementia (Alzheimer’s disease, Lewy body dementia, and frontotemporal dementia) were excluded. There was no restrictions on the ethnicity, gender, age, or disease duration of the participants in the trials. The HM interventions could be either (1) a single herb, (2) a preparation containing multiple herbs, (3) extracts from an herb, or (4) proprietary herbal products. They had to have been used alone or coadministered with conventional medications (OM). The control intervention had to have been either (1) a placebo, or (2) OM. Trials of all durations were included. Crossover studies were also accepted if the first phase fulfilled the above criteria. Outcome measures of interest were (1) Mini-Mental Status Examination (MMSE) [45], (2) Activities of Daily Living Scale (ADL) [46], and (3) Hasegawa Dementia Scale (HDS) [47]. The safety profile might be represented in (5) adverse effect count, (6) biochemical indications, or (7) number of withdrawals due to adverse events.


## 3.2. Search Strategy and Method of Review

We identified trials from the following electronic databases: (1) Ovid MEDLINE In-Process and Other Non-Indexed Citations and Ovid MEDLINE; (2) CINAHL; (3) EMBASE; (4) EBM Reviews; (5) AMED; (6) ACP Journal Club; (7) Cochrane Central Register of Controlled Trials; (8) Cochrane Database of Systematic Reviews; (9) Cochrane Methodology Register; (10) Database of Abstracts of Reviews of Effects; (11) Health Technology Assessment; (12) National Health Service Economic Evaluation; (13) China National Knowledge Infrastructure (CNKI); (14) Chinese Sci and Tech Journals (VIP); (15) CBM disc; (16) China Doctor Dissertations Full-Text Database; (17) China Master Theses Full-text Database. The search conducted in March 2011 followed a strategy (Table1) developed with reference to a Cochrane review on herbal medicine [48], regardless of language and publication status. Hand-search of a list of Chinese and English journals was carried out to find the latest studies. We also referred to the reference lists of relevant papers to identify potential studies.Table 1
Search strategy.
1exp Plant Extracts/or exp Drugs, Chinese Herbal/or exp Plants, Medicinal/or exp Medicine, Chinese Traditional/or exp China/or chinese medicine.mp. or exp Medicine, Oriental Traditional/or exp Phytotherapy/2drugs non prescription.mp. or exp Drugs, Non-Prescription/3medicinal herbs.mp4herbs medicinal.mp.5drugs non prescription.mp. or exp Drugs, Non-Prescription/6alternative medicine.mp. or exp Complementary Therapies/7complementary medicine.mp.8Phytotherapy/or Plants, Medicinal/or Plant Extracts/or Herb-Drug Interactions/or herbs.mp. or Drugs, Chinese Herbal/or Plant Preparations/9exp Phytotherapy/or exp Plants, Medicinal/or exp Plant Extracts/or exp Herb-Drug Interactions/or exp Alkaloids/or herbs.mp. or exp Drugs, Chinese Herbal/or exp Plant Preparations/101 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 911randomized controlled trials.mp. or exp Randomized Controlled Trials/12exp Random Allocation/or exp Clinical Trials/or exp Double-Blind Method/or double blind.mp. or exp Placebos/13single blind.mp. or exp Single-Blind Method/14clinical trials.mp.15prospective studies.mp. or exp Prospective Studies/16follow up studies.mp. or exp Follow-Up Studies/1711 or 12 or 13 or 14 or 15 or 1618exp Mental Retardation/or exp Dementia/or exp vascular dementia/or progressive brain disorder.mp. or exp Memory Disorders/19(vascular dementia).mp.2018 or 192110 and 17 and 20Two independent reviewers (K. W. Chan and S. C. Man) assessed the trials for their eligibility. The inclusion of trials was confirmed upon consensus of reviewers. Risk of bias assessment of the trials was performed according to the revised Consolidated Standards of Reporting Trials (CONSORT) statement [49]. Any disagreement was settled by discussion.


## 4. Results

### 4.1. Description of Included Studies

Using the search strategy as described, 116 studies were identified. Upon full-text examination we excluded 69, on the basis that (1) 13 were not randomized controlled trials, (2) four were repeat publications, (3) three did not state their inclusion criteria, (4) one included other forms of dementia, (5) 44 did not disclose adequate baseline information, and (6) four involved the use of non-HM intervention, such as acupuncture. These disqualifications left 47 studies for this systematic review.There were a total of 3725 participants (2423 male, 1302 female) in the 47 included trials. Among them, three had cross-over design while the remaining were parallel design studies. The age of participants ranged from 45–89 years old, and their disease duration ranged from two months to 12 years. Thirty-two studies were performed in a single center; one was performed in multiple centers; 14 trials did not give this information. The duration of trials lasted from one to seven months. All of the trials were conducted in mainland China, and all the subjects were of Chinese ethnicity.


### 4.2. Risk of Bias (Table2)

Table 2
Methodological quality of studies (CONSORT checklist).
Reported page number of each item*1AbstractsMethodRandomizationResultsDiscussionNumberAuthorYearTitle and abstractIntroductionParticipantInterventionObjectiveOutcomeSample sizeSequence generationAllocation concealmentImplementationBlindingStatistical methodsParticipant flowRecruitmentBaseline dataNumbers analyzedOutcomes and estimationAncillary analysesAdverse eventsInterpretationGeneralisabilityOverall evidence123456789101112131415161718192021221Wan et al.1998252525252425UUUUUUUU252626UU27U272Zhao et al.1999585585585586585586UUUUU586U585585585586U5875875875873Ji200010101011U11UUUUUUU1010U11UU11U114Lu et al.2000290290290290290290UUUUU290UU290290290UU290U2905Luo2001470U470470470471UUUU470471U470470472472472U4724734736Zhang et al.2001U515151U51UUUUUUU51515252U525252527Zhou and Yi2001141414141414UUUUUUUU141515UU15U158Cao et al.2002808080808080UUUU8081U80808181U8181U819Hong et al.2002U333U3UUUUU3U33444U55510Huang et al.2002301301301302301302UUUUU302UU302301302UU30330330311Liu et al.2002526526526526526526UUUUUUU526526U527UU527U52712Wang et al.2002U295296296U296UUUUUUU295295296296UU296U29613Yang et al.2002484849494849UUUU4849UU484949UU50515114Cai et al.2003482482482482482482U482UUU483UU482483483U48348348348315Guo et al.2003U931931931U931UUUUUUUU931931931UU931U93116Jia et al.2003202020202021UUUUU21U20202121U2122U2217Cheng et al.2004161616161616UUUUU16UU161717UU17171718Liao et al.2004112112112113112113UUUUU113U113112113113U11311311411419Shen and Du2004414142424142UUUUU42U42424243UU43434320Wang et al.2004679679679680679680U680680680680680681U679680680U68168168168121Wang et al.2004169116911691169216911692UUUUU1692U1691169116921692UU1693U169322Wu et al.2004333333UUUU33UU344U44U423Yu et al.2004424424424424424424UUUU424UU424424425425U42542542542524Zhao2004899989UUUUU9U9999U99U1025Feng et al.2005520520520520520520UUUUU521U520520521521UU52152252126Liu2005505050505050UUUUU505150515151U5151515127Liu et al.20051052105210521052U1052UUUUU1053U1053105210531053U105410541054105428Liu and Chen2005181818191819UUUUU19UU181919UU20U2029Tang et al.2005426426426427426427UUUUU427U426426427427U42742742742730Wang et al.200593U93949394U9494U9494U93949494U9594U9431Wang, Chen and Bai2005333334UUUUU4U3334UU45532Wang et al.2005260260261261260261UUUU261261UU260261261U261262U26233Wang2005404040404040UUUUU40U40404041UU41414134Zhou et al.2005111111111112UUUUU12U11111212UU13U1335Gao2006141414141415UUUUUUU14141515UU16U1636Hao et al.2006424424424424424424UUUUU425UU424425425U425425U42537Li et al.200648484848U48UUUUU48U48484848UU49494938Mou2006160716071607160716071607UUUUUUUU160716071607U1607UU160739Shi and Wang2006200200200200200200U200UU200200UU200201201UU20120120140Zhang and Lu2006680680680680680681UUUUUUUU680681681UU68168168141Chen et al.2007866866866867866867U867UU867867U866866867867UU86886886842Cui et al.2007646464646464U64UUU65U6464U65UU65U6543He200760U6060U60UUUU6060UU606060U6161U6144Jin et al.2007165716571657165816571658UUU165816581658UU165716581658U165916591659165945Yan200741U41414141UUUUUUUU414141UU41414246Chang2008241240240241240241UUUUUUU240241241241U241241U24147Li et al.2008369369369370369370UUUUU370U369369370370U371371371371Key*1: U = the relevant item was not found in the paper.We adopted the checklist of items suggested by CONSORT [50] in the evaluation of methodological quality (risk of bias). The checklist was divided into five sections, namely, title and abstract, introduction, methods, results, and discussion.Except for 4 studies [51–54], all had adequate information on the title and abstract. Four studies [55–58] did not give an appropriate introduction.With regard to method, none of the 47 studies reported details for sample size calculations. Eight [51–54, 57, 59–61] did not clearly state their objective of study. All but one study [62] poorly reported their randomization and blinding. Statistical method was not reported in 13 studies [51–53, 58, 59, 63–70].For the results section, only two studies [62, 71] reported with a flowchart. Patient recruitment, outcomes and estimation, and ancillary analyses were mentioned by the majority of studies. More than half of the studies did not report adverse event count.In the discussion section, both the interpretation and overall evidence were adequately reported by the studies; generalizability, however, was not sufficiently illustrated by 13 studies.


### 4.3. Randomization (Table2)

All of the included studies claimed to have allocated participants randomly to study groups. Six [72–77] reported the use of computer-generated sequences; the other 41 studies did not provide any description of how randomization was achieved.


### 4.4. Allocation Concealment (Table2)

Except for one study [71] which clearly stated that it did not use any blinding methods, 32 studies did not report whether they applied blinding or not. For those studies which reported the use of allocation concealment, 6 were single blind [52, 57, 66, 78–81], and 8 were double blind [55, 56, 62, 76, 82–85].


### 4.5. Eligible Criteria (Table3)

Table 3
Study properties.
StudyDesignSample and characteristicsDiagnostic criteriaHerbal interventionControlOutcome measuresITT*1Drop out*2ADR*31Wan et al. [63], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration68 VaD patients, age: 58–82; duration: 4.37–15.85 yrDSM-3-R, HDS, HIS, “TCM dementia differential criteria”*aFucong 150 mL, bid (37)Piracetam0.8 g, tid (31)MMSE, HDS, BEAM, hemodynamic changesNNU2Zhao et al. [74], China Monotherapy Single centerRandomized: method not mentioned; single blind; parallel design; 2 months duration46 VaD patients; age: 57–76; duration: 6 m –1 yrDSM-4, HIS, HDS, MMSE, “Protocol for new herbal drugs study on dementia”* bXianlong2.7 g, bid (24)Hydergine3 mg, bid (22)TCD, hemodynamic changesNNU3Ji [59], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration68 VaD patients; age: 58–82; duration: 1.45-3.24  yrDSM-3-R, HDS, HIS, “TCM dementia differential criteria”* aDangguishaoyao bid (37)Piracetam0.8 g, tid (31)MMSE, HDSNNU4Lu et al. [90], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration50 VaD patients; age: 56–82; duration: 2–6 yrDSM-3-R, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cShentong 10 g, tid (30)Hydergine1 mg, tid (20)MMSE, BBSNNU5Luo et al. [55], China Monotherapy MulticenterRandomized: method not mentioned; double blind: method not mentioned; parallel design; 75 days duration68 VaD patients; age: 49–79; duration: 0.99–2.07 yrDSM-4, ICD 10, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cShenmayizhi 1 g, tid (35)Hydergine1 mg, tid (33)MMSE, ADL, BEAM, Neurological deficitsNNU6Zhang et al. [51], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration61 VaD patients; age: 60–77; duration: 6 m–2.5 yr;NINDS-AIREN, HIS, HDS, “protocol for new herbal drugs study on dementia”* bJiannaotongluo 1.6 g, tid (30)Aniracetam 0.3 g, tid (31)HDS, hemodynamic changesNNU7Zhou and Yi [64], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration46 VaD patients; age: 60–80; duration: 8 m–3 yrDSM-3, “protocol for new herbal drugs study on dementia,”*b “protocol for new herbal drugs study on stroke”* bYinaoling 40 mL, bid (23)Piracetam 0.8 g tid (23)HDS, FAQ, CCSENNU8Cao et al. [82], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: method not mentioned; parallel design; 60 days duration53 VaD patients; age: 58–75; duration: 3 m–12 mDSM-4Congsheng tid (25)Hydergine tid (28)MMSE, BBS, TCD, EKG, SELFNNN9Hong et al. [54], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration86 VaD patients; age: 45–76; duration: 5 m–3 yrDSM-4, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c CORELATION, HISShouxing tid (48)Piracetam tid (38)MMSE, ADLNNU10Huang et al. [91], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration58 VaD patients; age: 57–79; duration: 6 m–3 yrDSM-4, MMSE, ADL, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNaohuandan 62 g/d (28)Piracetam tid (28)MMSE, ADL, E2, T, hemodynamic changesNNU11Liu et al. [65], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration64 VaD patients; age: 54–81; duration: 0.8–3 yrDSM-4, HIS, CT, MRITongqiaohuoxue-buyanghuanwu bid (36)Duxil 1 tabletbid (28)MMSE, HDS, hemodynamic changesNNU12Wang et al. [52] Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 30 days duration300 VaD patients; age: 52–83; duration: 7 m–7 yrDSM-3-R, DSM-4, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c HIS, CT, MRIYizhitongluo 0.9–1.2 g TID (200)Piracetam0.8 g tid (100)MMSE, HDS, GDS, ADL, hemodynamic changes, SELFNNU13Yang et al. [80], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 2 months duration90 VaD patients; age: 50–81; duration: 3 M–6.5 yrDSM-4-R, ICD10, CDR, MMSE, HDS-R, CORNELL, “protocol for new herbal drugs study on dementia”* bZhinao 1.5 g tid (60)Hydergine2 mg tid (30)MMSE, HDS, ADL, neurological deficits, hemodynamic changes, TCD, EEG, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”*cNNU14Cai et al. [72], China Monotherapy Center unclearRandomized: computer generated sequence; single blind: method not mentioned; parallel design; 3 months duration63 VaD patients; age: 65–78; duration: 3 m–94 mDSM-4-R, MMSE, HIS, CT, MRIKangxing 0.9 g tid (33)Hydergine2 mg tid (30)MMSE, ADL, hemodynamic changes, “protocol for new herbal drugs study on stroke”中藥 新 藥治療癡呆的 臨 床研究指導原則NYN15Guo et al. [53], China Adjunct therapy Center unclearRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration53 VaD patients; age: 55–73; duration: 1 yr–5 yrDSM-4, “protocol for new herbal drugs study on dementia,”* b “protocol for new herbal drugs study on stroke”* bBunaotongqiao + Duxil 1 tablet bid (28)Duxil 1 tablet bid (25)MMSE, HDS, hemodynamic changes,NNU16Jia et al. [92], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 60 days duration162 VaD patients; age: 54–71; duration: 0.8–3 yrDSM-4, CDR, imaging, HDSLuoshukang 1.5–2.5 g tid (108)Duxil 1 tablet bid (54)MMSE, BBS, “protocol for new herbal drugs study on dementia”* bNNN17Cheng et al. [93] Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 2 months duration36 VaD patients; age: 62–83; duration: 0.5–9 yrDSM-4-R, HIS, CT, MMSE, FAQ, HDS-R, ADLNaozhitong 4 pcs tid (18)Nimodipine20 mg tid (18)MMSE, FAQ, HDS-R, ADL, NONNU18Liao et al. [73], China Monotherapy Single centerRandomized: computer-generated sequence; single blind: method not mentioned; parallel design; 2 months duration60 VaD patients; age: 71–74; duration: 3.2–5.6 hrDSM-4, CT, MRI, HIS, MMSE, HDS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”*cShoulingjiannao 0.9 g tid (32)Hydergine1 mg tid (28)MMSE, HDS, “protocol for the selection of anti-aging herbal medicine and the corresponding outcome measures”* dNNN19Shen and Du [94], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 3 months duration70 VaD patients; age: 65–77; duration: 6 m –3 yrDSM-4, NINDS-AIREN, CT, MRI, “protocol for new herbal drugs study on dementia”* bBushenjianpiy-angxuehuoxue 0.9 g tid (40)Hydergine 2 mg tid (30)MMSE, ADL, ET, NO, HCY, E2, TNNU20Wang et al. [95], China Monotherapy Single centerRandomized: method not mentioned; double blind: details given; crossover design; 7 months duration (3 m + 1 m wash out + 3 m)18 VaD patients; age: 54–83; duration: 1–7 yrDSM-4, CT, MRI, HDS, MMSE, ADL-R, “protocol for new herbal drugs study on dementia”* bShenlong180 mL bid (18)Placebo 180 mL bid (18)HDS, MMSE-R, ADL-R, “protocol for new herbal drugs study on dementia”*bNNY (2, mouth dryness, sore throat)21Wang et al. [96], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 3 months duration100 VaD patients; age: 50–78; duration: 0.7–1.8 hrDSM-4, HIS, ADL, MMSE, SDS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* c, “protocol for new herbal drugs study on dementia”* bHuitian 0.8 g tid (50)Piracetam 08. g tid (50)MMSE, ADL, hemodynamic changes, “protocol for new herbal drugs study on dementia”*bNNU22Wu et al. [83], China Monotherapy Center unclearRandomized: method not mentioned; double blind: method not mentioned; parallel design; 30 days duration46 VaD patients; age: 62–77; duration: 0.8–4.7 yrDSM-4, CCDVD, CDSVD-R, MMSE, HISExtract fromHerba  Cistanches 2 tablets tid (23)Hydergine 2 tablet tid (23)MMSE, BBS, ADL, hemodynamic changesN2N23Yu et al. [66], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 14 days duration123 VaD patients; age: 57–74; duration: 0.4–1.4 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c CTFucong 30 mL od (72)Piracetam 0.8 g tid + vitamin E 0.1 g tid (51)SOD, LPO, TG, TCH, HDL, EEGNNY (2, mouth dryness, sore throat)24Zhao [97], China Monotherapy Center unclearRandomized: method not mentioned; double blinding not mentioned; Parallel design; 2 months duration90 VaD patients; age: 49–81; duration: 0.5–3.5 yrDSM, CT, MRI, clinical presentationJiannaoqingxin od (50)Duxil 1 tablet bid (40)MMSE, MMSE-R, hemodynamic changes, HDSNNN25Feng et al. [86], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration50 VaD patients; age: 59–82; duration: 2–5 yrPortera-sancheyYizhi bid (30)Piracetam1.6 g tid (20)MMSE, BBS, ADLNNU26Liu [71], China Monotherapy Single centerRandomized: method not mentioned; no blinding is applied; parallel design; 2 months duration142 VaD patients; age: 64–68; duration: 1.9–4.2 yrDSM-R, CT, MRI, HISBushenyinao3 g tid (98)Cerebroprot-ein Hydrolysate iv. 30 mL/day (44)HDS, hemodynamic changesN46Y27Liu et al. [60], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration92 VaD patients; age: 45–80; duration: 1–12 yrDSM, MMSE, ADL, CDR, HIS, “protocol for new herbal drugs study on dementia”* bHuatuozaizao 8 g tid (52)Duxil 1 tabletbid (40)MMSE, ADL, TC, TG, HDL-C, ET, NO, SELF, “protocol for new herbal drugs study on dementia”*bNNN28Liu and Chen [74], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design, 8 weeks duration86 hospitalized VaD patients; age: 60–79; duration: 4 m–6.5 yrDSM-4, HDS, HISBuyanghuanwu 12 g bid (43)Hydergine1 mg bid (43)HDS, FAQ, hemodynamic changes, MQ, “protocol for new herbal drugs study on dementia”*bNNU29Tang et al. [75], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design; 3 months duration80 VaD patients; age: 53–80; duration: 6 m–12 yrDSM-3-R, MMSE, CT, MRI, HIS, “TCM manual for neurological diseases”* eBushenhuoxie bid (40)Duxil 1 tablet bid, Nimodipine 30 mg tid (40)MMSE, ADL, WBHSV, WBLSV, PV, HCT, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNNN30Wang et al. [56], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: details given; crossover design; 7 months duration (3 m + 1 m wash out + 3 m)36 VaD patients; age: 52–83; duration: 1–7 yr.DSM-4, ADL-RShenlong180 mL bid (36)Placebo bid (36)MMSE-R, BBS, HDS, ADL-RNNY (4, sore throat, mouth dryness)31Wang et al. [98], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration140 VaD patients; age: 50–78; duration: 0.9–1.8 yrDSM-4, HIS, ADL, MMSE, SDS, “protocol for new herbal drugs study on dementia,”* b “TCM diagnostic criteria, differentiation and outcome measures on senile dementia” *cJiannaocongming 100 mL tid (100)Piracetam0.8 g tid (40)MMSE, ADL, hemodynamic changesNNU32Wang et al. [99], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration80 hospitalized VaD patients; age: 46–78; duration: 6–122 mDSM-4, NINDS-AIREN, MMSE, HDS, FAQ, HIS, “protocol for new herbal drugs study on dementia”*bTongxinluo3 pcs tid (40)Huperzine A 0.1 mg bid (40)MSME, HDS, FAQ, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNNY (nausea, decrease in appetite, etc.)33Wang [100], China, Adjunct therapy Single centerRandomized: method not mentioned; double blinding not mentioned, parallel design; 45 days duration66 VaD patients; age: 51–76; duration: 0.5–6 yrDSM-4-R, MMSE, HDS, CT, MRIBuyanghuanwu od + Piracetam 1.2 g bid, Nimodipine 20 mg tid (33)Piracetam 1.2 g bid, Nimodipine 20 mg tid (33)HDS-RNNU34Zhou et al. [101], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration62 VaD patients; age: 59–76; duration: 0.5–6 yrCCMD-2-R, DSM-4, MMSE, HDS, HISYiqifuzhi46 g tid (30)Piracetam0.8 g tid (32)Hemodynamic changes, SOD, MDA, “protocol for new herbal drugs study on dementia”* bNNU35Gao [67], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration98 VaD patients; age: 54–75; duration: 0.2–1.8 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* c, ADL, MMSEShumaiyinao 1.2 g tid (58)Piracetam1.2 g tid (40)MMSE, hemodynamic changes, Vmin, Qmin, RINNU36Hao et al. [102], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration100 VaD patients; age: 48–81; duration: 7–118 mICD10, CT, MMSE, IADL, HISTongxinluo3 pcs tid (50)Piracetam0.8 g tid (50)MMSE, NPI, IADL, HISNNY (16, GI discom-fort)37Li et al. [61], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration60 VaD patients; age: 45–80; duration: 1–12 yrDSM-4, ADL, MMSE, HIS, “protocol for new herbal drugs study on dementia”* bTongmaiyizhi 8 g tid (30)Duxil 1 tabletbid (30)MMSE, ADL, “protocol for new herbal drugs study on dementia”* bNNU38Mou [68], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration60 VaD patients; age: 57–89; duration: 2.5–4 yrDSM-4, HDSSelf-derived CHM 16 g 100 mL bid (30)Nimodipine 30 mg tid (30)MMSENNU39Shi and Wang [76], China Adjunct therapy Single centerRandomized: computer generated sequence; double blind: method not mentioned; parallel design; 3 months duration78 VaD patients; age: 50–80+; duration: 5 m–1.5 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c “Diagnostic manual for geriatrics”* fSelf-derived CHM 2 bid + nimodipine 40 mg tid, hydergine 2 mg tid (46)nimodipine40 mg tid,  hydergine 2 mg tid (32)ADL, MMSENNU40Zhang and Lu [69], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentoned; parallel design; 3 months duration72 VaD patients; age: 57–71; duration: 0.3–5.6 yrDSM-4, ICD10, HIS, HDL, TCBushenjiannao 300 mL bid (39)Piracetam 800 mg tid + hydergine 2 tablet bid (34)MMSE, HDS, hemodynamic changes, “protocol for new herbal drugs study on dementia”*bNNU41Chen et al. [84], China Monotherapy Single centerRandomized: method not mentioned; double blind: method not mentioned; parallel design; 3 months duration68 VaD patients; age: 60–86; duration: 1–7 yrDSM-4, HDS, MMSE, CT, MRIShenlong 600 mL/day (36)Piracetam1.6 g tid (32)MMSE, BBS, HDS, “protocol for new herbal drugs study on dementia”*bNNU42Cui et al. [77], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design; 3 months duration67 VaD patients; age: 56–83; duration: 2 m–31 mDSM-4, NINDS-AIREN, HIS, CDRShuangshencuzhi 8 g tid (51)Duxil 1 tabletbid (16)MMSE, BBS, HCY, CT, MRIN5U43He [57], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 8 weeks duration90 VaD patients; age: 48–80; duration: 2 m–6.5 yrNINDS-AIREN, SDSVD, CDR, HIS, “criteria for the diagnosis, the differentiation of syndrome and the evaluation of efficacy of vascular dementia for research studies”* gKangnao6 g tid (60)Hydergine2 mg tid (30)MMSE, hemodynamic changes, SELFNNN44Jin et al. [85], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: details given; crossover design (12 w + 4 w wash out + 12 w);72 VaD patients; age: 55–83; duration: 1–7 yrDSM-4-R, MMSE, ADL, HDS, CT, MRI, “protocol for new herbal drugs study on dementia”* bJiannaoyizhi2 g tid (72)Placebo tid (72)MMSE-R, HDS, ADL-R, “protocol for new herbal drugs study on dementia”*b, “protocol for new herbal drugs study on stroke”* bNNY (2, sore throat, mouth dryness)45Yan [58], China Adjunct therapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 1 month duration79 VaD patients; age: 51–78; duration: 0.5–9 yr.DSM-4-R, HDS-R, MMSE, CT, MRIBuyanghuanwu + Cerebroprotein Hydrolysate 10 mL 20 d, Aniracetam 0.12 g tid; Nimodipine 20 mg tid (36)Cerebroprot-ein Hydrolysate 10 mL 20 d, Aniracetam 0.12 g tid; Nimodipine 20 mg tid (43)HDS-RNNU46Chang et al. [70], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 12 weeks duration66 VaD patients; age: 60–78; duration: 1.3–3.6 yrDSM-4, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”*c MMSE, CT, MRI, HDSQihong 300 mL bid (33)Piracetam 0.4 g bid (33)HDS, MMSENNU47Li et al. [103], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration120 VaD patients; age: 59–75; duration: 0.6–6.2 yrDSM-4, MMSE-R, CDR, NINDS-AIREN, SDSVD, HIS, CSDD, “protocol for new herbal drugs study on dementia”* bShouwuyizhi2.4 g tid (80)Piracetam 0.8 g tid (40)MMSE, HDS, WMS, SDSVD, TCD, hemodynamic changes, SELFNNNKey:*1: N: intention-to-treat analysis is not used; Y: intention-to-treat analysis is applied.*2: N: no report of drop-out; Y: drop-out reported (with no. of dropouts in bracket).*3: N: report as no adverse events; Y: adverse events reported (with no. and details in bracket); U= adverse events unknown.*a: Quan et al. [104], *b: Guidance principle of clinical study on new drug of traditional Chinese medicine [105], *c: Fu [106], *d: Zhou [107], *e: Huang and Liu [108], *f: Wang et al. [109], *f: Tian et al. [88].BEAM: brain electrical activity mappingOnly two studies [82, 86] used a single diagnostic criterion to select participants. Other studies used two or more diagnostic criteria. Among them DSM III and IV were the most commonly adopted (42 studies used it) [39, 40]. The other criteria commonly used, listed in descending order of frequency, were HIS [43] (27 studies), MMSE [45] (25 studies); HDS [47] (17 studies); ADL [46] (11 studies); clinical dementia rating scale (CDR) [87] (6 studies); NINDS-AIREN [44] (five studies); ICD-10 [41] (four studies). Other measurement scales used included the scale for the differentiation of syndromes of vascular dementia (SDSVD) [88], Functional Activities Questionnaire (FAQ) [89], and self-derived criteria (SELF). Furthermore, some studies also carried out diagnostic imaging such as CT and magnetic resonance imaging (MRI) for participant selection.


### 4.6. Baseline Characteristics and Outcome Measures (Table3)

A number of batteries were employed to evaluate the baseline characteristics and outcome measures. The most commonly employed set of evaluative questionnaires included MMSE [45] (38 studies); HDS [47] (23 studies); ADL [46] (20 studies); Berg Balance Scale (BBS 8 studies); SELF (5 studies); memory quotient (MQ 1 study); geriatric dementia scale (GDS 1 study). Moreover, diagnostic imaging such as electroencephalography (EEG 6 studies) and CT (2 studies) were carried out. A number of studies also took into account the changes in hemodynamics (21 studies) and transcranial doppler (TCD 3 studies) as part of the outcome measures. Lastly, biochemical analysis, such as changes in the level of superoxidase dismutase (SOD), malondialdehyde (MDA), homocysteine (HCY), testerone (T), and 17 beta-estradiol (E2) were also adopted in assessing the efficacy and safety of interventions in the studies.The different batteries used in the studies resulted in variation in outcome measures. As the data were not suitable for meta-analysis, only qualitative appraisal could be carried out.


### 4.7. Herbal Medicine as Monotherapy (Table3)

There were altogether 43 trials testing herbal medicine as a monotherapy for VaD. Among them 15 studies compared different HM preparations with Piracetam alone (a nootropic agent). One study compared HM with another stronger nootropic compound Aniracetam. One study compared HM with Piracetam + hydergine and one study compare HM with Piracetam + Vitamin E + respiratory stimulant Duxil (Almitrine). Hydergine, (also known as ergoloid mesylates, another nootropic agent), was tested alone against HM in 11 studies. Five studies reported HM having similar efficacy to these nootropics; the remaining 23 claimed HM to be significantly better.Seven studies compared HM with Duxil (Almitrine) alone, a respiratory stimulant originally used to treat patients with chronic obstructive pulmonary disease. In one study, HM is compared with Duxil + Nimodipine (a dihydropyridine calcium channel blocker for the treatment of high blood pressure). One study reported HM to have similar efficacy with Duxil; the other seven claimed that HM is better than Duxil.Furthermore, HM was compared with Nimodipine in two studies, Huperzine A in one study, cerebroprotein hydrolysate in one study, and placebo in three studies. All of these studies concluded that HM is better than the control intervention.


### 4.8. Herbal Medicine as an Adjunct Therapy (Table3)

Four trials evaluated HM as an adjunct therapy for VaD. Two of them evaluated the adjunct effect of the CHM decoction BuYangHuanWuTang. Wang compared it with the coadministration of Piracetam and Nimodipine; Yan compared it with the co-administration of Aniracetam, Nimodipine, together with the injection of cerebroprotein hydrolysate. Shi and Wang studied the CHM decoction which, according to TCM theory, could “tonify the kidney, activating blood,” and tested its adjunct effect with nimodipine + hydergine (In TCM theory, the brain is considered an outgrowth of “kidney” energy. Neurodegenerative disorders such as dementia are caused by stagnation of “blood,” accumulation of “phlegm,” and deficiency of the “kidney.” In order to resist or halt the condition, TCM treatment targets the nourishment of the kidney by means of “kidney invigorating,” “blood activating” and “phlegm dissipating” herbal decoctions [110]. Guo et al. [53] studied another CHM BuNaoTongQiao decoction, which possesses nootropic properties, according to TCM theory, and compared it with Duxil. All these studies reported that when HM is used together with Western medications, both the efficacy and safety of OM could be enhanced.


### 4.9. Adverse Events and Withdrawal (Table3)

Among those 43 studies which tested HM as monotherapy, 25 studies did not report any cases of withdrawal. Ten studies claimed they did not observe any adverse events in groups treated with HM. Eight studies reported a number of mild adverse events, such as mouth dryness, sore throat, constipation, nausea, loss of appetite, and dyspepsia. These adverse events could be resolved without treatment. Serious adverse events were not observed. Occurrence of adverse events remained unclear in the four studies which tested HM as adjunct therapy.The dropouts or withdrawals were unclear in 44 out of 47 studies. Wu et al. [83] reported two dropouts in the course of intervention. Liu et al. [71] reported 46 dropouts during his trial. Cui et al. [77] reported five dropouts.


## 4.1. Description of Included Studies

Using the search strategy as described, 116 studies were identified. Upon full-text examination we excluded 69, on the basis that (1) 13 were not randomized controlled trials, (2) four were repeat publications, (3) three did not state their inclusion criteria, (4) one included other forms of dementia, (5) 44 did not disclose adequate baseline information, and (6) four involved the use of non-HM intervention, such as acupuncture. These disqualifications left 47 studies for this systematic review.There were a total of 3725 participants (2423 male, 1302 female) in the 47 included trials. Among them, three had cross-over design while the remaining were parallel design studies. The age of participants ranged from 45–89 years old, and their disease duration ranged from two months to 12 years. Thirty-two studies were performed in a single center; one was performed in multiple centers; 14 trials did not give this information. The duration of trials lasted from one to seven months. All of the trials were conducted in mainland China, and all the subjects were of Chinese ethnicity.


## 4.2. Risk of Bias (Table2)

Table 2
Methodological quality of studies (CONSORT checklist).
Reported page number of each item*1AbstractsMethodRandomizationResultsDiscussionNumberAuthorYearTitle and abstractIntroductionParticipantInterventionObjectiveOutcomeSample sizeSequence generationAllocation concealmentImplementationBlindingStatistical methodsParticipant flowRecruitmentBaseline dataNumbers analyzedOutcomes and estimationAncillary analysesAdverse eventsInterpretationGeneralisabilityOverall evidence123456789101112131415161718192021221Wan et al.1998252525252425UUUUUUUU252626UU27U272Zhao et al.1999585585585586585586UUUUU586U585585585586U5875875875873Ji200010101011U11UUUUUUU1010U11UU11U114Lu et al.2000290290290290290290UUUUU290UU290290290UU290U2905Luo2001470U470470470471UUUU470471U470470472472472U4724734736Zhang et al.2001U515151U51UUUUUUU51515252U525252527Zhou and Yi2001141414141414UUUUUUUU141515UU15U158Cao et al.2002808080808080UUUU8081U80808181U8181U819Hong et al.2002U333U3UUUUU3U33444U55510Huang et al.2002301301301302301302UUUUU302UU302301302UU30330330311Liu et al.2002526526526526526526UUUUUUU526526U527UU527U52712Wang et al.2002U295296296U296UUUUUUU295295296296UU296U29613Yang et al.2002484849494849UUUU4849UU484949UU50515114Cai et al.2003482482482482482482U482UUU483UU482483483U48348348348315Guo et al.2003U931931931U931UUUUUUUU931931931UU931U93116Jia et al.2003202020202021UUUUU21U20202121U2122U2217Cheng et al.2004161616161616UUUUU16UU161717UU17171718Liao et al.2004112112112113112113UUUUU113U113112113113U11311311411419Shen and Du2004414142424142UUUUU42U42424243UU43434320Wang et al.2004679679679680679680U680680680680680681U679680680U68168168168121Wang et al.2004169116911691169216911692UUUUU1692U1691169116921692UU1693U169322Wu et al.2004333333UUUU33UU344U44U423Yu et al.2004424424424424424424UUUU424UU424424425425U42542542542524Zhao2004899989UUUUU9U9999U99U1025Feng et al.2005520520520520520520UUUUU521U520520521521UU52152252126Liu2005505050505050UUUUU505150515151U5151515127Liu et al.20051052105210521052U1052UUUUU1053U1053105210531053U105410541054105428Liu and Chen2005181818191819UUUUU19UU181919UU20U2029Tang et al.2005426426426427426427UUUUU427U426426427427U42742742742730Wang et al.200593U93949394U9494U9494U93949494U9594U9431Wang, Chen and Bai2005333334UUUUU4U3334UU45532Wang et al.2005260260261261260261UUUU261261UU260261261U261262U26233Wang2005404040404040UUUUU40U40404041UU41414134Zhou et al.2005111111111112UUUUU12U11111212UU13U1335Gao2006141414141415UUUUUUU14141515UU16U1636Hao et al.2006424424424424424424UUUUU425UU424425425U425425U42537Li et al.200648484848U48UUUUU48U48484848UU49494938Mou2006160716071607160716071607UUUUUUUU160716071607U1607UU160739Shi and Wang2006200200200200200200U200UU200200UU200201201UU20120120140Zhang and Lu2006680680680680680681UUUUUUUU680681681UU68168168141Chen et al.2007866866866867866867U867UU867867U866866867867UU86886886842Cui et al.2007646464646464U64UUU65U6464U65UU65U6543He200760U6060U60UUUU6060UU606060U6161U6144Jin et al.2007165716571657165816571658UUU165816581658UU165716581658U165916591659165945Yan200741U41414141UUUUUUUU414141UU41414246Chang2008241240240241240241UUUUUUU240241241241U241241U24147Li et al.2008369369369370369370UUUUU370U369369370370U371371371371Key*1: U = the relevant item was not found in the paper.We adopted the checklist of items suggested by CONSORT [50] in the evaluation of methodological quality (risk of bias). The checklist was divided into five sections, namely, title and abstract, introduction, methods, results, and discussion.Except for 4 studies [51–54], all had adequate information on the title and abstract. Four studies [55–58] did not give an appropriate introduction.With regard to method, none of the 47 studies reported details for sample size calculations. Eight [51–54, 57, 59–61] did not clearly state their objective of study. All but one study [62] poorly reported their randomization and blinding. Statistical method was not reported in 13 studies [51–53, 58, 59, 63–70].For the results section, only two studies [62, 71] reported with a flowchart. Patient recruitment, outcomes and estimation, and ancillary analyses were mentioned by the majority of studies. More than half of the studies did not report adverse event count.In the discussion section, both the interpretation and overall evidence were adequately reported by the studies; generalizability, however, was not sufficiently illustrated by 13 studies.


## 4.3. Randomization (Table2)

All of the included studies claimed to have allocated participants randomly to study groups. Six [72–77] reported the use of computer-generated sequences; the other 41 studies did not provide any description of how randomization was achieved.


## 4.4. Allocation Concealment (Table2)

Except for one study [71] which clearly stated that it did not use any blinding methods, 32 studies did not report whether they applied blinding or not. For those studies which reported the use of allocation concealment, 6 were single blind [52, 57, 66, 78–81], and 8 were double blind [55, 56, 62, 76, 82–85].


## 4.5. Eligible Criteria (Table3)

Table 3
Study properties.
StudyDesignSample and characteristicsDiagnostic criteriaHerbal interventionControlOutcome measuresITT*1Drop out*2ADR*31Wan et al. [63], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration68 VaD patients, age: 58–82; duration: 4.37–15.85 yrDSM-3-R, HDS, HIS, “TCM dementia differential criteria”*aFucong 150 mL, bid (37)Piracetam0.8 g, tid (31)MMSE, HDS, BEAM, hemodynamic changesNNU2Zhao et al. [74], China Monotherapy Single centerRandomized: method not mentioned; single blind; parallel design; 2 months duration46 VaD patients; age: 57–76; duration: 6 m –1 yrDSM-4, HIS, HDS, MMSE, “Protocol for new herbal drugs study on dementia”* bXianlong2.7 g, bid (24)Hydergine3 mg, bid (22)TCD, hemodynamic changesNNU3Ji [59], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration68 VaD patients; age: 58–82; duration: 1.45-3.24  yrDSM-3-R, HDS, HIS, “TCM dementia differential criteria”* aDangguishaoyao bid (37)Piracetam0.8 g, tid (31)MMSE, HDSNNU4Lu et al. [90], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration50 VaD patients; age: 56–82; duration: 2–6 yrDSM-3-R, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cShentong 10 g, tid (30)Hydergine1 mg, tid (20)MMSE, BBSNNU5Luo et al. [55], China Monotherapy MulticenterRandomized: method not mentioned; double blind: method not mentioned; parallel design; 75 days duration68 VaD patients; age: 49–79; duration: 0.99–2.07 yrDSM-4, ICD 10, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cShenmayizhi 1 g, tid (35)Hydergine1 mg, tid (33)MMSE, ADL, BEAM, Neurological deficitsNNU6Zhang et al. [51], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration61 VaD patients; age: 60–77; duration: 6 m–2.5 yr;NINDS-AIREN, HIS, HDS, “protocol for new herbal drugs study on dementia”* bJiannaotongluo 1.6 g, tid (30)Aniracetam 0.3 g, tid (31)HDS, hemodynamic changesNNU7Zhou and Yi [64], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration46 VaD patients; age: 60–80; duration: 8 m–3 yrDSM-3, “protocol for new herbal drugs study on dementia,”*b “protocol for new herbal drugs study on stroke”* bYinaoling 40 mL, bid (23)Piracetam 0.8 g tid (23)HDS, FAQ, CCSENNU8Cao et al. [82], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: method not mentioned; parallel design; 60 days duration53 VaD patients; age: 58–75; duration: 3 m–12 mDSM-4Congsheng tid (25)Hydergine tid (28)MMSE, BBS, TCD, EKG, SELFNNN9Hong et al. [54], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration86 VaD patients; age: 45–76; duration: 5 m–3 yrDSM-4, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c CORELATION, HISShouxing tid (48)Piracetam tid (38)MMSE, ADLNNU10Huang et al. [91], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration58 VaD patients; age: 57–79; duration: 6 m–3 yrDSM-4, MMSE, ADL, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNaohuandan 62 g/d (28)Piracetam tid (28)MMSE, ADL, E2, T, hemodynamic changesNNU11Liu et al. [65], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration64 VaD patients; age: 54–81; duration: 0.8–3 yrDSM-4, HIS, CT, MRITongqiaohuoxue-buyanghuanwu bid (36)Duxil 1 tabletbid (28)MMSE, HDS, hemodynamic changesNNU12Wang et al. [52] Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 30 days duration300 VaD patients; age: 52–83; duration: 7 m–7 yrDSM-3-R, DSM-4, MMSE, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c HIS, CT, MRIYizhitongluo 0.9–1.2 g TID (200)Piracetam0.8 g tid (100)MMSE, HDS, GDS, ADL, hemodynamic changes, SELFNNU13Yang et al. [80], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 2 months duration90 VaD patients; age: 50–81; duration: 3 M–6.5 yrDSM-4-R, ICD10, CDR, MMSE, HDS-R, CORNELL, “protocol for new herbal drugs study on dementia”* bZhinao 1.5 g tid (60)Hydergine2 mg tid (30)MMSE, HDS, ADL, neurological deficits, hemodynamic changes, TCD, EEG, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”*cNNU14Cai et al. [72], China Monotherapy Center unclearRandomized: computer generated sequence; single blind: method not mentioned; parallel design; 3 months duration63 VaD patients; age: 65–78; duration: 3 m–94 mDSM-4-R, MMSE, HIS, CT, MRIKangxing 0.9 g tid (33)Hydergine2 mg tid (30)MMSE, ADL, hemodynamic changes, “protocol for new herbal drugs study on stroke”中藥 新 藥治療癡呆的 臨 床研究指導原則NYN15Guo et al. [53], China Adjunct therapy Center unclearRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration53 VaD patients; age: 55–73; duration: 1 yr–5 yrDSM-4, “protocol for new herbal drugs study on dementia,”* b “protocol for new herbal drugs study on stroke”* bBunaotongqiao + Duxil 1 tablet bid (28)Duxil 1 tablet bid (25)MMSE, HDS, hemodynamic changes,NNU16Jia et al. [92], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 60 days duration162 VaD patients; age: 54–71; duration: 0.8–3 yrDSM-4, CDR, imaging, HDSLuoshukang 1.5–2.5 g tid (108)Duxil 1 tablet bid (54)MMSE, BBS, “protocol for new herbal drugs study on dementia”* bNNN17Cheng et al. [93] Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 2 months duration36 VaD patients; age: 62–83; duration: 0.5–9 yrDSM-4-R, HIS, CT, MMSE, FAQ, HDS-R, ADLNaozhitong 4 pcs tid (18)Nimodipine20 mg tid (18)MMSE, FAQ, HDS-R, ADL, NONNU18Liao et al. [73], China Monotherapy Single centerRandomized: computer-generated sequence; single blind: method not mentioned; parallel design; 2 months duration60 VaD patients; age: 71–74; duration: 3.2–5.6 hrDSM-4, CT, MRI, HIS, MMSE, HDS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”*cShoulingjiannao 0.9 g tid (32)Hydergine1 mg tid (28)MMSE, HDS, “protocol for the selection of anti-aging herbal medicine and the corresponding outcome measures”* dNNN19Shen and Du [94], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 3 months duration70 VaD patients; age: 65–77; duration: 6 m –3 yrDSM-4, NINDS-AIREN, CT, MRI, “protocol for new herbal drugs study on dementia”* bBushenjianpiy-angxuehuoxue 0.9 g tid (40)Hydergine 2 mg tid (30)MMSE, ADL, ET, NO, HCY, E2, TNNU20Wang et al. [95], China Monotherapy Single centerRandomized: method not mentioned; double blind: details given; crossover design; 7 months duration (3 m + 1 m wash out + 3 m)18 VaD patients; age: 54–83; duration: 1–7 yrDSM-4, CT, MRI, HDS, MMSE, ADL-R, “protocol for new herbal drugs study on dementia”* bShenlong180 mL bid (18)Placebo 180 mL bid (18)HDS, MMSE-R, ADL-R, “protocol for new herbal drugs study on dementia”*bNNY (2, mouth dryness, sore throat)21Wang et al. [96], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 3 months duration100 VaD patients; age: 50–78; duration: 0.7–1.8 hrDSM-4, HIS, ADL, MMSE, SDS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* c, “protocol for new herbal drugs study on dementia”* bHuitian 0.8 g tid (50)Piracetam 08. g tid (50)MMSE, ADL, hemodynamic changes, “protocol for new herbal drugs study on dementia”*bNNU22Wu et al. [83], China Monotherapy Center unclearRandomized: method not mentioned; double blind: method not mentioned; parallel design; 30 days duration46 VaD patients; age: 62–77; duration: 0.8–4.7 yrDSM-4, CCDVD, CDSVD-R, MMSE, HISExtract fromHerba  Cistanches 2 tablets tid (23)Hydergine 2 tablet tid (23)MMSE, BBS, ADL, hemodynamic changesN2N23Yu et al. [66], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 14 days duration123 VaD patients; age: 57–74; duration: 0.4–1.4 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c CTFucong 30 mL od (72)Piracetam 0.8 g tid + vitamin E 0.1 g tid (51)SOD, LPO, TG, TCH, HDL, EEGNNY (2, mouth dryness, sore throat)24Zhao [97], China Monotherapy Center unclearRandomized: method not mentioned; double blinding not mentioned; Parallel design; 2 months duration90 VaD patients; age: 49–81; duration: 0.5–3.5 yrDSM, CT, MRI, clinical presentationJiannaoqingxin od (50)Duxil 1 tablet bid (40)MMSE, MMSE-R, hemodynamic changes, HDSNNN25Feng et al. [86], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration50 VaD patients; age: 59–82; duration: 2–5 yrPortera-sancheyYizhi bid (30)Piracetam1.6 g tid (20)MMSE, BBS, ADLNNU26Liu [71], China Monotherapy Single centerRandomized: method not mentioned; no blinding is applied; parallel design; 2 months duration142 VaD patients; age: 64–68; duration: 1.9–4.2 yrDSM-R, CT, MRI, HISBushenyinao3 g tid (98)Cerebroprot-ein Hydrolysate iv. 30 mL/day (44)HDS, hemodynamic changesN46Y27Liu et al. [60], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration92 VaD patients; age: 45–80; duration: 1–12 yrDSM, MMSE, ADL, CDR, HIS, “protocol for new herbal drugs study on dementia”* bHuatuozaizao 8 g tid (52)Duxil 1 tabletbid (40)MMSE, ADL, TC, TG, HDL-C, ET, NO, SELF, “protocol for new herbal drugs study on dementia”*bNNN28Liu and Chen [74], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design, 8 weeks duration86 hospitalized VaD patients; age: 60–79; duration: 4 m–6.5 yrDSM-4, HDS, HISBuyanghuanwu 12 g bid (43)Hydergine1 mg bid (43)HDS, FAQ, hemodynamic changes, MQ, “protocol for new herbal drugs study on dementia”*bNNU29Tang et al. [75], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design; 3 months duration80 VaD patients; age: 53–80; duration: 6 m–12 yrDSM-3-R, MMSE, CT, MRI, HIS, “TCM manual for neurological diseases”* eBushenhuoxie bid (40)Duxil 1 tablet bid, Nimodipine 30 mg tid (40)MMSE, ADL, WBHSV, WBLSV, PV, HCT, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNNN30Wang et al. [56], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: details given; crossover design; 7 months duration (3 m + 1 m wash out + 3 m)36 VaD patients; age: 52–83; duration: 1–7 yr.DSM-4, ADL-RShenlong180 mL bid (36)Placebo bid (36)MMSE-R, BBS, HDS, ADL-RNNY (4, sore throat, mouth dryness)31Wang et al. [98], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration140 VaD patients; age: 50–78; duration: 0.9–1.8 yrDSM-4, HIS, ADL, MMSE, SDS, “protocol for new herbal drugs study on dementia,”* b “TCM diagnostic criteria, differentiation and outcome measures on senile dementia” *cJiannaocongming 100 mL tid (100)Piracetam0.8 g tid (40)MMSE, ADL, hemodynamic changesNNU32Wang et al. [99], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration80 hospitalized VaD patients; age: 46–78; duration: 6–122 mDSM-4, NINDS-AIREN, MMSE, HDS, FAQ, HIS, “protocol for new herbal drugs study on dementia”*bTongxinluo3 pcs tid (40)Huperzine A 0.1 mg bid (40)MSME, HDS, FAQ, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* cNNY (nausea, decrease in appetite, etc.)33Wang [100], China, Adjunct therapy Single centerRandomized: method not mentioned; double blinding not mentioned, parallel design; 45 days duration66 VaD patients; age: 51–76; duration: 0.5–6 yrDSM-4-R, MMSE, HDS, CT, MRIBuyanghuanwu od + Piracetam 1.2 g bid, Nimodipine 20 mg tid (33)Piracetam 1.2 g bid, Nimodipine 20 mg tid (33)HDS-RNNU34Zhou et al. [101], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration62 VaD patients; age: 59–76; duration: 0.5–6 yrCCMD-2-R, DSM-4, MMSE, HDS, HISYiqifuzhi46 g tid (30)Piracetam0.8 g tid (32)Hemodynamic changes, SOD, MDA, “protocol for new herbal drugs study on dementia”* bNNU35Gao [67], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration98 VaD patients; age: 54–75; duration: 0.2–1.8 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia”* c, ADL, MMSEShumaiyinao 1.2 g tid (58)Piracetam1.2 g tid (40)MMSE, hemodynamic changes, Vmin, Qmin, RINNU36Hao et al. [102], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 6 months duration100 VaD patients; age: 48–81; duration: 7–118 mICD10, CT, MMSE, IADL, HISTongxinluo3 pcs tid (50)Piracetam0.8 g tid (50)MMSE, NPI, IADL, HISNNY (16, GI discom-fort)37Li et al. [61], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 3 months duration60 VaD patients; age: 45–80; duration: 1–12 yrDSM-4, ADL, MMSE, HIS, “protocol for new herbal drugs study on dementia”* bTongmaiyizhi 8 g tid (30)Duxil 1 tabletbid (30)MMSE, ADL, “protocol for new herbal drugs study on dementia”* bNNU38Mou [68], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 60 days duration60 VaD patients; age: 57–89; duration: 2.5–4 yrDSM-4, HDSSelf-derived CHM 16 g 100 mL bid (30)Nimodipine 30 mg tid (30)MMSENNU39Shi and Wang [76], China Adjunct therapy Single centerRandomized: computer generated sequence; double blind: method not mentioned; parallel design; 3 months duration78 VaD patients; age: 50–80+; duration: 5 m–1.5 yrDSM-4, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”* c “Diagnostic manual for geriatrics”* fSelf-derived CHM 2 bid + nimodipine 40 mg tid, hydergine 2 mg tid (46)nimodipine40 mg tid,  hydergine 2 mg tid (32)ADL, MMSENNU40Zhang and Lu [69], China Monotherapy Unclear centerRandomized: method not mentioned; double blinding not mentoned; parallel design; 3 months duration72 VaD patients; age: 57–71; duration: 0.3–5.6 yrDSM-4, ICD10, HIS, HDL, TCBushenjiannao 300 mL bid (39)Piracetam 800 mg tid + hydergine 2 tablet bid (34)MMSE, HDS, hemodynamic changes, “protocol for new herbal drugs study on dementia”*bNNU41Chen et al. [84], China Monotherapy Single centerRandomized: method not mentioned; double blind: method not mentioned; parallel design; 3 months duration68 VaD patients; age: 60–86; duration: 1–7 yrDSM-4, HDS, MMSE, CT, MRIShenlong 600 mL/day (36)Piracetam1.6 g tid (32)MMSE, BBS, HDS, “protocol for new herbal drugs study on dementia”*bNNU42Cui et al. [77], China Monotherapy Single centerRandomized: computer generated sequence; double blinding not mentioned; parallel design; 3 months duration67 VaD patients; age: 56–83; duration: 2 m–31 mDSM-4, NINDS-AIREN, HIS, CDRShuangshencuzhi 8 g tid (51)Duxil 1 tabletbid (16)MMSE, BBS, HCY, CT, MRIN5U43He [57], China Monotherapy Single centerRandomized: method not mentioned; single blind: method not mentioned; parallel design; 8 weeks duration90 VaD patients; age: 48–80; duration: 2 m–6.5 yrNINDS-AIREN, SDSVD, CDR, HIS, “criteria for the diagnosis, the differentiation of syndrome and the evaluation of efficacy of vascular dementia for research studies”* gKangnao6 g tid (60)Hydergine2 mg tid (30)MMSE, hemodynamic changes, SELFNNN44Jin et al. [85], China Monotherapy Unclear centerRandomized: method not mentioned; double blind: details given; crossover design (12 w + 4 w wash out + 12 w);72 VaD patients; age: 55–83; duration: 1–7 yrDSM-4-R, MMSE, ADL, HDS, CT, MRI, “protocol for new herbal drugs study on dementia”* bJiannaoyizhi2 g tid (72)Placebo tid (72)MMSE-R, HDS, ADL-R, “protocol for new herbal drugs study on dementia”*b, “protocol for new herbal drugs study on stroke”* bNNY (2, sore throat, mouth dryness)45Yan [58], China Adjunct therapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 1 month duration79 VaD patients; age: 51–78; duration: 0.5–9 yr.DSM-4-R, HDS-R, MMSE, CT, MRIBuyanghuanwu + Cerebroprotein Hydrolysate 10 mL 20 d, Aniracetam 0.12 g tid; Nimodipine 20 mg tid (36)Cerebroprot-ein Hydrolysate 10 mL 20 d, Aniracetam 0.12 g tid; Nimodipine 20 mg tid (43)HDS-RNNU46Chang et al. [70], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 12 weeks duration66 VaD patients; age: 60–78; duration: 1.3–3.6 yrDSM-4, HIS, “TCM diagnostic criteria, differentiation and outcome measures on senile dementia,”*c MMSE, CT, MRI, HDSQihong 300 mL bid (33)Piracetam 0.4 g bid (33)HDS, MMSENNU47Li et al. [103], China Monotherapy Single centerRandomized: method not mentioned; double blinding not mentioned; parallel design; 2 months duration120 VaD patients; age: 59–75; duration: 0.6–6.2 yrDSM-4, MMSE-R, CDR, NINDS-AIREN, SDSVD, HIS, CSDD, “protocol for new herbal drugs study on dementia”* bShouwuyizhi2.4 g tid (80)Piracetam 0.8 g tid (40)MMSE, HDS, WMS, SDSVD, TCD, hemodynamic changes, SELFNNNKey:*1: N: intention-to-treat analysis is not used; Y: intention-to-treat analysis is applied.*2: N: no report of drop-out; Y: drop-out reported (with no. of dropouts in bracket).*3: N: report as no adverse events; Y: adverse events reported (with no. and details in bracket); U= adverse events unknown.*a: Quan et al. [104], *b: Guidance principle of clinical study on new drug of traditional Chinese medicine [105], *c: Fu [106], *d: Zhou [107], *e: Huang and Liu [108], *f: Wang et al. [109], *f: Tian et al. [88].BEAM: brain electrical activity mappingOnly two studies [82, 86] used a single diagnostic criterion to select participants. Other studies used two or more diagnostic criteria. Among them DSM III and IV were the most commonly adopted (42 studies used it) [39, 40]. The other criteria commonly used, listed in descending order of frequency, were HIS [43] (27 studies), MMSE [45] (25 studies); HDS [47] (17 studies); ADL [46] (11 studies); clinical dementia rating scale (CDR) [87] (6 studies); NINDS-AIREN [44] (five studies); ICD-10 [41] (four studies). Other measurement scales used included the scale for the differentiation of syndromes of vascular dementia (SDSVD) [88], Functional Activities Questionnaire (FAQ) [89], and self-derived criteria (SELF). Furthermore, some studies also carried out diagnostic imaging such as CT and magnetic resonance imaging (MRI) for participant selection.


## 4.6. Baseline Characteristics and Outcome Measures (Table3)

A number of batteries were employed to evaluate the baseline characteristics and outcome measures. The most commonly employed set of evaluative questionnaires included MMSE [45] (38 studies); HDS [47] (23 studies); ADL [46] (20 studies); Berg Balance Scale (BBS 8 studies); SELF (5 studies); memory quotient (MQ 1 study); geriatric dementia scale (GDS 1 study). Moreover, diagnostic imaging such as electroencephalography (EEG 6 studies) and CT (2 studies) were carried out. A number of studies also took into account the changes in hemodynamics (21 studies) and transcranial doppler (TCD 3 studies) as part of the outcome measures. Lastly, biochemical analysis, such as changes in the level of superoxidase dismutase (SOD), malondialdehyde (MDA), homocysteine (HCY), testerone (T), and 17 beta-estradiol (E2) were also adopted in assessing the efficacy and safety of interventions in the studies.The different batteries used in the studies resulted in variation in outcome measures. As the data were not suitable for meta-analysis, only qualitative appraisal could be carried out.


## 4.7. Herbal Medicine as Monotherapy (Table3)

There were altogether 43 trials testing herbal medicine as a monotherapy for VaD. Among them 15 studies compared different HM preparations with Piracetam alone (a nootropic agent). One study compared HM with another stronger nootropic compound Aniracetam. One study compared HM with Piracetam + hydergine and one study compare HM with Piracetam + Vitamin E + respiratory stimulant Duxil (Almitrine). Hydergine, (also known as ergoloid mesylates, another nootropic agent), was tested alone against HM in 11 studies. Five studies reported HM having similar efficacy to these nootropics; the remaining 23 claimed HM to be significantly better.Seven studies compared HM with Duxil (Almitrine) alone, a respiratory stimulant originally used to treat patients with chronic obstructive pulmonary disease. In one study, HM is compared with Duxil + Nimodipine (a dihydropyridine calcium channel blocker for the treatment of high blood pressure). One study reported HM to have similar efficacy with Duxil; the other seven claimed that HM is better than Duxil.Furthermore, HM was compared with Nimodipine in two studies, Huperzine A in one study, cerebroprotein hydrolysate in one study, and placebo in three studies. All of these studies concluded that HM is better than the control intervention.


## 4.8. Herbal Medicine as an Adjunct Therapy (Table3)

Four trials evaluated HM as an adjunct therapy for VaD. Two of them evaluated the adjunct effect of the CHM decoction BuYangHuanWuTang. Wang compared it with the coadministration of Piracetam and Nimodipine; Yan compared it with the co-administration of Aniracetam, Nimodipine, together with the injection of cerebroprotein hydrolysate. Shi and Wang studied the CHM decoction which, according to TCM theory, could “tonify the kidney, activating blood,” and tested its adjunct effect with nimodipine + hydergine (In TCM theory, the brain is considered an outgrowth of “kidney” energy. Neurodegenerative disorders such as dementia are caused by stagnation of “blood,” accumulation of “phlegm,” and deficiency of the “kidney.” In order to resist or halt the condition, TCM treatment targets the nourishment of the kidney by means of “kidney invigorating,” “blood activating” and “phlegm dissipating” herbal decoctions [110]. Guo et al. [53] studied another CHM BuNaoTongQiao decoction, which possesses nootropic properties, according to TCM theory, and compared it with Duxil. All these studies reported that when HM is used together with Western medications, both the efficacy and safety of OM could be enhanced.


## 4.9. Adverse Events and Withdrawal (Table3)

Among those 43 studies which tested HM as monotherapy, 25 studies did not report any cases of withdrawal. Ten studies claimed they did not observe any adverse events in groups treated with HM. Eight studies reported a number of mild adverse events, such as mouth dryness, sore throat, constipation, nausea, loss of appetite, and dyspepsia. These adverse events could be resolved without treatment. Serious adverse events were not observed. Occurrence of adverse events remained unclear in the four studies which tested HM as adjunct therapy.The dropouts or withdrawals were unclear in 44 out of 47 studies. Wu et al. [83] reported two dropouts in the course of intervention. Liu et al. [71] reported 46 dropouts during his trial. Cui et al. [77] reported five dropouts.


## 5. Discussion

### 5.1. A Wide Variety of Herbal Remedies

Thirty-one out of 47 studies tested herbal mixtures prepared in the form of granules or capsules. Fifteen studies tested their herbal mixtures in the form of decoctions. One study tested the extract from a single herb. As some of the studies tested the same herbal mixture, altogether 42 different herbal mixtures were tested among these 47 studies (Table4). These herbal mixtures or extracts, according to the TCM theory, have the ability to “tonify the “kidney,” activate blood.” Despite the absence of pharmacological studies to verify their safety, these studies reported encouraging effects and high safety profiles. Upon further analysis of the constitutional ingredients in these herbal formulas, we ranked the 30 most commonly used herbal constituents together according to the dosages (Table 5).Table 4
Statistics on herbal intervention.
NumberChinese nameEnglish nameForm of preparationFrequencyStudy1補陽還五BuyanghuanwuDecoction/capsule3Liu and Chen [74]; Wang [56]; Yan [58]2參龍ShenlongDecoction3Wang et al. [62]; Wang et al. [56]; Chen et al. [84]3通心絡TongxinluoCapsule2Wang et al. [99]; Hao et al. [102]4仙龍XianlongCapsule1Zhao et al. [74]5復聰FucongDecoction1Wan et al. [63]6當歸芍藥DangguishaoyaoDecoction1Ji [59]7神通ShentongCapsule1Lu et al. [90]8參麻益智ShenmayizhiCapsule1Luo [55]9健腦通絡JiannaotongluoCapsule1Zhang et al. [51]10益腦YinaolingOral liquid1Zhou and Yi [64]11聰聖CongshengCapsule1Cao et al. [82]12壽星ShouxingCapsule1Hong et al. [54]13腦還丹NaohuandanCapsule1Huang et al. [91]14通竅活血-補陽還五Tongqiaohuoxue-buyanghuanwuDecoction1Liu et al. [65]15益智通絡YizhitongluoCapsule1Wang et al. [52]16智腦ZhinaoCapsule1Yang et al. [80]17康欣KangxingCapsule1Cai et al. [81]18補腦通竅BunaotongqiaoDecoction1Guo et al. [53]19絡舒康LuoshukangCapsule1Jia et al. [92]20腦智通NaozhitongCapsule1Cheng et al. [93]21首靈健腦ShoulingjiannaoCapsule1Liao et al. [73]22補腎健脾 養 血活血BushenjianpiyangxuehuoxueDecoction1Shen and Du [94]23回天HuitianTablet1Wang et al. [96]24蓯蓉總甙Extract from Herba CistanchisHerbal extract1Wu et al. [83]25復聰香FucongxiangOral liquid1Yu et al. [66]26健腦清心JiannaoqingxinDecoction1Zhao 200427益智YizhiDecoction1Feng et al. [86]28補腎益腦BushenyinaoCapsule1Liu [71]29華佗再造HuatuozaizaoTablet1Liu et al. [60]30補腎活血BushenhuoxieDecoction1Tang et al. [75]31健腦聰明JiannaocongmingOral liquid1Wang et al. [98]32益氣復智YiqifuzhiGranule1Zhou et al. [101]33舒脈益腦ShumaiyinaoCapsule1Gao [67]34通脈益智TongmaiyizhiTablet1Li et al. [61]35益智湯Self-derived CHM 1Decoction1Mou [68]36補腎活血自擬方Self-derived CHM 2Decoction1Shi and Wang [76]37補腎健腦BushenjiannaoDecoction1Zhang and Lu [69]38雙參促智ShuangshencuzhiGranule1Cui et al.[77]39康腦KangnaoTablet1He [57]40健腦益智JiannaoyizhiCapsule1Jin et al. [85]41芪紅QihongOral liquid1Chang et al. [70]42首烏益智ShouwuyizhiCapsule1Li et al. [103]Table 5
The 30 most commonly used herbal constituents.
Chinese nameScientific nameEnglish nameLatin nameFreq.Dose (g)1川芎Rhizoma ChuanxiongSzechwan Lovage RhizomeLigusticum  chuanxiong Hort.246–152何首烏Radix Polygoni MultifloriFleeceflower rootPolygonum  multiflorum Thunb.2410–203黃芪Radix AstragaliMilkvetch rootAstragalus  membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao2215–1204丹參Radix Salviae MiltiorrrhizaeDanshen rootSalvia  miltiorrhiza Bge.1410–205人參Radix GinsengGinsengPanax  ginseng C.A. Mey.136–106石菖蒲Rhizoma Acori TalarinowiiGrassleaf Sweetflag RhizomeAcorus  tatarinowii Schott.136–107當歸Radix Angelica SinensisChinese AngelicaAngelica  sinensis (Oliv.) Diels116–158山茱萸Fructus CorniAsiatic Cornelian Cherry fruitCornus  officinalis Sieb. et Zucc.1010–159遠志Radix PolygalaeThinleaf Milkwort rootPolygala  tenuifolia Willd.1010–1210益智仁Fructus Alpiniae OxyphyllaeSharpleaf Galangal fruitAlpinia  oxyphylla Miq.910–1511枸杞子Fructus LyciiBarbary Wolfberry fruitLycium  barbarum L.810–2012紅花Flos CarthamiSafflowerCarthamus  tinctorius L.; Crocus  sativus L.83–513黃精Rhizoma PolygonatiSolomonseal RhizomePolygonatum  sibiricum Red.; P.  cyrtonema Hua; P.  kingianum Coll. et Hemsl.815–3014九節菖蒲Rhizoma Anemonis AltaicaeIrkutsk Anemone RhizomeAnemone  altaica Fisch. ex. C.A. Mey.88–1215熟地Radix RehmanniaeRehmannia rootRehmannia  glutinosa Libosch.810–2016赤芍Radix Peaoniae RubraRed Peony rootPaeonia  lactiflora Pall.; P.  veitchii Lynch76–1517天麻Rhizoma GastrodiaeTall Gastrodia TuberGastrodia elata Bl.66–1018桃仁Semen PersicaePeach seedPrunus  persica (L.) Batsch; P.  davidiana (Carr.) Franch.63–1219淫羊藿/仙靈脾Herba EpimediiEpimedium herbEpimedium  brevicornum Maxim.; E.  sagittatum (Sieb. et Zucc.) Maxim; E.  pubescens Maxim.; E.  wushanense T.S. Ying; E.  koreanum Nakai61220鬱金Radix Curcumae WenyujinTurmeric Root TuberCurcuma  wenyujin Y. H. Chen et C. Ling; C.  longa L.; C.  kwangsiensis S.G. Lee et C. F. Liang; C.  phaeocaulis Val.610–1521白芍Radix Paeoniae AlbaWhite Peony rootPaeonia  lactiflora Pall.41522黨參Radix CodonopsisPilose Asiabell rootCodonopsis  pilosula (Franch.) Nannf.; C.  pilosula  Nannf. var. modesta (Nannf.) L.T. Shen; C.  tangshen Oliv.410–2023女貞子Fructus Ligustri LucidiGlossy Privet fruitLigustrum  lucidum Ait.31024山藥/淮山Rhizoma DioscoreaeCommon Yam RhizomeDioscorea  opposita Thunb.315–3025五味子Fructus Schisandrae ChinensisChinese Magnoliavine fruitSchisandra  chinensis (Turcz.) Baill.31026巴戟天Radix Morindae OfficinalisMorinda rootMorindae  officinalis How32027半夏Rhizoma PinelliaePinellia TuberPinellia  ternate (Thunb.) Breit310–1228白朮Rhizoma Atractylodis MacrocephalaeLargehead Atractylodes RhizomeAtractylodes  macrocephala Koidz.310–1529肉桂Cortex CinnamomiCassia BarkCinnamomum  cassia Presl3Unkno-wn30肉蓯蓉Herba CistanchesDesertliving CistanchesCistanche  deserticola Y.C.Ma310–20The first five in descending order of frequency of use are Rhizoma Chuanxiong (Chuanxiong in Chinese), Radix Polygoni Multiflori (Heshouwu in Chinese), Radix Astragali (Huangqi in Chinese), Radix Ginseng (Renshen in Chinese), and Rhizoma Acori Tatarinowii (Shichangpu in Chinese).Rhizoma Chuanxiong, originates from the plantLigusticum  chuanxiong Hort., which is used in TCM to “remove blood stasis.” Chemical analysis shows that it possesses an alkaloid named ligustrazine, which has antioxidant, anti-inflammatory, antifibrosis, and immune-modulative properties [111]. A clinical study is being carried out to evaluate its effect on patients’ recovery from cerebral vascular accidents [112]. The root of Polygonum  multiflorum Thunb. (Radix Polygoni Multiflori in English, the Chinese name is Heshouwu), commonly known as fleece flower root, is another popular HM used to treat premature aging and dementia. Past studies have shown it to have activity that may contribute to cardiovascular protection [113]. Long-term pretreatment with it may protect the brain against focal cerebral ischemia [114]. One animal study also suggests that it has anti-oxidant properties [115], with the capacity to prevent cognitive deficits [116], possibly even to promote learning and enhance memory [117]. A medical team in Taiwan is proposing a phase II clinical trial to assess the efficacy and safety of a new drug derived from it [118]. Radix Astragali (Huangqi), from Astragalus  membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, a commonly used herb to “vitalize spleen Qi” and “treat circulatory disorders” in TCM, possesses various components (astragalus saponins, astragalus polysaccharide) demonstrated to have anti-oxidation properties. These, together with its anti-cholinergic property, have been suggested to be the source of its significant anti-dementia effect [119]. A clinical trial is being carried out to determine the effect of an HM capsule with Radix Astragali (Huangqi in Chinese) as the main constituent on ischemic stroke [112]. Radix Salviae Miltiorrhizae (Danshen in Chinese), the root of Salvia  miltiorrhiza Bge., is used to “activate blood and resolve stasis” according to TCM. A laboratory study of its triterpenoids-enriched extract revealed that its antiatherogenic property was mediated by an anti-inflammatory mechanism [120]. Another animal study of Radix Salviae Miltiorrhizae (Danshen) reports it to reduce the area of cerebral infarct in ischemia-reperfusion injured rats, suggesting it has potential in the treatment of cerebral infarct in humans [121]. Radix Ginseng (Rensheng), the root of Panax  ginseng C.A. Mey., is a popular notifying herb in TCM, and its ginsenosides have been found to have protective effects on memory via antiapoptosis in a rat model with vascular dementia [122], and to stimulate angiogenesis and tissue regeneration [123], suggesting that it has potential to help VaD patients. In a Korean clinical study, Radix Ginseng was reported to be clinically effective in improving the cognitive performance of AD patients [124]. Rhizoma Acori Tatarinowii (Shichangpu), also named grassleaf or sweet-flag rhizome, the rhizome of Acorus  tatarinowii Schott., is used in TCM for resuscitation after coma. Pharmacological studies suggest this effect may be due to the increase in permeability of the blood-brain barrier [125]. In another pharmacological study, the fruit of Cornus  officinalis Sieb. et Zucc. (Shanzhuyu in Chinese), which is used in TCM to “tonify the kidney,” was found to possess an extract that has protective effects against oxidative stress-induced neurotoxic processes [126]. Other experimental reports have indicated that the triterpenoid saponins from the roots of Polygala  tenuifolia Willd. (Yuanzhi) possess neuroprotective effects [127, 128]. Study on extracts of Alpiniae  Oxyphyllae Miq. (Fructus Alpinae Oxyphyllae in English, the Chinese name is Yizhi) have found evidence that it protects neurons against ischemia-induced cell death [129] and that it prevents glutamate-induced apoptosis in cortical neurons [130]. In another study, it was reported that Rhizoma  Polygonati (known as Huangjing in Chinese, used in TCM as a notifying agent) could improve learning and memory in a scopolamine-induced mouse model of dementia by reducing the damaging effects of cerebral ischemia and anti-oxidation, having similar effects to those provided by vitamin E [131]. In a study to examine the anti-oxidative and neuroprotective effects of Paeonia  lactiflora Pall. (Baishao in Chinese), it was found to suppress the hydrogen peroxide-induced apoptosis in PC12 cells, suggesting that it could be a new antioxidant useful in the prevention of neuronal diseases [132]. Rhizoma Gastrodiae from Gastrodia  elata Bl. (Tianma in Chinese), a classic HM used to “extinguish wind and arrest convulsions” in TCM theory, possesses vasodilating [133], anti-inflammatory, and antiangiogenic activities [134], suggesting a potential VaD treatment. The total alkaloids found in Radix Codonopsis (Dangshen in Chinese used in TCM to “tonify Qi”) have been reported to potentiate neurite outgrowth induced by nerve growth factor in PC12 cells [135]. Glossy privet fruit, from Ligustrum  lucidum Ait. (Nüzhenzi in Chinese), a kidney-tonifying HM, can inhibit cell apoptosis by reducing apoptotic signals induced by cerebral ischemia/hypoxia [33].


### 5.2. Study Weaknesses

Though all the studies reported promising results of HM in the treatment of VaD, they demonstrated a number of weaknesses as well. The evidence drawn from the studies was insufficient for us to confirm the safety and efficacy of HM, because of the following issues(1)
The sample sizes of the studies ranged from 18 to 300, and none of them reported sample size calculations, as suggested by the CONSORT statement. Treatment effects can be exaggerated when sample size is inappropriate, and thus the results of these studies may not be conclusive.(2)
Different diagnostic criteria were used in the studies. Some of these criteria were even self-derived and their validities remained unknown. This produced much discrepancy.(3)
Differences in the baseline characteristics of the subjects limit the extent to which results can be compared with each other.(4)
Though all of the studies claimed to have participants allocated randomly, only a few reported the method of randomization. For those studies without detailed descriptions of randomization, we could not rule out the possibility of bias. Furthermore, unclear descriptions of allocation concealment, dropouts, and intention-to-treat analysis further hamper the ability to assess the validity of the evidence reported by these studies.(5)
Outcome measures varied and were incomplete in the studies. Some investigators employed self-developed scales, which could not be, or had not been, independently evaluated for their sensitivity and specificity. The validity is further questionable due to insufficient or inappropriate statistical treatment. Though meta-analysis techniques such as vote-counting may have been used for the analysis of the data, we avoid to do so because (1) the statistical significance or size of the results of the individual studies are ignored; and (2) vote-counting takes no account of the differential weights given to each study. [136](6)
Different HM were tested in the 47 studies included here, with great variation in terms of composition, dosage, and duration of interventions. This renders comparison of the studies impossible, and thus quantitative analysis could not be carried out.(7)
A number of studies (30 out of 47) did not mention safety issues. The investigators of these studies may have underestimated possible adverse events, and the safety of HM in these studies could not be guaranteed.


### 5.3. Implications for Further Studies

Regarding the published studies, methodology quality is the leading should concern. It is recommended that future clinical studies follow the guidelines as suggested by CONSORT to minimize bias as well as to ensure high validity, statistically reliable results and to permit comparison with other studies. Researchers should explicitly report methods for calculation of sample size. Widely recognized diagnostic criteria and outcome measures should be used. It is highly recommended to incorporate medical imaging techniques (such as perfusion computed tomography) to confirm the diagnosis of VaD. Appropriate statistical analyses should be carried out for baseline data and outcome results; long-term followup is also recommended and highly desirable.Our review has identified the individual herbs that appear most frequently in formulas for VaD. The top five are Rhizoma Chuanxiong (Chuanxiong), Radix Polygoni Multiflori (Heshouwu), Radix Astragali (Huangqi), Radix Ginseng (Renshen), and Rhizoma Acori Talarinowii (Shichangpu). The clinical efficacy and safety of these herbs, over centuries of use and during recent controlled studies, are a powerful combination of attributes. We believe that further high-quality clinical studies on these individual constituents, as well as the herbal mixtures resulted, could lead to the discovery of new drugs for effective treatment and prevention of VaD.


## 5.1. A Wide Variety of Herbal Remedies

Thirty-one out of 47 studies tested herbal mixtures prepared in the form of granules or capsules. Fifteen studies tested their herbal mixtures in the form of decoctions. One study tested the extract from a single herb. As some of the studies tested the same herbal mixture, altogether 42 different herbal mixtures were tested among these 47 studies (Table4). These herbal mixtures or extracts, according to the TCM theory, have the ability to “tonify the “kidney,” activate blood.” Despite the absence of pharmacological studies to verify their safety, these studies reported encouraging effects and high safety profiles. Upon further analysis of the constitutional ingredients in these herbal formulas, we ranked the 30 most commonly used herbal constituents together according to the dosages (Table 5).Table 4
Statistics on herbal intervention.
NumberChinese nameEnglish nameForm of preparationFrequencyStudy1補陽還五BuyanghuanwuDecoction/capsule3Liu and Chen [74]; Wang [56]; Yan [58]2參龍ShenlongDecoction3Wang et al. [62]; Wang et al. [56]; Chen et al. [84]3通心絡TongxinluoCapsule2Wang et al. [99]; Hao et al. [102]4仙龍XianlongCapsule1Zhao et al. [74]5復聰FucongDecoction1Wan et al. [63]6當歸芍藥DangguishaoyaoDecoction1Ji [59]7神通ShentongCapsule1Lu et al. [90]8參麻益智ShenmayizhiCapsule1Luo [55]9健腦通絡JiannaotongluoCapsule1Zhang et al. [51]10益腦YinaolingOral liquid1Zhou and Yi [64]11聰聖CongshengCapsule1Cao et al. [82]12壽星ShouxingCapsule1Hong et al. [54]13腦還丹NaohuandanCapsule1Huang et al. [91]14通竅活血-補陽還五Tongqiaohuoxue-buyanghuanwuDecoction1Liu et al. [65]15益智通絡YizhitongluoCapsule1Wang et al. [52]16智腦ZhinaoCapsule1Yang et al. [80]17康欣KangxingCapsule1Cai et al. [81]18補腦通竅BunaotongqiaoDecoction1Guo et al. [53]19絡舒康LuoshukangCapsule1Jia et al. [92]20腦智通NaozhitongCapsule1Cheng et al. [93]21首靈健腦ShoulingjiannaoCapsule1Liao et al. [73]22補腎健脾 養 血活血BushenjianpiyangxuehuoxueDecoction1Shen and Du [94]23回天HuitianTablet1Wang et al. [96]24蓯蓉總甙Extract from Herba CistanchisHerbal extract1Wu et al. [83]25復聰香FucongxiangOral liquid1Yu et al. [66]26健腦清心JiannaoqingxinDecoction1Zhao 200427益智YizhiDecoction1Feng et al. [86]28補腎益腦BushenyinaoCapsule1Liu [71]29華佗再造HuatuozaizaoTablet1Liu et al. [60]30補腎活血BushenhuoxieDecoction1Tang et al. [75]31健腦聰明JiannaocongmingOral liquid1Wang et al. [98]32益氣復智YiqifuzhiGranule1Zhou et al. [101]33舒脈益腦ShumaiyinaoCapsule1Gao [67]34通脈益智TongmaiyizhiTablet1Li et al. [61]35益智湯Self-derived CHM 1Decoction1Mou [68]36補腎活血自擬方Self-derived CHM 2Decoction1Shi and Wang [76]37補腎健腦BushenjiannaoDecoction1Zhang and Lu [69]38雙參促智ShuangshencuzhiGranule1Cui et al.[77]39康腦KangnaoTablet1He [57]40健腦益智JiannaoyizhiCapsule1Jin et al. [85]41芪紅QihongOral liquid1Chang et al. [70]42首烏益智ShouwuyizhiCapsule1Li et al. [103]Table 5
The 30 most commonly used herbal constituents.
Chinese nameScientific nameEnglish nameLatin nameFreq.Dose (g)1川芎Rhizoma ChuanxiongSzechwan Lovage RhizomeLigusticum  chuanxiong Hort.246–152何首烏Radix Polygoni MultifloriFleeceflower rootPolygonum  multiflorum Thunb.2410–203黃芪Radix AstragaliMilkvetch rootAstragalus  membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao2215–1204丹參Radix Salviae MiltiorrrhizaeDanshen rootSalvia  miltiorrhiza Bge.1410–205人參Radix GinsengGinsengPanax  ginseng C.A. Mey.136–106石菖蒲Rhizoma Acori TalarinowiiGrassleaf Sweetflag RhizomeAcorus  tatarinowii Schott.136–107當歸Radix Angelica SinensisChinese AngelicaAngelica  sinensis (Oliv.) Diels116–158山茱萸Fructus CorniAsiatic Cornelian Cherry fruitCornus  officinalis Sieb. et Zucc.1010–159遠志Radix PolygalaeThinleaf Milkwort rootPolygala  tenuifolia Willd.1010–1210益智仁Fructus Alpiniae OxyphyllaeSharpleaf Galangal fruitAlpinia  oxyphylla Miq.910–1511枸杞子Fructus LyciiBarbary Wolfberry fruitLycium  barbarum L.810–2012紅花Flos CarthamiSafflowerCarthamus  tinctorius L.; Crocus  sativus L.83–513黃精Rhizoma PolygonatiSolomonseal RhizomePolygonatum  sibiricum Red.; P.  cyrtonema Hua; P.  kingianum Coll. et Hemsl.815–3014九節菖蒲Rhizoma Anemonis AltaicaeIrkutsk Anemone RhizomeAnemone  altaica Fisch. ex. C.A. Mey.88–1215熟地Radix RehmanniaeRehmannia rootRehmannia  glutinosa Libosch.810–2016赤芍Radix Peaoniae RubraRed Peony rootPaeonia  lactiflora Pall.; P.  veitchii Lynch76–1517天麻Rhizoma GastrodiaeTall Gastrodia TuberGastrodia elata Bl.66–1018桃仁Semen PersicaePeach seedPrunus  persica (L.) Batsch; P.  davidiana (Carr.) Franch.63–1219淫羊藿/仙靈脾Herba EpimediiEpimedium herbEpimedium  brevicornum Maxim.; E.  sagittatum (Sieb. et Zucc.) Maxim; E.  pubescens Maxim.; E.  wushanense T.S. Ying; E.  koreanum Nakai61220鬱金Radix Curcumae WenyujinTurmeric Root TuberCurcuma  wenyujin Y. H. Chen et C. Ling; C.  longa L.; C.  kwangsiensis S.G. Lee et C. F. Liang; C.  phaeocaulis Val.610–1521白芍Radix Paeoniae AlbaWhite Peony rootPaeonia  lactiflora Pall.41522黨參Radix CodonopsisPilose Asiabell rootCodonopsis  pilosula (Franch.) Nannf.; C.  pilosula  Nannf. var. modesta (Nannf.) L.T. Shen; C.  tangshen Oliv.410–2023女貞子Fructus Ligustri LucidiGlossy Privet fruitLigustrum  lucidum Ait.31024山藥/淮山Rhizoma DioscoreaeCommon Yam RhizomeDioscorea  opposita Thunb.315–3025五味子Fructus Schisandrae ChinensisChinese Magnoliavine fruitSchisandra  chinensis (Turcz.) Baill.31026巴戟天Radix Morindae OfficinalisMorinda rootMorindae  officinalis How32027半夏Rhizoma PinelliaePinellia TuberPinellia  ternate (Thunb.) Breit310–1228白朮Rhizoma Atractylodis MacrocephalaeLargehead Atractylodes RhizomeAtractylodes  macrocephala Koidz.310–1529肉桂Cortex CinnamomiCassia BarkCinnamomum  cassia Presl3Unkno-wn30肉蓯蓉Herba CistanchesDesertliving CistanchesCistanche  deserticola Y.C.Ma310–20The first five in descending order of frequency of use are Rhizoma Chuanxiong (Chuanxiong in Chinese), Radix Polygoni Multiflori (Heshouwu in Chinese), Radix Astragali (Huangqi in Chinese), Radix Ginseng (Renshen in Chinese), and Rhizoma Acori Tatarinowii (Shichangpu in Chinese).Rhizoma Chuanxiong, originates from the plantLigusticum  chuanxiong Hort., which is used in TCM to “remove blood stasis.” Chemical analysis shows that it possesses an alkaloid named ligustrazine, which has antioxidant, anti-inflammatory, antifibrosis, and immune-modulative properties [111]. A clinical study is being carried out to evaluate its effect on patients’ recovery from cerebral vascular accidents [112]. The root of Polygonum  multiflorum Thunb. (Radix Polygoni Multiflori in English, the Chinese name is Heshouwu), commonly known as fleece flower root, is another popular HM used to treat premature aging and dementia. Past studies have shown it to have activity that may contribute to cardiovascular protection [113]. Long-term pretreatment with it may protect the brain against focal cerebral ischemia [114]. One animal study also suggests that it has anti-oxidant properties [115], with the capacity to prevent cognitive deficits [116], possibly even to promote learning and enhance memory [117]. A medical team in Taiwan is proposing a phase II clinical trial to assess the efficacy and safety of a new drug derived from it [118]. Radix Astragali (Huangqi), from Astragalus  membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, a commonly used herb to “vitalize spleen Qi” and “treat circulatory disorders” in TCM, possesses various components (astragalus saponins, astragalus polysaccharide) demonstrated to have anti-oxidation properties. These, together with its anti-cholinergic property, have been suggested to be the source of its significant anti-dementia effect [119]. A clinical trial is being carried out to determine the effect of an HM capsule with Radix Astragali (Huangqi in Chinese) as the main constituent on ischemic stroke [112]. Radix Salviae Miltiorrhizae (Danshen in Chinese), the root of Salvia  miltiorrhiza Bge., is used to “activate blood and resolve stasis” according to TCM. A laboratory study of its triterpenoids-enriched extract revealed that its antiatherogenic property was mediated by an anti-inflammatory mechanism [120]. Another animal study of Radix Salviae Miltiorrhizae (Danshen) reports it to reduce the area of cerebral infarct in ischemia-reperfusion injured rats, suggesting it has potential in the treatment of cerebral infarct in humans [121]. Radix Ginseng (Rensheng), the root of Panax  ginseng C.A. Mey., is a popular notifying herb in TCM, and its ginsenosides have been found to have protective effects on memory via antiapoptosis in a rat model with vascular dementia [122], and to stimulate angiogenesis and tissue regeneration [123], suggesting that it has potential to help VaD patients. In a Korean clinical study, Radix Ginseng was reported to be clinically effective in improving the cognitive performance of AD patients [124]. Rhizoma Acori Tatarinowii (Shichangpu), also named grassleaf or sweet-flag rhizome, the rhizome of Acorus  tatarinowii Schott., is used in TCM for resuscitation after coma. Pharmacological studies suggest this effect may be due to the increase in permeability of the blood-brain barrier [125]. In another pharmacological study, the fruit of Cornus  officinalis Sieb. et Zucc. (Shanzhuyu in Chinese), which is used in TCM to “tonify the kidney,” was found to possess an extract that has protective effects against oxidative stress-induced neurotoxic processes [126]. Other experimental reports have indicated that the triterpenoid saponins from the roots of Polygala  tenuifolia Willd. (Yuanzhi) possess neuroprotective effects [127, 128]. Study on extracts of Alpiniae  Oxyphyllae Miq. (Fructus Alpinae Oxyphyllae in English, the Chinese name is Yizhi) have found evidence that it protects neurons against ischemia-induced cell death [129] and that it prevents glutamate-induced apoptosis in cortical neurons [130]. In another study, it was reported that Rhizoma  Polygonati (known as Huangjing in Chinese, used in TCM as a notifying agent) could improve learning and memory in a scopolamine-induced mouse model of dementia by reducing the damaging effects of cerebral ischemia and anti-oxidation, having similar effects to those provided by vitamin E [131]. In a study to examine the anti-oxidative and neuroprotective effects of Paeonia  lactiflora Pall. (Baishao in Chinese), it was found to suppress the hydrogen peroxide-induced apoptosis in PC12 cells, suggesting that it could be a new antioxidant useful in the prevention of neuronal diseases [132]. Rhizoma Gastrodiae from Gastrodia  elata Bl. (Tianma in Chinese), a classic HM used to “extinguish wind and arrest convulsions” in TCM theory, possesses vasodilating [133], anti-inflammatory, and antiangiogenic activities [134], suggesting a potential VaD treatment. The total alkaloids found in Radix Codonopsis (Dangshen in Chinese used in TCM to “tonify Qi”) have been reported to potentiate neurite outgrowth induced by nerve growth factor in PC12 cells [135]. Glossy privet fruit, from Ligustrum  lucidum Ait. (Nüzhenzi in Chinese), a kidney-tonifying HM, can inhibit cell apoptosis by reducing apoptotic signals induced by cerebral ischemia/hypoxia [33].


## 5.2. Study Weaknesses

Though all the studies reported promising results of HM in the treatment of VaD, they demonstrated a number of weaknesses as well. The evidence drawn from the studies was insufficient for us to confirm the safety and efficacy of HM, because of the following issues(1)
The sample sizes of the studies ranged from 18 to 300, and none of them reported sample size calculations, as suggested by the CONSORT statement. Treatment effects can be exaggerated when sample size is inappropriate, and thus the results of these studies may not be conclusive.(2)
Different diagnostic criteria were used in the studies. Some of these criteria were even self-derived and their validities remained unknown. This produced much discrepancy.(3)
Differences in the baseline characteristics of the subjects limit the extent to which results can be compared with each other.(4)
Though all of the studies claimed to have participants allocated randomly, only a few reported the method of randomization. For those studies without detailed descriptions of randomization, we could not rule out the possibility of bias. Furthermore, unclear descriptions of allocation concealment, dropouts, and intention-to-treat analysis further hamper the ability to assess the validity of the evidence reported by these studies.(5)
Outcome measures varied and were incomplete in the studies. Some investigators employed self-developed scales, which could not be, or had not been, independently evaluated for their sensitivity and specificity. The validity is further questionable due to insufficient or inappropriate statistical treatment. Though meta-analysis techniques such as vote-counting may have been used for the analysis of the data, we avoid to do so because (1) the statistical significance or size of the results of the individual studies are ignored; and (2) vote-counting takes no account of the differential weights given to each study. [136](6)
Different HM were tested in the 47 studies included here, with great variation in terms of composition, dosage, and duration of interventions. This renders comparison of the studies impossible, and thus quantitative analysis could not be carried out.(7)
A number of studies (30 out of 47) did not mention safety issues. The investigators of these studies may have underestimated possible adverse events, and the safety of HM in these studies could not be guaranteed.


## 5.3. Implications for Further Studies

Regarding the published studies, methodology quality is the leading should concern. It is recommended that future clinical studies follow the guidelines as suggested by CONSORT to minimize bias as well as to ensure high validity, statistically reliable results and to permit comparison with other studies. Researchers should explicitly report methods for calculation of sample size. Widely recognized diagnostic criteria and outcome measures should be used. It is highly recommended to incorporate medical imaging techniques (such as perfusion computed tomography) to confirm the diagnosis of VaD. Appropriate statistical analyses should be carried out for baseline data and outcome results; long-term followup is also recommended and highly desirable.Our review has identified the individual herbs that appear most frequently in formulas for VaD. The top five are Rhizoma Chuanxiong (Chuanxiong), Radix Polygoni Multiflori (Heshouwu), Radix Astragali (Huangqi), Radix Ginseng (Renshen), and Rhizoma Acori Talarinowii (Shichangpu). The clinical efficacy and safety of these herbs, over centuries of use and during recent controlled studies, are a powerful combination of attributes. We believe that further high-quality clinical studies on these individual constituents, as well as the herbal mixtures resulted, could lead to the discovery of new drugs for effective treatment and prevention of VaD.


## 6. Conclusion

Currently available RCTs suggested that HM might be more effective and safer than OM for treatment of VaD. However, these studies have a number of weaknesses, mainly due to their methodological insufficiencies. With regard to the reports that did meet our selection criteria, the results indicated that HM, in a predominance of instances, can be superior to OM and useful in the treatment of VaD. Further multicenter trials with large sample sizes, high methodological quality, and standardized HM ingredients are needed to confirm the value of HM in treating VaD, in order to establish specific clinical recommendations.



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*Source: 426215-2011-10-20.xml*