Systematic reviews of complementary therapies – an annotated bibliography. Part 2: Herbal medicine
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 [7-71]. Eleven reports were not truly systematic reviews (not meeting inclusion criterion 2) [72-82], 5 dealt with isolated substances of plant origin [83-87] 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 [7-13]. 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 [13-17]. 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].
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 |
[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 |
The effectiveness of St. John's wort (Hypericum perforatum) extracts in depression was investigated in nine reviews [20-30] (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.
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 | 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 [31-38] (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 [40-43]. 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 [46-48], peppermint (Mentha piperita) oil for irritable bowel syndromes [49,50] and saw palmetto (Serenoa repens) for benign prostate hyperplasia [51-53] 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).
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 |
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.
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 |
[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 [94-98].
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.
Pre-publication history
The pre-publication history for this paper can be accessed here:
Acknowledgments
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.
References
- 1. ABC of complementary medicine: herbal medicineBMJ199931910501053[PubMed][Google Scholar]
- 2. Arzneimittel der besonderen Therapierichtungen (Naturheilmittel)In Arzneiverordnungs-Report 1998 Edited by Schwabe U, Paffrath D Berlin: Springer,1999621656[Google Scholar]
- 3. The booming US botanical market. A new overviewHerbalGram1998443351[Google Scholar]
- 4. Phytotherapy: consumer and pharmacist perspectivesHerbal medicine – a concise overview for professionals. Edited by Ernst E. Oxford: Butterworth Heinemann,20001933[Google Scholar]
- 5. EditorialJ Altem Complement Med19963323326[Google Scholar]
- 6. Systematic reviews of complementary therapies – an annotated bibliography. Part 1: acupunctureBMC Complementary and Alternative Medicine200113[PubMed][Google Scholar]
- 7. Ginkgo biloba extract for the treatment of intermittent claudication: a meta- analysis of randomized trialsAm J Med2000108276281[PubMed][Google Scholar]
- 8. Pharmacological management of intermittent claudication: a meta-analysis of randomised trialsDrugs20005910571070[PubMed][Google Scholar]
- 9. Ginkgo biloba in der Behandlung der Claudicatio intermittensFortschr Med19961148587[PubMed][Google Scholar]
- 10. Ginkgo-biloba-Extrakt bei peripheren arteriellen Verschlusskrankheiten. Meta Analyse von kontrollierten klinischen StudienArzneim-Forsch/Drug Res199242(1)428436[PubMed][Google Scholar]
- 11. Gingko-biloba-Extrakt EGb 761 und Pentoxifyllin bei Claudicatio intermittens. Sekundäranalyse zur klinischen WirksamkeitVASA199221403410[PubMed][Google Scholar]
- 12. Gingko biloba for intermittent claudication and cerebral insufficiencyKleijnen J. Food supplements and their efficacy. Maastricht: Rijksuniversiteit Limburg,19918394[Google Scholar]
- 13. Gingko-biloba-Extrakt (EGb 761) – Meta-Analyse von Studien zum Nachweis der therapeutischen Wirksamkeit bei Hirnleistungsstorungen bzw. peripherer arterieller VerschlusskrankheitMuench med Wschr199110138142[Google Scholar]
- 14. Ginkgo biloba for dementia: a systematic review of double-blind, placebo- controlled trialsClin Drug Invest199917301308[Google Scholar]
- 15. The efficacy of ginkgo biloba on cognitive function in Alzheimer diseaseArch Neurol19985514091415[PubMed][Google Scholar]
- 16. Nachweis der therapeutischen Wirksamkeit eines Ginkgo biloba-Spezialextraktes – Meta-Analyse von 11 klinischen Studien mit Patienten mit Hirnleistungsstörungen im AlterArzneim-Forsch /Drug Res199444(ll)10051013[PubMed][Google Scholar]
- 17. Gingko biloba for cerebral insufficiencyBr J din Pharmacol199234352358[Google Scholar]
- 18. Ginkgo biloba for tinnitus: a reviewClin Otolaryngol199924164167[PubMed][Google Scholar]
- 19. Ginkgo biloba extract for age-related macular degeneration (Cochrane Review)The Cochrane Library, Issue 1, 2000. Oxford: Update Software.[Google Scholar]
- 20. St John's wort for depression. A systematic reviewArch Intern Med2000160152156[PubMed][Google Scholar]
- 21. A systematic review of newer pharmacotherapies for depression in adults: Evidence report summaryAnn Int Med2000132743756[PubMed][Google Scholar]
- 22. Treatment of depression – newer pharmacotherapiesPsychopharmacol Bull199834409795[PubMed][Google Scholar]
- 23. St. John's wort for depression: A meta-analysis of well-defined clinical trialsJ Nerv Ment Dis1999187532539[PubMed][Google Scholar]
- 24. Hypericum for depression. An update of the clinical evidenceNeuropsychopharmacol19999501505[PubMed][Google Scholar]
- 25. St John's wort for depression (Cochrane Review)The Cochrane Library, Issue 4, 1998. Oxford: Update Software.[Google Scholar]
- 26. St John's wort for depression – an overview and meta-analysis of randomised clinical trialsBMJ1996313253258[PubMed][Google Scholar]
- 27. Controlled clinical trials of hypericum extract in depressed patients – an overviewPharmacopsychiat1997 30 (suppl)7275[Google Scholar]
- 28. St. John's Wort, an anti-depressant? A systematic, criteria-based reviewPhytomedicine199526771[Google Scholar]
- 29. Potential treatment for subthreshold and mild depression: A comparison of St. John's wort extracts and fluoxetineComprehensive Psychiatry2000 41 (suppl 1)133137[PubMed][Google Scholar]
- 30. Johanniskraut zur Therapie von Angstsyndromen bei depressiven VerstimmungenZtschr Phytother199819309317[Google Scholar]
- 31. Garlic: Effects on cardiovascular risks and disease, protective effects against cancer, and clinical adverse effectsEvidence Report/Technology Assessment: Number 202000[Google Scholar]
- 32. Garlic for treating hypercholesterinemia – a meta-analysis of randomized clinical trialsAnn Intern Med2000133420429[Google Scholar]
- 33. Garlic as a lipid lowering agent – a meta-analysisJ Roy Coll Phys1994283945[Google Scholar]
- 34. Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysisJ Roy Coll Pract London199630329334[Google Scholar]
- 35. Effect of garlic on total serum cholesterolAnn Int Med1993119599605[PubMed][Google Scholar]
- 36. A meta-analysis of the effect of garlic on blood pressureJ Hypertension199412463468[Google Scholar]
- 37. Controlled clinical trials in humans on the effects of garlic supplementsKleijnen J. Food supplements and their efficacy. Maastricht: Rijksuniversiteit Limburg,19917382[Google Scholar]
- 38. Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparationsBr J Clin Pharmacol198928535544[PubMed][Google Scholar]
- 39. Garlic for lower limb atherosclerosis (Cochrane Review)The Cochrane Library, Issue 4, 1998. Oxford: Update Software.[Google Scholar]
- 40. Echinacea for upper respiratory tract infectionJ Fam Pract199948628635[PubMed][Google Scholar]
- 41. Echinacea for prevention and treatment of the common cold (Cochrane Review)The Cochrane Library, Issue 1, 1999. Oxford: Update Software.[Google Scholar]
- 42. Immunmodulation mit Echinacea-haltigen Arzneimittein – eine kriteriengestützte Analyse der kontrollierten klinischen StudienForsch Komplementärmed199412636[Google Scholar]
- 43. Immunomodulation with Echinacea – a systematic review of controlled clinical trialsPhytomedicine19941245254[Google Scholar]
- 44. Cranberries for the prevention of urinary tract infections (Cochrane Review)In The Cochrane Library, Issue 4, 1998 Oxford: Update Software[Google Scholar]
- 45. Cranberries for the treatment of urinary tract infections (Cochrane Review)In The Cochrane Library, Issue 4, 1998 Oxford: Update Software[Google Scholar]
- 46. Mistletoe treatment for cancer. Review of controlled trials in humansPhytomedicine19941255260[Google Scholar]
- 47. Klinische Studien zur Misteltherapie karzinomatöser ErkrankungenTherapeutikon19896347353[Google Scholar]
- 48. Klinische Studien zur Misteltherapie der Krebserkrankung. Eine kritische WürdigungHerdecke: Dissertation,1989[Google Scholar]
- 49. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trialsAnn Intern Med2000133136147[PubMed][Google Scholar]
- 50. Peppermint oil for irritable bowel syndrome: a critical review and meta- analysisAm J Gastroenterol19989311311135[PubMed][Google Scholar]
- 51. Meta-analysis of clinical trials of Permixon in the treatment of symptomatic benign prostatic hyperplasiaUrology200055533539[PubMed][Google Scholar]
- 52. Serenoa repens for treatment of benign prostatic hyperplasia (Cochrane Review)The Cochrane Library, Issue 1, 2000. Oxford: Update Software.[Google Scholar]
- 53. Saw palmetto extracts for treatment of benign prostatic hyperplasia – a systematic reviewJAMA199828016041609[PubMed][Google Scholar]
- 54. Aloe vera: A systematic review of its clinical effectivenessBr J Gen Pract199949823828[PubMed][Google Scholar]
- 55. Artichoke leaf extract for serum cholesterol reductionPerfusion199811338340[Google Scholar]
- 56. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and responsesBr J Dermatol19891217590[PubMed][Google Scholar]
- 57. Feverfew as a preventive treatment for migraine: a systematic reviewCephalalgia199818704708[PubMed][Google Scholar]
- 58. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trialsIntern J Anesth200084367371[Google Scholar]
- 59. The efficacy of ginseng. A systematic review of randomised clinical trialsEur J Clin Pharmacol199955567575[PubMed][Google Scholar]
- 60. Horse-chestnut seed extract for chronic venous insufficiencyArch Dermatol199813413561360[PubMed][Google Scholar]
- 61. Efficacy of kava extract for treating anxiety: systematic review and meta- analysisJ Clin Psychopharmacol2000208489[PubMed][Google Scholar]
- 62. Report on milk thistle: Effects on liver disease and cirrhosis and clinical adverse effectsEvidence Report/Technology Assessment: Number 21[Google Scholar]
- 63. The efficacy of Phytodolor for the treatment of musculoskeletal pain – a systematic review of randomized clinical trialsNatural Medicine Journal1999Summer147[Google Scholar]
- 64. A systematic review of Cernilton for the treatment of benign prostatic hyperplasiaBr J Urol Int200085836841[PubMed][Google Scholar]
- 65. Cernilton for benign prostatic hyperplasia (Cochrane Review)The Cochrane Library, Issue 2, 2000. Oxford: Update Software.[Google Scholar]
- 66. Tea tree oil: a systematic review of randomised clinical trialsForsch Komplementärmed200071720[PubMed][Google Scholar]
- 67. Valerian for insomnia: a systematic review of randomized clinical trialsMedicine200019199[PubMed][Google Scholar]
- 68. Do cabbage leaves prevent breast engorgement? (Cochrane Review)The Cochrane Library, Issue 4, 1998. Oxford: Update Software.[Google Scholar]
- 69. The treatment of eczema with Chinese herbs: a systematic review of randomized controlled trialsBr J Clin Pharmacol199948262264[PubMed][Google Scholar]
- 70. Plants with hypoglycaemic activity in humansPhytomedicine199747378[Google Scholar]
- 71. Phyto-anti-inflammatories: a systematic review of randomized, placebo- controlled, double-blind trialsRheum Dis Clin North America2000261327[Google Scholar]
- 72. Is Evening Primrose Oil of value in the treatment of premenstrual syndrome?Controlled Clin Trials1996176068[PubMed][Google Scholar]
- 73. The role of oedema protective drugs in the treatment of venous insufficiency: a review of evidence based on placebo-controlled clinical trials with regard to efficacy and tolerancePhlebology1996112329[Google Scholar]
- 74. St. John's wort: an herbal remedy for depression?Canadian Family Physician19974317351736[PubMed][Google Scholar]
- 75. Evaluation of echinacea for treatment of the common coldPharmacotherapy200020690697[PubMed][Google Scholar]
- 76. St. John's wort: a new alternative for depression?Intern J Clin Pharmacol Ther199937111119[Google Scholar]
- 77. Teunisbloemolie. Een overzichtvan gecontroleerd onderzoekPharmaceutisch Weekblad1989124418423[Google Scholar]
- 78. Ginseng: pep of nep?Pharmaceutisch Weekblad1988123411[Google Scholar]
- 79. Medical marijuana and its use by the immunocompromisedAltern Ther Health Med199733945[PubMed][Google Scholar]
- 80. Die therapeutische Wirksamkeit von CrataegusFortschr Med1996 1142729[PubMed][Google Scholar]
- 81. Cholinesterase inhibitors and ginkgo extracts – are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months durationPhytomed20006393401[Google Scholar]
- 82. Herbal remedies in psychiatric practiceArch Gen Psychiatry19985510331044[PubMed][Google Scholar]
- 83. Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trialsJ Urol1998159433436[PubMed][Google Scholar]
- 84. Artemisin derivatives for treating uncomplicated malaria (Cochrane Review)The Cochrane Library, Issue 2, 2000. Oxford: Update Software.[Google Scholar]
- 85. Artemisin derivatives for treating severe malaria (Cochrane Review)The Cochrane Library, Issue 2, 2000. Oxford: Update Software.[Google Scholar]
- 86. Artemether for severe malaria: a meta-analysis of randomized clinical trialsClin Infect Dis199928597601[PubMed][Google Scholar]
- 87. Beta-sitosterols for benign prostatic hyperplasia (Cochrane Review)The Cochrane Library, Issue 1, 2000. Oxford: Update Software.[Google Scholar]
- 88. Efficacy and harm of pharmacological prevention of acute mountain sickness: a quantiative systematic reviewBMJ2000 321267272[PubMed][Google Scholar]
- 89. Can allium vegetables prevent cancer?Phytomed199747983[Google Scholar]
- 90. Polyunsaturated fatty acid (fish or evening primrose oil) for schizophrenia (Cochrane Review)The Cochrane Library, Issue 2, 2000. Oxford: Update Software.[Google Scholar]
- 91. Creams to prevent striae gravidarum (Cochrane Review)The Cochrane Library, Issue 4, 1998. Oxford: Update Software.[Google Scholar]
- 92. Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.)Eur J Clin Pharmacol199854589594[PubMed][Google Scholar]
- 93. Second thoughts about safety of St John's wortLancet199935420142015[PubMed][Google Scholar]
- 94. Health risks of herbal remediesDrug Safety1995138193[PubMed][Google Scholar]
- 95. Herbal medicine. Selected clinical considerations focusing on known or potential drug- herb interactionsArch Intern Med199815822002211[PubMed][Google Scholar]
- 96. Herb-drug interactionsLancet2000 355134138[PubMed][Google Scholar]
- 97. Possible interactions between synthetic and herbal medicinal products. Part 1: a systematic review of the indirect evidencePerfusion200013415[Google Scholar]
- 98. Possible interactions between synthetic and herbal medicinal products. Part 2: a systematic review of the direct evidencePerfusion2000136070[Google Scholar]