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Results | PMC10106287 | |||
Clinical characteristics | Depression | PURGING | Participants have been described previously (Keel et al., Clinical features associated with binge eating, purging, and their combinationBDI, Beck Depression Inventory (Beck et al., * | PMC10106287 |
Gastric emptying | PURGING | Analyses of gastric emptying under the placebo condition appear in Associations between gastric emptying, binge eating, purging, and their combinationFor the Unconditional Growth Model, change in fit is compared to the Unconditional Means Model (results not included in table) for which BIC = 8686.70, and Deviance (parameters) = 8666.84 (3).When gastric emptying was measured following administration of a single 10 mg dose of metoclopramide, the only significant predictor of acetaminophen concentrations across models was time ( | PMC10106287 | |
Subjective responses to the meal | gastrointestinal distress | PURGING | Models predicting gastrointestinal distress supported a main effect for purging [Gastric emptying was a significant predictor of gastrointestinal distress in the placebo condition [Participants endorsed | PMC10106287 |
Exploratory analyses of gut peptide responses | PD, gastrointestinal distress, eating disorder | PURGING | In prior analysis in this sample, we demonstrated significantly greater postprandial PYY release in PD compared to both control and BNp participants under the placebo condition (Keel et al., To understand whether PYY mediated the effects of medication and eating disorder features on gastrointestinal distress, we added PYY to the model along with medication, purging, binge eating, and their interaction. PYY was a significant predictor of greater gastrointestinal distress [ | PMC10106287 |
Discussion | Gastroparesis, bloating, nausea, nonpurging, increases gastric motility, illness, self-induced vomiting, eating disorders, vomiting, Camilleri, upper gastrointestinal symptom, PD, gastrointestinal distress, gastroparesis, eating disorder, DSM-5 | GASTROPARESIS, TARDIVE DYSKINESIA, DYSFUNCTION, SAID, MITCHELL, GASTROPARESIS, PATHOLOGY, DELAYED GASTRIC EMPTYING, PURGING | We sought to determine whether delayed gastric emptying was associated with purging, binge eating, or both, and results supported a specific association with purging. In addition, delayed gastric emptying was associated with greater postprandial gastrointestinal distress, suggesting that a mechanical disruption in the digestive process may contribute to urges to self-induce vomiting. Combined with prior findings of significantly greater postprandial release of PYY and insulin (Keel et al., Very limited research has been dedicated to understanding self-induced vomiting in eating disorders despite the presence of this feature in PD, AN, and BN. Indeed, the DSM-5 eliminated the DSM-IV's distinction between purging and nonpurging BN subtypes due to a lack of empirical support (van Hoeken, Veling, Sinke, Mitchell, & Hoek, In addition to providing novel insight into factors that may contribute to purging, current results may explain why efforts to alter gastric emptying proved ineffective in alleviating symptoms in BN. Devlin et al. (That said, specifying a link between self-induced vomiting and gastric emptying and using a pharmacological manipulation to eliminate group differences in gastric emptying did not open a promising avenue for developing an intervention for PD. Instead, findings provide a cautionary tale regarding the challenges in identifying and isolating a dysfunction within complex systems. Physiologically, metoclopramide increases gastric motility but it also enhances the release of gut peptides that impact feelings of satiation, satiety, and, at high levels, malaise, by increasing how quickly food enters the intestinal tract. In the case of PD, a medication that increases gastric motility may alleviate one cause of gastrointestinal distress while exacerbating another source – exaggerated PYY response. Exploratory analyses identified an association between gastric emptying and PYY release and demonstrated that medication robustly increased PYY response across participants. After the study was funded, the FDA released a black box warning regarding possible serious side effects associated with metoclopramide, which is a dopamine receptor antagonist that crosses the blood-brain barrier and has been linked to tardive dyskinesia. As such, the possible but unlikely anti-emetic benefits appear outweighed by the risks associated with extended treatment. These conclusions align with those regarding the management and treatment of gastroparesis in which delayed gastric emptying causes bloating, excessive fullness, nausea, and vomiting (Camilleri, Parkman, Shafi, Abell, & Gerson, Our novel use of a 2 × 2 factorial design dissociated effects linked to bingeing Our study enjoyed several strengths. Our rigorous inclusion and exclusion criteria eliminated several common confounds. Our use of a double-blind, placebo-controlled cross-over design permitted stronger inferences regarding group differences in gastric emptying and their downstream effects on subjective and gut peptide responses to food intake. Our measures included structured clinical interview assessments and self-report questionnaires that were selected based on their strong psychometric properties, which were further supported in our current study. Finally, our sample size is the largest in the published literature on gastric emptying in BN, including nearly twice the number of participants included in prior studies, is the first study of gastric emptying in PD, and used a rigorous analytic approach. Moreover, part of this study reflects an independent and successful replication of delayed gastric emptying in purging BN compared to healthy controls.Despite these strengths, limitations warrant consideration. First, despite our best efforts and a one-year no cost extension, we were unable to secure our target sample of 25 participants with BN who relied solely on nonpurging compensatory behaviors. This produced an unbalanced design in which a majority of those with binge eating were also purging and a majority of those who were not purging were healthy controls. To avoid biased estimates of the main effects of binge eating and purging, we reported results from models with all main and interaction effects and utilized an analytic approach that is well-suited to unbalanced designs. Second, our study utilized a combination of a cross-sectional and experimental design but does not permit causal inferences regarding associations with symptoms. All eating disorder participants were studied during the state of illness and compared to controls who never experienced eating pathology. Thus, we cannot determine whether delayed gastric emptying contributes to self-induced vomiting, is a consequence of self-induced vomiting, or is related to self-induced vomiting through an underlying third variable. Indeed, although our design shares some features with a clinical trial, it reflects a case-control observational design. Prior to comparing groups in the placebo condition, we did not know whether delayed gastric emptying would be associated with bingeing, purging, or their combination. In addition, our use of a single 10 mg dose of metoclopramide was not intended to produce meaningful changes in symptom levels. Instead, it was used to produce its FDA-approved effect on gastric motility to probe downstream consequences on differences in gastric emptying and gastrointestinal distress. We did not employ the current standard, a 4 h scintigraphy of a solid-phase meal, to measure delayed gastric emptying, or standard measures of upper gastrointestinal symptom severity, such as the Gastroparesis Cardinal Symptom Index (Camilleri et al., In conclusion, delayed gastric emptying is linked to purging and may further contribute to gastrointestinal distress described by individuals with PD. Future work may benefit from the use of wireless motility capsule assessment and standard assessments of upper gastrointestinal symptom severity (Camilleri et al., | PMC10106287 |
Acknowledgements | This work was supported by funding from the National Institute of Mental Health 2R01MH061836; R01MH111263 (Keel), University of Iowa CTSA UL1RR024979 (Hunninghake), The Council on Research and Creativity at Florida State University (Keel), and the Bernice S. Weisman Fund at Beth Israel Deaconess Medical Center (Jimerson). We acknowledge the dedicated technical support of Logan T. Murry, Pharm.D. for acetaminophen method validation and bioanalysis. The authors have no conflict of interest to report. | PMC10106287 | ||
References | PMC10106287 | |||
Background | A randomised trial of European Fans in Training (EuroFIT), a 12-week healthy lifestyle program delivered in 15 professional football clubs in the Netherlands, Norway, Portugal, and the United Kingdom, successfully increased physical activity and improved diet but did not reduce sedentary time. To guide future implementation, this paper investigates how those effects were achieved. We ask: 1) how was EuroFIT implemented? 2) what were the processes through which outcomes were achieved? | PMC10026416 | ||
Methods | RECRUITMENT | We analysed qualitative data implementation notes, observations of 29 of 180 weekly EuroFIT deliveries, semi-structured interviews with 16 coaches and 15 club representatives, and 30 focus group discussions with participants (15 post-program and 15 after 12 months). We descriptively analysed quantitative data on recruitment, attendance at sessions and logs of use of the technologies and survey data on the views of participants at baseline, post program and after 12 months. We used a triangulation protocol to investigate agreement between data from difference sources, organised around meeting 15 objectives within the two research questions. | PMC10026416 | |
Results | We successfully recruited clubs, coaches and men to EuroFIT though the draw of the football club seemed stronger in the UK and Portugal. Advertising that emphasized getting fitter, club-based deliveries, and not ‘standing out’ worked and attendance and fidelity were good, so that coaches in all countries were able to deliver EuroFIT flexibly as intended. Coaches in all 15 clubs facilitated the use of behaviour change techniques and interaction between men, which together enhanced motivation. Participants found it harder to change sedentary time than physical activity and diet. Fitting changes into daily routines, planning for setbacks and recognising the personal benefit of behaviour change were important to maintain changes. Bespoke technologies were valued, but technological hitches frustrated participants. | PMC10026416 | ||
Conclusion | EuroFIT was delivered as planned by trained club coaches working flexibly in all countries. It worked as expected to attract men and support initiation and maintenance of changes in physical activity and diet but the use of bespoke, unstable, technologies was frustrating. Future deliveries should eliminate the focus on sedentary time and should use only proven technologies to support self-monitoring and social interaction. | PMC10026416 | ||
Trial registration | ISRCTN81935608, registered 16/06/2015.
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12889-023-15419-y. | PMC10026416 | ||
Keywords | PMC10026416 | |||
Introduction | cancers | CANCERS, TYPE 2 DIABETES, DISEASES, CARDIOVASCULAR DISEASE | Low levels of physical activity and high levels spent in sedentary time are contributing to the increasing global prevalence of non-communicable diseases such as cardiovascular disease, type 2 diabetes and some cancers, [One approach to attracting men to lifestyle change is to offer programs in partnership with professional sports clubs, which is expected to attract men through the draw of the football club. [One adaptation of FFIT was the European Fans in Training (EuroFIT) program [Before recommending the widespread roll-out of EuroFIT, we wanted to investigate in more detail how it was implemented and whether it worked as we expected it to do. We thought this more detailed information could support future deliveries and add insight into how lifestyle change programs delivered in professional sports settings can work to both attract men and enable positive public health outcomes. Thus the aim of this paper is to examine the process through which EuroFIT achieved its effects. We do this by reporting a mixed-method process evaluation [Before describing our methods, we outline the EuroFIT program and the theories underpinning it (full description of these have been published elsewhere [ | PMC10026416 |
The EuroFIT program: an overview | The EuroFIT program was designed to support men to: become more physically active and less sedentary; improve their diets; and maintain these changes over the long term. It was delivered over 12, weekly, 90-min sessions that combined ‘classroom’ discussion, including ‘tools’ for behaviour change, with group-based physical activity. All sessions were led by football club community coaches. Full details of EuroFIT are published including a description of the program in the TIDieR template [EuroFIT Theory of ChangeRelational, physical and financial resources are needed to implement EuroFIT, including professional football clubs with sufficient commitment to try delivering the program and to recruit coaches willing to take part in training. The program also requires access to club facilities and materials for the program, and funding to pay for materials such as manuals and t-shirts (Fig. EuroFIT drew on theories derived from various schools of thought in psychology and sociology. From psychology, EuroFIT drew explicitly on contemporary theories of motivation specifically, self-determination theory [From sociological theory, EuroFIT – like FFIT—drew on accounts of gender, culture and performance. EuroFIT is responsive to masculine identities and practices [We developed bespoke technologies to support the delivery of EuroFIT. Participants were provided with a novel pocket-worn device (the ‘SitFIT’), about the size of a matchbox, to self-monitor their daily step count (for physical activity) and time spent upright (for sedentary behaviour) [For the duration of the research, the country-based research teams provided implementation support for football clubs. This included funding to deliver the program, guidance on recruiting participants, provision of detailed manuals for coaches, a two-day training program for club coaches and support for trouble shooting problems during delivery. Full details of the implementation process and support offered to clubs are already published [ | PMC10026416 | ||
Methods | PMC10026416 | |||
Process evaluation design | The mixed methods process evaluation reported here was embedded in the EuroFIT RCT (Trial registration ISRCTN81935608, registered 16/06/2015) [ | PMC10026416 | ||
Changes to protocol | MINOR, RECRUITMENT | In conducting analyses for this paper, we made some minor changes to methods described in the protocol.The protocol described eight methods, two of which (structured telephone questionnaire with participants opting out of the study and structured questionnaires to coaches on training and on program delivery) did not yield sufficient data to support mixed methods analysis and are not included here.The protocol did not describe two other methods which did prove useful in analysis. First, in recruiting football clubs and supporting clubs in their initial set up of the program, research teams in each country wrote implementation notes that were discussed at weekly team meetings. Both notes and discussion were useful in examining club recruitment. Second, to recruit participants to EuroFIT, clubs used social and other media adverts with a link to a web-based form for potential participants to express their interest in taking part. Data from this form were useful in examining participant recruitment.The protocol detailed 18 objectives, but we address only 15 in this paper. We have already reported participant demographic and health risk profile, [ | PMC10026416 | |
Data collection | Table Research objectives, Theory of Change element considered and data collection methods for the EuroFIT process evaluation | PMC10026416 | ||
Research team implementation notes | RECRUITMENT | Throughout the recruitment and delivery phases, the EuroFIT research team kept detailed notes on implementation. These notes were recorded in the minutes of regular meetings and provided data on issues that were faced. | PMC10026416 | |
Expressions of interest and | RECRUITMENT | Expressions of interest were captured via a web form, which provided data on the numbers of men interested in participating in EuroFIT. Potential participants were screened by telephone for eligibility from this database before recruitment began, as described elsewhere. [ | PMC10026416 | |
Participant questionnaires | All 1113 RCT participants (560 allocated to intervention and 554 to comparison group) were asked to complete self-report questionnaires at baseline, when the intervention group had finished the program, (post-program) and 12 months after it began (12-months). The intervention group participants were also asked to complete additional self-report questions about their experiences of the program both post-program and at 12-months. The pre-program questionnaire asked about motivations for joining EuroFIT. Post-program questionnaires asked which components and tools of the EuroFIT program men received, used or did not use, and which they found useful. The 12-month questionnaire was designed to assess participants’ views on the ongoing usefulness of the components and tools in EuroFIT. | PMC10026416 | ||
Participant attendance | Club coaches were asked to keep a record of attendance at each of the 12 EuroFIT sessions, via an online database provided by the research team. | PMC10026416 | ||
Participants’ SitFIT and MatchFIT usage logs | Participants registered on the MatchFIT app and then SitFIT and MatchFIT usage data were collected remotely from users on a dedicated server. Data generated included logs of data uploads, error reports, user clicks, logins and logouts. Each item of logged data included a timestamp, information about the web browser and device type being used, and (except for pre-registration and pre-login activities in MatchFIT) a unique SitFIT identifier. | PMC10026416 | ||
Observation of sessions | Observations of EuroFIT sessions were conducted in each of the 15 clubs by members of the local research teams, aiming for two sessions per club. We aimed to observe session 4, which covers multiple topics and activities, and one of session 3 or 5–12 in each club. We avoided sessions 1 and 2 to allow groups time to ‘form’ without feelings of being studies. Data were written down in note form using a standardised proforma, and written up in the style of thick descriptions [ | PMC10026416 | ||
Semi-structured interviews with coaches and football club representatives | We conducted semi-structured interviews with 16 coaches who delivered EuroFIT and with 15 football club representatives involved in managing EuroFIT when the program had been delivered.Interviews covered what they thought of the program, their experiences of what worked or did not work when launching EuroFIT, barriers to and facilitators of implementation, whether or not they saw a future for the program in the club, and what would be needed in the future to enable EuroFIT to continue at their club. Interviews were conducted by trained members of the research team, and were audio recoded and transcribed verbatim. | PMC10026416 | ||
Focus group discussions with participants | Focus groups were conducted in each football club with a sample of participants who attended six or more EuroFIT sessions at two time points, when the program ended and 12 months after the program started. We tried to recruit the same men at each time point. We prompted discussion on what men thought of the EuroFIT program sessions, any perceived impacts on their lives, which elements of the program they found helpful or unhelpful and ways in which the program might be improved. Focus groups were conducted by trained moderators who were assisted by note takers, and were audio recorded and transcribed verbatim. | PMC10026416 | ||
Data analysis | ’ [ | Our approach to data analysis is described in detail in our protocol paper [Quantitative data were summarised using SPSS (v21) and reported descriptively. Qualitative data (study team notes, observations, interviews, focus groups) were analysed following a framework approach [Finally, to compare findings from different data sources, we were guided by the mixed methods ‘triangulation protocol’ [ | PMC10026416 | |
Informed consent and ethical approvals | When participants agreed to join the study, they completed and signed an informed consent form, in the presence of a trained researcher. Participants received information sheets explaining the study, its aims and procedures, and were encouraged to read and ask any questions they had. They were asked to provide consent for each type of data collection they were involved in. All participants gave their written consent for the use of de-identified data collected during the study to be used in publications and outputs.Ethical approvals for the RCT and the process evaluation were obtained from appropriate country-specific ethics committees (Ethics Committee of the VU University Medical Center [2015.184]; Regional Committees for Medical and Health Research Ethics, Norway [2015/1862]; Ethics Council of the Faculty of Human Kinetics, University of Lisbon [CEFMH 36/2015]; and Ethics Committee at the University of Glasgow College of Medicine, Veterinary and Life Sciences [200140174]). All methods were deployed in this study were performed in accordance with relevant guidelines and regulations. | PMC10026416 | ||
Results | A summary of response rates by method can be found in Table
Response rates for survey and qualitative methods***Qualitative data extracts are labelled to indicate participant ID (P (participant); C (coach); and (club representative)), club (NOR1-3, UK1-5, POR1-3, NL1-4) and data source (PPFGD [post-program focus group], 12MFGD [12-month focus group], OBS [observations], INT [interview]. Additional examples from the qualitative data can be found in Additional File | PMC10026416 | ||
Discussion | RECRUITMENT, SAID, RECRUITMENT | Our analysis shows that EuroFIT was largely implemented as planned in professional football clubs in four countries, that coaches delivered the program as intended and that the program worked largely as expected for participants.The research project paid for deliveries of EuroFIT within the trial context which facilitated recruitment of professional football clubs to deliver the program, although the fact that we had to identify additional clubs when three dropped out, suggests that it might be more difficult to recruit clubs if funding for deliveries was not readily available. Coaches responded well to the training provided in EuroFIT session delivery, although high turnover of staff was a problem in some clubs. Recruitment strategies proved successful in all countries, but especially Portugal and the UK and it is possible that the ‘draw’ of the football club was not so clear amongst men in the Netherlands and Norway. The UK has a long history of community development activity in professional football clubs [Attendance at program sessions, e assumed would be necessary to initiate change, was good. Fidelity, assumed necessary for successful outcomes, was also good; and coaches responded flexibly to participants’ perceived needs, a feature of the program we think it essential to retain in subsequent implementation [EuroFIT was one of the first studies to deliberately engage motivation theory behaviour change strategies into the protocol. From both self-determination and achievement goal theories, we incorporated BCTs associated with autonomy, relatedness, competence, mastery and self-referenced goal strategies and coaches were very successful in using those strategies to foster behaviour change. Self-monitoring using the SitFIT and the setting of self-referenced goals were seen as particularly important by participants and coaches and reinforcement of BCTs was also important to maintain changes through the program. MatchFIT, on the other hand, did not seem to play an active role in encouraging maintenance of behaviour change in most countries, perhaps because of the technical difficulties encountered in its use, and unlike in the FFIT program[EuroFIT was not successful in supporting men to make long-term improvements to their sedentary behaviour. While there is good evidence for different approaches to, and the benefits of, becoming more active [That said, the mechanisms through which changes in physical activity were likely produced – i.e. goal setting, self-monitoring, action planning, social support and problem solving – are consistent with both the theory of change and with literature relating to behaviour change for physical activity in men [A novel feature of EuroFIT was its use of bespoke technologies. The SitFIT activity tracker [Our study suggests that it is possible to implement EuroFIT in different club settings. It also indicates ways in which clubs tailor EuroFIT to their own contexts and characteristics. Future research and practice relating to the delivery of health interventions in professional sports settings should ensure programs are designed with flexibility in mind, to ensure that variations in resource availability do not present barriers to implementation, although the key elements of how the program functions should be maintained. Given the significant public health benefits that have been demonstrated by such interventions [A final point of discussion raised by our study relates to harnessing the appeal of professional sports club settings and in being with other like them to attract participants to health interventions. As we have reported, our findings generally support the body of literature which argues that professional sports club settings are a powerful motivator for intervention participants, and perhaps particularly men [ | PMC10026416 | |
Strengths and Limitations | A major strength of this study is that it analysed data from four countries, in fifteen club settings, and derived the findings from a large body of data collected through multiple methods, allowing for triangulation across data sources. The study also deliberately employed behaviour change strategies informed by contemporary motivation theories. These strengths and the findings from the study underpin our confidence in the utility of the EuroFIT theory of change as a representation of the program’s mechanisms of action for men in the four countries studied. A limitation is that although we went to considerable efforts to standardise qualitative data collection and analysis across countries it was conducted by multiple teams, with varying levels of experience, in four different languages. The research team which produced the convergence matrix had limited ability to go back to original sources to check interpretations for themselves. This was mitigated through extensive cross-country dialogue, but remains a shortcoming that is faced in all cross-cultural work in which all analysts are not poly-lingual (see e.g., [ | PMC10026416 | ||
Conclusions | This paper has explored the processes through which EuroFIT achieved its outcomes and the extent to which the underpinning theory of change represented the program’s mechanisms of action. Through a mixed-methods approach, we have concluded that the theory of change is an effective representation of the EuroFIT program, with only three small areas of ambiguity. In relation to this latter point, we have suggested: that the dual focus on changing physical activity | PMC10026416 | ||
Acknowledgements | Mattias | We are grateful to participants who took part in the research, coaches and club managers at fifteen football clubs and UEFA’s Football and Social Responsibility department for supporting the proposal at bidding stage. Ciaran Clissman of Pintail Ltd managed the project and provided invaluable editorial input into the funding application and delivery of the program. Prof Nanette Mutrie was substantially involved in the development of the EuroFIT program. Dr Lisa Macauley administered the UK data collection in the UK and Alan Pollok supported some UK data collection. Dr Mattias Rost and Prof Mathew Chalmers were substantially involved in the development of MatchFIT and Drs Douglas Maxwell and Nikos Mourselas of PAL Technologies in the technical development of the SitFIT.Views and opinions expressed are those of the authors and do not necessarily reflect those of the European Union. | PMC10026416 | |
Authors’ contributions | CB, VP, NRC, EA, CG, KH, JGM, HM, MNS, HP, GCR, JR, OBR, MNS, MS, TVA, IVG, FVN, SW contributed to the analysis and interpretation of the data. CB, VP, NRC and SW conducted the triangulation phase of analysis. CB, VP, NRC and SW drafted the manuscript. All authors made contributions to the revision of the manuscript and read and approved the final manuscript. | PMC10026416 | ||
Funding | This project has received funding from the European Union’s Seventh Framework Program for research, technological development, and demonstration under grant agreement number 602170. The Health Services Research Unit, University of Aberdeen, receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | PMC10026416 | ||
Availability of data and materials | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10026416 | ||
Declarations | PMC10026416 | |||
Ethics approval and consent to participate | Ethical approvals for the RCT and the process evaluation were obtained from appropriate country-specific ethics committees (Ethics Committee of the VU University Medical Center [2015.184]; Regional Committees for Medical and Health Research Ethics, Norway [2015/1862]; Ethics Council of the Faculty of Human Kinetics, University of Lisbon [CEFMH 36/2015]; and Ethics Committee at the University of Glasgow College of Medicine, Veterinary and Life Sciences [200140174]). All methods were deployed in this study were performed in accordance with relevant guidelines and regulations, and all participants provided written informed consent. | PMC10026416 | ||
Consent for publication | Not applicable. | PMC10026416 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10026416 | ||
References | PMC10026416 | |||
Abstract | inflammation, Frailty, Thrombosis, postmyocardial infarction | INFLAMMATION, ATHEROSCLEROSIS, THROMBOSIS | Although inflammation is strongly associated with frailty, whether medications that lower inflammation decrease frailty is unclear and randomized trial evidence is scant. We sought to test whether canakinumab, a therapeutic monoclonal antibody that inhibits IL‐1β and reduces C‐reactive protein (CRP), can lower frailty risk. This was a post hoc analysis of the Canakinumab ANti‐inflammatory Thrombosis Outcome Study (CANTOS), a randomized double‐blind placebo‐controlled trial of 10,061 stable postmyocardial infarction patients randomized to subcutaneous canakinumab once every 3 months. Incident frailty was measured using a 34‐item cumulative‐deficit Frailty Index (FI). Time‐to‐event analysis using intent to treat. A total of 9942 CANTOS participants had data to calculate a baseline FI. Median age was 61 (IQR 54–68); 74% were male, 12% Asian, 3% Black, 80% White, and 16% Hispanic/Latino. At baseline, mean FI score was 0.12 and 13% were frail using a cutoff of 0.2. Over 5 years, 1080 participants (12.5%) became frail and mean FI scores increased to 0.14. There was no effect on frailty incidence according to randomization to any canakinumab dose versus placebo over time, HR 1.03 (0.91–1.17), In this post hoc analysis of the CANTOS trial, among stable adult patients with atherosclerosis, interleukin‐1b inhibition with canakinumab versus placebo did not lower the risk of incident frailty over 5 years. More randomized data are needed to understand the role of targeted anti‐inflammatory medications for frailty prevention in older adults.
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Abbreviations | Thrombosis | OSTEOPOROTIC FRACTURES, THROMBOSIS | body mass indexCanakinumab ANti‐inflammatory Thrombosis Outcome StudyC‐reactive proteinfrailty indexhazard ratiointerleukin 6major adverse cardiovascular eventsmyocardial infarctionnonsteroidal anti‐inflammatory drugsStudy of Osteoporotic Fractures | PMC10776110 |
INTRODUCTION | thrombosis, Frailty | THROMBOSIS, EVENTS, SYNDROME | Frailty is a geriatric syndrome of vulnerability, common in older adults, that increases the risk of cardiovascular events, functional decline, morbidity, and mortality (Afilalo et al., Canakinumab is a therapeutic monoclonal antibody that targets IL‐1β blockade leading to reductions in both IL‐6 and the hepatic acute phase reactant C‐reactive protein (CRP). In the recent multinational randomized placebo controlled canakinumab anti‐inflammatory thrombosis outcome study (CANTOS), canakinumab was shown to significantly reduce rates of major adverse cardiovascular events (MACE) (Ridker et al., The geroscience hypothesis suggests that drugs impacting multiple aspects of aging biology, such as the hallmarks of aging (Lopez‐Otin et al., | PMC10776110 |
METHODS | PMC10776110 | |||
Trial design | The CANTOS has been described in detail previously (Ridker et al., | PMC10776110 | ||
Outcomes | The primary outcome of this study was incident frailty over the duration of the trial. Secondarily, we assessed change in mean frailty score over time and change in self‐reported functional ability using the EQ‐5D questions for mobility, self‐care, and usual activities. In an exploratory analysis, we examined change in function according to baseline frailty level as prior trials have shown difference in physical function according to frailty level at enrollment (Butt, Dewan, Merkely, et al., | PMC10776110 | ||
Frailty | weight loss, presbyopia | PRESBYOPIA | Although there are multiple tools that can be used to assess frailty, in CANTOS, we primarily defined frailty according to the accumulation of deficits definition of frailty developed by Rockwood and Mitnitski (To be included in the FI, variables must (1) be related to health status, (2) increase in prevalence with age, (3) not saturate in the population (e.g., presbyopia), and (4) include a range of systems such as cognition, function, and morbidity (Searle et al., The number of deficits present for each individual was divided by the total possible number of deficits, with an overall score ranging 0–1 (e.g., 3 deficits/34 = 0.1). The 99th percentile for most populations 0.7 (Clegg et al., In a sensitivity analysis, we calculated an alternative definition of frailty based on the Fried physical phenotype of frailty. The Fried definition includes five interrelated variables: ≥5 lbs of unintentional weight loss in the last 2 years, self‐reported exhaustion, low‐energy expenditure according to kcal or energy, slow walking speed, and weak grip strength (Fried et al., | PMC10776110 |
Functional impairment | Self‐reported items from the EQ‐5D‐3L instrument were used to identify impairment in mobility, self‐care, or usual activity. Each variable was assessed as “no problems,” “some problems,” or “unable.” | PMC10776110 | ||
Major cardiovascular events | stroke, cardiovascular death | STROKE, EVENTS | The primary endpoint of the trial was time to the composite endpoint of MI, stroke, or cardiovascular death. All events were adjudicated by an adjudication committee who were blinded to the trial‐group assignments (Ridker et al., | PMC10776110 |
Other covariates | At baseline, information on age, sex, race, ethnicity, smoking status, body mass index (BMI), and blood pressure was measured. | PMC10776110 | ||
Analytic plan | REGRESSION, EVENT, SECONDARY | Descriptive statistics of the sample were computed overall and by frailty status.The FI was first validated by assessing the association between FI level and risk of mortality over follow‐up using Cox regression (Searle et al., For the primary outcome of incident frailty, we excluded those who were frail at study baseline and conducted an interval‐censored survival analysis for incident frailty using FI >0.2 as the cut point for frailty. Cumulative incidence curves for drug group versus placebo were run using logistic regression, adjusting for time point, drug group, a variable indicating qualifying MI event, and a variable indicating randomization status. These curves were repeated stratified by on‐treatment reduction of CRP and IL‐6 by more than the median at 3 months after study drug initiation, as this has previously been shown to identify greater benefit for cardiovascular endpoints in the trial (Ridker et al., For the secondary outcome of functional impairment, change in self‐reported mobility, self‐care, and usual activity was plotted over time and then stratified by frailty status as baseline frailty has been shown to be an effect modifier of function (Butt, Dewan, Merkely, et al., For the analysis of the main trial outcome stratified by frailty, we reran the primary intention to treat time to event analysis, using pairwise comparisons of individual dose groups with the placebo group, as well as any drug versus placebo and stratified the results by frailty level (nonfrail, prefrail, and frail).All models were run in SAS 9.4. | PMC10776110 | |
RESULTS | Among 10,061 participants in CANTOS, 9942 (99%) had sufficient data to calculate an FI at baseline (Figure Table Baseline characteristics of 9942 CANTOS participants by frailty category at baseline.
Those who were prefrail and frail had a higher risk of mortality over the duration of the trial (Table | PMC10776110 | ||
Incident frailty | IL‐6 reduction | Of the 8620 participants who were not frail at baseline, 1080 (12.5%) became frail during the 5‐year follow‐up period. There was no difference in rate of incident frailty according to randomization over time, comparing those allocated to any dose of canakinumab as compared to placebo or in comparisons of each dose separately to placebo (Figure Effect of canakinumab on incident frailty (Cumulative incidence curves stratified by on‐treatment CRP and IL‐6 demonstrate a reduction in incident frailty among participants whose inflammatory markers were lower, irrespective of drug assignment category. For those assigned to placebo with CRP reduction, HR was 0.81 (95% CI 0.62–1.05) and for those assigned to active drug HR was 0.83 (95% CI 0.71–0.97) (Figure Effect of canakinumab on incident frailty according to on‐treatment CRP and IL‐6 reduction. | PMC10776110 | |
Change in frailty score | Mean frailty scores increased from 0.12 at baseline to 0.14 at the end of the trial. There was no difference in mean frailty score between randomization groups over time (Figure Effect of canakinumab on change in mean frailty score ( | PMC10776110 | ||
Physical function | Overall, there was no difference in self‐reported mobility, self‐care, or usual activities over the follow‐up period in those assigned to active drug or placebo (all | PMC10776110 | ||
Major adverse cardiovascular events by baseline frailty | REGRESSION, REGRESSIONS | The primary trial outcome was rerun in the 9942 participants who had an FI available at baseline. Among those who were not frail 9.6% experienced a MACE outcome, while for those who were prefrail and frail, 15.8% and 27.4% experienced MACE, respectively. In the overall trial, the published HR (95% CI) compared with placebo for the 50‐, 150‐, and 300‐mg groups were 0.93 (0.80–1.07), 0.85 (0.74–0.98), and 0.86 (0.75–0.99); and for all doses versus placebo, it was 0.88 (0.79–0.97) (Ridker et al., Effect of canakinumab versus placebo on incident MACE, stratified by frailty.
Likelihood ratio test for trend from proportional hazard regression stratified by trial part.Rates are per 100 person years.Hazard ratio and confidence intervals from proportional hazard regressions stratified by trial part. | PMC10776110 | |
DISCUSSION | myocardial infarction, osteoarthritis, inflammation, mitochondrial dysfunction, anemia, proteotoxic stress, gout | MYOCARDIAL INFARCTION, OSTEOARTHRITIS, INFLAMMATION, ANEMIA, DISORDERS, LUNG CANCERS, SECONDARY, EVENTS, GOUT, MITOCHONDRIAL DYSFUNCTION, PATHOGENESIS | CANTOS has previously demonstrated that IL‐1b inhibition with canakinumab, compared with placebo, lowers the inflammatory biomarkers CRP and IL6 by 35 to 45 percent and significantly reduces rates of several clinical disorders associated with aging, including cardiovascular events, lung cancers, gout, anemia, and large joint osteoarthritis (Ferrucci & Fabbri, Although the underlying pathogenesis of frailty remains poorly defined, inflammation has been identified as a key contributor across diverse observational studies (Fulop et al., What are the implications of our study? It is possible that frailty may develop secondary to upstream hallmarks of aging phenomena that may contribute to inflammation, but which are not fully controlled by anti‐inflammatory interventions such as canakinumab. As such, future work should consider other hallmarks of aging, such as mitochondrial dysfunction, proteotoxic stress, senescence, and stem cell exhaustion that may be associated with frailty in those who also have inflammation, when considering therapeutics that target those mechanisms (Kulkarni et al., While prior evidence from randomized treatment trials of anti‐inflammatory agents to reduce frailty is scant, observational studies have been inconsistent. In an observational study that examined the role of aspirin and NSAIDs on risk of frailty in 12,101 men, regular aspirin use over an average of 11 years was associated with a significant reduction in frailty (Orkaby et al., We elected not to include CRP or IL‐6 in the frailty index for this study, as canakinumab is well‐known to lower these inflammatory biomarkers (Ridker et al., It is notable that risk of a major adverse cardiovascular events was highest in those who entered the trial with a frailty index >0.2, consistent with the prior literature that has highlighted the increased risk of cardiovascular events among those who are frail (Damluji et al., There are considerable strengths to our study, including its large sample size, prospective follow‐up, use of well‐validated frailty measures, and most important, random allocation to anti‐inflammatory therapy or placebo. Nonetheless, limitations of our study merit consideration. Although CANTOS participants had all survived myocardial infarction prior to trial initiation, participants were still healthier than the general older adult population. This is reflected in the maximal FI value in CANTOS of 0.46, which is lower than maximal FI values of 0.7 in US Medicare populations (Kim et al., | PMC10776110 |
CONCLUSION | ATHEROSCLEROSIS | Among stable adult patients with atherosclerosis, random allocation to interleukin‐1b inhibition with canakinumab as compared to placebo did not lower risk of incident frailty over 5 years. More randomized data are needed to understand the role of targeted anti‐inflammatory medications for prevention of frailty and functional decline in older adults. | PMC10776110 | |
AUTHOR CONTRIBUTIONS | PMR | ARO, RB, and PMR were involved in concept and design. PMR was involved in data curation and resources & supervision. AT, JM, and TGT were involved in analysis. All authors were involved in interpretation and writing—review & editing. ARO was involved in writing—original draft. | PMC10776110 | |
FUNDING INFORMATION | RTI | Novartis funded the CANTOS trial and the statistical analyses conducted for this manuscript. This post‐hoc analysis was investigator initiated. The funders approved the manuscript but were not otherwise involved in the conduct of this study. Dr. Orkaby is funded by VA CSR&D CDA‐2 award IK2‐CX001800 and reports consulting fees from Anthos Therapeutics. Ms. MacFadyen reports grants from Novartis during the conduct of the study. Dr. Ridker served as the Principal Investigator of the CANTOS trial which was funded by Novartis. Dr. Ridker has received institutional research grant support from Novartis, Kowa, Amarin, Pfizer, Esperion, NovoNordisk, and the NHLBI; has served as a consultant to Novartis, Flame, Agepha, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Omeicos, Health Outlook, Montai Health, New Amsterdam, Boehringer‐Ingelheim, RTI; Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). | PMC10776110 | |
CONFLICT OF INTEREST STATEMENT | None declared. | PMC10776110 | ||
Supporting information | APPENDIX |
Appendix S1
Click here for additional data file. | PMC10776110 | |
ACKNOWLEDGEMENTS | We are grateful to the participants in the CANTOS trial. | PMC10776110 | ||
DATA AVAILABILITY STATEMENT | Qualified external researchers may request access to patient‐level data and supporting clinical documents. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. | PMC10776110 | ||
REFERENCES | PMC10776110 | |||
Introduction | SD, anxiety | N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that induces a rapid and transient altered state of consciousness when inhaled or injected via bolus administration. Its marked and novel subjective effects make DMT a powerful tool for the neuroscientific study of consciousness and preliminary results show its potential role in treating mental health conditions. In a within-subjects, placebo-controlled study, we investigated a novel method of DMT administration involving a bolus injection paired with a constant-rate infusion, with the goal of extending the DMT experience. Pharmacokinetic parameters of DMT estimated from plasma data of a previous study of bolus intravenous DMT were used to derive dose regimens necessary to keep subjects in steady levels of immersion into the DMT experience over an extended period of 30 min, and four dose regimens consisting of a bolus loading dose and a slow-rate infusion were tested in eleven healthy volunteers (seven male, four female, mean age ± SD = 37.09 ± 8.93 years). The present method is effective for extending the DMT experience in a stable and tolerable fashion. While subjective effects were maintained over the period of active infusion, anxiety ratings remained low and heart rate habituated within 15 min, indicating psychological and physiological safety of extended DMT. Plasma DMT concentrations increased consistently starting 10 min into DMT administration, whereas psychological effects plateaued into the desired steady state, suggesting the development of acute psychological tolerance to DMT. Taken together, these findings demonstrate the safety and effectiveness of continuous IV DMT administration, laying the groundwork for the further development of this method of administration for basic and clinical research.N,N-Dimethyltryptamine (DMT) is a naturally occurring psychedelic with a mechanism of action linked to agonism at the 5-HT2A receptor (When ingested orally, DMT is rapidly metabolized in the gastrointestinal system by monoamine oxidase (MAO) (The development of a prolonged DMT experience would be an important step towards allowing for a closer study of its phenomenology and neurobiological effects, and would make it possible to control the length, intensity, and dynamics of the DMT experience, with the potential for real-time adjustment. This could make extended DMT a valuable tool in conjunction with therapy, to tailor the psychedelic effects to the individual needs of each patient and their clinical condition, as well as for consciousness research, whereby the intensity of the DMT experience can be adjusted according to specific hypotheses and research questions. In a previous study, continuous infusions of DMT were safely administered for up to 90 min (The present study developed the first systematic protocol for the continuous IV infusion of DMT and tested its effectiveness in healthy volunteers. The main goal of the study was to provide first steps towards establishing infusion parameters for maintaining a steady state of DMT effects for a chosen length of time. | PMC10851633 | |
Materials and methods | PMC10851633 | |||
Study design | In a single-blind, placebo-controlled study using a within-subjects repeated measures design, 11 healthy volunteers received up to four different doses of bolus plus slow-rate infusions of DMT over 30 min. Dosing sessions were separated by at least 2 weeks. On dosing visits, EEG activity as well as subjective and autonomic effects were measured acutely and retrospectively, and blood samples were collected for pharmacokinetic purposes (EEG findings and pharmacokinetic modelling will be published elsewhere). The study was approved by the National Research Ethics Service Committee London – Brent and the Health Research Authority and was conducted in accordance with the revised Declaration of Helsinki (2013), the International Committee on Harmonization Guidelines in Good Clinical Practice, and the National Health Service Research Governance Framework. The study was sponsored and approved by Imperial College London’s Joint Research and Compliance Office and the National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility gave site-specific approval for the study. The study was conducted under a Home Office licence for research with Schedule 1 drugs. | PMC10851633 | ||
Dosing schedule | Different dose regimens were simulated based on a separate population pharmacokinetic reanalysis of data from a previous study (Dosing schedule of continuous IV infusions of DMT. Doses are expressed for DMT fumarate. A bolus injection was given over 30 s, followed by a saline flush over 15 s. The continuous slow-rate infusion was started 1 min after the beginning of the bolus injection and maintained for 29 min. | PMC10851633 | ||
Study drugs | STERILE | On dosing days, DMT fumarate (Cole Parmer Instrument Company Limited, St Neots, Cambridgeshire, United Kingdom; Onyx Scientific, Sunderland, Tyne & Wear, United Kingdom) was reconstituted with saline to give a 5 mg/ml solution and sterile-filtered into sterile vials. To keep infusion rates equal across doses, DMT was drawn into syringes for the bolus and slow-rate infusion, then saline was added to create a total of 5 ml and 15 ml, respectively. The bolus injection and saline flush were administered by a study physician, and the constant-rate infusion was delivered with a BD Alaris GH plus syringe pump (BD Switzerland Sàrl, Eysins, Vaud, Switzerland), with the infusion rate set to 30 ml/h. | PMC10851633 | |
Participants | psychotic disorder, psychedelic drug, SD, psychiatric disorder, diabetes | DIABETES | Eleven healthy participants (seven male, four female, mean age ± SD = 37.09 ± 8.93 years, range = 26–51 years) took part in this study. Participants were recruited via word of mouth. Exclusion criteria for study participation were age <18, current or previously diagnosed psychiatric disorder, family history of psychotic disorder, a medically significant condition which rendered them unsuitable for the study (e.g., heart condition, diabetes), an abnormal physical exam, electrocardiogram, or blood test, no prior experience with a psychedelic drug, previous adverse response to a hallucinogenic drug, blood or needle phobia, a positive pregnancy test at screening or during the study, and excessive use of alcohol or other drugs (>40 units per week). Participants were asked to not consume any alcoholic drinks 48 h before each study visit, and to not consume any illicit drugs 2 weeks before their first study visit until 2 weeks after their last study visit. Drug of abuse tests and pregnancy tests (where applicable) were performed before each dosing visit. All subjects gave written informed consent in accordance with the Declaration of Helsinki. | PMC10851633 |
Study procedures | psychiatric | BLOOD | All volunteers attended a screening visit to determine eligibility to be enrolled in the study. During this visit, a physical examination (weight, ECG, blood pressure, heart rate (HR) and neurological examination) and routine blood test were performed, as well as a psychiatric interview (see ‘Participants’ for exclusion criteria). Subsequently, volunteers provided informed consent to be enrolled in the study and completed questionnaires.The dosing visits took place in a calm, decorated hospital room at Imperial College Research Facility. On dosing days, two research staff, one medic, and one research subject were present. Subjects were reminded of the study procedures and were asked to verbally provide re-consent if they wished to continue. Urine screens for drugs of abuse and pregnancy were performed. Participants were fitted with an EEG cap, an ECG was taken (to ensure safety), and cannulation took place on both arms. Blood samples were drawn from one cannula, and continuous infusions of DMT/placebo were administered via the other cannula. Participants were made comfortable in a semi-supine position and baseline EEG recordings were taken (eyes open and eyes closed). Shortly before dosing started, a body scan meditation was performed to help participants relax. During dosing, participants wore an eye mask and were instructed to keep their eyes closed. Low-volume ambient music ( | PMC10851633 |
Experience sampling of subjective effects | PMC10851633 | |||
Intensity | ’ | Subjective intensity of effects was assessed acutely via experience sampling from 8 min prior to 52 min after the start of the bolus injection. For this, audio prompts were played through headphones, and participants were instructed to verbally give subjective ratings of the intensity of the experience (from 0 = ‘no effects’ to 10 = ‘most intense imaginable’). These were collected at −8, −6, −4, −2, 0, 1, 2, 3, 4, and every 2 min thereafter, with minute 0 being the start of the bolus injection. | PMC10851633 | |
Anxiety | anxiety, ’ | Subjective ratings of anxiety were also collected every 4 min using a similar procedure (from 0 = ‘no anxiety’ to 10 = ‘most anxiety imaginable’) in order to assess the psychological safety of DMT infusions. | PMC10851633 | |
Retrospective assessments of subjective effects | PMC10851633 | |||
ASC and MEQ-30 | Auditory alterations, Oceanic boundlessness’, MEQ-30 | AUDITORY ALTERATION | Once the acute drug effects had subsided (~30 min following the end of administration), participants completed the altered states of consciousness (ASC) Scale and the Mystical Effects Questionnaire (MEQ-30). The ASC scale measures altered states of consciousness. The 94 items make up five dimensions (5D-ASC; ‘Oceanic boundlessness’, ‘Anxious ego dissolution’, ‘Visionary restructuration’, ‘Auditory alterations’, and ‘Reduced vigilance’; ( | PMC10851633 |
Dynamic subjective effects | Meaningfulness, Auditory hallucinations, ’ | Additionally, participants were asked to retrospectively provide ratings of various dimensions of their experience over time (from 0 = ‘none/not at all’ to 10 = ‘an extreme amount/extremely’). These dimensions included ‘Immersion’, ‘Entity encounters’, ‘Ego dissolution’, ‘Visual imagery’, ‘Emotional experience’, ‘Auditory hallucinations’, ‘Bodily dissociation’, ‘Bodily sensations’, ‘Meaningfulness’, ‘Metacognition’, ‘Overall richness’, and ‘Visual richness’ over time. The definitions for each item can be found in | PMC10851633 | |
Heart rate | HR was measured and monitored from 8 min before until 52 min after the beginning of the bolus injection with an E4 Empatica wristband (Empatica Srl, Milan, Italy) which participants wore on their wrist during the dosing period. The results reported here correspond to the recorded HR at 2-min intervals. | PMC10851633 | ||
Plasma DMT concentrations | BLOOD | Plasma levels of DMT were repeatedly assessed at baseline and 2, 5, 10, 20, 29, 32, 37, 40, 50, 60, 80, 100, 120, 150, and 180 min after the beginning of bolus injection of DMT. Blood samples (up to 6 ml) were collected into EDTA tubes, kept on wet ice, and centrifuged within 1h of collection. The harvested plasma was stored at −80°C before being shipped on dry ice to the University of Gothenburg for analysis. Samples were analysed according to a previously published liquid chromatography tandem mass spectrometry method ( | PMC10851633 | |
Statistical analysis | anxiety, MEQ-30 | Linear mixed-effects models (LMMs) were constructed to test the relationship between doses, timepoints, and the response variables of intensity, anxiety, HR, DMT plasma concentrations, ASC scores and MEQ-30 scores. LMMs exhibit several advantages over repeated measures Analyses of Variance (ANOVAs) in dealing with the present data: (1) LMMs control for the potential influence of random variables (i.e., subject-driven interindividual variability) by including them as random effects; (2) LMMs can cope with missing data; and (3) they are able to include grouping hierarchies such as the present partially crossed groups (i.e., each subject received multiple but not all DMT doses).LMM analyses were run in R (version 4.2.2) using the For variables that were measured at multiple timepoints (subjective intensity, anxiety, HR, and plasma DMT concentration), dose and timepoint were added as fixed effects, and the dependent variable was assessed via change scores from the placebo condition for the same subject at that given timepoint. For those models, both dose and time were treated as categorical variables, and the earliest timepoint (minute -8) of Dose 1 was specified as a reference. While the investigation of the differences between each pair of doses is of interest, the small sample size motivated us to reduce the number of comparisons by focusing the statistical analyses on contrasting higher doses against Dose 1. Consequently, we report the summary statistics of Dose 1 compared to placebo, and the added effects of higher doses compared to Dose 1. The resulting model for these outcome variables was specified as follows:
For variables that do not include a temporal dimension (5D-ASC and MEQ-30 scales), one LMM was fitted for each subscale. For these models, only Dose was added as a fixed effect, and analyses were performed on raw scores. The resulting model for these outcome variables was specified as follows:
For all mixed models, significance was estimated via the No statistical analysis was performed on the dimensions of the experience over time, as these were assessed retrospectively and hence were susceptible to recall bias. They are reported qualitatively to inform future studies employing acute experience sampling to investigate the extended DMT experience. | PMC10851633 | |
Experience sampling of subjective effects | PMC10851633 | |||
Intensity | Substantial increases in intensity ratings were observed with all tested doses, as shown in | PMC10851633 | ||
Anxiety | anxiety | Overall, participants experienced low levels of anxiety before and throughout dosing indicating that extended administration of DMT was well tolerated ( | PMC10851633 | |
Retrospective assessments of subjective effects | PMC10851633 | |||
ASC and MEQ-30 | Auditory alterations, Oceanic boundlessness’, Anxiety, MEQ-30 | AUDITORY ALTERATION | LMM analysis revealed significant increases on the 5D-ASC subscales ‘Oceanic boundlessness’ and ‘Visual restructuralization’ for all doses compared with placebo. There were significant increases for Dose 2, 3 and 4 compared with placebo on the 5D-ASC subscale ‘Dread of ego-dissolution’, and for Dose 2 and 3 compared with placebo on the 5D-ASC subscale ‘Auditory alterations’. For the 11D-ASC, LMM analysis showed significant increases on the subscales ‘Unity’, ‘Meaning’, ‘Spiritual experience’ ‘Blissful state’, ‘Insightfulness’, ‘Complex imagery’, and ‘Elementary imagery’ for all doses compared with placebo. Additionally, there were significant increases for Dose 3 compared with placebo on the subscale ‘Disembodiment’, and significant increases for Dose 2 and 3 compared with placebo on the subscale ‘Impaired cognition’. No significant differences between any dose and placebo were found for the subscales ‘Anxiety’ and ‘Audio/visual synaesthesia’. Lastly, LMM analysis revealed significant increases in the MEQ-30 total as well as all subscales for all doses with respect to placebo. Results are shown in Retrospective assessment of subjective effects induced by continuous infusions of placebo and different doses of DMT. LMM analysis revealed: (a) a significant increase for all doses compared with placebo in ‘Oceanic boundlessness’ and ‘Visual restructuralization’, for Dose 2, 3 and 4 compared with placebo in ‘Dread of ego-dissolution’, and for Dose 2 and 3 compared with placebo in ‘Auditory alterations’, (b) significant increases for all doses compared with placebo in ‘Unity’, ‘Meaning’, ‘Spiritual experience’ ‘Blissful state’, ‘Insightfulness’, ‘Complex imagery’, and ‘Elementary imagery’, for Dose 3 compared with placebo in ‘Disembodiment’, and for Dose 2 and 3 compared with placebo in ‘Impaired cognition’, and (c) a significant increase for all doses versus placebo on the MEQ-30 total and all subscales. Summary statistics can be found in | PMC10851633 |
Dynamic subjective effects | ’ | Retrospective assessment of different dimensions of the experience showed that participants’ experience of ‘Immersion’ and ‘Visual imagery’ largely followed subjective intensity scores over time, whereas ‘Entity encounters’ increased during the latter part of the infusion on Doses 3 and 4. Participants experienced minimal ‘Ego dissolution’ following the DMT infusions in this study (Retrospective assessment of ‘Immersion’, ‘Entity encounters’, ‘Ego dissolution’ and ‘Visual imagery’ over continuous infusions of placebo and different doses of DMT (minutes 0–30). DMT infusions induced sustained effects of ‘Immersion’, ‘Entity encounters’ and ‘Visual imagery’, while ‘Ego-dissolution’ remained low across doses. The data are expressed as the mean ± SEM. Additional results can be found in | PMC10851633 | |
Heart rate | Changes in HR following DMT dosing with respect to placebo are shown in Acute changes in HR following continuous infusions of placebo and different doses of DMT (minutes 0–30). While the initial period of DMT administration is associated with an elevated HR, this then returns to baseline levels and stabilises. Values are expressed as average differences in beats per minute (bpm) from baseline HR, defined as the average HR between minutes -8 and 0, ± SEM. | PMC10851633 | ||
Plasma DMT concentrations | Plasma concentrations of DMT over time for all doses of DMT are shown in DMT plasma concentrations after administration of DMT fumarate IV bolus dose followed by constant-rate infusion at four dose levels (minutes 0–30). Plasma concentrations peak after bolus IV injection and before the end of the continuous IV infusion. There was a significant dose-effect relationship for all doses, for all measured timepoints until minute 50. The data are expressed as the mean ± SEM. | PMC10851633 | ||
Discussion | reduction of sensory effects, Anxiety, anxiety, Disembodiment’, ’, MEQ-30 | EFFECTS INCREASED, ADVERSE EFFECTS, ADVERSE EVENTS, AUDITORY ALTERATION | The present dose-response study tested a novel methodology designed to extend the typically transient DMT experience via continuous IV infusion. This was combined with a bolus loading dose aiming to achieve prolonged effects within a short time span. Our results showed that IV infusions of DMT – at doses ranging from 6 mg + 0.6 mg/min to 18 mg + 1.9 mg/min – were psychologically and physiologically well tolerated, and that the protocol was effective at extending the duration of the psychological effects of DMT, achieving a steady-state of subjective effects, with low-to-negligible changes in anxiety. Subjective drug effects appeared within 1 min of the start of the bolus injection, peaked at 2 min, and settled at a slightly lower-than-peak intensity for the duration of the infusion. Subjective drug effects decreased in intensity shortly after the end of infusion, resolving almost entirely 20 min after the end of infusion. Intensity of the drug effects increased dose-dependently. Ratings of anxiety generally remained low during the duration of the infusion, with a transient increase in anxiety seen just around the start of DMT administration, suggesting psychological tolerability of the tested continuous infusion protocol. Significant differences between all DMT doses and placebo were found for all ASC subscales except ‘Dread of ego-dissolution’ and ‘Auditory alterations’ on the 5D-ASC, as well as, ‘Disembodiment’ and ‘Impaired cognition’ on the 11D-ASC, which showed significant increases only for the higher doses, and ‘Vigilance reduction’ on the 5D-ASC as well as ‘Anxiety’ and ‘Audio/visual synaesthesia’ on the 11D-ASC, which showed no significant differences. Conversely, there were significant increases between all DMT doses and placebo for the MEQ-30 total and all subscales. An initial peak in average plasma DMT concentrations was observed corresponding to the bolus IV injection. A second increase was observed corresponding to the continuous infusion, starting at minute 5–10 and continuing steadily until the end of infusion, at which point plasma levels dropped exponentially, reaching <1 nM within 90 min of the end of infusion. Plasma DMT concentrations increased dose-dependently. Finally, HR peaked quickly after the bolus IV injection, then exhibited significant decreases with respect to baseline within 10 min of the start of the bolus injection, suggesting it was in part anxiety-related and showing that longer infusions do not overload the autonomic system. This habituation of physiological effects while subjective effects remain elevated indicates physiological safety of extended DMT infusions and is consistent with previous findings showing the development of physiological tolerance following the administration of four closely spaced bolus injections of 20 mg of DMT fumarate (Importantly, although subjective ratings of intensity largely followed plasma concentrations of DMT during the first 20 min, a decoupling was observed from minute 20 onwards. While subjective intensity of drug effects decreased after an initial peak and remained stable with a slight downward slope for the remainder of the infusion, plasma levels of DMT generally increased throughout the infusion. These findings may suggest a progressive development of acute psychological tolerance to DMT during continuous infusion, a finding not seen in previous studies employing this compound. One potential explanation for the dissociation between subjective intensity and DMT plasma concentrations in the later part of the infusion is the development of psychological habituation to the effects over time, that is, effects of the same strength lose salience over time, whereas sharp transitions (i.e., as the one induced by the bolus), induce a stronger psychological response. However, the observed variability between individuals makes it difficult to draw any final conclusions based on this analysis. Future studies are needed to address the cause and extent of short-term tolerance induced by continuous DMT to better understand and develop infusion protocols that elicit desired subjective effects.Based on the apparent reduction of sensory effects over time, a refined infusion protocol may be required to better pair the subjective effects achieved through the bolus injection of DMT with those maintained by the continuous infusion and avoid a decrease over time. Additionally, the slight mismatch between peak concentrations achieved at the end of infusion and those achieved after the bolus dose could likely be avoided with slightly adjusted combinations of bolus doses and infusion rates. At the conception of this study, DMT plasma concentration data was only available from one previous study using bolus IV injections of DMT (Importantly, inter-individual variability in dose-concentration response and dose-effects response was large. A roughly two-fold range was observed for both plasma concentrations and intensity ratings for a single dose. Although variability in dose-response of this size is not unique to DMT – similar effects are seen for anaesthetic substances administered via bolus injection (Psychedelic therapy is increasingly showing transdiagnostic relevance for treating several mental health conditions (Psychedelics present an intriguing challenge in psychiatry as their psychological response is known to be highly variable and, at times, unpredictable. This unpredictability is usually accounted for by both dose and so-called non-pharmacological, or contextual variables, commonly described as (mind-) ‘set’ and ‘setting’ (This pilot study tested a novel method of DMT administration and assessed the stability and tolerability of different doses of the drug delivered via continuous IV infusions. DMT exhibits pharmacokinetic properties that make it suitable for continuous IV infusion, and this study demonstrated the safety and feasibility of this method of administration. Continuous IV infusions of DMT administered in doses of up to 18 mg + 1.9 mg/min were psychologically and physiologically well-tolerated in healthy, psychedelic-experienced volunteers. No significant acute or persistent adverse effects were observed. It is important to note some limitations of this study. Firstly, this study was conducted on a small sample of eleven participants. Due to the small number of resulting observations, we tested the effects of Dose 1 compared to placebo, and the added effects of higher doses compared to Dose 1. Dose-related effects between higher doses were only assessed in a qualitative fashion. Future studies including larger sample sizes may be able to investigate the differences between each pair of doses of interest. Secondly, due to safety considerations (i.e., participants receiving a maximum of four DMT doses) and dropouts, there was variability in doses administered, with not all participants receiving all doses investigated. Relatedly, although several of the dropouts occurred for personal reasons, it is not possible to rule out the possibility that participants did not wish to receive more doses. However, it is important to acknowledge that all tested doses seemed psychologically safe for most participants, as can be seen from ratings of anxiety and the adverse events presented in This study lays the groundwork for further explorations with extended IV infusions of DMT. The extended DMT experience may be valuable to explore further the phenomenology, neurobiology, and clinical outcomes associated with this unique state of consciousness. Furthermore, the successful and flexible extension of DMT administration poses a significant opportunity for the application of DMT in clinical and therapeutic settings, where the length, strength and dynamics of the psychedelic experience can be adjusted according to the needs of the individual. | PMC10851633 |
Supplemental Material | PMC10851633 | |||
References | PMC10851633 | |||
INTRODUCTION | cancers, breast cancer, cancer, Breast cancer, deaths | CANCERS, BREAST CANCER, INFLAMMATION, CANCER, BREAST CANCER, NODE-POSITIVE BREAST CANCER | A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. This research perspective summarizes evidences from our studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. Non-coding RNAs, particularly Breast cancer is one of the most common cancer types worldwide, accounting for approximately 25% of all female cancers. According to the World Health Organization, an estimated 685,000 women succumbed to breast cancer in 2020, making it the fifth leading cause of cancer-related deaths overall [ | PMC10317070 |
Progesterone regulates | toxicity, PR-positive, PR-negative breast cancer, breast cancer | PR-NEGATIVE BREAST CANCER, BREAST CANCER | Preoperative hormonal treatments, as opposed to neoadjuvant chemotherapy, are simpler to administer, easier to monitor, less expensive, and cause less toxicity [In a separate study, we conducted functional analysis of the components found to be significantly altered after performing an integrated genomic profiling of a panel of PR-positive and PR-negative breast cancer cell lines treated with progesterone to investigate the molecular action of progesterone in breast cancer cells [ | PMC10317070 |
An integrated representation of the multifaceted effects of progesterone in breast cancer. | breast cancer | INFLAMMATORY RESPONSE, CURB, BREAST CANCER | A schematic representation to describe the molecular mechanisms by which progesterone acts to curb cellular stress response and promote cell survival in breast cancer cells. Whole transcriptomic studies (represented by dotted lines) suggest that progesterone downregulates genes involved in the inflammatory response and | PMC10317070 |
Progesterone modulates the | breast cancer | Several studies have identified the regulatory functions of noncoding microRNAs and long noncoding RNAs (lncRNAs) in breast cancer progression [In a recent study, we described the regulatory role of noncoding RNAs in response to progesterone to mediate the cellular changes [ | PMC10317070 |
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