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

1472-6882-1-5 1472-6882 Research article Systematic reviews of complementary therapies – an annotated bibliography. Part 2: Herbal medicine Linde Klaus Klaus.Linde@lrz.tu-muenchen.de ter Riet Gerben GterRiet@EPID.UNIMAAS.NL Hondras Maria mhondras@interaccess.com Vickers Andrew vickersa@mskcc.org Saller Reinhard reinhard.saller@dim.usz.ch Melchart Dieter Dieter.Melchart@lrz.tu-muenchen.de

Centre for Complementary Medicine Research, Department of Internal Medicine II, Technische Universität, München, Kaiserstr. 9, 80801 München, Germany

Institute for Social Medicine & Epidemiology, Charité Hospital, Humboldt University, Berlin, Germany

HS Centre for Reviews & Dissemination, University of York, UK

Department of Epidemiology, Maastricht University, The Netherlands

Consortial Center for Chiropractic Research, Davenport, Iowa, USA

Memorial Sloan-Kettering Cancer Center, New York, USA

Division of Complementary Medicine Department of Internal Medicine, Universitätsspital Zurich, Switzerland

BMC Complementary and Alternative Medicine 1472-6882 2001 1 1 5 http://www.biomedcentral.com/1472-6882/1/5 10.1186/1472-6882-1-5 11518548 22 3 2001 20 7 2001 20 7 2001 2001 Linde et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

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 34. 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 7891011121314151617181920212223242526272829303132333435363738394041424344454647484950515253545556575859606162636465666768697071. Eleven reports were not truly systematic reviews (not meeting inclusion criterion 2) 7273747576777879808182, 5 dealt with isolated substances of plant origin 8384858687 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 9091).

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 78910111213. 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 1314151617. 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

Features

Author Year

Indication

Intervention

Comparisons

Studies

1/2/3/

Results

Author's Conclusion

4/5

Ginkgo (Ginkgo biloba)

Pittler 2000

intermittent

ginkgo

placebo

8 RCT

y/y/y/

Increase of pain-free walking

Evidence for a modest benefit of

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

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,

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

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

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

Kleijnen 91

intermittent

ginkgo

ginkgo vs.

y/y/y/

Many trials low quality. All trials

Ginkgo seems effective for

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

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

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

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 2021222324252627282930 (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

Features

Author

Indication

Intervention

Comparisons

Studies

1/2/3/

Results

Author's Conclusion

Year

4/5

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

Linde 98 &

depression

hypericum

placebo and

27 RCT

y/y/y/

Treatment response: RR 2.47

Hypericum more effective than

96 2526

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

Volz 97

depression

hypericum

placebo and

p/p/n/

Most placebo-controlled trials

A therapy with hypericum of mild

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

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;

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

depressed

amitriptyline

y/n

of anxiety symptoms over

depressed patients with anxiety

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

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

p/p/y/

Most studies with shortcomings.

No clear conclusion drawn

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

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

atheroscler.

y/-

significantly different between

groups

legend see table 1

Eight reviews have been performed on garlic (Allium sativum) for cardiovascular risk factors 3132333435363738 (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 40414243. 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 4445, mistletoe (Viscum album) for cancer 464748, peppermint (Mentha piperita) oil for irritable bowel syndromes 4950 and saw palmetto (Serenoa repens) for benign prostate hyperplasia 515253 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)

Features

Author

Indication

Intervention

Comparisons

Studies

1/2/3/

Results

Author's Conclusion

Year

4/5

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

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

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

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

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 6465, 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

Features

Author

Indication

Intervention

Comparisons

Studies

1/2/3/

Results

Author's Conclusion

Year

4/5

Vogler 99

various

aloe

placebo, other

6 RCT,4

y/y/y/

Positive results for genital

Promising results, but overall

& 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

lowering

leave

n/n

subgroup of participants with

extract

serum cholesterol > 210 mg/dl

Morse 89

atopic

evening

placebo

?/n/n/

Epogam significantly better

No conclusion drawn

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

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

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

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

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

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

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

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

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

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 9495969798.

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.

Competing interest

KL, DM, GtR, and AV have been involved in some of the reviews analyzed. These were extracted and assessed by other members of the team.

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.

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