553 - ADHD Treatment, Micro- and Nanoplastics, Loving My “Manyme’s”
From the Literature
1) ADHD Treatment and Major Outcomes
For many drugs, data about their long-term use and important outcomes such as mortality is often not available from the narrow, randomized controlled trials done to win US Food and Drug Administration (FDA) approval. We must rely instead on large and long duration observational studies (prospective or retrospective) for long-term outcomes. However, while cohort studies may be overall less expensive and easier to do, they are subject to biases that are sometimes difficult to control.
Cases in point, two articles in my “Take 3” inbox this week – both on the effects of Attention Deficit Hyperactivity Disorder (ADHD) pharmacotherapy on outcomes. The first study used European ADHD registry data to compare prior pharmacotherapy users with <1 dose/day users and >=1 dose/day users. They looked at the outcomes of acute coronary syndromes, stroke, heart failure, and a composite outcome of all three both during the 10 years of follow up. Adjustments were made for a variety of medical diagnoses (mental and physical comorbidities) and prescription medications.
Ultimately, the researchers found an association between increasing daily doses of ADHD medication and stroke and heart failure. Comparing highest dose users and prior users there was a relative risk of stroke of 1.2 (95% confidence interval (CI) 1.0 to 1.5; number needed to harm (NNH) 258), heart failure (RR 1.7; 95% CI: 1.3 to 2.2; number NNH 204), and the composite outcome (relative risk: 1.3; 95% CI: 1.1 to 1.5; NNH 116), but not for acute coronary syndromes (relative risk: 1.1; 95% CI: 0.8 to 1.4). There were only non-significant associations for <1 dose/day users. However, there were potential confounding variables not accounted for in the analyses: lifestyle, weight, smoking and exercise being the big ones. In addition, there were also increases in non-steroidal anti-inflammatory drugs (NSAIDs) correlated with increases in ADHD medications that were not apparently accounted for and could have increased the likelihood of CV outcomes.
Contrast that with a dataset study of ADHD medications in a teenager/young adult European cohort that examined all-cause mortality. Starting ADHD medications for recently diagnosed teenagers and adults decreased all-cause mortality at 2 years by 8.9 deaths per 10,000, 95%CI –17.3 to –0.6 (hazard ratio (HR) 0.79, 95%CI 0.70 to 0.88). Most of the reduction in death was in the category of unnatural causes (accidents, injuries, poisoning, suicide): 7.4 fewer deaths per 10,000, 95%CI –14.2 to –0.5 (HR 0.75, 95%CI 0.66 to 0.86). In this cohort, males had reduced overall death from unnatural causes only, while women had a reduction in death from natural causes only. The authors are careful to note that the observed reduction may not be due to medication per se, but possibly other factors associated with the decision to treat (counseling, support, etc.).
John’s Comments:
At a Virginia Academy of Family Physicians meeting last year, I heard a compelling presentation on ADHD treatment that emphasized the higher mortality of young adults with ADHD – primarily from accidents and injuries – and exhorted the audience to consider this in treatment decisions. The data above add to that argument. We should work to reduce cardiovascular risk factors in all our patients but perhaps provide additional encouragement for adults who require ADHD medication in the long term.
References:
· Holt A, Strange JE, Rasmussen PV, et al. Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. J Am Coll Cardiol. 2024;83(19):1870-1882. Link
· Li L, Zhu N, Zhang L, et al. ADHD Pharmacotherapy and Mortality in Individuals With ADHD. JAMA. 2024;331(10):850-860. Link
From The Literature
2) Health Impacts of Micro-nano Plastics (MNPs)
Microplastics (MPs) and nanoplastics (NPs) are small plastic particles which originate from the degradation of plastic or from industrial processes. These particles are typically less than 5 millimeters for microplastics and less than 100 nanometers for nanoplastics. They are ubiquitous in water, air, and soil, and very high quantities have been detected even in ecosystems as remote as Arctic Sea ice and deep-sea sediments.
Humans can be exposed to these substances through various routes, including ingestion, inhalation, and dermal contact in both indoor and outdoor environments. Within humans, they have been detected in breast milk, the placenta, myocardial tissue, liver, kidneys, testicles, and most recently in penile tissue. Indeed, a recently published study found micro-nano plastic (MNP) particle concentrations per liter of three popular brands of bottled water to be between 110,000 – 370,000 rather than the previously reported 300.
The toxicological impact of MNPs at the cellular level is an area of active research. NPs, due to their high surface area to volume ratio, are particularly concerning. They can generate reactive oxygen particles, leading to oxidative stress and damage to cellular components, including lipids, proteins, and DNA. This oxidative stress can trigger inflammatory pathways and disrupt cellular homeostasis. Additionally, MNPs can act as carriers for other toxic substances, such as persistent organic pollutants (POPs) and heavy metals, enhancing their potential toxicity.
Despite these findings, there is a paucity of research as to the impact these microplastics have on human health. What is known is that the chemicals often found in plastics are known to cause multiple health problems, including cancers, metabolic disorders, attention deficit/hyperactivity disorder, and fertility issues, thought to be due to oxidative stress, inflammation, and endocrine disruption.
The most widely known of these chemicals are the phenols, and in particular bisphenol A (BPA – an endocrine disruptor with estrogen-like activity), and its metabolites. BPA has been used by manufacturers to make plastics hard and clear since the 1950s, including in water bottles, baby bottles, and in the lining of food cans. In 2012, the FDA banned the use of BPAs in the production of baby bottles, sippy cups, and infant formula packaging but has taken no further action on a larger scale.
Another commonly used chemical class of concern are phthalates, which are used to make soft, flexible plastics such as PVC (“vinyl”) products and food packaging. They are also used to make fragrances found in beauty and skin care products.
A recently published prospective, multicenter, observational study has added to our understanding of the potential health impacts of MNPs. The authors studied excised carotid plaque specimens from patients who underwent carotid endarterectomy for asymptomatic carotid artery disease to look for evidence of MNPs. The specimens were analyzed with the use of pyrolysis–gas chromatography–mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs.
A total of 304 patients were enrolled in the study, and 257 completed a mean follow-up of 34 months. Polyethylene was detected in the plaque of 58% of patients, and 12% also had measurable amounts of polyvinyl chloride. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001).
Mark’s Comments:
As I synthesized my reading on this topic, it would have been quite easy to conclude, “Dude, we’re screwed.” However, there are some simple steps anyone can take to try and minimize MNP exposure. These include not microwaving or otherwise heating food and drinks in polycarbonate plastic (particularly recycle numbers 7 and 3 plastics), handwashing polycarbonate containers rather than putting them in the dishwasher, minimizing canned food consumption, using nonplastic storage materials for food and beverages (eg, glass or stainless steel – particularly for warm food), and, as noted above, not regularly drinking liquids that have been stored in plastic bottles. I have begun taking frozen foods out of their plastic containers prior to heating them and avoid drinking liquids stored in plastic bottles entirely. Afterall, I still want to believe that every little nano-bit makes a difference.
References:
· Marfella R, et al. Microplastics and Nanoplastics in Atheromas and Cardiovascular Events. N Engl J Med 2024;390:900-910. Link
· Woodruff T. Health Effects of Fossil Fuel–Derived Endocrine Disruptors. N Engl J Med 2024;390(1):922-933. Link
From PeerRxMed ( www.PeerRxMed.org )
3) Learning to Love My “Manyme’s”
"I contain multitudes." - Walt Whitman, from the poem “Song of Myself, 51”
Many years ago, one of my mentors shared with me that the practice of medicine is, to a certain degree, a “performance art” as we continually adapt ourselves to our patients, their context, and the dynamic environment we work within. He went on to share that as we rapidly shift from compassionate caregiver to decisive leader to so many other identities, our many physician "me's" are ever-changing. This fluidity can be both empowering and exhausting, and it is part of what makes our work profoundly human, deeply impactful, and perpetually challenging.
This week I received a touching reminder of the importance of regulating my many ”me’s” and how, when “the performance” is done well, the result can be life changing for those I care for. At the end of a visit with a very medically challenged young adult patient and his care-giver mother, she handed me an envelope and simply said, “Please read this later” and they both gave me a hug.
That evening, when I wasn’t distracted, I opened the one-page typed letter. It started, “I want to take the time to let you know how grateful I am that you are my son’s physician.” The letter went on to describe her challenges in caring for her special needs son as a single mother, and the impact my care and that of others had on him. Near the end, she wrote, “My son adores you and always looks forward to seeing you, which is quite unusual for him…,” and closed, “There is a special place in Heaven for doctors such as you.” Yes, the tears flowed.
What touched me most as I reflected on this letter was how, of the many “me’s” who regularly show up when I am caring for patients, this is who he, and she, experienced. They saw the good listener, the comforter, the jokester, the teacher. They experienced patient me, calm me, smiling me, and the “never-in-a-hurry” me. What they miraculously did not experience were the many other not so lovely “me’s” – the tired me, the “mad-at-the-computer” me, the “frustrated-with-stupid-paperwork” me, even the “I-really-don’t-have-time-for-a-student-today” me, just to name a few. Somehow for this family, our time together translated into the letter now sitting before me, and into the “there’s-a-special-place-in-Heaven-for-doctors-such-as-you” me. Wow …
This week, I invite you to reflect on your own “manyme's" and how they show up for you at work (and outside of work). Consider taking some time to share what you observe with your PeerRx partner. Even for those aspects that you perhaps find “unlovely” or “inconvenient,” recognize that they are part of who you are and someone got you to this point. Sure, I don’t want “grumpy” me, “distant” me or even “efficient” me to be the predominant me to who shows up at work or anywhere else. Yet, even they are showing up for a reason. And somehow, at least according to my patient and his mother, there’s a place in “Heaven” for them too.
PS: For an adorable short Sesame Street segment about our many “me’s” (circa 1991), click here: Link
Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.
Mark and John