Monthly Archives: June 2021
An article in the Daily Mail (I know, not my favorite newspaper either) reported about a UK court case against the father of an 11-year-old daughter who objected to her being given conventional life-saving treatments for her leukemia. The man was said to be worried about possible side effects and wanted to explore homeopathic and natural therapies, while his estranged wife favored the conventional approach.
Mr Justice Hayden decided that there is ‘no basis’ for the man’s homeopathic option and that specialists can lawfully carry out the conventional treatments. But the father said he believed that previous chemotherapy had already weakened his daughter’s immune system and that the conventional treatment proposed has further side effects. He, therefore, wanted to try homeopathic and natural therapies, including ozone therapy. ‘I am not waiting for her to deteriorate and get worse,’ he told the judge. ‘Chemotherapy is not the only way. There are so many other different therapies I am hoping to try – anything as long as it doesn’t really affect her.’
A specialist treating the girl told the judge that the treatments proposed are the best option and that they know of no homeopathic options which would help. Mr Justice Hayden approved Great Ormond Street’s plan and said doctors should start the treatments as soon as possible. ‘If she receives no treatment then her life expectancy is weeks,’ he said. ‘There is no basis for the father’s homeopathic option.’
This case highlights the indirect risks of homeopathy and similar treatments in an exemplary fashion. The therapies per se might be harmless but the therapists are clearly not. There are enough homeopaths who are deluded enough to persuade their patients that homeopathy can alter the natural history of even serious conditions such as cancer. And, as we have discussed recently, these irresponsible fools are not just from the ranks of the lay-homeopaths (homeopaths who have not been to medical school) who might not know better; they also include medically trained homeopaths and even professors at leading medical schools.
Qigong can be described as a mind-body-spirit practice that improves one’s mental and physical health by integrating posture, movement, breathing technique, self-massage, sound, and focused intent. But does it really improve health?
The purpose of this review was to evaluate the effectiveness of Qigong in improving the quality of life and relieving fatigue, sleep disturbance, and cancer-related emotional disturbances (distress, depression, and anxiety) in women with breast cancer.
The PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Sinomed, Wanfang, VIP, and China National Knowledge Infrastructure databases were searched from their inceptions to March 2020 for controlled clinical trials. Two reviewers selected relevant trials that assessed the benefit of Qigong for breast cancer patients independently. A methodological quality assessment was conducted according to the criteria of the 12 Cochrane Back Review Group for risk of bias independently. A meta-analysis was performed using Review Manager 5.3.
A total of 17 trials were found in which 1236 cases were enrolled. The quality of the included trials was generally low, as only 5 of them were rated high quality. 14 studies were conducted in China. The types of qigong included Baduanjin Qigong (9 trials), Chan-Chuang Qigong (1 trial), Goulin New Qigong (2 Trials), Tai Chi Qigong (2 Trials), and Kuala Lumpur Qigong (1 trial). The course of qigong ranged from 21 days to more than 6 months. Four trials compared qigong to no treatment, one sham Qigong, seven compared to other types of exercise, and 6 to usual care.
The results showed significant positive effects of Qigong on quality of life (n = 950, standardized mean difference (SMD), 0.65, 95 % confidence interval (CI) 0.23–1.08, P = 0.002). Depression (n = 540, SMD = −0.32, 95 % CI −0.59 to −0.04, P = 0.02) and anxiety (n = 439, SMD = −0.71, 95 % CI −1.32 to −0.10, P = 0.02) were also significantly relieved in the Qigong group. There was no significant benefit on fatigue (n = 401, SMD = −0.32, 95 % CI 0.71 to 0.07, P = 0.11) or sleep disturbance relief compared to that observed in the control group (n = 298, SMD = −0.11, 95 % CI 0.74 to 0.52, P = 0.73).
The authors concluded that this review shows that Qigong is beneficial for improving quality of life and relieving depression and anxiety; thus, Qigong should be encouraged in women with breast cancer.
No, this review does not show that Qigong is beneficial for improving quality of life and relieving depression and anxiety!
- Most primary studies were of very poor quality.
- Most were from China, and we know (and have often discussed) that such trials are most unreliable.
- No trial even attempted to control for placebo effects.
A better conclusion would therefore be something like this:
Even though most trials conclude positively, the value of Qigong can, for a range of reasons, not be determined on the basis of the evidence available to date.
On 7/10/2020, I discussed a study suggesting that homeopathy improves the quality of life and survival of cancer patients. Now, these data have been carefully scrutinized by a group of members of the „INH“ and „Initiative für Wissenschaftliche Medizin“.
By guest bloggers Norbert Aust and Viktor Weisshäupl
The first impression of the results of the study on the adjunctive homeopathic treatment of patients with non-small cell lung cancer (NSCLC) is that of a seemingly rigorous trial with valid results. But a more thorough review yields different insights:
- The methods and definitions were pre-determined in a protocol and seem to have been maintained up to the end. But the date given in the document pointing at some point in time before enrollment began is wrong and misleading: This protocol was first published by uploading it to the register only two months after data assessment was completed with outcomes presumably available.
- The data initially saved to the register are not in agreement with the information given in the published paper: important definitions were subjected to considerable modifications while the study was underway. None of these modifications are mentioned in the paper, neither a rationale nor a comment of their impact on the results was provided.
- Some of the modifications with presumably heavy impact on the results were introduced with the upload of the protocol only, that is two months after data collection was completed. These were (a) a massive extension of the exclusion criteria: the number increased from 1 during initial registration to 20 in the final paper. and (b) an equally massive reduction of the follow-up time for the primary endpoint from two years to 18 weeks.
- The paper discloses no reason why the additional exclusion criteria were introduced. Their selection seems arbitrary without any apparent necessity arising from the trial itself.
- The patients who did not meet the added criteria and were thus excluded are not mentioned in the publication. The CONSORT flow chart does not give information either of their number or of the point in time when they were excluded.
- The survival curves of the placebo and verum groups show some aspects that arise if the inter-group difference was due to the exclusion of unfavorable data.
- It is hard to imagine that, in this trial, the homeopathic preparations had strong effects on the patients’ health, while other rigorous studies or systematic reviews failed to notice such effects.
Altogether, it seems much more plausible to assume that the positive results were achieved by post hoc data manipulation, namely by omitting patients with unfavorable outcomes, than by rigorous and valid science. A retraction of the paper seems the only appropriate measure to avoid misleading the public.
Due to its outstanding results, the study about adjunct homeopathic treatment of non-small cell lung cancer patients was met among homeopaths with enthusiasm. However, in this article, we will show that the enthusiasm is unjustified because the results may not be based on a rigorous trial meeting established scientific criteria. Crucial definitions were modified, while the study was underway or even after data collection was completed. It stands to reason that this introduced bias in favor of homeopathy.
For this analysis, we considered the following sources of information :
- the text of the published paper (link)
- the data that were uploaded during registration (link)
- the history of changes of the registered data (link)
- the study protocol included in the registration (link)
As all of this information is readily available on the internet, it is easy to double-check our findings and verify our statements. We also submitted a letter to the editor of the Oncologist, the journal where the paper was published which has not yet been published (status 06-06-2021).
At first glance, the study meets the requirements for reliable evidence.
- There is a study protocol dated January 11, 2011, well before recruiting of participants started. It provides definitions that were used until the end.
- The study was registered at ClinicalTrials.gov before recruiting started.
- The methods of randomization and blinding are suitable to meet the requirements for a low risk of bias rating.
- The presentation of the paper follows the principles set out in the CONSORT-Statement.
- The paper was published in a peer-reviewed journal of some reputation.
The study yielded formidable results in favor of homeopathy: In the group that received the adjunctive homeopathic treatment, the quality of life improved continuously throughout the follow-up time, while the patients in the placebo group deteriorated. In addition, the median survival time was only about two-thirds compared to the patients in the homeopathy group. However, the impression of a valid study does not stand up to closer scrutiny when the history of changes is taken into account.
Changes in study parameters
Between the initial registration and data upload in January 2012 (Link), shortly before recruiting started in February 2012, and the publication in October 2020, multiple changes in essential study parameters occurred:
|Registration January 2012||Publication October 2020|
|Number of participants||600||150|
|Number of study arms||2||3|
|Number of exclusion criteria||1||20|
|Follow-up time for Quality of life||104 weeks (*)||18 weeks|
|Number of cancer types||3||1|
|(*) Derived from “Time Frame: 7 Years” minus the recruitment period of 5 years.|
Note the drastic reduction in the follow-up time for quality of life by more than 80 % which was defined as the primary endpoint. Furthermore, note the substantial increase in the number of exclusion criteria. Both issues will be discussed in more detail below.
In contrast to the requirements for a rigorous and valid trial, these modifications are not mentioned in the published paper, and no rationale is given as to why they became necessary. As a consequence, the authors do not discuss the possible impact these modifications may have had on the results.
The study protocol
A study protocol is available in the registration database. It was first uploaded on September 18, 2019, about two months after the end of data collection in July 2019 (Link). The document itself is dated January 11, 2011, which would place it about a year before the study was registered. However, this date is obviously wrong: there are substantial discrepancies between the parameters specified in the protocol and the data provided one year later during initial registration:
|Protocol, allegedly January 2011||Registration January 2012|
|Number of participants||300||600|
|Number of study arms||3||2|
|Number of exclusion criteria||9||1|
|Follow-up time for Quality of life||18 weeks||104 weeks (*)|
|Number of cancer types||1||3|
|(*) Derived from “Time Frame: 7 Years” minus the recruitment period of 5 years.|
We see no sensible explanation why the parameters given in the study protocol allegedly compiled in January 2011 are in line with the publication nine years later, but not with the registration only one year after the protocol was compiled. The only sensible conclusion seems to be that this protocol was not completed on the date indicated, but at a much later point in time, maybe just shortly before its upload (September 2019). This impression is corroborated by the information presented in the document that was not available on the date given: On page 10 the software package used in data analysis is referenced as “IBM SPSS statistics 25.0” while, at the beginning of 2011, when the protocol was allegedly compiled, the current version number of this package was 19 only.
A second clue: Also on page 10 there is a reference “(EORTC-QLQ-C30 remaining dimensions; SF-36; subjective well-being)25.” with the number 25 indicating some reference. And some references that is, but not in the protocol – this does not have any references – but in the published paper, where the 25 indicates a paper on the SF-36 questionnaire. So it stands to reason that the number in the protocol originates from some messed up copy and paste procedure from the draft of the paper. Which would indicate that the paper and the protocol were at least partially developed in parallel.
It seems therefore reasonable to assume, that the protocol was finished only shortly before it being uploaded in September 2019, that is two months after data collection was completed.
However, the obviously inaccurate date given in the protocol supports the impression that the study parameters were set a year before the study began and were consistently maintained during the course of the trial, which is not the case, as the above tables show.
Change in exclusion criteria
The initial registration data list pregnancy as the only exclusion criterion. But with the upload of the protocol, which took place two months after data collection was completed, the number of exclusion criteria was increased to nine, only to be enlarged once again in the final publication to the final number of twenty. It is beyond any doubt that at least the final increase of eleven criteria took place after the data collected from the patients were available. But all this is neither disclosed in the final paper nor is there any rationale given for this action.
The patients excluded by the additional criteria never appear anywhere, they are not included in the CONSORT-flow-chart, Fig 3 in the study. It is obvious that some patients were excluded: What was the reason to define such an abundance of criteria, if they were not to be applied? As a consequence, the CONSORT diagram seems to be incomplete which would be in violation of the CONSORT statement.
Thus, an unknown number of patients seems to have been excluded from the study by criteria defined at a time after data collection was completed with outcomes available. After all, eleven of the exclusion criteria were established even after the protocol had been uploaded, at least those were established well after the patients’ results were available.
This raises the question of why these exclusion criteria were introduced. One would assume that an intervention to treat stage III and stage IV lung cancer patients should be effective under the conditions that are usually present in such patients. One would expect that patients somewhat advanced in age, like in this study, usually suffer from some health problems, regardless of their cancer condition. What is the sense of excluding patients with hematological, hepatic, or renal pathology, with coronary heart disease or rheumatism? Homeopathy is claimed to be able to treat comorbidities based on the assessment of symptoms independent of what disease they belong to. And this apparently was the idea at the start of the trial where only pregnancy was specified as an exclusion criterion, while it was understood that elderly patients to be enrolled in the study would suffer from some additional medical problems.
On the other hand, not all health conditions that are associated with advanced age were excluded. Diabetes, hypertension, gastrointestinal diseases, or COPD were no reason to exclude any patient from participation. Only very few of the criteria are somewhat self-explanatory as to why they were defined as exclusion criteria, e.g. if a patient was unwilling to give her informed consent.
Altogether, the assumption seems reasonable that more patients had participated in the trial than accounted for in the publication, and that an unknown number of them were excluded according to criteria that were not present until after data collection was completed. If so, a substantial bias was introduced.
Median survival time
Here, we will focus on the comparison between the homeopathy and placebo groups and leave aside the third group not receiving any additional treatment at all.
If the favorable result in survival really was established by dropping unfavorable data, this might be recognized in some characteristics of the survival curves. Therefore, we modeled this situation starting with two random distributions somewhat tweaked to resemble the typical shape of natural survival functions.
This graph shows the two distributions (n = 80) defined in the range of 0 to 200 as thin lines. Both are very similar to each other with median survival at 27 weeks. If 15 of the 20 patients with the shortest survival are dropped from the thin blue line this would result in the solid blue line (“Hom”). If, on the other hand, 15 out of 20 patients with the longest survival are dropped from the other distribution this would yield the solid red line (“Plac”).
The new functions show some characteristic properties:
- In the red line, median survival drops by 8 weeks to 19 weeks.
- In the blue line median survival rises by 12 Weeks to 39 weeks.
- The difference between the two functions arises from of the first 12 weeks alone. With the blue line, 8 people died, with the red line 23 people died during the first 12 weeks. After week 12 up to week 80, the same number of fatalities occur in both groups (blue: 36, red: 37).
After week 80, the two functions start to converge, which is due to the fact that at some future point all the patients of both groups will be dead. The survival functions that are reported in the study show the same characteristics.
Assuming that homeopathy did not have any effect, both groups should show more or less identical survival functions. In the paper 10.1 months = 303 days is cited from literature as to be expected under conventional care, maybe with some margin to the better because the data that yielded this value of 10.1 months were more than six years old at the time of the trial. The survival functions allegedly found in the trial show:
- Median survival time with the placebo group is reduced by 46 days compared to conventional care alone.
- Median survival time with the homeopathy group is increased by 132 days compared to conventional care alone.
- The advantage of homeopathy arises within the first 9 weeks alone, where only two patients died (out of 51) in the homeopathy group compared to 11 (out of 47) in the placebo group. After this initial phase, the groups developed in parallel: By the end of the two-year follow-up time an additional 26 patients died with homeopathy, and about the same, namely 25 patients died with placebo.
The inevitable convergence of both functions apparently started outside the two-year follow-up. In other words, the survival functions given in the study for placebo and homeopathy treatments show characteristics that match what you would be expected, if two very similar functions were manipulated by dropping unwanted results, i.e. “good” survival data from placebo and “bad” survival data from homeopathy functions. After week 9, the two functions develop parallel to each other, indicating a lack of effect of homeopathy even though the treatment continued until the death of the patient or the end of the study. However, with ongoing effective treatment, the functions should continue to diverge. It seems implausible that homeopathy should be effective on a short time basis only, with a sudden complete loss of effectiveness later on.
Reduction of observation time
Quality of life was defined as the primary endpoint. On initial registration, it was specified that patients should be observed for the entire seven-year duration of the study which, allowing for the recruitment period of five years, results in a follow-up time of two years or 104 weeks for each individual patient. According to the information provided in the study, this was indeed done: “Patients were followed up every nine weeks until death” (or until the end of the study, of course), and questionnaires were completed to determine the quality of life.
The reduction of follow-up time from 104 to 18 weeks was first introduced when the protocol was uploaded. So it is obvious that this substantial reduction occurred after data collection was completed and that data from more than 80 % of the originally defined follow-up were omitted.
Incomplete outcome reporting, especially when a larger scope was defined at the beginning of the study, is considered a source of substantial bias and a major shortcoming in clinical trials: Maybe patients initially experienced an improvement in their quality of life due to whatever effect – but what were the results after this initial phase? Why were they omitted? Perhaps because they got worse than in the placebo group? The long-term development would have been a vital aspect for the evaluation of efficacy – and the study originally was designed to evaluate such long-term effects. Yet, the authors’ conclusions on the quality of life – notably: the primary outcome criterion – are based on less than 20 % of the follow-up in which a positive effect may have occurred due to bias or by chance. To extrapolate from this short time to the total period is not justified and may be misleading. A detailed review of the quality of life results is meaningless: they do not disclose any long-term effects and they are subject to bias caused by the post hoc exclusion of patients anyway.
The overall evidence on the effectiveness of homeopathy is not encouraging. The quintessence of all systematic reviews that have looked at homeopathy as a whole is that some marginal effect may be found, if all studies are included in the review, regardless of their quality. But this result is questionable due to the generally low quality of the primary studies (Link, in German). However, when quality is taken into account, the systematic reviews do not produce robust evidence for any positive effect beyond placebo. In addition, no review could identify a single condition in which homeopathy is of well-established therapeutic benefit.
This study on NSCLC contradicts the long-established and often-confirmed evidence. During the follow-up time for the patients who actually received the prescribed homeopathic preparations, the quality of life improved steadily in all subscales – even down to the patients’ financial situation – whereas the opposite was observed in the placebo patients. In addition, the mean survival time was about two-thirds longer for the homeopathy patients than for the placebo group.
After 200 years of clinical research into homeopathy, it seems unlikely that such a powerful effect of homeopathy should not have been noticed before. Another scenario seems to be much more plausible:
- The survival times of the placebo group were worse than the data from the literature. This could be due to the fact that patients with relatively good outcomes were excluded by the introduction of additional exclusion criteria.
- The survival times of the homeopathy group were considerably better than expected. This could also be due to the additional exclusion criteria, in that patients with poor outcomes were excluded retrospectively.
- The long time frame where the survival functions run in parallel from week 9 onwards until the end of the two years observation period indicates the lack of effect of the homeopathic treatment. The advantage occurring in the first nine weeks alone seems to be the result of unwanted data being dropped.
- In the case of quality of life (after all, not a “hard” criterion, but based on information from the patients ), the advantage in survival would have initially created a positive effect for the homeopathy group. Then, reporting was discontinued, once the initial positive effects presumably caused by the selective omission of patients had ended.
In conclusion, it seems likely that the substantial modifications of crucial study parameters that occurred after the study had been started and results had become available biased the results in favor of homeopathy. Therefore, this study does not meet strict scientific standards that were established to exclude any confounding factors or biases. If our analysis is correct, the results of this study are invalid, and the authors’ conclusions are not justified. Retraction of this study seems to be appropriate.
Reference Frass M, Lechleitner P, Gründling C et al. Homeopathic Treatment as an Add-On Therapy May Improve Quality of Life and Prolong Survival in Patients with Non-Small Cell Lung Cancer: A Prospective, Randomized, Placebo-Controlled, Double-Blind, Three-Arm, Multicenter Study. The Oncologist 2020;25:e1930–e1955 https://theoncologist.onlinelibrary.wiley.com/doi/epdf/10.1002/onco.13548
The Higher Administrative Court of Bremen has rejected as inadmissible the application for a judicial review by a Bremen physician against the deletion of the ‘HOMEOPATHY’-title from the further training regulations of the Bremen Medical Association (decision of June 2, 2021). Thus, the new regulation for postgraduate training of the Bremen Medical Association without the additional designation of homeopathy has been upheld.
“We are very pleased that the Court shares our legal opinion and has rejected the plaintiff’s application,” said Heike Delbanco, Chief Executive Officer of the Bremen Medical Association. “This is also a clear signal for other German medical associations where comparable lawsuits against the removal of homeopathy from the canon of additional designations are pending.”
The Assembly of Delegates of the Medical Association had decided in September 2019 on a new training regulation, which – unlike the previous regulation – no longer provided for the postgraduate training in homeopathy. After the expiry of a transitional period, the qualification of homeopathy can therefore no longer be acquired at the Bremen Medical Association; however, titles already acquired can continue to be held.
A physician from Bremen, who holds the title of homeopathy, brought an action before the Higher Administrative Court against the cancellation of the additional title. He claimed that the removal of the additional designation from the continuing education regulations interfered with his fundamental right to freedom of profession and his fundamental right to property and complained of a violation of the general principle of equality. The medical association considered the action inadmissible.
The Higher Administrative Court now rejected the application, since a violation of the plaintiff’s rights could not be recognized. The plaintiff can continue to use his title HOMEOPATHY also under the new regulations.
The expectations presented by him – in particular, the expectation to find suitable practice representatives and to be able to sell his practice on retirement at a profit – do not justify any legal positions protected by fundamental rights and consequently also no obligation of the Bremen Medical Association to enable physicians to obtain the additional title of homeopathy in future.
As several further medical associations in Germany have banned homeopathy in the same way as Bremen and were consequently also taken to court by homeopathy enthusiasts, one can be optimistic that these cases will also go against homeopathy.
“I don’t take chemicals,
I prefer natural herbal remedies!”
How often have we heard such statements? They are usually pronounced with an air of smug superiority and condescending pity towards those poor consumers who swallow paracetamol, ibuprofen, or other chemicals when having a headache or other health problem.
But the air of superiority seems misplaced because these ‘herbivores’ actually consume many more chemicals than the ‘chemivores’. What those who swear by ‘non-chemical’ medicines ignore is the fact that herbal remedies are packed with many different chemicals.
Below I have listed the main active chemical compound of some very well-known herbal remedies:
- Calendula (Calendula officinalis L.): flavonoids, triterpene alcohols, triterpene saponins, carotenoids, polysaccharides, essential oil
- Chamomile (Matricaria recutita L.): essential oil, sesquiterpenes, dicycloethern
- Echinacea (Echinacea purpurea): polysaccharides, caffeic acid derivatives, alkamides, polyacetylenes, essential oil.
- Eucalyptus (Eucalyptus globulus Labill.): cineole, euglobales, macrocarpales
- Garlic (Allium sativum L.): alliin [(+)- S-allyl-L-cystein sulfoxide], allicin (allyl 2- thiosulphate propane)
- Hops (Humulus lupulus L.): phloroglucinol derivates, essential oil
- Lavender (Lavandula angustifolia Mill.): linalyl acetate and linalool, tannins
- Liquorice (Glycyrrhiza glabra L.): triterpenoid, flavonoids, isoflavones, polysaccharides
- Peppermint (Mentha x piperita L.): menthol, menthone, menthyl acetate, tannins, flavonoids
- Valerian (Valeriana officinalis L.): essential oil, sesquiterpene acids, iridoids, lignans, caffeic acid derivatives, alkaloids
Whenever I explain this to a ‘herbivore’ (here defined as a person who prefers herbal to conventional medicine), she is initially taken aback but, as soon as she has recovered from the shock, she regains their superior attitude and says: “Ah yes, but these are natural chemicals; they cannot do any harm, you know.”
“No, I don’t know!” I then reply, “There are two errors in what you just said: firstly, many chemicals that plants produce are highly poisonous – in fact, some of the most potent toxins we know come from plants – and secondly there is no difference between a chemical XY produced by a plant and the same chemical produced in a factory.”
At this stage, we usually change the subject or part our ways.
Despite the widespread use of herbal medicines, documented herb-drug interactions are sparse. We have reviewed the literature to determine the possible interactions between the seven top-selling herbal medicines (ginkgo, St John’s wort, ginseng, garlic, echinacea, saw palmetto and kava) and prescribed drugs. Literature searches were performed using the following databases: Medline (via Pubmed), Cochrane Library, Embase and phytobase (all from their inception to July 2000). All data relating to herb-drug interactions were included regardless of whether they were based on case reports, case series, clinical trials or other types of investigation in humans. In vitro experiments were excluded. Data were extracted by the first author and validated by the second author. 41 case reports or case series and 17 clinical trials were identified.
The results indicate that St John’s wort (Hypericum perforatum) lowers blood concentrations of cyclosporin, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline; furthermore it causes intermenstrual bleeding, delirium or mild serotonin syndrome, respectively, when used concomitantly with oral contraceptives (ethinylestradiol/desogestrel), loperamide or selective serotonin-reuptake inhibitors (sertaline, paroxetine, nefazodone). Ginkgo (Ginkgo biloba) interactions include bleeding when combined with warfarin, raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone. Ginseng (Panax ginseng) lowers blood concentrations of alcohol and warfarin, and induces mania if used concomitantly with phenelzine. Garlic (Allium sativum) changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin and produces hypoglycaemia when taken with chlorpropamide. Kava (Piper methysticum) increases ‘off periods in Parkinson patients taking levodopa and can cause a semicomatose state when given concomitantly with alprazolam. No interactions were found for echinacea (Echinacea angustifolia, E. purpurea, E. pallida) and saw palmetto (Serenoa repens).
In conclusion, interactions between herbal medicines and synthetic drugs exist and can have serious clinical consequences. Healthcare professionals should ask their patients about the use of herbal products and consider the possibility of herb-drug interactions.
The article was so successful that the journal ‘DRUGS’ asked us to publish an update. As the journal is highly respected we obliged with pleasure; here is the abstract of the update of 2009:
The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John’s wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John’s wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John’s wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John’s wort, may have serious clinical consequences.
Angelo Izzo is a lovely man and a highly skilled pharmacologist. He came to my department in 2000 as a guest researcher (on his own funds) and worked with us for several months. This is how the 2001 paper was created. After he returned to his native Naples, Italy, he became a professor of pharmacology with a special interest in plant pharmacology. He has published many further important papers and, together with his Italian colleagues, a most useful book entitled ‘Phytotherapy: A Quick Reference to Herbal Medicine‘. I warmly recommend it to anyone interested in herbal medicine.
The subject of herb-drug interactions is in my view hugely important. When Angelo and I first approached it in 2001, it was woefully under-researched; in that year, there were just 37 Medline-listed papers on the subject. This has now increased very significantly; since 2011 there are about 150 articles on the topic each year. It is tempting to think that Angelo (and I) had a tiny influence on this positive development.
Tai chi is a form of exercise that combines deep breathing and relaxation with meditative, slow movements. Originally developed as a martial art in 13th-century China, tai chi is now practised around the world as a health-promoting exercise. Despite its popularity, its therapeutic value is not clear.
This randomized, assessor-blinded trial examined the therapeutic efficacy of tai chi for the management of central obesity. A total of 543 participants with central obesity were randomly assigned in a 1:1:1 ratio to:
- a control group with no exercise intervention (n = 181),
- conventional exercise consisting of aerobic exercise and strength training (EX group) (n = 181),
- a tai chi group (TC group) (n = 181). Interventions lasted 12 weeks.
Outcomes were assessed at baseline, week 12, and week 38. The primary outcome was waist circumference (WC). Secondary outcomes were body weight; body mass index; high-density lipoprotein cholesterol (HDL-C), triglyceride, and fasting plasma glucose levels; blood pressure; and incidence of remission of central obesity.
The adjusted mean difference in WC from baseline to week 12 in the control group was 0.8 cm (95% CI, -4.1 to 5.7 cm). Both intervention groups showed reductions in WC relative to control (adjusted mean differences: TC group vs. control, -1.8 cm [CI, -2.3 to -1.4 cm]; P < 0.001; EX group vs. control: -1.3 cm [CI, -1.8 to -0.9 cm]; P < 0.001); both intervention groups also showed reductions in body weight (P < 0.05) and attenuation of the decrease in HDL-C level relative to the control group. The favorable changes in WC and body weight were maintained in both the TC and EX groups, whereas the beneficial effect on HDL-C was only maintained in the TC group at week 38.
The authors concluded that Tai chi is an effective approach to reduce WC in adults with central obesity aged 50 years or older.
This is a decent trial with an odd conclusion: it is not just the Tai chi intervention but both types of exercise that yield significantly positive effects on the primary outcome measure. So, why did the authors not conclude exercise is an effective approach to reduce WC in adults with central obesity aged 50 years or older?
Could it be that such a conclusion would have meant stating the obvious?
The delivery man was sweating heavily, and when he handed over the two packages I realized why: they weighed like lead. They contained the new edition of The Oxford Textbook of Medicine.
It comes in 4 large volumes, is over 6000 pages long, and has several hundred contributors who include the foremost experts in their fields (and costs a bomb). On Amazon, it is advertised as the foremost international textbook of medicine. Unrivalled in its coverage of the scientific aspects and clinical practice of internal medicine and its subspecialties, it is a fixture in the offices and wards of physicians around the world, as well as being a key resource for medico-legal practitioners. Accessible digitally with regular updates, as well as in print, readers are provided with multiple avenues of access depending on their need and preference.
More comprehensive, more authoritative, and more international than any other textbook; Oxford Textbook of Medicine focuses on offering both perspective and practical guidance on clinical management and prevention of disease…
I think that describes the book rather well. But why, you rightly ask, did I receive a copy, and why do I write about it here? The simple reason is, that I contributed a chapter. My contribution is just 6 pages long (does that mean the importance of so-called alternative medicine [SCAM] to healthcare is 1/1000th of the total?), but I am nevertheless not half proud of it. Here is a nice quote from my chapter:
When used as a true alternative to mainstream medicine, CAM can become a hazard to patients even if the treatment itself is without risk. In many countries, including the United Kingdom, CAM is practised mostly by healthcare professionals who are not medically trained, often in the absence of stringent regulation, leading many to be concerned that vulnerable patients may be exploited.
I believe this to be the most important message about SCAM and I am pleased that it is expressed in one of the world’s most important textbooks.
This systematic review and meta-analyses explored the strength of evidence on efficacy and safety of Ayurvedic herbs for hypercholesterolemia. Methods: Literature searches were conducted and all randomized controlled trials on individuals with hypercholesterolemia using Ayurvedic herbs (alone or in combination) with an exposure period of ≥ 3 weeks were included. The primary outcomes were total cholesterol levels, adverse events, and other cardiovascular events.
A total of 32 studies with 1386 participants were found. They tested three Ayurvedic herbs:
- Allium sativum (garlic),
- Commiphora mukul (Guggulu),
- Nigella sativa (black cumin).
The average duration of intervention was 12 weeks. The meta-analysis of the trials showed that
- Guggulu reduced total cholesterol and low-density lipoprotein levels by 16.78 mg/dL (95% C.I. 13.96 to 2.61; p-value = 0.02) and 18.78 mg/dL (95% C.I. 34.07 to 3.48; p = 0.02), respectively.
- Garlic reduced LDL-C by 10.37 mg/dL (95% C.I. -17.58 to -3.16; p-value = 0.005).
- Black cumin lowered total cholesterol by 9.28 mg/dL (95% C.I. -17.36, to -1.19, p-value = 0.02).
Reported adverse side effects were minimal.
The authors concluded that there is moderate to high level of evidence from randomized controlled trials that the Ayurvedic herbs guggulu, garlic, and black cumin are moderately effective for reducing hypercholesterolemia. In addition, minimal evidence was found for any side effects associated with these herbs, positioning them as safe adjuvants to conventional treatments.
For the following reasons, I fail to see how these conclusions can be justified:
- Too many of the included studies are of poor quality.
- Only for garlic are there a sufficient number of trials for attempting to reach a generalizable conclusion.
- Giving garlic to patients with hypercholesterolemia is hardy Ayurvedic medicine.
- Even the effect of the best-tested herbal remedy, garlic, is not as large as the effects of conventional lipid-lowering drugs.
- Conclusions about the safety of medicines purely on the basis of RCTs are unreliable.
- The affiliations of the authors include the College of Integrative Medicine, Maharishi International University, Fairfield, USA, the School of Science of Consciousness, Maharishi University of Information Technology, Noida, India, and the Maharishi International University, Fairfield.
You may have noticed that my patience with homeopathy, homeopaths, and other providers of so-called alternative medicine (SCAM) has diminished. In fact, I do not think much of quacks of all shades and no longer muster much understanding. It is better, so I mean after approximately 30 years of discussions with snake oil salesmen and other charlatans, to offer such people Parole. Facts are facts, and no one should be allowed to ignore that without contradiction.
That was not always the case.
When I began as Chair of Complementary Medicine at Exeter in 1993, I was optimistic. It was clear to me that my task of scrutinizing this field would not be easy and could occasionally bring me into conflict with enthusiasts. But I was determined to build bridges, to remain polite, and to muster as much understanding as necessary.
And so I began to build a multidisciplinary team, conduct research, and publish it. My goal was to do as rigorous science as possible and, if avoidable, not to step on anyone’s toes in the process. Especially with regard to homeopathy, my general attitude was quite positive. Accordingly, my articles were as favorable as the evidence allowed. My goal was to emphasize the good aspects of homeopathy wherever possible.
What, you find that hard to believe?
Then you are in good company!
Homeopaths like to claim that I was out to malign not only homeopathy but all of SCAM from the beginning. That this assumption is not true, I tried to demonstrate in an article entitled ‘Homeopathy and I’. In this paper, I merely extracted typical passages from my publications. From them, you can probably see how my attitude slowly changed over the years. See for yourself (sorry for the length of the list):
- 1. homeopathic remedies are believed by doctors and patients to be almost totally safe (Ernst E, White A. Br J Gen Pract 1995; 45: 629-30)
- 2. it might be argued that arnica … is ineffective but homeopathy may still work (Ernst E. BMJ 1995; 311: 510-1)
- 3. homeopathy, I fear, has soon to come up with … more convincing evidence (Ernst E. Forsch Komplementarmed 1995; 2: 32)
- 4. future evaluations of homeopathy should be performed to a high scientific standard (Ernst E. Br Homeopath J 1995; 84: 229)
- 5. the best way forward is clearly to do rigorous research (Ernst E, Kaptchuk TJ. Arch Intern Med 1996; 156: 2162-4)
- 6. the most pressing question, ‘Is homeopathy clinically more effective than placebo’, needs to be answered conclusively (Ernst E. Br J Clin Pharmacol 1997; 44: 435-7)
- 7. there is evidence that homeopathic treatment can reduce the duration of ileus (Barnes J, Resch KL, Ernst E. J Clin Gastroenterol 1997; 25: 628-33)
- 8. the published evidence to date does not support the hypothesis that homeopathic remedies … are more efficacious than placebo (Ernst E, Barnes J. Perfusion 1998; 11: 4-8)
- 9. the claim that homeopathic arnica is efficacious beyond a placebo effect is not supported by rigorous clinical trials (Ernst E, Pittler MH. Arch Surg 1998; 133: 1187-90)
- 10. … the trial data … do not suggest that homeopathy is effective (Ernst E. J Pain Sympt Manage 1999; 18: 353-7)
- 11. … the re-analysis of Linde et al. can be seen as the ultimate epidemiological proof that homeopathic remedies are, in fact, placebos (Ernst E, Pittler MH.J Clin Epidemiol 2000; 53: 1188)
- 12. … homeopathy is not different from placebo (Ernst E, Pittler MH. J Clin Epidemiol 2002; 55: 103-4)
- 13. … the best clinical evidence … does not warrant positive recommendations (Ernst E. Br J Clin Pharmacol 2002; 54: 577-82)
- 14. the results of this trial do not suggest that homeopathic arnica has an advantage over placebo (Stevinson C, Devaraj VS, Fountain-Barber A, Hawkins S, Ernst E. J R Soc Med 2003; 96: 60-5)
- 15. this study provides no evidence that adjunctive homeopathic remedies … are superior to placebo (White A, Slade P, Hunt C, Hart A, Ernst E. Thorax 2003; 58: 317-21)
- 16. … this systematic review does not provide clear evidence that the phenomenon of homeopathic aggravations exists (Grabia S, Ernst E. Homeopathy 2003; 92: 92-8)
- 17. … the proven benefits of highly dilute homeopathic remedies … do not outweigh the potential for harm (Ernst E.Trends Pharmacol Sci 2005; 26: 547-8)
- 18 Our analysis … found insufficient evidence to support clinical efficacy of homeopathic therapy (Milazzo S, Russell N, Ernst E. Eur J Cancer 2006; 42: 282-9)
- 19. … promotion can be regrettably misleading, or their effectiveness? (Ernst E. J Soc Integr Oncol 2006; 4: 113-5)
- 20. … homeopathy is not based on solid evidence and, over time, this evidence seems to get more negative (Ernst E, Pittler MH, Wider B, Boddy K. Perfusion 2006; 19: 380-2)
- 21. the evidence from rigorous clinical trials … testing homeopathy for childhood and adolescence ailments is not convincing enough for recommendations in any condition (Altunc U, Pittler MH, Ernst E. Mayo Clin Proc 2007; 82: 69-75)
- 22. … context effects of homeopathy … are entirely sufficient to explain the benefit many patients experience (Ernst E. Curr Oncol 2007; 14: 128-30)
- 23. among all the placebos that exist, homeopathy has the potential to be an exceptionally powerful one (Ernst E. Br J Clin Pharmacol 2008; 65: 163-4)
- 24. … recommendations by professional homeopathic associations are not based on the evidence (Ernst E. Br J Gen Pract 2009; 59: 142-3)
These quotes speak for themselves, I think. But what was the reason for the change? As far as I can judge in retrospect, there were three main reasons.
1. The data became clearer and clearer
When I started researching homeopathy, at least the clinical evidence was not clearly negative. In 1991, Jos Kleinjen had published his much-noted systematic review in the BMJ. Here is its conclusion:
At the moment the evidence of clinical trials is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality and because of the unknown role of publication bias. This indicates that there is a legitimate case for further evaluation of homoeopathy, but only by means of well performed trials.
Subsequently, more and better clinical trials were published, and the overall picture became increasingly negative. Kleinjen, who had become somewhat of a hero in the realm of homeopathy, re-reviewed the evidence in 2000 and concluded that there are currently insufficient data to either recommend homoeopathy as a treatment for any specific condition or to warrant significant changes in the provision of homoeopathy.
The 24 citations above reflect this development quite nicely. Today, there is no longer much doubt that highly-diluted homeopathic remedies are pure placebos. This is perhaps most clearly expressed in the now numerous statements of high-ranking international bodies.
2. The lack of understanding on the part of homeopaths
So the evidence is now clear. But it may not fully explain why my patience with homeopaths diminished. To understand this better, one must consider the utter lack of insight of today’s homeopaths (think, for example, of the incredible Ebola story).
It is of course understandable that a homeopath would be less than enthusiastic about the increasingly negative evidence. But homeopaths are also physicians or at least medically untrained practitioners (lay homeopaths). As such, they have an obligation to acknowledge the overwhelming evidence and act accordingly. That they quite obviously do not do so, is not only regrettable but also highly unethical and shameful. In any case, I find it difficult to have much patience for such people.
3. Personal attacks
In the many years that I have now been scrutinizing SCAM, I have become used to being attacked. The attacks and insults I have received, especially from homeopaths, are legion. For example, when we published our arnica study, we were threatened with letter bombs. However, one should keep one thing in mind: ad hominem attacks are a victory of reason over unreason. If one is personally attacked by one’s opponent, it only shows that he has run out of rational arguments.
Perhaps the most impressive example of an attack was not directed against me personally, but across the board against all who dare to doubt homeopathy. Christian Boiron is the boss of the world’s largest homeopathic manufacturer, Boiron. In an interview he was once asked what he thought of homeopathy critics; his answer: “Il y a un Ku Klux Klan contre l’homéopathie” (There is a Ku Klux Klan against homeopathy).
Yes, many of these attacks even have something comical about them; nevertheless, they are not likely to increase my patience with homeopaths. This does not mean, however, that I will soon hang my opponents from the nearest tree in the old KKK tradition. I’ll gladly leave such tasteless ideas to Christian Boiron.