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Wormwood (Artemisia absinthium) suppresses tumour necrosis factor alpha and accelerates healing in patients with Crohn's Disease - a controlled clinical trial.


Suppression of tumour necrosis factor alpha (TNF-[alpha]) and other interleukins by wormwood (Artemisia absinthium) extracts were reported recently in in vitro studies. The aim of the present study was to find out if this effect can be also be observed in Crohn's Disease (CD) patients where TNF-[alpha] appears to play an important role. In a controlled trial, 10 randomly selected patients suffering from CD were given in addition to their basic CD therapy 3 x 750 mg dried powdered wormwood for 6 weeks. Ten patients, also randomly selected who met the inclusion criteria served as control group. Minimum score of 200 on Crohn's Disease Activity Index (CDAI) was required at baseline for inclusion in each group. Patients who received infliximab or similar were excluded from the trial. TNF-[alpha] level in serum were measured at baseline, and after three and six weeks. During this period all concomitant CD medications was maintained at the baseline dose levels. Average serum TNF-[alpha] level fell from 24.5 [+ or -] 3.5 pg/ml at baseline to 8.0 [+ or -] 2.5 pg/ml after six weeks. The corresponding levels in the control group were 25.7 [+ or -] 4.6 (week 0), and 21.1 [+ or -] 3.2 (week 6). On the clinical side, CDAI scores fell from 275 [+ or -] 15 to below 175 [+ or -] 12 in wormwood group with remission of symptoms in eight patients (CDAI score below 170 or reduction by 70 points), compared to only two in the placebo group (CDAI of placebo group 282 [+ or -] 11 at baseline and 230 [+ or -] 14 on week 6). IBDQ also reflected accelerated clinical response with wormwood. Of clinical significance were the findings that wormwood also improved mood of the CD patients, as reflected in Hamilton's Depression Scale. These findings provide a base to test wormwood in clinical conditions thought to be mediated by increased production of pro-inflammatory cytokines such as TNF-[alpha].

[c] 2009 Published by Elsevier GmbH.



Wormwood ([Seda-Crohn.sup.R]) lowers TNF-[alpha]

Wormwood accelerates healing of Crohn's disease


The inflammatory process in Crohn's disease (CD) is characterised by increased production of pro-inflammatory cytokines such as tumour necrosis factor (TNF-[alpha]), interleukin-1 (IL-1), and interleukin-6 (1L-6) (Mahida et al. 1989; Reinecker et al. 1993; MacDonald et al. 1990). TNF-[alpha] level in serum (Murch et al. 1991), as well as in stool (Braegger et al. 1992) were found to be elevated in patients with active CD in comparison with normal controls. TNF-[alpha] is now considered to be actively involved in the inflammatory process in CD (Van Dullemen et al. 1995). Strong support for this involvement comes from clinical studies with infliximab, a TNF-[alpha] inhibitor (Gauss et al. 1992). TNF-[alpha] inhibitors are now being employed for severe cases of CD and other autoimmune diseases. These inhibitors are proteins that need to be injected and, sooner or later, are associated with serious side effects. It is therefore justified to look for safer TNF-[alpha] inhibitors that can be given orally.

Plants have been the basis of treatment of human diseases from time immemorial. Artemisia absinthium (wormwood) is a well known traditional herb, mentioned in almost all books of herbal medicine in the western world. It is readily available and enjoys, since centuries, broad traditional use in many health disorders. Suppression of TNF-[alpha] and other interleukins by wormwood extracts were reported recently in in vitro studies (Choi et al. 2006; Hatziieremia et al. 2006; Lee et al. 2004). The aim of the present study was to find out if this effect can also observed in Crohn's Disease (CD) patients where TNF-[alpha] appears to play a central role.

Material and Methods

Artemisia absinthium

commonly known as wormwood, is described in the pharmacopoeia books of all European countries. For medicinal purposes, leaves and stems not thicker than 4 mm are used (Deutsches Arzneibuch DAB VII; List and Horhammer 1973). The dry leaves and stems contain, among others, 0.25-1.32% essential oil, absinthin, anabsin, artemisinin, anabsinthin, artabsin and matricin (List and Horhammer, 1973; Kordali et al. 2005). The essential oil contains high concentrations of thujone and thujyl alcohol and other terpene-derivatives, which are neurotoxic at high doses (Juteau et al. 2003). The herb is usually standardized based on absinthin. High-quality wormwood should contain at least 0.2% absinthin (List and Horhammer 1973)

Standardization of Wormwood

We used powdered wormwood in capsules being marketed under the name of [Seda-Crohn.sup.R] by According to the data provided by the company the wormwood used in [Seda-Crohn.sup.R] was cultivated in Germany under standardized biological conditions that was supplied by Galke Arzneipflanzen, Gittelde, Germany (Control No. D-NI-LG-12-9304-BC, Code-No. DE-012-OKO, EU regulation No. 2092/91). Leaves and stems not thicker than 4 mm were used for processing. The herb was thoroughly washed, air-dried, powdered, mixed with powdered carriers (cardamom seeds and resin of mastic), and finally filled in capsules of the size 00. HPLC finger-print were obtained using absinthin as marker. The preparation [Seda-Crohn.sup.R] contains 0.32-0.38% absinthin.

Toxicity Data

In 1979, the FAO/WHO Codex Committee on Food additives restricted the use of [alpha]- and [beta]-thujones to the maximum levels of 5 ppm in products for human consumption. The analysis of the thujone contents was done according to the Official Methods of Analysis of the Association of Official Analytical Chemists, 13th Ed, 1980, section 9.129. The amount of absinthin present in the trial batch was 0, 35% as required by "Deutsches Arzneibuch" (DAB VII) for good medicinal wormwood (data provided by Acute (24 h), sub-acute (4 weeks) and chronic (6 months) toxicity data of the above composition in powder form was provided by LiTaka Pharmaceutical Laboratories, Pune, India. This laboratory has been assigned the Labeler Code No 58317 by the Department of Health and Human Services, Food and Drug Administration, Rockville, MD, USA. Thirteen week toxicity study of wormwood has been reported by Muto and his colleagues (Muto et al. 2004). There were no such findings in these toxicological studies that prevent the human use of this herb.

Application form and Dose

Each 400 mg of [Seda-Crohn.sup.R] capsule contains 250 mg of powdered wormwood. A typical dose of wormwood herb is 2-3 g/day (Deutsches Arzneibuch DAB VII; List and Horhammer 1973; Monography of the Commission E of Germany; European Monography of Wormwood). Patients were asked to take 3 capsules of [Seda-Crohn.sup.R] three times a day. The dose of wormwood was thus within the recommended dose limits.

Study Design

This trial, being one of the early pilot experiences, necessitated to keep the number of patients to a minimum for the approval by the ethical committee. An approval was obtained from the regional ethical committee after providing them with the necessary toxicological data, study protocol and other required documents. Informed consent of the patients was obtained. This was a randomized, open label, multi-centre trial carried out on out-patients referred by general practitioners in Germany. We recruited 20 patients according to the inclusion criteria set below. The CD was previously verified by coloscopy and histology and for inclusion, has to be of at least 3 months duration with a score of 200 or above on Crohn's Disease Activity Index (CDAI) (Best et al. 1976). Patients between the age of 18-80, receiving CD treatments with 5-aminosalicylates, if dose remained constant for at least 4 weeks prior to entering the trial were selected for the trial. Patients receiving azathioprine, stable dose for 8 weeks, or methotrexate stable dose for 6 weeks and steroids with stable dose in the range of 20-30 mg (equivalent to dexamethasone) also qualified, however patients who were treated with TNF-[alpha] inhibitors such as infliximab and similar were excluded.

Patients were screened for eligibility one week prior to entering the trial based on their medical history, physical examination, routine blood tests, electrocardiogram (ECG), urine analyses and CD medication. For women, pregnancy tests were done at baseline evaluation where appropriate. Patients with serious pathological findings in ECG, liver, kidney and heart functions, or coexisting organic diseases such as a history of cancer, asthma or other autoimmune disease, or pregnancy were excluded from the trial. Any condition that, in the investigators opinion, placed the patient at undue risk by participating in the six weeks study were also excluded from taking part in the study. Other exclusion criteria were parasites in the patient's stools, positive Clostridium difficile toxin test and active fungal or viral infection. During trial, the patients were excluded from the study if their CD or general health condition worsened. Worsening was defined as an increase in CDAI of at least 70 points from the qualifying baseline score. Any condition that necessitated the introduction of a new treatment or the addition of steroids, or hospitalisation for any reason also resulted in the removal of patients from the study.

The recruited patients were assessed with the help of CDAI, IBDQ (German Version of the Inflammatory Bowel Disease, Gesundheitswesen 2005; 67: 656-664) and 21-item HAMD (Hamilton's Depression Scale) at baseline (week 0). None of the concomitant medications, including that of steroids, already being taken by the eligible patients were increased, decreased or discontinued during the entire study period of six weeks. The eligible patients were assigned randomly to take wormwood or no additional medication (control group). The trial medication was given for 6 weeks. Their blood was taken after 3 and 6 weeks for routine laboratory safety tests and to determine the levels of TNF-[alpha]. TNF-[alpha] in serum was measured by Bioscientia laboratories in Ingelheim, Germany. The sensitivity of the method for TNF-[alpha] was 4.5 pg/ml.

Response to treatment in CD patients is generally defined as decrease of at least 30% or 70 points from the qualifying score. For the HAMD scale, the primary outcome measure was the absolute decrease of the Hamilton's total depression score between baseline and the following treatment weeks. We defined response as a decrease in total score of 50% from baseline and remission as a score 10 points in HAMD scores.

Statistical methods: Baseline continuous data were compared using the 2-sample t test and baseline categorical data were compared using the [[chi].sup.2]-test or Fisher exact test because of small sample size. A p value of 0.05 was set to define significance.


The patient population comprised 9 men and 11 women with a median age of 55 (range 18-80) years. Their baseline disposition, medication and other characteristics are summarized in the Table 1.
Table 1

Demographic data.

                                  Wormwood (n=10)      Control Group

Age (years)                     54,3 [+ or -] 14,3  57,5 [+ or -] 12.5
Males                           6                   3
Females                         4                   7
Duration of disease (years)     17,3 [+ or -] 6,2   18,7 [+ or -] 5.4
Present episode (weeks)         8,7 [+ or -] 2,2    9,8 [+ or -] 3,1
Azathioprine dose (mg)          100 [+ or -] 25     125 [+ or -] 25
Mesalazine (g/day               3,0 [+ or -] 1,0    3,0 [+ or -] 1.0
Extraintestinal manifestations  2                   3

Serum TNF-[alpha] levels

TNF-[alpha] serum levels were measured in all twenty patients at baseline (week 0), and then after three and six weeks. The results are presented in Fig. 1. TNF-[alpha] levels decreased from 24.5 [+ or -] 3.5 pg/ml at week 0 to 8.0 [+ or -] 2.5 pg/ml at week 6. Levels of TNF-[alpha] in placebo group were 25.7 [+ or -]4.6 pg/ml at week 0, and 21.1 [+ or -]3.2 pg/ml at week 6. The decrease was statistically significant (p = 0,5).


Clinical Improvements

There was a steady improvement in CD symptoms in all patients who received wormwood as reflected in their CDAI, IBDQ and HAMD scores. After 6 weeks, in 6 patients who received wormwood, CDAI-Score was below 150. This drop indicated a significant clinical improvement. In the placebo group there were no such patient ([[chi].sup.2]-test; p = 0,05). Table 2 shows the development in the two treatment-groups on CDAI, IBDQ and HAMD scores after six weeks. Average CDAI-score fell from 275 [+ or -] 15 to below 175 [+ or -] 12 in the wormwood group. In the placebo group the CDAI-score was 282 [+ or -] 11 at baseline and 260 [+ or -] 14 at the end of treatment. The sores of the IBDQ. and HAMD showed patterns similar to that of CDAI. HAMD total score decreased by an average of 9.8 [+ or -] 5.8 points for wormwood group and by 3.4 [+ or -] 6.6 points for placebo group. No "out of the line" side effect was reported that could be attributed to wormwood administration. There was no drop out during the six week study period.
Table 2

Mean values of Crohn's Disease Activity Index (CDA1), Inflammatory
Bowel Disease Questionnaire scores (IBDQ) and 21-item Hamilton's
Depression Scale scores (HAMD) at baseline and after six weeks of
concomitant treatment with wormwood (n = 10) as compared to the
control group (n = 10).

Scores/Levels                  Wormwood Group (n = 10)

                           Baseline       After 6 weeks

TNF-[alpha] (pg/ml)  24.5 [+ or -] 3.5  8.0 [+ or -] 2.5
CDAI                 275,0 [+ or -] 15  175 [+ or -] 12
IBDQ                 120,5 [+ or -] 14  175 [+ or -] 11
HAMD                 22,7 [+ or -] 8    7,7 [+ or -] 5
Response CDAI                           8
Response HAMD                           6

Scores/Levels                Control Group (n = 10)

                          Baseline        After 6 weeks

TNF-[alpha] (pg/ml)  24.7 [+ or -] 4.6  22.1 [+ or -] 3.2
CDAI                 282 [+ or -] 11    260 [+ or -] 14
IBDQ                 122 [+ or -] 17    135 [+ or -] 16
HAMD                 23,1 [+ or -] 6    19 [+ or -] 4
Response CDAI                           2
Response HAMD                           1

Response was defined as a decrease in the CDAI score of at least 70
points from the qualifying score, or a decrease in 50% of HAMD score
from the baseline score.


This is an unusual finding that a herb when given orally is capable of suppressing TNF-[alpha] and at the same time exhibits marked effect on clinical symptoms and associated depressed mood of CD patients who were almost refractory to standard CD-treatment when they entered the trial. The observed clinical effect of wormwood on CD may have been mediated by TNF-[alpha] suppression. Cardamonin, a chalcone isolated from wormwood, has demonstrated anti-inflammatory activity in cellular models of inflammation (Hatziieremia et al. 2006). Cardamonin suppresses both NO and iNOS and key molecules in the NF[kappa]B pathway, and as well as TNF-[alpha]. Thus, it is possible that cardamonin present in the wormwood preparation may be playing an important role, when not the crucial role, in the observed anti-inflammatory activity of wormwood. The findings of Hatziieremia et al. and our results make cardamonin a potential anti-inflammatory drug lead that targets the NF[kappa]B pathway and TNF-[alpha]. A sensitive and selective flow injection method for the assay of cardamonin over the range 1.0 x [10.sup.-8] to 8.0 x [10.sup.-6] g/ml is available (Zhang et al. 2005). A flavonoide isolated from wormwood was also shown to exhibit anti-inflammatory activity. Lee and his colleagues reported the effect of 5, 6, 3', 5'-tetramethoxy 7, 4'-hydroxyflavone (p7F) on TNF-[alpha] and NF[kappa]B, both in vitro and in vivo on mice models. p7F was found to suppress both (Lee et al. 2004). Besides the flavonoide p7F, artemisin and its metabolite artesunate present in wormwood, though in very small amounts, may also have played a role in the observed effect of this herb. Xu et al. explored the effect of artesunate on TNF-[alpha]-induced production of IL-1[beta], IL-6 and IL-8 in human rheumatoid arthritis fibroblast-like synoviocytes (FLS) and further investigated the signal mechanism by which this compound modulates those cytokines' production (Xu et al. 2007). Artesunate decreased the secretion of IL-1[beta], IL-6 and IL-8 from TNF-[alpha]-stimulated rheumatoid arthritis FLS in a dose-dependent manner. Artesunate also prevented TNF-[alpha]-induced nuclear NF[kappa]B translocation, DNA-binding activity and gene transcriptional activity. The authors postulated that artesunate inhibits the production of IL-1[beta], IL-6 and IL-8 through the inhibition of NF[kappa]B signaling pathway. Xu et al. also showed that artesunate prevented Akt phosphorylation, and that the inhibition of Akt activation might inhibit IL-1[beta], IL-6 and IL-8 production induced by TNF-[alpha]. Choi and his colleagues demonstrated that DA-9601 - a standardized aqueous extract of Artemisia asiatica, blocks TNF-[alpha]-induced IL-8 and CCL20 production by inhibiting p38 kinase and NF[kappa]B pathways in human gastric epithelial cells (Choi et al. 2006). All these findings become crucial to test wormwood in clinical conditions thought to be mediated by increased production of pro-inflammatory cytokines.

In this context it is also necessary to draw the attention to possible synergy effects between constituents of wormwood and cardamom seeds which might be responsible for additive or potentiated pharmacological synergy effects (Wagner and Ulrich-Merzenich 2009).

However, exclusive suppression of TNF-[alpha] may not be sufficient to explain the clinical improvement observed, as a study with pentoxifylline, another TNF-[alpha] suppressor, failed to demonstrate clinical improvement in refractory CD (Bauditz et al. 1997; Reimund et al. 1997). Also, the effect of anti-TNF-[alpha] infliximab is attributed not only to its direct effect on TNF-[alpha] but rather to the combination of other immune-modulating effects. Some studies have shown that there is a high prevalence of DNA virus such as CMV, HHV6 and EBV in CD (Wakefield et al. 1992; Berk et al. 1985). In one experiment reported by Wakefield and his colleagues high prevalence of CMV (81%), HHV6 (76%), and EBV (76%) in CD patients was found. Control tissue exhibited low frequencies of these viruses (CMV 29%, EBV 19%). Yanai and his colleagues detected EBV in tissues of CD (63.8%) and ulcerative colitis (60%) and none in the non-inflammatory areas of colon specimen (Yanai et al. 1999). It appears that these virii, with some other DNS virii, might be playing some role in the pathogenesis of CD. Efferth and his colleagues reported that artesunate found in artemisia species is an effective, non-cytotoxic inhibitor of CMV in vitro (Efferth et al. 2002). Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an in vitro replication system was studied by Bhakuni et al. (2001). Antiviral immune-modulations by wormwood can also have contributed to its clinical activity in this study.

An interesting observation was the improvement in mood and feelings of well-being by patients suffering from CD. Infection, inflammation, and autoimmune processes are accompanied by serious disturbances of well-being, psychosocial functioning, cognitive performance, and behaviour. CD patients usually suffer from mood disturbance. Studies of Pollmaecher in association with his colleague showed that human cognitive behaviour is very sensitive to host defence activation. A small amount of endotoxin, which affects neither body temperature nor neuroendocrine systems, but slightly stimulates the secretion of inflammatory cytokines, has a negative effect on sleep and cognition. According to present knowledge TNF-[alpha] is most probably a key mediator of these effects (Pollmaecher et al. 2000). These findings may explain the unusual effect of wormwood observed in this study on mood and sleep parameters as expressed by a significant reduction in HAMD-Scale. But it can not be excluded that wormwood has its own antidepressant effect. This will not be a wonder when one looks at the past history of wormwood and its alcoholic "green fairy" absinthe, so extensively consumed in the 17th. Century intellectuals to "stimulate thoughts".

Therapy for CD is rapidly evolving with the emergence of new discoveries in disease pathogenesis. Besides TNF-[alpha] inhibitors such as infliximab, etanercept and onercept some of the possible future therapies are: a) Inhibitors of lymphocyte trafficking: e.g. natalizumab. b) Monoclonal antibodies of IL-12, interferon-gamma (INF[gamma]) and anti-INF[gamma]. c) Immunoregulatory cytokines IL-10 and IL-1 and IL-5 and inhibitors of nuclear factor kappaB (NFkB). d) Epidermal growth factor and keratinocyte growth factor (Wilhelm et al. 2006; Kurtovic and Segal 2004; Srinvasan and Lichtenstein 2004). The use of toxic thalidomide is also being justified because of its suppression of TNF-[alpha] and other pro-inflammatory cytokines (Wettstein and Meagher 1997;Ehrenpreis et al. 1999; Vasiliauskas et al. 1999). The long term outcome of the efficacy of these emerging treatments is uncertain. Despite the lack of scientific data in the form of controlled trials for efficacy, there is a widespread use of alternative medicine by patients with inflammatory bowel disease. There is limited controlled evidence indicating efficacy and safety of traditional medicines, such as aloe vera gel, wheat grass juice, Boswellia serrata and bovine colostrum enemas in colitis. Contrary to popular belief, "natural therapies" are not necessarily always safe. Interactions with conventional drugs are potentially dangerous (Morris and Zhang 2006). A recent double blind study by Omer et al. suggested that Wormwood may help patients with Crohn's disease because of its steroid-sparing effects (Omer et al. 2007). Taken together, what has been said, wormwood can be clinically applied, at least as an adjuvant, for the TNF-[alpha] targeting diseases. This traditional and well known herb, because of the absence of side effects at its recommended dose levels, may also prove to be a better alternative to thalidomide that is enjoying a come back as backup in TNF-[alpha] targeted diseases, but has extremely disturbing side effects such as sedation and polyneuropathia.


The authors thank those physicians who referred their patients for this trial. Competing interests: The [Seda-Crohn.sup.R] capsules and other trial materials for this study were provided by Noorherbals. com, Delaware, USA. The authors have not received any consulting fee from


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Simone Krebs (a), *, Talib N. Omer (b), Bilal Omer (c)

(a) Department of Nuclear Medicine, Faculty of Medicine, University of Freiburg, Germany

(b) Laboratory of Molecular Neurosurgery, Department of Stereotactic Neurosurgery, Faculty of Medicine, University of Freiburg, Germany

(c) Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

* Corresponding author. Tel.: +49 7623 62430; fax: +49 7623 8469.

E-mail address: (S. Krebs).

doi: 10.1016/j.phymed.2009.10.013
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Author:Krebs, Simone; Omer, Talib N.; Omer, Bilal
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2010
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