Last week we talked about the actions of the Nazis, which resulted in the World Medical Association’s Declaration of Helsinki. The declaration provides an ethical guideline for physicians engaging in research involving humans. It has since become a requirement in most medical research. Unfortunately, in America, a study that began seven years prior to World War II undermined this ideal. It wouldn’t be until the 1970s that this study was exposed, and America was faced with its own dark practice of human research.

In 1932, doctors at the Tuskegee Institute (Now called Tuskegee University) started a fundamentally unethical experiment. The road to this study winds from good intentions to simple, terrible means. The historical context behind the study involves the Julius Rosenwald Fund, a wholly honorable philanthropic endeavor. This fund built schools in the South, funded Booker T. Washington to attend the Tuskegee Institute, and worked with the U.S. Public Health Service to provide medical services to the poorest Black Americans in the South. One of these medical service endeavors was providing syphilis treatment. Part of this effort involved cataloging the rate of syphilis in several areas. The great depression and Julius Rosenwald’s death brought much of this to a halt, and the syphilis project ended in 1932.

Other scientists wanted to pick up where the Julius Rosenwald Fund left off. These scientists believed that different races experienced diseases differently. The new study would observe the ravages of untreated syphilis in Black populations. They already had the groundwork built. They had a large number of men with untreated syphilis, a nearby hospital at Tuskegee Institute, a bank of goodwill built by Rosenwald, and a store of trust in medical professionals and the U.S. Public Health Service. The scientists successfully exploited all of these. They intentionally coerced and deceived 400 Black Americans into their study. The study had no protocol, patients had no informed consent, and one of the major endpoints was to wait until patients died and then deceive their loved ones into allowing an autopsy. This alone is terrible, but it was – unfortunately – much worse. After the end of World War II, an effective treatment for syphilis became widely available: penicillin. The researchers didn’t provide this to their patients and, in fact, actively thwarted its use in this population. They convinced hospitals, government agencies, and even the U.S. military that the torturous observation of sick and dying people was more important than their health and well-being. This continued for 40 years and only ended in 1972 after the experiment started getting public attention and press.

The Tuskegee study ended almost a decade after the Declaration of Helsinki and prompted the passage of the National Research Act and the creation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. A group of 11 people spent four years developing the Belmont Report.  Whereas the Declaration of Helsinki outlines ethical standards to follow, the Belmont Report gives specific guidelines and actionable procedures for determining the legitimacy of research involving human participants. It was initially incorporated into federal law in 1981 as the Protection of Human Subjects.

The Belmont Report first outlines the difference between medical practice and research. The goal of practice is normal therapy with a reasonable chance of success, while the goal of research is to test a hypothesis and answer a question. Whereas practice follows the needs of the patient, research follows well-defined, written protocols. The Belmont Report maintains the same three ethical principles in the Declaration of Helsinki – Respect for Persons, Beneficence, and Justice. It then outlines the practical, actionable processes: Informed Consent, Risk/Benefit Assessment, and Subject Selection.

Respect for Persons is the idea that most people can make their own choices, and those that can’t must be afforded special protection. These protections must be assessed by third parties, protect participants from harm, and be periodically reevaluated. The Belmont Report applies respect for persons as Informed Consent. Informed consent requires that before a study begins, all information, including the procedure, risks, etc. be clearly written and organized. It requires comprehension by all potential human participants of the above information. Patients cannot be enrolled if they do not understand the informed consent, and the information can’t be written in tiny print and put off to the side like a used car ad. This also means that vulnerable populations (those with limited comprehension, like children) must have extra protection, and third parties (like parents) must help determine comprehension. Finally, informed consent is only given if it is voluntary. This means no large sums of money, threats, or exaggerated promises can be used to coerce people into studies. This can make it more difficult to enroll patients but is critical to avoiding disasters like the Tuskegee syphilis study.

Beneficence is the obligation to secure the well-being of patients and to do no harm. Researchers may not injure some people to help others. This is applied as Risk/Benefit Analysis. Under this concept, all benefits must be weighed against potential risks. Risks are a possibility of harm, and include the chance harm will occur and the severity of the harm. This may include things like pain from the site of an injection and must be clearly laid out in the informed consent. Risk/Benefit Analysis is done by researchers, but is overseen and double-checked by Institutional Review Boards (IRBs) – third party boards that oversee studies involving human participants. The Belmont Report lays out specific ways these IRBs assess the risks of a study. These are then weighed against benefits. Benefits are a positive change in health or welfare and are usually much clearer – the alleviation of symptoms from being in a medical study, for instance.

Justice is an equal distribution of burdens and benefits across society. Further, justice demands that the groups that participate in research should be the ones that receive the benefits. The racially biased attitudes that formed the basis of the Tuskegee study are the prime example of a failure of justice. These groups were denied benefits, and researchers demanded they take the burdens. The Belmont Report applies justice by way of Selection of Subjects. On the individual level this means that all subjects get fair treatment: you can’t give UF fans all of the investigational medication and FSU fans all placebo, for instance. Societally, the selection of subjects should be done in ways that minimize risks, like choosing adults before children. Selection should be done as fairly as possible and should target the populations that will benefit from research.

Unfortunately, the Tuskegee study has undermined trust in government and research in some communities for the past 80 years. From this historical tragedy have arisen solid, unambiguous rules for conducting human research. These ensure safety, oversight, and mitigation of risk so participating in clinical research is beneficial for the community. With the Belmont Report, communities can get access to new medications, find relief from symptoms, and help define their legacy to find possible cures for future generations.

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

References:

National Commission for the Protection of Human Subject of Biomedical and Behavior Research. (1977). U.S. Department of Health and Human Services. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

Baker, S. M., Brawley, O. W., & Marks, L. S. (2005). Effects of untreated syphilis in the negro male, 1932 to 1972: a closure comes to the Tuskegee study, 2004. Urology, 65(6), 1259-1262. https://doi.org/10.1016/j.urology.2004.10.023

Brandt, A. M. (1978). Racism and research: the case of the Tuskegee Syphilis Study. Hastings center report, 21-29. https://doi.org/10.2307/3561468

Gray, F. D. (1998). The Tuskegee syphilis study: The real story and beyond. NewSouth Books.

In 1945-1946, after the conclusion of the Second World War, several Nazi German leaders and doctors stood trial for crimes against humanity, war crimes, and other atrocious crimes.  One of the trials, the so-called Doctor’s Trial (U.S.A. v. Karl Brandt et al.), helped shape how we view and perform clinical research today. One of the major defenses in the Doctor’s Trial was a lack of international law or agreement against the horrible activities the Nazis were doing. To remedy this, the trial ruling (in which seven defendants were sentenced to death) gave an outline of “Permissible Medical Experiments.” This was called the Nuremberg Code and was later expanded by the World Medical Association into the Declaration of Helsinki.

The Declaration of Helsinki, originally released in 1964, is the cornerstone of modern clinical research. The medical atrocities during the Holocaust showed that the unsaid rules of medicine needed to be said, printed, and widely distributed. The World Medical Association’s original Declaration of Helsinki has been revised seven times and has since grown by 300%. It concerns the ethical treatment of human participants in medical research.

The foundational notions of the Declaration of Helsinki rest on the following two ideas: “The health of my patient will be my first consideration” and “A physician shall act in the patient’s best interest when providing medical care.” The fact that these were up for debate is wild to me, but thanks to the Declaration of Helsinki these are now universal statements. The rest of the Declaration of Helsinki has similar “this should be obvious” content but has been critical for ensuring the safe and ethical treatment of people in research.

The document first states that human medicine must be tried in humans at some point. There are also stipulations about what must happen before a study can begin. A protocol must be written that outlines the entire study. An independent review board (IRB) must approve the protocol and any changes. Funding and results should be transparent and public. The document also outlines in broad terms how to do this with respect, beneficence, and justice.

Respect comes from the assertion that individual people matter more than new knowledge. This is how we get concepts like informed consent – that all trial participants must have full knowledge of what they are getting into before signing up. Respect also states that patients must voluntarily sign up and be able to discontinue at any time. Further, special protections must be in place for vulnerable populations – like children, prisoners, and people with mentally disabilities.

Beneficence is the concept of weighing benefits against risks. In medical research, the benefits must always outweigh the risks. Benefits must help the individual person, a population, or society. Risks must be minimized wherever possible. This is one reason you often see a long list of things that can exclude a person (like being pregnant) from a study: to minimize risks. Beneficence also mandates that studies must be stopped if the risks become too high – if an unintended side effect emerges, for instance.

Justice is the concept that research should be for the benefit of everyone. Medications that would target a specific population should be researched in that population. If left-handed people made up 90% of smokers, for instance, then smoking cessation studies should aim to enroll mostly left-handed people. Justice also means groups should be fairly selected and that studies should help people who live where the studies take place. You shouldn’t test a pants-lengthening drug on people in Bermuda (for their Bermuda shorts) and refuse to sell it to them.

Altogether, these seem like common-sense rules to have in place, but they need to be written. The Nazis claimed the ends justify the means – even though their end goals were abhorrent. In this world, however, there are no ends – only means.

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

References:

Bošnjak, S. (2001). The declaration of Helsinki: The cornerstone of research ethics. Archive of Oncology, 9(3), 179-184.

Nuremberg Trials Project (n.d.). NMT case 1. Harvard Law School. https://nuremberg.law.harvard.edu/nmt_1_intro

Shrestha, B., & Dunn, L. (2019). The Declaration of Helsinki on medical research involving human subjects: a review of seventh revision. https://elibrary.nhrc.gov.np/handle/20.500.14356/1367 

Taylor, T. (1955). Nuremberg Trials, The. Colum. L. Rev., 55, 488. https://www.jstor.org/stable/1119814?read-now=1&seq=38

United States Holocaust Memorial Museum, Washington, DC. (n.d.). The Nuremberg code. Holocaust Encyclopedia. Accessed 5/13/2024. https://encyclopedia.ushmm.org/content/en/article/the-nuremberg-code 

World Medical Association. (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama, 310(20), 2191-2194. https://jamanetwork.com/journals/jama/fullarticle/1760318/

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

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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

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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:

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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