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may 2019 Supplement

Special Issue

Sleep and Circadian Rhythm

Light Pollution Linked to Suicide Risk

Does Melatonin Increase Aggression?

Light Therapy for Depression in Teens

Wearable Sleep Trackers— Help or Hype?

The Neurotransmitters Involved in Sleep and Wakefulness

Clock Genes and Aging Quality

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Copyright © 2018 by the Natural Medicine Journal. All rights reserved.

special issue

Sleep and Circadian Rhythm may 2019 Vol. 11, no. 51 (Suppl)

Contents Abstracts & Commentary   6 Wearable Devices: Usable or Useless Information? 10 Should Aggression Be Added to Melatonin’s Adverse Effects? 14 Light Therapy Glasses for Depression in Teens 18

Outdoor Light Pollution Linked to Increased Depression and Suicide Risk

22 Clock Genes and Aging in the Elderly

expert interview


Neurotransmitters in Sleep and Wakefulness

sponsored interview 31 Restorative Sleep Strategies: A Conversation with Christopher Shade, PhD

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http://www.naturalmedicinejournal.com/blog Natural Medicine Journal Blog

Contributors Kurt Beil, ND, Lac, MPH, is a naturopathic and Chinese medicine practitioner in New York’s Hudson Valley region. He completed his post-doctoral research at the National University of Natural Medicine (NUNM) Helfgott Research Institute, where he focused on biomarker and psychometric assessment of the restorative and therapeutic effect of natural environments. He is the founding cochair of the Health & Nature subcommittee of the Intertwine Alliance, a 150+ member coalition of nonprofits, governmental agencies, and private businesses promoting the parks, trails, and natural areas of the Portland Metro region. Beil speaks frequently on the health benefits of contact with nature and maintains a Facebook group (“Naturopaths for Nature”) about this topic. He can be reached by email or at www.hudsonvalleynaturalhealth.com. Catherine Darley, ND, is the director of The Institute of Naturopathic Sleep Medicine in Seattle. Her clinical work focuses on the treatment of sleep disorders in adults and children using behavioral and naturopathic medicine. Additionally she regularly trains corporate employees and emergency personnel on a variety of sleep, performance, and safety issues. Darley graduated from Bastyr University in Kenmore, Washington, in 2002 with her naturopathic doctorate. Currently she is adjunct faculty at Bastyr University and the National University of Natural Medicine in Portland, Oregon. She has served on the Board of the Washington Association of Naturopathic Physicians. Learn more about her work at www.naturalsleepmedicine.net.

Tina Kaczor, ND, FABNO, is editorin-chief of Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National University of Natural Medicine and completed her residency in naturopathic oncology at Cancer Treatment Centers of America, Tulsa, Oklahoma. Kaczor received undergraduate degrees from the State University of New York at Buffalo. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Portland, Oregon. John Neustadt, ND, received his naturopathic doctorate from Bastyr University. He was founder and medical director of Montana Integrative Medicine and is founder and president of Nutritional Biochemistry, Inc. (NBI) and NBI Pharmaceuticals. He is a medical expert for TAP Integrative and has published more than 100 research reviews. Neustadt’s continuing education podcast, Insomnia: An Integrative Approach is available at no cost through Natural Medicine Journal. His research into the underlying pathophysiology of sleep disturbance was the basis for his latest NBI creation, Sleep Relief. Kaycie Rosen Grigel, ND, is a naturopathic doctor who specializes in endocrinology, digestion, and family health. She graduated magna cum laude from the University of Colorado at Boulder and received her doctorate in naturopathic medicine from Bastyr University. She practiced in Anchorage, Alaska before returning to her home state of Colorado. She has owned the Golden Naturopathic Clinic, LLC since 2006. Rosen lives, practices, cooks, and plays with her husband, 2 daughters, and dog in Golden, Colorado.

4 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

Copyright © 2017 by the Natural Medicine Journal. All rights reserved.

Editor-in-chief Tina Kaczor, ND, FABNO

Message from the Publisher

Abstracts & ­commentary Editor Jacob Schor, ND, FABNO

The Importance of Addressing ­ Circadian Rhythm in Clinical Practice

Publisher Karolyn A. Gazella associate publisher Kathi Magee vp, content & communications Deirdre Shevlin Bell Design Karen Sperry Published by Impact Health Media, Inc. 1610 Pace St. Unit 900 #305 Longmont, CO 80504 Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by Impact Health Media, Inc. Copyright © 2019 by Impact Health Media, Inc. 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; Impact Health Media, Inc. 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. Impact Health Media, Inc. 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.

Because one-third of Americans typically don’t get the recommended 7 hours of sleep a night, the Centers for Disease Control and Prevention has declared that we have a sleep epidemic on our hands. The clinical ramifications of this epidemic are immense. We now know that lack of sleep is linked to type 2 diabetes, heart disease, and cancer, as well as obesity and mental health issues like depression and anxiety. Of course, it is well known that the circadian rhythm governs the sleep-wake cycle. But it also affects hormones, digestion, body temperature, and other important body functions. That’s why we wanted to publish an entire issue about addressing disrupted circadian rhythms in clinical practice. In this issue we have 5 different studies that we’ve asked our authors to comment on. Our Editor-in-Chief Tina Kaczor, ND, FABNO, tackles the fascinating topic of clock genes while John Neustadt, ND, looks at sleep devices. Kaycie Rosen Grigel, ND, and Kurt Beil, ND, LAc, MPH, look at studies involving depression, one in adolescents and one in adults. Sleep expert Catherine Darley, ND, evaluates a fascinating study on melatonin and aggression. We also have 2 expert interviews in this issue. In one, Kazcor interviews Robyn Kutka, ND, on the neurotransmitters involved in sleep and wakefulness. And finally, I had the opportunity to conduct a video interview with Christopher Shade, PhD, about GABA, botanicals, CBD, and THC as they relate to enhancing sleep in clinical practice. It’s a packed issue and we hope you enjoy it as much as we did creating it! If you like what you read, please share it with your colleagues. Thanks to the talented authors who participated in this issue. In health,

Karolyn A. Gazella Publisher, Natural Medicine Journal

©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  5

abstract & commentary

Wearable Devices: Usable or Useless Information? A critical review Reference

Peake JM, Kerr G, Sullivan JP. A critical review of consumer wearables, mobile applications, and equipment for providing biofeedback, monitoring stress, and sleep in physically active populations. Front Physiol. 2018; 9:743. Objective

To summarize features of wearable health technologies and evaluate their suitability for consumer use by assessing whether the data has been validated, is reliable, and does for consumers what the manufacturers claim. Design

Review of commercially available wearable health technology devices. Investigators identified devices for inclusion in the review by searching the internet and databases of scientific literature (eg, PubMed) using key terms such as “technology,” “hydration,” “sweat analysis,” “heart rate,” “biofeedback,” “respiration,” “muscle oxygenation,” “sleep,” “cognitive function,” and “concussion.” Study parameters assessed

The researchers examined the websites of commercial technologies for links to research, and where applicable, they sourced published research literature. They then divided technologies into the following categories: • Devices for monitoring hydration status and metabolism • Devices, garments, and mobile applications for monitoring physical and psychological stress • Wearable devices that provide physical biofeedback (eg, muscle stimulation, haptic feedback) • Devices that provide cognitive feedback and training • Devices and applications for monitoring and promoting sleep • Devices and applications for evaluating concussion Primary outcome measures

The investigators evaluated the available information based on 4 measurements: 1. What does the technology claim to do? 2. Has the technology been independently validated against some accepted standard(s)? 3. Is the technology reliable, and is any calibration needed? 4. Is the technology commercially available or still under development? Key findings

The researchers identified and evaluated 89 devices; some were commercially available and others were not. They found the vast majority (82/89) had never been formally validated. Only 10% had been used in research settings. Nearly all the devices (87/89) had no published reliability testing. Calibration of the devices fell into 1 of 3 categories: 1) not reported; 2) reported as “self-­ calibrating;” and 3) manufacturers stated there was no need for calibration. Regarding sleep tracking devices specifically, of the 15 wearables reviewed, only 3 had validation information (UP, FitBit Charge2, OURA), and none of those had undergone reliability testing. The 1 device that did have reliability data (FitBit Flex) did not report any validation testing

6 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

John Neustadt, ND Practice implications This study was the first to evaluate various types of wearable devices to determine if data produced by wearable devices is valid and reliable. The wearable device industry is growing annually at 15% and is expected to be worth $51.50 billion globally by 2020.1 Undoubtedly, clinicians have encountered and will continue to encounter patients who use wearables. Understanding the technology, especially regarding a given device’s claims, is essential to having thoughtful conversations with patients, who are likely to use data from their device as “medical information” in clinic visits. However, the vast majority of devices evaluated by the researchers failed on all accounts. The manufacturers did not validate the data the devices produce, most didn’t calibrate the data to ensure consistency of data readings over time, and they also did not conduct reliability testing or disclose how reference limits were created. Therefore, unless otherwise confirmed, clinicians should not assume that data generated by wearable devices is accurate. For example, the 2 devices that had validation data (UP and FitBit Flex) were compared to the gold standard for sleep studies, a polysomnography. Each device correlated with total sleep time and time in bed, but they did not correlate with deep sleep, light sleep, or sleep efficacy.2,3 Despite the current limitations on accuracy, a potential benefit of wearable technology is that it can create an opportunity to help raise (continued on page 8)


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abstract & commentary

patient awareness of certain health concerns. For example, a sleep tracker could provide a starting point for a helpful conversation about sleep and how to improve it. Through that conversation the clinician can better assess sleep quality and quantity. This may lead to conversations on how to improve sleep or help determine if a more formal sleep study is warranted. A 2018 systematic review and meta-analysis published in the American Journal of Health Promotion evaluated the efficacy of wearable devices to improve physical activity in patients with diagnosed cardiometabolic disease.4 Primary outcomes included physical activity as measured by steps per day and moderate to vigorous physical activity [MVPA], which can include activities such as jogging, lap swimming, tennis or racquetball, bicycling, aerobics, and dancing.  Thirty-five studies involving 4,528 volunteers met the inclusion criteria. The pooled data showed significant increases in physical activity and MVPA in volunteers who used wearable devices.4 This study supports the notion that wearable devices can promote physical activity by making patients more aware of their activity levels. Similarly, wearable devices that monitor other health parameters, such as stress and emotions, heart rate, and blood oxygen levels, may provide an opportunity to focus further clinical evaluations on patient concerns and help them either validate or refute the data from the given device. While the current study revealed that manufacturers are bringing to market products that have not been validated, researchers are conducting post-market studies to test the accuracy and reproducibility of specific devices. A 2019 study by Nelson and Allen evaluated the heart rate accuracy of Apple Watch 3 and Fitbit Charge 2 and compared the data they produced to an ambulatory ECG (Vrije Universiteit Ambulatory Monitoring System).5 The authors concluded, “The Apple Watch 3 and the Fitbit Charge 2 provided acceptable heart rate accuracy (<±10%) across the 24 hour period

  The silver lining, however, is that these devices may bring opportunities to encourage healthier patient behaviors while verifying (or debunking) potential health problems through more rigorous and validated testing methods.

and during each activity, except for the Apple Watch 3 during the daily activities condition.”5 The caveat to Nelson and Allen’s review is that devices may perform well only under specific conditions. However, it may not be possible to know those limitations from the manufacturer’s literature alone. This leaves clinicians in a difficult situation. Without manufacturers divulging the limitations of their devices, it’s not possible to know under which specific use conditions devices might be more or less accurate. The silver lining, however, is that these devices may bring opportunities to encourage healthier patient behaviors while verifying (or debunking) potential health problems through more rigorous and validated testing methods. references

1 Wearable devices market is expected to exceed US$ 51.50 billion by 2022 [press release]. MarketWatch; August 27, 2018. 2 Montgomery-Downs HE, Insana SP, Bond JA. Movement toward a novel activity monitoring device. Sleep Breath. 2012;16(3):913-917. 3 Mantua J, Gravel N, Spencer RM. Reliability of sleep measures from four personal health monitoring devices compared to research-based actigraphy and polysomnography. Sensors (Basel). 2016;16(5):646. 4 Kirk MA, Amiri M, Pirbaglou M, Ritvo P. Wearable technology and physical activity behavior change in adults with chronic cardiometabolic disease: a systematic review and meta-analysis [published online ahead of print December 26, 2018]. Am J Health Promot. 5 Nelson BW, Allen NB. Accuracy of consumer wearable heart rate measurement during an ecologically valid 24-hour period: intraindividual validation study. JMIR Mhealth Uhealth. 2019;7(3):e10828.

8 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

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abstract & commentary

Should Aggression Be Added to Melatonin’s Adverse Effects? A randomized, placebo-controlled trial Reference

Jinting L, Zhong R, Xiong W, Liu H, Eisenegger C, Zhou X. Melatonin increases reactive aggression in humans. Psychopharmacology. 2017;234:2971-2978. Design

Randomized, placebo-controlled, double-blind, between-­participant design. Objective

To assess whether melatonin treatment impacts human aggression Participants

Sixty-four healthy young men, mean age 21.3 years, participated in this study. They all typically went to sleep between 11:00 pm and 12:00 am and woke between 7:00 am and 8:00 am. For 2 hours prior to and during the study they abstained from food and drink (other than water), and for 24 hours prior (and during) abstained from caffeine, cigarettes, alcohol, and exercise. Exclusion criteria included shift work or transmeridian travel for the month prior to the study. All participants had full color vision. One person was excluded from the data analysis because he reported suspicion of the Taylor Aggression Paradigm (TAP). Intervention

Participants in the treatment group were given 5 mg melatonin at 1:40 pm, while those in the control group were given a placebo of 200 mg starch at the same time. Testing with the TAP and Stroop tasks were done at 3:10 pm. During the TAP, participants “compete” with others via a computer interface. When a participant “wins” he can choose to give either a high or low punishment to the opponent. The results of the game are computer-controlled and pseudorandomized so that each participant has wins and losses against both a low-provoking and high-provoking opponent. High punishment was the highest tolerable noise (based on earlier individual threshold tests) and a financial loss of game money, while lowest punishment was the quietest audible noise and a smaller financial loss. Four sessions were played, each with 10 rounds against a low-provoking opponent and 10 against a high-­ provoker. Outcome Measures

The Stanford Sleepiness Scale was administered before melatonin or placebo was ingested, and just before the test session. Testing included both the TAP and the Stroop Color Word Task, which was included to assess whether melatonin was affecting inhibitory ability. Key Findings

The participants who received 5 mg of melatonin administered the high punishment more than those in the placebo group. They also gave more high punishment to the high-provoking opponent, indicating that fairness was preserved. The authors conclude that the study provides direct evidence that melatonin is involved in human social interactions. 10 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

Catherine Darley, ND Practice Implications Over the last several decades, melatonin has become one of the most highly used over-thecounter supplements, with 1.3% of US adults and 0.7% of children using it in 2012. This is more than twice the number of adults just since 2007.1 With the growing popularity of nutritional supplements in general, and melatonin in particular, any untoward effects may have significant societal impact. A well-­ established side effect of melatonin in animals is aggression.2 The current study under review evaluated a dose of midday melatonin and aggressive tendencies in young healthy men. Currently established side effects of short-term melatonin use are mild and include headache, nausea, dizziness, and sleepiness. Likewise, side effects from long-term use are considered mild and comparable to placebo. Due to lack of data, use of exogenous melatonin by pregnant or breastfeeding women and longterm use by children and adolescents is not recommended.3 Most studies on the association of melatonin and aggression have been done in animals, many using an intruder challenge.4 In humans, aggression is classed in 2 subtypes. Proactive/controlled aggression is premeditated for goal attainment and accompanied by low emotional arousal, while reactive/ impulsive aggression is a highly emotional response to perceived provocation. There are 3 published reports in humans evaluating melatonin and aggression. In the first, a case study of brain injury–induced aggression, improvement was achieved by treatment with agomelatine (a melatonin receptor agonist).5 The second, a small study of 6 inpatients with

abstract & commentary

dementia, found equivalent or increased aggression in patients treated with 2.5 mg melatonin combined with bright light therapy, as opposed to bright light therapy alone.6 The third was an observational report of 400 children with autism spectrum disorder. The study found that children with aggressive behavior disorder had a higher rate of sleep problems and melatonin use.7 Exogenous melatonin taken in the middle of the day is known to sharply increase sleepiness and decrease core body temperature.8 These effects are the same as those of the nocturnal melatonin pattern naturally occurring in dim light conditions. The natural nocturnal peak of melatonin occurs at the core body temperature nadir. At that time motivation is at its lowest, as is performance and mood. Another model that induces sleepiness is sleep deprivation. Sleep deprivation can be partial or total, acute or chronic. Sleep deprivation studies allow us to look at the impact of sleepiness itself on aggression, as partial sleep deprivation is not associated with elevated melatonin levels. Sleep deprivation is associated with increased physical aggression in youth, and youth with the shortest sleep duration report the most aggression.9 There are other reports of increased irritability and anger with increased sleepiness. So, in this study is it the melatonin that directly increases aggression, or is it the associated increased sleepiness? The authors evaluated this question through the Stanford Sleepiness Scale given before intervention (melatonin or placebo ingestion) and 90 minutes after. The sleepiness was not found to be related to aggression; increased aggression was only associated with melatonin intervention. This is a significant distinction that moves our understanding forward. We don’t know whether naturally elevated nocturnal melatonin levels are associated with aggression. But assuming they are, what would be the evolutionary advantage? Historically, people slept in dark conditions, and bedtime was preceded by a period of dim light in many parts of the world, and during the winter. This allows melatonin to increase significantly, starting before bedtime, thereby decreasing sleep latency and promoting sound sleep through the night. Many of us have

  Because melatonin is most commonly used before bedtime, it would be useful for future research to evaluate aggression after evening supplementation.

probably experienced negative reactions to being awakened in the night, which may be due in part to the element of surprise, but at least some of the reaction may be due to higher melatonin levels at that time. Is there a protective mechanism to reacting with aggression when woken in the night? There may be, if faced with an intruder, although more often than not it is a loved one who needs attention for some reason, making any aggressive reaction most undesirable. There is also seasonal variation in melatonin release, with a longer duration of secretion during the long nights of winter.10 Although human beings are not seasonal breeders like many of these animal models, winter historically has been a time of reduced resources. Therefore, increased melatonin with associated increased aggression could provide a competitive advantage when resources are limited. In this study, the melatonin was taken in the middle of the day, at 1:40 pm. Participants then took the TAP at 3:10 pm, 1.5 hours after melatonin ingestion. In clinical practice, patients typically take melatonin preceding bedtime, and therefore are less likely to be interacting with others 90 minutes later. Based on these results, if patients did interact in the night, they’d be more likely to be involved in aggressive interactions. So, applying the results of this study clinically, if your patient anticipates being awakened in the night to interact with others, that would merit discussion and caution. Situations that come to mind are people who take care of loved ones, children, or elderly persons overnight, and employees who are on call and may be woken up in the night.

©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  11

abstract & commentary

Additionally, some people may use melatonin during the day as a sleep aid, including shift workers when they arrive home in the morning. Also, people with delayed sleep-wake phase disorder may use melatonin in the afternoon to phase advance. These people would be in normal modern lighting situations after ingestion (as opposed to the study participants, who were in dim light), so it’s unknown whether the light exposure would decrease any associated aggression. Because melatonin is most commonly used before bedtime, it would be useful for future research to evaluate aggression after evening supplementation. Comparison studies of aggression provoked in the absence of supplementation, when participants are simply experiencing the naturally occurring melatonin release that occurs in dim light conditions, would also be useful. For now, it is unknown whether naturally occurring melatonin levels and increases due to supplementation produce the same effects on aggression. Another notable feature of this study is that it included exclusively male participants. It’s been well established in the research literature that melatonin levels decline over the lifespan, and that there are gender differences. Young and midlife women tend to have higher melatonin levels than men, while older women have lower levels.11 There are other areas

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of physiology that show gender differences as well. Clarifying whether women also have increased reactive aggression with melatonin supplementation would be valuable. Conclusion This is the first of what may be an emerging body of evidence regarding a newly recognized adverse effect of melatonin. Given that so many Americans use melatonin supplements (and the number continues to grow), this study deserves attention. It is reasonable to warn patients who use melatonin of a possible aggressive reaction 90 minutes after ingestion, and advise them to take the supplement approximately 30 minutes before bedtime. Patients on melatonin should be encouraged to safeguard their sleep from interruptions (which is always a good idea anyway). For those patients who do eldercare or childcare in the night, or are otherwise on call, it may be more suitable to use a sleep aid that is known not to have the aggression side effect and will not impair the ability to perform nighttime tasks. This is a line of research to keep an eye on as the science matures. References

1 Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Report. 2015;10(79):1-16. 2 Jasnow AM, Huhman KL, Bartness TJ, Demas GE. Short days and exogenous melatonin increase aggression of male Syrian hamsters (Mesocricetus auratus). Horm Behav. 2002;42(1):13-20. 3 Andersen LH, Gögenur I, Rosenberg J, et al. The safety of melatonin in humans. Clin Drug Investig. 2016;36(3):169. 4 Koolhaas JM, Coppens CM, de Boer SF, Buwalda B, Meerlo P, Timmermans PJ. The resident-intruder paradigm: a standardized test for aggression, violence and social stress. J Vis Exp. 2013;77:e4367. 5 O’Neill B, Gardani M, Findlay G, Whyte T, Cullen T. Challenging behaviour and sleep cycle disorder following brain injury: a preliminary response to agomelatine treatment. Brain Inj. 2014;28(3):378-381. 6 Haffmans PM, Sival RC, Lucius SA, Cats Q, van Gelder L. Bright light therapy and melatonin in motor restless behaviour in dementia: a placebo-controlled study. Int J Geriatr Psychiatry. 2001;16(1):106-110. 7 Hill AP, Zuckerman KE, Hagen AD, et al. Aggressive behavior problems in children with autism spectrum disorders: prevalence and correlates in a large clinical sample. Res Autism Spectr Disord. 2014;8(9):1121-1133 8 Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature and performance. Proc Natl Acad Sci USA. 1994;91(5):1824-1828. 9 Street NW, McCormick MC, Austin SB, Slopen N, Habre R, Moinar BE. Sleep duration and risk of physical aggression against peer in urban youth. Sleep Health. 2016;2(2):129-135. 10 Levitan, RD. The chronobiology and neurobiology of winter seasonal affective disorder. Dialogues Clin Neurosci. 2007;9(3):315-324. 11 Obayashi K, Saeki K, Tone N, et al. Lower melatonin secretion in older females: gender difference independent of light exposure profiles. J Epidemiol. 2015;25(1):38-43.

12 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

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abstract & commentary

Light Therapy Glasses for Depression in Teens Sustained improvement observed after 2 weeks Reference

Kirschbaum-Lesch I, Gest S, Legenbauer T, Holtmann M. Feasibility and efficacy of bright-light therapy in depressed adolescent inpatients. Z Kinder Jugendpsychiatr Psychother. 2018;46(5):423-429. Design

Open-label, single-arm, prospective clinical trial Objectives

To assess extended use (4 weeks) of blue light therapy (BLT) glasses on several measures of depression in teenage inpatients and compare the outcomes of BLT glasses to a prior study at the same institution that used a bright light therapy box for 2 weeks in a similar population. Participants

Thirty-nine teenagers (32 female, 7 male, aged 12-18 years) admitted to the hospital for at least 4 weeks with moderate to severe depression were enrolled. Depression was defined by the Beck Depression Inventory II (BDI-II), a 21-item self-assessment questionnaire for depressed mood over the past 2 weeks. Thirty-two participants indicated “severe depressive symptoms” according to BDI-II scores. Bright light therapy was administered in addition to treatment as usual (TAU). This treatment was unspecified, but 36% of the participants received pharmacological antidepressant therapy. Exclusion criteria included diagnosis of schizophrenia; symptoms of psychosis or suicidal tendencies; treatment with anti-

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psychotics or beta blockers; pregnancy; hypersensitivity to light; and eye disease. Comparator group from prior study (n=39) at the same institution using blue light box therapy had no significant differences in age, gender, antidepressant use, or baseline BDI-II scores. Intervention

Participants received 4 weeks of BLT via bright light glasses (brand name Luminette) each weekday for 30 minutes in the morning. The glasses provided 10,000 lux of blue light directed toward the bottom of the eyes, which allowed participants to go about their normal morning activities. Study Parameters Assessed

Participants were assessed at the start of the trial (T1), 2 weeks into the trial (T2), at the end of the 4-week intervention (T3), and 2 weeks after the conclusion of the trial (T4) for the following objective and subjective measures: • Depression, as determined by the BDI-II • Sleep, as evaluated by the Schlaffragebogen B revised (SF-BR), a 31-item questionnaire to determine the quality and restorative nature of sleep • Chronotype, as determined by the Morningness-Eveningness Questionnaire (D-MEQ), a 15-item questionnaire that assesses circadian preference and phase shift • Global severity of symptoms and overall change throughout the study, as determined by the Clinical Global Impressions (CGI) scale, completed by the therapist. The previous study used a light box that provided 10,000 lux of white light. This intensity is comparable to sunlight 40 minutes after sunrise. Primary Outcome Measures

Effectiveness of the blue light therapy glasses on subjective and objective measures listed above; comparison to historical data of a 2-week trial at the same institution using a light box with equivalent lux. Key Findings

The BDI-II results improved from the beginning to the end of the study (T1 to T4), with statistically significant change between T1 and T2. Clinical Global Impressions scores were significantly improved between T2-T4 and T3-T4. Sleep improved from the start of the study (T1) to week 4 (T3). Chronotype did not change significantly. The hypothesis that a longer duration (4 weeks) of BLT may have better effects than 2 weeks’ duration was disproven in this study. Depression and sleep were no different at 4 weeks (T3) with the use of BLT glasses for 4 weeks vs BLT boxes for 2 weeks.

14 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

abstract & commentary

Practice Implications It has been well-established that BLT can be useful for treating seasonal and nonseasonal depression.1-3 Especially in places with low light throughout the winter months, light boxes have become more and more popular. This study specifically compares the efficacy of a new type of treatment device, light “glasses,” to the more widely available light boxes. The light glasses are worn like regular glasses but have a sort of visor that comes out an inch or so from the face and shines a light down over the eyes. The disadvantage of a light box is that the user must remain stationary and is asked to look directly at the light box a few times during the treatment. The light glasses emit light that encompasses the lower half of the eye without needing to look directly into the light. This allows a person to go about his or her normal morning routine while using them, which could potentially increase compliance. This study is interesting because it offers a simple tool to help depressed teens improve mood with a very low-force intervention. Another intriguing finding is that the efficacy of BLT glasses peaked after 2 weeks. Extending the treatment to 4 weeks did not show further improvement, so it appears that BLT treatments quickly affect underlying pathophysiology and there is a sustaining quality to this change. Would exposure to natural sunlight have similar effects? Several studies looked at reported sun exposure and found that it is inversely correlated with depressive symptoms, but a PubMed search failed to find any studies that directly compare sunlight vs bright light therapy.4-6 Perhaps in the context of an inpatient facility, a light box or light glasses are easier to control than outdoor light exposure, from a study design perspective. However, it would be useful to know if there are unique antidepressive effects to BLT as glasses or box vs sending the affected teen outside for 30 minutes of unshaded sun exposure each day. One interesting difference between the light boxes and glasses is the type of light emitted. Light boxes use white light, and the glasses use blue light only. Both emit the same intensity of light, 10,000 lux, which approximates the intensity of sunlight 40 minutes after sunrise. Wavelengths from the blue portion

of the visible spectrum, however, are the most potent regulator of circadian rhythm and more closely approximate the stimulation one feels from sunlight.7 Blue light decreases the release of melatonin, which can increase wakefulness. Conversely, blue light–blocking glasses worn for 3 hours before bedtime significantly decrease the amount of time it takes to go to sleep and improve the overall restfulness of sleep.8 It makes sense that exposing the body to natural light and dark cycles will help to regulate and enhance the quality of sleep, but how does this impact mood? Is disruption in sleep causing depression, is depression causing disruption in sleep, or are they concurrent features of the same process? Participants in this study all took a morningness-eveningness questionnaire and none of them were determined to be strongly morning people. Eveningness is generally associated with depression, particularly in adolescents.9-12 So we see that disrupted circadian rhythm and sleep/wake cycles are associated with depression, but what happens physiologically with exposure to light that helps to improve mood? From a biochemical perspective, several neurotransmitters are responsive to light and dark cycles. Melatonin, serotonin, dopamine, and norepinephrine all respond to BLT. Melatonin, dopamine, and serotonin are all produced in the retina. Retinal dopamine production is stimulated by BLT; conversely, dopamine deficiency is associated with symptoms of depression.13,14 Blue light therapy also suppresses the production of retinal melatonin, and blue light–blocking glasses stimulate melatonin production. In normal circumstances, melatonin is highest at night and during sleep. People with sleep disorders and depression exhibit disruption in the normal circadian levels of plasma melatonin.15,16 Tryptophan, serotonin, and catecholamines such as dopamine and norepinephrine are also implicated in the relationship between light exposure and symptoms of depression. Several studies have utilized tryptophan depletion to induce a relapse in depressive symptoms in patients who are in a BLT-induced stable remission.17-19 Tryptophan depletion is achieved by feeding patients a tryptophan-free amino acid blend, limiting the substrate needed for production to 5-HTP

©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  15

abstract & commentary

(hydroxytryptophan) and subsequent serotonin production. Secretion of serotonin is then reduced even with bright light treatment, which causes the resurgence in depressive symptoms.20 Similar studies show the return of depressed symptoms with catecholamine depletion. This study highlights the fascinating interplay between light and dark cycles and our internal circadian rhythm. Being awake and exposed to morning sunlight initiates the release of neurotransmitters that improve energy and mood during the day. Conversely, dim light and darkness encourage melatonin to help calm the brain and initiate restful sleep. By using a simple, low-force intervention to replicate morning sunlight we can help patients improve mood and sleep. references

1 Gold AK, Kinryn G. Treating circadian rhythm disruption in bipolar disorder. Curr Psychiatry Rep. 2019;21(3):14. 2 Melo MC, Abreu RLC, Linharen Neto VB, et al. Chronotype and circadian rhythm in bipolar disorder: a systematic review. Sleep Med Rev. 2017;34:46-58. 3 Kervezee L, Cuesta M, Cermakian N, et al. The phase-shifting effect of bright light exposure on circadian rhythmicity in the human transcriptome. J Biol Rhythms. 2019;34(1):84-97. 4 Knippenberg S, Damoiseaux J, Bol Y, et al. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand. 2014;129(2):123-131. 5 Benedetti F, Colombo C, Barbini B, et al. Morning sunlight reduces length of hospitalization in bipolar depression. Affect Disord. 2001;62(3):221-223.

6 Thomas J, Al-Anouti F. Sun exposure and behavioral activation for hypovitaminosis d and depression: a controlled pilot study. Community Ment Health J. 2018;54(6):860865. 7 Esaki Y, Kitajima T, Ito Y, et al. Wearing blue light-blocking glasses in the evening advances circadian rhythms in the patients with delayed sleep phase disorder: an open-label trial. Chronobiol Int. 2016;33(8):1037-1044. 8 Burkhart K, Phelps JR. Amber lenses to block blue light and improve sleep: a randomized trial. Chronobiol Int. 2009;26(8):1602-1612. 9 Au J, Reece J. The relationship between chronotype and depressive symptoms: a meta-analysis. Affect Disord. 2017;218:93-104. 10 Keller LK, Zöschg S, Grünewald BZ, et al. Chronotype and depression in adolescents – a review Kinder Jugendpsychiatr Psychother. 2016;44(2):113-126. 11 Levandovski R, Dantas G, Fernandes LC, et al. Depression scores associate with chronotype and social jetlag in a rural population. Chronobiol Int. 2011;28(9):771778. 12 Li SX, Chan NY, Man Yu MW, et al. Eveningness chronotype, insomnia symptoms, and emotional and behavioural problems in adolescents. Sleep Med. 2018;47:93-99. 13 Oren DA. Retinal melatonin and dopamine in seasonal affective disorder. J Neural Transm Gen Sect. 1991;83(1-2):85-95. 14 Belujon P. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol. 2017;20(12):1036-1046. 15 Srinivasan V. Melatonin, biological rhythm disorders and phototherapy. Indian J Physiol Pharmacol. 1997;41(4):309-328. 16 Pandi-Perumal SR, Trakht I, Spence DW, et al. The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders. Nat Clin Pract Neurol. 2008;4(8):436-447. 17 Neumeister A, Praschak-Rieder N, Hesselmann B, et al. The tryptophan depletion test. Basic principles and clinical relevance. Nervenarzt. 1997;68(7):556-562. 18 Neumeister A, Praschak-Rieder N, Hesselmann B, et al. Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy. Arch Gen Psychiatry. 1997;54(2):133-138. 19 Neumeister A, Turner EH, Matthews JR, et al. Effects of tryptophan depletion vs catecholamine depletion in patients with seasonal affective disorder in remission with light therapy. Arch Gen Psychiatry. 1998;55(6):524-530. 20 Masson J. Serotonin in retina [published online ahead of print November 9, 2018]. Biochimie.

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abstract & commentary

Outdoor Light Pollution Linked to Increased Depression and Suicide Risk A cross-sectional study of Korean adults Reference

Min J, Min K. Outdoor light at night and the prevalence of depressive symptoms and suicidal behaviors: a cross-sectional study in a nationally representative sample of Korean adults. J Affect Disord. 2018;227:199-205. Study Objective

To assess the association between outdoor light at night (LAN) and prevalence of depression and suicide in a population of adults in South Korea Design & Participants

This cross-sectional population study used data from the 2009 South Korean National Community Health Survey to compare severity and rates of self-reported depression (n=113,119) and suicidal ideation and/or attempts (n=152,159) with the intensity of ambient environmental outdoor LAN surrounding each participant’s residential location. Study Parameters Assessed

Intensity of outdoor LAN around each participant’s residence was reported from the database of the Korean National Centers for Environmental Information, as captured by satellite imagery and assessed as radiance (nanowatt/cm2/steradian [sr]). This data was divided into quartiles (Q1-Q4), from the darkest rural areas (Q1: radiance <13.19) to the brightest urban (Q4: radiance >60.44). Participants’ depression scores were measured using the Center for Epidemiologic Studies Depression Scale (CESD). Number of suicidal ideation events and past suicide attempts were provided by self-report. Primary Outcome Measures

Prevalence of depression and suicide attempts/ideation in the various quartiles of LAN. The association between depression/suicide and LAN was determined by statistical analysis, adjusting for participants’ age, sex, marital status, education, monthly income, smoking status, alcohol consumption, and physical activity level. Environmental data (nighttime noise level, airborne particulate matter [PM10], and residential proximity to parks or other green spaces) around each participant’s residence was also included in model adjustments, as these factors have also shown direct influence on mood states. Key Findings

There was a statistically significant relationship between outdoor LAN and measures of depression and suicidal ideation when using the fully adjusted model (controlling for multiple individual and neighborhood environmental factors). Compared to participants living in the darkest (Q1) rural areas, odds ratios (ORs) demonstrated a 22% to 29% increase in depressive symptoms (P<0.001) and 17% to 27% increase in suicidal ideation (P<0.001) for participants living in areas with greater outdoor LAN (Q2-4), in a dose-response relationship. 18 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

Kurt Beil, ND, LAc, MPH Practice Implications Outdoor LAN creates a condition often known as “light pollution,” which is increasingly recognized as a public health threat.1 Like many other forms of pollution, it develops insidiously, seeming to occur in the environmental background without causing noticeable acute harm. Only when examined en masse, in large-scale epidemiological studies like this current one, do the true detrimental effects of chronic exposure start to present themselves. Like other forms of light exposure, outdoor LAN is thought to create its negative health effects through photon stimulation of receptors in the retina, activating nerves that innervate the suprachiasmatic nucleus (SCN), suppressing melatonin production and altering the function of serotonin and other neurotransmitters that determine mood.2 These LAN exposures are well-known for altering circadian rhythm and inflammatory metabolic pathways,3 and it has been shown that indoor LAN is linked with an increased rate of depression,4 thus supporting the “sleep hygiene” practice of maintaining a darkened bedroom. This study is not able to show if darkening bedroom windows to block out outdoor LAN would increase serotonin or improve mood disorders. However, it is known that outdoor light pollution has multiple detrimental health effects to both humans and ecosystems, in a dose-dependent manner similar to the findings of this current study.5,6 This strongly suggests that environmental light pollution has physiological effects on all life, disrupting the natural circadian rhythms that arose from evolutionary adaptation to the 24-hour day-night cycle. Disruption of this cycle from outside LAN and subsequent effects on depressive symptoms and suicidal ideation are most pronounced in urban areas (Q4 in this study), where light pollution is greatest. This may be a contributing factor for the

abstract & commentary

increased prevalence of depression and other mental illness in cities,7,8 an idea supported by multiple comparative brain scan studies.9,10 These experiences of “urban stress” are often attributed to ambient noise, air pollution, and lack of restorative green space, but this current study controlled for these factors, allowing for the possibility that high outdoor LAN may play a role. We already know that living in urban settings artificially shifts melatonin production cycles away from their natural circadian rhythms, and that spending time in more natural, low-LAN settings restores these patterns.11 It may be that urban light pollution is causing neurochemical and neurostructural changes in the brain. However, the mood disorder effects of LAN may not be entirely physiological. Researchers in the field of ecopsychology talk about the “missing sky factor,” that is, how light pollution creates absence of nighttime sky and loss of the grandeur of infinite stars. This in turn can limit feelings of joy as well as experiences of awe and wonder that allow children (and adults) to ponder life’s deeper meanings.12 The ability of natural scenes as a whole to produce awe and other positive psychological states is well known,13,14 and it may be that residents in areas of greater LAN are missing out on these experiences that allow viewing of the night sky and pondering of one’s own value and purpose in the cosmos. In an environment where it is rare to see more than a handful of stars against a “light washed” sky, it may be easier to become depressed and suicidal without a higher source of stellar inspiration. It is also interesting to wonder if the sense of loss of night sky viewing, rather than merely its absence, plays a role in contributing to mood disturbance. This association between depression and environmental loss has been measured in more terrestrial-based natural settings15,16 and has even been given the name of “solastalgia,” the distress produced by environmental change.17 Loss of beloved natural features is a common occurrence in the modern world and could certainly be contributing to the increased prevalence of depression seen around the globe.18 In his excellent book End of Night, author Paul Bogard discusses the many ways light pollution is a factor in this trend.19

It is also interesting to wonder if the sense of loss of night sky viewing, rather than merely its absence, plays a role in contributing to mood disturbance.

Fortunately, awareness of the negative health effects of light pollution and outdoor LAN, both physiological and psychological, is growing. An entire field of “medical chronobiology” is developing to address circadian rhythm imbalances resulting from too much light exposure, as this entire special issue of Natural Medicine Journal addresses. From an environmental perspective, the International Dark-Sky Association (IDA) works to promote awareness of light pollution and its impact on human and ecological health. The IDA advocates for the reduction of outdoor LAN in both urban and rural communities, through the hooding of outdoor house lights, street lamps, and stadium lighting, as well as the transition away from high-intensity LED (light-emitting diode) lights that tend to produce more damaging blue light.20 No studies are available yet on the impact of this work on mental health rates, but outdoor LAN in certain areas has begun to decrease.21 Limitations A significant limitation of this study is the lack of individual outdoor LAN exposure measurement. Outdoor LAN data was taken from environmental datasets for given geographical areas and may not accurately reflect true outdoor LAN exposure for every individual. Similarly, no biomarkers were collected from participants in this study, leaving us to speculate about the mechanism of action for these findings. Researchers conducting further studies in this area may want to collect biomarker data (eg, melatonin) and provide each

©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  19

abstract & commentary

participant with body sensors to measure individual outdoor LAN exposure. Because this was a cross-sectional study using self-­report survey data, the validity of the findings are limited. However, it may not be ethical to conduct a more rigorous experimental study with human participants, given that the outcome measures are depression and suicidal ideation. Conclusions Based on the data findings of this and previous studies, it appears that outdoor LAN plays some role in the determination of mood states that influence mental health, likely through impact on circadian rhythm and neurotransmitter production, with possible contribution from psychological mechanisms. Reestablishing optimal environmental conditions that reflect naturally occurring exposures of nighttime darkness may be an effective way to decrease rates of depression and suicide while supporting greater individual and ecosystem health.

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1 Chepesiuk R. Missing the dark: health effects of light pollution. Environ Health Perspect. 2009;117(1):20-27. 2 Bedrosian TA, Nelson RJ. Timing of light exposure affects mood and brain circuits. Transl Psychiatry. 2017;7(October 2016):e1017-26. 3 Plano SA, Casiraghi LP, García Moro P, Paladino N, Golombek DA, Chiesa JJ. Circadian and metabolic effects of light: implications in weight homeostasis and health. Front Neurol. 2017;8(October):1-21. 4 Obayashi K, Saeki K, Iwamoto J, Ikada Y, Kurumatani N. Exposure to light at night and risk of depression in the elderly. J Affect Disord. 2013;151(1):331-336. 5 Kraus LJ; American Medical Association. Human and Environmental Effects of Light Emitting Diode (LED) Community Lighting CSAPH Report 2-A-16; 2016. https://www. ama-assn.org/sites/ama-assn.org/files/corp/media-browser/public/about-ama/ councils/Council%20Reports/council-on-science-public-health/a16-csaph2.pdf. Accessed April 9, 2019. 6 Dominoni DM, de Jong M, Bellingham M, et al. Dose-response effects of light at night on the reproductive physiology of great tits (Parus major): integrating morphological analyses with candidate gene expression. J Exp Zool Part A Ecol Integr Physiol. 2018;329(8-9):473-487. 7 Lecic-Tosevski D. Is urban living good for mental health? Curr Opin Psychiatry. 2019;32(3):204-209. 8 Peen J, Schoevers R, Beekman AT, Dekker J. The current status of urban-rural differences in psychiatric disorders. Acta Psychiatr Scand. 2010;121(2):84-93. 9 Lambert KG, Nelson RJ, Jovanovic T, Cerdá M. Brains in the city: neurobiological effects of urbanization. Neurosci Biobehav Rev. 2015:1-16. 10 Abbott A. City living marks the brain. Nature. 2011;474(7352):429. 11 Beil K. Can camping reset melatonin production? Real-world exposures shift production patterns. Natural Medicine Journal. 2017;9(7). 12 Blair A. An exploration of the role that the night sky plays in the lives of the Dark Sky Island community of Sark. J Skyscape Archaeol. 2017;3(2):236-252. 13 Ballew MT, Omoto AM. Absorption: how nature experiences promote awe and other positive emotions. Ecopsychology. 2018;10(1):26-35. 14 Capaldi CA, Passmore H-A, Nisbet EK, Zelenski JM, Dopko RL. Flourishing in nature: a review of the benefits of connecting with nature and its application as a wellbeing intervention. Int J Wellbeing. 2015;5(4):1-16. 15 Hendryx M, Innes-Wimsatt KA. Increased risk of depression for people living in coal mining areas of central Appalachia. Ecopsychology. 2013;5(3):179-187. 16 Eisenman D, McCaffrey S, Donatello I, Marshal G. An ecosystems and vulnerable populations perspective on solastalgia and psychological distress after a wildfire. Ecohealth. 2015;12(4):602-610. 17 Albrecht G, Sartore G-M, Connor L, et al. Solastalgia: the distress caused by environmental change. Australas Psychiatry. 2007;15(s1):S95-S98. 18 Friedrich MJ. Depression is the leading cause of disability around the World. JAMA. 2017;317(15):1517. 19 Bogard P. The End of Night: Searching for Natural Darkness in an Age of Artificial Light. Boston, MA: Back Bay Books; 2013. 20 Holzman DC. What’s in a color? The unique human health effects of blue light. Environ Health Perspect. 2010;118(1):A23-A27. 21 Bogard P. The End of Night: Searching for Natural Darkness in an Age of Artificial Light. Boston, MA: Back Bay Books; 2013.

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abstract & commentary

Clock Genes and Aging in the Elderly Prospective study in very elderly population Reference

Pagliai G, Sofi F, Dinu M, et al. CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians – The MUGELLO Study. Sci Rep. 2019;9(1):1472. Design

Prospective, observational cohort of an ongoing epidemiological study Objective

To find associations between genotypes of the CLOCK gene and quality of aging Participants

All participants (n=356; 237 women, 99 men) were between the ages of 86 and 106 years, living in or near the Mugello region in Tuscany, Italy. All were participating in the MUGELLO study, an ongoing epidemiological study investigating many parameters of aging to gauge associations with quality of life. Study outcome measures

All participants underwent genotyping for 3 polymorphisms of the CLOCK gene (rs1801260, rs11932595, rs4580704). Data was collected by home/nursing home visits where blood was drawn and objective parameters (ie, blood pressure, weight, waist circumference, height) were assessed and BMI calculated. Objective measures of cognitive function included the Mini-Mental Status Exam and Clock Drawing Test. Basic activities of daily living were also assessed. Laboratory measurements included a cholesterol panel and fasting glucose. Questionnaires were used to evaluate sleep, mood, and diet. Sleep was tracked through a questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and a SenseWear Armband calorimeter was used for objective sleep pattern assessment (worn for 1 week of study). A short form of the Geriatric Depression Scale (GDS) was used to detect possible depression. The Mediterranean Diet Score (MDS) was used to gauge adherence to the Mediterranean diet. Key findings

There was an association between CLOCK gene polymorphisms and weight, glycemia, low-density lipoprotein (LDL) cholesterol, and triglycerides in this elderly population. In addition, there were significant associations of individual polymorphisms (and various haplotypes) with cognitive decline, depressive state, and quality of diet. The authors postulate that all the parameters measured—cholesterol levels, weight gain, cognitive function, and dietary choices—are partly regulated by circadian rhythm. They hypothesize that polymorphisms in the CLOCK gene may be at least partly responsible for differences in the quality of life and health conditions of nonagenarians.

22 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

Tina Kaczor, ND, FABNO Practice implications This is the first study to look at polymorphisms in the CLOCK gene relative to quality of aging in an elderly population. To date, variations in clock gene expression due to shift work, sleep deprivation, light at night exposure, aging itself, and genetic variations of the CLOCK gene have been associated with obesity, type 2 diabetes, mood disorders, cardiovascular diseases, psychiatric disorders, and various cancers.1-4 The term “clock genes” is used to describe “genes involved in maintaining the internal coordination of multiple oscillators within and between various organs systems, in order to increase physical fitness of an organism and provide the most efficient response to the periodical environmental events such as the day/ night cycle.”5 Such oscillators are found throughout nature, including in bacteria, fungi, plants, insects, and mammals.6 In addition to presence across kingdoms, clock genes are found within cells in nearly all tissues of the body, including all glandular tissues, fat stores, bone marrow, tendons/ligaments, skin, and immune cells. Clock genes are the central players in a complex system of endogenous time-keeping that, while entrained by light from the environment, act independently of light to oscillate bodily functions within a 24-hour biorhythm. The gene locus in the current study being reviewed is the CLOCK gene, which stands for the Circadian Locomotor Output Cycle Kaput gene, and it was one of the first clock genes discovered. It encodes the corresponding CLOCK protein, which is part of a transcription factor complex controlling 2 other clock gene types—Period genes (PER1, PER2, PER3) and the Cryptochrome genes (CRY1, CRY2). As an upstream controller, the CLOCK gene/protein has greater influence on circadian regulation than its downstream products, whose transcription is essentially under its control.7

abstract & commentary

The current study under review found that differences in weight, cholesterol levels, mood, cognition, and quality of life in participants over 90 years old were associated with polymorphisms in the CLOCK gene. It is well known that aging often leads to changes in circadian rhythm, typically an earlier time of day to fall asleep, greater sleep disturbance, and shortened sleep time, all of which are influenced by clock genes.8 However, how much circadian disruption contributes to diseases and conditions of aging is not well-studied. Pagliai and colleagues confirmed that there is a genetic variation in circadian rhythm that is under the control of the CLOCK gene, and that this is associated with various conditions of aging. For example, they confirmed that single nucleotide polymorphism (SNP) rs1801260 is associated with better sleep patterns and less risk of being overweight. (This was specifically associated with haplotypes AAG and

GGC.) That better sleep correlates to better weight control is in keeping with evidence linking poor sleep and weight gain.9 The relationship between clock genes and blood glucose is an area of ongoing study, with a growing appreciation for the 24-hour entrainment of clock gene expression from not only light/dark cycles, but also from feeding/fasting cycles.10 In addition, most human clock genes are expressed in pancreatic islet cells, where they take part in glucose regulation by regulating a background of rhythmic insulin secretion.11 In this study, the GGC haplotype for all 3 polymorphisms was associated with a lower risk of hyperglycemia, while other SNPs in rs1801260 and rs11932595 were related to higher levels of fasting glucose. The authors postulated that “the effects of the CLOCK gene on glucose metabolism in the peripheral organs may be a mechanism involved in the development of

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©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  23

abstract & commentary

hyperglycemia.” This corroborates evidence for the involvement of clock genes in the underlying pathophysiology in type 2 diabetes.12,13 They also confirmed that polymorphisms in clock genes, and specifically the CLOCK gene, is associated with dyslipidemia. This is not surprising. Inherent rhythmicity of circulating lipids has been known for some time, and recently there is evidence that it is under the control of clock genes.14 In keeping, this study showed that higher triglycerides and LDL cholesterol were associated with an SNP in rs4580704 and that the haplotype AAG was associated with high triglycerides and higher total cholesterol. Ultimately, variations in clock genes may, at least partly, account for the apparent familial disposition in cholesterol levels. Lastly, there were associations between CLOCK gene polymorphisms and cognitive function as well as depressive state. The authors propose that in the case of depression and cognitive function it is not only clock genes’ regulation of circadian rhythm but clock gene involvement in the hypothalamic-pituitary-adrenal stress response.14 For example, in this study, those who were homozygous (GG) for SNP rs1801260 had worse scores on the geriatric depression scale. This same cohort, however, had better scores on clock drawing, implying better hand-eye skills and abstract thinking. The authors propose that better clock drawing as well as a tendency toward depressive states in those with this variation of the CLOCK gene may be due to a heightened cellular sensitivity to endogenous glucocorticoids from acute stressors. In this study, the quality of aging, as measured by various objective and subjective parameters, was associated with CLOCK gene variations in an elderly population. This implies that clock genes not only regulate the 24-hour rhythm but are involved in peripheral cellular responses to changes in that rhythm as well. Regardless of underlying SNPs or haplotypes of clock genes in our patients, the continuing work to elucidate how these genes keep us in sync with a 24-hour planetary biorhythm

Disruptions to normal circadian rhythms, which are common in this population, may be linked to conditions that are associated with specific underlying CLOCK gene polymorphisms.

should remind us all to pan back when assessing a person’s health. No matter why a given patient is being seen, it will be difficult if not impossible to completely correct underlying pathophysiology without normalization of their circadian rhythm, which is always anchored by a proper sleep cycle. References

1 Valladares M, Obregón AM, Chaput J-P. Association between genetic variants of the clock gene and obesity and sleep duration. J Physiol Biochem. 2015;71(4):855860. 2 Schuch JB, Genro JP, Bastos CR, Ghisleni G, Tovo-Rodrigues L. The role of CLOCK gene in psychiatric disorders: evidence from human and animal research. Am J Med Genet Part B Neuropsychiatr Genet. 2018;177(2):181-198. 3 Garbazza C, Benedetti F. Genetic factors affecting seasonality, mood, and the circadian clock. Front Endocrinol (Lausanne). 2018;9:481. 4 Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett. 2014;342(1):9-18. 5 Pagliai G, Sofi F, Dinu M, et al. CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians – The MUGELLO Study. Sci Rep. 2019;9(1):1472. 6 Saini R, Jaskolski M, Davis SJ. Circadian oscillator proteins across the kingdoms of life: structural aspects. BMC Biol. 2019;17(1):13. 7 CLOCK clock circadian regulator [Homo sapiens (human)]. https://www.ncbi.nlm. nih.gov/gene/9575. Updated April 15, 2019. Accessed April 27, 2019. 8 Gibson EM, Williams WP, Kriegsfeld LJ. Aging in the circadian system: considerations for health, disease prevention and longevity. Exp Gerontol. 2009;44(12):51-56. 9 Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14(4):402-412. 10 Javeed N, Matveyenko A V. Circadian etiology of type 2 diabetes mellitus. Physiology. 2018;33(2):138-150. 11 Pulimeno P, Mannic T, Sage D, et al. Autonomous and self-sustained circadian oscillators displayed in human islet cells. Diabetologia. 2013;56(3):497-507. 12 Prasai MJ, George JT, Scott EM. Molecular clocks, type 2 diabetes and cardiovascular disease. Diabetes Vasc Dis Res. 2008;5(2):89-95. 13 Karthikeyan R, Spence DW, Brown GM, Pandi-Perumal SR. Are type 2 diabetes mellitus and depression part of a common clock genes network? J Circadian Rhythms. 2018;16:4. 14 Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci U S A. 2012;109(7):2625-2629.

24 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

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expert interview

Neurotransmitters in Sleep and Wakefulness An interview with Robyn Kutka, ND

To treat patients with sleep disturbances, it’s important to understand how neurotransmitters affect sleep and wakefulness. In this interview, NMJ’s Editor-in-Chief Tina Kaczor, ND, FABNO, sat down with neurotransmitter expert and practicing naturopathic physician Robyn Kutka, ND, to learn more about how GABA, melatonin, histamine, acetylcholine, dopamine, serotonin and ­lesser-known neurotransmitters are involved in the circadian rhythm. Kutka shared a wealth of clinically relevant knowledge about neurotransmitters, hormones, stress, and sleep that any practitioner who sees patients with sleep issues can put into practice. As diurnal beings, what drives us to sleep at night?

We think about our circadian rhythm, our circadian Process C, but it’s actually more than that. When it comes to sleep, we have a couple of processes that work together to balance that out and promote our sleep patterns. We have our Process C, which is our circadian process, that is mostly endogenous. We think about our body temperature, our melatonin production—but it’s adapted to our local environment and our external time cues … things like daylight, timing of sleep, timing of meals, work schedule, social interaction. It can change based on those things. But then the Process C is balanced with something called Process S. That’s our sleep homeostasis, our sleep pressure so to speak. It’s this drive for sleep that builds as we wake and accumulates until we start our sleep, at which point it starts to decrease. When we have an imbalance in those 2 systems, that’s where we start to see some sleep disruptions. When you say it’s our drive for sleep, do you mean our habits and our lifestyle?

No, it’s more of an internal, biochemical process regulated by things like some of our neurotransmitters. A great example of disruption is when people drink alcohol thinking it’ll help them sleep. What happens is it disrupts some of the chemical process of this Process S and actually shortens it at the end, and so we then end up waking earlier. A lot of people will fall asleep nicely but then they wake up sooner than they want to, because they’ve disrupted their normal process. (continued on page 28) 26 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

Play Now Approximate listening time: 32 minutes

About the expert

Robyn Kutka, ND, is an expert in naturopathic medicine, hormones and menopause. She uses this knowledge, coupled with her laboratory medicine experience and the latest in scientific research, to develop customized treatment plans designed to address the cause of health concerns. Kutka received her medical education from the National University of Natural Medicine, where she trained as a general practitioner and tailored her studies to receive more focused training in the field of women’s health, completing a 3-year women’s health clinical internship. She has spent more than a decade educating women on the topics of sexual health and romance enhancement in their relationships and continues to advance her knowledge in the field, studying with the International Society for the Study of Women’s Sexual Health and the American Academy of Anti-Aging Medicine. In addition to practicing at Inspire Your Health in Portland, Oregon, Kutka is the director of clinical services and lead staff physician at Labrix Clinical Services. She serves as an educational resource for providers across the world on the topic of hormone balancing and bioidentical hormones and has shared her knowledge by speaking for organizations including the American Academy of Anti-Aging Medicine, the Association for the Advancement of Restorative Medicine and the Integrative Healthcare Symposium. 



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expert interview

What neurotransmitters are involved with sleep?

There are several involved in sleeping and wakefulness. Just like all of our processes, it’s a balance between our neurotransmitters that will help promote sleep. We have sleep promoters, which are inhibitory neurotransmitters, things like GABA and melatonin. GABA’s probably your largest sleep promoter, and those are common to us. But then there’s a couple others, like adenosine and galanin, that we probably aren’t used to talking about. Wakefulness promoters are more of our excitatory neurotransmitters, so histamine, acetylcholine, dopamine, serotonin. Serotonin’s a little tricky; it can be both a sleep promoter and wakefulness promoter. Then norepinephrine, epinephrine, and then one called orexin or hypocretin is another. Let’s talk about histamine. We know that Benadryl, an antihistamine, puts people to sleep. So what’s going on there?

Histamine is probably our strongest contributor to arousal or staying awake. So using an antihistamine and blocking that neurotransmitter can help promote sleepiness. Histamine also plays a limited role in our muscle tone and control while we’re sleeping. A lot of the major pharmacological treatments work on histamine to promote sleep. Are antihistamine diets helpful for people who have sleep issues?

There aren’t a lot of great placebo-controlled, double-blind studies out there using an antihistamine diet, but for people who have higher histamine levels, higher stress levels, things like that, there actually could be some breach of integrity to the blood-brain barrier. It’s not necessarily because we’re consuming so much histamine. Maybe it’s because we’re not breaking our histamine down as well. But in somebody who has higher levels of histamine, decreasing the amount coming in could be beneficial. People taking drugs or supplements to increase serotonin often have sleep issues. How do we know when serotonin should be supported and when it shouldn’t?

If there are indications that someone might be lower in serotonin—like in postmenopausal women who might be a little lower in estrogen, which promotes serotonin—you can try promoting serotonin to see there’s some relief. That’s in the short term, but you’d want to think about testing too. Serotonin’s a tricky one, though. With too little you won’t get great sleep. But too much could actually promote wakefulness and decrease REM sleep. A lot of people will try 5-HTP, a serotonin precursor, before bed. If it helps, that’s a pretty good indication that they need that serotonin support and maybe melatonin support, because down the road serotonin becomes melatonin. But if it causes more sleep disruptions or irritability on waking, serotonin probably isn’t the issue. Is there a role for other neurotransmitters to control serotonin?

GABA will help to decrease the activity of our wakefulness promoters, so histamine, serotonin, norepinephrine. GABA will not necessarily decrease serotonin per se but will block serotonin messaging in different parts of the brain. In a lecture you gave, you mentioned norepinephrine levels increase most when focused cognitive effort is interrupted. It made me think of what a busy world we live in, and all the interruptions we constantly face. Is that what you mean?

Yeah. Serotonin is elevated as we sustain our cognitive concentration, but norepinephrine is going to rise as we interrupt it. I call it shiny goldfish syndrome. If you’ve watched Finding Nemo, Dory’s all over the place. That’s what we’re thinking about. Another way to look at that is our ADD/ADHD meds. They’re working on norepinephrine and raising and sustaining those levels so people can concentrate. We’re watching something, we get interrupted and move on to the next thing, and we get this increase in norepinephrine. In a way it’s our body trying to maintain that focused concentration that’s lacking. And so disruption in that system makes it difficult and we see that sustained with medication, but I think there’s other ways we could do it.

28 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

expert interview

So when we’re trying to concentrate on one thing, maybe we should put blinders on.

Newer medications actually work on this system—not like the hypnotic medications that are used.

Absolutely. We see a huge lack of mindfulness in our culture and this idea of, “We’re so busy.” We go from one thing, to the next thing, to the next thing. It’s keeping us in a sympathetic versus parasympathetic state. We’re increasing those norepinephrine levels. We’re in this fight-or-flight mode all the time, and that’s causing a disruption in some of our neurotransmitters.

Can you give us a little review about glutamate and how we can assess and/or balance that?

So whether it’s helping our patients practice deep breathing, or taking 10 minutes a day on their own, or any of the herbs or things that we might be doing, what we’re really doing is trying to promote more time spent in that parasympathetic state so we can lower some of these excitatory neurotransmitters. What should dopamine be doing in the daytime and in the nighttime? Is there an ideal rhythm for dopamine?

Dopamine is another wakefulness promoter. It doesn’t necessarily decrease toward bedtime, but when we have disturbances in dopamine you’ll see some disturbances in sleep. We commonly see disturbances in REM sleep in Parkinson’s patients or increased sleep disturbances in people with schizophrenia where dopamine is associated. It can help control sleep and wake, and as we wake up it actually down-regulates melatonin. So I suppose it does have its own little rhythm there. You mentioned a neurotransmitter I wasn’t familiar with. What is orexin?

Orexin has only been really studied since the late 90s. It’s another neuromodulator/neurotransmitter that helps coordinate sleep. When we don’t have enough of it, it’s actually associated more with narcolepsy. It’s influenced by a lot of our main energy factors—things like our monoamines, so serotonin, dopamine, norepinephrine, nutrients, blood sugars, leptin, ghrelin. It also coordinates our regulation of energy balance, and sleep, and wakefulness.

Glutamate, like many of our other neurotransmitters, can be looked at in neurotransmitter testing. Glutamate becomes GABA. So when glutamate is too high and it’s not converting properly to GABA, we see insomnia symptoms or difficulty falling asleep. Having proper conversion so we have adequate GABA levels to promote sleep is important there. Glutamate might rise because people are supplementing or it’s in their protein powders and they’re not converting it properly. Some people are more sensitive to glutamic acids in foods. If they have an issue converting it or don’t have the right cofactors to do that, then we’re going to see imbalances. Do cofactors in larger quantities push these pathways? For instance, if glutamate were high and GABA were presumed to be low, could we push these pathways just by giving the cofactors?

In a perfect world where all enzymes work properly without any variance and we don’t have any SNPs in them—an environment with low inflammation, low pollution, low toxicity, people aren’t malnourished—I think we could get a lot of benefit by working on the cofactors. But I would always think about making sure cofactors are replete and optimal before I give any amino acid precursors or building blocks. It’s an interesting difference between repletion and mega-dosing, where you’re giving intentionally large doses a cofactor to make the neurotransmitters.

Absolutely. The other thing I think about is iron deficiency. Both women and men can be iron insufficient, but menstruating women are often insufficient in iron. Labs might not show that. They’re going to look “normal” when really they’re considered iron deficient. Obviously we wouldn’t mega-dose iron, but we’d want to replete iron before we give amino acid precursors.

©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)  29

expert interview

Iron is so important for so many of these enzymes that create the neurotransmitters in the brain.

Yes, for that initial step of conversion toward serotonin, toward dopamine, we need iron, vitamin D, B6, and biopterin. So we think about it as a methylation step as well. Perimenopausal and postmenopausal women often tell me they wake up in the middle of the night with a busy brain. One patient called it “monkey mind.” It kicks in and she can’t turn it off and she can’t get back to sleep. What’s going on with these women?

This is one of my favorite things to work with because 97% of the time it’s so easy to fix. As we become perimenopausal we start having more anovulatory cycles. And of course postmenopausally we’re not cycling at all. We’re not expecting that egg, so we don’t have the tissue hanging around that would express a lot of progesterone. Progesterone and its metabolite allopregnanolone actually work at the GABA receptors. We have 2 different GABA receptors; progesterone works at one and its metabolite works at the other. As progesterone levels drop, those GABA receptors aren’t being stimulated as much as they have in the past. GABA is probably the most important neurotransmitter we have in sleep promotion. It’s why most sleep medications and anxiolytics work at GABA receptors. For women in that period of life, their body’s own anxiolytic has really decreased substantially.

When that happens they’re going to have what you called “monkey mind.” We can provide some excellent relief by working at the GABA receptors. We typically do that with oral progesterone. Let’s talk about testing. What’s some basic testing, and what is a more thorough approach to sleep issues?

For basic testing, there are some blood tests that we want to do on the vast majority of people who are going to come in with some of these symptoms—ferritin, vitamin D, CBC, B12, and folate to get an idea of how they’re using those important cofactors. Of course with sleep disturbances I’m thinking about potential thyroid imbalances too, so I would look at those. Starting there, maybe doing some stress management techniques and optimizing any nutrient deficiencies. Beyond that, we can look at almost all neurotransmitters in urine. We don’t have a great assay for acetylcholine or some newer ones like orexin or adenosine. But the main ones that promote sleep and wakefulness can be tested in an easy spot urine test. From there if we wanted to get an idea of how we’re breaking it down, there’s another test that will look at the metabolites of neurotransmitters. I would also think about hormones—particularly cortisol levels and finding any dysregulations in the HPA axis. Thanks so much for your time and your expertise. Neuro­trans­ mitters can be a pretty confusing topic, so thank you explaining it in such a clinically relevant way. Absolutely. Thanks so much for having me.

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Editor’s note: This is an edited version of the interview. A full transcript is available on our website.

30 ©2019 Natural Medicine Journal. All rights reserved. NMJ, may 2019 Supplement—Vol. 11, No. 51 (Suppl)

sponsored interview

Restorative Sleep Strategies: A conversation with Christopher Shade, PhD Sponsored by Quicksilver Scientific

During this video interview, Christopher Shade, PhD, discusses targeted nutrients to support restorative sleep in patients who are struggling with sleep issues. Shade focuses on the neurotransmitter gamma-aminobutyric acid (GABA), key botanicals, cannabidiol (CBD), and tetrahydrocannabinol (THC). Approximate viewing time: 31 minutes

About the expert

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Natural Medicine Journal Sleep & Cognition Special Issue  

One-third of Americans typically don’t get the recommended 7 hours of sleep a night. The clinical ramifications of this epidemic are immense...

Natural Medicine Journal Sleep & Cognition Special Issue  

One-third of Americans typically don’t get the recommended 7 hours of sleep a night. The clinical ramifications of this epidemic are immense...