Systematic reviews of complementary therapies – an annotated bibliography. Part 2: Herbal medicine

  • Klaus Linde1, 2Email author,

    Affiliated with

    • Gerben ter Riet3, 4,

      Affiliated with

      • Maria Hondras5,

        Affiliated with

        • Andrew Vickers6,

          Affiliated with

          • Reinhard Saller7 and

            Affiliated with

            • Dieter Melchart1

              Affiliated with

              BMC Complementary and Alternative Medicine20011:5

              DOI: 10.1186/1472-6882-1-5

              Received: 22 March 2001

              Accepted: 20 July 2001

              Published: 20 July 2001

              Abstract

              Background

              Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with herbal medicine. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of herbal medicines; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pre-tested form and summarized descriptively.

              Results

              From a total of 79 potentially relevant reviews pre-selected in the screening process 58 met the inclusion criteria. Thirty of the reports reviewed ginkgo (for dementia, intermittent claudication, tinnitus, and macular degeneration), hypericum (for depression) or garlic preparations (for cardiovascular risk factors and lower limb atherosclerosis). The quality of primary studies was criticized in the majority of the reviews. Most reviews judged the available evidence as promising but definitive conclusions were rarely possible.

              Conclusions

              Systematic reviews are available on a broad range of herbal preparations prescribed for defined conditions. There is very little evidence on the effectiveness of herbalism as practised by specialist herbalists who combine herbs and use unconventional diagnosis.

              Introduction

              In this second part of our series on systematic reviews in complementary therapies we report our findings on herbal medicines. Herbal medicines (defined as preparations derived from plants and fungi, for example by alcoholic extraction or decoction, used to prevent and treat diseases) are an essential part of traditional medicine in almost any culture [1]. In industrialized countries herbal drugs and supplements are an important market. Some countries like Germany have a long tradition in the use of herbal preparations marketed as drugs and figures for prescriptions and sales are stable or slightly declining [2]. In the US and the UK herbal medicinal products are marketed as "food supplements" or "botanical medicines". In recent years sales of such products have been increasing strongly in these countries [3, 4]. In the Third World herbs are mainly used by traditional healers [5].

              Methods

              A detailed description of the methods used in this review of reviews is given in the first part of this series [6]. For searches in Medline 50 single plant names and the 'exploded' term 'medicinal plants' were combined with the standard search strategy for systematic reviews. As a specific intervention-related inclusion criterion we required that reports reviewed prospective (not necessarily controlled) clinical trials of substances extracted from plants in humans. Reviews dealing with single substances (e.g., artemisin derivatives) derived from plants were excluded on the grounds that such agents are comparable to conventional drugs. Disease-oriented reviews including a variety of interventions were included only if they reviewed at least 4 herbal medicine trials.

              Results

              From a total of 79 potentially relevant reviews preselected in the literature screening process, 58 (published in 65 papers) met the inclusion criteria [771]. Eleven reports were not truly systematic reviews (not meeting inclusion criterion 2) [7282], 5 dealt with isolated substances of plant origin [8387] and 4 were excluded for other reasons (one disease- focused review with less than 4 herbal medicine trials [88], one review not on preventative or therapeutic use [89], two reviews not truly herbal medicine [90, 91]).

              More than half of the reports reviewed gingko, hypericum or garlic preparations. No less than 13 systematic reviews dealed with ginkgo (Ginkgo biloba) extracts (see table 1). Seven of these reviewed trials (total number of trials covered in any of the reviews 15) in patients with intermittent claudication [713]. Most of these reviews concluded that ginkgo extracts were significantly more effective than placebo in increasing measures like walking distance but the clinical relevance of the effects was felt to be moderate by some reviewers. The five reviews dealing with dementia and cerebral insufficiency (total number of trials included about 50) all draw positive conclusions [1317]. However, many of the older trials were in patients with minor cognitive impairment and more evidence is needed to decide whether ginkgo extracts have clinically relevant beneficial effects in more severe forms of dementia. Finally, one review found that ginkgo extracts might be effective in the treatment of tinnitus [18] and another found insufficient evidence for efficacy in patients with macular degeneration [19].
              Table 1

              Systematic reviews of clinical trials of ginkgo biloba extracts

              Author Year

              Indication

              Intervention

              Comparisons

              Studies

              Features 1/2/3/4/5

              Results

              Author's Conclusion

              Ginkgo ( Ginkgo biloba )

              Pittler 2000

              intermittent

              ginkgo

              placebo

              8 RCT

              y/y/y/

              Increase of pain-free walking

              Evidence for a modest benefit of

              [7]

              claudication

                 

              y/y

              distance over placebo after 12

              uncertain clinical relevance

                    

              or 24 weeks 34 m (95%CI 26–

               
                    

              43 m)

               

              Moher 2000

              intermittent

              ginkgo*

              placebo

              5 RCT

              y/y/y/

              Increase of pain-free walking

              Inconsistent results from the few

              [8]

              claudication

                 

              n/y

              distance over placebo after 24

              available small studies do not

                    

              weeks 32 m (95%CI 14–50 m)

              allow firm conclusions

              Ernst 96 [9]

              intermittent

              ginkgo

              placebo,

              10

              p/ p/ n/

              Most studies low quality.

              Available evidence promising but

               

              claudication

              extract

              other drugs

              RCT/CCT

              n/n

              Increase of walking distance

              further high quality research

                

              EGb761

                 

              compared to placebo 24 to 160

              needed

                    

              m. At least similar

               
                    

              effectiveness compared to

               
                    

              other drugs.

               

              Schneider 92

              intermittent

              ginkgo

              placebo,

              7 RCT/CCT

              ?/n/n/

              mean effect size d = 0.75

              Effectiveness over placebo clearly

              [10]

              claudication

               

              other

              (vs. plac.), 2

              y/y

              (95%CI 0.44–1.07) over

              shown

                 

              treatment

              RCT/CCT

               

              placebo

               
                  

              (other)

                 

              Letzel 92

              intermittent

              ginkgo

              ginkgo vs.

              5 RCT

              ?/p/n/

              Pooled increase of walking

              Ginkgo extract EGb761 more

              [11]

              claudication

              extract

              plac.,

              ginkgo

              y/y

              distance: 45% over placebo for

              effective than placebo and

                

              EGb 761

              pentoxifyllin

              9 RCT

               

              gingko and 57% for

              similarly effective as pentoxifyllin

                 

              vs. plac.

              pentoxifyllin

               

              pentoxifyllin

               

              Kleijnen 91

              intermittent

              ginkgo

              ginkgo vs.

              15

              y/y/y/

              Many trials low quality. All trials

              Ginkgo seems effective for

              [12]

              claudication

               

              plac.,

              RCT/CCT

              n/n

              with positive results. Evidence

              intermittent claudication but further

                 

              pentoxifyllin

              (ginkgo), 5

               

              similar as for pentoxifyllin

              high quality studies are needed

                 

              vs. placebo

              RCT/CCT

                 
                  

              pentoxif.

                 

              Weiss 91

              cerebral ins.,

              ginkgo

              placebo

              17RCT/CCT

              ?/p/p/

              10 of 12 interpretable trials on

              Effectiveness for both conditions

              [13]

              intermittent

              extract

               

              (cerebral

              n/n

              cerebral insufficieny and all 4

              biometrically shown

               

              claudication

              EGb761

               

              ins.), 8

               

              interpretable trials on

               
                  

              RCT/CCT

               

              intermittent claudication with

               
                    

              significant positive results

               

              Ernst 99 [14]

              dementia

              ginkgo

              placebo

              9 RCT

              y/y/y/

              Results collectively suggest

              Encouraging findings warranting

                   

              y/n

              that ginkgo is more effective for

              large scale trials

                    

              dementia than placebo

               

              Oken 98 [15]

              Alzheimer

              ginkgo

              placebo

              4 RCT

              y/y/n/

              Significant effect over placebo

              Clinical relevance of the observed

               

              dementia

                 

              y/y

              for cognitive function (Hedges

              effects has to be confirmed in

                    

              g= 0.41, 95%CI 0.22–0.61)

              further research

              Hopfenmüller

              cerebral

              ginkgo

              placebo

              10 RCT, 1

              n/ n/ n/

              Global response (based on

              Ginkgo extract superior to placebo

              94 [16]

              insufficiency

              extract LI

               

              CCT

              y/y

              symptom scores): OR 1.98

               
                

              1370

                 

              (95%C11.39–2.57) in favour of

               
                    

              Ginkgo

               

              Kleijnen 92

              cerebral

              ginkgo

              ginkgo vs.

              40 RCT/

              y/y/y/

              Many trials low quality. Virtually

              Ginkgo seems effective for

              [17]

              insufficiency

               

              plac.

              CCT

              n/n

              all trials reported positive

              cerebral insufficiency but further

                 

              hydergine

              (ginkgo), 4

               

              results. Evidence similar as for

              high quality studies are needed

                 

              vs. plac.

              RCT/CCT

               

              hydergine

               
                  

              (hydergine)

                 

              Ernst 99 [18]

              tinnitus

              ginkgo

              placebo,

              5 RCT

              y/y/y/

              3 trials favour ginkgo over

              Results suggest that extracts of

                 

              other

               

              y/n

              placebo, 1 no difference, in one

              ginkgo biloba are effective in

                 

              treatment (1

                

              trial ginkgo better than another

              treating tinnitus

                 

              trial)

                

              treatment

               

              Evans 2000

              macular

              ginkgo

              placebo

              1 RCT

              y/y/y/

              one small trial reporting

              Insufficient evidence to

              [19]

              degeneration

                 

              y/-

              improvement

              recommend ginkgo for age-related

                     

              macular degeneration

              Features: 1 = comprehensive search, 2 = explicit inclusion criteria, 3 = formal quality assessment, 4 = summary of results for each included study, 5 = meta-analysis; y = yes, p = partly, n = no, - = not applicable, ? = unclear review on all pharmacologic treatments for the respective condition RCT = randomized controlled trials, CCT = non-randomized controlled trials, CS = cohort studies, UCS = uncontrolled studies; OR = odds ratio, RR = rate ratio

              The effectiveness of St. John's wort (Hypericum perforatum) extracts in depression was investigated in nine reviews [2030] (total number of trials covered 29; see table 2). Mainly due to slight differences in the inclusion criteria (for example, restriction to trials with a minimum of 6 weeks observation or with a minimum quality score) the respective study collections differed to a considerable amount. However, the conclusions were very similar. Hypericum extracts have been shown to be superior to placebo in mild to moderate depressive disorders. There is growing evidence that hypericum is as effective as other antidepressants for mild to moderate depression and causes fewer side effects but further trials are still needed to establish long-term effectiveness and safety.
              Table 2

              Systematic reviews of clinical trials of hypericum and garlic preparations

              Author Year

              Indication

              Intervention

              Comparisons

              Studies

              Features 1/2/3/4/5

              Results

              Author's Conclusion

              St John's wort ( Hypericum perforatum )

              Gaster

              depression

              hypericum

              placebo and

              8 RCT

              p/y/p/

              4 placebo-controlled trials with

              Data suggest that hypericum is

              2000 [20]

                

              antidepressants

               

              y/n

              positive results, in 4 trials

              superior to placebo, insuffcient

                    

              standard antidepr. tended to be

              evidence re equivalence with

                    

              slightly better

              antidepressants

              Williams

              depression

              hypericum

              placebo and

              14 RCT

              y/y/n/

              Treatment response: RR 1.9

              Data suggest that hypericum is

              2000 &

               

              (and other

              antidepressants

               

              y/y

              (95%C11.2–2.8) vs. placebo and

              superior to placebo, insuffcient

              Mulrow 98

               

              drugs)

                 

              1.2 (1.0–1.4) vs. antidepressants

              evidence re equivalence with

              [21, 22]

                    

              antidepressants

              Kim 99 [23]

              depression

              hypericum

              placebo and

              6 RCT

              p/y/y/

              Treatment response: RR 1.48

              Hypericum more effective than

                 

              antidepressants

               

              y/y

              (95%C11.03–1.92) vs. placebo

              placebo and similarly effective as

                    

              and 0.98 (0.67–1.28) vs.

              low dose antidepressants; quality

                    

              antidepressants

              problems

              Stevinson

              depression

              hypericum

              placebo and

              6 RCT

              y/y/y/

              Only trials published after Linde

              Data confirm findings of earlier

              99 [24]

                

              antidepressants

               

              y/n

              96; trials show effects better

              trials, but still insuff. evidence to

                    

              than placebo/similar to

              assess equivalence with

                    

              antidepressants

              antidepressants

              Linde 98 &

              depression

              hypericum

              placebo and

              27 RCT

              y/y/y/

              Treatment response: RR 2.47

              Hypericum more effective than

              96 [25, 26]

                

              antidepressants

               

              y/y

              (95%C11.69–3.61) vs. placebo

              placebo. Inadequate evidence to

                    

              and 1.01 (0.87–1.16) vs.

              assess equivalence with

                    

              antidepressants

              antidepressants

              Volz 97

              depression

              hypericum

              placebo and

              15

              p/p/n/

              Most placebo-controlled trials

              A therapy with hypericum of mild

              [27]

                

              antidepressants

              RCT/CCT

              n/n

              positive; similarly effective as

              and moderate depression can be

                    

              (not adequately dosed)

              attempted. Further studies needed

                    

              antidepressants

               

              Ernst 95

              depression

              hypericum

              placebo and

              11 RCT

              y/y/y/

              Most of 8 placebo-controlled

              Hypericum is superior to placebo

              [28]

                

              antidepressants

               

              y/n

              trials positive. 3 trials against

              and seems equally effective as

                    

              standard medication with similar

              standard medication

                    

              effects

               

              Volz 2000

              mild to

              hypericum

              fluoxetine

              17+9

              n/y/n/

              No direct comparison of

              Response rates are similar;

              [29]

              mod.

                

              CCT

              y/n

              hypericum and fluoxetine

              findings difficult to interpret

               

              depression

                  

              available. Mean depression

              because of the indirect comparison

                    

              score (HAMD) reduction in

               
                    

              hypericum trials 53%, in

               
                    

              fluoxetine trials 55%

               

              Friede 98

              anxiety in

              hypericum

              placebo,

              8 RCT

              ?/y/y/

              Trials collectively show reduction

              Hypericum is effective for

              [30]

              depressed

               

              amitriptyline

               

              y/n

              of anxiety symptoms over

              depressed patients with anxiety

               

              p.

                  

              placebo. Only 1 trial vs

               
                    

              amitriptyline

               

              Garlic ( Allium sativum )

              Lawrence

              cardiovasc.

              garlic

              mainly placebo;

              45 RCT

              y/y/y/

              37 trials consistently show small

              Insufficient data to draw conclusion

              2000 [31]

              risk factors

               

              no & other

               

              y/y

              short-term effects over placebo

              regarding clinical cardiovascular

                 

              treatment

                

              for cholesterol reduction. No

              outcomes. Garlic preparations may

                    

              consistent effects on blood

              have small, positive, short-term

                    

              pressure, promising effects re

              effects on lipids

                    

              platelet aggregation and

               
                    

              fibrionolytic activity

               

              Stevinson

              hyperchol-

              garlic

              placebo

              13 RCT

              y/y/y/

              Pooled total cholesterol

              Available data suggest that garlic is

              2000 [32]

              esterolemia

                 

              y/y

              reduction over placebo 0.41

              superior to placebo. The size of the

                    

              (95% Cl -0.66 to -0.15) mmol/l;

              effect is modest. The use of garlic

                    

              when analysis restricted to high

              for hyperchol. is therefore of

                    

              quality trials 0.11 (-0.30 to 0.08)

              questionable value

              Silagy 94 &

              cholesterol

              garlic

              placebo

              16 RCT

              y/p/y/

              Pooled cholesterol reduction

              Meta-analysis suggests positive

              Neil 96

              lowering

                 

              y/y

              over placebo 0.65 (95% Cl 0.53–

              effects but reviewers are sceptic

              [33, 34]

                   

              0.76) mmol/l

              (low quality; own replication

                     

              negative)

              Warshafsky

              cholesterol

              garlic

              placebo

              5 RCT

              p/y/y/

              Pooled cholesterol reduction

              Available evidence supports the

              93 [35]

              lowering

                 

              y/y

              over placebo 0.59 (95%Cl 0.44–

              use of garlic as one modality to

                    

              0.74) mmol/l

              decrease cholesterol levels

              Silagy 94

              lowering

              dried garlic

              placebo, other

              8 RCT

              y/p/y/

              Pooled reduction over placebo:

              Garlic maybe of some clinical use

              [36]

              blood

              (Kwai)

              treatment

               

              y/y

              SBP 7.7 (95% Cl 4.3–11.0), DBP

              in subjects with mild hypertension.

               

              press.

                  

              5.0 (2.9–7.1) mm Hg

              Further research needed

              Kleijnen 91

              cardiovasc.

              garlic

              placebo

              18

              p/p/y/

              Most studies with shortcomings.

              No clear conclusion drawn

              [37]

              risk factors

              supplements

               

              RCT/CCT

              y/n

              The majority of trials with pos.

               
                    

              results but inconsistent effect

               
                    

              sizes

               

              Kleijnen 89

              cardiovasc.

              garlic &

              unclear

              10 RCT,

              y/p/n/

              All trials with severe

              Inadequate evidence to justify

              [38]

              risk factors

              onions

               

              8 CCT

              y/n

              shortcomings. Fresh garlic with

              supplementation, further research

                    

              beneficial effcts, onions and

              needed

                    

              commercially available

               
                    

              supplements yielded

               
                    

              contradictory results

               

              Jepson 97

              lower limb

              garlic

              placebo

              1 RCT

              y/y/y/

              Walking distance not

              Insufficient evidence

              [39]

              atheroscler.

                 

              y/-

              significantly different between

               
                    

              groups

               

              legend see table 1

              Eight reviews have been performed on garlic (Allium sativum) for cardiovascular risk factors [3138] (total number of trials covered about 50) and lower limb atherosclerosis [39] (see table 2). A modest short-term effect over placebo on lipid-lowering seems to be established but the clinical relevance of these effects is uncertain. Data from randomised trials on cardiovascular mortality are not available. Effects on blood pressure seem to be at best minor. The available results on fibrinolytic activity and platelet aggregation are promising but insufficient to draw clear conclusions. A specific problem in research on garlic is the great variety of garlic preparations used: the exact content of bioactive ingredients in these is often unclear.

              Three reviews (covering a total of about 30 trials) have been performed on preparations containing extracts of Echinacea (Echinacea purpurea, pallida or angustifolia), two of which by the same study group [4043]. The results suggest that Echinacea preparations may have some beneficial effects mainly in the early treatment of common colds. Similar to garlic a major problem is the high variaton of bioactive compounds between different Echinacea preparations. Cranberries (Vaccinium macrocarpon) for urinary tract infections [44, 45], mistletoe (Viscum album) for cancer [4648], peppermint (Mentha piperita) oil for irritable bowel syndromes [49, 50] and saw palmetto (Serenoa repens) for benign prostate hyperplasia [5153] have each been subject to two reviews. For saw palmetto there is good evidence for efficacy over placebo while for the other three the data are inconclusive (see table 3).
              Table 3

              Systematic reviews of clinical trials of herbal medicines (at least 2 reviews per herb)

              Author Year

              Indication

              Intervention

              Comparisons

              Studies

              Features 1/2/3/4/5

              Results

              Author's Conclusion

              Echinacea ( Echinacea purpurea, angustifolia and pallida )

              Barrett

              upper resp.

              echinacea

              placebo

              13RCT

              y/p/y/

              Overall quality modest. All 4

              Echinacea may be beneficial for

              99 [40]

              infections

              (incl.

                

              y/n

              prevention studies show only

              early treatment of acute upper

                

              combinations)

                 

              minor trends, 8 of 9 treatment

              respiratory infections; little evidence

                    

              studies with generally positive

              to support the prolonged use for

                    

              results

              prevention

              Melchart

              common

              echinacea

              placebo, no

              16 RCT

              y/y/y/

              Minor effects in prevention and

              Echinacea extract can be efficacious

              99 [41]

              cold

              (incl.

              treatment

               

              y/p

              treatment, promising effects in

              for the common cold, but evidence

                

              combinations)

                 

              early treatment. Heterogen.

              insufficient for recommendations

                    

              preparations

               

              Melchart

              immuno-

              echinacea

              placebo, no

              18 RCT, 8

              y/y/y/

              Most studies low quality. Most

              Echinacea extracts can be

              94

              stimulation

              (incl.

              treatment

              CCT

              y/n

              studies show immunostimulating

              efficacious immunostimulators, but

              [42, 43]

               

              combinations)

                 

              effects

              evidence insufficient for

                     

              recommendations

              Cranberries ( Vaccinium macrocarpon )

              Jepson

              urinary

              cranberries

              placebo

              4 RCT

              y/y/y/

              In 3 of 4 trials cranberries effective

              Insufficient evidence, further research

              98 [44]

              tract inf.

                 

              y/n

              for at least one of the outcomes of

              needed

               

              (prevent)

                  

              interest

               

              Jepson

              urinary

              cranberries

               

              O RCT

              y/y/-/

              No trials meeting the inclusion

              No evidence available

              98 [45]

              tract inf.

                 

              -/-

              criteria

               
               

              (treatm.)

                    

              Mistletoe ( Viscum album )

              Kleijnen

              cancer

              mistletoe

              placebo, no

              11

              y/y/y/

              Most studies low quality. Most

              Insufficient evidence to recommend

              94 [46]

                

              treatment

              RCT/CCT

              n/n

              studies show longer survival with

              mistletoe outside of clinical trials

                    

              mistletoe but not the best trial

               

              Kiene 89

              cancer

              mistletoe

              no treatment,

              2 RCT, 33

              y/n/n/

              Most studies low quality. 9 of 12

              Available evidence supports positive

              [47, 48]

                

              none

              CCT, 11

              y/n

              interpretable studies suggest

              effects of mistletoe

                  

              other

               

              positive effects on survival

               
                  

              studies

                 

              Peppermint ( Mentha piperita )

              Jailwala

              irritable

              1. peppermint

              placebo

              1. 3 RCT

              p/y/y/

              Chinese herbal therapy trial rated

              In both cases efficacy not clearly

              2000*

              bowel

              oil

               

              2. 1 RCT

              n/n

              as positive, one of three

              established

              [49]

              syndr.

              2. Chinese

                 

              peppermint oil trials rated as

               
                

              herbal

                 

              positive

               
                

              therapy

                   

              Pittler 98

              irritable

              peppermint

              placebo,

              8 RCT

              y/y/y/

              Global improvement rates

              The role of peppermint oil for IBS

              [50]

              bowel

              oil

              other

               

              y/y

              significantly higher compared to

              has not been established beyond

               

              syndr.

               

              treatment

                

              placebo. Quality of trials doubtful

              reasonable doubt

              Saw palmetto ( Serenoa repens )

              Boyle

              ben.

              Permixon®

              placebo,

              11 RCTs,

              ?/n/n/

              peak urine flow 2.20 (95% Cl 1.20–

              Despite some limitations strong

              2000 [51]

              prostate

              (saw

              other

              2 UCS

              y/y

              3.20) ml/s increase over placebo;

              evidence that the extract tested has

               

              hyperplasia

              palmetto)

              treatment

                

              significant decrease nocturia

              beneficial effects

              Wilt 2000

              ben.

              saw palmetto

              placebo,

              14 RCT

              y/y/y/

              Saw palmetto superior to placebo

              Evidence suggests that saw

              &98

              prostate

               

              other

              (plac),

              y/y

              for nocturia, self rating, peak urine

              palmetto improves urological

              [52, 53]

              hyperplasia

               

              treatment

              5 RCT

               

              flow; similar effects as finasteride

              symptoms and flow measures.

                  

              (other)

                

              Further studies needed

              legend see table 1

              Single systematic reviews have been published on aloe (Aloe vera) [54], artichoke (Cynara scolymus) leave extract [55], evening primrose (Oenothera biennis) oil [56], feverfew (Tanacetum parthenium) [57], ginger (Zingiber officinialis) [58], ginseng (Panax ginseng) [59], horse chestnut (Aesculus hippocastanum) seeds [60], kava (Piper methysticum) [61], milk thistle (Silybum marianum) [62], a fixed combination of three herbal extracts [63], rye-grass pollen (Secale cereale) extract [64, 65], tea tree (Melaleuca alternafolia) oil [66], and valerian (Valehana officinalis) root [67] (see table 4). The only review which focused on a herbal intervention which is not marketed as a drug or food supplement was on cabbage leaves for breast engorgement and included a single small-scale trial [68]. Chinese herbal therapy for atopic eczema [69] and a variety of herbs for lowering blood glucose [70] and for analgesic and anti-inflammatory purposes [71] have also been reviewed. For some of these herbal preparations the evidence is promising but further studies are considered necessary to establish efficacy in almost every case.
              Table 4

              Systematic reviews of clinical trials of herbal medicines

              Author Year

              Indication

              Intervention

              Comparisons

              Studies

              Features 1/2/3/4/5

              Results

              Author's Conclusion

              Vogler 99

              various

              aloe

              placebo, other

              6 RCT,4

              y/y/y/

              Positive results for genital

              Promising results, but overall

              [54]

                

              & no treatment

              CCT

              y/n

              herpes, psoriasis, hyper-

              evidence insufficient

                    

              lipidemia, diabetes;

               
                    

              contradictory for wound healing

               

              Pittler 98

              cholesterol

              artichoke

              placebo

              1 RCT

              y/y/y/

              Effects over placebo only in the

              More trials needed

              [55]

              lowering

              leave

                

              n/n

              subgroup of participants with

               
                

              extract

                 

              serum cholesterol > 210 mg/dl

               

              Morse 89

              atopic

              evening

              placebo

              9

              ?/n/n/

              Epogam significantly better

              No conclusion drawn

              [56]

              eczema

              primrose oil

               

              RCT/CCT

              y/y

              than placebo for most

               
                

              (Epogam)

                 

              outcomes

               

              Vogler 98

              migraine

              feverfew

              placebo

              5 RCT

              y/y/y/

              Majority of trials favor feverfew

              Effectiveness has not been

              [57]

                  

              y/n

              over placebo

              established beyond reasonable

                     

              doubt

              Ernst 2000

              nausea and

              ginger root

              placebo,

              6 RCT

              y/y/y/

              2 of 3 trials on postoperative

              Evidence promising but insufficient

              [58]

              vomiting

               

              metoclopramide

               

              y/p

              nausea positive (best

              to draw firm conclusions

                    

              negative), trials on

               
                    

              seasickness, morning sickness

               
                    

              and chemotherapy-induced

               
                    

              nausea positive

               

              Vogler 99

              various

              ginseng root

              placebo, other

              16 RCT

              y/p/y/

              Contradictory results re.

              The efficacy of ginseng root extract

              [59]

               

              extract

              treatment (1

               

              y/n

              physical performance (7 trials),

              is not established beyond

                 

              trial)

                

              psychological function (5),

              reasonable doubt for any of these

                    

              immunomodulation (2),

              indications

                    

              positive results in diabetes and

               
                    

              herpes simplex (1 trial

               
                    

              respectively)

               

              Pittler 98

              venous

              horse

              placebo, other

              13 RCT

              y/y/y/

              Significant effects over placebo

              horse chestnut seeds seem to be

              [60]

              insufficieny

              chestnut

              treatment

               

              y/n

              and similar effects compared to

              effective; further tials needed

                

              seeds

                 

              other treatments

              (confirmation, long-term results,

                     

              combination)

              Pittler 2000

              anxiety

              kava

              placebo

              7 RCT

              y/y/y/

              All trials suggest superiority

              Available data suggest that kava is

              [61]

                  

              p/p

              over placebo; 3 trials with data

              a treatment option for anxiety.

                    

              for meta-analysis show sign.

              Further studies needed

                    

              superiority

               

              Lawrence

              liver

              milk thistle

              placebo, other

              33 RCT,

              y/y/y/

              Variety of conditions studied,

              Efficacy is not established.

              2000 [62]

              diseases

               

              & no treatment

              1 CCT

              y/y

              studies often poor quality.

              Possible benefit shown most

                    

              Mixed and inconsistent findings

              frequently for aminotransferases.

              Ernst 99

              musculoskel.

              Phytodolor®

              placebo, other

              10 RCT

              y/p/y/

              Placebo-controlled trials show

              The data suggest that the

              [63]

              pain

              populus,

              treatments

               

              y/n

              superiority over placebo and

              combination is effective in the

                

              fraxinus,

                 

              similar effects as NSAIDs

              symptomatic treatment of

                

              solidago

                  

              muskuloskeletal pain

              MacDonald

              ben. prostata

              rye grass

              placebo, other

              4 RCT

              y/y/y/

              Signif. improvement over

              Available evidence suggests that

              2000 &

              hyperplasia

              pollen

              therapy

               

              y/y

              placebo in subjective, but not

              Cernilton® is well tolerated and

              Wilt 2000

               

              extract

                 

              objective symptoms; no

              modestly improves subjective

              [64, 65]

                   

              differences compared to

              symptoms. Further studies needed

                    

              tadenan and paraprost

               

              Ernst 2000

              dermatologic

              tea trea oil

              placebo, other

              4 RCT

              y/y/y/

              2 trials vs. placebo positive, 3

              Data promising but insufficient

              [66]

              conditions

               

              treatment

               

              y/n

              trials vs. other treatments

               
                    

              similar effects

               

              Stevinson

              insomnia

              valerian root

              placebo

              9 RCT

              y/y/y/

              Highly heterogeneous studies

              Available evidence is promising but

              2000 [67]

                  

              y/n

              with sometimes contradictory

              not fully conclusive. Further,

                    

              and inconsistent findings

              rigorous trials needed

              Renfrew

              breast

              cabbage

              usual care

              1 RCT

              y/y/n/

              fewer women stopping breast

              Further research desirable

              84 [68]

              engorgement

              leaves

                

              y/n

              feeding among those receiving

               
                    

              cabbage leaves

               

              Armstrong

              atopic

              Chinese

              placebo

              2 RCT

              y/y/n/

              2 positive studies by the same

              Evidence encouraging but

              99 [69]

              eczema

              herbal

                

              y/n

               

              insufficient given the potential of

                

              therapy

                 

              treat analysis

              relevant side effects

              Ernst 97

              hypoglyc.

              all plants

              no treatment,

              7 RCT, 4

              y/p/n/

              Most studies low quality. Most

              Use of hypoglcemic plant remedies

              [70]

              activity

               

              placebo, none

              CCT, 10

              y/n

              papers report positive effects

              not supported by rigorous

                  

              UCS

               

              on a variety of plants

              research. Further studies required

              Ernst 2000

              analgetic or

              various

              placebo

              18 RCT

              y/y/y/

              Trials on evening primrose oil,

              The results suggest that several

              [71]

              inflamm.

                 

              y/n

              blackcurrant seed oil, borage

              herbal remedies have potential in

               

              treatment

                  

              oil, harpagophytum, willow

              alleviating the pain of rheumatic

                    

              bark, feverfew, and 3

              diseases. More research urgently

                    

              combinations; almost all trials

              needed

                    

              positive

               

              legend see table 1

              Discussion

              Our overview shows that a considerable number of systematic reviews on herbal medicines is available. In the majority of cases the reviewers considered the available evidence as promising but only very rarely as convincing and sufficient as a firm basis for clinical decisions. The methodological quality of the primary studies has been criticized by many reviewers.

              Our summary of the existing studies must be interpreted with caution. What we performed is a systematic review of systematic reviews which inherently bears a large risk of oversimplification. Readers who want to reliably assess the evidence for a given herb for a defined condition should read the respective reviews. Our collection – which to the best of our knowledge is complete up to summer 2000 – is aimed at facilitating the access and giving an idea of the amount of the available evidence. Based on the increase of herbal medicine reviews in recent years we expect that at least ten new publications will become available in the year 2001.

              Most of the currently available systematic reviews address herbal preparations which are marketed and widely used in industrialized countries. However, the widespread traditional use of herbs in the Third World is rarely ever investigated and has not been subjected to systematic reviews. The many herbs used in folk medicine or other traditional uses of herbs (for example, hypericum is used for a variety of ailments other than depression including enuresis, diarrhoea, gastritis, bronchitis, asthma, sleeping disorders etc.) seem to be rarely investigated. Furthermore, practitioners of herbal medicine often combine different herbs and use unconventional diagnostic approaches to adapt prescriptions to single patients. It seems likely that these traditional forms of herbal medicine will remain underresearched relative to single herbal preparations due to the lack of financial incentive for sponsors and due to methodological problems.

              Herbal medicines products are not, in general, subject to patent protection. This reduces the motivation for drug companies to invest in trials. Many of the existing herbal medicine manufacturers are comparably small companies, often with limited research resources and expertise. Maybe partly for these reasons, the quality of many older herbal medicine trials is low. Furthermore, negative trials which could threaten the company's survival might not become published.

              A fundamental problem in all clinical research of herbal medicines is whether different products, extracts, or even different lots of the same extract are comparable and equivalent. This is a major issue in the expert research community and a major obstacle to a reliable assessment for the non-expert. For example, Echinacea products can contain other plant extracts, use different plant species (E. purpurea, pallida or angustifolia), different parts (herb, root, both), and might have been produced in quite different manners (hydro- or lipophilic extraction). Pooling studies that use different herbal products in a quantitative meta- analysis can be misleading. Health care professionals and patients considering to prescribe or take a particluar herbal product should check carefully whether the respective product or extract has been tested in the trials included in a review. On the health food store shelf the high quality, standardized products used in the trials might not be available. Only a herbal medicine expert can judge with some certainty whether the results can be extrapolated to the product of interest.

              On the level of health care policies the available systematic reviews more often provide insight into the deficiencies of the evidence than guidance for decision making. Trials on hard endpoints are very rarely available and observation periods have generally been short. The clinical relevance of the observed effects is not always clear.

              Herbal medicines are generally considered as comparably safe. While this is probably correct case reports show that severe side effects and relevant interactions with other drugs can occur. For example, hypericum extracts cause considerably fewer side effects than tricyclic antidepressants [92] but can decrease the concentration of a variety of other drugs by enzyme induction [93]. Several reviews summarizing side effects and interactions have been published [9498].

              In conclusion, the systematic reviews collected for this analysis are a good tool to get an overview of the available evidence from clinical trials in the area of herbal medicine. However, applying the findings to patients care is problematic for those who are not experts in herbal medicine. In this case it might be better to directly search the literature for clinical trials of the respective product.

              Declarations

              Acknowledgements

              KL's work was partly funded by the NIAMS grant 5 U24-AR-43346-02 and by the Carl and Veronica Carstens Foundation, Essen, Germany. We would like to thank Brian Berman for his support, his help to get funding and his patience in awaiting the completion of our work.

              Authors’ Affiliations

              (1)
              Centre for Complementary Medicine Research, Department of Internal Medicine II, Technische Universität, München
              (2)
              Institute for Social Medicine & Epidemiology, Charité Hospital Humboldt University
              (3)
              HS Centre for Reviews & Dissemination, University of York
              (4)
              Department of Epidemiology, Maastricht University
              (5)
              Consortial Center for Chiropractic Research, Davenport
              (6)
              Memorial Sloan-Kettering Cancer Center
              (7)
              Division of Complementary Medicine Department of Internal Medicine, Universitätsspital Zurich

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