1. Herbal Medicine

AND

2. Disorders/complaints (see section “Indications Suitable for Treatment with Herbal Medicines”). Depending on the ailment, the term “herbal medicine” was combined with a, b, c, d, or e respectively:

AND

3. Clinical Trial

Reasons for exclusion criteria:

a, b: Authors should be able to read and understand the full text; c: clinical results should have been obtained from a study; d, e, f, g, h, i: selected in order to filter all available information on legally approved (in Europe in particular in Germany) herbal medicines or the respective standardized extract (HMPC Monographs of the European Medical Agency - EMA) only; j: preclinical evidence should be excluded; k, l: alternative naturopathic therapy forms should be excluded; m: children should be excluded due to different drug metabolism; n, o: healthy volunteers should be excluded in order to obtain information on clinical therapeutic benefits; p: predominant comorbidities should be excluded because they can affect the efficacy of the herbal drug in particular when co-administered with other drugs; q; clinical benefits from single cases are difficult to generalize; r: excluded for methodological reasons, e.g., data interpretation.

The use of herbal medicines in depressive disorders is well examined and in particular the clinical benefits of SJW are well supported by clinical studies of high quality. All 37 selected studies on the use of SJW in depressive disorders ranging from mild to severe forms have been double-blind randomized controlled trials (quality group 4). Study duration was predominantly between 4 and 8 weeks and only few studies examined the effects for longer time periods of up to 6 months. The majority of the studies reported positive therapeutic effects concerning Hamilton depression rating scale (HAMD) as primary outcome parameter and only 5 of them (Shelton et al., 2001; Davidson et al., 2002; Bjerkenstedt et al., 2005; Moreno et al., 2006; Rapaport et al., 2011) did not demonstrate superiority as compared to placebo or pre-post.

In six studies (published predominantly before the year 2000) comparing SJW with tricyclic anti-depressive drugs the clinical benefits of the herbal drug in respect to placebo or in pre-post comparison was at least equal to the synthetic drug no matter if it was imipramine (Vorbach et al., 1994; Vorbach et al., 1997; Philipp et al., 1999; Woelk, 2000), maprotiline (Harrer et al., 1994) or amitriptyline (Wheatley, 1997). However, with regards to tolerability, SJW was clearly superior to any of the tricyclic antidepressants.

The more recent studies compared the efficacy of SJW with the selective serotonin reuptake inhibitors (SSRI) paroxetine, sertraline, citalopram and fluoxetine. In most of the 18 studies the therapeutic benefits of SJW were at least equal to those of the SSRIs (Harrer et al., 1999; Berger et al., 2000; Brenner et al., 2000; Friede et al., 2001; van Gurp et al., 2002; Bjerkenstedt et al., 2005; Gastpar et al., 2005; Szegedi et al., 2005; Anghelescu et al., 2006; Gastpar et al., 2006; Sarris et al., 2012). In two studies SJW was even superior to fluoxetine (Fava et al., 2005) or paroxetine (Seifritz et al., 2016) in reducing depressive symptoms. In one study the responders of a previous study were included in a further RCT testing the efficacy of SJW against citalopram. Here the numbers of patients with relapse was lower in the SJW group as compared to citalopram (Singer et al., 2011). The results of one study indicated that SJW was less efficacious than both fluoxetine and placebo, however in this study the group on SJW had the lowest remission rates (Moreno et al., 2006). In two studies no statistical differences in HAMD scores between SJW, placebo and citalopram (Rapaport et al., 2011) or sertraline (Davidson et al., 2002) could be found with adverse effects in the SJW and the SSRI groups.

In most of the above-mentioned studies, comparing the efficacy of SJW to standard therapy, a placebo group was included. However, in 13 studies SJW was tested exclusively against placebo whereby two of these studies examined the efficacy of different dosages of SJW extract (Laakmann et al., 1998; Kasper et al., 2006). In these studies, the higher concentrations had the better clinical benefits. In a continuation study of the effect of SJW in long term treatment a higher dosage (1,200 mg/d) was not superior to the lower one (600 mg/d) (Kasper et al., 2007). Interestingly the higher dosages were still well tolerated although mild adverse events related to gastrointestinal disorders were observed in a small portion of the patients (Kasper et al., 2006). In only one of our selected studies SJW was not effective in comparison to placebo for the treatment of major depression but safe and well tolerated (Shelton et al., 2001). In all other studies SJW was superior to placebo no matter if given in low (Laakmann et al., 1998; Lecrubier et al., 2002; Randlov et al., 2006), medium (Kasper et al., 2006; Kasper et al., 2007; Mannel et al., 2010) or in high (Hansgen et al., 1994; Harrer et al., 1994; Sommer and Harrer, 1994; Kalb et al., 2001; Uebelhack et al., 2004; Kasper et al., 2006; Kasper et al., 2007; Kasper et al., 2008) dosages.

For the efficacy of Rhodiola rosea in treatment of depressive disorders only few studies were performed so far. Therefore, a clear conclusion cannot be drawn, especially as the outcomes are not homogenous. While one study investigating the efficacy of R. rosea against placebo and the SSRI sertraline reported on a statistically not-significant inferiority of the herbal medicine (Mao et al., 2015) another study demonstrated clinical benefits concerning the symptoms of depression, insomnia, emotional instability and somatization against placebo. In this study two dosages of R. rosea were tested and the higher dose (680 mg/d) showed even positive effects on self-esteem (Darbinyan et al., 2007).

Interestingly the search for qualitatively high clinical studies (according to our inclusion and exclusion criteria) revealed only few studies. The majority of them investigated the efficacy of valerian alone (Donath et al., 2000) or in combination with hops (Koetter et al., 2007) compared to placebo (Donath et al., 2000; Koetter et al., 2007) or to oxazepam (Dorn, 2000; Ziegler et al., 2002). All studies reported clinical benefits, however while the one research group reported that valerian alone was efficacious against insomnia (Donath et al., 2000) the other group reported on clinical benefits only in combination with hops (Koetter et al., 2007). Both study designs were placebo-controlled. In comparison to oxazepam valerian was not inferior and both therapy options improved sleep quality (SF-B) in a similar fashion (Dorn, 2000; Ziegler et al., 2002).

Herbal Medicines with lavender extracts were clinically studied for the treatment of anxiety. Between 2010 and 2019 six qualitatively high studies performed in Germany, Austria and Switzerland reported on the beneficial effects of lavender against symptoms of anxiety with improvements on the Hamilton anxiety rating (HAMA) scale as primary outcome (Kasper et al., 2010; Woelk and Schlafke, 2010; Kasper et al., 2014; Kasper et al., 2015; Kasper et al., 2016; Seifritz et al., 2019) and all studies used the same extract (WS1265). Four of the 6 studies were performed by the same group, however the study design differed. In these studies the efficacy of lavender was either compared to placebo (Anghelescu et al., 2006; Kasper et al., 2010; Kasper et al., 2016; Seifritz et al., 2016) and/or to paroxetine (Kasper et al., 2014) and lorazepam (Woelk and Schlafke, 2010). Overall, the lavender preparation was regarded as efficacious and safe.

We selected 10 studies investigating the efficacy of ginkgo biloba extract in the treatment of cognitive impairment and Alzheimer’s Disease (AD) with 8 of them testing against placebo (Le Bars et al., 1997; Le Bars et al., 2002; Le Bars, 2003; van Dongen et al., 2003; Schneider et al., 2005; Napryeyenko et al., 2007; Gavrilova et al., 2014; Gschwind et al., 2017), one against rivastigmine (Nasab et al., 2012) and one against donepezil (Mazza et al., 2006). In three of the studies two different ginkgo extracts did not show superiority over placebo regarding the primary outcome. In detail 5 of the studies showed that extracts of ginkgo biloba lead to a decrease in NPI composite score (Gavrilova et al., 2014) improved significantly ADAS-Gog and GERRI (Le Bars et al., 1997; Le Bars et al., 2002; Le Bars, 2003), or the SKT test battery (Napryeyenko et al., 2007) as outcome parameters. In three studies ginkgo extracts did not show superiority over placebo regarding the primary outcome parameters ADAS-cog (Schneider et al., 2005), gait analyses (Gschwind et al., 2017) or SKT test-battery (van Dongen et al., 2003), whereby in one of these studies the primary outcome parameter ADAS-cog also declined in the placebo group rendering the results of the study inconclusive (Schneider et al., 2005). With respect to the AD conventional medication rivastigmine, ginkgo biloba extract was inferior regarding the primary outcome parameters MMSE and SKT test-battery (Nasab et al., 2012). Finally one study in which gingko biloba was more efficacious than placebo and equal to the second generation cholinesterase inhibitor donepezil (Mazza et al., 2006) was heavily criticized by two other groups (Corrao et al., 2007; Korczyn, 2007), making it difficult to estimate if the use of ginkgo containing herbal medicines are justified for the treatment of mild to moderate AD.

In studies examining the clinical benefits of black cohosh for the treatment of menopausal symptoms, sample sizes ranged from n = 62 to n = 6,141. Treatment duration was between 12 weeks and 9 months. The herbal drug dosages ranged from 20 to 127.3 mg.

In comparison to HRT, the benefit-risk-balance points to significant non-inferiority and superiority of black cohosh (Bai et al., 2007). In three other studies menopausal complaints improved overall, but differences between black cohosh and HRT were not significant (Wuttke et al., 2003; Nappi et al., 2005; Friederichsen et al., 2020). The combination of black cohosh with SJW significantly reduced menopausal complaints and was superior to transdermal estradiol (Briese et al., 2007). Independent of a high or low dose, menopausal complaints decreased significantly (Liske et al., 2002; Drewe et al., 2013). Adverse events rates were lower in the low dose group (Drewe et al., 2013) or similar to the high dose group (Liske et al., 2002). Menopausal symptoms decreased significantly more for black cohosh compared to placebo (Osmers et al., 2005). In another study with 62 participants, the difference between the symptom scores just approached significance (Wuttke et al., 2003). Interestingly, this also applies to the comparison of conjugated estrogens and placebo. Adverse events rates did not differ significantly between black cohosh and placebo (Wuttke et al., 2003; Osmers et al., 2005). Significant and clinically relevant reductions in menopausal symptoms (Vermes et al., 2005) or higher quality of life (Julia Molla et al., 2009) were observed after treatment with black cohosh compared to therapy start. Sage taken for 8 weeks significantly decreased the number of menopausal hot flushes from week to week (Bommer et al., 2011). Observed treatment-related adverse events were mild and occurred in only one person. However, no comparison was made to another treatment or placebo.

Eight studies dealt with the treatment of PMS with VAC. The sample sizes ranged from n = 43 to n = 1,634. Treatment duration was three cycles; Berger et al. (2000) added three subsequent cycles without treatment. The administered dosages ranged from 1.6 to 20 mg extract.

Results of studies comparing VAC with pyridoxine or placebo were similar. PMS symptom reduction was significantly more pronounced for VAC compared to pyridoxine (Lauritzen et al., 1997) or placebo (Schellenberg, 2001; Bachert et al., 2009; Barrett et al., 2010; Schellenberg et al., 2012). Rates of adverse events were similar between groups in each study (Loch et al., 2000; Schellenberg, 2001; Barrett et al., 2010; Schellenberg et al., 2012). Schellenberg et al. (2012) compared a VAC reference dose to a lower and higher dose; the results were in favor for the reference dose compared to the low dose. No significant differences between the high and reference dose emerged. The number of participants with adverse events was slightly elevated for the high dose. In single-arm studies, symptoms of PMS significantly decreased after three cycles of VAC treatment (Berger et al., 2000; Loch et al., 2000; Momoeda et al., 2014). Only mild PMS-like adverse events were observed. Berger et al. demonstrated a gradual symptom return after therapy completion (Berger et al., 2000). PMS symptoms were significantly higher compared to the end of the treatment, but still 20% lower than at baseline.

A clinical study testing the efficacy of SJW in treating mild PMS (Canning et al., 2010) demonstrated significant improvements in physical (e.g., food craving) and behavioral (e.g., confusion) symptoms compared to placebo. The effect on mood (e.g., irritability) and pain (e.g., cramps) was not significant.

Trials on steatohepatitis, cirrhosis and different kinds of hepatitis (n = 18) included patient cohorts ranging from 14 to 200 participants, all of them aged >18 years. Patients were treated with silymarin orally or intravenously (Pares et al., 1998; Tanamly et al., 2004; Ferenci et al., 2008; Hawke et al., 2010; Fried et al., 2012; Adeyemo et al., 2013; Fathalah et al., 2017; Tanwar et al., 2017) with dosages ranging from 280 to 2,100 mg/day or 5–20 mg/kg/day, respectively. Six studies compared the HM group to a placebo group (Pares et al., 1998; Tanamly et al., 2004; Hawke et al., 2010; Fried et al., 2012; Adeyemo et al., 2013; Tanwar et al., 2017). Silymarin did not reduce virus titers and/or serum alanine transaminase (ALT) in patients with Hepatitis C and non-alcoholic Steatohepatitis C, compared to placebo (Adeyemo et al., 2013). The same observation has been made by others (Hawke et al., 2010). Furthermore, the integration of silymarin into a PEGylated (Peg)-interferon based regimen did not improve the outcome of HCV patients in terms of HCV RNA suppression and Enhanced Liver Fibrosis score performance (Tanamly et al., 2004). There was also no effect of silymarin on HCV patients who were previously unsuccessfully treated with interferon (multicenter, double-blind, placebo-controlled trial) (Fried et al., 2012). Although HCV-patients reported to “feel better” after 12 months of silymarin therapy in a further study, symptoms and quality of life (QOL) scores did not differ between the silymarin and the placebo group (Tanamly et al., 2004). Treatment with silymarin was also well tolerated over a period of 2 years. However, the course of liver cirrhosis in this patient cohort has not been improved (Pares et al., 1998). Contrasting these results, dose escalating studies on HCV cirrhotic patients revealed positive effects of silymarin or silibinin (also milk thistle), in a way that high-dosed silymarin (1,050 mg/day) improved QOL and biochemical parameters of chronic HCV-decompensated cirrhotic patients with no serious adverse events (Ferenci et al., 2008; Fathalah et al., 2017) compared to low-dosed silymarin (420 mg/day). Notably, silibinin exerted a dose-dependent antiviral effect on Peg-interferon/ribavirin non-responders (Ferenci et al., 2008; Fathalah et al., 2017).

Between 2007 and 2009, three clinical trials on CD or IBD have been conducted, two in Germany (quality groups 1 and 2) and one in the United States (quality group 4) (Huber et al., 2007; Omer et al., 2007; Krebs et al., 2010). Patients were treated with wormwood or tormentil for 3–10 weeks. A total of 30 patients were treated with wormwood or placebo (Omer et al., 2007; Krebs et al., 2010). In this context, wormwood decreased tumor necrosis factor alpha levels and the CD activity index score, whilst scores for IBD questionnaire and Hamilton depression scale have been improved, compared to the controls (Omer et al., 2007; Krebs et al., 2010). Daily intake of tormentil reduced clinical activity index scores in all patients, however, during the wash out phase scores increased again. Tormentil has been proven to be safe for ulcerative colitis patients in dosages up to 3,000 mg/day (Huber et al., 2007).

Symptoms of IBS were treated with STW 5 and STW 5-II or SJW (both studies were quality group 4) (Madisch et al., 2004b; Saito et al., 2010). The clinical trial carried out by Madisch et al. compared the effects of the treatment group with those of bitter candytuft mono-extract and placebo. STW 5 and STW 5-II (60 drops/day over 4 weeks) significantly reduced the total abdominal pain and the IBS score compared to placebo and bitter candytuft mono-extract (Madisch et al., 2004b). The study carried out by Saito and others investigated the clinical efficacy of SJW pointing to a lower effect as compared to placebo (Saito et al., 2010).

Six studies on patients suffering from FD were performed, including treatment with either a WS 1520/WS 1340 combination (n = 3) (Madisch et al., 1999; Rich et al., 2017; Storr and Stracke, 2022) or with STW 5 (von Arnim et al., 2007) and/or STW 5-II (n = 3) (Rösch et al., 2002; Madisch et al., 2004a). WS 1340/WS 1520 was documented to be a “valuable” (Storr and Stracke, 2022) or an “effective” therapeutic regimen (Rich et al., 2017), as it relieved pain and improved disease-specific QOL, compared to placebo. The primary outcome of WS 1340/WS 1520 was also proven to be comparable to the prokinetic agent cisapride (Madisch et al., 1999).

It is to be noted that the use of cisapride has meanwhile be restricted by the EMA due to the risk of potentially life-threatening cardiac arrhythmia [https://www.ema.europa.eu/en/medicines/human/referrals/cisapride].

Similar results have been presented in the STW 5 and STW 5-II trials. The gastrointestinal symptom score was significantly lowered when compared to the placebo group (Madisch et al., 2004a; von Arnim et al., 2007), with a therapeutic response comparable to cisapride (Rösch et al., 2002).

Several studies investigated the standardized herbal extract BNO 1045 which contains Centaurium erythraea Rafin, herba (Centaury); Levisticum officinale Koch, radix (Lovage); and Rosmarinus officinalis L., folium (Rosemary). In two studies, the clinical benefits of BNO 1045 in preventing UTI in high-risk women undergoing urodynamic studies (UDS) (Miotla et al., 2018) or urogynecological surgeries (Wawrysiuk et al., 2022) was evaluated. High-risk women were defined as: age over 70, elevated postvoid residual urine>100 mL, recurrent UTI, pelvic organ prolapse (POP) ≥II in POP-Q scale, and neurogenic bladder. No statistical differences in UTI incidence were found between patients receiving antibiotics or BNO 1045. No superiority of antibiotics over BNO 1045 has been confirmed as well in a subsequent prospective study on postoperative UTI after midurethral sling surgery (MUS) (Rechberger et al., 2020). In another study, an herbal mixture based on D-mannose, Arctostaphylos uva-ursi, Betula pendula, and Berberis aristata was compared to BNO 1045 in reducing symptoms of UTI after MUS (Rechberger et al., 2022). The rationale was based on the EAU 2022 guidelines which recommended D-mannose as prophylaxis of UTI. In this context, BNO 1045 was proven to be similar effective, compared to the herbal mixture. The use of BNO 1045 has been documented here to be a potential and valuable alternative to antibiotics for UTI prevention. All four trials have been carried out in the same institution involving the same main investigators which were (partially) associated with the manufacturer of BNO 1045.

A randomized, double-blind, multicenter Phase III clinical trials compared the efficacy and of BNO 1045 to antibiotics concerning symptoms and recurrence rates in women with uncomplicated UTI. Based on the endpoints “UTI-recurrence” and “additional antibiotics use”, BNO 1045 was proven to be non-inferior to antibiotic treatment (Wagenlehner et al., 2018). In a retrospective cohort study, data from outpatients in Germany with at least one diagnosis of acute cystitis or UTI and a prescription of either BNO 1045 or standard antibiotics were analyzed (Holler et al., 2021). Compared to antibiotics, BNO 1045 was associated with significantly fewer recurrence rates of UTI and with reduced additional antibiotic prescription. BNO 1045 was propagated to be an effective and safe symptomatic treatment option for acute cystitis or UTI.

In an open-labeled, randomized, controlled trail the effect of BNO 1045 to prevent recurrences of cystitis in younger women was evaluated (Sabadash and Shulyak, 2017). All patients received an antibacterial therapy, the test group was additionally treated with BNO 1045. The integration of BNO 1045 prevented bacteriuria and recurrent cystitis episodes more frequently (primary outcome), compared to the control group without BNO 1045. This may indicate superiority of the combination therapy. However, interpretation of the results of the study is limited due to the lack of blinding on both sides - patients and physicians. A further study without any involvement of the manufacturer (no conflicts of interest noted) included younger women with acute uncomplicated cystitis. All patients received the same therapy, the nonsteroidal anti-inflammatory drug ketoprofen in combination with BNO 1045 (Kulchavenya, 2018). Quite interestingly, although the majority of the patients responded well to the therapy, the investigators also observed patients who only slightly responded, or did not respond to treatment at all. The authors concluded that uncomplicated cystitis might be cured by BNO 1045 instead of antibiotics which may be required only in minor cases. Still, the data seems to be over-interpreted, since patients were treated with both ketoprofen and BNO 1045 which does not allow to conclude to one drug alone.

Aside from BNO 1045, further herbal medicines have been investigated in clinical studies. Tablets with a standardized herbal extract containing Armoraciae rusticanae radix (Horseradish root) (80 mg) and Tropaeoli majoris herba (Nasturtium) (200 mg) have been applied to patients suffering from chronically recurrent UTI symptoms, with the result that recurrent UTI symptoms were less, compared to the placebo group (Albrecht et al., 2007). However, a subsequent trial failed to demonstrate non-inferiority of this extract to antibiotics due to a poor recruitment rate (Stange et al., 2017). Actually, no respective clinical trials with sufficient statistical power are underway.

Clinical studies have also been conducted with an herbal medicine containing the standardized extracts WS 1473 Sabal serrulata Schult.f (Sabal fruit) (160 mg) and WS1031 Urtica dioica L (Urtica root) (120 mg). All studies were related to the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). The study protocols (placebo-controlled, double-blind, multicentric) were similar in all trials with the International Prostate Symptom Score (I-PSS), quality of life index, uroflow and sonographic parameters as the outcome measures for treatment efficacy. In one study (Lopatkin et al., 2005) patients were randomized to either the herbal medicine (WS 1473 and WS1031) (treatment group) or placebo (control group) while in another study patients received either WS 1473 and 1031 or the α1-adrenoceptor antagonist tamsulosin (Engelmann et al., 2011). A further study was based on the previous mentioned study (Lopatkin et al., 2005), whereby all patients were offered participation in a further 48-week follow-up with WS 1473/1031 (Lopatkin et al., 2007). Independent on the study design, it was concluded that WS 1473/1031 is superior to the placebo, and not inferior to tamsulosin in the treatment of LUTS. In a later re-evaluation of the data sets, WS 1473/1031 was shown to significantly improve nocturnal voiding frequency compared to placebo, with similar effects compared to tamsulosin or the 5α-reductase inhibitor finasteride (Oelke et al., 2014). No further studies have been enrolled since then. However, a database search in 2022 including 3,000 private practices in Germany revealed a significant association between WS 1473/1031 prescription and reduced incidence of urinary incontinence and urinary retention compared to tamsulosin and tamsulosin/dutasteride (5α-reductase blocker), as well as reduced incidence of erectile dysfunction compared to dutasteride (Madersbacher et al., 2023). In all four studies the manufacturer of the extract was involved.

One observational study was investigating the effectiveness of a standardized herbal extract containing a combination of Cucurbita pepo L (Marrow), Rhus aromatica bark (Fragrant sumac), and hops, in women with overactive bladder (Gauruder-Burmester et al., 2019). Of the 113 patients included, nearly the half (61 patients) used concomitant medications (e.g., antihypertensive, levothyroxine, lipid/cholesterol lowering agents, low dose ASS, NSAIDS) within the frame of a routine clinical setting. Considering the noninterventional character of this study, the herbal combination was demonstrated to improve overactive bladder symptoms and quality of life. A controlled study has not yet been initiated.

Studies on treatment of acute sinusitis and acute rhinosinusitis used a follow-up period between 7 and 14 days, with the (adapted) Sinusitis Severity Score (SSS) (N = 2), the Major Symptom Score (MSS) (N = 4), the Total Symptom Score (N = 1) and facial pain relief (N = 1) as primary endpoints. All studies reported significantly improvement of the intervention group over the placebo or control group.

The treatment of acute sinusitis and acute rhinosinusitis with Eps 7630 (standardized root extract of Pelargonium sidoides DC (Pelargonium) was studied in two double blind randomised placebo controlled trials (Bachert et al., 2009; Dejaco et al., 2019) and in one prospective (Perić et al., 2020), randomized, open-label, non-inferiority study comparing study medication to Amoxicillin All three studies reported a significant superiority resp. Non-inferiority for Eps 7630. The use of the standardized herbal extract BNO 1016 (Primulae flos (Primrose), Gentiana lutea Ruiz and Pav. Ex G.Don (Yellow gentian), Rumicis herba (Sorrel), Sambuci flos (Elderflower) and verbenae herba (Vervain) was tested in two randomised placebo controlled trials (Jund et al., 2015), one of which was blinded (Jund et al., 2015). Both studies showed stronger impact on the symptom score for BNO 1016 compared to placebo. One more study tested BNO 1016 in a multicenter, prospective, open-label study comparing its effect to intranasal fluticasone furoate, with patients in both groups showing improvement (Passali et al., 2015). ELOM-080 (standardized herbal drug preparation containing specially destilled oils from Eucalyptus (Eucalypt) and Citrus ×sinensis (Sweet orange) and Myrtus (Myrtle) and Citrus limon (L.) Osbeck (Lemon oil)) was evaluated once in a double blind randomised placebo controlled trial (Federspil et al., 1997) and once in a prospective, non-interventional parallel-group trial where the control group received BNO 1016 (Gottschlich et al., 2018). In both studies BNO 1016 showed superior results.

The use of extracts containing Echinacea for the treatment of common cold was positively tested in two studies, reporting on total number of facial tissues used in three to 7 days after intervention start (Naser et al., 2005) and on the Total Daily Symptom Scores (TDSS) after 7 days (Goel et al., 2004). No statistically significant differences were observed between treatment groups for the total symptom score (SS) after 14 days. In two other studies testing capsules/pills containing Echinacea angustifolia root and Echinacea purpurea root and E. purpurea herb there was no statistically significant difference between the intervention and placebo group concerning severity and duration of self-reported symptoms (Barrett et al., 2002) or global severity (Barrett et al., 2010).

In a double blind randomised placebo controlled trial BNO 1016 was tested for the treatment of chronic rhinosinusitis. The results reveal that the herbal drug was not superior over placebo regarding the Major Symptom Score (MSS) in week 8 and week 12 (Palm et al., 2017).

For bronchitis, nine studies were included, of which six were double-blind randomized placebo-controlled trials, testing EPs 7630 (N = 5) (Matthys et al., 2003; Chuchalin et al., 2005; Matthys and Heger, 2007; Matthys et al., 2010; Kähler et al., 2019) or ELOM-080 (N = 1) (Gillissen et al., 2013). The prospective observational studies included a standardized syrup of Hedera helix L (Ivy leaves) (N = 1) (Fazio et al., 2009), pills with ethanolic Ivy-leaves dry extracts (N = 1) (Hecker et al., 2002) and EPs 7630 (N = 1) (Matthys and Heger, 2007).

Using a follow-up period of 7 days to 4 weeks, all but one (double-blinded placebo controlled trial) (Matthys et al., 2003) reported positive effects of the study medication on either Bronchitis Severity Scores, change of symptoms and coughing frequency.

The treatment of acute cough with EA-575 (standardized extract from H. helix L.) was tested against placebo in one double blind randomized placebo controlled trial and reported a significantly better improvement of cough severity (CS) assessed by Visual Analogue Scale (VAS) in the intervention group after 1 week as compared to placebo (Schaefer et al., 2016).

We included one retrospective cohort study comparing people with acute lower and upper tract respiratory infections who were prescribed a phytopharmaceutical to those who were not prescribed such drugs. They found that extract EPs 7630 (description see 3.5.1) (odds ratio (OR) 0.49 [95% CI: 0.43–0.57]) and thyme extract (OR 0.62 [0.49–0.76]) compared to no phytopharmaceutical prescription exhibited the strongest decrease in antibiotics prescriptions among patients treated by general practitioners (Martin et al., 2020).