A plethora of past studies have highlighted a negative association between phone use and well-being. Recent studies claimed that there is a lack of strong evidence on the deleterious effects of smartphones on our health, and that previous systematic reviews overestimated the negative link between phone use and well-being. In a three-week long in-the-wild study with 352 participants, we captured 15,607 instances of smartphone use in tandem with rich contextual information  as well as self-reported well-being measures. We conducted an additional study to gather users’ perception of the impact of phone use on their well-being in different daily contexts. Our findings show that context and personal characteristics greatly impact the association between screen time and subjective well-being. This study highlights the complexity of the relationship between phone use and well-being and it deepens our understanding of this problem. Smartphones are the most ubiquitous device in human history and the phenomena related to its use are unsurprisingly discussed across a wide range of scientific domains. One particular theme that fuelled an ongoing debate is the relationship between smartphone use and our well-being. For several years, the predominant view was almost unipolar—studies highlighted the undesirable impact of phone use, including social isolation , depressTo deepen our understanding in this area, the importance of solving the methodological issues rooted in self-reported screen time measurements has been demonstrated in multiple records –10. Selfcompany), location, and time of the day, as well as personal characteristics .Inspired by prior work, in this paper we unravel the unexplored detail around the ways that mobile phone users’ personalities and the real-world activities and context associated with phone use contribute to their subjective perception of well-being. We captured screen time from smartphone sensors, along with rich contextual information  through Ecological Momentary Assessments delivered five times a day over a period of three weeks from 352 participants. We further extend and thoroughly analyse the associations between screen time and well-being by considering various additional factors, as well as the interplay between them. These include contextual information such as detailed descriptions of activities, surrounding people  research. Designing interfaces to enhance user’s emotional well-being in a digital service lead to its increased use, therefore the designers of digital services have been lately focusing more on making services enjoyable rather than solely optimising for a usability . A recenSubjective well-being (SWB) refers to how people evaluate and experience their lives . The litself-reported smartphone usage metrics, which was one of the core methodological issues that called into question the previous findings and even opened a new research theme on exploring misreports of the smartphone use.Smartphones are tightly embedded in our everyday life, and an ample interest in the effects of their use both by the scientific communities and the media does not come as a surprise. Previous work highlighted a myriad of negative effects of smartphone usage both in the context of a typical as well as of atypical  phone use. Undesirable impact was reported in the relationship with well-being , cognitiIn a study focusing on smartphone addiction , the autpassively measured screen time. Mehrotra et al. [This prompted a great deal of studies to delve deeper into the links between well-being and a et al.  examineda et al.   administered as Ecological Momentary Assessments (EMAs) , andA qualitative survey, in which we probed the perceived subjective well-being associated to smartphone usage in different daily contexts (Section 6).The goal of the quantitative study was to understand associations between objectively measured screen time and self-reported well-being measures, with respect to contextual information, personal characteristics, and individuals’ patterns of using the phone.To complement the quantitative analysis, we administered an extensive survey with an objective to understand which contexts users associate with more positive or more negative emotional responses. The survey was designed considering the quantitative study—we selected the activities, companies and locations that were most frequently reported or that were linked to the polarised emotional responses.Therefore, we delved into the associations between phone use and subjective well-being both from a subjective self-reflection standpoint as well as from the statistical analysis using longitudinal data captured in-situ. In addition, we also analysed the users’ declarative statements to acquire a descriptive layer of the same phenomenon in Section 6.3.The data for this study was obtained using a custom-built Android App, designed to collect passively phone usage events from smartphone sensors and well-being from self-reported questionnaires. Phone usage events included the timestamps when the phone was unlocked, and when the screen was turned on and off. Data was sampled every time one of these events occurred. Using Ecological Momentary Assessments (EMAs), the app prompted users to rate two dimensions of subjective well-being—happiness and worthwhileness . The momentary subjective well-being was rated on a 1 to 10 scale (1 being the lowest) at five instances each day during the study. Notifications were sent at a random time within five time windows: 8:00 AM–10:00 AM, 10:30 AM–12:30PM, 13:00 PM–3:00 PM, 3:30 PM–5:30 PM, 6:00 PM–8:00 PM. EMA notifications were not sent during night time in order not to interfere with sleep. If a user did not attend an EMA prompt, a reminder was sent after 15 minutes. A 30 min gap between each time slot prevented overlaps in subsequent EMA reports, and to provide users with enough time to answer the questions. Participants were asked to use the app for a period of 3 weeks. In compliance with the EU’s GDPR, participants were presented with a consent form describing details of the data collection and purpose of the study upon installing the app. Thereafter, participants completed an onboarding process in which we captured basic demographic questions  and the Big Five personality traits using the 50 item-International Personality Item Pool (IPIP) questionnaire . No persAs we outlined in Section 4.1, the user may report multiple activities, locations and company in each EMA. In all three context categories, the majority of EMAs reported only one instance. In particular 86.3% of the EMAs reported a single activity, 97.4% reported only one location and 92.2% a single company. For our analysis, we treated each of the activities reported in the EMA as different data instances and kept the same start and end of intervals. For simplicity, we assigned the first reported location and company to all the data instances corresponding to the EMA. There were a total of 53,244 EMAs collected, which were used to generate 62,221 data instances.total screen time duration and percentage screen time duration in each of the data instances corresponding to EMA reports. As first step, phone usage events were utilized to extract sessions of phone usage. We labelled the timestamp of each unlock event as the start of the session and the timestamp of the subsequent screen-off event as the end of this phone use session. Screen time duration of each session was directly computed as the number of minutes between the start and the end of the session. A total of 1,493,553 phone usage events were collected, which were transformed into 431,044 sessions.For the purpose of our study, we extracted the Similarly, we processed the data collected through EMAs to build the time interval that the reported contextual information belonged to. For instance, considering the exemplary EMA report from total screen time duration. The total screen time gives the absolute effect of the number of minutes spent using the phone while each specific context  is ongoing; with it, we aimed to discover the effect of spending more/less minutes using the phone while in the context. Secondly, we compute the proportion of time the user spent on the phone during an EMA interval by dividing the total screen time duration with the EMA reported duration. This resulted in the second target variable for our analysis: the percentage screen time duration. The percentage screen time duration gives the relative effect of using the phone while in each context, which is important in this study as well because the self reports vary in length; with it, we aimed to discover the effect of spending a larger/smaller part of the time in the context using the phone. For instance, considering the exemplary timeline from total screen time duration of 30 minutes and a percentage screen time duration of 50%.Next we proceed with extracting the screen time features per EMA report. Let us consider a person A commuting for an average of 120 minutes to get to work with a moderate total phone usage duration during this period of 60 minutes, equivalent to 50% of percentage duration of screen time, against a person B commuting for an average of 10 minutes to get to work with a moderate total phone usage duration during this period of 5 minutes, equivalent to 50% of percentage duration of screen time. There is a clear difference between the two examples in terms of total duration of screen time, while the difference disappears when considering the percentage duration of screen time. This highlights the importance to consider both metrics. We computed the total screen time duration per EMA report. For each data instance, the total screen time duration was obtained by finding all the sessions of phone usage that overlapped with the EMA’s interval and by aggregating the amount of time they overlapped with that interval. This resulted in one of our target variables: the From the self-reported activities, companions and locations, we obtained the categories that were frequently reported to use as different contexts in our analyses. As users were allowed to input their own categories through a free text entry, we disregarded categories that have less than 100 entries in to analyse the statistical significance between groups. Moreover, we included in the categories of personal characteristics available from the onboarding questionnaire, such as gender, age and personality. We expanded the contexts reported with the time-based categories in order to explore the association between phone use and well-being at certain time windows during the day, as well as during holidays. We categorised the time when the EMA was completed into: morning (from 6AM to 12PM), afternoon (from 12PM to 6PM), evening (from 6PM to 12AM), and the day as a holiday if it was a weekend or public holiday as well as if the user reported as being on holidays. Since we did not send notifications during sleeping hours, we only had 7 EMA reports filled at night (despite of not sending the reminders), hence this time interval was excluded from our analysis. With respect to personality, we utilized the answers from the Big Five questionnaire  and inclIn total, the data from 921 users was collected for this study. The participants were recruited from five different countries  by an external recruitment agency from February to August 2018. Participants were asked to use the application for a period of 3 weeks, and upon a successful completion of the study they were rewarded with a monetary compensation of EUR 40.As the first step in the analysis, we performed a correlation analysis using Spearman’s rank correlation coefficient between the well-being scores provided by the users in the EMA reports and the corresponding (passively captured) screen time measurements depending on the main categories defined in In order to control for the false discovery rate, we used the two-stage step-up method of Benjamini, Krieger and Yekutieli . This teThird, in order to leverage the fact that the activity, location and company contexts are features that capture the state of a user, we train linear mixed effects regression models for analysing the relationship between different aspects of phone usage and momentary subjective well-being. Mixed linear regression models with fixed effects were used to analyse the relationship between different aspects of phone usage and momentary or experienced happiness reports as dependent variable in the following configurations: (1) screen time features only, (2) screen time features with activities and their interaction, (3) screen time features with activities and company features and their interaction, and finally (4) screen time features with activity, company and location and their interaction. For all models, we utilised the user identifier as group to leverage that we have multiple EMA reports for each user. When using all the categories from The data collected included 53,244 EMAs and 1,493,553 phone usage events from a total of 921 participants. We analysed the phone usage patterns and EMA responses per hour of the day and visualized it in Further, we analysed the duration of activities reported on EMA and the phone use while the activity was realised. As shown in Finally, we analysed the subjective well-being of our participants, measured through reported happiness and worthwhileness scores, in the different contexts and their evolution during the week. Both happiness and worthwhileness measures have a similar distribution as shown in Overall, we observed a significant low negative correlation between phone use and worthwhileness, yet only before correction for multiple hypotheses. Adding context as a dimension revealed several siginificant positive associations between phone use and well-being, after correction for multiple hypotheses: (a) when performing certain activities such as studying, listening to music, exercising, commuting, taking a nap, (b) when being in the presence of family, or partner, (c) when being outdoors, or at their friends house, (d) for introverts, or individuals with high agreeableness. Moreover, we observe negative associations between phone use and well-being: (a) when browsing internet, waiting, (b) when being on holidays, (d) for 35–44y olds, (e) across both female and male genders, and (f) being an extrovert, or neurotic, or individuals with low agreeableness, or low conscientiousness.We observe that context plays a significant role when evaluating the associations between screen time and well-being. Overall, we observe more positive associations rather than negative ones from correlations. Beyond activity, location, company, and time contexts, personality and age appear as well significant when considering the association between phone use and well-being.p < 0.01) in the first model only, and its effect disappeared when contexts and interactions were added. These results further suggest the importance of contexts in the association between screen time and subjective well-being. Yet, due to the design of this particular study, we refrain from making conclusions related to the causal link between screen time and the subjective well-being.The results are presented in p < 0.01), but when location was incorporated it disappeared—possibly because the association was related to being at work where people share space with colleagues most of the time.The fixed effects models take into account the effect of each context and its interaction with the screen time, showing numerous significant correlations with the experienced happiness. The positive associations of fixed effects that were significant in all the models in which they were included are: the activities eating and taking a nap and being in the company of friends or kids. In contrast, the negative associations that were significant in all models are: waiting, being alone and being at work. There were some significant associations that disappeared as new context categories were added. For instance, watching TV, having a conversation or listening to music were positively associated at a significant level only when company and location were not considered. These activities often involve the company of other people, which might be the reason why these effects disappear when company categories are included. Also, the company of colleagues had a significantly negative association  and two are positive , illustrated in N = 171) to better understand users’ perception towards the impact of smartphone usage on their well-being.We conducted an online survey  for our analysis. Almost half of the participants were aged between 26–34 (N = 69), while others belonged to various age ranges, including 35–44 (N = 33), 18–25 (N = 20), 45–54 (N = 14), 55–64 (N = 5) and 65+ (N = 2). Additionally, they lived in different continents around the world including North America/Central America (N = 55), Asia (N = 53), Europe (N = 33), Africa (N = 1) and South America (N = 1).μ = 4.8, σ = 1.35); however, they also slightly agree that would like to decrease their phone usage . This re-iterates that it is important to explore those situations in which phone usage is detrimental to well-being.First, participants were asked to rate from 1–7  if they believed that using a smartphone had a negative or a positive impact on their well-being. Additionally, they were also asked to select from 1–7 (1 being strongly disagree) if they wanted to reduce their phone usage. On average, we observed that people believe that using smartphones has a slight positive impact on their well-being  when using their phone during those contexts. A box-plot of these ratings, grouped per context is presented in Most people find their phone to be a useful resource, as long as it does not interfere with their ongoing activity Most people think that their phones help them feel connected and better, when they are alone Most people think that they spend the majority of their time on their phones using social media Most people use their phones to take a break from work (66.43%) rather than for working (18.18%), while the remaining use their phones for both.(Q1)‘Are there certain experiences in your everyday life when using your smartphone improves your mood and makes you happy?’ and (Q2)‘Are there certain experiences in your everyday life when using your smartphone worsens your mood and makes you unhappy?’ Most users answered with short texts that were less than 20 words in length. For these qualitative responses, we performed a simple clustering exercise to explore if their answers could be grouped into overarching themes or observations. The following observations emerged from their answers:In addition to asking users to rate their well-being during different contexts, we had two free-text questions to understand if there are certain experiences in participants’ everyday life that improve or worsen their well-being. These questions were: Q1 included: “When I talk or text with a friend.”, “…talking to friends through social media like Facebook and WhatsApp…”, “Using my smartphone makes me happy when I communicate with my friends or family.”, and “Talking to my friends when I’m feeling lonely helps a lot. Especially in these tough times.”. Interestingly, many users specifically mention video calling—“Video chatting with my family members decreases my work pressure”, “Making a video call with my wife while away from home improves my mood.” and “Video calling friends/family while doing housework.”.Smartphones improve well-being when they are used for their original intended purpose—talking and texting with friends and family. Answers to Q1 related to music included: “Listening to music and/or podcasts on my phone when I do exercise, sunbathe, etc. makes me feel good.”, “Listening to music when I’m on the street or at home doing stuff around the house and want to block any surrounding sounds.”, “Being able to listen to music while on public transportation to block out noise improves my mood.” and “When I’m prepping dinner, or getting ready to do a really stressful workload I’ll turn on apple music playlist on my iPhone/smartphone”Listening to music with smartphones improves well-being: Numerous participants reported that listening to music or podcasts improves their well-being. Some answers to Q1 included: “Listening to meditation, using it for exercise videos, using it to learn (i.e. a language), speaking to family and friends”, “I have several spiritual apps that send me notifications with positive messages throughout the day. They bring me good feelings and inspirations.”, “…Tracking my walking and cycling activities via GPS is also a great motivator (and the mapping is great for route finding)”. Some users also reported that listening to music on their smartphones encourages them to exercise. Answers included: “Listening to a favorite play list when going for a morning exercise has always made my mood awesome.” and “…I also listen to a lot of music, which encourages me to exercise and be active.”.Using smartphones to help with meditation, learning and exercise improves well-being: When smartphones are used as enablers to do these activities, users reported that it improves their well-being. Answers to Q1 included: “I usually use the mobile phone to see what’s coming up on social media. Although I am lonely when used, a feeling of being with others is prevalent.”, “Scrolling on social media improves my mood when I’m bored”, “When I have some alone time and I go on my phone to browse news and social media it improves my mood.” and “…usage of social media on my smartphone most especially twitter has always done great wonder to my mood.”. However, answers to Q2 included: “…Using Instagram also worsens my mood, I can’t help and use it but it makes you compare your life with others’ and that may not always be so positive.”, “When I scroll through Facebook for 30 minutes, and realize I’ve just wasted 30 minutes” and “When I see something on social media that I don’t like too much and it affects me.”.Social media usage both improves and worsens well-being. Answers to Q1 answers included: I play video games in my smartphone often and it helps me to be in a happy mood. and “Playing video games on my smartphone when I am less busy improves my mood..”. Q2 answers included: “Sometimes by playing the games make me mood upset.”, “Playing longtime games makes me stressful” and “playing games”.Users reported that playing video games both improved and worsened their well-being. Q2 included: “Using phone in the evenings when my husband has finished work. We both use our phones so don’t talk. Also—WhatsApp messages can be so distracting. There is so much pressure to respond to all the messages you receive from various platforms”, “…Using it while out with friends, as then we won’t have really meaningful conversations.”, “When my wife used her mobile phone and she doesn’t respond to me. That time I get irritated.” and “when I have family time, and a really urgent text comes through on my iPhone, family members get upset with me because my time is not focused on them, and then I become upset with myself and my phone usage.”.Many users reported that using phones when you’re physically with friends and family worsens their well-being. Answers to Q2 answers included: “Non-stop messages and notifications from work chats and programs, work almost in each program we use  -> no personal space and no silence. Even on holidays you are online and reachable. No respect to personal time (even at night is fine to write)”, “Using my phone to check work emails worsens my mood because my partner gets upset, but I can’t avoid it.” and “When I use it for work and it sometimes makes me feel as if I’m always on…”.Users reported worse well-being when smartphones enable work life to invade personal and social life. Q2 answers: “Reading news articles on my phone about sad things going on in the world puts me in a bad mood”, “Seeing bad news”, “when there are same stories like Facebook news and other things nothing to cheer you up and you miss something real, that time it worsen the experience.”, “some times WhatsApp messages from groups about some political nature make me so uncomfortable, because i know the reality of that messages and they are created only from the frustration or agony against the opposite groups”.Users also don’t like to read bad news on their mobile devices, indicated by these Both the correlation and regression analyses in this study suggest a weak association between screen time and subjective well-being. This is inline with recent reports, such as , 42 whicConsistent with the previous literature, we found that the overall phone use association with subjective well-being is a negative one, regardless of context see . Howeverp < 0.001) with experienced happiness, the association of its interaction with screen time and happiness is significantly negative (p < 0.05). This indicates that eating is positively associated with experienced happiness, but the use of the phone while eating has a negative component. Moreover, we’ve found that using the screen time in the presence of company produces a weak positive association with experienced happiness. We hypothesised that this may happen in the presence of people with whom the user is comfortable with, such as partner and family . We encourage further research to dive and dissect these results, as it would be interesting to discover for instance in which cultures this happens, as well as in the presence of which company (since partner may be labelled as family as well).The regression results show that in the configurations where contextual features were added, the screen time features lost their significance. We revealed five interactions that remained significant when adding both context and screen time features. The first is that while eating has a significantly positive correlation (p < 0.001) that the using the phone during waiting is negatively associated with experienced happiness . One possible explanation for this is that not all idle time should be filled with screen time, and one should preserve this time for reflection. Another possible interpretation of this result is that when we have a lower experienced happiness while waiting, we use the phone more.While the previous results are not unexpected, interestingly, we hypothesised that while waiting, the user may find screen time as a positive activity . Surprisingly, we’ve found a strong evidence , yet we hypothesised that using the phone in outdoor activities would have the opposite effect. We encourage further research in this line to discover which outdoor activities were positively associated with experienced happiness.Our main finding is that indeed people report that context plays a big role into whether they perceive the impact of the phone use on well-being as positive or negative. Moreover, while we did not explore causal links in the quantitative study analysis, the qualitative study allowed us to explore suggestions of causal links. When diving deeper into people’s testimonials, it becomes evident that the majority of statements include at least one context that influences the association between phone use and well-being. For instance, users reported that when being on holidays or with family, receiving a text on their smartphone related to work causes a decrease in their well-being, shedding a light on the importance of considering the context when evaluating the impact of phone usage on well-being. Moreover, we observe that certain smartphone uses are perceived to be both positive and negative, such as using the phone for social media alone, versus scrolling for a long time, which are observable passively only when combined with available contextual information, in this case activity and company, and duration.We further compared the perceived effects of smartphone use on well-being from the qualitative survey responses with the findings from the quantitative study. Some differences and similarities arise. For instance, we observed that people perceive that their well-being is negatively affected when they are with company , while it is positively impacted when they listen to music and exercise. While the quantitative study indicates that well-being does improve when people listen to music or exercise, it also shows that there is a positive association between well-being and phone use when people report being in the company of family or their partner. Moreover, qualitative data does give us a layer of depth that is difficult to obtain from quantitative data. As an example, people provided very detailed responses under which circumstances certain smartphone uses were positive or negative. Using the free-text entries from our qualitative data, we noted that playing video games or using social media both improves and worsens mood, and people were very descriptive of the contexts when this happens. Bringing together both subjective views and objective measurements allowed us to further highlight the importance of considering context when evaluating smartphone usage impact on well-being.p < 0.001) between happiness and worthwhileness. The high correlation between the two metrics suggests that the two dimensions of well-being do not differ largely from each other for the sample population under observation. Indeed, we did not find a single difference in direction of association between screen time and one dimension of well-being against the other, i.e. there are no associations that are positive with happiness and negative with worthwhileness or the opposite. In general, the insights observed for happiness and worthwhileness are in line and coincide when considering the direction of association with screen time. Further research could dive deeper to explore whether there are any differences between the well-being dimensions when considering individual differences in well-being.We observed a Spearman correlation coefficient of 0.76 (p < 0.001) between percentage duration and total duration of screen time. In general, the insights observed from the total duration of screen time and percentage duration of screen time are in line and coincide when considering the direction of association. The strength of the association and the significance may vary across the two depending on the context . This investigation’s results show how context plays a big role into whether the associations with reported well-being are positive or negative.There is much potential for further innovation of designing for well-being as well as in the space of digital phenotyping and individual tracking apps that give insights into everyday screen time and device use. Church et al.  say thatMoreover, designing mobile phones to raise awareness to users of how the context of phone use plays a role into their individual well-being could potentially lead to an improvement in their well-being. We envisage a future application, where depending on the valence of the association, the user would be prompted to reflect on whether the phone use in that (passively detected or reported) context is necessary at that time and requires their full attention. Such design maintains users’ control on their phone use, but at the same time prompts the user on reflecting whether the potential negative impact on their well-being can be avoided. Such prompts could be particularly targeting those situational contexts that were shown to have a negative association with well-being in this study.Finally, further innovation for designing virtual interactions through mobile phones during various contextual situations could be explored, such as leveraging positive or negative rewards depending on the context. One such example is given in  where thOne limitation of our study is that we rely on self-reported well-being measures. Recent studies exploit latest developments in automated emotions detection, such as the study by Sarsenbayeva et al.  which usAnother limitation of this study is the fact that the screen time is measured only during the duration reported in the EMAs collected in order to obtain a mapping between context and smartphone use. Therefore, the findings can be affected by users’ memory, as the duration of an activity may be reported only approximately. This mainly affects the raw total duration screen time measurement, where we measure the amount of time the user spent on the phone during the context reported. We partly addressed this limitation by computing the percentage screen time measurement, as it is relative to the duration reported in the EMA. A more advanced potential solution to this problem is to explore acquiring contextual information in a passive manner as well.An additional limitation is that our study was not designed to explore causal effects on the EMA’s. To study the causal links, the study would have to have captured experienced happiness before and while performing the activities reported in the EMA’s to see how experienced happiness changes according to screen time usage within each context. Such study would be very difficult to put in practice in the wild as it requires knowing when the participant is going to start an activity and prompting the participant for self-reports while the activity is ongoing. For that reason, the analyses performed in this paper present associations between experienced happiness and screen time together with context, and we refrain from making firm claims on the causal effects of screen time on experienced happiness.Finally, we explored users’ perception of screen time impact in various contexts using a different sample population, mainly due to the initial study being ran for a wider list of hypotheses and completed more than a year ago. We were still interested in how users perceive smartphone use in different contexts and therefore ran a separate qualitative survey to enrich this study from this dimension. Another limitation of this survey is that the recruitment was done through social media and similar means, and thus the results may suffer from this selection bias.In our study participants belonged to a plethora of countries, both in the quantitative and qualitative studies, as an extra consideration was given to ensure that a diverse cross-country sample is collected. Yet our study was not designed to evaluate the cross-cultural aspect of the phone use relationship with well-being. We encourage future studies with a balanced sample across more cultures covering different continents to explore the role of culture in the relationship between screen time and well-being.Moreover, even though we attempted to remove the subjectivity by collecting passively the screen time, we still relied on active data for reporting activities duration and self-reported well-being measures. We encourage a future study to look at leveraging latest methods in emotional states detection and context  and worsens (when wasting time) well-being highlight how useful it is to consider a persons well-being in the first place, when diving into the valence of the associations between well-being and screen time.Finally, we encourage work in this area to dive deeper into deviant individuals and deviant screen time use associations with well-being. In particular, it would be interesting to discover whether happy or unhappy individuals  rate differently their SWB in different phone use contexts. Moreover, we encourage future work to explore the “threshold” for problematic screen time use, and the associations between SWB and screen time for deviant individuals (for instance as defined based on their screen time use). Lastly, we encourage future work to explore the associations between SWB and deviant screen time uses  in different contexts.Smartphones have become a central part of our daily lives, regardless of the controversy around its effects on our well-being. Prior studies have argued in plentiful numbers that using smartphones is associated with poorer well-being , 24 and S1 Fig(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(PDF)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.


The visual is an underutilized modality through which to investigate experiences of memory loss in older people. We describe a visual ethnography with older adults experiencing subjective or objective memory loss, receiving a cognitive well-being group intervention designed to prevent cognitive decline and dementia (APPLE-Tree program). We aimed to explore lived experiences of people with memory concerns, how participants engaged with this photography and codesign project, and how collaboration with an artist/photographer enhanced this process. Nineteen participants shared photographs reflecting what they valued in their daily lives, their experiences of memory concerns, and the intervention. Fourteen participated in qualitative photo-elicitation interviews, and 13 collaborated with a professional artist/photographer to cocreate an exhibition, in individual meetings and workshops, during which a researcher took ethnographic field notes. Eight participants were reinterviewed after the exhibition launch.We contextualize images produced by participants in relation to discourses around the visual and aging and highlight their relationship with themes developed through thematic analysis that interconnects photographic, observational, and interview data. We present themes around the use of photographs to: (1) celebrate connections to nature as a lifeline; (2) anchor lives within the context of relationships with family; and (3) reflect on self and identity, enduring through aging, memory concerns, pandemic, and aging stereotypes. We explore visual research as a powerful tool for eliciting meaningful accounts from older adults experiencing cognitive change and to connect the arts and social sciences within aging studies. Cultural gerontology is characterized by explorations of social identity, subjective experiences, and cultural depictions of aging, agism, and embodiment , 2015b, Cultural gerontology highlighted not only the arrival of the humanities into aging studies but also increased interconnections between the social sciences and arts; artists and social scientists collaboratively bringing novel perspectives and methodologies , 2015b. Cristofovici asks how photographers depict the “inner realities” of aging . In thisThe research method of participatory photography responds to criticisms of “inequity of power, the politics of representation and the objectification of the other” , p. 4 anCreated Out of Mind residency codesigned multiple performances and exhibitions with participants with dementia  conducted photo-elicitation interviews between March and September 2022. S. Parnell Johnson (artist/photographer) and E. Whitfield facilitated exhibition codesign, in individual and group sessions, between April and August 2022. After the exhibition, E. Whitfield conducted further interviews.Following established methods of using participant-generated photographs in photo-elicitation interviews , E. WhitE. Whitfield conducted semistructured interviews with participants, mostly in their homes, two by video-call. She invited participants to share and discuss photographs taken, and a topic guide shaped discussions of their experiences of memory concerns, broader lives, and identities. This included asking participants about their involvement in APPLE-Tree and if they had spoken to friends and family about having concerns about their memory. Interviews were audio-recorded and transcribed.The use of interview prompts following discussion of photos follows methods used by Participants in this part of the project met with S. Parnell Johnson and E. Whitfield individually through video-call sessions once or twice before they attended small-group workshops, depending on what felt useful and possible for them. Timings varied but were usually for around 30–60 min. Participants provided photographs before sessions, including those explored in photo-elicitation interviews, and additional photographs that spoke to “things that are important to me.”S. Parnell Johnson led these video-call sessions discussing images, experiences, and stories participants wished to convey to audiences, and exhibition work (photographic arrangements) they wanted to develop; E. Whitfield took observational fieldnotes. S. Parnell Johnson used appropriate software to display and explore images and advised on lighting and other technical considerations. This online visual method was developed by her in her work with students during the COVID lockdown. The kinetic visual element was critical, enabling her to move images around in dialogue with participants, making new groupings/arrangements/sequences that prompted different connections. Most participants used their phones or own cameras and two borrowed cameras from the project.Next, we held four half-day workshops  for four or five participants each. Developed photographs and printed arrangements from initial video-calls were given to participants at the beginning of the face-to-face workshops. Photographs were sent to virtual workshop participants after the session. Participants responded to each other’s photos, wrote sticky notes on their own to describe meanings, arranged photographs, and wrote accompanying text. E. Whitfield and S. Parnell Johnson continued to support participants to develop their work after the workshops through email and video-call, and in some instances for E. Whitfield to further explore their thoughts, feelings, and reflections on the images. Participants had a designated space on the exhibition display boards and were invited to display photos and text. S. Parnell Johnson collaborated with participants on how to present work creatively, suggested other types of display for some sets of photos, and laid out the designs using appropriate software, to be printed onto large boards.Next, we organized two coproduction meetings to plan the exhibition and accompanying film and catalog, with four and five participants each, and study team members (academics and a Public and Patient Involvement representative). S. Parnell Johnson presented images and initial overarching exhibition themes that she and E. Whitfield had developed, and the group discussed the meanings behind their images. The second meeting included a visit to the exhibition site.London (Camden and Kings Cross) Research Ethics Committee (Reference: 20/LO/0034) approved the APPLE-Tree study in March 2020, and all participants resigned consent forms after an amendment dated December 16, 2021, to include this study. Participants signed consent forms covering potential uses of donated photographs; with further image-specific consent forms for photographs including identifiable images, by all people potentially identifiable. All participants chose to be named in the exhibition beside exhibition pieces, and on a catalog insert. To protect identities, we have altered some minor details of case studies while maintaining the integrity of narratives .Textual data  were analyzed alongside photographs and other visual exhibition works. We drew on Gleeson’s method of polytextual thematic analysis with photographs  and BrauWe asked interview participants to take photos that relate to memory concerns and the APPLE-Tree intervention, extending this during the collaborative process to include “things that are important to me.” Although some images shared with us directly engaged with the first two themes, participants primarily shared images, and collaborated to produce artwork, that reflected what was important to them, their everyday lives, and identities. Analysis was guided by looking at how participants used images to express and reflect on their lives, within and across sets of photos, in their accounts and in developing pieces for the exhibition. E. Whitfield and S. Parnell Johnson discussed ideas for themes that appeared to be emerging during the collaborative process, and with other members of the study team. We present overarching conceptual themes, and developed case studies that illustrate how these themes were woven through the participants’ engagement.We identified three themes. “Nature as a lifeline” explores how tangible connections to the material anchor and reassure. As illustrated in the case studies, familiar places brought comfort and trees were recurrent emblems of continuity and stability. In a second theme, “Family,” participants portrayed how mutual love and support, past and present, are important to their sense of self and place. Photographs reflected family relationships, including people lost.“Self and Identity” is defined by reflections on self and identity, enduring through aging, memory concerns, pandemic, and aging stereotypes. This was illustrated in self-reflexive artworks, using memories, experiences, life, and family history to ground and make sense of identity over time.Authors discussed and agreed on a selection of four case studies to showcase themes, how our methods and breadth of visual and textual material contributed to their development, interconnections between them, and to illustrate diversity of experiences.We will draw on the humanities to enhance our understanding of experiences of aging and the visual, making connections to Sara Ahmed’s writing on the power of objects, physical and otherwise, to orient the self; an aspect of participants’ lives that photography makes visible .This case illustrates the power of photographs to pull us into the materiality of a participant’s world. Jill, who is in her late 70s, lives alone. She shared more than 30 photographs in a photo-elicitation interview, which spoke to the intertwining of biography and identity , and broHer exhibition piece was autobiographical; photographs from her childhood to the present, including images of close family members, mixing sad with happier times. It charted how relationships (Theme 2) and life experiences shaped her personal identity, and how this and her enjoyment of life endured despite memory concerns (Theme 3).People, places, objects, and photos of art are combined in Jill’s artwork, including photos of herself across the life course (including photos of old photos). This expresses a sense of her “sequential self states,” and an intertwined continuity and discontinuity that is important for photography of aging to engage with . The entJill’s artwork celebrated nature and valued the solidity of the material world (Theme 1), connecting it with her pagan beliefs; represented by a photograph of flowers in her garden that are her “saviours.” Her photos included places in her hometown, which evoked important memories and emotion. A postbox reminded her of a relative joking they would post her into it as a child ; a localThese images and reflections speak to an “embodied” sense of place and how memories attach to everyday activities , p. 9.Jill’s images reflect resilience (Theme 3). She reflected on physical aging in an image of her hand. Just as Rosy She likened herself to the poppies in one of her photos, which stood tall when the plants around them had wilted. She stated in a text for the exhibition that the possibility of future memory loss is her next “challenge”:My life has consisted of fantastic highs but many, many lows from which I have fought back from with a vengeance in the past, this may be more of a challenge, but I am sure as hell going to try as there is so much more I want to do.A photograph of her shadow taken during the pandemic represents fears of becoming “a shadow of my former self.” She recalled how her voice had changed with less use, and isolation had affected her memory. She is “throwing” herself into activities now and described her exhibition work as an exhortation for people to fight against what might be “round the corner,” reflecting the “event horizon” of the fourth age .Her exhibition piece reflected a playful, “theatrical” personality. Photos were printed onto a magnetized board, with her sticky notes as vinyl pieces so that the audience could move them and some images resisted or played with age-related stereotypes, such as a photograph of her dancing. She embraced this idea, which reflected a resilient identity based on deep connections to the material world, within shifting scenes in life. Opposing stereotypes can be inadvertently reproduced in research seeking alternative images of aging . Jill’s Her artwork, entitled “Uncertainty,” was brave and moving and attracted a lot of interest; Jill “really enjoyed” explaining it to people. She reflected after the exhibition on how her “higgledy-piggledy” arrangement reflected the course of her life, looking back. She felt that the project was cathartic and it seemed to enable what Beatrice’s work celebrated the natural world (Theme 1), and the development of new rituals that enhance older age . She useThe first images that Beatrice shared included two of herself: one in sunglasses and another with a badly bruised face from falling a few weeks after her 90th birthday. In her plans to use this powerful image of vulnerability for a painted self-portrait, she illustrated creativity in adversity, confronting her experience of vulnerability with resilience through art. She later sent us this image within a cubist-style self-portrait . While JBeatrice lives alone and during the pandemic lockdown, she was afraid to go out. Walking in the local park early one day when it was quiet, she photographed a ginkgo biloba tree. She has photographed it many times since, from different angles and in different seasons , and expits roots there and, you know, as I said, if it’s bare or green, you know, when it loses its leaves, it’s still there and I feel happy about it, it varies. It’s OK, things are going to be OK, fine. Life is good, it keeps me going I think that treeBeatrice sent us many photographs of the tree over the course of the project and we emailed feedback and encouragement. Visiting it was a ritual or “refrain” through which a person’s sense of “going on being” is “held” . She desBeatrice displayed a photograph of the apple tree in her garden in the exhibition, taken with a new skill of using a short depth of field that blurs the background, to express her thoughts about the mind and memory . She desEarly one Sunday walk, I noticed a Ginkgo Biloba tree in my local park. Taking a photo of it to send to my daughter proved I had been out for the necessary walk. This unique “living fossil” has become an important lifeline for me. Every time I photograph “my ginkgo” I see something different about it! The camera’s “blurring eye” made my brain think again—how to? With so many photos taken, I found it difficult to eliminate as each one was a moment taken in my life. Every photo was meaningful. My synapses fired—I made some collages. How to arrange some of the leaves and photograph them? Haiku writing kicked in, another way of expressing joy!A family history of Alzheimer’s, and memory concerns, motivated Beatrice to take part in APPLE-Tree. It was clear how much she valued the photography project. She described actively exploring connections between current and past images through her visual imaginary, writing “My brain is ignited and I remember the energetic days of Uni again”; and “I no longer feel afraid.” This speaks directly to Ahmed’s work describing how people turn away from fearful objects and towards positive possibilities. Bringing Beatrice’s words together with Ahmed’s theory highlights the disorientating effect of fear, with the project as a reorientating object of hope that created a new sense of possibility , via theThe image of her hand touching the ginkgo tree  shows coBeatrice was proud to exhibit her work and ordered multiple copies of her print and book for family/friends. Her work shows the transformative potential for this kind of collaborative project, as she embraced the ongoing creation of her own subjectivity , which tNatasha is in her early 80s and lives with her husband. Originally from Hungary, she enjoys art galleries and belongs to a photography club. Natasha has word-finding difficulties and mobility problems following a stroke. Natasha shared photographs from her large existing collection. She approached these thematically and used symbolism, often giving them titles and abstract meanings. In early sessions, she and S. Parnell Johnson discussed images that spoke to bodily and health constraints, aging, memories, feelings of being blocked and curtailed, and dichotomies of choice. A tree in winter represented death. She also expressed a love of color, structure, and light as positive elements in images.Her final piece, “Reflections and Imaginations” , includeHer symbolic use of scenes and objects to represent aging and physical constraints renders her physical form invisible and externalizes her affective experiences. These images speak to Natasha’s negative experiences of aging whereas the artistry brings a form of comfort. It also shows how photographers can depict internal responses to aging, finding novel ways to express “the inner screen of aging” , p. 18.Her accompanying text (“thoughts about getting older”) described the constraints of aging and thought of death. She described how colors and symbols have become a great consolation to her in later years:For several years I have been interested in photography, films and arts in general. In my years now they are like a raft that keeps me afloat and happy to deal with shapes, forms, colours. What they mean, and their symbolism are with me and make my life bearable.Art mixes with science or even theology and all that begins to mean more to me now, than in my youth. Ideas and messages are appearing in images, there are so many meanings to everything if given a chance.The arts seem to act as her anchor in a world that feels more restricted.Natasha used a powerful image in her postexhibition interview to communicate her experience of pain: a postcard of an Antony Gormley sculpture of a suspended figure stabbed with nails, which showed how she feels when walking, “because everything aches when I am walking.” This is reminiscent of Deborah Padfield’s work on the therapeutic value of expressing inarticulate pain via photographic images .Her photographs and reflections speak to the importance of understanding how older people experience suffering and pain and what modulates or mediates this experience; representing or communicating the experience of suffering through language is an area that presents a particular challenge within gerontology .John is in his late 60s and lives with his wife Helen and adult daughter. John spoke of the reciprocity and depth of love in his relationship with Helen, who accompanied him to the workshop. John took many images of Helen during the project but deleted them as none represented his internal image, a palimpsest softened and shaped by years of memories . John deUnfortunately, John left the project early due to illness but said that he had “really enjoyed” the memories that it brought up. With his support, S. Parnell Johnson created a piece based around photos of his children and grandchildren and the reversed photo of his wife, using his images and plans. He wrote text to display alongside, beginning:My family has always been the most important thing to me.My children and grandchildren are so very important to me; I remember where and when I first met my wife, I remember all my children being born and the first loving words I said to them all.It described familial love, including love from parents and between siblings when he was a child, as a point of continuity throughout life, and spoke to creative ways of evoking multiple “sequential self states” over time . PhotogrGenerations, in particular grandparenthood, was an important theme in another photography exhibition looking at “New Images of Age(ing)” , often tExhibition artwork spoke to questions of nature and place, the importance of relationships, biography, identity, generation, and the aging process itself. Participants captured their own lived experiences and reflections, where aging was not necessarily foregrounded but was implicit. It was important to honor the artworks by staging the exhibition imaginatively and professionally. Artworks were accompanied by text that deepened the audience’s understanding of their meaning and by participants’ reflections on the APPLE-Tree intervention. Attendees spoke of the insight the rich and diverse pieces gave them into participants’ lives.The exhibition, titled “Reimagination: The reframing of Memory,” was initially displayed for one day at the Wellcome Collection in London , attended by around 200 people . PhotogrThe therapeutic potential in relation to memory concerns, of working with a professional artist/photographer in this way, is reflected by Beatrice, who told us how the project helped her to move past her fear of memory loss. Another participant described how it helped her resolve to persevere with challenges, suggesting an increased confidence. She has used it to discuss her memory issues with friends, showing them images from the exhibition.We have presented themes developed through participant engagement with the project, in which photographs were seen to celebrate connections to nature as a lifeline; anchor lives within the context of relationships with family; and reflect on self and identity, enduring through aging, memory concerns, pandemic, and aging stereotypes.We described how creative collaborative photography can help in accessing interior worlds, thoughts and feelings, and be an important, positive experience for participants, with potential to create the space to “embrace creative, reflexive, complicated selves,” as described by Working with the artist/photographer individually and in small groups produced images and artworks that gave new insights into ways of representing and exploring aging, from the subjective perspective of older people. This contrasts with projects where representation is directed by a professional photographer and the rich diversity of participants’ experiences can be overlooked . In liaiThe photographs and other data discussed here speak to important areas within social gerontology as well as age studies, including ageism , the embCompleting this project and reflecting on the artwork and reflections produced from it, we wonder what more could be done with this method, and how it might be extended to allow more time and opportunities to explore the creative potential of using photographs in conversation with an artist/photographer and other participants; further reflections on aging identities may emerge from this process.There was inevitably an element of self-selection in those who took part. We separated recruitment for the interviews and the exhibition to try to broaden participation.Unfamiliarity with technology can be a potential obstacle in using these methods with older people ; use of The majority of participants were White British and most of those from minority ethnic groups were White Europeans from outside the UK. This reflected the make-up of the sample from which we recruited (the APPLE-Tree intervention). There were two further interviews with participants from other minority ethnic groups, but as they did not share photographs we did not include them in this analysis. It is likely that participants had greater cultural capital than those who declined to participate and this helped to shape their engagement. Most did not have an arts background, though Beatrice and Natasha did have some previous involvement in arts creation.This article has reflected on the use of participatory photography with participants with memory concerns engaged in a dementia-prevention study. It has traced the process through photo-elicitation interviews, collaborations in zoom sessions, workshops, coproduction meetings, and a cocreated exhibition. It has shown the creative possibilities that this can engender and capture, the potential to generate rich data that enhance the study of aging, and the positive effects that can be experienced by participants. Moreover, it demonstrates the rich cross-fertilization that engagements between the arts and humanities and gerontological research can have in extending our understanding of the lived experience of later life in its myriad forms.


Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the  positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis. A review is a survey of the existing literature on a given subject and the analysis of it by the author(s). Even if the interpretation of the author(s) about the facts is important, it should be identified as such. The present review presents a critical assessment of the existing literature on melatonin effects, including the conclusions drawn by their authors. Such a critical assessment is, by nature, subjective and has to be further discussed by the community in order to reach a consensus on where the field stands in terms of its hypotheses and facts. The new consensual hypothesis and perspective should then guide future research, which will go through the usual cycle of data acquisition that will then be submitted for peer review.Melatonin is a natural compound synthesized in the pineal gland during the nighttime, discovered by Lerner et al. .Melatonin is synthesized in the pineal gland under the control of the hypothalamic suprachiasmatic nucleus, such that it is high during the night and low during the day. In humans, circulating melatonin is lowest during the day, at <2 pg/mL 8 pM), and is at 30–70 pg/mL (130–300 pM) during the night . The bio pM, and 1 and MT2, which have high affinities for the hormone 1 nM and lower. The receptors are activated by circulating levels of melatonin at night and are believed to translate most of its physiological actions [The main targets of endogenous melatonin in mammals are its two G-protein coupled receptors, MT actions .The history of melatonin use can be divided into two periods:The first period is characterized by the establishment of a wide consensus about the nature of melatonin’s role, its synthesis and its regulation with outstanding discoveries on those subjects, and was followed by progress on the molecular mechanisms by which melatonin exerts its effect on biological rhythms  and sleeThe second period of melatonin research is still ongoing and addresses the possible role of melatonin as an antioxidant and scavenger molecule; however, this is characterized by the absence of a general consensus in the field . HundredIn order to be entered into a clinical trial, a compound should have shown activity on the defined pathological model(s), exhibit low or no toxicity and be superior to the existing drugs (if there are any). Dietary “supplements”, as melatonin is defined in the USA, do not have the same legal constraints as pharmaceuticals, and their marketing information must not infer their use to treat diseases.In general, such clinical trials are directed at a specific pathological condition and are based on a body of relevant preclinical studies. In the case of melatonin, it seems that almost all the pathological conditions one can think of have been reported in the literature to be ameliorated by melatonin! Thus, the conditions for which melatonin has been tested in clinical studies are extensive and are listed in www.ClinicalTrials.gov, accessed on 23 January 2023, see below), the declaration comprises a series of keywords/categories, according to which the compound tested would have an effect—presumably—on the disease discussed  all the studies on a compound are not necessarily declared on this site, and (ii), more surprisingly, the data obtained are not necessarily published or made public. They belong to the initiator of the study and remain its property, translating into an absence of published results in most cases.One should also point out that some of these studies are purely observational, aimed at measuring the levels of melatonin in patients with particular pathological conditions.www.poison.org/ accessed on 4 February 2023). Indeed, the review by Vines et al. [Melatonin is sold over the counter in several Western countries, such as Western Europa and the USA, in doses ranging from 1 to 10 mg. In clinical trials, doses of up to 100 mg have been reported see . Severals et al.  indicates et al. . Furthers et al. , which ws et al. . Of notes et al. . While ts et al.  , we found an impressive number (742) of clinical studies on melatonin on the conditions listed in Interrogating the This body of trials comprises all the declared trials in the past, present and future. As a basis for comparison, we did the same query for “resveratrol”, a natural product also reported having many beneficial actions in traditional medicine, and found 147 studies, or “vitamin C”, and found 453 trials (400 of which are completed). Melatonin has attracted a lot of attention, as the diversity of conditions  covers most, if not all, human diseases.From the trial list, we have removed 118 conditions where the status is “unknown”. Another 40 studies were reportedly withdrawn, without obvious reasons, but one might speculate that this was due to difficulties in recruiting patients or to the lack of results, particularly on delirium prophylaxis, Parkinson’s disease, coronary artery calcification, intensive care elderly population or “melatonin inhibition of NLRP3 inflammasome in COVID19 patients”, to name only but a few.Looking at the 56 trials currently recruiting, one can separate them into two main categories: observational and interventional. The first section, “observational”, comprises all the studies in which the patient’s melatonin levels are measured as a function of (i) their pathological conditions and (ii) their daily circadian rhythms. Those studies are basically clinical biochemistry research trials and are extremely useful for our understanding of the dependence of circadian rhythms on pathological conditions. Among the pathological conditions that have been studied are Cushing’s syndrome, autism, hypo-hidrotic ectodermal dysplasia, bipolar disorder, frail elderly, etc. The data arising from those studies may be expected to have a major impact on our understanding of how melatonin synthesis and release are influenced by pathological conditions. In our view, those studies are quite important, hopefully leading to scientific paper(s) explaining the results, as those in the Harpsoe et al. review , includiThe intervention group comprises all the studies in which melatonin is tested as a therapeutic agent. Because cancer is one of the most documented and searched domains in pathology, we have selected the trials in which cancer patients were treated with melatonin. Sixty-five studies tested its effectiveness in various cancer-related parameters, such as a loss of appetite, sleep quality, etc. Those studies also comprised trials in which the effects of melatonin as an anti-cancer adjuvant or drug, with direct effects on the disease itself, were reported. Half of the trials are reported as completed (32 studies), yet only the following four had published their results. We have briefly summarized their results and their conclusions:Trial NCT00513357 (USA): Conclusion: “In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo” .Trial NCT00668707 (Canada): Conclusion: “Melatonin may benefit cancer patients who are also receiving chemotherapy, radiotherapy, supportive therapy or palliative therapy by improving survival and ameliorating the side effects of chemotherapy” .Trial NCT00925899 (Denmark): Conclusion: “In the current study, oral melatonin at a dose of 20 mg was not found to improve fatigue or other symptoms in patients with advanced cancer” .Trial NCT04137627 (Indonesia): Conclusion: “In patients with squamous cell carcinoma of the oral cavity, the addition of 20-mg melatonin to neoadjuvant chemotherapy reduced the expression of miR-210 and CD44 and decreased the percentage of tumor residue; however, no statistically significant result was observed”.The survey of those trials currently recruiting is a good image of the other ongoing trials: from those using small to large dosages of melatonin, 50 to 100 patients, spanning a month to more than a year. We would argue that the spectrum of diseases and/or conditions cannot seriously be attributed to a single melatonin-related cause.It is very often under-regarded that melatonin has poor bioavailability. Indeed, the vast majority (>80%) of melatonin is hydroxylated by cytochrome P450 , conjugamax is low (~10 nM), even if it is two orders of magnitude higher than the nocturnal produced level. If one is given 100 mg, the circulating concentration of the compound is in the 0.5 µM range [The wide range of dosages for the patients undergoing these recruiting trials varies from 0.5 to 100 mg, with most of them in the low milligram range. Once again, one should recall that at low ‘physiological’ doses—those in the 1 to 3 mg range, the resulting CµM range , as reviµM range , althougµM range  clearly µM range . This prIn the preclinical studies upon which trials are usually based, melatonin was generally used at concentrations higher than 1 µM—and even 1 mM. Thus, those concentrations are not expected to be naturally reached in living animals or in humans, and certainly not for prolonged periods. Thus, the transposition to clinical trials of those data might be considered more an act of faith than an experimental reality.The main issue to be considered here is that nearly 4000 patients have entered these trials and have been treated with 0.5 mg to 100 mg melatonin daily. Furthermore, some of those studies are designed to run for very long periods . In one clinical trial on melatonin and autoimmune diseases , it is planned that 50 patients recruited because of their neurological conditions will receive a daily administration of 100 mg of melatonin, or a placebo, orally between 10 pm and 11 pm for 24 months. Finally, several studies are using newborn children (from a few hours to a few days old) with quite desperate health conditions—a feature that is commented on below.In a survey  of melatonin used for cardio-protection, the authors stated that the data was difficult to generalize due to the numerous possible biases, the low number of patients and their high heterogeneity . Note thIn conclusion, many clinical studies appear to have been based on scientifically poor experimental  studies or overenthusiastic interpretations of the preclinical experimental data, thus explaining the overall poor outcome of these studies. The use of small populations of patients—elderly people as well as infants and toddlers in desperate health conditions—may have ethical considerations.The first reports of the administration of melatonin to children were conducted by Jan and colleagues more than 28 years ago ,65,66 inSince melatonin in the USA is not considered a drug, there is no requirement to report adverse events. The latest such report, covering 2012–21, documented more than 250,000 pediatric ingestions, 45,000 symptomatic effects, 3211 serious outcomes and 2 deaths . FurtherIt is true that one cannot be sure that melatonin played a significant role in the deaths of infants. It is, however, an indication that melatonin is being recklessly administered to children in the absence of any formal safety information. Even the pharmaceutical companies that sell melatonin say not to take melatonin during pregnancy or when breastfeeding.The uncertainty about the use of (high dosages of) melatonin by mothers during pregnancy and lactation remains. Indeed, in their thorough review of the subject, Vine et al.  concludeOverall, our feeling is that, while the study could not directly attribute the deaths to the use of melatonin, they concluded that “Melatonin is not known to be acutely toxic; however, it causes a multitude of systemic effects by way of mechanisms of action that are not entirely understood, especially in developing infants. More guidance is critical for parents and pediatricians who use melatonin as a routine sleep aid for young children” .In an initial influential paper, melatonin, as well as other indole-based molecules, was shown to be a good scavenger in an a-cellular system. Then, to render the experiment transposable to a “living” system, the tissue homogenate was added to the medium, and it was found that the trapping operation still occurred. Thus, melatonin was called a scavenger. As a direct consequence, more than 1727 (23 February 2023) articles have been published using the words “melatonin” and “scavenger”. The initial publications can be pinpointed to Poeggeler et al.  and. TheThe statement that melatonin and many other purported antioxidants are scavengers is common in the introduction of hundreds of publications. We consider the term “scavengers” to be misleading because, while these compounds can react with oxidants, they are generally no more reactive than the thousands of other compounds in cells . Thus, tScavengers do not exist in complex media, living systems, etc. A true antioxidant defense is provided by enzymes that remove superoxide and hydrogen peroxide with rate constants that are hundreds of thousands to more than a million times greater than that of melatonin. For hydroxyl radical, no compound is an effective scavenger, and the antioxidant defense involves the prevention of its formation rather than its removal .Many of the compounds purported to have antioxidant activity can react with Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1), sparing Nrf2 from degradation and thereby activating transcription of the genes for antioxidant enzymes. Several compounds have been reported as such protectors for Keap1 degradation: TBE-31 ,77, CDDOThe toxicity of ROS and oxidative stress is controlled by several enzymes, the activity of which detoxifies ROS, such as the three superoxide dismutases  anywhere. In 1994, it was reported that melatonin binds to the receptor RZRα and activates it . AnotherThe idea that bacteria produce melatonin has been formulated in statements such as the following one: “Evolution’s best idea” is that melatonin is supposedly produced in bacteria. From there, because bacteria colonized cells several million years ago, eukaryotic cells became mitochondria; mitochondria are thus full of melatonin. Additionally, melatonin is there to protect mitochondria, cells and living organisms from oxidative stress .This statement can be challenged as follows:Melatonin synthesis in microorganisms has been reviewed by Que et al. . Indeed,proof of bacterial melatonin synthesis.It is interesting to look closely at those articles cited to provide E. coli using the necessary enzymatic machinery for this bacterium to produce melatonin, the only mention of two bacterial melatonin productions is in the following sentence: “Melatonin is predicted to have evolved from the precursor bacteria of mitochondria and chloroplasts, such as Rhodospirillum rubrum and Cyanobacteria, respectively, via an endosymbiotic event with their ancestral eukaryotic host” [In an article by Byeon and Back on the cloning of ic host” . This isRhodospirillum rubrum [Rhodospirillum rubrum and other purple non-sulfur bacteria, predicted to be at the origin of mitochondria according to the endosymbiotic theory of mitochondria [Manchester et al. reported a melatonin immunoreactivity in this m rubrum ; howeverchondria , it is sAgrobacterium tumefaciens, Bacillus amyloliquefaciens, Bacillus thuringiensis and barely in Pseudomonas sp.Jiao et al.  reportedLactobacillus had been patented for their production of melatonin. Furthermore, they wrote: “If these speculations are valid, the beneficial effects in consumption of these products may, at least partially, be explained by the presence of melatonin and its isomers” [Lactobacillus produce melatonin. For example, in a trial on abdominal pain in children, Lactobacillus and exogenous melatonin were used for the health of the patient [Lactobacillus was not enough to obtain the desired effect. In another study, melatonin was shown to increase the amount of Lactobacillus previously decreased by sleep deprivation as if the production of melatonin by Lactobacillus was not enough to counterbalance the decrease in circulating melatonin [Lactobacillus [Lactobacillus as a source of melatonin production remains, at the very least, unclear.A review by Tan et al., while not providing any experimental data on bacteria melatonin production , stated isomers” . This st patient , as if melatonin . Finallybacillus ; howeverErythrobacter longus, Tilden et al. [In n et al.  reportedn et al. ,104.N-acetyltransferase gene, xoSNAT3, in the bacteria Xanthomonas oryzae [Very recently, Chen et al. reported the discovery of the gene encoding for a serotonin s oryzae . The syns oryzae , includis oryzae ,108; howWe conclude that whether bacteria widely produce melatonin remains to be proven.Melatonin is claimed to be present/enriched in mitochondria ,109.However, robust and, in particular, quantitative data are not available. To our knowledge, massive amounts of melatonin have not been reported in mitochondria. Furthermore, if melatonin is a ROS scavenger, it would be expected to be transformed into hydroxy-melatonin or possibly into a kynurenamine, as shown by mass spectrometry analyses ,111. To It is assumed that the mitochondria occupy a tenth to a twentieth of the total cellular volume . TherefoThe question of intra-mitochondrial melatonin synthesis has been recently reexamined by Suofo et al. . The autRhodospirillum rubrum and related species to provide evidence for the assumption that mitochondria are producing melatonin because the bacteria engulfed millions of years ago already produced this molecule. Collectively, the experimental evidence for melatonin synthesis in mitochondria and, in particular, its quantitative aspects and generalization to all mitochondria-containing cells is still weak. This includes the presence of its main precursors, such as serotonin, as well as its main metabolites that could be expected, assuming the highly oxidative environment of the mitochondrial matrix.In summary, evidence on melatonin synthesis in bacteria remains weak and warrants independent replications. Other bacterial strains should be investigated to determine how generalizable they are. Studies should focus on Although not really related to the previous points but providing an example of how ideas may emerge, a third melatonin receptor was reported  and systThe suspected beneficial effect of melatonin in such a large spectrum of diseases is often justified by the involvement of melatonin in a large spectrum of biological processes, as reported in preclinical  studies. To illustrate this diversity in terms of the melatonin effects, the following 30 randomly selected examples were extracted from a PubMed interrogation with the words “melatonin” and “inhibit”, which retrieved 400 items in total between 2018 and the end of 2022.1 receptor [2+ channels (about 40% at 10 µM) [In also the following publications, the effect of melatonin is associated with a molecular target  in a way that might suggest to the reader that melatonin is indeed binding to those targets. This is not the case; in most of the publications, the authors suggest that melatonin does “something” that leads to a pathway acting through one of these proteins without convincingly demonstrating a molecular interaction between melatonin and a protein. Melatonin protects from experimental models of newborn hypoxic-ischemic brain injury via the MTreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatonreceptor . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Howevert 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Melatont 10 µM) . Of notet 10 µM) , breast t 10 µM)  or, moret 10 µM) ; however(i)50 value. Low EC50 values generally hint at specific molecular targets, whereas a high EC50 value hints at targets with lower specificity. The absence of EC50 values (no saturation) may hint at a general property, such as membrane fluidity or intactness. Unfortunately, many of the articles describing the effects of melatonin use only a single (often high) melatonin concentration/dose.The concentration of melatonin needed for most of the abovementioned effects is high, e.g., in the range of 1µM and up to several mMs. This leads to two remarks: (1) whether these effects are specific for melatonin or would they also be observed in structurally related molecules; (2) related to this first point is the question of the molecular target(s) or mechanism(s) behind it. Most studies lack the appropriate experimental conditions to—or at least start to—address these questions appropriately. For the first point, the most obvious structurally related candidate class of molecules is indoles The reported effects of melatonin tend to be over-interpreted. The effects are not only system-dependent but, on their own, do not necessarily allow for conclusions on the precise mechanism or targets involved. These ‘descriptive’ data should therefore be interpreted with caution, not only in terms of the molecular mechanism and specificity but also in terms of translatability into another cell type, tissue and its relevance for pathologies. Unfortunately, the often-used perspective phrase “… these findings open new avenues in therapeutics” should be used with more precaution, considering the high melatonin concentrations used and the fact that almost all experimental protocols use melatonin in a preventive paradigm instead of a treatment paradigm.This snapshot of articles is not meant to be exhaustive, as the search using keywords will always return only a partial picture. Nevertheless, we found the exercise quite informative on two counts:Another misleading habit is the transformation of the working hypotheses and ideas formulated in an article into a fact in the following article and then propagated from review to review. This is nicely illustrated by the literature associating melatonin with the recent COVID-19 pandemic. A PubMed search using the terms “melatonin” and “COVID” retrieved 217 publications (25 February 2023) in just a three-year period. Incidentally, most of the papers claim that melatonin is active because it is an antioxidant and scavenger and has anti-inflammatory properties , and thuAltogether, we conclude that the use of high melatonin doses can be problematic in terms of specificity and engagement of molecular targets, two aspects that are rarely addressed but need to be clarified based on experimental evidence .As we detailed previously, particularly in the recommendations on melatonin-related publications , the necN-acetylserotonin is a better compound for antioxidant activity than melatonin, especially at 10 µM, at which the concentration of melatonin is almost inactive in this cellular model [2O2) or following glutamate-induced cell death, N-acetyltryptamine, as well as melatonin, were reported to protect the cells against those injuries, although at concentrations from 10 to 500 µM. The authors suggested that the protection occurred via the induction of NF-κB [50 values are highly desirable in future studies to better understand the effects associated with melatonin, in particular, at high concentrations. From a therapeutic point of view, the putative interchangeability of indole-based compounds, such as melatonin, N-acetyltryptamine, etc., would increase the number of therapeutic choices to minimize the harmful effects, depending on the disease context.Concerning indole-based compounds, it is interesting to evaluate some of the examples that addressed the question of specificity: (a) serotonin was found to be the most effective compound for inhibiting amyloid-β peptide aggregation. Almost all the indole compounds tested in this study prevented amyloid-β peptide fibril formation and increased cell viability between 9 and 25%. Melatonin and serotonin were found to be the most active. Moreover, serotonin increased the expression of SIRT-1 and 2, heat shock protein 70, and heme oxygenase activity—as melatonin is reported to do as well—this being a possible mechanism underlying the observed neuroprotective effect . This paar model . (d) Wheof NF-κB . The sysFor several years now, a growing number of claims can be said to have distracted melatonin research and trivialized the role that endogenously produced melatonin has in maintaining circadian sleep patterns, metabolism and mental health.Indeed, the disruption of light rhythms in our cities and the constant use of electronic devices with artificial light have led to questions about the way public health is affected by such changes. In the meantime, significant resources—intellectual, financial and societal—are potentially wasted by moving forward the working repetitive claims/hypotheses that are not, or only insufficiently, supported by experimental evidence with all the required scientific rigor. Clearly, only the clarification of the basics and not the extension of non-consensual theories will lead to a general consensus in the scientific community to eventually move on in a coordinated manner and on a solid scientific basis to address the most relevant questions and challenges.Another way to reduce the impact of misleading claims is to discourage reviews of the literature that simply and uncritically repeat statements or discuss experiments.Another point should be stressed: the use of melatonin at very high dosages in patients and infants should be restricted as a precautionary principle. Indeed, as pointed out on several occasions, melatonin toxicity, in vivo, remains unexplored territory at these dosages, even at moderate dosages. There have been no rigorous toxicity studies reported in humans, and the repeated claims that a compound being natural cannot be toxic, are potentially harmful.