The Truth About Vitamin Drips and IV Therapy

[T_Nation]

by Cy Willson

Placebo or Panacea?

Getting vitamins and electrolytes through IV infusion is all the rage. But is it actually beneficial? Let's look at the real science.

Joe Rogan is a fan of getting certain micronutrients and other anti-oxidative agents intravenously. He’s not alone. IV therapy clinics have popped up all over the country. Some will even come to your house. These products are touted as having near-miraculous effects, but the scientific evaluation is scant, and what little does exist isn’t very promising.

The basic idea behind vitamin drips stems from the notion that oral administration isn’t as effective as intravenous. Consequently, proponents argue, you can achieve concentrations that could never be reached orally.

Let’s Start With What’s True

• Oral bioavailability (the amount reaching the bloodstream) for most micronutrients isn’t going to be 100%. This may be due to limited/poor absorption or extensive metabolism, referred to as the “first-pass effect” by the liver and/or GI tract.

• IV administration allows 100% of the administered dose to reach the bloodstream (bypassing the issues above) and allows for high concentrations that could never be reached with tablets and powders.

• IV administration allows for a much more rapid rise in concentrations of a given micronutrient than oral.

But Wait, Does Any of That Matter?

At facilities outside these IV clinics, like hospitals, IV administration is rarely used in situations where severe vitamin/mineral deficiencies are likely and where it may make sense to provide for a rapid and large micronutrient increase.
Even in these situations, if at all possible, oral administration is the preferred method once a patient is discharged.

Yes, IV administration provides for higher plasma concentrations, but the difference between 40-60% and 100% reaching your bloodstream is negligible when it comes to physiological effects (1,2). Furthermore, IV administration won’t provide a superior pharmacokinetic profile, so daily or at least weekly administration would still be required.

This leaves only the potential for achieving much higher concentrations in the bloodstream with IV versus oral administration as a potential advantage. However, IV administration is really only effective if you’re attempting to bypass an area responsible for a first-pass effect (the liver or GI tract).

IV administration doesn’t solve issues with other pharmacokinetic variables. For example, it doesn’t solve issues with rapid elimination from plasma (at least not inherently), and it doesn’t solve poor distribution and penetration issues to target tissues or high protein binding once it reaches the bloodstream.

Take testosterone, for example. Oral administration has very low bioavailability, but intravenous administration doesn’t solve the issue of rapid elimination. You’d have to walk around with an IV bag every day.

Who Really Needs the Needle?

In rare cases where you’re dealing with someone who’s extremely deficient in a micronutrient, rapidly hitting higher plasma concentrations makes sense, at least initially. However, it’s not a long-term solution unless you’re planning on daily or weekly IVs.

Also, we’re not talking about your friend Billy, who has a poor diet and doesn’t work out. We’re talking about people living in developing nations who haven’t eaten in a week, and what little they did eat consisted of tree bark. Or it may be someone who’s missing a substantial portion of their intestines.

Alternatively, IV drips make sense for people who are critically ill, septic, have intestinal cancer, or are unable to ingest anything (3). IV administration of micronutrients is called for in those circumstances. Otherwise, it’s effectively a waste for a normal, healthy adult.

But What About Hitting Those Magic Levels?

Proponents argue that there’s a physiological range for various micronutrients and other agents that serves basic functions. But to really experience downright amazing benefits, you must get those concentrations into a “pharmacological” range.

This concept is nothing new, and there’s no evidence that anything worthwhile occurs. Even if a high concentration of a given micronutrient is able to hit a given molecular target (albeit transiently), what actual benefit would you see unless you’re doing this constantly, every single day? Probably not much, and even then, it’s questionable.

Take vitamin C for example. It’s touted as a panacea for everything from infections to cancer. However, randomized controlled trials failed to show a consistent and significant effect. Well, proponents argue, that’s because you need really high concentrations to get the benefit, and those concentrations can only be reached via IV administration.

That’s a reasonable enough argument, yet studies administering large doses of vitamin C intravenously still failed to find these benefits, producing either no results or actually having a detrimental effect (4-7).

Even moderate doses of oral vitamin C can diminish the adaptational effects of resistance exercise (8,9). While lower concentrations of vitamin C have an anti-oxidative effect, higher concentrations actually produce a pro-oxidative effect.

The former is what exercise enthusiasts have long thought would be beneficial to counteract the pro-oxidative effects of exercise. As it turns out, the opposite may be true (8-10).

For the latter, some argue that pro-oxidative effects are beneficial in certain conditions (to kill foreign pathogenic organisms or cancer cells), but again, the studies evaluating these effects are disappointing (4-7).

What About Hangovers?

Much of the popularity of these IV solutions is owed to their claimed ability to help with hangovers (3). The hypothetical reason? Alcohol consumption causes dehydration and vitamin/electrolyte deficiencies, leading to hangover symptoms.

But again, there’s no good evidence that acute alcohol consumption leads to severe dehydration or vitamin/electrolyte deficiencies, nor are they the cause of hangovers (11-14).

“It Worked for Me!” – Placebo Pete

Most of the alleged benefits from IV solutions are probably due to a strong placebo effect (15). The fact that you’re paying good money to have a trusted healthcare provider inject you with something they claim provides benefits produces a pretty powerful psychological effect.

In fact, there’s evidence suggesting that the physical procedure of receiving an injection, even with nothing in the syringe, provides significant pain relief due to a placebo effect (16,17). That’s not to say the placebo effect itself isn’t beneficial; the question is if these treatments do as they claim. The answer is probably not.

The Risks

Since these formulations are administered intravenously, they cross over from being food (or dietary supplements) into regulated prescription drugs. While trained clinicians are supposed to administer them, and their production is supposed to be closely regulated, you’re putting a lot of faith in a clinic and its personnel. That’s saying a lot. Remember, excessive electrolyte administration, for example, can be fatal.

Additionally, while established products obtained from large manufacturers are likely safe, compounded products aren’t always produced under the best conditions (conditions you wouldn’t want to eat in, let alone produce sterile drug products in). The federal government primarily leaves enforcement up to the states.

Some people have had serious infections from IV vitamin bags (18). I’m not sure about you, but injecting a product that could be contaminated directly into my bloodstream is something I consider risky.

The Verdict

There’s no good evidence that IV-based micronutrient/hydration products are necessary or even helpful in most cases. At best, you’re spending money to get something you could probably get with regular pills or powders. At worst, you’re taking an unnecessary risk.

References

References

1. Modak, Ketan1; John, M Joseph2. PB2548: Comparison between weekly intravenous versus daily oral vitamin B12 supplementation in anemia with vitamin B12 deficiency. HemaSphere 7(S3) e81647a8, August 2023. | DOI: 10.1097/01.HS9.0000976888.81647.a8
2. Anura V. Kurpad, Roshni M. Pasanna, Shalini G. Hegde, Mallikarjun Patil, Arpita Mukhopadhyay, Harshpal S. Sachdev, Kishor G. Bhat, Ambily Sivadas, Sarita Devi, Bioavailability and daily requirement of vitamin B12 in adult humans: an observational study of its colonic absorption and daily excretion as measured by [13C]-cyanocobalamin kinetics, The American Journal of Clinical Nutrition, 2023.
3. Chan LN, Seres DS, Malone A, Holcombe B, Guenter P, Plogsted S, Teitelbaum DH. Hangover and hydration therapy in the time of intravenous drug shortages: an ethical dilemma and a safety concern. JPEN J Parenter Enteral Nutr. 2014 Nov;38(8):921-3. doi: 10.1177/0148607114553233. PMID: 25342585.
4. Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, Cook DJ, Battista MC, Day AG, Guyatt GH, Kanji S, Parke R, McGuinness SP, Tirupakuzhi Vijayaraghavan BK, Annane D, Cohen D, Arabi YM, Bolduc B, Marinoff N, Rochwerg B, Millen T, Meade MO, Hand L, Watpool I, Porteous R, Young PJ, D’Aragon F, Belley-Cote EP, Carbonneau E, Clarke F, Maslove DM, Hunt M, Chassé M, Lebrasseur M, Lauzier F, Mehta S, Quiroz-Martinez H, Rewa OG, Charbonney E, Seely AJE, Kutsogiannis DJ, LeBlanc R, Mekontso-Dessap A, Mele TS, Turgeon AF, Wood G, Kohli SS, Shahin J, Twardowski P, Adhikari NKJ; LOVIT Investigators and the Canadian Critical Care Trials Group. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022 Jun 23;386(25):2387-2398. doi: 10.1056/NEJMoa2200644. Epub 2022 Jun 15. PMID: 35704292.
5. Labbani-Motlagh Z, Amini S, Aliannejad R, Sadeghi A, Shafiee G, Heshmat R, Jafary M, Talaschian M, Akhtari M, Jamshidi A, Mahmoudi M, Sadeghi K. High-dose Intravenous Vitamin C in Early Stages of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Double-blind, Randomized, Controlled Clinical Trial. J Res Pharm Pract. 2022 Dec 14;11(2):64-72. doi: 10.4103/jrpp.jrpp_30_22. PMID: 36798102; PMCID: PMC9926917.
6. Agarwal A, Basmaji J, Fernando SM, Ge FZ, Xiao Y, Faisal H, Honarmand K, Hylands M, Lau V, Lewis K, Couban R. Parenteral vitamin C in patients with severe infection: a systematic review. NEJM Evidence. 2022 Aug 23;1(9):EVIDoa2200105.
7. Reintam Blaser A, Alhazzani W, Belley-Cote E, Møller MH, Adhikari NKJ, Burry L, Coopersmith CM, Al Duhailib Z, Fujii T, Granholm A, Gunst J, Hammond N, Ke L, Lamontagne F, Loudet C, Morgan M, Ostermann M, Reinikainen M, Rosenfeld R, Spies C, Oczkowski S. Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline. Acta Anaesthesiol Scand. 2023 Nov;67(10):1423-1431. doi: 10.1111/aas.14311. Epub 2023 Jul 27. PMID: 37500083.
8. Martínez-Ferrán M, Berlanga LA, Barcelo-Guido O, Matos-Duarte M, Vicente-Campos D, Sánchez-Jorge S, Romero-Morales C, Munguía-Izquierdo D, Pareja-Galeano H. Antioxidant vitamin supplementation on muscle adaptations to resistance training: A double-blind, randomized controlled trial. Nutrition. 2023 Jan;105:111848. doi: 10.1016/j.nut.2022.111848. Epub 2022 Sep 13. PMID: 36283241.
9. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol. 2016 Sep 15;594(18):5135-47. doi: 10.1113/JP270654. Epub 2016 Jan 18. PMID: 26638792; PMCID: PMC5023714.
10. Petersen AC, McKenna MJ, Medved I, Murphy KT, Brown MJ, Della Gatta P, Cameron-Smith D. Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. Acta Physiol (Oxf). 2012 Mar;204(3):382-92. doi: 10.1111/j.1748-1716.2011.02344.x. Epub 2011 Sep 29. PMID: 21827635.
11. Greenlund IM, Cunningham HA, Tikkanen AL, Bigalke JA, Smoot CA, Durocher JJ, Carter JR. Morning sympathetic activity after evening binge alcohol consumption. Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H305-H315. doi: 10.1152/ajpheart.00743.2020. Epub 2020 Nov 13. PMID: 33185112; PMCID: PMC7864252.
12. Sailer CO, Refardt J, Bissig S, Bologna K, Imber C, Christ-Crain M. Effects of alcohol consumption on copeptin levels and sodium-water homeostasis. Am J Physiol Renal Physiol. 2020 Mar 1;318(3):F702-F709. doi: 10.1152/ajprenal.00458.2019. Epub 2020 Jan 21. PMID: 31961713.
13. Ylikahri RH, Pösö AR, Huttunen MO, Hillbom ME. Alcohol intoxication and hangover: effects on plasma electrolyte concentrations and acid-base balance. Scand J Clin Lab Invest. 1974 Dec;34(4):327-36. doi: 10.3109/00365517409049888. PMID: 4460229.
14. Briggs, Blake MD. Clinical Controversies: Bananas Bags Make No Real Difference in Intoxicated Patients or Those with AUD. Emergency Medicine News 44(8) 5, August 2022. | DOI: 10.1097/01.EEM.0000855792.28780.98
15. Ali A, Njike VY, Northrup V, Sabina AB, Williams AL, Liberti LS, Perlman AI, Adelson H, Katz DL. Intravenous micronutrient therapy (Myers’ Cocktail) for fibromyalgia: a placebo-controlled pilot study. J Altern Complement Med. 2009 Mar;15(3):247-57. doi: 10.1089/acm.2008.0410. PMID: 19250003; PMCID: PMC2894814.
16. Tambiah JRS, Simsek I, Swearingen CJ, Kennedy S, Cole BJ, McAlindon TE, Yazici Y. Comparing Patient-Reported Outcomes From Sham and Saline-Based Placebo Injections for Knee Osteoarthritis: Data From a Randomized Clinical Trial of Lorecivivint. Am J Sports Med. 2022 Mar;50(3):630-636. doi: 10.1177/03635465211067201. Epub 2022 Jan 10. PMID: 35005990.
17. Previtali D, Merli G, Di Laura Frattura G, Candrian C, Zaffagnini S, Filardo G. The Long-Lasting Effects of “Placebo Injections” in Knee Osteoarthritis: A Meta-Analysis. Cartilage. 2021 Dec;13(1_suppl):185S-196S. doi: 10.1177/1947603520906597. Epub 2020 Mar 18. PMID: 32186401; PMCID: PMC8808779.
18. Food and Drug Administration. FDA highlights concerns with compounding of drug products by medical offices and clinics under insanitary conditions. 10/25/2021. https://www.fda.gov/drugs/human-drug-compounding/fda-highlights-concerns-compounding-drug-products-medical-offices-and-clinics-under-insanitary

[stevenmiller]

This was pretty much the argument against steroids in the 1980’s. Doesn’t work they said, but yet people spend money on it and lots of them are really successful people. Hmmm…

[micahpro7]

@stevenmiller

in

Fair, but when they said steroids didn’t work they were just kinda saying it. There were no studies to back up what they were saying and tons of clinical as well as anecdotal evidence otherwise. In this situation there is some anecdotal evidence, both for and against, and lots of clinical evidence against; which basically screams placebo

[Fitnessbunny]

You talk about evidence, the main stream medical establishment offers sick care not health care and are well undereducated in nutritional therapies therefore do not use them in hospital settings. The studies you might be looking at are probably based on biased companies and not real people. Also keep in mind that people age faster because their nutrients are much depleted causing a rapid aging and slowing down process. B12 for example is commonly depleted In most adults causing methylation problems leading to aging at a faster rate. Along with gut issues and depleted nutritional soil due to pesticides, gmo’s etc.Most people are deficient in several nutrients, and look older than their age. Iv’s benefit so much. The evidence shows in ones skin, energy levels and overall health. Furthermore, its not a one size fits all by any means, some with genetic snips might benefit more that others but it’s definitely a game changer.

[Over_50]

Cy - FYI, IV administration is the standard method for just about any / all treatments here in Japan. The Japanese do seem to have a bit of a fixation with bodily fluids / blood though.

[PSacramento]

Studies, and how people react to them, are funny things.
If a study confirms what we want something to be, we are all for it and cite it often, when it doesn’t, we call into question how it was done, why and who was behind it. Confirmation bias is something we all suffer from and would do well to keep in check.

That said, as someone would no “dog in this fight”, I think the studies are interesting and would note that, no matter how much a fan Rogan is of the IV drip, he still supplements daily and only uses it on “special occasions”.

[Slinglead]

IV hydration is like many other alternative therapies in that the basic premise is sold en masse with benefits that may not be as valuable as proposed. That being said, there is definitive value in applying it to maintain or re-establish hydration balance. Hangovers, as you suggest, cannot be fixed by fluids as alcohol has a fixed metabolic clearance rate. However, alcohol directly inhibits antidiuretic hormone. ADH is responsible for helping the body retain fluid and thereby hydration/electrolyte balance. Fluids would and do correct such an imbalance or we would not use them in the ER or OR for acutely intoxicated patients, or really any patient that presents for nearly any reason. All hydration therapy clinics by law must utilize most commonly nurses and sometimes EMTs depending on state law to establish IV access, both of which are licensed to start IVs so the infection rate is the same as all IV placement infection rates and should an infection develop it is most commonly due to care for the site after the IV is removed not due to antiseptic practice during establishment. I also have some doubts about the vitamin therapy piece but the foundational application of restoring hydration balance using IV fluids including various electrolyte solutions is sound or, again, such treatments would not be used for the exact same reasons in a more formal medical or hospital setting. I am not at all condoning all the applications but like many tools it can be used appropriately and beneficially while also being a stretch of the imagination in some applications. Caution and research for recieving the therapy is prudent but I would contend that the ultimate verdict suggested is reasonable opinion of choice rather than established proof of hypothesis.

[Cy_Willson]

Agreed. I can see some parallels but it was also a much more controversial issue as you had researchers publishing from both perspectives since the 70’s. It wasn’t unanimous that they didn’t work. Some were of the opinion that they clearly did work but had side effects while some held the opinion that while they work, they wouldn’t necessarily translate to improved performance. There were also controlled studies showing they worked but they weren’t large in size and didn’t control for other variables as well as they should have. And of course you had studies concluding they didn’t work, along with their own limitations.

For the IV hydration formulations on the other hand, it’s nothing but the unpublished anecdotal reports of patients/customers.

I can’t say that I’d use what some successful people report doing as a criterion for effectiveness. I’ve seen successful people do all sorts of crazy things. I think at least some successful people get to a point in life that they are willing to try just about anything for a perceived benefit as they can afford to. Same with people spending money on things. There’s a long history of fads that people have spent large sums of money on.

[Cy_Willson]

I’m all for evidence. You mentioned skin health, energy levels and overall health. We can measure those vua objective variables and with subjective questionnaires. An RCT measuring these variables and comparing to a placebo would be all that’s needed to convince me of effectiveness but there’s nothing out there in the literature that I can find.

[Atreides88]

Bioviability of magnesium is very low. Transdermal application solves this to some degree. But the only way I have found to raise magnesium levels - as measured with a blood test - is to get it in an IM shot or IV drip.

Yes I take ZMA or Elite Pro depending on the month.

[Cy_Willson]

Vasopressin (ADH) is definitely decreased with ethanol consumption but more recent papers which I cited show that in cases of bing drinking (4-5) drinks in a 2-hour peroid, doesn’t result in a substantial change in hydration status, presumably due to this effect upon vasopressin being biphasic or delayed along with increased thirst perception. Definitely some interesting research from these groups. If you’re working in an ER, that’s definitely another story as I suspect those individuals aren’t there from that amount of rinking but are likely highly intoxicated, recurrent vomiting, etc., in which case IV hydration makes sense.

[tombrown]

More likely than not the soft plastic bags and soft plastic tubing used contain BPA and also result in some microplastics entering the bloodstream. Hopefully microplastics we accidentally eat aren’t readily absorbed by the gut but that isn’t the case when they’re mainlined into the bloodstream. Some early evidence out there that microplastics are detected in some folks’ myocardium, etc.

i donate whole blood regularly but I also worry about folks who donate specifically plasma and platelets (often weekly) wherein their blood is taken out and the plasma or plts are separated out and then the red cells are put back in their body- all via plastic tubing and bags.

[Fitnessbunny]

I would check out Dr. Gabby. Here a bit about his view.
Blessings

Alan R. Gaby, MD, received his undergraduate degree from Yale University, his master of science in biochemistry from Emory University, and his doctor of medicine from the University of Maryland. He is past president of the American Holistic Medical Association and gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of numerous books and scientific papers in the field of nutritional medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, Washington, from 1995 to 2002. In 2011, he completed a 30-year project, the textbook Nutritional Medicine,1 and has recently completed the updated second edition of the book. For more information, please visit https://doctorgaby.com/.

Integrative Medicine: A Clinician’s Journal (IMCJ): The body of literature on nutritional research can include some very contradictory results. Has this discrepancy been addressed by any formal research?

Dr Gaby: Well, the research is contradictory. Everybody knows that. The question is: What do you do about that? How do you come to a conclusion? Obviously a lot of times it’s an interim conclusion. One of the things that has been done is meta-analyses where research is pooled and researchers come out with a final number. Then, they come up with a conclusion. Some people use meta-analysis to say, “The totality of the research says so and so, and therefore the individual studies are less important.” However, many scientists—and I totally agree with this—have pointed out that meta-analyses can lead you in the wrong direction. They assume that the studies are homogeneous: that the designs are the same, that the patient populations are the same, and that the dosages are the same. They are not. So in my opinion, the proper way to analyze any body of research is to look at differences in design, population, dosage, et cetera, between studies. You have to read each study—it takes a lot of time, and it takes a lot of effort.

Sometimes, it’s possible to come up with explanations of why the results are conflicting. For example, some of the studies using fish oil to treat rheumatoid arthritis used olive oil as a placebo. Now, olive oil is not a placebo, because it has anti-inflammatory activity. So, the use of an active placebo weakened the result that one would have obtained with fish oil. You have to go back and look at each individual study and try to decide in your own mind which ones are the most reliable. From that, you can come up with a more reliable conclusion than you can by pooling the lousy studies with the good studies.

You also have to look at who funded the study, because the presence of conflicts of interest can alert you to the possibility of bias in the design of a study or in the interpretation of results. For example, about 10 or 15 years ago, a couple of studies examined St John’s Wort as a treatment for depression. The results of 2 negative studies made the cover of one of the major news magazines: “St. John’s Wort Ineffective.” Many people were using the herb successfully, and there were over 20 double-blind, placebo-controlled trials showing that St John’s wort was effective for depression. Then this study came out, and in the tiny 6-point type, the acknowledgements stated that it was funded by Pfizer. Pfizer sells Zoloft, which at the time was a $2-billion a year antidepressant drug.

Then if you continued to read the small print, it said the funding source played a role in the design of the study. So now you start wondering whether some conflict of interest existed in the way they designed it. A positive response is generally defined as a 50% improvement in a certain depression rating scale. Looking at the study, 15% of the people who received St John’s wort had a positive response. Only 5% of the people in the placebo group had a positive response, and that difference was statistically significant.

So if you’re coming down from Mars and you don’t know anything about bias, you would say, “Okay. St John’s wort showed a statistically significant advantage over placebo.” But the authors of the study, some of whom also had potential conflicts of interest—they received funding support from various drug companies—concluded that because the normal placebo response rate in a depression trial is 30% and the St John’s wort response rate was only 15% in this study, that it was ineffective.

The researchers basically ignored their own data and came up with a conclusion contrary to what they actually found. Probably what happened is that they chose patients who had previously failed to respond to antidepressant medications and were therefore less likely to improve with any treatment. The conclusion that the St John’s wort response rate was lower than the normal placebo response rate was irrelevant, because the placebo response rate in this study was only 5%.

I’m explaining this in detail just to show that authors sometimes either misrepresent their findings or don’t understand them. Therefore, one has to really dig into this. We all have biases. I have biases, too. My belief, my bias, is that nutritional therapy is a safe, effective, low-cost alternative to a lot of what’s being done in conventional medicine. Despite my bias, I do my best to view the evidence objectively. In my book, Nutritional Medicine,1 if I don’t think something works, I say so.

IMCJ: So then do factors exist in nutritional research that require differences in design compared with standard trials?

Dr Gaby: Yes, some do require differences. The standard model in medicine is a pharmaceutical drug, so you compare a single pill to a placebo. That is relatively straightforward—1 variable—and it either produces an effect or it doesn’t. In nutrition studies, you can use that design if you are only investigating the effect of a single nutrient, but the problem is that nutrients work as a team in the body, and a combination of nutrients is usually more effective than individual nutrients. If you’re trying to get your best result, you have to do multiple interventions at the same time. To bring the design back to a single pill or a single regimen of pills, sometimes you can devise a formula that you might think is the most effective and you’d compare that formula to a placebo. In that respect, the design is fairly similar to that of pharmaceutical research.

That approach was used in a trial a couple years ago with heart patients. Investigators compared a 28-component, high-dose multivitamin and mineral supplement to a placebo and found that the composite endpoint of heart attacks and heart disease-related mortality occurred 37.5% less often in the multivitamin group than in the placebo group. This benefit was seen in the subset of patients who were not taking statin drugs. The details of the study are not so important, except to illustrate that you can use the standard design in some cases.

On the other hand, nutritional therapy also involves diet, and diet is much harder to study because most of the time you can’t do a placebo control. Sometimes you can; for example, studying a gluten-free diet, you can give people muffins that contain or don’t contain gluten. In that sense, you can do a placebo-controlled trial, but when you’re looking at the Mediterranean diet or the DASH diet—the one for hypertension—they have so many different variables and the compliance rate varies from person to person, so it gets pretty muddy. Many times, it’s harder to prove a nutritional intervention is effective or ineffective than it is for a single drug or nutrient. So we have to recognize the limitations in what we’re studying.

IMCJ: In the process of discussing some of the issues here, we’ve described a number of issues to look out for, but what other advice can you offer practitioners for evaluating nutrition research?

Dr Gaby: The first things I look at are who funded the study and where was it published. If there’s a potential conflict of interest, let’s say they’re looking at a probiotic and the study was funded by the company that sells the probiotic, that doesn’t mean the study is invalid, but it indicates one should study the paper in greater detail and with greater scrutiny. One should regard it with a little more skepticism because people can twist things around in order to make the evidence look better than it really is. I’ll go over a couple of the ways that can be done.

Where was it published? That question has become much more important in recent years because there are thousands of open-access journals in publication, where the person submitting the article pays to have the article published. It’s a per-page fee. People have many reasons to get their research published, but in open-access, pay-per-page journals, the peer-review process in some cases appears to be pretty sloppy. The financial model for these journals is that they make money when articles are published. If they don’t accept an article for publication, they don’t make money. Some research has looked at the peer-review process in these open-access journals. One can conclude from that research that if an article is published in one of these journals, you need to be a more alert to the possibility that the study was weak or that there’s bias.

The next thing I look at is what type of study it is. Was it an observational study, was it a randomized, controlled trial, or was it a case report? Observational studies do not prove causation. Let’s say you find that people who do A are more likely to experience B. That does not prove that A causes B. This fact is pretty well known, but it’s often forgotten.

One of the common examples I see concerns people with lower levels of vitamin D, which is measured as 25-hydroxyvitamin D. People with lower 25-hydroxyvitamin D levels have a higher incidence of many diseases. Researchers and practitioners often conclude that if you give a vitamin D supplement to people with low 25-hydroxyvitamin D levels, you will prevent various diseases. However, that conclusion does not follow at all from an observational study. Observational studies prove associations, but they do not prove that intervening to change the variable in question—in this case, increasing the 25-hydrxyvitamin D level—would be useful.

One of the confounding factors is that 25-hydroxyvitamin D levels decline in response to inflammation. If you have a chronic inflammatory disease—and many diseases have an inflammatory component—your vitamin D level is going to be lower than if you don’t have such a disease. Therefore, the association between 25-hydroxyvitamin D and various diseases may simply mean that people with inflammation have more health problems than people without inflammation, and it may have nothing to do with vitamin D itself.

In order to find out if the vitamin D will prevent or reverse the condition, you have to do randomized controlled trials. You give half the people vitamin D and half the people a placebo and you see what happens. Unfortunately, the vast majority of vitamin D intervention trials, randomized, controlled trials, show very little benefit, if any, and so the observational studies are probably confounded by other factors and do not demonstrate that vitamin D is useful. Again, you have to understand the difference between observational studies and randomized controlled trials.

Now, when you get into randomized controlled trials, you have to know a little bit about statistics. There’s something called the beta error. An example of a possible beta error was in a study where people received vitamin C or placebo for a number of months. The people in the vitamin C group had 22% fewer days ill than the people who got the placebo. That’s pretty good—a 22% reduction. But then when you do the statistics, you find that it was not statistically significant. Very frequently, the authors of a study conclude that since it was not statistically significant, it didn’t work. That’s not the correct conclusion. We see that all the time, though: “Not statistically significant, therefore ineffective.”

What people don’t understand is that the failure to demonstrate that something was statistically significant is not the same as demonstrating that it was ineffective. The correct conclusion from that study would be: There was a 22% reduction in the number of days ill, but since it was not statistically significant we are less than 95% certain that that improvement was real. In other words, there was more than a 5% probability that the 22% improvement was due to chance. What you need to do is use statistics to test additional hypotheses. For example, what is the probability that there is less than a 10% improvement? What is the probability of less than a 20% improvement? There are ways to make those calculations, but the main point here is that failure to find statistical significance is not the same as proving that something didn’t work.

If I see a study that shows a 20% to 30% improvement and the treatment is safe and low-cost and a reasonable possibility exists that the 20% to 30% improvement is real, I very well might try that treatment with my patients, even though it’s not statistically significant.

There’s also something called regression to the mean. I’ll give you an example. Let’s say you give a treatment—it doesn’t matter what the treatment is—and for people with high cholesterol, the cholesterol comes down. For people with low cholesterol, the cholesterol comes up. So a researcher might conclude, “This treatment is an adaptogen because when the level is high, it comes down and when the level is low, it comes up.”

[Cy_Willson]

You might just be in the minority. Here’s a good review paper.

https://www.sciencedirect.com/science/article/abs/pii/S0899900721001568