MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

vitamin

I want to thank our friend ‘OLD BOB’ for alerting me to Patrick Holford’s comment on a recent trial of vitamin C for COVID-19. Here are three short quotes from Holford:

… Overall, 5 out 26 people (19%) died in the vitamin C group while 10 out of 28 (36%) receiving the placebo died. That means that vitamin C almost halved the number of deaths. Those on vitamin C were 60% more likely to survive.

… Of those most critically ill, 4 people (18%) in the vitamin C group died, compared to 10 (50%) in the placebo group. That’s two-thirds less deaths. Statistically this meant that of those most critically ill who were given vitamin C, they were 80% less likely to die…

… now there is another proven treatment – vitamin C…

And here is the abstract of the actual trial Holford refers to:

Background: No specific medication has been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19.

Methods: This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 hours for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way. The primary outcome was invasive mechanical ventilation-free days in 28 days(IMVFD28). Secondary outcomes were 28-day mortality, organ failure, and inflammation progression.

Results: Only fifty-six critical COVID-19 patients were ultimately recruited due to the early control of the outbreak. There was no difference in IMVFD28 between two groups. During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO2/FiO2 (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P=0.01). Patients with SOFA scores ≥3 in the HDIVC group exhibited a trend of reduction in 28-day mortality (P=0.06) in univariate survival analysis. IL-6 in the HDIVC) group was lower than that in the placebo group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P=0.04) on day 7.

Conclusion: This pilot trial showed that HDIVC might show a potential signal of benefit for critically ill patients with COVID-19, improving oxygenation even though it failed to improve IMVFD28.

The following points are, I think, worth mentioning:

  • This was, according to its authors, a PILOT study.
  • It was far too small (n=56) to provide reliable results on mortality.
  • The trial authors know that and interpret their findings with sufficient caution.
  • The primary endpoint, the IMVFD28, showed NO significant difference between the groups.
  • The secondary endpoint: HDIVC infusion exhibited a non-significant trend of reduction in 28-day mortality (P=0.06).
  • In more severe patients (SOFA score ≥3), univariate survival analysis and Cox regression showed a similar results (P=0.07, HR, 0.32 [95% CI 0.10-1.06]).

And what does all of this mean? It means that, in this pilot study, vitamin C failed to produce a significant result. Only in a subgroup analysis related to a secondary endpoint was there a slight advantage of vitamin C. This effect is, of course, interesting and needs further investigation (I am sure that is happening as we speak). It could have some clinical significance but, just as likely, it could just be due to chance. There is not way of knowing which is which.

In other words, to hype the findings and to even make statements such as ‘now there is another proven treatment, vitamin C’ is not just exaggerated, it is irresponsible.

This begs the question: why does Mr Holford do it? In case you don’t already know about this man, go on the Internet, and you will quickly find possible answers. Here is an excerpt from his Wiki page which might give you a clue:

Patrick Holford is a British author and entrepreneur who endorses a range of controversial vitamin tablets. As an advocate of alternative nutrition and diet methods, he appears regularly on television and radio in the UK and abroad. He has 36 books in print in 29 languages. His business career promotes a wide variety of alternative medical approaches such as orthomolecular medicine, many of which are considered pseudoscientific by mainstream science and medicine.

Holford’s claims about HIV and autism are not in line with modern medical thought, and have been criticised for putting people in danger and damaging public health.

In 2006 Holford was discovered to be using his PR advisor to delete critical content from his Wikipedia page…

Holford has been the subject of criticism for his promotion of medically dubious techniques and products including hair analysis, his support of the now struck off doctor Andrew Wakefield, and advocating the use of “non-drug alternatives for mental health” for which he has been given an award by the Church of Scientology-backed Citizens Commission on Human Rights.

SAY NO MORE!

This study assessed the patterns of dietary supplement usage among cancer survivors in the United States in a population-based setting. National Health and Nutrition Examination Survey (NHANES) datasets (1999-2016) were accessed, and adult respondents (≥ 20 years old) with a known status of cancer diagnosis and a known status of dietary supplements intake were included. Multivariable logistic regression analysis was then used to assess factors associated with dietary supplements intake. Moreover, and to evaluate the impact of dietary supplements on overall survival among respondents with cancer, multivariable Cox regression analysis was conducted.

A total of 49,387 respondents were included in the current analysis, including a total of 4,575 respondents with cancer. Among respondents with cancer, 3,024 (66.1%) respondents reported the use of dietary supplements; while 1,551 (33.9%) did not report the use of dietary supplements. Using multivariable logistic regression analysis, factors associated with the use of dietary supplements included:

  • older age (OR: 1.028; 95% CI: 1.027-1.030);
  • white race (OR for black race vs. white race: 0.67; 95% CI: 0.63-0.72);
  • female gender (OR for males vs. females: 0.56; 95% CI: 0.53-0.59),
  • higher income (OR: 1.13; 95% CI: 1.11-1.14),
  • higher educational level (0.59; 95% CI: 0.56-0.63),
  • better self-reported health (OR: 1.36; 95% CI: 1.17-1.58),
  • health insurance (OR: 1.35; 95% CI: 1.27-1.44),
  • history of cancer (OR: 1.20; 95% CI: 1.10-1.31).

Using multivariable Cox regression analysis and within the subgroup of respondents with a history of cancer, the use of dietary supplements was not found to be associated with a difference in overall survival (HR: 1.13; 95% CI: 0.98-1.30).

The authors concluded that dietary supplement use has increased in the past two decades among individuals with cancer in the United States, and this increase seems to be driven mainly by an increase in the use of vitamins. The use of dietary supplements was not associated with any improvement in overall survival for respondents with cancer in the current study cohort.

Many cancer patients, when they first get diagnosed, are tested for vitamin D levels and found to be low or borderline. Consequently, they get a prescription for supplements. Other than this, there is rarely an indication to take any vitamins or other dietary supplements. Yet, cancer patients take them because they think these ‘natural’ preparations can do no harm (and because the industry can be persuasive [there is big money at stake] and the odd breed of ‘integrated’ oncologists might even recommend them). Sadly, this assumption is not correct. The biggest danger, in my view, is the possibility of supplements to interact with one of the many drugs that cancer patients need to take. So, in a way, it is reassuring that, on average, there is no detrimental effect on overall survival.

The paper will probably also reignite the perennial discussion about the effects of vitamin C on the natural history of cancer. My understanding is that there is none (and this verdict seems to be supported by the findings reported here). But I am, of course, aware that this is a ‘hot potato’ and that some readers will think differently. To them I say: please show me the evidence.

Several strands of evidence have indicated that vitamin D supplementation might be helpful for COVID-19 infections. Now we also have a study testing whether it works.

Spanish researchers evaluated the effect of calcifediol treatment on Intensive Care Unit Admission and Mortality rate among patients hospitalized for COVID-19 in a randomized, double blind clinical trial. A total of 76 consecutive patients hospitalized with COVID-19 infection and clinical picture of acute respiratory infection (confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale) were included. All patients received as best available therapy the same standard care. This consisted of a combination of:

  • hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days),
  • azithromycin (500 mg orally for 5 days.

Eligible patients were allocated at a 2 calcifediol : 1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths.

Of the 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %). Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.

The authors concluded as follows:

Our pilot study demonstrated that administration of calcifediol may improve the clinical outcome of subjects requiring hospitalization for COVID-19. Whether that would also apply to patients with an earlier stage of the disease and whether baseline vitamin D status modifies these results is unknown. Therefore, a multicenter randomized controlled trial using calcifediol, properly matched (Prevention and Treatment With Calcifediol of COVID-19 Induced Acute Respiratory Syndrome (COVIDIOL)), in 15 Spanish hospitals, funded by Clinical Research Program at COVID-19 “Progreso y Salud” Foundation and Foundation for Biomedical Research of Córdoba (FIBICO), Spain, (registered as NCT04366908 in NIH Trialnet database) will be carried out with the number of patients recalculated from the data provided by this study.

An interesting perspective of the new COVIDIOL trial with the recently available information, could be to evaluate calcifediol associated to dexamethasone or other corticoid vs. dexamethasone or other corticosteroid, since dexamethasone, which has potent anti-inflammatory actions, has recently been shown to reduce mortality in hospitalized patients on Covid-19 who are on respiratory assistance; so that treatment guidelines have been updated to recommend the use of glucocorticoids (including dexametasone), now proposed as the best available treatment in many hospitals around the world.

It is undeniable that this trial has several important limitations (and its authors are very honest to point them out). However, it is equally undeniable, in my view, that it is an important contribution to our current knowledge.

During the last decades, the sales-figures for so-called alternative medicine (SCAM) have been increasing steadily and substantially. A recent report predicts this trend to continue:

… The global market for alternative and complementary medicines is projected to experience substantial growth in the next few years. The rising expenditure of the healthcare facilities is considered as the major factor that is likely to encourage the growth of the overall market in the coming years. In addition, the increasing number of initiatives being taken by Governments across the globe to promote alternative and complementary medicines is projected to accelerate the market’s growth. Thanks to these factors, the global alternative and complementary medicine market is likely to exhibit a promising growth rate in the near future.

A significant rise in the number of initiatives by NGOs and government organizations to encourage the use of alternative and complementary medicines is estimated to bolster global market in the near future. In addition to this, technological advancements in this field and the rising inclination of consumers towards these medicines and practices are likely to offer lucrative growth opportunities for the leading players operating in the alternative and complementary medicine market across the globe. However, the lack of scientific results is expected to hamper the overall growth of the market in the next few years…

From a regional perspective, Europe is considered as one of the leading segment, thanks to the significant revenue contribution in the last few years. This region is expected to account for a large share of the global alternative and complementary medicine market with the rising use of botanicals. In addition to this, the increasing awareness among consumers regarding the availability of effective alternative and complementary medicines and the benefits they offers are expected to encourage the growth of the Europe market in the coming years.

Furthermore, with the rising popularity of medical tourism, the alternative and complementary medicine market in Asia Pacific is projected to witness a steady growth in the next few years. Moreover, the presence of a large number of new players operating in this region is likely to offer promising growth opportunities over the forecast period. The Middle East and Africa segment is anticipated to experience a healthy growth in the alternative and complementary medicine market in the near future.

The global market for alternative and complementary medicines is presently at a highly competitive stage and is predicted to experience an intense level of competition among the leading players in the coming years. The prominent players in the market are focusing on the expansion of the product portfolio so as to attract a large number of consumers across the globe. This is likely to help them in creating a brand name and acquiring a leading position in the global market. Some of the leading players operating in the alternative and complementary medicine market across the globe are Herb Pharm, Yoga Tree, Quantum Touch Inc., Helio USA Inc., Pure encapsulations, Inc., Pacific Nutritional Inc., Deepure Plus, Herbal Hills, Iyengar Yoga Institute, The Healing Company, and Nordic Naturals.

Yes, I know, this is little more than hot air mixed with platitudes and advertisements to purchase the full report. I used to buy such documents for my department and research but was invariably disappointed. They provide are expensive and of very little of value.

Yet, one thing has been confirmed over the years: the prediction of steady growth of the SCAM-industry is rarely wrong (certain sections, such as homeopathy, have been shrinking in some regions, but the industry as a whole is financially healthy). The scientific evidence seems to get less and less convincing, yet consumers buy more and more of these products. They may do little good and have the potential to cause quite a bit of harm, but consumers continue to waste their money on them.

The question is: why?

There are, of course, many reasons. An important one is that the gullible public wants to believe in SCAM, and the SCAM-industry is highly skilled in misleading us. What is worse: many governments, instead of limiting the damage, are mildly or even overtly supportive of the SCAM-industry.

Whenever I contemplate this depressing state of affairs, I realise that my blog is important. It is only a drop in the ocean, I know, but still…

 

 

 

Dr Mathias Rath, the German born purveyor of multiple food supplements, and his organisation puzzle me a great deal. As previously reported, the ‘Dr Rath Foundation’ published an article about me. In it, the author got my name right, but not much more. Here is its opening passage [the numbers in square brackets refer to my comments below].

Professor Edzard Ernst: A Career Built On Discrediting Natural Health Science? [1]

Professor Edzard Ernst, a retired German [2] physician and academic, has recently [3] become a prominent advocate of plans that could potentially outlaw [4] the entire profession of naturopathic doctors [5] in Germany. Promoting the nonsensical idea that naturopathic medicine somehow poses a risk to public health, Ernst attacks its practitioners as supposedly having been educated in “nonsense” [6]. Tellingly, however, given that he himself has seemingly not published even so much as one completely original scientific trial of his own [7], Ernst’s apparent attempts to discredit natural healthcare approaches are largely reliant instead on his analysis or review of handpicked negative studies carried out by others [8].

  1. When I was appointed at Exeter to research alternative medicine in 1993, I had already been a full professor at Hannover, Germany and subsequently at Vienna, Austria. If anything, coming to Exeter was a big step down in terms of ‘career’, salary, number of co-workers etc. (full details in my memoir)
  2. I am German-born, became an Austrian citizen in 1990, and since 2000 I am a British national.
  3. I have been critical about the German ‘Heilpraktiker’ for more than 20 years.
  4. This refers to the recent ‘Muensteraner Memorandum’ which is the work of an entire team of multidisciplinary experts and advocates reforming this profession.
  5. ‘Heilpraktiker’ are certainly not doctors; they have no academic or medical background.
  6. This is correct, and I stand by my statement that educating people in vitalism and other long-obsolete concepts is pure nonsense.
  7. Since I am researching alternative medicine, I have conducted and published about 40 ‘scientific trials’, and before that time (1993) I have published about the same number again in various other fields.
  8. This refers to systematic reviews which, by definition, include all the studies available on a defines research question, regardless of their conclusion (their aim is to minimise random and selection biases)  .

Rath states about himself that “Dr. Rath heads a research and development institute in nutritional and Cellular Medicine. His institute is conducting basic research and clinical studies to scientifically document the health benefits of micronutrients in fighting a multitude of diseases.”

But this is equally puzzling.

Firstly, because research does not aim ‘to scientifically document the health benefits of ‘ anything; it is for testing hypotheses; Rath surely must know that. Secondly, on Medline, I find dozens of publications by Rath. These refer mostly to mechanistic in-vitro or animal studies about the mode of action of vitamins and other natural compounds.

But ‘clinical studies‘?

None!

Hold on! My Medline searches did deliver one clinical trial – just one – (Rath himself lists more, but they seem to be meaningless observational studies without a control group). It was published as an abstract on his own website. Here is the abstract:

Healing of bone fractures is a prolonged process that can be affected by nutrition. Our objective was to critically evaluate the effect of supplementation with an essential nutrient complex, containing ascorbic acid, lysine, proline, and vitamin B6 on healing time of tibial fractures.

Design:

Random double-blind placebo-controlled study

Setting:
Dr. Jamdar Hospital, Jabalpur, India

Subjects and Intervention:
113 patients with unilateral displaced closed or grade I open tibial fractures were randomized to receive either standard care with placebo or with supplementation with an essential nutrient complex containing ascorbic acid, lysine, proline, and vitamin B6. Qualifying patients, on admission to the study, were clinically examined, radiographs of the affected limbs taken, fractures reduced under anesthesia, and above knee plaster casts applied. Radiographs were taken at each follow-up visit to confirm reduced alignment of fracture and proper callus formation.

Primary Outcome Measure:
The primary outcome measure was the number of weeks required for fracture to be healed. Healing was defined as absence of abnormal mobility at fracture site clinically, absence of pain elicited by stressing the fracture or by walking, and radiographic confirmation of callus formation.

Results:
Data analysis demonstrated reduced fracture-healing time associated with experimental supplementation. For PP analysis group, fracture healing time in 75% of the supplemented group of patients (N=21) was 17 weeks or less and 19 weeks or less in 75% of the placebo group patients (N=36). The percentage of patients with fractures healing in 10 weeks or less was 33.3% for the supplemented group and 11.1% for the placebo group. However, the difference in healing time between the two groups did not reach statistical significance.

Conclusion:
Results showed encouraging trends that fracture-healing time is reduced by supplementation with an essential nutrient complex containing ascorbic acid, lysine, proline, and vitamin B6. In addition, the nutrient supplemented participants reported improved feeling of well-being with use of the supplement.

This is odd in several ways:

  1. Even though the conclusions hide it quite well, the trial was in fact negative, i. e. it failed to show a significant difference between the verum and the placebo in the primary outcome measure.
  2. The trial was never published as a peer-reviewed full paper. The website refers to its publication as a ‘letter to the editor’ (LTTE) in the notorious JACM (a LTTE is not normally peer-reviewed).
  3. Why was it never properly published?
  4. Could it be because there was no ethics approval [none was mentioned in the LTTE]?
  5. Could it be because there was no informed consent [none was mentioned in the LTTE]?
  6. The LTTE mentions that a larger study with 200 patients is planned. This was 16 years ago, and to date there is no trace of such a trial.

Rath’s latest contribution to the world of science is a paper implying that his supplements could play a role in the fight against the present pandemic; it is entitled ‘Effective and safe global public health strategy to fight the COVID-19 pandemic: Specific micronutrient composition inhibits Coronavirus cell-entry receptor (ACE2) expression’. Here is the abstract which clearly shows that Rath has not a jot of clinical evidence:

Optimum micronutrient intake is the only scientifically proven way to improve general immune resistance against infections, a fact documented in every leading textbook of biology.  This study provides scientific evidence that, in addition, specific micronutrient compositions are powerful tools in the fight against the COVID-19 pandemic.

Both, SARS-CoV-2 – the virus that causes the current pandemic – and other coronaviruses enter body cells via a specific receptor, the Angiotensin-Converting-Enzyme 2 (ACE2). The ACE2 receptor is expressed by many cell types, including lung epithelial cells as well as endothelial cells of the vascular system.

Based on our earlier research that demonstrated that specific micronutrients can block several mechanisms of viral infections, we tested the efficacy of these natural compounds in suppressing the expression of the ACE2 receptor on human endothelial cells and small airway epithelial cells.

Our results show that a micronutrient composition comprising vitamin C as well as certain amino acids, polyphenols, and trace elements is able to suppress this viral ‘entry door’ into the body under both normal and inflammatory conditions, which are associated with infections.

Thus, vitamin-rich nutrition and micronutrient supplementation should be implemented as effective, safe and affordable public health strategies to fight the COVID-19 pandemic and help prevent future outbreaks.  Optimizing the micronutrient status of the entire population should form the basis for any global strategy to help prevent future pandemics across the world, including the developing nations.

The Wiki-page on Rath lists 10 (!) legal cases in which he has been involved. This looks like he easily sues people who disagree with his often bizarre views and sales techniques. Considering this suspicion, I better be careful what I say here. Therefore let me conclude by meekly repeating the title of this post which comes from my friend Ben Goldacre who, together with THE GUARDIAN won a famous and expensive legal battle against Rath:

Rath is an example of the worst excesses of the alternative therapy industry.

 

 

 

PS

What I like best about the many supplements sold by Rath is the footnote in the patient leaflets:

THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE OR PREVENT ANY DISEASE

I have to admit that the ‘Asian Journal of Pharmaceutical Research and Development‘ did not formerly belong to my reading list. This will have to change, I guess, because any journal capable of publishing such a hilarious spoof ought to be read regularly.

The article in question is entitled ‘An Integrative Medicine Is Prudential Hope for Covid-19 Therapeutics‘ and is authored by Mayank dimri, Rajendra Singh Pawar, Virbal Singh Rajwar, Luv Kush from the SBS University Balawala, Dehradun- Uttarakhand, India. The paper is so unique that I simply could not resist showing you an excerpt. I hope  you have as much fun reading it as I had when I was alerted to this masterpiece.

Antiviral Astrological Rationality The viral infectivity is governed by Saturn, Rahu and Ketu. COVID-19 is geminian virus, ruled by mercury. It rules lungs / respiratory system and also health/ nutrition house (6th). Antiviral astrological advices are: Stay away from crowds, maintain maximum cleanness and personal hygiene, dietary regimens should be enriched by vitamins, vegetables, nuts and fruits. The foods and drinking water should be warm. The cold and unhealthy environment may be avoided.

The complimentary / alternative integrative medicine conceptualized ethical use of traditional re- medies with
self-responsibility. The concept of herd immunity (epidemological) relates to population. The orthomolecular
medicine10prescribe nutritional supplements for restoration of antiviral immunity. Both have antiviral benefits for fighting global pandemic of COVID-19.

The desirable antiviral activities are anti-replicating to block viral replication, anti-inflammatory for preventing
viral inflammation. Immune stimulatory for strengthening innate immunity and anti-mutagenic for curbing viral mutations.

The ayurvedic herbs have antiviral phytochemicals. Some of them are listed here: Ursolic acid, Apigenin, Rosmarinic acid, Oleanolic acid, Elenoic acid, Hypercin,Liquiritigenin, Acetoside, Glycyrrhizin etc. They have anti RSV activity and possibly prevent viral entry to host cells. The plant extract of Plantago asiatica and Clerodendrum trichotomum proved to be effective antiviral. Fifatrol is an ayurvedic prized medicine against viruses. It is useful in treatment of viral upper respiratory infections and relief from nasal congestion. It is a supportive therapy against COVID-19 virus.

The synergism of vitamins (A, C, D, E) acts as revitaler for fighting against COVID-19. Vitamin C has great potential
as antiviral for respiratory infections. It prevents cytokine induced lung damage and natural immune booster.

Eucalyptus oil has multiple benefits.It is supporter of respiratory system, immune booster and anti-inflammatory. Aromadendrene is an aroma therapeutical, present in oil and moderate antiviral….

I know that the last few months have not been easy for many of us. Therefore, we should be all the more thankful for those who lighten our spirits with some comic relief…

 

 

… or did they actually mean what they wrote?

Intravenous (IV) vitamin C seems to be recommended more and more, particularly by practitioners of so-called alternative medicine (SCAM). At least this is what this survey suggests:

We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA’s Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25g/50ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers’ yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue.

Yet, the potential harm associated with the use of IV vitamin C has not been systematically assessed. An international team of researchers aimed to fill this gap by reviewing the available evidence on harm related to such treatment. They included studies in adult populations that reported harm related to IV high-dose vitamin C which they defined as greater than or equal to 6 g/d, greater than or equal to 75 mg/kg/d, or greater than or equal to 3 g/m/d.

They identified 8,149 reports, of which 650 full text were assessed for eligibility, leaving 74 eligible studies. In these studies, 2,801 participants received high-dose vitamin C at a median (interquartile range) dose of 22.5 g/d (8.25-63.75 g/d), 455 mg/kg/d (260-925 mg/kg/d), or 70 g/m/d (50-90 g/m/d); and 932 or more adverse events were reported. Among nine double-blind randomized controlled trials (2,310 patients), adverse events were reported in three studies with an event rate per patient for high-dose vitamin C identical to placebo group in one study (0.1 [1/10] vs 0.1 [1/10]), numerically lower in one study (0.80 [672/839] vs 0.82 [709/869]), and numerically higher in one study (0.33 [24/73] vs 0.23 [17/74]). Six double-blind randomized controlled trials reported no adverse event in either group. Five cases of oxalate nephropathy, five cases of hypernatremia, three cases of hemolysis in glucose-6-phosphate dehydrogenase deficiency patients, two cases of glucometer error, and one case of kidney stones were also reported overall.

The authors concluded that there is no consistent evidence that IV high-dose vitamin C therapy is more harmful than placebo in double-blind randomized controlled trials. However, reports of oxalate nephropathy, hypernatremia, glucometer error, and hemolysis in glucose-6-phosphate dehydrogenase deficiency patients warrant specific monitoring.

So, is IV vitamin C safe or not?

I would interpret these findings as follows:

  • Clinical trials are often very poor yard-sticks for estimating safety; they are too small and often neglect to mention adverse effects.
  • When it come to evaluating the safety of therapeutic interventions, we must therefore often rely on case-reports, case series and other uncontrolled data.
  • Such data show that IV vitamin C has been associated with adverse effects, some of which are serious.
  • The incidence of such event remains unclear.

When I discuss published articles on this blog, I usually focus on recent papers. Not so today! Today I write about a small study we published 17 years ago. It was conducted in Canada by researchers whom I merely assisted in designing the protocol and interpreting the findings.

They trained 8 helpers to pretend being customers of health food stores. They entered individually into assigned stores; the helpers had been informed to browse in the store until approached by an employee. At this time they would declare that their mother has breast cancer. They disclosed information on their mother’s condition, use of chemotherapy (Tamoxifen) and physician visits, only if asked. The helpers would then ask what the employee recommend for this condition. They followed a structured, memorized, pretested questionnaire that asked about product usage, dosage, cost, employee education and product safety or potential for drug interactions.

The helpers recorded which products were recommended by the health food store employees, along with the recommended dose and price per product as well as price per month. Additionally, they inquired about where the employee had obtained information on the recommended products. They also noted whether the employees referred them on to SCAM practitioners or recommended that they consult a physician. Full notes on the encounters were written immediately after leaving the store.

The findings were impressive. Of the 34 stores that met our inclusion criteria, 27 recommended SCAMs; a total of 33 different products were recommended. Here are some further findings:

  • Essiac was recommended most frequently.
  • The mean cost of the recommended products per month was $58.09 (CAD) (minimum $5.28, median $32.99, maximum $600).
  • Twenty-three employees (68%) did not ask whether the patient took prescription medications.
  • Fifteen (44%) employees recommended visiting a healthcare professional; these included: naturopaths (9), physicians (5) and nutritionists (1).
  • Health food store employees relied on a variety of sources of information. Twelve employees (35%) said they had received their information from books, 5 (15%) from a supplier, 3 (9%) had formal education in SCAM, 2 (6%) had in-store training, and 12 (35%) did not disclose their sources of information.

Since our paper has been published, several other investigations have addressed similar issues. Here are a few excerpts:

But why do I mention all this today?

The answer is that firstly, I think it is important to warn consumers of the often dangerous advice they might receive in HFSs. Secondly, I feel it would worthwhile to do further research, check whether the situation has changed and repeat a similar study today. Ideally, a new investigation should be conducted in different locations comparing several countries. If you have the possibility to plan and conduct such an experiment, please drop me a line.

There are many proponents of so-called alternative medicine (SCAM) who advocate the use of high-dose vitamin D for the prevention or treatment of corona-virus infections. Considering that ethnic minorities are disproportionately affected with Covid-19 further research seems justified, especially as there is clear evidence that vitamin D deficiency is particularly common in these ethnic groups.

However, an international team of experts strongly caution against doses higher than the upper limit (4000 IU/day; 100 µg/day); and certainly of very high doses of vitamin D (in some reports, 10 000 IU/day (250 µg/day) of vitamin D are being promoted) unless under personal medical advice/clinical advice by a qualified health professional. Instead, they advocate the following lifestyle strategies for avoiding vitamin D deficiency and ensuring a healthy, balanced diet.

  1. Supplementation with vitamin D according to Government guidelines (eg, 400 IU/day (10 µg/day) for the UK;7 600 IU/day (15 µg/day) for the USA (800 IU/day (20 µg/day) for >70 years) and Europe. These recommendations were established to ensure that 25OHD concentrations in the majority of the population are above 25 nmol/L (UK) in order to protect musculoskeletal health or above 30 nmol/L (USA) to minimise the risk of vitamin D deficiency (the USA recommendation was also established to optimise musculoskeletal health in the population using a 25OHD concentration of 50 nmol/L). Supplementation with vitamin D is particularly important during times of self-isolation associated with limited sunlight exposure. This is in line with the UK Scientific Advisory Committee on Nutrition (SACN) recommendations for vitamin D, and the US Institute of Medicine (IOM) recommendations for vitamin D, both of which were established under the assumption of minimal exposure to sunlight. Thus, re-emphasis of advice on safe sun exposure (below) and reinforcing government advice on supplements especially when sunlight exposure is low would further boost vitamin D status. The UK SACN, US IOM and EU European Food Safety Agency recommend that vitamin D intake (total from both foods and dietary supplements) should be limited to 4000 IU/day (100 µg/day) for adults, and there is broad international consensus that the general public should avoid higher dose supplements that risk total intake from all sources exceeding this level.
  2. Consumption of a nutritionally balanced diet, for example, according to the UK Eatwell Guide and US Food Pyramid including vitamin D rich foods, that is, oily fish, red meat, egg yolk and fortified foods, such as breakfast cereals in the UK, as well as fortified milk in the USA and Canada.
  3. Safe sunlight exposure to boost vitamin D status. Safe sunlight exposure will enable vitamin D production in skin from March through September in the UK, and at most northern latitudes. Dermal synthesis of vitamin D is most efficient with short, regular (daily) exposures when the sun is at its strongest (in the middle of the day). The efficiency of vitamin D synthesis declines well before the threshold for sunburn is reached but the desirable dose is skin-type dependent and so exposure times required differ for different skin types. For the UK about 10 min of exposure at around lunchtime, in-season appropriate clothing, can meet vitamin D needs for white-skinned people; this increases to about 25 min for those of skin type V (ie, South Asian, brown skin tones). What is key is to try to achieve the sunlight exposure without leaving home (eg, in the garden/balcony); and if that is not possible ensure that social distancing is maintained at all times. Increasing the unprotected skin area (skin not protected by clothing or sunscreen) will increase the vitamin D supply from skin while keeping exposure times short and sub-erythemal. Exposing as much skin as temperature and social comfort allow will maximise vitamin D supply through this route. For those of skin type V and VI (brown or black skin) the exposure requirements in UK sunlight are more challenging to achieve than for white-skinned people and oral vitamin D intake is especially important.
  4. Appropriate diet and lifestyle measures, as emphasised by the WHO at this time, including adequate nutrition to protect the immune system.
  5. Targeted nutritional advice, for example, for UK Military personnel as advised by the Defence Nutrition Advisory Service, with specific reference to COVID-19.
  6. Vitamin D—advice for bone health. The Royal Osteoporosis Society provides specific guidelines on the management of vitamin D deficiency in adults with, or at risk of developing, bone disease.

In conclusion, the experts recommend appropriate RCTs to evaluate the effects of vitamin D supplementation on COVID-19 infections. Until there is more robust scientific evidence for vitamin D,  they strongly caution against the use of high vitamin D supplementation (greater than the upper limit of 4000 IU/day (100 µg/day)). Rather, they strongly endorse avoidance of vitamin D deficiency in the population (as per the six points above) and complete adherence to government’s advice worldwide on the prevention of the spread of COVID-19.

I am sure that this will not stop self-appointed SCAM-experts to continue recommending mega-doses of vitamin D. Therefore it is perhaps worth reminding consumers that an excess of vitamin D will lead to a condition called hypervitaminosis D. It is characterised by the following symptoms:

  • Anorexia
  • Dehydration
  • Fatigue
  • Frequent urination
  • Irritability
  • Tinnitus
  • Dizziness
  • Disorientation
  • Confusion
  • Weight loss
  • Muscle weakness
  • Vomiting
  • Excessive thirst
  • High blood pressure
  • Arrhythmias
  • Passing large amounts of urine

It can lead to serious complication, including permanent kidney damage.

When John Ioannidis publishes a paper, it is well worth, in my view, to pay attention. In the context of this blog, his latest article seems particularly relevant.

The researchers identified the top 100 best-selling books and assessed for both the claims they make in their summaries and the credentials of the authors. Weight loss was a common theme in the summaries of nutritional best-selling books. In addition to weight loss, 31 of the books promised to cure or prevent a host of diseases, including diabetes, heart disease, cancer, and dementia.

The nutritional advice given to achieve these outcomes varied widely in terms of which types of foods should be consumed or avoided and this information was often contradictory between books. Recommendations regarding the consumption of carbohydrates, dairy, proteins, and fat in particular differed greatly between books.

To determine the qualifications of each author in making nutritional claims, the highest earned degree and listed occupations of each author was researched and analyzed. Out of 83 unique authors, 33 had an M.D. or Ph.D degree. Twenty-eight of the authors were physicians, three were dietitians, and other authors held a wide range of jobs, including personal trainers, bloggers, and actors. Of 20 authors who had or claimed university affiliations, seven had a current university appointment that could be verified online in university directories.

The authors concluded that this study illuminates the range of the incongruous information being dispersed to the public and emphasizes the need for future efforts to improve the dissemination of sound nutritional advice.

The authors also provide a ‘sample of claims that appear disputable and/or unsubstantiated according to our expertize and opinion’:

1. “Carbs are destroying your brain”—Grain Brain

2. “Have high blood pressure? Hibiscus tea can work better than a leading hypertensive drug-and without the side effects. Fighting off liver disease? Drinking coffee can reduce liver inflammation. Battling breast cancer? Consuming soy is associated with prolonged survival.”—How Not to Die

3. “Zero Belly diet attacks fat on a genetic level, placing a bull’s-eye on the fat cells that matter most: visceral fat, the type of fat ensconced in your belly.”—Zero Belly Diet

4. “SKIP THE CRUNCHES: They just build muscle under the fat…LESS (EXERCISE) IS MORE”—This Is Why You’re Fat (And How to Get Thin Forever)

5. “Eating pasta, bread, potato, and pizza will actually make you happier, healthier, and thinner—for good”—The Carb Lovers Diet

6. “Skip breakfast, stop counting calories, eat high levels of healthy saturated fat, work out and sleep less, and add smart supplements”—The Bulletproof Diet

7. “Modern “improvements” to our food supply—including refrigeration, sanitation, and modified grains—have damaged our intestinal health. Dr. Axe offers simple ways to get these needed microbes, from incorporating local honey and bee pollen into your diet to forgoing hand sanitizers and even ingesting a little probiotic-rich soil”—Eat Dirt

8. “Overeating doesn’t make you fat; the process of getting fat makes you overeat.”—Always Hungry?

9. “Do you have an overall sense of not feeling your best, but it has been going on so long it’s actually normal to you? You may have an autoimmune disease, and this book is the “medicine” you need.”—The Immune System Recovery Plan

10. “Shows you how to grow new receptors for your seven metabolic hormones, making you lose weight and feel great fast!”—The Hormone Reset Diet

11. “The world’s foremost expert on the therapeutic use of culinary spices, takes an in-depth look at 50 different spices and their curative qualities, and offers spice “prescriptions”–categorized by health condition–to match the right spice to a specific ailment.”—Healing Spices

12. “The idea that people simply eat too much is no longer supported by science”—The Adrenal Reset Diet

13. “Most of us think God is not concerned with what we eat, but the Bible actually offers great insight and instruction about the effects of food on our bodies”—Let Food Be Your Medicine

14. “Dieters can actually lose weight by eating foods, nutrients, teas, and spices that change the chemical balance of the brain for permanent weight loss—a major factor contributing to how quickly the body ages. In fact, everyone can take years off their age by changing their brain chemistry.”—Younger (Thinner) You Diet

15. “Weight gain is not about the food, but about the body’s environment. Excess weight is a result of the body being in a toxic, inflammatory state. If your body is not prepared or ‘primed’ for weight loss, you will fight an uphill biochemical battle”—The Prime

16. “Throwing ice cubes in your water to make it more “structured”. Skipping breakfast, as it could be making you fat. Eating up to 75 percent of your calories each day in fat for optimal health, reduction of heart disease, and cancer prevention”—Effortless Healing

To call these statements ‘disputable’ must be the understatement of the year!

I have long been concerned about the dangerous rubbish published in so-called ‘self-help books’. In 1998, we assessed for the first time the quality of books on so-called alternative medicine (SCAM) [Int J Risk Safety Med 1998, 11: 209-215. [for some reason, this article is not Medline-listed]. We chose a random sample of 6 such books all published in 1997, and we assessed their contents according to pre-defined criteria. The findings were sobering: the advice given in these volumes was frequently misleading, not based on good evidence and often inaccurate. If followed, it would have caused significant harm to patients.

In 2006, we conducted a similar investigation the results of which we reported in the first and second editions of our book THE DESKTOP GUIDE TO COMPLEMENTARY AND ALTERNATIVE MEDICINE. This time, we selected 7 best-sellers in SCAM and scrutinised them in much the same way. We found that almost every treatment seemed to be recommended for almost every condition. There was no agreement between the different books which therapy might be effective for which condition. Some treatments were even named as indications for a certain condition, while, in other books, they were listed as contra-indications for the same problem. A bewildering plethora of treatments was recommended for most conditions, for instance:

  • addictions: 120 different treatments
  • arthritis: 131 different treatments
  • asthma: 119 different treatments
  • cancer: 133 different treatments

This experience, which we published as a chapter in the above-mentioned book entitled AN EPITAPH TO OPINION-BASED MEDICINE, confirmed our suspicion that books on SCAM are a major contributor to the  misinformation in this area.

The new paper by Ioannidis et al adds substantially to all this. It shows that the problem is wide-spread and has not gone away. Since such books have a huge readership, they are a danger to public health. Now that the problem has been identified and confirmed, it is high time, I think, that we do something about it … but I wish I knew what.

ANY SUGGESTIONS?

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