Natural Medicine Journal Special Issue February 2024 by Diversified Communications

SPECIAL ISSUE

Do Omegas Help With Depression in Patients With High Inflammation?

Specific E Coli Strain for Ulcerative Colitis

Methylsulfonylmethane and Hair Health

Addressing Post-Acute Sequelae of SARS CoV-2 Infection

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Contents 4

Contributors

Welcome

Abstracts & Commentary 8

Prescription: Nature Kurt Beil, ND, LAc, MPH

Do Omegas Help With Depression in Patients With High Inflammation? Peter Bongiorno, ND, LAc

Racial Considerations in Breast Cancer Screening Aminah Keats, ND, FABNO

Specific E Coli Strain for Ulcerative Colitis Mark Davis, ND, FABNG, and Gabrielle Richards

Featured Peer-Reviewed Paper 19

Methylsulfonylmethane and Hair Health Rodney Benjamin, Janaina Rosa Cortinoz, Lucas Offenbecker Guerra, and Neelam Muizzuddin, PhD

Expert Interviews 30

Addressing Post-Acute Sequelae of SARS CoV-2 Infection A roundtable discussion with Tina Kaczor, ND, FABNO; Daniel Chong, ND; and Heather Zwickey, PhD

Research Update on Psilocybin

A discussion with integrative mental health expert Emily Whinkin, ND

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SPECIAL ISSUE

FEBRUARY 2024 VOL 16, NO. 201 (SUPPL)

Tina Kaczor, ND, FABNO Editor In Chief

Lise Alschuler, ND, FABNO

Editor, Abstracts & Commentary

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Diversified Communications 121 Free Street Portland, ME 04101 Natural Medicine Journal (ISSN 2157-6769) is published 13 times per year by Diversified Communications. Copyright © 2024 by Diversified Communications. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; Diversified Communications assumes no liability for any information published herein. Advertisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publication. Diversified Communications is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.

Contributors

Kurt Beil, ND, LAc, MPH Kurt Beil, ND, LAc, MPH, is a naturopathic physician and licensed acupuncturist and holds a master’s degree in public health focused on the benefits of green space as a sustainable public-health promotion tool. He did his postdoctoral work at the Helfgott Research Institute on biomarker and psychometric assessment of the restorative and therapeutic effects of natural vs built urban environments. Beil has been an advisor to the Children & Nature Network’s “Nature Research Database” and was the founding cochair of the Nature & Health subcommittee of the Intertwine Alliance in Portland. He also moderates a Facebook group (“NDs for Nature”) for the naturopathic medicine community on the clinical health benefits of contact with nature. Beil maintains a clinical naturopathic and Chinese medicine practice in Happy Valley, Oregon, focusing on chronic disease. He can be reached at www.drkurtbeil.com.

Rodney Benjamin Rodney Benjamin has worked extensively with methylsulfonylmethane (MSM) since April 1997. He is currently director of research, development, and client technical services for Bergstrom Nutrition. He holds degrees in both chemistry and business administration and is the inventor of numerous MSM patents. He has delivered several interviews and technical presentations both domestically and internationally on the topic of MSM.

Janaina Rosa Cortinoz Janaina Rosa Cortinoz graduated in biological sciences from São Paulo State University (Unesp). She received her master’s and doctorate degrees in ecology from the State University of Campinas (UNICAMP). She is the scientific manager at the company ALS Allergisa Pesquisa Dermato Cosmética Ltda.

Mark Davis, ND, FABNG

Peter Bongiorno, ND, LAc Peter Bongiorno ND, LAc, is passionate about rewriting the psychiatric model to one that considers the whole person and doesn’t run to drugs when other natural approaches are available. Bongiorno received his medical degree from Bastyr University after researching mental health at the National Institutes of Health. He has thriving New York clinics and has authored numerous books to teach both physicians and patients how to use natural care for mental illness. More information can be found at drpeterbongiorno.com.

Mark Davis, ND, FABNG, is a 2011 graduate of National University of Natural Medicine. He’s licensed in Maryland, the District of Columbia, Oregon, and California, but he’s currently on sabbatical from clinical care. He’s on the board of directors of the Gastroenterology Association of Naturopathic Physicians and the editorial board of the Natural Medicine Journal. He teaches the gastroenterology course at Southwest College of Naturopathic Medicine and has focused on patients with inflammatory bowel disease since 2016.

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

Aminah Keats, ND, FABNO

Neelam Muizzuddin, PhD

Gabrielle Richards

Aminah Keats, ND, FABNO, received her undergraduate degree in psychology from Spelman College and completed premedical coursework at Rutgers University. After completing her naturopathic medical training at the University of Bridgeport College of Naturopathic Medicine, Keats completed a 2-year, hospital-based residency in naturopathic oncology at Cancer Treatment Centers of America (CTCA). She then continued her work at CTCA as a naturopathic oncology consultant and director of naturopathic medicine. She currently practices naturopathic medicine and specializes in naturopathic oncology at Capital Integrative Health in Bethesda, Maryland. Keats also serves as a faculty member at Maryland University of Integrative Health. She is a member of the American Association of Naturopathic Physicians, the Oncology Association of Naturopathic Physicians, and member of the OncANP Board of Directors. You can find Keats on Facebook and on Instagram @draminahkeats or at her website: drkeats.com.

Neelam Muizzuddin, PhD, operates a consulting company where she offers skin clinical research designing, testing, data mining, and training, as well as preparing manuscripts for publication. Muizzuddin has worked in the cosmetic industry for over 3 decades as a clinical research scientist. She has extensive expertise in managing GCP-compliant clinical studies pertaining to safety and efficacy of topical materials and is proficient in utilizing skin bioengineering instrumentations for skin measurements. She has several publications as book chapters, patents, and peer-reviewed journal papers. She is currently president of Skin Clinical Research Consultants LLC and adjunct professor at State University of New York at Stony Brook.

Gabrielle Richards is a third-year naturopathic medical student at Sonoran University of Health Sciences. She graduated from Barrett the Honors College at Arizona State University with a bachelor’s degree in business and a concentration in sustainability. Her current interests include gastroenterology, autoimmune disease, and botanical medicine.

Lucas Offenbecker Guerra Lucas Offenbecker Guerra graduated in biological sciences from the University of São Paulo, with a master’s degree in biochemistry and molecular biology from the University of São Paulo and a specialization in safety assessment of cosmetic products from the University of Brussels. He is a PhD candidate in clinical medicine at UNICAMP and director of research and development at ALLERGISA.

Welcome Dear Readers,

On behalf of the Natural Medicine Journal, I am thrilled to bring you this special issue. As I reflect on the last year and plan for a successful 2024, I would be remiss if I didn’t take a moment to thank you, our community, for your continued support of this publication. We strive to bring you the very best, informative, educational content avaailable to natural and integrative healthcare professionals, and we could not do it without your support. We have a lot of exciting plans this year and look forward to bringing you along for the ride. With that being said, I wanted to take a moment to talk about the Integrative Healthcare Symposium. As you may recall, Natural Medicine Journal joined the Integrative Healthcare Symposium and Integrative Practitioner family a couple of years ago, as we shared a mission of fostering communication, collaboration, and community in the fields of natural and integrative medicine. To support this shared vision, we at Natural Medicine Journal decided to switch up our special issues to align the first publication with our upcoming Symposium, to be held February 15-17, 2024, at the Hilton Midtown in New York City. I could not be more thrilled, as this means our readers who attend the event will be able to connect with us in-person, ask questions, pitch ideas, and share your feedback on this issue directly with our team. For those unable to join us in-person, fear not—we have numerous activities planned during the conference that will be livestreamed or recorded and shared with this community at a later date. Please check back regularly and connect with us on social media for the latest updates. If you are at the Symposium, please stop by our booth #2215 and say hello; I would love to meet you in person. And for our colleagues from afar, know our virtual door remains open and we welcome your thoughts on how we can best support you. Please email info@naturalmedicinejournal.com to connect with our team. Now, I would like to take a moment to introduce you to Christina Henderson, Event Director of the Integrative Healthcare Symposium. Christina brings more than 10 years of event, trade show and conference experience to the Symposium, and most recently she was named a Trade Show Executive 2023 Woman to Watch. In addition to her experience, Christina is bringing a renewed focus to the Symposium with an emphasis on creating a space for connection, relationship building, and learning. We are so happy to have her as a leader on our team, and hope you enjoy this special message from her.

It is an immense privilege to be part of and support the integrative health industry. The passion that drives this community is truly inspiring, and in my time spent working on the Integrative Healthcare Symposium, I have witnessed and been inspired by the dedication and enthusiasm that define this field. This is my first Symposium as Event Director, and I couldn’t be more excited to build upon this important event, create meaningful onsite experiences and ensure practitioners leave with new resources, relationships, and ideas. Our aim is for the Integrative Healthcare Symposium to not solely be a conference, but rather a platform for connection, education, and inspiration. The Symposium is a celebration of this industry, and we cannot wait to share it with you all.

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Director Natural Medicine Journal Integrative Practitioner

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2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

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ABSTRACTS & COMMENTARY

Prescription: Nature

A meta-analysis of nature Rx studies Kurt Beil, ND, LAc, MPH

REFERENCE Nguyen P-Y, Astell-Burt T, Rahimi-Ardabili H, Feng X. Effect of nature prescriptions on cardiometabolic and mental health, and physical activity: a systematic review. Lancet Planet Health. 2023;7(4):e313-328.

STUDY OBJECTIVE To synthesize evidence on the effectiveness of nature prescriptions and determine which factors are important for their success

KEY TAKEAWAY Nature prescriptions (NRx) given by healthcare and socialservice providers have been shown to improve systolic and diastolic blood pressure and scores of depression and anxiety and to increase step-count and time spent engaging in moderate physical activity through regular involvement in local natural environmental settings.

DESIGN Systematic review and meta-analysis

PARTICIPANTS From an initial search of 5 databases from 1999 to July 2021 (MEDLINE [Ovid], Embase [Ovid], PsycINFO [Ovid], CINAHL [EBSCO], and CENTRAL/CDSR [Cochrane]), investigators reviewed a total of 4,309 unique records and assessed 615 reports, of which 92 studies were included in the final systematic review and 28 were included in meta-analysis. The total number of participants was N=9,304, with a mean study size of n=102. Studies were from a variety of countries, including South Korea (n=18; 20%), USA (n=16; 17%), Japan (n=10; 11%), UK (n=7; 8%), and China (n=5; 5%). A diverse range of ages, from children to elderly, and socioeconomic backgrounds was represented. The reasons for NRx included many different clinical diagnoses, with mental health (n=13; 14%), cardiovascular (n=12; 13%), and musculoskeletal (n=6; 7%) conditions being the most common. Inclusion criteria were for controlled trials of naturebased interventions (NRx, see below) recommended by health or social providers that collected data on physical, psychological, cognitive, or behavioral health outcomes.

Exclusion criteria included nonhuman participants, noncontrolled studies, simulated nature exposure (eg, video, virtual reality), specialized environments (eg, wilderness therapy), and school/after-school based activities.

INTERVENTIONS The reviewed NRx studies used a variety of naturebased settings. The most common were forests and nature reserves (n=32; 35%), urban parks (n=26; 28%), or community/allotment, botanical, or personal gardens (n=25; 27%). NRx activities included walking in nature (n=42; 46%), individual or group sports (n=30; 33%), gardening (n=27; 29%), meditation/breathwork (n=25; 27%), arts and crafts (n=4; 4%), and just relaxing/enjoying the setting (n=2; 2%). Frequency and duration of exposures were highly variable between studies.

STUDY PARAMETERS ASSESSED Data included in the meta-analysis were systolic blood pressure, diastolic blood pressure, depression (various scales), anxiety (various scales), daily step counts, and weekly time spent on moderate physical activity. Risk of bias was determined to be moderate to high, based on small study sizes, high study dropout/noncompletion rates without participant explanation, the inherently subjective nature of many of the psychometric scales used in the various studies, and (based on the intervention method) a lack of possible blind/double-blind study designs.

KEY FINDINGS NRx resulted in improvements in: • Systolic blood pressure (mean difference –4.82 mm Hg [–8.92 to –0.72], I²=60%); • Diastolic blood pressure (mean difference –3.82 mm Hg [–6.47 to –1.16], I²=59%); • Depression scores (postintervention standardized mean difference –0.50 [–0.84 to –0.16], I²=83%); • Depression change from baseline (standardized mean difference –0.42 [–0.82 to –0.03], I²=0%); • Anxiety scores (postintervention standardized mean difference –0.57 [–1.12 to –0.03], I²=91%); • Anxiety change from baseline standardized (mean

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

ABSTRACTS & COMMENTARY

difference –1.27 (–2.20 to –0.33); • Daily step counts greater than control conditions (mean difference 900 steps [790 to 1010]); and • Weekly time of moderate physical activity (mean difference 52.9 min [33.7 to 72.1]).

TRANSPARENCY Study funding was provided through the Australian National Health and Medical Research Council Boosting Dementia Research Leader Fellowship (1140317) and the National Health and Medical Research Council Career Development Fellowship (1148792). Authors declared “no competing interests” in the conduct or publication of this study.

Practice Implications & Limitations Exposure to the natural world is increasingly recognized as a mechanism for health promotion, disease prevention, and even disease treatment.1,2 Contact with nature has been shown to positively affect biomarkers of allostatic load (ie, heart rate, blood pressure, heart rate variability, and salivary cortisol);3 measures of brain activity (ie, electroencephalogram [EEG], functional magnetic resonance imaging [fMRI]);4 and mental well-being,5 vitality,6 and quality of life.7 Presence and use of natural “green spaces” is associated with lower rates of mortality,8 cardiovascular disease,9 type 2 diabetes,10 obesity,11 depression, and anxiety.12 The health benefits of natural spaces are truly holistic and extend beyond physical and mental/emotional benefits to include enhancement of social,13 spiritual,14 and even environmental health.15

One recent method of promoting more time in nature is the use of formal nature prescriptions by physicians and other healthcare and social service providers.24 People have shown they are more likely to engage in a lifestyle or health-behavior change when given formal prescriptions.25,26 Use of nature Rx is increasingly common as providers understand the scientific validity of empirical studies identifying the health benefits of time in nature and recognize NRx as an accepted and available professional practice. People have shown they are more likely to engage in a lifestyle or health-behavior change when given formal prescriptions. These methods are being increasingly adopted in countries like the UK, where the National Health Service has begun a £5.77million ($7.06-million) “green social prescribing” program to improve health outcomes and address health inequalities.27 In Japan, people commonly visit national “forest bathing centers” to engage in physician-personalized, nature-based mindfulness nature walks known as shinrin-yoku.28 In the United States, resources like Park Rx America are facilitating the writing and inclusion of NRx in patient EHR (electronic health record) charts.29 To increase adherence/compliance and optimize health outcomes of a NRx program, it is best to adopt a patientcentered approach, integrating experience and communication

This is especially pertinent in an era of simultaneous, epidemic levels of chronic disease, increasingly indoor and sedentary lifestyles, growing social isolation, and ecological destruction.16-18 Data support the theory of biologist EO Wilson’s “biophilia hypothesis”19 that human affinity for the natural world is an intrinsic adaptation resulting from millions of years of co-evolutionary exposure with our surrounding environments.20 The dearth of contact with the natural world in modern society has been suggested to contribute to a variety of chronic physical and mental/emotional conditions known colloquially as “nature deficit disorder.”21 Recent events like the global Covid-19 pandemic have demonstrated how essential contact with nature is and how opportunities to access local green spaces benefit individuals’ and community’s physical, mental, and social health.22,23

ABSTRACTS & COMMENTARY

between various partners (ie, healthcare, recreation, social services, transportation, etc).30 An optimal NRx includes: • Patient choice of activity to reflect personal interests and cultivate self-efficacy; • Specific “dosage” of NRx, including activity, frequency, and duration; • Sharing information about specific health benefits for conditions being addressed; • Information about local resources (eg, parks), including location, proximity, amenities, hours, and contact info; • Opportunities for individual or group social experience; and • Clinical followup and opportunities for patient accountability, input, and feedback. Incorporation of NRx in the clinical treatment plan can be a simple and effective method of improving multiple aspects of patient health and well-being. Limitations of the current study include the inherent moderateto-high risk of bias (see above); the aggregation of meta-data preventing detection and/or recommendation of potential NRx benefits for specific demographic groups based on age, sex/gender, socioeconomic status, etc; and the relatively recent inclusion and study of NRx in healthcare results in high meta-analytic heterogenicities (I2). Standardization of clinical and research protocols will allow for more uniform and reliable collection of data and detection of health-related outcomes.

References 1. Jimenez MP, Deville NV, Elliott EG, et al. Associations between nature exposure and health: a review of the evidence. Int J Environ Res Public Health. 2021;18(9):4790. 2. World Health Organization - Europe. Urban Green Spaces and Health: A Review of the Evidence. Copenhagen; 2016. 3. Twohig-Bennett C, Jones A. The health benefits of the great outdoors: a systematic review and meta-analysis of greenspace exposure and health outcomes. Environ Res. 2018;166(June):628-637. 4. Norwood MF, Lakhani A, Maujean A, Zeeman H, Creux O, Kendall E. Brain Activity, Underlying Mood and the Environment: A Systematic Review. Vol 65. Academic Press; 2019:101321. 5. Houlden V, Weich S, de Albuquerque JP, Jarvis S, Rees K. The relationship between greenspace and the mental wellbeing of adults: a systematic review. PLoS One. 2018;13(9):e0203000. 6. van den Berg MMHE, van Poppel M, van Kamp I, et al. Visiting green space is associated with mental health and vitality: a cross-sectional study in four European cities. Heal Place. 2016;38:8-15.

7. Dyer SM, Liu E, Gnanamanickam E, et al. Associations between quality of life and outdoor access in nursing homes: a cross-sectional study. Ann Long-Term Care. 2021:1-9. 8. Rojas-Rueda D, Nieuwenhuijsen MJ, Gascon M, Perez-Leon D, Mudu P. Green spaces and mortality: a systematic review and meta-analysis of cohort studies. Lancet Planet Heal. 2019;19(970):e469-e477. 9. Liu X-X, Ma XL, Huang W-Z, et al. Green space and cardiovascular disease: a systematic review with meta-analysis. Environ Pollut. 2022;301:118990. 10. Cami-Bernal F, Soriano-Moreno DR, Fernandez-Guzman D, et al. Green space exposure and type 2 diabetes mellitus incidence: a systematic review. Health Place. 2023;82:103045. 11. Lachowycz K, Jones AP. Greenspace and obesity: a systematic review of the evidence. Obes Rev. 2011;12(501):183-189. 12. Liu Z, Chen X, Cui H, et al. Green space exposure on depression and anxiety outcomes: a meta-analysis. Environ Res. 2023;231:116303. 13. Huang W, Lin G. The relationship between urban green space and social health of individuals: a scoping review. Urban For Urban Green. 2023;85:127969. 14. Naor L, Mayseless O. The therapeutic value of experiencing spirituality in nature. Spiritual Clin Pract. 2020;7(2):114-133. 15. Barragan-Jason G, Loreau M, de Mazancourt C, Singer MC, Parmesan C. Psychological and physical connections with nature improve both human well-being and nature conservation: a systematic review of meta-analyses. Biol Conserv. 2023;277:109842. 16. Beyer KMM, Szabo A, Hoormann K, Stolley M. Time spent outdoors, activity levels, and chronic disease among American adults. J Behav Med. 2018;41(4):494503. 17. O’Malley A. Nature as ally in our chronic disease epidemic. Ecopsychology. 2020;12(3):180-187. 18. Alves S, Betrabet Gulwadi G, Nilsson P. An exploration of how biophilic attributes on campuses might support student connectedness to nature, others, and self. Front Psychol. 2022;12(793175). 19. Wilson EO. Biophilia. Cambridge: Harvard University Press; 1984. 20. Schiebel T, Gallinat J, Kühn S. Testing the biophilia theory: automatic approach tendencies towards nature. J Environ Psychol. 2022;79:101725. 21. Louv R. Last Child in the Woods: Saving Our Children From Nature Deficit Disorder. Chapel Hill, North Carolina: Algonquin Press; 2005. 22. Nigg C, Petersen E, MacIntyre T. Natural environments, psychosocial health, and health behaviors during COVID-19 – a scoping review. J Environ Psychol. 2023;88(October):102009. 23. Lin D, Sun Y, Yang Y, Han Y, Xu C. Urban park use and self-reported physical, mental, and social health during the COVID-19 pandemic: an on-site survey in Beijing, China. Urban For Urban Green. 2023;79:127804. 24. Kondo MC, Oyekanmi KO, Gibson A, South EC, Bocarro J, Hipp JA. Nature prescriptions for health: a review of evidence and research opportunities. Int J Environ Res Public Health. 2020;17(4213). 25. Little M, Rosa E, Heasley C, Asif A, Dodd W, Richter A. Promoting healthy food access and nutrition in primary care: a systematic scoping review of food prescription programs. Am J Heal Promot. 2022;36(3):518-536. 26. Lifestyle Prescriptions: A Review of the Clinical Evidence. Ottawa, Ontario; 2014. 27. National Health Service England. Green social prescribing. National Health Service England website. https://www.england.nhs.uk/personalisedcare/ social-prescribing/green-social-prescribing/. Accessed April 16, 2023. 28. Kotera Y, Richardson M, Sheffield D. Effects of shinrin-yoku (forest bathing) and nature therapy on mental health: a systematic review and meta-analysis. Int J Ment Health Addict. 2020. 29. Park Rx America website. https://parkrxamerica.org/. Accessed October 30, 2023. 30. Lawson J, Foley H, Leach M, Feng X, Astell-Burt T, Brymer E. Towards key principles for the design and implementation of nature prescription programs. Sustain. 2023;15(12):9530.

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

ABSTRACTS & COMMENTARY

Do Omegas Help With Depression in Patients With High Inflammation? Trial suggests higher dosages may work better Peter Bongiorno, ND, LAc

REFERENCE

PRIMARY OUTCOME

Mischoulon D, Dunlop BW, Kinkead B, et al. Omega-3 fatty acids for major depressive disorder with high inflammation: a randomized dose-finding clinical trial. J Clin Psychiatry. 2022;83(5):21m14074.

Whether omega-3 fatty acid administration vs placebo affects inflammatory markers and symptoms of depression in patients with major depression.

STUDY OBJECTIVE

In 45 volunteers who completed the study, ingesting 4 grams EPA per day correlated significantly with a decrease in percent change of plasma hs-CRP and percent change of symptom reduction as recorded via the IDS-C30 at 12 weeks (P=0.19).

To compare omega-3 fatty acid administration vs placebo on inflammatory markers and symptoms of depression in depressed patients with a body mass index (BMI) above 25 kg/m2

KEY TAKEAWAY In depressed patients with a BMI above 25 kg/m , 4 grams of eicosapentaenoic acid (EPA) per day moderately lowered inflammation and significantly lowered symptoms of depression. 2

DESIGN Randomized, controlled trial

PARTICIPANTS Researchers recruited 61 nonmedicated adults (75% female, median 45.5 years of age) with a BMI greater than 25 kg/m2; 45 patients completed the study.

INTERVENTION In the intervention group, participants received 1 gram, 2 grams, or 4 grams per day EPA (each capsule had 590 mg EPA and 152 mg docosahexaenoic acid [DHA]), with a ratio of 3.9:1 EPA to DHA. The control group received a placebo made from soybean oil (comprised of 54% omega-6 and 6% omega-3, with no EPA component). • Study Parameters Assessed • Blood interleukin-6 levels (IL-6) • Plasma high-sensitivity C-reactive protein (hs-CRP) • Production of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) by peripheral blood mononuclear cell cytokines (PBMC) • Inventory of Depressive Symptoms (IDS-C30) scores

KEY FINDINGS

All groups had intragroup improvements, with response rates for EPA 4 g/d of 64%, vs 40% for placebo (odds ratio [OR]=2.63); 38% for EPA 1 g/d; and 36% for EPA 2 g/d (all P>0.05). No EPA dose produced a ≥0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF.

TRANSPARENCY This study was funded by the National Institutes of Health’s National Center for Complementary and Integrated Health (NCCIH). Mischoulon received research support from Nordic Naturals, and many of the other 16 authors disclosed industry relationships. These can be found under “Relevant Financial Relationships.”

Practice Implications & Limitations This paper is authored by clinical researchers well-known in the field of using supplements to support mental health. For the last decade, both David Mischoulon and Maurizio Fava have increased our knowledge base for employing fish oils and folate in depressed patients.1 This new study furthers our understanding of the optimal dosing of fish oil for depression, the effective ratio of EPA to DHA, and specifically which patients may benefit the most.

ABSTRACTS & COMMENTARY

In this work, depressed and inflamed obese patients were given either 1 gram, 2 grams, or 4 grams EPA (included in a nearly 4:1 ratio of EPA to DHA fish oil) per day or a placebo. The results suggest that ingesting 4 grams a day of EPA can help obese, depressed patients with high levels of hs-CRP both lower inflammation and improve symptoms of depression within 12 weeks. This study also shows that even lower levels of EPA supplementation (both 1 gram and 2 grams) also lowered plasma hs-CRP in a dose-dependent manner, while the soybean oil placebo had little effect. Additionally, each treatment group intervention lowered IDS-C30 scores (meaning fewer depression symptoms), with the 4-gram dose demonstrating the greatest response of 64%; the 1-gram and 2-gram doses resulted in a 36% to 40% response rate, while placebo showed a 20% response rate overall. Notable in this study was that the placebo group nonsignificantly outperformed both 1- and 2-gram EPA dosing. So, from a clinical perspective, this suggests using 4-gram EPA per day is likely to improve therapeutic effect over lower doses. Interestingly, there were some placebo patients who did respond as well. Those participants already had lower baseline IDS-C30 scores (meaning they were less depressed already) and lower baseline interleukin-6 scores (less inflammation), which could mean that the soy oil (with mostly omega-6 and some omega-3) was enough to shift these measurements in patients with milder levels of depression and inflammation. Adverse events were minor in nature and lowest in the treatment group, with no patient needing to discontinue in any group. Unique to this study is that the participants were not taking any antidepressant drugs. This paper adds to the body of research supporting the use of fish oil for depressed, obese patients. However, there are some clinical considerations. First, this work is based on a small sample size, as the authors were hoping for at least 100 subjects to fully participate in the study. This smaller subject number may increase the level of false positive results. Secondly, this study would have been an opportunity to study both baseline fatty acid levels and changes in fatty acids, and how these may correlate with changes in symptomology and inflammation in these patients. Levels of baseline fatty acids are a predictor of future antidepressant-treatment results.2 In the future, we, as clinicians, may want to start tracking this parameter

to better understand who may benefit most from fatty acid administration. Finally, a recent meta-analysis suggests an optimal ratio of EPA to DHA may actually be closer to a 3:2 ratio.3 Michael Lewis, another well-known researcher and expert in fish oil use for brain health,4 has also suggested, via personal communication, that the optimal EPA to DHA ratio may be 3:2. So, this study corroborates prior research on the effectiveness of fish oil higher in EPA, despite the ratio differences. Unique to this study is that the participants were not taking any antidepressant drugs. This gives naturopathic and integrative physicians an opportunity to clearly evaluate, as a monotherapy, the benefits of using fish oil in our patient populations of concomitantly obese and inflamed patients. It is my opinion that combined therapies including naturopathic lifestyle, diet, and relaxation work aimed at lowering adiposity and inflammation would probably create an even more powerful result than using fish oil alone. Furthermore, this paper underscores that higher-end doses are needed to achieve a therapeutic result. Oftentimes we clinicians may minimize dosing in our patients because patients tend to prefer taking fewer gel caps, or because the gel cap size is too large, or because they may not prefer a liquid dose. Lastly, I find synergistic natural agents along with fish oil can have a better effect than fish oil alone. For example, in patients with inflammation, the use of curcumin, which is also known as an effective monotherapy to lower symptoms of depression,5 may further enhance the anti-inflammatory and mood-enhancing effect we see with fish oil.

Conflict-of-Interest Disclosure Peter Bongiorno, ND, LAc, is a consultant for Pure Encapsulations Douglas Laboratories.

References 1. Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70 Suppl 5:12-17 2. Cussotto S, Delgado I, Oriolo G, et al. Low omega-3 polyunsaturated fatty acids predict reduced response to standard antidepressants in patients with major depressive disorder. Depress Anxiety. 2022;39(5):407-418. 3. Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190. 4. Lewis MD. Concussions, traumatic brain injury, and the innovative use of omega-3s. J Am Coll Nutr. 2016;35(5):469-475. 5. Fusar-Poli L, Vozza L, Gabbiadini A, et al. Curcumin for depression: a meta-analysis. Crit Rev Food Sci Nutr. 2020;60(15):2643-2653.

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

ABSTRACTS & COMMENTARY

Racial Considerations in Breast Cancer Screening Recommendations based on race and ethnicity Aminah Keats, ND, FABNO

REFERENCE

PRIMARY OUTCOME

Chen T, Kharazmi E, Fallah M. Race and ethnicity-adjusted age recommendation for initiating breast cancer screening. JAMA Netw Open. 2023;6(4):e238893.

The primary outcome was death due to invasive breast cancer regardless of histology and disease stage.

STUDY OBJECTIVE

In this study, breast cancer–specific deaths totaled 415,277 female patients, including:

To provide starting age recommendations for breast cancer screening based on race and ethnicity, using data based on race and ethnic disparities in breast cancer mortality as a guide

KEY FINDINGS

• 1,880 (0.5%) American Indian or Alaska Native • 12,086 (2.9%) Asian or Pacific Islander • 28,747 (6.9%) Hispanic

KEY TAKEAWAY

• 62,695 (15.1%) Black

Unique screening guidelines should be considered for Black women due to their increased risk of developing breast cancer at an earlier age compared to other racial and ethnic groups.

• 309,869 (74.6%) White

DESIGN Nationwide population-based cross-sectional study

PARTICIPANTS Investigators collected from US Mortality Data 415,277 breast cancer deaths involving women in the United States between 2011 and 2020. They collected race and ethnicity details from the National Vital Statistics System, which relies on death-certificate reporting by funeral directors. Data providers classified patients into 6 groups: Hispanic, non-Hispanic American Indian or Alaska Native, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, non-Hispanic White, and unknown Hispanic origin. Investigators excluded patients of unknown Hispanic origin from the study (approximately 903 patients).

STUDY PARAMETERS ASSESSED Investigators calculated the risk-adapted starting age of breast cancer screening based on the 10-year cumulative risk of breast cancer–specific death by age, race, and ethnicity. The 10-year cumulative risk of breast cancer death was defined as the risk of dying due to breast cancer within the subsequent 10 years at each benchmark age.

Investigators observed differences in breast cancer–specific mortality based on race and ethnicity before age 50. Between the ages of 40 to 49 years, breast cancer mortality rate per 100,000 person-years were as follows: • Mean rate among total US females, 15 deaths • Black females, 27 deaths • White females, 15 deaths • American Indian or Alaska Native, 11 deaths • Asian or Pacific Islander, 11 deaths • Hispanic females, 11 deaths Investigators created different benchmarks based on age to calculate a risk threshold. If the entire female population were screened at 50 years of age, the 10-year cumulative risk of breast cancer would be 0.039%. If this is an acceptable risk threshold (which is arbitrary), then to achieve an equivalent risk of 0.039% over a 10-year period, Black women would begin screening at 42 years of age. Additionally: • Non-Hispanic White women would begin screening at 51 years. • American Indian, Alaska Native, and Hispanic females would begin screening at 57 years. • Asian and Pacific Islander females would begin screening at 61 years.

ABSTRACTS & COMMENTARY

A screening age of 45 years for all women, regardless of race or ethnicity, gives a mean 10-year cumulative risk of breast cancer death of 0.235%. The age of screening to achieve this risk threshold percentage of 0.235% would be: • Black women, 38 years. • Non-Hispanic White women, 46 years. • Hispanic women, 49 years. • Asian and Pacific Islander women, 50 years. • American Indian or Alaska Native females, 51 years. Lowering the screening age to 40 years for women would achieve an overall mean 10-year cumulative risk of breast cancer death of 0.154%. To achieve this 0.154% risk threshold percentage based on race and ethnicity: • Black females would need to be screened at age 34 years, • White females at age 41 years, • Hispanic females at age 43 years, and • American Indian or Alaska Native and Asian or Pacific Islander females at age 43 years.

TRANSPARENCY Supported by grants 2019YFE0198800 from the National Key Research Development Program of China and 2021R52020 from the Ten-Thousand Talents Plan of Zhejiang Province and by Start-up Funds for Recruited Talents in Zhejiang Cancer Hospital.

Practice Implications & Limitations Current screening mammography guidelines do not consider racial differences in breast cancer survival.1 Breast cancer screening guidelines recommend starting ages for screening that range from 40 to 50 years and differ based on the issuing organization. The American Cancer Society recommends an initial mammography for women at average risk starting at age 45 and can begin as early as age 40.2 The American College of Obstetricians and Gynecologists recommends initial screening no later than age 50 for women at average risk but can be initiated beginning at age 40.3 And the United States Preventive Services Task Force recommends that screening begin at age 50 for women at an average risk for breast cancer.4 Although the current screening guidelines have been associated with a reduction in breast cancer mortality, the disparity in risk reduction for Black women persists. In general, Black females had an increased risk of dying due to early-onset breast cancer and so could be screened up to 8 years earlier than the recommended starting age of 50 years. The authors report, “In general, Black females had an increased 14

risk of dying due to early-onset breast cancer and so could be screened up to 8 years earlier than the recommended starting age of 50 years. Black females reached the risk threshold level at age 42 years, that were equivalent to White females at age 51 years, American Indian or Alaska Native and Hispanic females at age 57 years, and Asian or Pacific Islander females 11 years later, at age 61 years. Race and ethnicity–adapted starting ages for Black females were consistently lower to achieve similar risk of breast cancer mortality, specifically they were 6 years earlier for mass screening at age 40 years and 7 years earlier for mass screening at age 45 years.”5 In a study published in the Annals of Internal Medicine in 2021, the Cancer Intervention and Surveillance Modeling Network found that biennial screening from ages 40 to 74 years could be associated with a 57% decrease in the breast cancer mortality gap between Black and White women.1 From the study under review here, the authors write, “BC mortality depends on many factors, such as differences in distribution of breast size and density, quality of screening tests, host tumor microenvironment, treatment access and quality, competing mortality, distribution of phenotype prevalence of BC, tumor grading and staging at diagnosis, initiation of breast cancer treatment, type of treatment received, barriers to health care access, poverty level, biological and genetic differences in tumors, and prevalence of risk factors associated with the periods during and after cancer treatment, and other factors. But these factors cannot justify the higher mortality of early-onset breast cancer in Black females younger than the recommended age of mass screening.”5 The study findings justify the need to adjust the current 1-sizefits-all screening guidelines for breast cancer to improve survival and reduce mortality risk.

References 1.

Summary for patients: equitable mammogram screening strategies for Black women in the United States. Ann Intern Med. 2021;174(12):I16.

American Cancer Society. ACS breast cancer screening guidelines. ACS website. https://www.cancer.org/cancer/types/breast-cancer/screening-testsand-early-detection/american-cancer-society-recommendations-for-the-earlydetection-of-breast-cancer.html. Accessed September 4, 2023.

The American College of Obstetrics and Gynecologists. ACOG statement on breast cancer screening guidelines. ACOG wevbsite. https://www.acog.org/news/news-releases/2016/01/acog-statement-on-breastcancer-screening-guidelines. Accessed September 4, 2023.

Davidson KW, Barry MJ, Mangione CM, et al; US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977

Chen T, Kharazmi E, Fallah M. Race and ethnicity-adjusted age recommendation for initiating breast cancer screening. JAMA Netw Open. 2023;6(4):e238893

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

ABSTRACTS & COMMENTARY

Specific E Coli Strain for Ulcerative Colitis

Results from a double-blind, placebo-controlled study Mark Davis, ND, FABNG, and Gabrielle Richards

REFERENCE Park SK, Kang SB, Kim SS, et al. Additive effect of probiotics (Mutaflor) on 5-aminosalicylic acid therapy in patients with ulcerative colitis. Korean J Intern Med. 2022;37(5):949-957.

STUDY OBJECTIVE To assess the effect of Escherichia coli Nissle 1917 (EcN, brand name Mutaflor®) in patients with ulcerative colitis (UC) taking aminosalicylate (5-ASA) medicines and determine whether EcN therapy impacts clinical outcomes and health-related quality of life when compared with placebo

REFERENCE Park SK, Kang SB, Kim SS, et al. Additive effect of probiotics (Mutaflor) on 5-aminosalicylic acid therapy in patients with ulcerative colitis. Korean J Intern Med. 2022;37(5):949-957.

DESIGN Multicenter, double-blind, randomized, placebo-controlled study

PARTICIPANTS Investigators randomly assigned 133 patients (mean age 46 years; 64% male in the EcN group and 73% male in the placebo group) with mild-to-moderate UC (Mayo score 3–9) to receive either EcN or placebo. Overall, 118 patients (EcN, 58; placebo, 60) completed the study. Exclusion criteria included proctitis, medication other than 5-ASA, and hospitalization.

INTERVENTION Participants received sealed, single-dose sachets containing either EcN at a dose of 2.5 billion colony

forming units (CFU) or a placebo. Patients were asked to take EcN once daily in the morning (1 capsule/day from day 1 to day 4 and 2 capsules/day from day 5 through the end of the 8-week study period). Patients continued taking 5-ASA (mesalamine or balsalazide) either orally or as suspension enemas at stable doses for the duration of the 8-week study. Other medications, such as steroids, antibiotics, probiotics, and antidiarrheal drugs, were not administered.

STUDY PARAMETERS ASSESSED Inflammatory bowel disease questionnaire (IBDQ) score

PRIMARY OUTCOME MEASURE The primary outcome was an increase in the IBDQ score of more than 16 points from baseline at 8 weeks. Secondary outcomes included: 1. Clinical remission (partial Mayo score ≤ 1, assessed at week 4, or Mayo score ≤ 2, assessed at week 8) 2. Clinical response (> 2-point reduction in partial Mayo score assessed at week 4 or > 3-point reduction in Mayo score assessed at week 8) 3. Improved endoscopic scores and remission (endoscopic subgroup Mayo score = 0 at week 8) 4. Endoscopic response (> 1-point reduction in endoscopic subgroup score at week 8) 5. Microbial composition changes in the stool

KEY FINDINGS Primary endpoint: At the end of the treatment period, both groups showed statistically significant increases in IBDQ scores (mean increase in the EcN group, 22 points, P<0.001; mean increase in the placebo group, 19 points, P<0.001). Therefore, researchers did not find EcN to be superior to placebo in this regard. However, they did find that IBDQ scores decreased in significantly fewer patients in the EcN group than in the placebo group (1 [1.7%] vs 8 [13.3%]; intention to treat [ITT], P=0.02).

ABSTRACTS & COMMENTARY

At week 4, a significantly higher number of patients in the EcN group showed a clinical remission (decreased Mayo score) than patients in the placebo group (23 [39.7%] vs 13 [21.7%], P=0.04). Researchers detected no differences in clinical remission or clinical response rates between the 2 groups at week 8 and no differences in stool frequency at 4 or 8 weeks. Significantly more patients in the EcN group reported abdominal pain improvement than patients in the placebo group at 4 weeks (91.4% vs 61.7%, P<0.001) and 8 weeks (86.2% vs 66.7%, P<0.001). Significantly more patients in the EcN group achieved endoscopic remission than patients in the placebo group (26 [46.4%] vs 16 [27.1%], P=0.03). Researchers observed no statistically significant differences in α-diversity or β-diversity in stool samples from the placebo and EcN groups, either at baseline or at week 8. Nor did they observe any significant differences in the abundance of the Escherichia or Shigella genera, even in patients who showed a clinical response in the EcN group.

TRANSPARENCY This trial was registered as NCT04969679 and funded by Kangbuk Samsung Hospital, Republic of Seoul, Korea.1 The authors did not have any disclosures in the article.

Practice Implications E coli Nissle 1917 (brand name Mutaflor) contains 2.5 billion viable organisms per capsule and requires refrigeration. It’s typically used at 1 capsule by mouth twice daily (after a 4-day lead-in of 1 cap per day to reduce flatulence and other minor side effects), or the contents of 1 to 2 capsules in 40 mL of water by rectum for patients with UC. This fascinating probiotic was first isolated in 1917 by Professor Alfred Nissle, after he noticed a soldier who did not develop infectious diarrhea like his comrades despite being stationed in a region heavily contaminated with Shigella. After further investigation of the soldier’s intestinal flora, Nissle determined that EcN was responsible for the soldier’s impressive resistance to the pathogen, and he used the strain to develop the probiotic product Mutaflor.2 EcN is not distributed in the United States due to US Food and Drug Administration (FDA) restrictions (allegedly due to concern that the US public would have trouble distinguishing between pathogenic E coli and probiotic E coli). Still, US consumers may be able to purchase Mutaflor from international sources. 16

Mechanism of Action EcN is a nonpathogenic strain of E coli that does not produce any known toxins. It can effectively colonize the human intestine by adhering to intestinal cells, forming biofilms, and successfully competing with pathogens for tissue-binding sites. EcN has been shown to have antimicrobial properties against several pathogenic strains of E coli, both by stimulating intestinal epithelial-cell defensin production and blocking toxin synthesis. It additionally acts as an inflammation modulator to decrease serum levels of pro-inflammatory cytokines while increasing levels of anti-inflammatory cytokines. Furthermore, EcN is able to regulate T cell expansion within the intestinal mucosa without interfering with tissue-bound T cell function, leading to lower levels of gut inflammation. EcN is also thought to contribute to gut integrity by upregulating the expression of zonula occludens proteins (ZO-1 and ZO-2) to reinforce tight junctions.2

Adverse Events EcN is not associated with adverse effects in the majority of published clinical trials. Side effects are often similar to those noted in the control group and, therefore, not attributed to EcN. In a multicenter clinical trial studying EcN as a treatment for functional gastrointestinal disease or chronic inflammatory bowel disease in 1,074 patients, only 1.5% of cases reported adverse reactions that needed treatment or led to termination of the therapy, while 2.8% of cases reported initial side effects that resolved without the need for treatment.3 Similarly, a study that used stem cell–derived human intestinal organoid tissues found EcN to be safe, inducing no mucosal damage, and even to have protective qualities against pathogenic E coli.4 In a 2021 open-label trial testing the additive effect of EcN on UC patients in remission, 7 out of 94 patients experienced side effects possibly associated with EcN therapy and were prompted to discontinue the probiotic and begin steroid therapy. The symptoms leading to discontinuation were diarrhea and hematochezia, which are also symptoms of UC, so these may have been UC symptoms that were not prevented by EcN, rather than symptoms caused by EcN; the authors recommended that randomized controlled trials be conducted to help understand this better. The study concluded that the probiotic is relatively safe and suggested that clinicians should monitor for side effects within the first 3 months of treatment since this seems to be the time frame within which side effects arise.5

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

ABSTRACTS & COMMENTARY

EcN is registered as a drug in several European countries and recommended by the Korean Association for the Study of Intestinal Diseases6 and the European Crohn’s and Colitis Organisation2 for maintenance of UC remission. A sizable body of evidence regarding EcN’s effect on UC exists. A 2015 systematic review comparing EcN to mesalazine for UC patients recommended EcN as an alternative to mesalazine for the maintenance of remission in UC, based on the results of 4 trials.7 Data from the only study comparing EcN to mesalazine for induction of remission trended in favor of EcN, but did not reach statistical significance.7 In the time since that systematic review was published (and before the paper we are reviewing here was published), 1 other clinical trial on oral EcN was conducted—a 2021 open-label trial for UC patients in clinical remission with elevated calprotectin. It concluded that EcN may have the ability to substantially decrease some UC symptoms and lower some biomarkers without impacting calprotectin.5 In addition, rectally administered EcN may be effective, in a dose-dependent manner, at shortening the time to remission and inducing mucosal healing in patients with UC taking mesalazine.8 EcN has also shown promise in a variety of other gastrointestinal conditions, including Crohn disease,9 diverticulitis,10 chronic constipation,11 and functional bowel diseases.3 The data on EcN and irritable bowel syndrome (IBS) are mixed. EcN may provide benefit superior to placebo, particularly in the subgroups of those who experienced gastroenteritis and/ or took antibiotics prior to developing IBS12 and those with diarrheal IBS (IBS-D), although EcN may worsen difficult straining in those with a mixed diarrhea/constipation variety of IBS (IBS-M).13 Additionally, EcN therapy has been shown to improve liver function and lower endotoxemia in patients with liver cirrhosis when compared to placebo.14,15 In patients with hepatic encephalopathy, EcN was able to reduce ammonia content and serum proinflammatory cytokines while also normalizing Bifidobacteria/Lactobacilli abundance and improving cognitive function.16 E coli Nissle’s benefits have even been shown to extend to dermatalogic conditions. In a 2016 randomized controlled trial, 89% of patients with acne, papular-pustular rosacea, or seborrheic dermatitis who treated with conventional topical therapy, vegetarian diet, and oral EcN responded with

significant improvement or complete recovery, compared to 56% in the group receiving only topical and diet therapy. EcN also seemed to prompt a shift toward Bifidobacteria and Lactobacilli and a decrease in pathogenic microbes in the majority of patients compared to no change in the control group without E coli Nissle.17 This ability of EcN to modify the composition of the gut microbiome was again demonstrated in a study involving newborn infants orally inoculated with EcN over the first 5 days after birth. Colonization with true and potential bacterial pathogens was significantly reduced in infants receiving EcN compared to placebo, both with respect to numbers of pathogens and the spectrum of species.18 This study further confirms what we’ve seen in previous trials and systematic reviews: E coli Nissle is a safe probiotic for our patients with UC, especially when abdominal pain is a predominant symptom. If exacerbation of UC symptoms occurs while a patient is on EcN, it’s most likely to happen in the first 3 months of use. EcN appears to be about as effective as standard-of-care 5-ASA drugs at maintaining clinical remission, improving some UC symptoms, and accelerating tissue healing, including in UC patients in remission who still have elevated fecal calprotectin. Use a lead-in dose of 1 capsule per day for the first 4 days to reduce minor adverse events, and then maintain at 1 capsule orally twice daily, ongoing. EcN may additionally benefit our UC patients with comorbid IBS-D, but it may exacerbate straining difficulties in those with IBS-M.

ABSTRACTS & COMMENTARY

References 1.

Additive effect of probiotics (Mutaflor®) in patients with ulcerative colitis on 5-ASA treatment. Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/ NCT04969679. Accessed February 25, 2023.

Scaldaferri F, Gerardi V, Mangiola F, et al. Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients: an update. World J Gastroenterol. 2016;22(24):5505-5511.

11. Möllenbrink M, Bruckschen E. Behandlung der chronischen Obstipation mit physiologischen Escherichia-coli-Bakterien. Ergebnisse einer klinischen Studie zur Wirksamkeit und Verträglichkeit der mikrobiologischen Therapie mit dem E.-coliStamm Nissle 1917 (Mutaflor) [Treatment of chronic constipation with physiologic Escherichia coli bacteria. Results of a clinical study of the effectiveness and tolerance of microbiological therapy with the E. coli Nissle 1917 strain (Mutaflor)]. Med Klin (Munich). 1994;89(11):587-593. 12. Kruis W, Chrubasik S, Boehm S, Stange C, Schulze J. A double-blind placebocontrolled trial to study therapeutic effects of probiotic Escherichia coli Nissle 1917 in subgroups of patients with irritable bowel syndrome. Int J Colorectal Dis. 2012;27(4):467-474.

Schütz E. Behandlung von darmerkrankungen mit Mutaflor. Eine multizentrische retrospektive erhebung [The treatment of intestinal diseases with Mutaflor. A multicenter retrospective study]. Fortschr Med. 1989;107(28):599-602.

Pradhan S, Weiss AA. Probiotic properties of Escherichia coli Nissle in human intestinal organoids. mBio. 2020;11(4):e01470-20.

13. Faghihi AH, Agah S, Masoudi M, Ghafoori SM, Eshraghi A. Efficacy of probiotic Escherichia coli Nissle 1917 in patients with irritable bowel syndrome: a double blind placebo-controlled randomized trial. Acta Med Indones. 2015;47(3):201-208.

Oh GM, Moon W, Seo KI, et al. Therapeutic potential of Escherichia coli Nissle 1917 in clinically remission-attained ulcerative colitis patients: a hospital-based cohort study. Korean J Gastroenterol. 2021;77(1):12-21.

14. Lata J, Novotný I, Príbramská V, et al. The effect of probiotics on gut flora, level of endotoxin and Child-Pugh score in cirrhotic patients: results of a double-blind randomized study. Eur J Gastroenterol Hepatol. 2007;19(12):1111-1113.

Choi CH, Moon W, Kim YS, et al. Second Korean guidelines for the management of ulcerative colitis. Intest Res. 2017;15(1):7-37.

Losurdo G, Iannone A, Contaldo A, Ierardi E, Di Leo A, Principi M. Escherichia coli Nissle 1917 in ulcerative colitis treatment: systematic review and metaanalysis. J Gastrointestin Liver Dis. 2015;24(4):499-505.

Matthes H, Krummenerl T, Giensch M, Wolff C, Schulze J. Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN). BMC Complement Altern Med. 2010;10:13.

15. Lata J, Juránková J, Príbramská V, et al. Vliv podání Escherichia coli Nissle (Mutaflor) na strevní osídlení, endotoxemii, funkcní stav jater a minimální jaterní encefalopatii u nemocných s jaterní cirhózou [Effect of administration of Escherichia coli Nissle (Mutaflor) on intestinal colonisation, endo-toxemia, liver function and minimal hepatic encephalopathy in patients with liver cirrhosis]. Vnitr Lek. 2006;52(3):215219.

Malchow HA. Crohn’s disease and Escherichia coli. A new approach in therapy to maintain remission of colonic Crohn’s disease? J Clin Gastroenterol. 1997;25(4):653658.

10. Fric P, Zavoral M. The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated diverticular disease of the colon. Eur J Gastroenterol Hepatol. 2003;15(3):313-315.

16. Manzhalii E, Moyseyenko V, Kondratiuk V, Molochek N, Falalyeyeva T, Kobyliak N. Effect of a specific Escherichia coli Nissle 1917 strain on minimal/mild hepatic encephalopathy treatment. World J Hepatol. 2022;14(3):634-646. 17. Manzhalii E, Hornuss D, Stremmel W. Intestinal-borne dermatoses significantly improved by oral application of Escherichia coli Nissle 1917. World J Gastroenterol. 2016;22(23):5415-5421. 18. Lodinová-Zádniková R, Sonnenborn U. Effect of preventive administration of a nonpathogenic Escherichia coli strain on the colonization of the intestine with microbial pathogens in newborn infants. Biol Neonate. 1997;71(4):224-232.

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2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

FEATURED PEER-REVIEWED PAPER

Methylsulfonylmethane and Hair Health

Effect of a sulfur-containing supplement on improving hair condition Rodney Benjamin, Janaina Rosa Cortinoz, Lucas Offenbecker Guerra, and Neelam Muizzuddin, PhD

Abstract Introduction

Methylsulfonylmethane (MSM), an organosulfur compound, is gaining importance as an antioxidant and anti-inflammatory, as well as a source of sulfur for the body. Maintenance of hair strength and health requires a steady supply of sulfur, which oral supplementation with MSM can provide. A clinical study was designed to observe the efficacy of MSM as an oral supplement (OptiMSM® [Bergstrom Nutrition, Vancouver, Washington, USA]) for mitigating hair loss and improving hair thickness and density as well as overall appearance via subject perception and micrometric measurements of hair thickness.

Method

A total of 41 female and male subjects, aged between 19 and 60 years and presenting telogen effluvium hair loss, were recruited for the study. An area of 1.7 cm x 1.0 cm was marked on the head and shaved for the phototrichogram analysis. The hair fibers within the delimited area were cut

Introduction Hair decorates the face and is a physical medium of social communication. It protects from trauma, insect penetration, and electromagnetic radiation and insulates against heat loss and heat gain.1,2 The scalp contains a high density of hair growth with an abundance of sebaceous glands.2 This forms a distinct microenvironment with significant differences from the rest of the skin. This environment is a rich habitat for microbes.3 There are no significant differences in the number of hair follicles between men and women or between All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

and photographed. From an adjacent site, a minimum of 30 hair fibers were extracted for micrometric measurements. The measurements were repeated after 120 days of product use.

Results

Significant improvements of hair density, hair-density terminal, and hair diameter were observed after 120 days of OptiMSM use. Subject self-assessment determined that the product was effective in reducing hair loss as well as improving the strength/resistance and volume of hair. The subjects observed growth of new hairs and declared that their hair was more voluminous and less brittle after 45, 90, and 120 days of product use.

Conclusion

Based on the confines and conditions of this study, MSM supplementation was effective in reducing hair loss and improving hair diameter and thickness.

different races.4 Hair appearance varies due to the type of hair originating from the follicle and individual hair-care practices.3,5 As a result of diet deficiencies and the aging process, hair changes color (graying) and hair production is reduced. In addition, structural properties of the hair fiber, such as diameter, curvature, elasticity, torsional rigidity, and lipid composition, also change, thus impacting the manageability and overall appearance of hair.5 19

FEATURED PEER-REVIEWED PAPER

Hair Structure Hair is made up of 95% keratin, synthesized by the epidermal keratinocytes. It is a fibrous, helicoidal protein that forms part of the skin and all its appendages (body hair, nails, etc.). Keratin is insoluble in water, thus conferring impermeability and protection for the hair. There are 18 amino acids found in

hair, including proline, threonine, leucine, arginine, cysteine, and methionine.6 Keratin is especially rich in cysteine, which is a sulfur-containing amino acid capable of forming disulfide bonds between molecules, thus adding strength and elasticity to the entire structure (Figure 1). The sulfur compounds impart burning-hair smell especially during styling or excessive sun exposure.6

FIGURE 1: Schematic of hair fiber: The hair fiber is enclosed in the cuticle, a barrier protecting the underlying cortex. The cuticle comprises 8–10 layers of flat, overlapping cells stabilized and held in place by disulfide bonds. The cortex is in the center of each hair fiber and consists of long, tightly packed keratin spindles stabilized by disulfide bonds. These keratin spindles are arranged in a hierarchy, starting with the smallest structure, the keratin proteins, to the largest and final structure, the cortex. The keratin protein is a helicoidal group of cysteine-containing protein complexes with primary, secondary, and tertiary structures held together by peptide bonds, disulfide bonds, and hydroxide bonds. The disulfide bonds impart covalent bonding between adjacent protein chains and confer rigidity to the hair structure. Supplementation with OptiMSM provides an additional source of sulfur to strengthen the hair fiber.

Keratin-associated proteins are initially produced in the cytoplasm among keratin bundles that accumulate in cortical and cuticle cells of hair.7 When sulfur is readily available, keratin is made from strong disulfide bonds. When not enough sulfur is available, the body creates keratin with much weaker saline and hydrogen bonds. The primary source of sulfur is amino acids rich in this element, such as cysteine and methionine. The main source of these sulfur-containing amino acids is animal protein, which gives rise to important proteins, such as keratin, for hair-follicle growth.8 As a result of structural deformities and/or a reduction in the sulfur-containing amino acids cysteine and/or methionine, hair structure becomes fragile9-11 and vulnerable to excessive shedding. Ageing and excessive exposure of hair to solar irradiation cause dryness, roughness, and reduced strength and elasticity, which changes the hair appearance to a lackluster, stiff, brittle, and overall dull and unhealthy look.12 Severe degeneration of the

cuticle and hair cortex has been observed in conditions of sulfurdeficient hair (such as trichothiodystrophy).13 Sulfur contained in MSM could transfer to keratin and help strengthen the bonds between keratin molecules in hair (Figure 1).

Hair follicles go through cell cycles that include the following phases: anagenic, catagenic, and telogenic. The anagen phase is the actively growing phase during which hairs are produced at a rate of approximately 1 centimeter per month. In humans, the anagenic phase lasts 3 to 7 years. The catagenic phase starts after the anagen phase when the follicle no longer produces hair and starts to recede; it lasts approximately 10 days. Cellular division stops, and the follicle contracts toward the surface. The telogenic phase is a resting phase during which the hair strands shed. It lasts approximately 3 to 4 months until some unknown stimulus arouses the root, when it returns to the anagenetic phase. In a normal adult, approximately 85% to 95% of the follicles are in the anagenic phase, 1% to 2% are ©

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in the catagenic phase, and 10% to 14% are in the telogenic phase.14 Hair loss, known as telogen effluvium, occurs when the normal balance between growing and resting hair is altered and the telogen phase predominates. Several mechanisms can lead to telogen effluvium, but all involve the simultaneous entry of strands into the telogen phase.15 Telogen effluvium usually involves temporary, diffuse hair loss, while androgenetic alopecia is permanent and typically develops as a receding hairline or bald patch. Oxidative metabolism, smoking, ultraviolet radiation, inflammation from microbial aggression, pollutants, irritants, and oxidized scalp lipids are some of the stress factors that affect hair fiber conditions before emergence of the hair from the scalp.16-18 Some oxidative stresses further impact emerged hair fiber; these include solar irradiation and chemical insults from oxidizing hair treatments such as colorants (Figure 1).19 Hair emerged from an unhealthy scalp has an altered cuticle with surface roughness, cuticle rigidity, and/or breakage. Rough cuticle surface appears as lackluster and dull-looking hair. Biochemical modifications, including alterations of protein and lipid components (mainly due to oxidative damage), also occur in hair emerged from an unhealthy scalp.20-23 Studies on reversal of hair loss indicate that the adult mammalian skin and hair follicle contain several distinct populations of stem cells that support substantial ability for regeneration. Hair follicle regeneration is contingent on the interaction between epithelial precursors located in the “bulge” and specialized mesenchymal cells found at the base of the follicle, called the dermal papilla.24-25 Dermal papilla cells provide instructive signals to induce epithelial bulge cell proliferation and consequent initiation of anagen (actively growing) follicle growth (Figure 1).26-27

Oxidative Stress and Hair Oxidative stress is observed as an imbalance between the production of reactive oxygen species (ROS) and their elimination by protective mechanisms. Inflammatory pathways are triggered by oxidative stress, leading to subclinical, as well as chronic, inflammation. Oxidative stress is commonly detected in pathological conditions such as dandruff, seborrheic dermatitis, psoriasis, atopic dermatitis, All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

telogen effluvium, and ultimately alopecia,28 and it plays a significant role in premature hair loss. The scalp commensal organism Melassezia spp has been recognized to be a source of oxidative damage. Investigators have reported that oxidative stress can cause elevated myocardial ischemia markers in patients with telogen effluvium.29 Several studies have demonstrated that oxidative stress is associated with alopecia areata, and one showed an association between oxidative stress and androgenic alopecia.30-35 Oxidative stress causes lipid oxidation36 and lipid peroxides and may induce the apoptosis of hair follicle cells, followed by early onset of the catagen phase.23,37 MSM, as a known antioxidant, could quench these free radicals and reverse some of the oxidative damage (Figure 1).

Methylsulfonylmethane (MSM) MSM occurs naturally in humans and animals, as well as some allium vegetables, green plants, and food items such as milk, grains, nuts, seeds, eggs, fruit, vegetables, turkey, beef, fish, and chicken.38-39 MSM is a source of sulfur for amino acids such as methionine and cysteine.40 Methionine is an essential amino acid, and as such, it cannot be synthesized in the body, so it has to be supplied by diet. On the other hand, cysteine is synthesized by the human body, but the process requires a steady supply of sulfur, which supplementation with MSM can provide.41-42 Pharmacokinetic studies indicate that orally administered MSM is rapidly absorbed in rats.38 In a human study, 45 subjects ingested 1, 2, or 3 grams of MSM daily for 16 weeks.44 Plasma MSM concentration correlated with the ingestion dose, indicating that MSM is rapidly absorbed in the upper gastrointestinal tract, slowly removed from the serum, and efficiently excreted from the body.43-44 Cysteine and methionine contribute significantly to the cellular pool of organic sulfur and general sulfur homeostasis, as well as carbon metabolism.45 Sulfur in these amino acids impacts the cellular redox state, thereby affecting the maintenance and integrity of the cellular systems, as well as the capacity to neutralize free radicals and reactive oxygen species.46 Quenching of free radicals reduces inflammation.46-47 Inflammation is a major manifestation of oxidative stress. Chronic inflammation, signified by the presence of lymphocytes and histiocytes, has been found in the tissue specimens of patients with hair loss.4 MSM has been reported 21

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to possess powerful anti-inflammatory properties. Studies show that MSM inhibits nuclear factor kappa-light-chainenhancer of activate B cells (NF-kB), an intracellular protein complex involved in activating multiple inflammatory genes.

In mechanistic studies done on rodents, MSM reduced the production of cytokines such as tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6), which are signaling proteins linked to systemic inflammation (Figure 2).49

FIGURE 2: Various stress factors, including oxidative metabolism, smoking, inflammation from microbial aggression, environmental pollutants and irritants, ultraviolet radiation, and chemical insults from oxidizing hair colorants, cause damage to the scalp. The most common manifestation of hair emerging from an unhealthy scalp is an impaired hair follicle, weak and rigid hair fiber, and reduction in hair volume and hair loss. Supplementation with OptiMSM delivers anti-inflammatory and antioxidative resources, as well as an additional source of sulfur, which collectively heal the scalp, reduce hair loss, and aid in the emergence of thicker hair.

MSM is a “Generally Recognized As Safe” (GRAS)–approved substance. It is well-tolerated by most individuals at dosages of up to 4 grams daily, with few reported side effects,36 and has been reported to be nontoxic.38,50-51 Since MSM is a potent antioxidant and anti-inflammatory, as well as a source of sulfur for hair, it can be hypothesized that supplementation with this nutrient could improve hair condition. Previous studies indicate that oral supplementation with MSM influences skin and hair.52-54 This clinical study was designed to study the efficacy of oral supplementation with MSM on retarding hair loss and improving hair thickness, strength, and density, as well as overall appearance, under conditions of normal use.

Material The subjects ingested 1 vegi-cap containing 1,000 mg of methylsulfonylmethane (OptiMSM®) orally for 120 days, with or without food intake. 22

Methods This was a noncomparative clinical study conducted on the local population in Sau Paolo, Brazil. Female and male subjects, aged between 19 and 60 years (mean age: 43 years), presenting self-declared straight, wavy, curly, or frizzy hair of length longer than 10 cm (maintained during the study), were recruited for the study. The subjects were diagnosed by a dermatologist as having telogen effluvium hair loss at the inclusion. A total of 48 study subjects were recruited, out of which 41 completed the study (Figure 3). Six subjects discontinued due to product-unrelated reasons. This study was conducted in compliance with the Declaration of Helsinki principles, the applicable regulatory requirements, including Resolution CNS no. 466/12, and according to the Good Clinical Practices, Document of the Americas, and ICH E6. This study was approved by the Independent Ethics Committee (IEC) of Investiga -Instituto de Pesquisas, registered by the National Research Ethics Commission ©

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FIGURE 3: CONSORT flow diagram of subject recruitment and participation.

(CONEP), Number 54859722.4.0000.5599, Opinion number: 5.263.427, 02/24/2022.

Subject Inclusion and Exclusion Criteria The subjects were healthy males and females (aged 18 to 60 years) presenting telogen effluvium hair loss at the inclusion visit as assessed by a dermatologist. The subjects agreed to refrain from changing their hair dye routine for the course of the study. They were allowed to dye their hair 4-7 days before the visits (T0-D0, T45-D0, T90-D0, and T120-D0); however, they agreed to discontinue hair treatment products for hair loss, dandruff, supplements, etc for the course of the study. They also agreed to refrain from performing chemical treatments on the hair (smoothing, relaxing, progressive straightening, etc) as well as their hairstyle for the course of the study. All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

The subjects exhibited the ability to provide a consent for participating in the study and agreed to comply with the procedures, requirements, and schedules of the study. The subjects agreed to allow the shaving of an area of the scalp approximately 1.7 cm x 1.0 cm in size, as well as to the plucking of at least 30 hairs at visits T0-D0 and T120-D0. Subjects diagnosed with cicatricial alopecia or pathological hair loss such as scalp disease (alopecia areata, universalis, or totalis) and those receiving chemotherapy were excluded from the study. The subjects did not suffer from type 1 diabetes mellitus, insulin-dependent diabetes, complications resulting from diabetes (retinopathy, nephropathy, neuropathy), dermatosis related to diabetes (lipoidica necrobiosis, plantar ulcer, ring granuloma, opportunistic infections), antecedents of episodes of hypoglycemia, diabetic ketoacidosis, 23

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hyperosmolar hyperglycemic syndrome, or skin diseases such as vitiligo, psoriasis, or atopic dermatitis. They were not on systemic corticosteroids or immunosuppressant treatment, and they were not pregnant or lactating. They did not report reaction to the category of product tested. The subjects were excluded if they had moderate-to-intense dandruff or if they had more than 50% white hair and/or lightblonde hair color. The test site was devoid of moles, tattoos, scars, and any signs of skin irritation.

Methodology On the initial visit (T0-D0), the subjects were informed of the study objective, methodology, and duration, and also about possible expected benefits and constraints related to the study. They were instructed to read and sign an informed consent form (ICF) and an informed consent for image release (ICIR). An area sized 1.7 cm x 1.0 cm was marked and shaved on the top of the head for the phototrichogram analysis. Hair fibers, within the delimited area, were cut using fine curved tip scissors and shaved with a tricotomizer. Using the FotoFinder leviacam® device, a trained technician captured images of this area, which were then used for the analysis of the phototrichogram (scalp micrograph). Digital images were obtained for photographic documentation using a Canon EOS 60D digital still camera. From a site adjacent to the shaved area, at least 30 hair fibers were plucked by a trained technician for hair micrometric measurements. The hair fibers were pulled 1 by 1 from the subject’s head. The subjects returned to the institute 48 hours after the shaving (T0-D2), and a new image was acquired for phototrichogram analysis. A similar 2-day procedure was repeated after using the supplement for 45 (T45-D0), 90 (T90-D0), and 120 (T120-D0) days. At each visit, the subjects were checked for compliance and possible signs of discomfort. Subjects completed a self-assessment questionnaire and had the same 1.7 cm x 1.0 cm area determined at the first visit shaved again. The subjects returned to the institute 48 hours after shaving (T45-D2, T90-D2, and T120-D2) and for additional images for phototrichogram analysis. At time point T120-D0, the subjects also underwent manual traction extraction of at least 30 hair fibers for micrometric measurements. 24

Dermatological Clinical Assessment Study subjects were assessed by a dermatologist at the initial visit (T0-D0), to check the inclusion and exclusion criteria of the study. At all visits, the subjects were examined for possible adverse events or discomfort sensations and to confirm compliance with the instructions given to subjects at the start of the study.

Scalp Micrograph: Phototrichogram with FotoFinder leviacam®55 Phototrichogram (photographic trichogram) is used for in vivo study of the hair growth cycle. With the aid of a sanitized comb, a trained technician selected an area sized approximately 1.7 cm x 1.0 cm at the top of the head for shaving. The selected area was marked such that the FotoFinder leviacam® (Birnbach, Germany) captured the images from the same site at every visit. A measured area on the scalp was marked, and hairs were shaved within the target area. Photographs were obtained immediately after shaving (D0) and 48 hours after shaving (D2) with a digital closeup camera with epiluminescence microscopy for each evaluated time point. Tricholab software was used for image analysis. The software recognizes individual hair fibers in the photographs from D0 and D2 and measures the density of total hair fibers and density of hair fibers assigned as terminal hair (large and pigmented hair). By comparing the length of hair fibers in D0 and D2, the software can determine which hairs are growing and which are not.56-57 This method is employed for the study of hair growth rate, size of hair fibers, and frequency of telogen hair follicles and to quantify shed hair. In this project, the total hair density per square centimeter, as well as terminal hair density per square centimeter, was analyzed. The phototrichogram analysis was performed at the following time points: •

T0-D0: Before OptiMSM intake.

•

T0-D2: 48 hours after shaving at T0-D0.

•

T45-D0: After 45 days of OptiMSM intake, before shaving.

•

T45-D2: 48 hours after shaving at T45-D0.

•

T90-D0: After 90 days of OptiMSM intake, before shaving.

•

T90-D2: 48 hours after shaving at T90-D0.

•

T120-D0: After 120 days of OptiMSM intake, before shaving.

•

T120-D2: 48 hours after shaving at T120-D0.

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Photograph for Documentation Digital images of the head of all subjects (vertex) were obtained in a standardized configuration. Each subject’s hair was parted in the center. The subject’s head was then positioned on a Canfield Scientific hair photograph device (Canfield, New Jersey, USA) for full head/hair image capture, and a black cape was used to standardize color background. Digital images were obtained with a Canon EOS 60D (Canon, Tokyo, Japan) digital still camera, and medium standard views fixed lighting and vertex. Images of the entire head were taken with an aerial photo. Images were captured at the following time points: •

T0-D0: Before OptiMSM intake.

•

T45-D0: After 45 days of OptiMSM intake, before shaving.

•

T90-D0: After 90 days of OptiMSM intake, before shaving.

•

T120-D0: After 120 days of OptiMSM intake, before shaving.

Hair Diameter Assessment The hair diameter (determined in the hair base) was measured using a Mitutoyo (Mitutoyo, Illinois, USA) micrometer (μm), a device capable of measuring the exact linear dimensions

Timepoint

of an object, and the measurements were exported to the Instron® for analysis (Instron® Universal Testing System, Massachusetts, USA). At least 30 hair fibers were collected from each subject, including 25 hair fibers for measurements and 5 for replacement if necessary. The hairs were kept under controlled temperature and humidity before measurements. The Instron was used to measure hair diameter at the following time points: •

T0-D0: Before OptiMSM intake.

•

T120-D0: After 120 days of OptiMSM intake, before shaving.

Self-Assessment Questionnaires Performed by the Study Subjects Final approval by consumers is what signifies the success of a product; thus, subject self-assessments were employed to provide a complete picture of product effect. The assessment by the subject was performed by following the “Standard Guide for Sensory Claim Substantiation” (ASTM E 1958-06, 2006), using a questionnaire for sensory studies to validate product claims. The study subjects were instructed to answer the following questionnaire:

Statement

Scale

The product reduces hair loss/fall. The product improved the strength and resistance of my hair. Does my hair feel thicker? T45-DO /

I observed the growth of new hairs.

T90-DO /

The product makes my hair move voluminous.

T120-DO /

1- Completely disagree 2 - Somewhat disagree 3 - Neither agree nor disagree 4 - Somewhat agree 5 - Completely agree

My hair feels less brittle.

Regarding GROWTH SPEED, after using the product, my hair:

TABLE 1: Time points, statements, and scale of the self-assessment questionnaires

STATISTICAL ANALYSIS Excel statistical package was used for all statistical analysis. In addition to descriptive statistics, the Student’s T-test was applied to

determine statistically significant differences from baseline at 95% confidence (two tailed).

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Results PHOTOTRICHOGRAM ANALYSIS Hair micrograph density and terminal hair density count per cm2 are presented in Figure 4. A statistically significant (P<0.05) improvement of hair density was observed after 120 days of OptiMSM use. Hair density terminal also improved significantly (P<0.01) after 120 days of OptiMSM use. Figure 4b shows the number of subjects exhibiting improvement; 33%, 55.3%, and 66.7% of the subjects exhibited improvement in hair density after 45, 90, and 120 days, respectively. Terminal hair density per cm2 improved for 50% of the subjects after 45 days of MSM use, which increased to 57.9% and 82% after 90 and 120 days, respectively.

SUBJECT SELF-ASSESSMENT The subjects assessed their hair condition using a 5-point grading scale where a grade of 3 was neutral and above 3 indicated an improvement. When asked if they observed a reduction in hair loss, 77% of the population observed a reduction after 45 days, a percentage that improved to 82.9% after 120 days. Increased Strength and resistance of hair were observed by 85% of the population after 45 days of use and by 87.8% after 120 days (Figure 5).

FIGURE 5: Shows the number of subjects with scores of 4–5, which indicated improvement. Over 75% of the subjects observed a reduction in hair loss and improvement in strength and resistance of hair after 45 days, which increased further after 120 days. After using OptiMSM, over 80% of the subjects observed an increase/ improvement of hair amount and hair thickness after 45 days, which increased slightly after 120 days. Growth of new hairs was observed by over 90% of the subjects after 45 days, and the effect was maintained for the course of the study. Speed of hair growth was not very noticeable to many subjects; however, 80% of the subjects noticed that their hair became more voluminous after using OptiMSM, which was maintained for the course of the study. Additionally, 75% of the subjects noticed their hair to be less brittle after using OptiMSM, which increased to 87.8% after 120 days of use.

FIGURE 4: Figure 4a represents hair micrograph density and terminal hair density count per square centimeter. A single * indicates statistical significance with P<0.05, and a double ** indicates statistical significance with P<0.001. A statistically significant improvement in hair density was observed after 120 days of OptiMSM use. In addition, a statistically significant improvement of hair density terminal was observed after 120 days of OptiMSM use. Figure 4b shows the number of subjects exhibiting improvement.

After using OptiMSM for 45 days, 80% of the subjects observed an increase/improvement of hair amount and hair thickness, which increased slightly (82.9%) after 120 days. Growth of new hairs was observed by 92.5% of the subjects after 45 days, and the effect was maintained for the course of the study. Speed of hair was not very noticeable by many subjects; nevertheless, 27.5% of the participants did notice an improvement by 45 days, which increased to 39% after 120 days of use. Additionally, 80% of the subjects noticed that their hair became more voluminous after using OptiMSM, and this was maintained for the course of the study. Also after 45 days, 75% of the subjects noticed their hair to be less brittle after using OptiMSM, and this percentage increased to 87.8% after 120 days of use. Digital images of subjects’ heads (Figure 6) show a reduced appearance of the scalp.

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HAIR DIAMETER ASSESSMENT The hair diameter measured at the base of the hair, using a micrometer, exhibited a significant (P<0.05) increase in hair diameter after 120 days of OptiMSM use (Figure 7). Wide hair diameter contributes to thicker, more-voluminous-looking hair.

FIGURE 6: Photographs of the scalp before and after 16 weeks of treatment with OptiMSM. The scalp patches appear smaller after treatment.

FIGURE 7: The hair diameter measured using a micrometer (μm) shows a significant (P<0.05) increase in hair diameter after 120 days of OptiMSM use.

Discussion Human hair serves to protect the scalp, as well as contributing to the beauty, personality, and confidence of the consumer. External factors like exposure to the sun, smoking, dietary factors (including malnutrition of essential fatty acids and vitamins), and chemicals applied to the hair and scalp through shampoos and other treatments all can damage existing hair and impair hair growth. Age-related decline in keratin synthesis leads to deterioration of stability and flexibility of the hair shaft, leaving hair vulnerable to dryness and breakage with brushing and the use of styling products and tools. There is a myriad of topical hair treatment products professing to repair hair damage; however, nourishment of hair from within provides hair follicle cells the vital nutrients necessary to generate healthy hair. Oral supplementation with OptiMSM can benefit skin health because OptiMSM acts as a sulfur donor to keratin and also has antioxidant and anti-inflammatory properties. Inflammation in the scalp and hair follicles can potentially contribute to dandruff, itchiness, and other conditions that can result in hair loss or stunt hair growth. By reducing inflammation, MSM may soothe the scalp and support healthy hair. In this study, 75% of the subjects noticed their hair to be less brittle after using OptiMSM, and this percentage increased to 87.8% after 120 days.

When sulfur is readily available, keratin is made from strong disulfide bonds. Hair density refers to the number of hair strands growing per square centimeter of scalp, and a reduction in this permutation indicates hair loss. Hair loss can be reversed via the regeneration of stem cells present in the hair follicle. In this study, hair density and terminal hair density count increased significantly after oral supplementation with OptiMSM, indicating a reversal of hair loss. MSM is known to promote the formation of bonds at the follicle level. These bonds strengthen existing hair strands and help promote new growth, which was noticed by the 82% of participants who reported a reduction in hair loss after using OptiMSM

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in this study. Over 80% of the subject population also noticed increased/improved hair amount and hair thickness. Growth of new hairs was observed by 92.5% of the subjects, and 80% of the subjects declared their hair was more voluminous, indicating a significant role of OptiMSM supplement for providing nutritional benefits to hair. The primary risk factor for baldness is the loss of hair thickness (diameter). This process starts in the hair follicle and, if untreated, leads to a decrease in the thickness of the hair shaft and, ultimately, hair loss. The hair diameter clinical scale via micrometer measurements indicates that the diameter of very thin hair is between 30 to 40 µm; medium hair is 50 to 80 µm; and thick hair is 90 to 110 µm.55 In this study, hair diameter increased significantly after using OptiMSM for 4 months. The sulfur in MSM is readily absorbed into amino acids such as creatine and methionine. This may encourage the formation of keratin and contribute to thicker hair. Improvement in hair strength and resistance was noticed by 87.8% of the subjects after using OptiMSM for 120 days. While the results of this study are encouraging, additional studies are being designed to replicate these results, as well as to determine if this supplement could be useful for other causes of hair loss.

Funding This research received no external funding. The study was fully funded by the sponsor, Balchem Corp.

Conflicts of Interest RB is employed by Balchem, the supplier of the dietary supplement tested in this study. JRC and LOG contributed to the execution of the study design and collection of data. They declare no conflict of interest.

Funding This research received no external funding. The study was fully funded by the sponsor, Balchem Corp.

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26. Rompolas P, Deschene ER, Zito G, et al. Live imaging of stem cell and progeny behavior in physiological hair-follicle regeneration. Nature. 2012;487:496-499. 27. Rahmani W, Abbasi S, Hagner A, et al. Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla, and modulate hair type. Dev Cell. 2014;31(5):543-558. 28. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol. 2006;126:2565-2575. 29. Savci U, Senel E, Oztekin A, Sungur M, Erel O, Neselioglu S. Ischemia modified albumin as a possible marker of oxidative stress in patients with telogen effluvium. An Bras Dermatol. 2020;95:447-451. 30. Akar A, Arca E, Erbil H, Akay C, Sayal A, Gür AR. Antioxidant enzymes and lipid peroxidation in the scalp of patients with alopecia areata. J Dermatol Sci. 2002;29:85-90. 31. Prie BE, Iosif L, Tivig I, Stoian I, Giurcaneanu C. Oxidative stress in androgenetic alopecia. J Med Life. 2016;9(1):79-83. 32. Abdel Fattah NS, Ebrahim AA, El Okda ES. Lipid peroxidation/antioxidant activity in patients with alopecia areata. J Eur Acad Dermatol Venereol. 2011;25:403-b408. 33. Motor S, Ozturk S, Ozcan O, et al. Evaluation of total antioxidant status, total oxidant status and oxidative stress index in patients with alopecia areata. Int J Clin Exp Med. 2014;7:1089-1093. 34. Bakry OA, Elshazly RM, Shoeib MA, Gooda A. Oxidative stress in alopecia areata: a case-control study. Am J Clin Dermatol. 2014;15:57-64. 35. Yenin JZ, Serarslan G, Yönden Z, Ulutaş KT. Investigation of oxidative stress in patients with alopecia areata and its relationship with disease severity, duration, recurrence and pattern. Clin Exp Dermatol. 2015;40:617-621. 36. Niki E, Yoshida Y, Saito Y, Noguchi N. Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochem Biophys Res Commun. 2005;338:668676. 37. Naito A, Midorikawa T, Yoshino T, Ohdera M. Lipid peroxides induce early onset of catagen phase in murine hair cycles. Int J Mol Med. 2008;22:725-729. 38. Magnuson BA, Appleton J, Ames GB. Pharmacokinetics and distribution of (35S) methylsulfonylmethane following oral administration to rats. J Agric Food Chem. 2007;55(3):1033-1038. 39. Nimni ME, Han B, Cordoba F. Are we getting enough sulfur in our diet? Nutr Metab (Lond). 2007;4:24. 40. Richmond VL. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sci. 1986;39(3):263-268. 41. Wong T, Bloomer RJ, Benjamin RL, Buddington RK. Small intestinal absorption of methylsulfonylmethane (MSM) and accumulation of the sulfur moiety in selected tissues of mice. Nutrients. 2018;10(19);1-9. 42. Otsuki S, Qian W, Ishihara A, Kabe T. Elucidation of dimethylsulfone metabolism in rat using a 35S radioisotope tracer method. Nutr Res. 2002;22:313-322.

50. Barrager E, Veltmann JR, Schauss AG, Schiller RN. A multicentered, open-label trial on the safety and efficacy of methylsulfonylmethane in the treatment of seasonal allergic rhinitis. J Altern Complement Med. 2002;8(2):167-173. 51. Borzelleca JF, Sipes IG, Wallace KB. Dossier in support of the generally recognized as Safe (GRAS) status of OptiMSM (methylsulfonylmethane; MSM) as a food ingredient. United States Food and Drug Administration; Vero Beach, Florida, USA: 2007. 52. Muizzuddin N, Benjamin R. Beneficial effects of a sulfur-containing supplement on hair and nail condition. a prospective, double-blind study in middle-aged women. Nat Med J. 2019;11(11):1-8. 53. Muizzuddin N, Benjamin R. Beauty from within: oral administration of a sulfurcontaining supplement methylsulfonylmethane improves signs of skin ageing. Int J Vitam Nutr Res. 2022;92(3-4):182-191. 54. Shimomura Y, Ito M. Human hair keratin-associated proteins. J Investig Dermatol Symp Proc. 2005;10:230-233. 55. Lacharrière OD, Deloche C, Misciali, C, et al. Hair diameter diversity: a clinical sign reflecting the follicle miniaturization. Arch Dermatol. 2001;137(5):641-646. 56. Saitoh M, Uzuka M, Sakamoto M. Human hair cycle. J Invest Dermatol. 1970;54:65-81. 57. Hoffmann R. TrichoScan: combining epiluminescence microscopy with digital image analysis for the measurement of hair growth in vivo. Eur J Dermatol. 2001;11:362-368.

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43. Krieger DR, Schwartz HI, Feldman R, et al. A pharmacokinetic dose-escalating evaluation of MSM in healthy male volunteers. Miami Research Associates; Miami, Florida, USA: 2009. 44. Bloomer RJ, Butawan M, Lin L, Ma D, Yates CR. Blood MSM concentrations following escalating dosages of oral MSM in men and women. J Nutr Food Sci. 2019;9(1):1-5. 45. Townsend DM, Tew KD, Tapiero H. Sulfur containing amino acids and human disease. Biomed Pharmacother. 2004;58:47-55.

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ADDRESSING POST-ACUTE SEQUELAE OF SARS COV-2 INFECTION A roundtable discussion Post-acute sequelae of Covid-19 (PASC), also called long-Covid, has been the subject of increasing research. PASC describes the ongoing, relapsing, or new symptoms or conditions present 30 or more days after infection, and it has become a major clinical and public health concern. This roundtable discussion focuses on cognitive, cardiovascular, and autoimmune effects of long-Covid. Roundtable experts include naturopathic oncologist and Editor-in-Chief of the Natural Medicine Journal, Tina Kaczor, ND, FABNO; cardiovascular expert and clinician, Daniel Chong, ND; and immunologist and professor Heather Zwickey, PhD. KAROLYN A. GAZELLA: Nearly 18 million people have or have had long-Covid since the pandemic began, with more than 26% of those individuals reporting a significant negative impact on quality of life. Long-Covid symptoms can last for months or even years following the infection. Dr Kaczor, I’d like to start with you regarding brain function. What new information exists about the connection between long-Covid and brain function? TINA KACZOR, ND, FABNO: I think the most intriguing new finding is from a paper that was published in the journal Cell in October of 2023. In this paper, the authors propose that there may be a unifying theory in at least a subset of people who present with long-Covid. The heart of this unifying theory is a low amount of circulating serotonin. This is from Penn Medicine, which is at the University of Pennsylvania. They recruited 58 patients who came to their medical center with the complaint of long-Covid and broke them out into 8 different types of long-Covid according to their records of 1,500 plus people. They recruited 58 of those 1,500 original as representative of different ways of presenting with long-Covid. The second group was 30 people who had just had Covid acutely and recovered completely. A third group was 60 people with acute Covid. The researchers looked at the blood samples of all 3 of these 30

groups. Using metabolomics and specifically looking at amino acids between these 3 groups, they found the level of circulating serotonin dips during acute viral infection, which is normal—it happens with viral infections in general. But what was intriguing is that those with long-Covid had low circular serotonin, while those who fully recovered had serotonin levels that recovered completely. The researchers postulate that serotonin never fully recovers in those with long-Covid. They also looked at the stool samples of their long-Covid patients and found viral particles in the stool—specifically RNA remnants of the virus that persisted long after the acute infection was over. The theory is that those viral remnants that persist in the gut long after the acute infection is over induce type I interferons, an inflammatory reaction to be produced. Type I interferons are made in the small intestinal cells. Those interferons set up something akin to a slow simmer of inflammation in the background. Ultimately what the researchers proved is there’s a block in this pathway that stops the absorption of tryptophan in the intestines. Tryptophan is the substrate for serotonin production. So it blocks the absorption of tryptophan from the gut into the bloodstream, reducing the storage of serotonin in the platelets and enhancing the action of enzymes that metabolize serotonin. ©

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Those interferons basically lead to the lower serotonin and circulation by blocking absorption, lowering storage, and enhancing its breakdown. There is no lowering of serotonin within the brain; this is not a direct relation. What the study found, and this is the part I found the most intriguing, was it involves the gut-brain axis. They found that the low circulating serotonin leads to a reduced activity of the vagus nerve. The vagus nerve innervates the gut directly and goes straight to the brain. It’s associated with hippocampal dysfunction, memory loss. Basically, the brain is tricked into responding as if there’s an active viral infection. Ultimately it’s due to the RNA remnants that are informing the vagus nerve and leading to less vagus nerve signaling in the brain. That gut-brain axis is really at the heart of all of the low serotonin. This is a mind-blowing new theory to me. We all knew parts and pieces of this, but they put it all together into one singular theory. This is just one of many, and it’s not unique to post-Covid. This is postviral — any symptoms that mimic long haul Covid or long-Covid that are post viral. GAZELLA: How can we use this new information to help inform treatment decisions for long-Covid patients? KACZOR: I think we use it as one of the many theories that we have. It melds very well with some of the theories we have for chronic fatigue syndrome. Will serotonin reuptake inhibitors help? Maybe. I don’t know. It doesn’t seem like the serotonin is really the issue, it’s the gut. So this is good old naturopathic medicine—heal the gut. These are RNA remnants; they’re not active virus. I would imagine anything we can do to heal the duodenum, in particular, would be helpful. HEATHER ZWICKEY, PHD: I’m so excited you brought up that paper because there was a study that came out of Germany in 2022 that showed the kynurenine pathway, which All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

is essentially what you just described, was heavily involved in post-Covid syndrome. When you don’t shuttle tryptophan into the production of serotonin, instead you shuttle it into the production of kynurenine and the quinolones. What they showed was that people with long-Covid had higher levels of kynurenine and weren’t making serotonin, they were making kynurenine. The researchers thought that that could be a useful marker. As of right now, the diagnosis is just symptombased. There isn’t a lab test that we can do that says this person has post-Covid syndrome. In Germany, they’re planning to try kynurenine measurement to look at whether or not people are suffering from post-Covid. That fits with exactly what you said, Dr Kaczor. I think that’s super exciting. I was at Mayo this fall and talking to some of the doctors there. They have a study that shows that 80% of people who are experiencing post-Covid may not have GI symptoms but still have dysbiosis. We like to say dysbiosis is happening when people are experiencing diarrhea, constipation, gut pain, but 80% of these folks are experiencing dysbiosis in their gut with no symptoms. There have also been 2 studies by the same group looking at luteolin, which is a component of olive oil. The suggestion is that liposomal luteolin works for brain fog associated with chemo brain, and it may work for brain fog associated with post-Covid, although it has not been tested in people with post-Covid. It makes me curious as to the mechanism: If it’s reducing inflammation, is it reducing those type I interferon? DANIEL CHONG, ND: I’m seeing a lot of postural orthostatic tachycardia syndrome (POTS), various arrhythmias, and different things that that you might categorize at least partially in the cardiovascular realm. I saw another study related to that, which ties into what Dr Kaczor was saying. It looked at the vagus nerve again, but in this case, they did postmortem analysis 31

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and found SARS-CoV-2 RNA together with inflammatory cell infiltrates literally in the vagus nerves of patients who had suffered POTS-like syndrome. The essential conclusion was that SARS‑CoV‑2 virus directly induces vagus nerve inflammation. That leads to autonomic dysfunction, which could contribute to the level of critical disease status these people had, but also to the dysautonomia that’s related to long-Covid. A second study just came out in July using transcutaneous auricular vagus nerve stimulation (tVNS) for the treatment of long-Covid. It was a pilot study, with 20 patients who are all suffering from long-Covid and exhibiting dysautonomia-type symptoms, as well as many other symptoms, with fatigue being the most common one. These people did 10 daily 30-minute sessions with this little auricular or ear nerve stimulation treatment using a Parasym device. Every patient at least had some significant improvement in just 10 days. Just stimulating the vagus nerve by itself helped relieve a laundry list of longCovid symptoms. GAZELLA: While we’re in the cardiovascular realm, what do we know about long-Covid and heart disease? CHONG: Covid, whether it’s acute or post-acute Covid, is not very nice to the cardiovascular system. In the acute phase, there’s a wide variety of very common things that can happen. Even with mild or asymptomatic cases, there’s still the potential for direct injury to the heart, cardiovascular system, the endothelium, et cetera. We’re seeing a number of different related long-term issues, especially myocarditis, potentially clotting, potentially increased risk for both the genesis of plaque in the vascular system and also the instability of plaque that’s already there, leading to increased risk for a heart attack or stroke. Anybody seeing long-Covid patients should be doing very thorough cardiovascular workups because the cardiovascular system doesn’t always give you direct symptoms that there’s a problem going on. Another very important point to mention is exercise. Even patients with asymptomatic or very mild illness should not exercise for 10 days after the symptom onset or a positive test. People with moderate disease should not exercise for 10 days after the resolution of symptoms. And then people with anything more severe should be really sort of thoroughly evaluated before they get back to exercise. So that’s an important 32

thing to mention. I hear a lot of people say, “Oh, I felt fine, so I was still able to exercise,” and that makes me a little bit nervous given the potential for serious cardiovascular issues. KACZOR: I think it’s important to emphasize Dr Chong’s point about taking the time to do nothing when you have Covid, and not to resume regular activity, especially if that activity is strenuous. Don’t resume regular activity until your body is 110% recovered. Don’t push yourself. Rest now so you don’t end up with long-Covid. GAZELLA: How much do we know about what may be causing the connection between Covid and cardiovascular concerns? CHONG: You can categorize it into direct or indirect injury. During the acute phase, the virus can cause direct damage to the heart cells and endothelial cells. That can result in a wide variety of acute circumstances—arrhythmias, myocarditis, inflammation of the endothelium. There’s also indirect injury, which would be from the massive levels of inflammation created in response to the virus. That’s harmful to the vascular system because of the chemical nature of the inflammatory response. Furthermore, the hypercoagulability or increased clotting that can happen in response to Covid is can have direct effects on the vascular system as well. And hypoxia occurs during acute Covid, that also will lead to injury in the vascular system. There are so many different angles of harm, which is why so many people exhibit cardiovascular symptoms. ZWICKEY: I just add one additional mechanism by which Covid can impact the cardiovascular system, and that’s related to the gut microbiome. Metabolites like trimethylamine N-oxide (TMAO) can be detrimental to the cardiovascular system as well. So if people are experiencing gut dysbiosis, we’re also adding that onto the damage when the virus binds to the angiotensin-converting enzyme (ACE) receptor on the heart muscle. Downregulation of ACE2 has all these other effects that Dr Chong so eloquently described. GAZELLA: What is the research telling us about the connection between Covid and the development of autoimmune conditions? ZWICKEY: There is an obvious increase in the development ©

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of autoimmunity with Covid. We’ve known that for all sorts of viral and bacterial infections that they do stimulate autoimmunity both through molecular mimicry and through bystander effect, which is this idea that we have higher levels of inflammation, so we can activate an immune response in a tissue that is peripheral to what we’re trying to attack. If we’re trying to attack the virus, but the virus is in the pancreas, we’re going to develop diabetes. So that’s been well known, this idea of bystander effect and molecular mimicry. What we are seeing right now with post-Covid is as much as a 42% higher likelihood of acquiring an autoimmune condition within 3 to 15 months after infection. That’s really significant because usually, we say 3 to 18 years to develop an autoimmune disease post-infection, and Covid has seemed to shorten that window. GAZELLA: Are specific types of autoimmune conditions associated with long-Covid? Is it dermatologic mostly, is it joint, is it GI, or is it all of the above? ZWICKEY: It’s all of the above. One of the things that’s starting to be sorted through is whether different variants of Covid are triggering different types of autoimmunity, but as of right now, we’re seeing a threefold increase in rheumatoid arthritis and lupus. We’re seeing a twofold increase in inflammatory bowel disease and type 1 diabetes. Psoriasis has increased. In Korea where they’ve done a large study, they saw a lot more dermatological conditions, so a lot of alopecia as well. In general, it’s consistent across all age groups, and this is different as well. Usually we see more autoimmunity as people age, but with Covid, we’re seeing it in teenagers and in children. GAZELLA: A stressful event is often a trigger for the development of an autoimmune condition. Is it too simplistic to say, Covid is stressful; you had an underlying predisposition to autoimmune conditions and now you have one? KACZOR: For any complicated and chronic condition, it’s going to be multifactorial. I do a lot of cancer care. In that case too, sometimes people have a ton of stress and it does affect the immune system. Is that what caused someone’s cancer? Maybe it contributed, but we don’t know. So I would say that’s an oversimplification, but stress does have clear ramifications on immune function. And the hypothalamic-pituitary-adrenal (HPA) axis is very much involved in autoimmune disease and in controlling the All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

disease. When I’m seeing someone with an autoimmune condition, I concentrate on 2 systems: the HPA axis and the gut. There are very old books from the ‘50s and ‘60s where they used antibiotics for rheumatoid arthritis, and that seemed to help. What that shows is an underlying change of the microbiota in the gut can change symptomology. I go back to good old naturopathic medicine over and over. You can’t go wrong with creating a healthy upper intestine and gut in general. And that’s true for the brain health as well. I mean, I don’t care if it’s Covid or Parkinson’s or Alzheimer’s. We now know that changes in the microbiota, and dysbiosis in general, can precede these dementias and they are closely related. Back to your question on stress, I think it changes the way we digest food and it changes the way our HPA acts, so yeah, I think it can be a contributor. ZWICKEY: I completely agree. Immunologically, the cytokine TGF-beta can control autoimmunity and TGF-beta production is in the gut, and it is related to the production of short-chain fatty acids. We think about food that leads to us making short-chain fatty acids, which then leads to the production of TGF-beta, which then shuts down an autoimmune response. What we’re eating absolutely is going to impact whether or not we go on to develop an autoimmune reaction. Unfortunately, the standard American diet is not a good producer of TGF-beta. Interestingly, as Dr Kaczor mentioned earlier, fasting increases the taxa that produce short-chain fatty acids. So all of a sudden those microbes in your gut, instead of making toxic metabolites like TMAO that might contribute to cardiovascular risk, start producing short-chain fatty acids that reduce risk of inflammation. CHONG: Autoimmune responses may also contribute to cardiac issues because of their effects on the various tissues in the heart. This autoimmune theory helps explain some of these long-lasting, clearly cardiac-related issues that are happening in people with long-Covid, long past the persistence of the acute activity of the virus. GAZELLA: I’d like to hear from each of you: What’s your clinical bottom line when it comes to this topic? KACZOR: We have to recognize that we no longer treat sickness and convalesce as we should. We need to slow things 33

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down and ignore our cultural bias for the go, go, go. Anytime you’re sick, convalesce, take some time off, eat well. I think that fasting and eating lightly may be part of the way to get through this successfully. And again, taking the time to convalesce, proper hydration, and sleep, and taking it easy is something that we don’t do so well anymore. CHONG: I have a mantra that I repeat over and over again: Test, don’t guess. When we’re talking about cardiovascular health and preventing the variety of things that are happening to people out there, don’t just assume things are fine. I’m a big proponent of thorough, proactive assessment, not the classic waiting till you have chest pain and then checking it out. That needs to be emphasized now more than ever, in light of Covid.

ZWICKEY: I think we need to be looking at things with compassion because so many people are experiencing so much pain. Being able to look beyond what we’re experiencing to see the pain of others and to treat them with love and compassion because we don’t understand what they’re going through. We know that this is presenting differently in every single person, likely due to the fact that we all have different genetics and we have different microbiota and different epigenetics, and so we’re going to have to be creative, and we’re going to have to think outside the box. But mostly, we’re going to have to treat people with compassion. This is an edited and condensed version of our interview. Listen to the full interview here.

ABOUT the Experts TINA KACZOR, ND, FABNO, is editor in-chief of Natural Medicine Journal and the creator of Round Table Cancer Care. Kaczor is a naturopathic physician board certified in naturopathic oncology. She received her naturopathic doctorate from the National University of Natural Medicine and completed her residency at Cancer Treatment Centers of America. She is also the editor of the Textbook of Naturopathic Oncology and cofounder of The Cancer Pod, a podcast for cancer patients, survivors, caregivers, and everyone in between. DANIEL CHONG, ND, is a licensed naturopathic physician who has been practicing in Portland, OR, since 2000. He earned his naturopathic doctorate from National University of Natural Medicine. Chong’s focus is on risk assessment, prevention, and drug-free treatment strategies for cardiovascular disease and diabetes. In addition to his degree in naturopathic medicine, Chong has completed certificate training in cardiometabolic medicine at The Academy of Anti-Aging Medicine, a BaleDoneen Method Preceptorship, and served for 4 years as a clinical consultant for Boston Heart Diagnostics. He currently maintains a telehealth-based practice. You can learn more about him at cardiowellnessconsults.com. HEATHER ZWICKEY, PHD, is a professor of immunology and chair of the Department of Health Sciences at the National University of Natural Medicine in Portland, Oregon. She launched the Helfgott Research Institute, which advances the science of natural medicine. Zwickey founded the school of graduate studies and developed masters programs in research, nutrition, and global health. Zwickey has received the Champion of Naturopathic Medicine Award from the American Association of Naturopathic Physicians. She currently leads a National Institutes of Health–funded clinical research training program focused on integrative medicine research and studies the gut-brain axis in neuroinflammation.

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RESEARCH UPDATE ON PSILOCYBIN A discussion with integrative mental health expert Emily Whinkin, ND Interest and research regarding psilocybin has grown considerably over the past several years. In this interview, Emily Whinkin, ND, discusses the latest research and provides clinical guidance on the use of psilocybin. Whinkin is a naturopathic physician with the Advanced Integrative Medical Science Institute in Seattle, where she also conducts research and explores altered states of consciousness. KAROLYN GAZELLA: Can you tell us a bit about what psilocybin is and how it works? EMILY WHINKIN, ND: Psilocybin is a tryptamine that is a constituent of many species of fungal spores and fruiting bodies that are native to the Americas. Most psilocybincontaining species of mushrooms contain an average of about 1% of this tryptamine, but up to 2.25% of a dried, fruiting body of a mushroom could be the psilocybin constituent. The active constituent is actually its metabolite, psilocin, which is found itself in several fruiting bodies as well, but the human body can transform psilocybin into psilocin. Psilocin is active at the 5-HT2A receptor, commonly known as the serotonin receptor. This receptor is found in the central nervous system, throughout the cardiovascular system, and in the gut tissue. We think that through agonism of this 5-HT2A receptor, psilocin impacts learning, mood, memory, and neurogenesis in the central nervous system. It also seems to reduce blood flow and therefore function of the default mode network, a kind of a neural network in the brain that is responsible for self-referential thinking and internal processing. The default mode network is also most active when we are retrieving memories about ourselves, as well as imagining our future and our place in it. So if this area of the brain or this network of the brain is getting less blood flow, if it’s de-emphasized as our background way of thinking and being, there are novel ways to experience the world and ourselves and to imagine ourselves in the world. We think that this has to do with what’s been shown to be powerful about psilocin and psilocybin in terms of treatment for mood

disorders, including depression and anxiety. GAZELLA: You coauthored a paper about psilocybin and palliative care that was recently published in the journal Current Geriatrics Report. Tell us about that paper and its conclusions. WHINKIN: This was a 5-year review that looked at papers from 2017 to the point of publication (early 2023) to better understand if there was a role for psilocybin in palliative care specifically. Our definition of palliative care included total pain, which is not just physical pain, but includes psychospiritual pain, emotional pain, and the disconnection from community that patients can sometimes experience because of a condition that warrants palliative care medicine. We wanted to explore the role with psilocybin for each of these concerns independently—physical pain, existential distress that can come with a life-limiting illness, and cognitive issues. We found some compelling research to support each of these targets. Psilocin seems to support neuroplasticity that can promote novel modes of thinking and problem solving. It can help with rebuilding of neuronal tissue, so it can be helpful for people who have suffered traumatic brain injury or cognitive injury as well as readdressing someone’s interpretation of their of their own pain. For pain that has become centralized in the nervous system, psilocin offers almost a rebranding of the person’s interpretation of that and sometimes reduces the secondary impact of being seen as a palliative care patient. GAZELLA: Interesting. How does psilocin help other conditions? 35

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WHINKIN: The way we think psychedelics work, including psilocybin-containing fungi, is they seem to have 2 central modes of action. One is more neurochemical. As I mentioned, the 5-HT2A receptor seems to be prominent in psilocybin effect. The other mode is more of a psycho-spiritual or psychological benefit. The ways that those 2 things are helpful are how they work together. When we think about where psilocybin and other psychedelics have been suggested to be particularly beneficial, we think about major depressive disorder, generalized anxiety disorder, obsessive compulsive disorder (OCD), and problematic substance use. These are all situations where there’s extra rigidity in the mind. So we’re thinking about the depth of neuronal grooves where people seem to suffer from thinking the same thoughts, feeling the same feelings, or pursuing the same behaviors over and over again, and there becomes this rigidity internally. Psychedelics open up an opportunity to have a different experience internally based on new thinking pathways, new opportunities to connect memories to emotions, novel ways of interpreting our somatic cues, and reflecting on our own experience. So overall, psychedelics seem to help in particular with rigid types of thinking and feeling states by facilitating more openness, more access to novel connections in the mind—and that reflects more hope or the ability to shift our own perspective about what could be possible for healing. GAZELLA: It’s fascinating. What does the research tell us about the safety of psilocybin? WHINKIN:We need more long-term data. Psilocybin is still a Schedule 1 drug in the United States, and under the Controlled Substances Act of 1970 is restricted in terms of how we can access and appropriately study some of the longterm effects. So whereas ketamine, for example, has been used and studied robustly since the 1970s and we have a lot of data about its safety, we don’t have the benefit of 50 years of data for psilocybin. What we do know, based on its function at

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the 5-HT2A receptor is that it may have some cardiovascular adverse events or effects with longer term use. We know that when this receptor is targeted by other pharmaceuticals, there can be some damage to the endothelial cells along the vascular system and potentially some damage to heart valves. But contrary to other pharmaceuticals that target that receptor, research suggests that psilocybin doesn’t need to be used even multiple times for durable effect. So we’re measuring weeks of benefit after a single dose of psilocybin. That’s very different than other medications for similar concerns, like antidepressants or anxiolytics. There is probably a lesser risk of damage, but we just don’t have the long-term data. GAZELLA: The term “microdosing” comes up a lot with psilocybin. Can you tell us more about that? WHINKIN: I’ll start with macrodosing as a comparison. We think that between 2 and 5 grams of whole fruiting body of a mushroom, which is the above-ground part of the fungus dried, appears to be a macrodose. Most of the single-dose studies isolate 25 mg of psilocybin to determine the outcomes that they’re tracking. That equates at the 1% profile average that I mentioned earlier—maybe a 2.5 gram whole, dried mushroom equivalent. Microdosing is about a fifth of that, maybe 1 to 5 mg psilocybin. The reason we’re using ranges is because there’s a lot of variety in the extracts, the strains within the psilocybin-containing mushrooms, and the way the mushroom is prepared. Microdosing is more regular use, which tends to be a few days a week. Common protocols are 3 days on in a row and then 4 consecutive days off, for example, with the goal being a subperceptual effect. With microdosing, there’s not a cognitive impairment so we are able to function, go about our day, and show up to our lives. But there may be some benefits, including feeling a little uplifted, feeling a little more clearheaded. Some people microdose for the creative benefits and the neuronal neurogenesis, promoting novel ways of thinking and problem-solving.

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

EXPERT INTERVIEWS

GAZELLA: Is there a way to standardize psilocybin extract? WHINKIN:I think that’s coming. There are certainly ways to measure the amount of psilocybin and psilocin. And there are efforts to extract and standardize just those constituents. As a naturopathic doctor, I am curious about that because in other facets of herbalism, we know that using the whole herb has its own benefits. There are likely other constituents within these fungal fruiting bodies and these organisms that probably mediate the effects of psilocybin and psilocin and probably complicate the interaction with the human body in a way that I think should be studied. We don’t necessarily know if that’s harmful to us or if it facilitates some of the benefits of microdosing and macrodosing. GAZELLA: Do you have concerns about the quality of the psilocybin products that are presently on the market or people who are doing their own thing with it? WHINKIN:I do have concerns. I practice from a harm reduction model with most of my patients who report to me that they’re using what they believe to be psilocybin. I can’t verify that’s what they’re ingesting. Sometimes they don’t know what strain they’re using or how much they’re taking. So it’s a challenge to practice in a way that ethically respects that person’s agency from a harm reduction model, while also trying to give them as much information as I can about how to use this in a safer way. I do hear stories where harm has occurred. Not medical harm, but people are underprepared for the experience of ingesting and being with a psilocybincontaining substance or a psychedelic in general, and there’s not enough appropriate support afterward for what we call integrating the experience or making sense of a big shift in perception. Sometimes there are new insights or confrontation with pre-existing belief models that can occur during that experience. So it’s more of a psychological risk that I’m hearing about and kind of concerned about. Of course, there’s also a chance for a more physiological or medical concern to arise. GAZELLA: It does seem like there are a lot of people using psilocybin, sometimes without proper guidance or any guidance. How do you advise people get the proper support when using psilocybin? WHINKIN:It’s a great question. One part is making sure the medical community is well informed so they can field questions from their patients appropriately and without shame or judgment. From a harm reduction lens, we ask, “If this person, All rights reserved / NMJ, February 2024 / Vol 16, No. 201 (Suppl)

in their own agency, is going to use the substance, how can we work together to not just reduce the harm, but consider that there might be benefit for this person and try to optimize the benefits?” So one part is clinician education, and that includes psychotherapists and counselors, as well as other traditional healing routes like chaplains. The other piece is making sure that if we are not able to provide the support, then making an appropriate referral, just like we do for any other concern. I often refer people to a website called Psychedelic Passage, which connects people who are independently choosing to and sourcing psilocybin to trained guides for integration work or answering questions regarding these substances. GAZELLA: For people without mental health concerns, are there any potential benefits to psilocybin? WHINKIN: There may be benefits to psilocybin-containing mushrooms in a way that’s not contained within a medical model. That is to say that there are there are potential psychospiritual, psycho-emotional benefits of consulting these plant medicines. Taking an open stance towards what would happen, maybe what I confront, what is something that maybe I haven’t even thought of, to ask myself or look at internally that that could facilitate some personal growth. I like that there is interest in that realm and it’s not so contained within a clinical model where people have to meet criteria in order to access these medicines. They’ve been used traditionally for eons— originally, we think by the Mayan and Aztec people in what is now the Amazonian region. Were they thinking through the DSM-V and vetting people and diagnosing people before they could access these plant medicines and the insights therein? No. I think that should certainly be part of the conversation about how we move forward. GAZELLA: As you mentioned, psilocybin is a Schedule 1 drug, so what is the exact legal status regarding its use for therapeutic purposes? WHINKIN:Federally, it’s still Schedule 1, which means there’s basically no acknowledged therapeutic benefit out of out of federal level. But we do have some examples within the United States, specifically in Oregon and Colorado, where they’re creating policy and pursuing the belief that this should be accessible to some extent and should be regulated so people can receive the potential benefits in an above-ground way. In Oregon, this is regulated by measure 109, which has a 3-pronged approach. First is that there’s regulation of 37

EXPERT INTERVIEWS

the growth and distribution of the psilocybin-containing mushroom itself. Second, there’s regulation of the Certified Service Centers where a psilocybin experiential session could occur. That means there are sites and venues specifically certified, meaning it’s not legal to use psilocybin in somebody’s house or out in the woods. Third is regulation of who can facilitate a psilocybin session, so they have accredited training programs and an exam to pass.

RESOURCES

GAZELLA: What would you like to see next when it comes to psilocybin?

Whinkin E, Opalka M, Watters C, Jaffe A, Aggarwal S. Psilocybin in palliative care: an update. Curr Geriatr Rep. 2023;12(2):50-59. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC10106897/

WHINKIN:I would love to see more science around the whole fungus. What can we learn about the other constituents? Can we assume there’s an intelligence in the way that psilocybin has been used as a whole plant for thousands of years and also consult some people who are who are familiar with whole plant extracts within other mushrooms? There’s a lot of good evidence and clinical herbalism with other mushroom species, so why not? I think this also reflects more of the real world, what people tend to be utilizing for microdosing, or when they source their own mushrooms. I’d love to see more research on the phenomenology of these altered states, including acknowledging what we know and what we don’t. The results we get are only as thorough as the questions we’re asking and what we’re able to measure. So almost liberating ourselves from a strict medical monitor model and appreciating that there might be a lot of other planes of change that people are experiencing by utilizing these substances. For the percentage of folks who don’t respond as expected, or maybe the duration of the benefit doesn’t last, I want to know why that is. Are we not measuring the change that they do experience? Or is it different type of depression, for example, that would be better benefited from a different tool? Or are there things like single nucleotide polymorphisms or other changes in the enzyme that converts psilocybin to psilocin and that, for example, could explain why certain people benefit more in the ways we’re able to measure? I think there are a lot of questions around who is really a good fit for this as a tool within the medical model, but also branching out and thinking a little bit more broadly about the benefits outside of a medical model. This is an edited and condensed version of our interview. Listen to the full interview here.

AIMS Institute in Seattle: https://www.aimsinstitute.net/ Oregon.Gov: https://www.oregon.gov/oha/ph/preventionwellness/pages/psilocybinlicense-facilitator.aspx Psychedelic Alpha for tracking legal status in the US: https://psychedelicalpha.com/ data/psychedelic-laws Podcast: The Revolution will not be Psychologized: https://podcasts.apple.com/us/ podcast/the-emerald/id1465445746 Psychedelic Passage (Connecting with a guide):https://psychedelicpassage.com/

STUDIES

Whinkin E, Eparwa TRJ, Julseth MC, Schneider A, Aggarwal SK. Reductions in anxiety and depression symptoms in a subset of outpatients with problematic substance use who received ketamine-assisted psychotherapy: a two-year retrospective chart review. Front Psychiatry. 2023;14:1160442. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC10498542/

ABOUT the Experts EMILY WHINKIN, ND (she/they), is an integrative mental health practitioner, researcher, and psychonaut currently practicing at the Advanced Integrative Medical Science Institute in Seattle. She holds Washington and Oregon licenses in naturopathic medicine and graduated with a master of science degree in integrative mental health from the National University of Natural Medicine in Portland, OR. Clinically, Whinkin works to provide person-centered, relationally informed care at the confluence of entheogenic spiritual medicine, mental health, and reproductive/ generative health. As an undergraduate, she studied both biology and religious studies, formally launching her work to explore and affirm the interdependence of mind, body, and spirit with a focus on cycles, transitions, and environment. Community connection, belonging, and collective transformation are central to Whinkin’s vision of being well in the world. She works to reflect this framework in caring for each patient’s foundational vitality, resilience, and health contexts as ‘root cause’ approaches to healing. She is certified in perinatal mental health (PMH-C) by Postpartum Support International and Holistic Pelvic Care™ with Tami Kent, and she often weaves mindful somatic therapy and botanical medicine within psycho-spiritual work with all genders across the lifespan. KAROLYN A. GAZELLA is the founder of the Natural Medicine Journal and the host of the Natural Medicine Journal Podcast series. She also co-hosts the Five to Thrive Live weekly radio show on the Cancer Support Network, which is also widely available as a podcast. She has been writing and publishing integrative health information since 1992 and is the author or co-author of several books and booklets on a variety of holistic health topics.

2024 NATURAL MEDICINE JOURNAL SPECIAL ISSUE

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EXPLORE THE LATEST SPECIAL ISSUE: Cognition and Mental Health Natural Medicine Journal publishes specialty-specific special issues as a supplement to our regular monthly publication. TOPICS INCLUDE: • Beta-Alanine Applications for Older Adults • Egg Yolk Choline and Cognitive Function • PLUS, podcast update on Psilocybin research

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