Summary of Systematic Reviews of Randomised Controlled Trials (RCTs) of Prolotherapy

Osteoarthritis & Lateral Epicondylitis: there exist 2 positive systematic reviews from 2005 and 2009 for Osteoarthritis and Lateral Epicondylitis respectively, without any new RCTs since their publication that were found;

1.       A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet-rich plasma. – Rabago D 2009 (Positive for Lateral Epicondylitis)

2.    A systematic review of prolotherapy for chronic musculoskeletal pain. – Rabago D 2005 (Positive for Osteoarthritis)

3.    A retrospective audit of patients with osteo-arthritic knees treated with prolotherapy in a general practice. – Jacks 2008 (Positive for Knee Osteoarthritis)

The Research Evidence Base for Sublingual Immunotherapy


Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe adverse systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route.

Sublingual Immunotherapy (SLIT) is a safe alternative to injection immunotherapy, as the incidence of reported severe systemic reactions or anaphylaxis are rare, and none of the systemic reactions report requiring the use of adrenaline. SLIT has also proven to be a very effective form of immunotherapy, as it has been shown in numerous reviews to significantly reduce symptoms and medication requirements in allergic rhinitis and asthma caused by pollen exposure in adults. The size of this benefit compared to that of other available therapies, particularly injection immunotherapy, is not clear, having been assessed directly in very few studies. For house dust mite asthma, evidence is still inconsistent.

Sublingual Immunotherapy for Allergic Rhinitis

Sublingual immunotherapy for allergic rhinitis.

Wilson DR, Torres LI, Durham SRCochrane Database Syst Rev. 2003;(2):CD002893. Update in Cochrane Database Syst Rev. 2010;12:CD002893.

Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis.

Wilson DR, Lima MT, Durham SR. Allergy. 2005 Jan;60(1):4-12.

The Cochrane Controlled Trials Register, MEDLINE (1966-2002), EMBASE (1974-2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify randomised controlled trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment.

Twenty two trials involving 979 patients were included. There were 6 trials of SLIT for House Dust Mite allergy, 5 for Grass Pollen, 5 for Parietaria, 2 for Olive and one each for, Ragweed, Cat, Tree and Cupressus. Four studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, 3 by drops subsequently spat out and 2 by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6-12 months and 4 studies for greater than 12 months. All included studies were double-blind placebo-controlled trials of parallel group design. Overall there was a significant reduction in both symptoms (SMD -0.34, 95% confidence interval -0.69 to -0.15; p=0.002) and medication requirements (SMD -0.43 [-0.63, -0.23]; p=0.00003) following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants were small, casting doubt on the validity of the conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data were available to analyse this factor.

CONCLUSION: SLIT is a safe treatment which significantly reduces symptoms and medication requirements in allergic rhinitis. The size of this benefit compared to that of other available therapies, particularly injection immunotherapy, is not clear, having been assessed directly in very few studies. Further research is required concentrating on optimising allergen dosage and patient selection.

Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials.

Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, Canonica GWAnn Allergy Asthma Immunol. 2006 Aug;97(2):141-8.

A comprehensive search of the EMBASE, MEDLINE, LILACS, and CINAHL databases from January 1966 to February 10, 2006, was performed to evaluate the efficacy of sublingual immunotherapy (SLIT) in the treatment of allergic rhinitis in children.

Randomized, double-blind, placebo-controlled trials of SLIT in the treatment of allergic rhinitis in patients 18 years or younger were selected. Outcomes measured were symptom scores and rescue medication use. Analysis was performed with standardized mean differences (SMDs) and a random-effects model.

Seventy articles were identified and reviewed. Ten studies, published between 1990 and 2004, fulfilled the selection criteria. Five hundred seventy-seven patients were initially included in the studies. Of these patients, 484 (245 SLIT and 239 placebo) had a final clinical evaluation and could be evaluated. Overall, there was a significant reduction in both symptoms (SMD, 0.56, 95% confidence interval, 1.01-0.10; P = .02) and medication use (SMD, 0.76; 95% confidence interval, 1.46-0.06; P = .03) after immunotherapy. The subanalyses performed for treatment duration and type of allergen showed that SLIT for more than 18 months and with pollen extracts was effective compared with SLIT courses shorter than 18 months and with mites.

The results of this meta-analysis showed that, compared with placebo, SLIT with standardized extracts is effective in pediatric patients with allergic rhinitis.

Sublingual immunotherapy for allergic rhinitis.

Radulovic S, Calderon MA, Wilson D, Durham SCochrane Database Syst Rev. 2010 Dec 8;(12):CD002893.

This is an update of a Cochrane Review first published in The Cochrane Library in Issue 2, 2003. We searched the Cochrane ENT Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished randomised, double-blind, placebo-controlled trials of sublingual immunotherapy in adults or children. The date of the most recent search was 14 August 2009.

Primary outcome measures were symptom and medication scores. We used the standardised mean difference (SMD) with a random-effects model to combine data. We included a total of 60 randomised controlled trials in the review. Forty-nine were suitable for pooling in meta-analyses (2333 SLIT, 2256 placebo participants).

Overall, we found a significant reduction in symptoms (SMD -0.49; 95% confidence interval (CI) -0.64 to -0.34, P < 0.00001) and medication requirements (SMD -0.32; 95% CI -0.43 to -0.21, P < 0.00001) in participants receiving sublingual immunotherapy compared to placebo. None of the trials included in this review reported severe systemic reactions or anaphylaxis, and none of the systemic reactions reported required the use of adrenaline.

This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and has been proven to be a safe route of administration.

Systematic reviews of sublingual immunotherapy (SLIT).

Radulovic S, Wilson D, Calderon M, Durham S. Allergy. 2011 Jun;66(6):740-52. doi: 10.1111/j.1398-9995.2011.02583.x. Epub 2011 Mar 28.

Allergic rhinitis is common worldwide, with significant morbidity and impact on quality of life. In patients who don’t respond adequately to anti-allergic drugs. Subcutaneous allergen immunotherapy is effective although requires specialist administration. Sublingual immunotherapy may represent an effective and safer alternative. This Cochrane systematic review is an update of one published in 2003. We searched Cochrane ENT Group Trials Register, Central, PubMed, EMBASE, CINAHL, Web of Science, Biosis Previews, Cambridge Scientific Abstarcts, mRCT and additional sources. We included randomised, double-blind, placebo- controlled trials of sublingual immunotherapy in adults and children. Two authors selected studies and assessed them for quality. Data were put into RevMan 5.0 for a statistical analysis. We used standardised mean difference (SMD), with a random effect model to combine data. Sixty studies were included, with 49 suitable for meta-analysis. We found significant reductions in symptoms (SMD -0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) and medication requirements (SMD -0.32; 95%CI (-0.43 to -0.21, P < 0.00001)) compared with placebo. None of the trials reported severe systemic reactions, anaphylaxis or use of Adrenaline. This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and appears a safe route of administration.

Sublingual Immunotherapy for Asthma

Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature.

Sopo SM, Macchiaiolo M, Zorzi G, Tripodi S. Arch Dis hild. 2004 Jul;89(7):620-4.

To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) in respiratory allergy in children a systematic literature review was conducted. The search was focused on all the double blind studies. Search strategy: Medline, Embase, Cochrane Controlled Trial Register, Abstract of Cochrane Airways Group, hand search, and archives of some SLIT producers. All the selected studies were assessed and evaluated for quality in a standardised independent way.

Eight randomised, double blind, placebo controlled studies on SLIT were selected. Five studies were run with house dust mite (HDM), one with olive pollen, one with wall pellitory (Parietaria) pollen, and one with grass pollen. A quantitative evaluation of the studies was not possible because the outcomes and the results of single studies were presented according to different criteria. Therefore only qualitative analysis was performed. No clinically relevant results were shown, independently from statistical significance, in the use of SLIT for respiratory allergies due to seasonal allergens (olive, wall pellitory, and grass pollens) and, on the whole, for rhinoconjunctivitis due to HDM in children. For mild to moderate persistent asthma due to HDM, statistically significant and low to moderate relevant clinical effects were observed.

SLIT can be currently considered to have low to moderate clinical efficacy in children of at least 4 years of age, monosensitised to HDM, and suffering from mild to moderate persistent asthma. This benefit seems to be adjunctive with respect to the environmental preventive measures against HDM.

The Research Evidence Base for Chinese Medical Herbal Formulas

An overview of the research evidence supporting the use of 11 of the most commonly used herbal patent formulas in chinese medicine

The following summary offers a small glimpse of the practice of chinese herbal patent medicine which relies on traditional formulas, that in many cases have remained unchanged since 200CE when they were first formulated. The summary for each of the 11 herbal patents includes examples of some of the clinical studies and research that have been conducted using that particular patent formula, but also lists the pharmacological effects that have been identified experimentally; possible clinical applications and either traditional usage of the therapeutic actions attributed to the formula according to traditional chinese medicine (TCM).

Bupleurum & Tang Kuei Formula (Xiao Yao San) – Rambling Powder


Pharmacological Effects:

1.        CNS: Administration of Xiao Yao San in mice and rats was associated with a mild inhibitory effect on the central nervous system to relieve pain and decrease the risk of seizures and epilepsy.[1]

2.        Hepatoprotective: Administration of this formula was associated with marked hepatoprotective effect against carbon tetrachloride induced liver damages. The formula reduced damage to liver cells, lowered liver enzymes, and promoted the generation of new liver cells.[ii]

3.        Endocrine: Administration of the formula was associated with an increase in weight of the uterus in laboratory animals. The effect was voided in animals whose ovaries had been surgically removed. The study suggested that the formula has an endocrine effect as it stimulated the ovary and increased the weight of the uterus.[iii]

4.        Gastrointestinal: Administration of the formula was associated with increased gastric acid production in mice and relaxation of the smooth muscles of the intestines in rabbits.[iv]

Clinical Studies & Research:

1.        Affective psychosis: 26 cases were treated with modified Xiao Yao San with significant improvement in 16 cases, moderate improvement in 7 cases, and no benefit in 3 cases.[v]

2.        Depression: One study reported 93.3% effectiveness using modified Xiao Yao San to treat depression in 60 patients. The patients also received counseling. Of 60 patients, the study reported complete recovery in 32 patients, significant improvement in 16 patients, moderate improvement in 8 patients, and no improvement in 4 patients.[vi]

3.        Neurosis: One study reported 96% effectiveness using modified Xiao Yao San to treat 47 patients with neurosis. Of the 47 patients, the study reported complete recovery in 31 patients, improvement in 14 patients, and no improvement in 2 patients.[vii]

4.        Premenstrual Syndrome (PMS): Xiao Yao San has been confirmed in many studies to successfully treat PMS. Use of the formula in 32 women was associated with 96.88% effectiveness. [viii] In another study, use of Xiao Yao San plus Xiang Fu (Rhizoma Cyperi) and Yu Jin (Radix Curcumae) was assocaited with 98% effectiveness in treating 62 women with PMS characterized by edema, breast distention, headaches, and emotional disturbance.[ix]

5.        Menstrual Pain: 48 patients with menstrual pain were treated with modified Xiao Yao San with significant improvement in 30 patients, moderate improvement in 12 patients, and no effect in 6 patients. The overall effective rate reported was 87.5%. The ages of the patients ranged from 15-45 years. [x]

6.        Irregular Menstruation: One study reported 91.4% effectiveness using modified Xiao Yao San to treat various types of irregular menstruation. Two additional herbs were added for each irregularity: early, late, unpredictable (early / late), hypermenorrhea (metrorrhagia?), hypomenorrhea, and prolonger menstruation (menorrhagia). Of 58 women, the study reported significant improvement in 45 patients, moderate improvement in 8 patients, and no improvement in 5 patients.[xi]

7.        Liver cirrhosis: 17 patients with liver cirrhosis were treated with modified Xiao Yao San with significant improvement in 6 patients, moderate improvement in 9 patients, and no improvement in 2 patients.[xii]

8.        Cholecystitis: Administration of modified Xiao Yao San was associated with good results in treating 168 patients with cholecystitis (32 with acute and 136 with chronic cholecystitis). Of 168 patients, the study reported significant improvement in 79 patients and moderate improvement in 89 patients.[xiii]

9.        Irritable Bowel Syndrome (IBS): Administration of modified Xiao Yao San for 1-2 months in 52 patients with IBS was associated with complete recovery in 34 patients and improvement in 18 patients.

Free & Easy Wanderer Plus – Jia Wei Xiao Yao San

Pharmacological Effects:

Anxiolytic: Use of Jia Wei Xiao Yao San showed anxiolytic effects through the neurosteroid synthesis followed by gamma-amino-butyric acid A/benzodiazepine (GABA(A)/BZP) receptor simulations in male mice.[xiv]

Clinical Studies & Research

1.        Menopause: A randomized, controlled pilot stud was preformed to evaluate and comapre the clinical effects of a 16-week treatment with Jia Wei Xiao Yao san and hormone replacement therapy (Premelle) in non-hysterectomized post-menopausal women. This study evaluated quality of life, and measured physiological parameters, such as follicle –stimulating hormone and estradiol levels. Both the herbs and drug effectively alleviated most of the menopausal symptoms with no significant differences. The formula demonstrated good compliance and safety, and was associated with a lower discontinuation rate due to lack of adverse side effects. The researchers concluded that Jia Wei Xiao Yao San is a safe and efficacious therapy and might be an alternative choice for relief of climacteric symptoms in post-menopausal women.[xv]

2.        Panic Disorder: 4 patients diagnosed with panic disorder with agoraphobia, in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, were successfully treated with herbal medicine. Two patients were treated with Jia Wei Xiao Yao San, and 2 with Ban Xia Hou Po Tang (Pinellia and Magnolia Bark Decoction). Both formulas successfully relieved panic attacks, anticipatory anxiety and agoraphobia. The study concluded that these formulas may be useful as additional or alternative treatments for panic disorder.[xvi]

Rehmannia Six Formula – Liu Wei Di Huang Wan – Six Ingredient Pill with Rehmannia

Pharmacological Effects:

1.        Reproductive: in laboratory experiments, the use of Liu Wei Di Huang Wan was associated with an increase in the weight of the sex organs, such as the ovaries, uterus, and testicles. There was also an increase in sperm counts in the male subjects. In addition, after ingestion of the herbs for 10 days, there was an increase in sexual activity by up to 40%.[xvii]

2.        Metabolic: In lab experiments, the use of Liu Wei Di Huang wan for 6 weeks lowered plasma cholesterol and triglycerides significantly in rats with elevated levels. In addition, there was an increase in HDL. However, the formula had little effect on plasma cholesterol and triglycerides in healthy rats.[xviii]

3.        Immunostimulant: Use of Liu Wei Di Huang Wan was associated with an increase in WBC count and activity.[xix] Moreover, use of this formula reversed the immune suppression induced by dexamethasone.[xx]

4.        Adaptogenic: Administration improved the physical performance of mice. After ingesting the herbs orally for 2 weeks, the mice were able to swim for 14.9 minutes, compared to 11.5 minutes for the placebo group that did not receive herbs.[xxi]

5.        Hepatoprotective and nephroprotective: administration of Liu Wei Di Huang Wan had protective effects on both the liver and kidneys. It has a hepatoprotective effect against damages induced by such substances as carbon tetrachloride, thioacetamide, and prednisolone.[xxii] It also increased blood perfusion to the kidneys, improved the kidney function, and reduced protein and uric acid in the urine.[xxiii]

Clinical Studies and Research

1.        Diabetes Mellitus: Liu Wei Di Huang Wan is considered one of the most effective formulas for treating diabetes mellitus. One study reported 93.55% effectiveness using a modified formula to treat 62 patients with non insulin dependent diabetes. Of 62 patients, the study reported complete recovery in 17 patients, improvement in 41 patients, and no benefit in 4 patients.[xxiv]

In another study, 20 patients with adult onset diabetes were treated with Liu Wei Di Huang Wan for 3-6 months with staibilization in 12 patients and improvement in 8 patients.[xxv]

In another study, modified Liu Wei Di Huang Wan was used for 20 days to treat 53 patients with diabetes, with marked improvement in 46 patients, improvement in 5 patients, and no benefit in 2 patients.[xxvi]

Lastly, one study reported that use of modified Liu Wei Di Huang Wan was associated with 89.2% effectiveness in 65 patients with non-insulin dependant diabetes mellitus.[xxvii]

2.        Menopause: In one clinical study, 23 patients with menopausal symptoms were treated with Liu Wei Di Huang Wan and experienced marked improvement in 9 patients (39.1%), and moderate improvement in 14 patients (60.9%). Clinical improvements included relief of hot flashes, tidal fever, perspiration, palpitations, anxiety, restlessness, insomnia, forgetfulness, and others. In addition, after taking the herbs continuously for one year, it was noted that there was a decrease in FSH and an increase of estradiol. The mechanism fo action was attributed to the formula’s stimulating effect on the endocrine system.[xxviii]

3.        Hypertension: Administration of 5-10 packs of Liu Wei Di Huang Wan effectively reduced blood pressure in all 31 patients with primary hypertension. In follow up visits one year later, 23 patients had normal blood pressure, and 8 still had hypertension.[xxix]

4.        Chronic Nephritis: Use of Liu Wei Di Huang wan plus Yu Mi Xu (Stigma Maydis) was reported in one study to be effective in treating patients with chronic nephritis with hypertension and proteinuria. The study found that administration of the combination in decoction daily for 3-24 months in 77 patients with chronic nephritis was associated with complete recovery in 22 patients, near complete recovery in 36 patients, partial recovery in 13 patients, and no benefit in 6 patients. The study noted that most patients with chronic nephritis had underlying Kidney yin deficiency and damp heat.[xxx]

5.        Infertility: Modified Liu Wei Di Huang Wan was used to treat infertility in 42 patients (16 males and 26 females between the ages of 22 to 37). The duration of marriage of the patients ranged from 1-14 years. After 3-6 months of herbal treatment, the study reported marked resutls in 31 patients, moderate results in 9 patients, and no benefit in 2 patients. (Note: criteria for evaluation was not given).[xxxi]

Yin Qiao San / Yin Chiao Formula

Clinical Applications:

Common cold, influenza, high fever, pneumonia, acute upper respiratory infection, pharyngo-conjunctival fever, tonsillitis, parotitis, canker sores, viral myocarditis, epidemic encephalitis B, and drug induced dermatitis.

Pharmacological Effects:

Antibiotic: According to in vitro studies, Yin Qiao San has broad spectrum of inhibitory effects against such pathogens as Staphylococcus aureus, Bacillus subtilis, Bacillus proteus, Pseudomonas aeruginosa, and Candida albicans. The minimum inhibitory concentration was 110 mg/ml (equivalent to 550mg/ml of raw herb).[xxxii]

Clinical Studies and Research:

1.        Common cold and influenza: 300 patients with infectious viral infection were treated with Yin Qiao San with most reporting improvement after 1-2 doses.[xxxiii]

2.        High Fever: In one study, 102 children with high fever caused by infection were treated with 87.25% effectiveness usign modified Yin Qiao San. After using 1-3 packs of the herbs, the study reported improvement in 89 of 102 patients.[xxxiv]

3.        Acute Upper Respiratory Infection: In one report, 1150 patients with wind heat exterior infection were treated with Yin Qiao San with relief of fever within an average of 2.7 days.[xxxv]

4.        Pneumonia: One study reported recovery in all 25 children with pneumonia after they were treated with 3-5 packs of modified Yin Qiao San.[xxxvi]

5.        Tonsillitis: Modified Yin Qiao San successfully treated 36 patients with acute tonsillitis. Of 36 patients, 24 had complete recovery and 12 had improvement. The average duration of treatment was 9 days.[xxxvii]

Liu Jun Zi Tang / Six – Gentleman Decoction

Pharmacological Effects:

1.        Gastrointestinal: According to lab experiments in rabbits, administration of Liu Jun Zi Tang was associated with regulatory effects on the intestines. Depending on the condition of the subject, it will either increase or decrease intestinal peristalsis.[xxxviii]

According to another study, Liu Jun Zi Tang to have a prokinetic action on gastric emptying to treat chronic dyspepsia.[xxxix]

In regards to plasma levels of gut related peptide, administration of Liu Jin Zi Tang caused significant increases in plasma somatostatin and gastrin levels at 60 to 240 minutes compared with a placebo group.[xl]

2.        Gastroprotective: In one study in rats, use of Liu Jun Zi Tang had a dose dependent effect and significantly inhibited gastric mucosal damage caused by absolute ethanol at doses over 500mg/kg. The mechanism of this gastroprotective effect occurred partly through nitric oxide, not through prostaglandins or sulfhydryls.[xli]

Clinical Studies and Research

1.        Abdominal Pain: Patients with abdominal pain were treated with modified Liu Jun Zi Tang for 20 days. The causes of abdominal pain included chronic gastritis, gastric ulcer, and duodenal ulcer. The formula included the adition of Yan Hu Suo (Rhizoma Corydalis) and Bai Shao (radix Paeoniae Alba). Out of 123 patients, the study reported significant improvement in 49 patients, moderate improvement in 65 patients, and no effect in 9 patients. The overall efficacy rate reported was 92.7%.[xlii]

2.        Gastritis: According to one study, administration of Liu Jun Zi Tang to 207 patients with acute or chronic gastritis was associated with significant improvement in 62.9% and moderate improvement in 82.3% of patients. The treatment protocol was to administer 2.5g of the herbs in powder form, three times a day before meals.[xliii]

Si Wu Tang / Four Substance Decoction

Pharmacological Effects:

1.        Hematopoietic: Si Wu Tang, Si Jun Zi Tang (Four Gentlemen Decoction), and Shi Quan Da Bu Tang (All-Inclusive Great Tonifying Decoction), were given orally to mice to evaluate their effect for treatment of anemia. The study concluded that Shi Quan Da Bu Tang was most effective, followed by Si Wu Tang. The mechanism of action was attributed to increased activity of CSF.[xliv]

2.        Cognitive: Administration of Si Wu tang was associated with a dose dependent effect to improve memory and cognitive functions in rats. The dose given ranged from 0.5 to 1.0g/kg of the dried herbs.[xlv]

Clinical Studies and Research:

1.        Menstrual Pain: Many studies have shown that menstrual pain can be treated effectively with Si Wu Tang or augmented versions of the formula. In one study, of 57 patients, significant improvement was reported in 25 patients, moderate improvement in 25 patients,

The Research Evidence Base for Homeopathy


The following is a summary of the research evidence basis for homeopathic medicine; one of the various modalities used in naturopathic medicine. It is organized from the highest grade of evidence, beginning with the systematic reviews and meta-analyses, which are themselves critical reviews of the controlled trials done on homeopathy; the systematic reviews critically analyze the quality and content of the studies, while the meta-analyses focus on the statistical sum of the combined studies. These are then followed by a short review of the randomized controlled trials completed to date, along with some descriptive studies assessing the cost effectiveness and perceived benefit from clinical observations studies. Basic laboratory science studies on the properties of water and various materials then follows, along with some studies of cellular, molecular and animal systems which round up the evidence basis

Although the more valued systematic reviews and meta-analyses carry more weight as offering substantial evidence, it is note worthy that there exists further positive evidence from other areas such as molecular and animal systems that lend significant support for the evidence basis of homeopathic medicine. In total, it is evident from this brief summary that there exists substantial support for the effectiveness and efficacy of homeopathy as a clinical therapy, and evidence of the action of homeopathic dilutions on biological systems.

Systematic reviews of randomised controlled trials (RCTs) of homeopathy

• Four of five major comprehensive reviews of RCTs in homeopathy have reached broadly positive conclusions.1,2,3,4 Based on a smaller selection of trials, a fifth review came to a negative conclusion about homeopathy.5

• Positive conclusions have been reported in 9 of 23 reviews of RCTs in specific categories of medical condition (the other 14 are largely inconclusive):

• allergies and upper respiratory tract infections6

• childhood diarrhoea7

• influenza treatment 8

• post-operative ileus9

• rheumatic diseases10

• seasonal allergic rhinitis11,12,13

• vertigo.14


·        Shang et al 2005 (8 of 110 studies): (Negative conclusion – validity suffers from significantly poor and questionable methodology; please see below);

·        Cucherat et al 2000* (16 High Quality (Hi-Qt) studies; Quality assessed using SAPEH scores (Score for Assessment of Physical Experiments on Homeopathy), high-quality > 6): + (Positive conclusion)

·         Linde & Melchart 1998* (32 Hi-Qt studies): + (Positive conclusion)

·         Linde etal 1997* (89 studies): + (Positive conclusion)

·         Boissel etal 1996 (15 Hi-Qt studies): + (Positive conclusion)

·         Kleijnen etal 1991 (105 studies): + (Positive conclusion)

*Included in UK DARE: (Database of Abstracts of Reviews of Effects)

Shang et al 2005 Meta-analysis

·         This particular Meta-Analysis is a good example of a poorly done and biased study, that arrived at a negative conclusion following a poorly described and improperly used methodology that compared a very small selection of homeopathic trials to an even smaller selection of conventional medical trials.

·         The study’s conclusion was based on comparison of 8 homeopathy vs. 6 conventional medicine trials, after narrowing both groups down from a selected representation of 110 trials each;

·         Criteria for the selection of the 8 high-quality trials was not given and no references were given;

·         The study did not conform with QUOROM guidelines for systematic reviews which require full disclosure of the methods and criteria used to obtain the final study groups that contribute to the analysis;

·         As a result of the poor quality of the study whose conclusions are contrary to the evidence already shown in other meta-analyses, the study is not classified as a systematic review by UK DARE (Database of Abstracts of Reviews of Effects);

·         Nonetheless, as the most recently completed meta-analysis, the study continues to garner attention and notice despite its poor and misleading results.

RCTs of homeopathy – the original peer-reviewed research literature

• Up to the end of 2008, 138 RCTs had been published: 60 positive;10 negative; 68 not statistically conclusive. In addition to the above seven conditions, there is positive evidence from two or more RCTs in each of the following three areas:

• fibromyalgia15,16

• osteoarthritis17,18

• sinusitis.19,20

• There is evidence from single RCTs in favour of homeopathy for a number of other conditions, including: acute otitis media,21 ankle sprain,22 bronchitis,23 chronic fatigue,24 premenstrual syndrome.25

Cost effectiveness of homeopathy

• Incorporation of homeopathy with conventional treatment is associated with better clinical outcomes for similar or lower costs.26,27,28

Clinical observational studies

• 70.7% of 6,544 follow-up patients, treated at Bristol Homeopathic Hospital for a wide range of chronic medical complaints, reported positive health changes.29

• Many patients attending the Royal London Homoeopathic Hospital were able to reduce or stop conventional medication following homeopathic treatment.30

Basic Science

• Laboratory research has obtained evidence that water may retain information about homeopathically-prepared solutes.31,32,33

• Additional laboratory studies have shown that homeopathic dilutions can exert biological effects.e.g. 34,35,36

Evidence from Material Sciences

·         NMR evidence (5/5 Hi-Qt* pub): (+)37

*Quality assessed using SAPEH scores, high-quality > 6

Molecular and cellular systems (in-vitro studies)

·         Enzymatic reactions (7/9 Hi-Qt* pub) (+)38

·         Cultured cells (5/9 Hi-Qt pub) (+)38

·         Basophil degranulation (8/11 Hi-Qt pub) (+)38

*Quality assessed using SAPEH scores, high-quality > 6

Animal Systems (in-vitro & in-vivo studies)

One review in 1998 (no access);

·         One review in immunology in 2006;

·         Immunostimulation (16 publications);

·         Immunoregulation, inflammatory processes (20 publications);

·         No systematic review in this area despite wide use and high number of experiments;

Overview of Selected Case Studies of Animal Systems

·         A number of studies have demonstrated that a seven hundredth or 7c dilution (approximately 10-14 M, in terms of molar concentration) of arsenic and bismuth is capable of increasing the urinary eliminatin of these same metals by rats intoxicated with them39, 40. The arsenic had no effect on bismuth intoxication and vice versa, indicating specificity of action.

·         This property has not been observed with lead, in that high dilutions of this metal failed to modify the excretion kinetics of lead in rats41. The arsenic experiments have been repeated using more updated and controlled methods42; the results were substantially the same: the intraperitoneal injections of arsenic (as aresnic trioxide, As2O3, or arsenic acid, H2AsO3), diluted and dynamized, reduced the blood levels, and increased the excretion of arsenic in rats treated with high doses (10mg/kg) of arsenic trioxide. In a series of dilutions tested (5c, 7c, 9c, 11c, 13c, 15c, 17c, 19c, 21c, 23c, 25c, 27c, 29c, 31c), the most active dilutions in the protective sense were 7c and 17c, and the difference versus dilutions of dynamized water alone was highly significant. It is of interest to note that the protective effect of the high dilutions was abolished if they were subjected to heating to 120 degrees for 30 minutes.

·         On the basis of the analogy of existing on both the biological and anatomicopathological planes between carbon tetrachloride (CCl4) intoxication and phosphorus intoxication, the Bildet group have demonstrated the protective effect of high dilutions (7c and 15c) of phosphorus and of the 7c dilution of carbon tetrachloride on CCl4 – induced toxic hepatitis in the rat43.

·         The effect of high dilutions of CCl4 confirmed similar data reported in the non-homeopathic literature, testifying to an increased resistance of the liver after treatment with low doses of a toxic agent 44, 45. It has also been reported that small doses of cadmium reduce the renal toxicity caused by that metal in the rat46. It is likely that a synthesis inducing mechanism (of so called stress proteins) or a mechanism increasing the enzyme activity of the detoxification systems play some role in this type of phenomenon.

The Research Evidence Base for Apitherapy (BVT or Bee Venom Therapy)


History of Bee Venom Therapy

The use of bee venom as a therapy goes back to antiquity. Hippocrates himself was said to practice apitherapy – or the medical use of honeybee products, having used bee stings for the treatment of rheumatic conditions, and honey for a variety of infections. Bee venom continued to be used in a similar fashion up until the present time, primarily by lay practitioners, naturopathic doctors, herbalists, acupuncturists, and those afflicted with arthritis or multiple sclerosis, who learnt the practice from local bee keepers. In the 1800s and 1900s, various medical doctors, including Drs. Beck, and Broadman, brought the practice into the clinic, and wrote of their experiences using the therapy, thus helping to bring the practice out of obscurity. The first scientific inquiry into bee stings began in the late 19th century when an Austrian physician, Philip Terc, noticed that his rheumatism patients experienced positive results from bee stings1.

Of the conditions which are most often indicated for bee venom by apitherapists, Charles Mraz2, a beekeeper in Middlebury, Vermont who has popularized bee venom therapy for the past 60 years, listed the following:

1.        Arthritis (Osteo & Rheumatoid), and other systemic inflammations:  Bee venom therapy can be useful in both rheumatoid and osteoarthritis, helping both pain and swelling.  In the case of rheumatoid arthritis, rheumatoid nodules can lessen in size.  Other connective tissue diseases such as scleroderma have been (anecdotally) helped by bee venom therapy.  Even systemic inflammations not related to joints, such as ulcerative colitis or even asthma, may warrant a trial of bee venom.  A possible mechanism of action is due to the stimulation of endogenous cortisol through the hypothalamus-pituitary-adrenal axis, and its resulting anti-inflammatory effect. With regards to clinical studies of BVT in the treatment of arthritis, there have been multiple published studies, including several from the 1930s3, 4, 5, as well as more recently 6, 7.

2.        Acute and chronic injuries:  Bursitis, tendonitis and other areas of injury respond well to bee venom therapy.  Local anti-inflammatory effects, and the immune responses to a foreign protein might be involved here.  Chronic back and neck pain will respond, as will other aches and pains.

3.        Scar tissue:  Keloids and other scar tissue are broken down and softened by the hyaluronidase and other substances in the bee venom.  These often respond by flattening out and fading in color.  Internal scar tissue, such as adhesions from previous surgery, may respond to treatment over the area.

4.        Multiple Sclerosis:  This use of bee venom is poorly understood, and needs to be studied further.  The common responses are increased stability, less fatigue, and less spasm. More than 1,300 people with MS have sent testimonials to the American Apitherapy Society in support of the therapy.

5.        Desensitization: It is estimated that 1-2% of the population is allergic to bee stings. Such an allergy is typically an anaphylactic reaction, which can involve decreased blood pressure, skin rashes, tachycardia, chills, generalized pallor, and more serious symptoms such as shortness of breath, heart palpitations and constriction, syncope and possible death. Bee venom can be used in minute doses to desensitize such people to insect stings. This is the only conventional use of bee venom.

Components of Honey Bee Venom, or Apitoxin

Apitoxin, or honey bee venom, is a bitter colorless acidic liquid (pH 4.5 – 5.5), that is produced in the abdomen of worker bees, and contains a complex mixture of 18 active proteins, that cause local inflammation and act as an anticoagulant on injection. 0.1 mg of venom is injected via the honeybee’s stinger. Mellitin, the most prevalent substance, comprising 52% of venom peptides, is one of the most potent anti-inflammatory agents known (100 times more potent than hydrocortisone). It induces the production of cortisol in the body6, and is a powerful stimulator of phospholipase A2. Melittin also exhibits potent anti-microbial activity, having been shown to exert “profound inhibitory effects” on Borrelia burgdorferi7, as well as the yeast Candida albicans8, while also being able to exert suppressive action on Mycoplasma hominis and Chlamydia trachomatis infections9. At Washington University School of Medicine in St. Louis, very small nanite “nanobee” devices are being used to carefully deliver melittin, which is known to disrupt cellular walls and thus destroy cells, to tumor cells10.

Research Overview

Bee Venom Acupuncture for Musculoskeletal Pain (Positive)

The currently only existing systematic review of apitherapy is Lee’s 2008 Journal of Pain study11 – Bee venom acupuncture for musculoskeletal pain: a review, which reviewed the effectiveness of bee venom therapy for musculoskeletal pain when combined with an acupuncture approach; injecting diluted BV into acupoints and is used for arthritis, pain, and rheumatoid diseases.

Seventeen electronic databases were systematically searched up to September 2007 with no language restrictions. All randomized clinical trials (RCTs) of BVA for patients with musculoskeletal pain were considered for inclusion if they included placebo controls or were controlled against a comparator intervention. Methodology quality was assessed and, where possible, statistical pooling of data was performed. A total of 626 possibly relevant articles were identified, of which 11 RCTs met our inclusion criteria, and were included in the review (n=475). Sample sizes ranged from 26 to 80 participants. Trial quality varied, but was on average moderate. The degree of confidence that acupuncture was applied appropriately ranged from 60 per cent to 90 per cent.

Overall, bee venom acupuncture was associated with reduced pain compared to control treatments in 10 trials. A statistically significant difference in pain was seen for the four trials comparing bee venom acupuncture plus classic acupuncture with saline injection plus classic acupuncture, the two trials comparing bee venom acupuncture plus classic acupuncture with classic acupuncture alone, and the three trials comparing bee venom acupuncture with classic acupuncture. Pain was significantly lower with BVA plus classic acupuncture than with saline injection plus classic acupuncture. The total number of RCTs included in the analysis however, and the total sample size were too small to draw definitive conclusions. Future RCTs should assess larger patient samples for longer treatment periods and include appropriate controls.

BVT for Treating Multiple Sclerosis

Despite, its long therapeutic history, considerable anecdotal evidence, and the promising biochemical makeup of the venom and its physiological actions in both animal and human models, it has to date, received very little critical examination, in regard to both safety and effectiveness in its role in the treatment of MS. That of course, has not prevented considerable interest and demand from MS sufferers, in light of the continued progression of their disease. In the United States, it has been estimated that nearly 10000 people with MS have used BVT to some extent 12. In addition to the great need for evaluating potential new therapeutic options in the treatment of MS, as this therapy entails the real risk of fatal allergic reactions as well as emotional and economic costs, properly conducted studies of safety and efficacy of bee venom therapy are needed.

Anecdotal Reports of the use of BVT in the Treatment of MS

As for what might be expected based on anecdotal reports, Dr. Bradford Weeks, MD (Clinton, Washington), past president of the American Apitherapy Society, had found from his experience that those most severely afflicted by the disease could expect to gain strength, lessen their fatigue substantially, and find their mood improving. Those less chronically afflicted, could find a greater sense of energy upon first initiating therapy, followed by the possibility of better neurological transmission, including improved sensation, proprioception, and less sensation of wall walking, and ataxia. Among chronic progressive patients on BVT, and using the nutritional protocols which Dr. Weeks required of his patients, he found that: 5% got out of their wheelchairs, 40% traded their walker for a cane, and about 55% retire their cane13. Dr. Weeks theorizes that those who fail to respond to BVT are malnourished or have bad health habits such as smoking, which prevents their adrenals from producing cortisol properly in response to the bee venom.

Honeybee Venom Extract as a Possible Treatment for Patients with Progressive Forms of Multiple Sclerosis – (Inconclusive – Mixed Results)

H.J. Castro, M.D., J.I. Mendez-Inocencio, M.D., B. Omidvar, M.D., J. Omidvar, M.D.,

J. Santilli, M.D., H.S. Nielsen, Ph.D., A. P. Pavot, M.D., J. R. Richert, M.D., & J. A. Bellanti, M.D.

(Allergy and Asthma Proc 200: 26:470 –476)

A total of nine patients with progressive forms of MS, were entered into the study, and responses to therapy were evaluated by questionnaire, functional neurological tests, and changes in measurement of somatosensory-evoked potentials. Although no serious adverse allergic reactions were observed in any of the nine subjects, four experienced worsening of neurological symptoms, requiring termination in the study; this could not be ascribed to side effects of the therapy, nor was it correlated to dosage. These consisted of, e.g., increased spasticity, decreased ambulation, increasing fatigue, new-onset nystagmus, new-onset gaze paresis, and worsening bowel/bladder dysfunction. Of the remaining five subjects, three felt that the therapy had subjective amelioration of symptoms and two showed objective improvement. Objective neurological measures showed improvement in two subjects, clear worsening in four subjects, equivocal worsening in one subject, and stability in two subjects.

Although this preliminary study suggests safety, because of the small numbers studied, there were no definite conclusions regarding efficacy and therefore there was little evidence to support the use of honeybee venom in the treatment of MS. Larger and more carefully conducted multicenter studies will be required to establish efficacy.

A Randomized Crossover Study of Bee Sting Therapy for Multiple Sclerosis (Negative)

T. Wesselius, MD*; D.J. Heersema, MD, PhD*; J.P. Mostert, MD; M. Heerings, NP;

F. Admiraal-Behloul, PhD; A. Talebian, MD; M.A. van Buchem, MD, PhD; and J. De Keyser, MD, PhD

(NEUROLOGY 2005;65:1764–1768)

In this randomized, crossover study, 26 patients with relapsing-remitting or relapsing secondary progressive MS, who were not receiving any immunosuppressive or immunomodulating drug treatment, were assigned to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week to the upper leg, with gradual increment of one additional sting at each session, to a maximum of 20 bee stings per session.

Patients were assessed using MRI to determine whether there were any beneficial effects on lesions in the nervous systems – either a reduction in the number of new lesions or progression of existing lesions. In addition, patients were assessed using a variety of Quality of Life Questionnaires and disability status scales.

While the treatment was well-tolerated, no beneficial effects were seen on the MRIs or clinically among these patients; there was no improvement of disability, fatigue, or quality of life.

Bee-Venom Therapy for Treating Multiple Sclerosis – A Clinical Trial (Positive)

Ross A. Hauser, M.D., Marylou Daguio, R.N., David Wester, P.A., Marion Hauser, M.S., R.D., Anne Kirchman, R.N., and Catherine Skinkis, M.A.

(Alternative & Complementary Therapies, 2001: Vol. 7, No. 1, pp. 37-45)

51 subjects were enrolled in this year long study. Demographic information on these 51 subjects were as follows:

14% relapsing–remitting MS; 86% chronic-progressive; 29.4% male; 70.5% female; mean age, 48.4; and average length of diagnosis, 10.1 years. Initial dosing was 1 injection every other day for 1 week, with an increase in dosage every week by one injection per session until positive clinical effects of the venom reached a plateau. In relation to the production of endogenous cortisol, this could be interpreted as a means to triturating the anti-inflammatory effects to the necessary dose-response, as would be similarly done with prednisone.

Gross analysis showed that more than 68 % showed some kind of positive effect, with 58% demonstrating a noticeable improvement. The most dramatic improvements in the first 3 months came in fatigue, endurance, and bowel control. By the end of 12 months, improvements in fatigue were still the greatest. Balance was the second greatest area of improvement, followed by endurance, coordination, and bowel control. Except for memory, vision numbness, concentration, mood, and sexual function, all findings were significant (P<0.021 or less) using the Friedman statistical test.