It’s spring, which means lots of sneezing, sweets, and sunlight! Of those three, sunlight is probably the healthiest, so let’s shine a light on what sunlight does in the body and why we need it. First, the sun is vital for keeping the planet habitable. Without the sun, we would all die very fast as oxygen would solidify on the surface, and we’d be unable to breathe. Beyond being vital to life, sunlight is used by the skin to produce Vitamin D!

Vitamin D is actually a collection of very similar molecules called calciferols. These are fat-soluble steroid hormones that are used throughout the body. Vitamin D deficiency is a worldwide problem, and affects at least ⅓ of Americans. It is linked to complications in bones, kidneys, heart, and brain, as well as to diabetes, immune system issues, obesity, and poor pregnancy outcomes. Though indications of this deficiency seem robust, the solutions are anything but. Unfortunately, the effects of supplemental vitamin D, and therefore sunlight, are grossly understudied. Trial after trial after trial (check the extensive references list) shows that supplemental vitamin D – and in some cases supplemental light – does not have a significant effect on measurable outcomes for patients. These trials consistently find that the levels of circulating vitamin D in the bloodstream are increased, but symptoms are unaffected. The only results I could find from randomized, placebo-controlled clinical trials showing actual benefits to patients were for those with sickle-cell disease and in reducing respiratory infections in elderly patients.

This is counter to “common knowledge” and to the assumed knowledge found in several research papers. Observational studies, where scientists look at populations, find a myriad of problems associated with vitamin D and sunlight deficiency. Let’s try to illuminate why clinical trials haven’t found benefits when giving supplemental vitamin D. The answer is likely that the problems that cause vitamin D deficiency aren’t solved by supplementation! Vitamin D production starts in the skin, then goes to the liver and kidneys before the body can use it. The symptoms associated with low levels of vitamin D may not improve if there are underlying liver or kidney issues, though those conditions can hinder the production of Vitamin D.

Further, observational studies look at a population and investigate the correlations between items. This can tell us things that may be associated with each other but does not indicate that one thing is causing the other. An example would be looking at the availability of toilet paper and used car prices over the last 10 years. In 2020 toilet paper was unavailable and used car prices soared! This wasn’t because we needed toilet paper to run our used cars or anything; there was a pandemic disrupting supply chains! In the case of vitamin D deficiency, the lack of vitamin D is probably the effect of not going outside! If a mental disorder like depression keeps people indoors, this would lower the vitamin D they produce, not the other way around. On top of this, it is very difficult for scientists to isolate sunlight (and therefore vitamin D) from exercise. People who stay inside and never see the sun are, on average, less active. This can lead to some of the problems we associate with vitamin D deficiency, including bone issues, obesity, diabetes, and heart problems. In these cases vitamin D deficiency is more a canary in the coal mine than the smoke of a fire.

So, what can we take away from this? First and most importantly is that in all of these clinical trials supplemental vitamin D has been found to be safe. If vitamin D helps you with an issue, there is nothing wrong with continuing your care. Always consult with your doctor before making changes to your medication. Second, clinical trials are vital to our medical system! Observational studies are no substitute for actual experimentation in a placebo-controlled, randomized trial. The common knowledge is that sunlight and vitamin D are good for us. This is true, but it’s best to start at the source, the sun (if you can), rather than supplementing after the fact. We should spend more time outside in the nice weather, but remember your sunscreen.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

References:

Aranow, C., Kamen, D. L., Dall’Era, M., Massarotti, E. M., Mackay, M. C., Koumpouras, F., … & Diamond, B. (2015). Randomized, double‐blind, placebo‐controlled trial of the effect of vitamin D3 on the interferon signature in patients with systemic lupus erythematosus. Arthritis & rheumatology, 67(7), 1848-1857. https://doi.org/10.1002/art.39108

Burns, A. C., Saxena, R., Vetter, C., Phillips, A. J., Lane, J. M., & Cain, S. W. (2021). Time spent in outdoor light is associated with mood, sleep, and circadian rhythm-related outcomes: a cross-sectional and longitudinal study in over 400,000 UK Biobank participants. Journal of affective disorders, 295, 347-352. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892387/

Eckard, A. R., O’Riordan, M. A., Rosebush, J. C., Lee, S. T., Habib, J. G., Ruff, J. H., … & McComsey, G. A. (2018). Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth. Antiviral therapy, 23(4), 315-324. https://doi.org/10.3851/imp3199

Guralnik, J. M., Sternberg, A. L., Mitchell, C. M., Blackford, A. L., Schrack, J., Wanigatunga, A. A., … & STURDY Collaborative Research Group. (2022). Effects of vitamin D on physical function: results from the STURDY trial. The Journals of Gerontology: Series A, 77(8), 1585-1592. https://doi.org/10.1093/gerona/glab379

Ginde, A. A., Blatchford, P., Breese, K., Zarrabi, L., Linnebur, S. A., Wallace, J. I., & Schwartz, R. S. (2017). High‐dose monthly vitamin D for prevention of acute respiratory infection in older long‐term care residents: a randomized clinical trial. Journal of the American Geriatrics Society, 65(3), 496-503. https://pubmed.ncbi.nlm.nih.gov/27861708/

Hansen, K. E., Johnson, R. E., Chambers, K. R., Johnson, M. G., Lemon, C. C., Vo, T. N., & Marvdashti, S. (2015). Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. JAMA internal medicine, 175(10), 1612–1621. https://doi.org/10.1001/jamainternmed.2015.3874

Huiberts, L. M., & Smolders, K. C. (2021). Effects of vitamin D on mood and sleep in the healthy population: Interpretations from the serotonergic pathway. Sleep Medicine Reviews, 55, 101379. https://www.sciencedirect.com/science/article/pii/S1087079220301222

Javed, A., Kullo, I. J., Balagopal, P. B., & Kumar, S. (2016). Effect of vitamin D3 treatment on endothelial function in obese adolescents. Pediatric obesity, 11(4), 279-284. https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12059

Juraschek, S. P., Miller III, E. R., Wanigatunga, A. A., Schrack, J. A., Michos, E. D., Mitchell, C. M., … & Appel, L. J. (2022). Effects of vitamin D supplementation on orthostatic hypotension: results from the STURDY trial. American journal of hypertension, 35(2), 192-199. https://doi.org/10.1093/ajh/hpab147

Karsy, M., Guan, J., Eli, I., Brock, A. A., Menacho, S. T., & Park, M. S. (2019). The effect of supplementation of vitamin D in neurocritical care patients: RandomizEd Clinical TrIal oF hYpovitaminosis D (RECTIFY). Journal of neurosurgery, 1–10. Advance online publication. https://doi.org/10.3171/2018.11.JNS182713

Michos, E. D., Kalyani, R. R., Blackford, A. L., Sternberg, A. L., Mitchell, C. M., Juraschek, S. P., … & Appel, L. J. (2022). The relationship of falls with achieved 25-Hydroxyvitamin D levels from vitamin D supplementation: the STURDY trial. Journal of the Endocrine Society, 6(6), bvac065. https://doi.org/10.1210/jendso/bvac065

Okereke, O. I., Reynolds, C. F., Mischoulon, D., Chang, G., Vyas, C. M., Cook, N. R., … & Manson, J. E. (2020). Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: a randomized clinical trial. Jama, 324(5), 471-480. https://jamanetwork.com/journals/jama/fullarticle/2768978

Osunkwo, I., Ziegler, T. R., Alvarez, J., McCracken, C., Cherry, K., Osunkwo, C. E., … & Tangpricha, V. (2012). High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study. British journal of haematology, 159(2), 211-215. https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.12019

Øverland, S., Woicik, W., Sikora, L., Whittaker, K., Heli, H., Skjelkvåle, F. S., … & Colman, I. (2020). Seasonality and symptoms of depression: A systematic review of the literature. Epidemiology and psychiatric sciences, 29, e31. https://www.cambridge.org/core/journals/epidemiology-and-psychiatric-sciences/article/seasonality-and-symptoms-of-depression-a-systematic-review-of-the-literature/375F49B0149E903EFBDEDF9D53431B15

Palacios, C., & Gonzalez, L. (2014). Is vitamin D deficiency a major global public health problem?. The Journal of steroid biochemistry and molecular biology, 144, 138-145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018438/

Ponda, M. P., Liang, Y., Kim, J., Hutt, R., Dowd, K., Gilleaudeau, P., Sullivan-Whalen, M. M., Rodrick, T., Kim, D. J., Barash, I., Lowes, M. A., & Breslow, J. L. (2017). A randomized clinical trial in vitamin D-deficient adults comparing replenishment with oral vitamin D3 with narrow-band UV type B light: effects on cholesterol and the transcriptional profiles of skin and blood. The American journal of clinical nutrition, 105(5), 1230–1238. https://doi.org/10.3945/ajcn.116.150367

Rorie, A., Goldner, W. S., Lyden, E., & Poole, J. A. (2014). Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: áaárandomized study. Annals of allergy, asthma & immunology, 112(4), 376-382. https://www.annallergy.org/article/S1081-1206(14)00012-X/abstract

Sadock, B.J., Sadock, V.A., & Ruiz, P. (2017). Comprehensive textbook of psychiatry (Vol. 1/2). Sadock, B.J., Sadock, V.A., & Ruiz, P. (Eds.). Philadelphia: Lippincott Williams & Wilkins.

Sokol, S. I., Srinivas, V., Crandall, J. P., Kim, M., Tellides, G., Lebastchi, A., … & Alderman, M. H. (2012). The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease. Vascular medicine, 17(6), 394-404. https://journals.sagepub.com/doi/10.1177/1358863X12466709

Shaffer, J. A., Edmondson, D., Wasson, L. T., Falzon, L., Homma, K., Ezeokoli, N., … & Davidson, K. W. (2014). Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosomatic medicine, 76(3), 190-196. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008710/

Simha, V., Mahmood, M., Ansari, M., Spellman, C. W., & Shah, P. (2012). Effect of vitamin D replacement on insulin sensitivity in subjects with vitamin D deficiency. Journal of investigative medicine, 60(8), 1214-1218. https://doi.org/10.2310/jim.0b013e3182747c06

Sokol, S. I., Srinivas, V., Crandall, J. P., Kim, M., Tellides, G., Lebastchi, A., … & Alderman, M. H. (2012). The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease. Vascular medicine, 17(6), 394-404. https://doi.org/10.1177/1358863×12466709

Wei, W., Shary, J. R., Garrett-Mayer, E., Anderson, B., Forestieri, N. E., Hollis, B. W., & Wagner, C. L. (2017). Bone mineral density during pregnancy in women participating in a randomized controlled trial of vitamin D supplementation. The American Journal of Clinical Nutrition, 106(6), 1422-1430. https://doi.org/10.3945/ajcn.116.140459

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May 20th is Clinical Trials Day. Of course, we are biased and think it should become a national holiday, but until that day arrives, let’s celebrate the day by studying a clinical trial designed by our founder and CEO, Dr. Michael J. Koren. The trial we will study, published in 2006, was called the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events, or ALLIANCE. In case you are unaware, the sponsors of clinical trials are all very clever and enjoy coming up with neat acronyms.

ALLIANCE was a large, 16-center study conducted around the turn of the millennium and enrolled 2,442 patients. All patients had coronary heart disease – blockage of a major blood vessel to the heart. The study was designed to determine the difference in outcomes for patients with coronary heart disease when taking atorvastatin, marketed as Lipitor, at a full dose of 80 mg versus usual treatment with statins or other cholesterol drugs. Patients treated with high dose atorvastatin were monitored to keep their LDL less than 80 mg/dL.

Outcomes in a clinical trial are the variables measured: what researchers are monitoring for change. Typical outcomes will include things like changes in symptoms, cure, or death. The ALLIANCE patients had coronary heart disease, so the main outcomes being monitored were: 

• low-density lipoprotein (LDL – the “bad” cholesterol)
• heart-related hospitalization
• heart attack
• death due to heart attack

This study was significant because it looked at the difference between medications given in a clinical trial setting and “usual care” for people enrolled in managed care health plans (they all had insurance).

The study results were, frankly, amazing. In the “usual care” group, patients saw their average LDL levels drop by over 23 mg/dL, a significant decrease. These are nice results, but the “more aggressively treated” group did even better. They saw LDL levels drop by more than 34 mg/dL, a 50% greater reduction! Furthermore, the aggressive treatment led to 17% fewer events, including a whopping 47% fewer heart attacks! Needless to say, the aggressive atorvastatin treatment was a resounding success.

The stated goal of the study was to discover the effectiveness of the investigational medication, but the ALLIANCE study also measured the difference between clinical trials and standard care. The aggressive treatment group received clinical-trial-level care with specialist medical professionals and frequent check-ins. Patients had a lot of contact, and researchers were interested in any and all health changes. The study showed great success for the sponsor. It helped make Lipitor the best-selling medication of all time (recently broken by Humira). It gave us solid evidence that the clinical trial process doesn’t just lead to new potential medications but also potentially better health outcomes for patients.

Thanks, Dr. Koren, for taking leadership of this trial and the ENCORE Research Group.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

Listen to the article here:

Sources:

Koren, M. J., Hunninghake, D. B., & Alliance Investigators. (2004). Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. Journal of the American College of Cardiology, 44(9), 1772-1779. https://www.sciencedirect.com/science/article/pii/S0735109704016365

Listen to the article here:

Sticks and stones may break my bones, but words can never hurt me. But what if words could hurt you? Meet the nocebo effect, the evil twin of placebo. The nocebo effect is an increase in negative symptoms in response to patient expectations. This occurs in both clinical trials and normal clinical care. In clinical trials, this frequently presents as adverse events occurring during a placebo administration (such as a sugar pill instead of a blood pressure med), but it’s important to note that nothing needs to be administered for an increase in symptoms. Nocebo effects may sound like no big deal, but symptoms can be significant. In clinical trials, 4-26% of patients who discontinue medication do so because of nocebo reactions.  Unfortunately this burden isn’t evenly spread. Women experience an outsized effect, as do those suffering from certain psychiatric illnesses, such as anxiety and depression. Furthermore, both pessimistic and type A individuals experience higher rates of nocebo effect.

So how does it work, and are the effects real? Nocebo effects are due to our own expectations. When a doctor, nurse, or researcher states the potential side effects for a medication or procedure, patients are more likely to experience those effects. This has been shown in several anecdotal settings, but also in multiple research studies. During the COVID clinical trials, patients were reporting serious side effects that tracked popular media descriptions – even when they were given saline instead of the real vaccine!

These effects show the power of negative expectations, one of the three psychological mechanisms underpinning the nocebo effect. Negative results are a direct result of expectations. Researchers in one study tested the effect of word phrasing on pain outcomes. When pregnant women were preparing to get an anesthesia injection the researchers talked them through what might happen. Half the patients were given the standard spiel, “You are going to feel a big sting and burn in your back now”. The other half were given the same information in much more neutral language: “We are going to inject the local anesthetic that will numb the area.“ The neutral language group experienced significantly less pain during the injection – just from phrasing! Scientists think the negative expectations might increase focus on symptoms. The expectations don’t have to come just from doctors or nurses, however. Seeing someone else suffer a side effect or hearing stories can produce the same effect!

Two other psychological underpinnings for the nocebo effect are less direct. Misattribution is the blaming of normal aches and pains to a new medicine. Progressive disease effects can also be misattributed to a placebo medication. Finally, conditioning has a large effect. Conditioning is the long-term associations we make between seemingly related things. Some patients feel nauseous at the smell of a hospital, for instance. This can also be very specific; the color of a pill can induce distinct side effects. Patients taking blue sugar pills are more likely to experience and report drowsiness than those taking pink sugar pills. Psychology shows us the framework for understanding what’s happening, but what’s going on under the hoodie?

Our brains experience changes at suggestions. Scientists think these changes may be due in large part to anticipatory anxiety. Anticipatory anxiety activates at least two pathways in the brain: pain and stress. Part of the pain pathway is called the CCKergic pronociceptive [pro-no-si-cep-tive] system. It is activated by a peptide called cholecystokinin [kow·luh·si·stuh·kai·nuhn] (CCK), and increases our perception of pain at the spinal level. This undermines anesthesia and increases our feelings of pain. The stress pathway moves through a few brain regions along the hypothalamus–pituitary–adrenal (HPA) axis and produces cortisol. Cortisol is a hormone that causes all of the classic signs of stress – increased heart rate and blood pressure, sweating and breathing, among others. The activation of these two major pathways primes our brain and bodies to experience worse symptoms – especially those we are expecting.

So what can be done? Well, reading this article is a great start! Around 75% of patients haven’t heard of or don’t believe in the nocebo effect, even though they experience it. Thinking about risks in terms of percentages instead of raw numbers can help. Four in a thousand may increase anxiety more than 0.4%.Other methods may be in the hands of medical professionals. Positive framing, such as with the injection example above, can make a lot of difference. In addition, identifying risky patients may help with how information is presented. Fortunately, understanding the mechanistic nature behind the nocebo effect can help lessen your anxiety – and symptoms!

Written By Benton Lowey-Ball, BS Behavioral Neuroscience

Sources:

Kong, J., Gollub, R. L., Polich, G., Kirsch, I., LaViolette, P., Vangel, M., … & Kaptchuk, T. J. (2008). A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. Journal of Neuroscience, 28(49), 13354-13362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649754/

Planès, S., Villier, C., & Mallaret, M. (2016). The nocebo effect of drugs. Pharmacology research & perspectives, 4(2), e00208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804316/

Varelmann, D., Pancaro, C., Cappiello, E. C., & Camann, W. R. (2010). Nocebo-induced hyperalgesia during local anesthetic injection. Anesthesia & Analgesia, 110(3), 868-870. https://doi.org/10.1213/ANE.0b013e3181cc5727

Our patients are enthusiastic and excited to take part in clinical research.  There are a variety of reasons a patient would want to participate in a clinical trial: they join to benefit future generations, to advance medicine, to get medical help and compensation, and to increase diversity. The most frequent reason for joining a clinical study, however, is to help others. Clinical research is the best framework for ensuring the safety and effectiveness of new medications, devices, and procedures. This includes everyone from participants of phase 1 clinical trials to final consumers after FDA approval. But what does the process actually look like for patients?

People hear about us from a wide variety of sources: advertisements, community outreach programs, the internet, and personal referrals from family and friends. Thousands of our patients are referred to us by friends, family, and their own physicians. People’s great experiences with us make them very likely to recommend us to others. Most of our patients are repeat offenders. In fact, over 99% of our patients return for another study. 

When you are interested in an ENCORE Research Group study, our experienced and compassionate recruiters will talk with you. These experts care about your time more than anything else. They will run through a quick checklist to see if you prequalify for a study. If you prequalify, they will schedule an evaluation. They will find a time that works best for you to come in or receive a call with a research coordinator.

Here the compassionate and attentive nature of ENCORE Research Group excels. You will receive forms to fill out your medical history, medications, and contact information. During your appointment, our attentive and detail-oriented staff will review your documents. They will confirm and expand on any medical conditions that may affect your participation. This step makes sure you are always safe and gives our staff personal knowledge to help you during your study. Patient safety is always our number one priority.

After an evaluation, if you choose to participate, you will start the informed consent process. Here you will review the clinical trial process and the plan for your specific study. Research coordinators will explain and review a highly detailed and regulated consent form. This document informs you about the study, potential side effects, the goals and endpoints of the study, your rights, and what to expect. This is a vital step. We will also remind you that you can end participation in the study at any time for any reason. Your voluntary participation does not oblige you to continue at any point.

What happens from here depends on your specific study, but some things will remain constant. Our doctors and medical staff will talk with you. Other patients describe them as professional, friendly, and compassionate. You may receive medication, a placebo, device, or undergo a procedure. This will have been explained in detail during the informed consent process. One big difference between ENCORE Research Group and a normal doctor’s office is the comprehensiveness and amount of follow-up. Our doctors give you their full, undivided attention when you are in their office. They have plenty of time and want to know the intricacies of your medical history. For most studies, our staff will periodically check up on you after you leave. We are also keenly interested in knowing if you experience any new or changing symptoms. This will continue until your study has concluded. Then, if you wish, we will contact you if you qualify for more studies.

This process results in a streamlined, professional, and personal system. You get to help medicine and society, but also experience top-quality, attentive care for a variety of conditions. Join the clinical trial process with ENCORE Research Group and see why nearly all of our patients come back!

By Benton Lowey-Ball, BS Behavioral Neuroscience