{"paper_id":"059205ef-e834-4ad9-97e1-714128f5976c","body_text":"Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls Birinder S. Cheema, Mitchell Low, Shelley Kay, Justine Stehn, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7028112/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Dec, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose To investigate endocannabinoid system (ECS) and affective state responses to acute aerobic exercise in adult cancer patients versus their healthy peers. Methods Participants engaged in 30 min of quiet rest followed by 30 min exercise. Exercise involved 5-min warm-up/cool-down procedures and 20 min of moderate-intensity training (64–76% of age-predicted maximal heart rate) on treadmill or cycle. Blood samples and 10 Visual Analog Scales (VAS) were collected before and after rest each condition. Participants were also asked after exercise: ‘Did you experience a Runner’s high. ’ Blood samples were analysed for endocannabinoids: N-arachidonoylethanolamine (AEA; anandamide), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), and mediators: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA). Results Cancer patients had lower circulating AEA, OEA and log SEA versus controls across all timepoints (all p < 0.06). In the total cohort, exercise increased AEA, log 1-AG, OEA, PEA and log SEA (all p = 0.05) while log 2-AG did not change. Of 10 VAS scales, only Happiness increased with exercise in the total cohort (p = 0.02). There were no group x time effects or associations between ECS and VAS responses to exercise. Five patients per group (50%) reported experiencing a Runner’s high . Conclusions Exercise increased endocannabinoid and endocannabinoid-like lipid mediators in the total cohort. However, cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers indicating potential ECS dysfunction. Additional research is required to investigate the effect of various modalities and dosages of exercise on ECS markers and the clinical interpretation of these adaptations across a range of cancer populations. Australian New Zealand Clinical Trials Registry #: ACTRN12623000193673 oncology exercise physiologist cannabis health runner’s high quality of life rehabilitation therapy training Figures Figure 1 Figure 2 Implications for Cancer Survivors Acute, moderate-intensity aerobic exercise increased endocannabinoids anandamide (AEA) and 1-AG along with endocannabinoid-like mediators (OEA, PEA and SEA) and subjective feelings of Happiness in both cancer patients and their healthy peers; However, the cancer patients exhibited lower levels of anandamide (AEA), OEA and SEA both before and after exercise versus their healthy peers; More research is required to investigate how cancer treatments and exercise affect the endocannabinoid system and the clinical meaningfulness of these changes across a range of cancer populations. INTRODUCTION Clinical trials over the past 40 years have shown that exercise in cancer patients is safe and can counteract many side effects of treatment, as well as elicit an array of health-related benefits including enhanced quality of life (QoL). 1 , 2 Despite these findings, the vast majority of cancer patients do not meet minimum physical activity guidelines. 3 Many are challenged by self-reported symptoms including fatigue (low energy), pain, appetite dysregulation, insomnia, cognitive impairment, depression, anxiety, low self-efficacy and poor motivation. 4 These symptoms often act as barriers to exercise participation while, paradoxically, the data also show that exercise can mitigate these conditions. 5 , 6 However, the biological adaptations underlying the subjectively-experienced benefits of exercise in cancer patients are not known and require investigation. Evidence from apparently healthy adults has shown that acute exercise can improve mood and induce transient pleasurable sensations including a state of euphoria colloquially known as the Runner’s high . 7 Additional terms ascribed to the pleasurable sensations induced by exercise have also included: ‘happiness’, ‘elation’, ‘joy’, ‘inner harmony’, ‘boundless energy’ and ‘ecstasy.’ 8 The Runner’s high was believed to be induced by the release of opiate peptides (endorphins) given their effect on pleasure-inducing and pain-mitigating (analgesic) biochemical pathways. 9 However, the central role of endorphins has not been supported by the evidence to date. 9 More recent data suggest that the endocannabinoid system (ECS) may be involved in mediating the improvement of subjective, mood-related outcomes (i.e. affective states). 10 , 11 The ECS consists of G protein-coupled cannabinoid receptors subtypes (CB 1 and CB 2 ), endocannabinoids that have affinity for these receptors (e.g. N-arachidonoylethanolamine (AEA, anandamide, i.e. the bliss molecule ), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG)), 12 endocannabinoid-like lipid mediators (e.g. palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA)) 13 and the enzymes, cells and neural pathways involved in endocannabinoid signalling and metabolism. 14 Recent systematic reviews have demonstrated that acute, moderate-to-vigorous intensity aerobic exercise (~ 30min) can significantly increase circulating endocannabinoids (AEA and/or 2-AG) and specific endocannabinoid-like lipid mediators (i.e. PEA and OEA) in healthy adults, and those with specific chronic conditions including mental health disorders (e.g. major depressive disorder, post-traumatic stress disorder, substance abuse). 15 – 17 These responses have been consistently accompanied by the improvement of affective states including increased euphoria and vigour, and reduced anxiety, depression and fatigue. Such adaptations may be of clinical importance to cancer patients at risk of experiencing treatment-related side effects. We have recently synthesized evidence indicating that cancer patients may suffer from ECS dysfunction, which may induced by disease-specific risk factors, the cancer itself (e.g. tumour microenvironment) and cancer treatment. 17 For example, altered CB 1 and CB 2 expression, heteromerization and function have been shown to play a role in the genesis of common cancers (e.g. breast, prostate, colorectal, lung) along with elevated concentrations of AEA and 2-AG in tumor versus normal tissue. In terms of treatment effects, a recent study in cancer patients suffering from chemotherapy-related cognitive impairment demonstrated seven perturbed gene expression pathways involved in neurotransmission, including impaired endocannabinoid signalling. 18 The adverse effects of chemotherapy have also been noted in preclinical studies showing that paclitaxel and cisplatin administration can induce ECS anomalies of the central nervous- and gastrointestinal systems which have been implicated in the genesis of both peripheral neuropathy and pain. 19 , 20 To our knowledge, there has been no investigation of ECS responses to exercise in any cancer population to date. 17 Therefore, the aim of this pilot study was to collect preliminary data comparing the effect of an acute (single) bout of aerobic exercise on circulating ECS markers and accompanying subjective mood (affective state) responses in adult cancer patients receiving chemotherapy versus their healthy peers. METHODS Study design and setting This study involved a controlled trial comparing the effect of a single bout of moderate-intensity aerobic exercise on circulating endocannabinoids and affective state (mood) responses in cancer patients versus their healthy peers. The St Vincent's Hospital Human Research Ethics Committee approved all procedures (2022/ETH00098) and all participants provided written informed consent. The study was performed in accordance with the World Medical Assembly Declaration of Helsinki 2008. Data were collected at the Supportive Care and Integrative Oncology Department of the Chris O’Brien Lifehouse (i.e. the COBL LivingRoom), Camperdown, NSW, between April 2022 and November 2024. Participants and recruitment As a pilot study, sample size estimates were pragmatic. We aimed to recruit 20 participants, 10 patients and 10 healthy controls. Participants were recruited through flyers advertisements and snowballing effect. Chris O’Brien Lifehouse healthcare personnel, including oncologists and oncology nurses were also consulted to directly refer patients into the study. Eligibility was assessed using standardized pre-screening checklists. Eligibility criteria : All participants were required to have sufficient English to understand study procedures. Cancer patients : Adults (> 18 years) currently receiving chemotherapy treatment for a non-hematological cancer with a 2 or 3-weekly protocol; Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 21 , medical approval of the treating oncologist ( via email). Healthy controls : Adults (> 18 years); gender-, age- (±5 years maximum) and BMI-matched (±5 kg/m 2 maximum) to a recruited cancer patient; no history of cancer; no history of cardiac, metabolic, pulmonary, neurological and/or uncontrolled risk factors. Exclusion criteria : current use of any cannabis products (e.g. CBD oil); current use of anti-depressant and/or anxiolytic medication; current use of steroids with the exception of standard chemotherapy protocols in cancer patients; any absolute or relative contraindication to clinical exercise testing. 22 Procedures and Outcomes All participants attended the COBL Living Room for a single data collection session lasting approximately 1.5 hr. The procedure involved a 30 min resting condition (control) followed by a 30 min exercise condition, with outcomes collected before and after each condition (Fig. 1). The session was scheduled for a day when cancer patients were not receiving any treatments and was timed prior to the next chemotherapy cycle including pre-treatment medications (e.g. steroids). All participants were instructed to avoid exercise and use of complementary therapies (e.g. acupuncture, massage, reflexology, yoga or meditation) within the previous 24 hr. Baseline data collection All participants completed a standardized demographic and medical history form including the assessment of height and body mass and using standard procedures. 22 Body mass index (BMI) was computed from these outcomes. Participants were also requested to self-select their exercise modality (i.e. standard exercise cycle, recumbent cycle, or treadmill). Cancer patients also completed an assessment of overall symptomology via the Edmonton Symptom Assessment Scale-17 (ESAS-17) and depression/anxiety symptoms via the Hospital Anxiety Depression Scale (HADS), both validated for use in clinical trials in this cohort. 23 , 24 Affective (mood) states : All participants then completed ten Visual Analog Scales (VAS); i.e. by placing a vertical slash mark on a 100mm horizontal line ranging from 0 to 100 indicating their current emotional state for: (i) pain, (ii) nausea, (iii) anger, (iv) sadness, (v) happiness, (vi) energy, (vii) fatigue, (viii) anxiety, (ix) euphoria, and (x) depression. This method has been employed in a previous trial evaluating ECS responses to acute exercise in healthy adults, 10 and validated and utilised in clinical trials and cancer care to identify symptoms of concern and their acute responses to treatment interventions. 25 . The VAS scales were re-assessed following a 30 min resting condition and 30 min exercise condition (Fig. 1). Blood sample for circulating ECS markers Blood samples were taken directly after baseline data collection, after the 30 min resting condition and after the 30 min exercise condition (Fig. 1). The baseline data collection concluded with the first of three blood samples being taken. All blood samples were collected by a trained professional into 10 mL heparinised tubes. A small cannula was inserted in the non-dominant arm and then removed at the end of the session. Resting condition (control, 30 min) : Immediately after the baseline data collection, participants were instructed to quietly rest (seated or lying down) in a quiet space with the option of reading a book or magazine of their choice for a 30-minute period. Mobile phones were placed on silent and out of reach of the participant. Heart rate and oxygen saturation (SpO 2 ) were collected at the beginning of the resting condition and at 1 min intervals thereafter, while blood pressure was collected at the beginning of the seated rest condition and at 5 min intervals thereafter. The VAS scales were collected immediately after the final round of observations (i.e. heart rate, SpO 2 and blood pressure) followed by the second blood sample. Exercise condition (30 min) : Immediately following the 30 min resting condition, the participant was asked to transfer to the exercise equipment; time taken to transfer was recorded. The participant was familiarised with the exercise equipment (i.e. Precor treadmill or Precor upright cycle or Monark RT2 recumbent cycle ergometer). Participants were required to achieve a moderate intensity heart rate (i.e. 64–76% of age-predicted maximal heart rate (HR max =208 – (0.7 × age)) 22 after a 5 min warm-up and then maintain this HR intensity range (64–76% of HR max ) for the next 20 minutes. Participants were then instructed to perform a 5-min cool-down with the aim of reducing heart rate to < 60% HR max . Treadmill speed/grade and cycle resistance were adjusted as required by the lead exercise physiologist (S.K.). Heart rate and SpO2 were collected at 1 min intervals throughout the exercise condition via iHealth pulse oximeter, while blood pressure (via manual Welsh Allyn DS66 trigger aneroid sphygmomanometer) and rating of perceived exertion (RPE) were recorded every 5 minutes. Recommended criteria for prematurely terminating the exercise condition was adhered to, as defined by the American College of Sports Medicine. 22 At the end of the exercise bout, the VAS scales were re-assessed, followed by a third blood sample. Runner’s High after the completion of the exercise bout, participants were asked “Did you experience a Runner’s high ” (Yes / No / I don’t know), as implemented in a previous trial. 10 Blood samples and assays Blood samples were immediately centrifuged under refrigeration (4°C) for 10 min at 2000g, and the plasma separated into aliquots before freezing at -80 o C. Heparinized plasma were stored until the end of the study and then analyzed at the National Institute of Complementary Medicine, Westmead, NSW. ECS markers, including endocannabinoids (i.e. AEA, 2-AG, 1-AG) and related biogenic lipids (i.e. PEA, OEA and SEA), were separated from plasma by a modified QuEChERS system and were quantified by subsequent LC-MS/MS analysis. The method and validation are fully described in Appendix A. Adverse events Adverse events were monitored throughout the present study, according to standard procedures. 26 Statistical analyses Statistical analyses were carried out using IBM SPSS Statistics Version 30.0.0 (IBM Corporation, Armonk, USA). All data were inspected visually and statistically for normality. Non-normally distributed variables were log-transformed prior to entry into linear models or analyzed using a nonparametric test (e.g. independent-samples median test). Main effects for time and group x time on dependent variables (i.e. baseline vs. post rest; post rest vs. post exercise) were evaluated using a general linear model (repeated measures). Normally distributed variables were described using mean ± SD and non-normally distributed data using median and ranges. Between group differences on continuous variables were evaluated using an independent samples T-test. Pearson and Spearman correlation coefficient was used to evaluate relationships between changes in circulating ECS markers and changes in affective states from rest to exercise. Statistical significance was set at p < 0.05. Effect sizes were reported as partial eta-squared (h p 2 ). RESULTS Participant flow A participant flow diagram is presented in the Supplementary material. In brief, 33 cancer patients and 22 healthy controls were reviewed; 10 participants per group were enrolled, consented and completed all study procedures. Participant characteristics are presented in Table 1. There were no significant differences between groups in terms of age, sex and BMI. Three healthy controls reported meeting exercise guidelines for both aerobic and resistance training, while three cancer patients reported sufficient aerobic exercise only and one healthy control reported sufficient resistance training only. 22 Nine healthy controls (90%) and three cancer patients (30%) currently consumed alcohol and only one cancer patient of was a current smoker. All cancer patients (n=10) had an ECOG score of 0 indicating ‘fully active, without restriction’. The ESAS-17 survey indicated low symptom burden with median scores across 17 domains ranging from 0-3 (out of a maximum score of 10). Two patients with the highest symptom burden scored ³5/10 on only 4 of 17 scales. All patients (n=10) scored in the ‘normal’ range for HADS-Depression, while nine patients scored ‘normal’ and one patient scored ‘borderline’ for HADS-Anxiety. The majority of patients had gastrointestinal cancer (7/10, 70%) and were treated with a fluorouracil-centred chemotherapy regimen (Table 1). Resting and exercise data Mean systolic and diastolic blood pressure and SpO 2 were also not significantly different between groups during the resting or exercise condition. However, mean resting heart rate was significantly elevated in the cancer patients (75±12 beats/min) during versus the healthy controls (61±11 beats/min; p=0.02). Three participants (one healthy control and two cancer patients) selected the treadmill as their preferred modality while all other participants selected the upright cycle. Mean heart rate achieved during the training period (20 min) were 75±3% and 75±5% of age-predicted maximal heart rate for the cancer patients and healthy controls, respectively. There were no significant differences in mean RPE or mean training intensity (expressed as %HR max ) between groups. Adverse events All participants completed the exercise protocol without adverse reactions and no adverse events were reported subsequent to the completion of all study protocols. Circulating ECS markers Notably, the cancer patients had lower levels of circulating AEA, OEA and log SEA versus the healthy controls at all timepoints (Table 2; Figure 2). These differences were significant (p<0.05) with the exception of one trend in AEA post exercise (p=0.06) There were also trends toward lower PEA in the cancer patients after the resting condition (p=0.07). Resting condition: Circulating ECS markers did not change from baseline to after the resting condition with the exception AEA, which decreased significantly in the cancer patients versus the healthy controls (h p 2 = 0.25; p=0.03; Table 2; Figure 1a). There was also a trend toward reduced log 2-AG (p=0.09) and log SEA (p=0.06) in the total cohort after the resting condition. Exercise condition: Circulating AEA (p=0.013; h p 2 =0.29), log 1-AG (p=0.048; h p 2 =0.20), OEA (p<0.001; h p 2 =0.59), PEA (p=0.004; h p 2 =0.37) and log SEA (p=0.006; h p 2 =0.35) all significantly increased with a large effect size after the exercise condition in the total cohort (time effect), while log 2-AG did not change (Table 2; Figure 1a-f). There were no significant between group (group x time) interaction effects for any circulating ECS marker. However, trends toward a larger increase of log 1-AG in the cancer patients (p=0.073) and a larger increase of OEA in the healthy controls (p=0.056) were detected (Table 1). Affective states No significant differences were noted between groups on any VAS outcome at any timepoint, indicating a low symptom burden reported by the cancer patients. Resting condition: Sadness decreased in the total cohort over time (p=0.02) with no other VAS changes noted after the resting condition. Exercise condition: Happiness increased in the total cohort (p=0.02; h p 2 =0.30) with no other VAS changes noted after the exercise condition. Experience of a Runner’s high Upon completion of the exercise condition, five of 10 participants in each group (50%) responded ‘yes’ to: “Did you experience a Runner’s high? ” Two cancer patients and three healthy controls replied ‘no’, while the remaining patients replied ‘don’t know’. Those who responded ‘yes’ to experiencing a Runner’s high did not experience a significantly greater response of any circulating ECS marker after exercise versus those who responded ‘no’ (all p³0.21). Relationships between ECS and affective states changes with exercise No associations were detected between changes in any affective state (VAS) scale and changes in circulating ECS outcomes from rest to exercise. DISCUSSION This pilot study compared the effect of acute, moderate-intensity aerobic exercise on circulating ECS markers and mood responses between cancer patients receiving chemotherapy and their apparently healthy peers. There were several key findings. In the total cohort, exercise significantly and with a large effect increased circulating endocannabinoids AEA and 1-AG, and endocannabinoid-like lipid mediators (i.e. OEA, PEA and SEA) with no change in 2-AG (Table 2 ; Fig. 2a-f). The cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers across all timepoints indicating potential ECS dysfunction (Fig. 2). Of the 10 affective states, only Happiness increased in the total cohort after exercise (p = 0.023) while 50% of participants (5 per group) reported experiencing a Runner’s high. Changes in ECS markers were not associated with changes in affective states. Our findings for core endocannabinoids, AEA and 2-AG, align with the evidence base. 15 In healthy adults, acute moderate-intensity aerobic exercise has consistently increased circulating AEA, while the effect on 2-AG is equivocal with 59.1% of studies reporting no change and 40.9% of studies reporting an increase according to systematic review data. 15 In the present study, the AEA response to exercise in cancer patients were not different to those experienced by their healthy peers. However, AEA remained at significantly lower or trending toward lower (p = 0.06), concentrations across all timepoints in the cancer patients (Fig. 2a). Sailler et al. 27 have documented lower plasma AEA (p < 0.001) coupled with higher plasma 2-AG (p < 0.001) in cancer patients with localised disease versus age- and sex-matched controls. However, AEA levels were elevated in patients with metastatic disesase. 27 Moreover, a separate study noted two-fold higher concentrations of circulating AEA and 2-AG in patients with cancer cachexia (BMI < 20kg/m 2 ) versus age and sex-matched peers (both p < 0.001). 28 Both endocannabinoids were positively correlated with C-reactive protein (CRP) (both p < 0.002), 28 a powerful predictor of cancer progression and mortality. 29 Our findings add support for investigating the clinical significance of circulating AEA and 2-AG in cancer progression, and the anti-cancer (risk reduction) effects of acute and chronic exercise on these biomarkers. Our 1-AG data is unique to the exercise literature. The exercise condition significantly increased 1-AG in the total cohort (p = 0.048) driven largely by an increase in the cancer group with a trend toward a group x time interaction effect (Fig. 2e; p = 0.073). This effect was also seen to a lesser degree in 2-AG (Fig. 2d; p = 0.15). 2-AG is considered to be the less thermodynamically stable monoacyl glycerol isomer, which is susceptible to rapid non-enymatic isomerisazation (acyl migration) in protic solvents to form 1-AG. 30 1-AG is considered an endocannabinoid due to its affinity for the CB 1 receptor, although it is reportedly far less potent than 2-AG. 12 However, previous studies of acute exercise in humans have not reported whether or not they achieved chromatographic resolution of 1-AG from 2-AG. 31 , 32 Such studies may have potentially reported 2-AG as the sum of both markers. Alternatively, 1-AG may have been disregarded by other studies, due to the common but not universal perception that is predominately formed ex vivo artefactually. 33 Additional research is required to provide transparant reporting on both 1-AG and 2-AG, as to clarify the effects of acute exercise and the clinical implications of these effects. The exercise condition significantly increased OEA (p < 0.001; h p 2 =0.59), PEA (p = 0.004; h p 2 =0.37) and log SEA (p = 0.006; h p 2 =0.35) with a large effect in the total cohort. These signalling lipids have endocannabinoid-like structure and function 13 are classified as N-acylethanolamines (NAEs), like AEA. 13 However, OEA, PEA and SEA have no affinity for CB 1 and CB 2 receptors and rather activate other G-protein coupled receptors, and ion channel and nuclear receptors. 13 Bioactivity of these NAEs includes anti-inflammatory, neuroprotective, anorectic and analgesic effects. 13 There is evidence that OEA 11 , 34 – 38 and/or PEA, 10 , 11 , 34 – 36 can be increased with prescribed, moderate-intensity aerobic exercise in healthy adults and those with mental health conditions including major depressive- and post-traumatic stress disorders. By contrast, self-selected intensities 34 , 38 and non-conventional exercise modalities (e.g. arm cycling) 39 have shown no effect on OEA, PEA or SEA, while acute resistance training has been shown to significantly decrease OEA and PEA. 40 Like AEA, our data showed that OEA and SEA levels were significantly lower in the cancer patients versus healthy controls across all timepoints (Fig. 2b,c,f). The significance of these findings is unclear. Hay et al. 41 noted that circulating OEA was significantly elevated in dogs with multicentric lymphoma versus their healthy controls. Additional research on the clinical significance and exercise effects on these NAEs is needed in humans. AEA, widely known as the bliss molecule , is considered a tonic neuromodulator as it continuously signals in the basal state and according to preclinical studies has been shown to elicit analgesic, anxiolytic and anti-depressant effects. 13 Studies in adult cohorts have shown that exercise-induced increases in circulating AEA correlate with increased vigor, 34 and reduced state anxiety, depression and fatigue, 38 however such associations have not been consistent. 42 While the total cohort did experience an improvement in Happiness (p = 0.023), we found no evidence that exercise-induced increases in AEA or other ECS marker were associated with affective state responses or the experience of the Runner’s high . There may be multiple reasons for these findings including low statistical power (sample size) and/or the measurements utilized. VAS are an adequate method to assess acute changes in affective state responses, including changes in euphoria in exercise studies. 16 However, the cancer patients in our study reported a low symptom burden, i.e. no difference in any VAS outcome versus the healthy controls. We cannot deduce whether this low symptom burden was accurate, or the result of study participation, e.g. the Hawthorne effect. 43 It is possible that scales other than VAS might have been more appropriate and responsive to change in the cohort we studied. For example, in a study of advanced cancer patients, the VAS scale was less preferred for reporting symptoms versus the Numerical Rating Scale and Categorial Response Scale. 44 Endocannabinoids (e.g. AEA and 2-AG) readily cross the blood-brain barrier and researchers have posited that they may play a mechanistic role in the subjective experience of exercise-induced euphoria in humans. 16 , 45 However, to date, there is no direct evidence that acute increases in peripheral endocannabinoids correlate with or directly contribute to ECS responses within the central nervous system. It could be that such effects are mutually exclusive, and that circulating ECS markers play a key role in mediating the normal sympathetic nervous system response to moderate-intensity exercise (i.e. along with pro-inflammatory markers such as CRP and interleukin-6 and − 10) rather than mediating affective states. 46 These are areas for future exploration. 16 In the resting condition, AEA decreased significantly while PEA tended to decrease in the cancer patients versus the healthy controls, while log 2-AG and log SEA tended to decrease in the total cohort. We were unable to determine if the resting condition induced a relaxation effect. Sadness significantly decreased in the total cohort after the resting condition (p = 0.02), but no other VAS scale changed. To our knowledge, there has been no formal investigation of the acute effect of meditation or other relaxation therapies on circulating ECS markers and this remains an avenue for further scientific inquiry. The main limitations of this study include the small sample size (low statistical power) and that we did not utilize a randomised, double-blind, cross-over study design, which is the gold standard for this type of investigation. Accordingly, we cannot rule that the ECS changes in our study were not influenced by factors such as circadian rhythm. 47 Future trials should aim to address such limitations. In summary, this study has demonstrated that acute, moderate-intensity aerobic exercise can significantly increase a number of circulating ECS markers in cancer patients and healthy adults including AEA, 1-AG, OEA, PEA and SEA). However, the cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers across all timepoints indicating potential ECS dysfunction. Of 10 affective states, only Happiness increased in the total cohort after exercise (p = 0.023). There was no correlation found between changes in circulating biomarkers and changes in affective states. Additional research is required to investigate the effect of various modalities and dosages of acute and chronic exercise on ECS markers and the clinical interpretation of these adaptations across a number of cancer populations. Declarations Conflicts of interest/competing interests All authors declare they have no competing interests. Funding information This research was supported by a research grant from the SurFebruary Fund. Author Contribution BSC is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. BSC, JL, SK, JS, and ML conceived and designed the study. SK, JL, JS, AG, SW, MH contributed to participant recruitment, data collection and data entry. Blood samples were analysed by ML and DH. BSC performed the statistical analyses and drafted the manuscript. All authors interpreted the data, revised the draft and have read and approved the final version of the manuscript. 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Tables Table 1: Characteristics of the healthy control and cancer patient groups Characteristic Healthy Control Group (n=10) Cancer Patient Group (n=10) Age (y) 54.3 ± 15.7 54.0 ± 15.4 Women:Men 6:4 6:4 Body weight (kg) 72.1 ± 13.5 70.1 ± 16.1 Height (cm) 171.9 ± 7.4 169.9 ± 6.8 Body Mass Index (kg/m 2 ) 24.2 ± 2.7 23.9 ± 4.3 Lifestyle habits (n): -Moderate-intensity aerobic exercise >150min/wk -Resistance training >2 sessions/wk -Current smoker -Current alcohol intake 3 4 0 9 3 0 1 3 Cancer Type (n): - Pancreatic - Colorectal - Periampullary - Gastro-esophageal - Biliary tract - Breast - Ovarian N/A 3 2 1 1 1 1 1 Chemotherapy protocol (n) - FOLFIRINOX - FOLFOX - FOLFIRI - Cisplatin and gemcitabine - Oxaliplatin and capecitabine - TCHP N/A 3 3 1 1 1 1 Continuous variables reported according to mean ± standard deviation FOLFIRINOX: folic acid, fluorouracil, irinotecan, oxaliplatin; FOLFOX: folinic acid, fluorouracil, oxaliplatin; FOLFIRI: folic acid, fluorouracil, irinotecan; TCHP: docetaxel, carboplatin, trastuzumab, pertuzumab Table 2: Summary of outcome measures and effects of the exercise condition Healthy Control Group Cancer Patient Group Exercise Effects Baseline Post Rest Post Exercise Baseline Post Rest Post Exercise Time (p-value) Group x Time (p-value) Circulating ECS markers AEA (ng/mL) 0.274 ± 0.064 0.281 ± 0.086 0.380 ± 0.205 0.195 ± 0.077 † 0.158 ± 0.070 †* 0.229 ± 0.125 0.013 0.66 Log 2-AG 0.383 ± 0.270 0.271 ± 0.241 0.264 ± 0.257 0.308 ± 0.277 0.215 ± 0.336 0.344 ± 0.319 0.19 0.15 Log 1-AG 0.335 ± 0.261 0.247 ± 0.295 0.255 ± 0.255 0.232 ± 0.344 0.222 ± 0.340 0.388 ± 0.317 0.048 0.073 OEA (ng/mL) 1.66 ± 0.54 1.71 ± 0.68 2.54 ± 1.17 1.04 ± 0.36 † 1.02 ± 0.39 † 1.37 ± 0.53 † <0.001 0.056 PEA (ng/mL) 1.37 ± 0.27 1.40 ± 0.44 1.57 ± 0.49 1.14 ± 0.39 1.07 ± 0.33 1.28 ± 0.43 0.004 0.70 Log-SEA -0.174 ± 0.253 -0.222 ± 0.273 -0.154 ± 0.316 -0.441 ± 0.135 † -0.472 ± 0.139 † -0.393 ± 0.116 † 0.006 0.82 Visual Analog Scales (0-100) Pain 1 (0-24) 0 (0-5) 3 (0-9) 7 (0-35) 3.5 (0-12) 2.5 (0-21) 0.87 1.0 Nausea 0 (0-9) 0 (0-5) 0 (0-4) 3.5 (0-43) 5 (0-25) 3 (0-24) 0.88 0.30 Anger 0 (0-10) 0 (0-1) 0 (0-3) 1.5 (0-26) 0 (0-13) 0.5 (0-4) 0.92 0.58 Sadness 7 (0-19) 0 (0-4) ‡ 0 (0-3) 10 (0-37) 0 (0-15) ‡ 0 (0-15) 0.64 1.0 Happiness 72 ± 13 71 ± 23 78 ± 14 68 ± 18 72 ± 16 78 ± 8 0.023 0.37 Energy 59 ± 20 62 ± 20 75 ± 20 56 ± 15 62 ± 12 65±15 0.25 0.43 Fatigue 14.5 (0-70) 30 (0-72) 22 (0-74) 25.5 (0-63) 23 (0-58) 28 (0-63) 0.87 1.0 Anxiety 15.5 (0-50) 7.5 (0-37) 9 (0-100) 0.5 (0-67) 3 (0-50) 0.5 (0-34) 0.41 1.0 Euphoria 34 (0-80) 50 (0-87) 66 (8-84) 36.5 (0-65) 50 (0-92) 67.5 (1-88) 0.24 0.66 Depression 0 (0-21) 3 (0-21) 0 (0-5) 1.5 (0-50) 2.5 (0-50) 2 (0-27) 0.87 0.58 Data presented as mean + standard deviation except 8 of 10 visual analog scales (i.e. pain, nausea, anger, sadness, fatigue, anxiety, euphoria, depression) with non-parametric distribution, which are presented as median (range). * Significant group x time effect for the resting condition ‡ Significant time effect for the resting condition † Significantly lower versus healthy control group at corresponding timepoint Additional Declarations No competing interests reported. Supplementary Files CheemaECSsupplementary.docx CheemaECBAppendixA.docx Cite Share Download PDF Status: Published Journal Publication published 02 Dec, 2025 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 17 Oct, 2025 Reviewers agreed at journal 25 Sep, 2025 Reviews received at journal 23 Sep, 2025 Reviewers agreed at journal 19 Sep, 2025 Reviewers invited by journal 18 Sep, 2025 Editor assigned by journal 10 Aug, 2025 Submission checks completed at journal 04 Jul, 2025 First submitted to journal 02 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-7028112\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":522495435,\"identity\":\"56277464-c900-4542-9c18-f42650d257a3\",\"order_by\":0,\"name\":\"Birinder S. 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09:48:14\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":50033,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eConditions and timepoints for data collection\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7028112/v1/16950d9d0e4029f16a483acc.png\"},{\"id\":92491365,\"identity\":\"c862f0a5-4bb9-4fb3-9e02-92083ca56d1a\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 09:40:14\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":167675,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eCirculating ECS markers across three timepoints († significantly lower [ ] versus healthy control group, all p\\u0026lt;0.05)\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7028112/v1/813150e2e4acc793530017d3.png\"},{\"id\":97724817,\"identity\":\"03988625-3dd2-4d56-aee9-97cef9b9137d\",\"added_by\":\"auto\",\"created_at\":\"2025-12-08 16:13:37\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1183101,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7028112/v1/bf7972ab-121c-404f-9c80-091054a79591.pdf\"},{\"id\":92491366,\"identity\":\"1fd677fb-a25b-4f83-a544-11ddd14b29e3\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 09:40:14\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":28425,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"CheemaECSsupplementary.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7028112/v1/890a53665f45f7ba48ff63e4.docx\"},{\"id\":92491375,\"identity\":\"c148390a-df8d-477d-b7cb-8a18988bea4f\",\"added_by\":\"auto\",\"created_at\":\"2025-09-30 09:40:14\",\"extension\":\"docx\",\"order_by\":3,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":34442,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"CheemaECBAppendixA.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7028112/v1/7c55cd7ce493ff7f1cf4c660.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls\",\"fulltext\":[{\"header\":\"Implications for Cancer Survivors\",\"content\":\"\\u003cul\\u003e\\n \\u003cli\\u003eAcute, moderate-intensity aerobic exercise increased endocannabinoids anandamide (AEA) and 1-AG along with endocannabinoid-like mediators (OEA, PEA and SEA) and subjective feelings of Happiness in both cancer patients and their healthy peers;\\u003c/li\\u003e\\n \\u003cli\\u003eHowever, the cancer patients exhibited lower levels of anandamide (AEA), OEA and SEA both before and after exercise versus their healthy peers;\\u003c/li\\u003e\\n \\u003cli\\u003eMore research is required to investigate how cancer treatments and exercise affect the endocannabinoid system and the clinical meaningfulness of these changes across a range of cancer populations. \\u0026nbsp;\\u003c/li\\u003e\\n\\u003c/ul\\u003e\"},{\"header\":\"INTRODUCTION\",\"content\":\"\\u003cp\\u003eClinical trials over the past 40 years have shown that exercise in cancer patients is safe and can counteract many side effects of treatment, as well as elicit an array of health-related benefits including enhanced quality of life (QoL).\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e Despite these findings, the vast majority of cancer patients do not meet minimum physical activity guidelines.\\u003csup\\u003e\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e\\u003c/sup\\u003e Many are challenged by self-reported symptoms including fatigue (low energy), pain, appetite dysregulation, insomnia, cognitive impairment, depression, anxiety, low self-efficacy and poor motivation.\\u003csup\\u003e\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e These symptoms often act as barriers to exercise participation while, paradoxically, the data also show that exercise can mitigate these conditions.\\u003csup\\u003e\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u003c/sup\\u003e However, the biological adaptations underlying the subjectively-experienced benefits of exercise in cancer patients are not known and require investigation.\\u003c/p\\u003e\\u003cp\\u003eEvidence from apparently healthy adults has shown that acute exercise can improve mood and induce transient pleasurable sensations including a state of euphoria colloquially known as the \\u003cem\\u003eRunner’s high\\u003c/em\\u003e.\\u003csup\\u003e\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e Additional terms ascribed to the pleasurable sensations induced by exercise have also included: ‘happiness’, ‘elation’, ‘joy’, ‘inner harmony’, ‘boundless energy’ and ‘ecstasy.’\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e The \\u003cem\\u003eRunner’s high\\u003c/em\\u003e was believed to be induced by the release of opiate peptides (endorphins) given their effect on pleasure-inducing and pain-mitigating (analgesic) biochemical pathways.\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e However, the central role of endorphins has not been supported by the evidence to date.\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003eMore recent data suggest that the endocannabinoid system (ECS) may be involved in mediating the improvement of subjective, mood-related outcomes (i.e. affective states).\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u003c/sup\\u003e The ECS consists of G protein-coupled cannabinoid receptors subtypes (CB\\u003csub\\u003e1\\u003c/sub\\u003e and CB\\u003csub\\u003e2\\u003c/sub\\u003e), endocannabinoids that have affinity for these receptors (e.g. N-arachidonoylethanolamine (AEA, anandamide, i.e. \\u003cem\\u003ethe bliss molecule\\u003c/em\\u003e), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG)),\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e endocannabinoid-like lipid mediators (e.g. palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA))\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e and the enzymes, cells and neural pathways involved in endocannabinoid signalling and metabolism.\\u003csup\\u003e\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e Recent systematic reviews have demonstrated that acute, moderate-to-vigorous intensity aerobic exercise (~ 30min) can significantly increase circulating endocannabinoids (AEA and/or 2-AG) and specific endocannabinoid-like lipid mediators (i.e. PEA and OEA) in healthy adults, and those with specific chronic conditions including mental health disorders (e.g. major depressive disorder, post-traumatic stress disorder, substance abuse).\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR16\\\" citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e These responses have been consistently accompanied by the improvement of affective states including increased euphoria and vigour, and reduced anxiety, depression and fatigue. Such adaptations may be of clinical importance to cancer patients at risk of experiencing treatment-related side effects.\\u003c/p\\u003e\\u003cp\\u003eWe have recently synthesized evidence indicating that cancer patients may suffer from ECS dysfunction, which may induced by disease-specific risk factors, the cancer itself (e.g. tumour microenvironment) and cancer treatment.\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e For example, altered CB\\u003csub\\u003e1\\u003c/sub\\u003e and CB\\u003csub\\u003e2\\u003c/sub\\u003e expression, heteromerization and function have been shown to play a role in the genesis of common cancers (e.g. breast, prostate, colorectal, lung) along with elevated concentrations of AEA and 2-AG in tumor versus normal tissue. In terms of treatment effects, a recent study in cancer patients suffering from chemotherapy-related cognitive impairment demonstrated seven perturbed gene expression pathways involved in neurotransmission, including impaired endocannabinoid signalling.\\u003csup\\u003e\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e The adverse effects of chemotherapy have also been noted in preclinical studies showing that paclitaxel and cisplatin administration can induce ECS anomalies of the central nervous- and gastrointestinal systems which have been implicated in the genesis of both peripheral neuropathy and pain.\\u003csup\\u003e\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003eTo our knowledge, there has been no investigation of ECS responses to exercise in any cancer population to date.\\u003csup\\u003e\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u003c/sup\\u003e Therefore, the aim of this pilot study was to collect preliminary data comparing the effect of an acute (single) bout of aerobic exercise on circulating ECS markers and accompanying subjective mood (affective state) responses in adult cancer patients receiving chemotherapy versus their healthy peers.\\u003c/p\\u003e\"},{\"header\":\"METHODS\",\"content\":\"\\u003cp\\u003e\\u003cb\\u003eStudy design and setting\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eThis study involved a controlled trial comparing the effect of a single bout of moderate-intensity aerobic exercise on circulating endocannabinoids and affective state (mood) responses in cancer patients versus their healthy peers. The St Vincent's Hospital Human Research Ethics Committee approved all procedures (2022/ETH00098) and all participants provided written informed consent. The study was performed in accordance with the World Medical Assembly Declaration of Helsinki 2008. Data were collected at the Supportive Care and Integrative Oncology Department of the Chris O’Brien Lifehouse (i.e. the COBL LivingRoom), Camperdown, NSW, between April 2022 and November 2024.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eParticipants and recruitment\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eAs a pilot study, sample size estimates were pragmatic. We aimed to recruit 20 participants, 10 patients and 10 healthy controls. Participants were recruited through flyers advertisements and snowballing effect. Chris O’Brien Lifehouse healthcare personnel, including oncologists and oncology nurses were also consulted to directly refer patients into the study. Eligibility was assessed using standardized pre-screening checklists.\\u003c/p\\u003e\\u003cp\\u003e\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003eEligibility criteria\\u003c/span\\u003e: All participants were required to have sufficient English to understand study procedures. \\u003cem\\u003eCancer patients\\u003c/em\\u003e: Adults (\\u0026gt; 18 years) currently receiving chemotherapy treatment for a non-hematological cancer with a 2 or 3-weekly protocol; Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 \\u003csup\\u003e21\\u003c/sup\\u003e, medical approval of the treating oncologist (\\u003cem\\u003evia\\u003c/em\\u003e email). \\u003cem\\u003eHealthy controls\\u003c/em\\u003e: Adults (\\u0026gt; 18 years); gender-, age- (±5 years maximum) and BMI-matched (±5 kg/m\\u003csup\\u003e2\\u003c/sup\\u003e maximum) to a recruited cancer patient; no history of cancer; no history of cardiac, metabolic, pulmonary, neurological and/or uncontrolled risk factors.\\u003c/p\\u003e\\u003cp\\u003e\\u003cspan type=\\\"Underline\\\" class=\\\"Underline\\\" name=\\\"Emphasis\\\"\\u003eExclusion criteria\\u003c/span\\u003e: current use of any cannabis products (e.g. CBD oil); current use of anti-depressant and/or anxiolytic medication; current use of steroids with the exception of standard chemotherapy protocols in cancer patients; any absolute or relative contraindication to clinical exercise testing.\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eProcedures and Outcomes\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eAll participants attended the COBL Living Room for a single data collection session lasting approximately 1.5 hr. The procedure involved a 30 min resting condition (control) followed by a 30 min exercise condition, with outcomes collected before and after each condition (Fig.\\u0026nbsp;1). The session was scheduled for a day when cancer patients were not receiving any treatments and was timed prior to the next chemotherapy cycle including pre-treatment medications (e.g. steroids). All participants were instructed to avoid exercise and use of complementary therapies (e.g. acupuncture, massage, reflexology, yoga or meditation) within the previous 24 hr.\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eBaseline data collection\\u003c/em\\u003e\\u003c/p\\u003e\\u003cp\\u003eAll participants completed a standardized demographic and medical history form including the assessment of height and body mass and using standard procedures.\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e Body mass index (BMI) was computed from these outcomes. Participants were also requested to self-select their exercise modality (i.e. standard exercise cycle, recumbent cycle, or treadmill). Cancer patients also completed an assessment of overall symptomology \\u003cem\\u003evia\\u003c/em\\u003e the Edmonton Symptom Assessment Scale-17 (ESAS-17) and depression/anxiety symptoms \\u003cem\\u003evia\\u003c/em\\u003e the Hospital Anxiety Depression Scale (HADS), both validated for use in clinical trials in this cohort.\\u003csup\\u003e\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eAffective (mood) states\\u003c/em\\u003e: All participants then completed ten Visual Analog Scales (VAS); i.e. by placing a vertical slash mark on a 100mm horizontal line ranging from 0 to 100 indicating their current emotional state for: (i) pain, (ii) nausea, (iii) anger, (iv) sadness, (v) happiness, (vi) energy, (vii) fatigue, (viii) anxiety, (ix) euphoria, and (x) depression. This method has been employed in a previous trial evaluating ECS responses to acute exercise in healthy adults,\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e and validated and utilised in clinical trials and cancer care to identify symptoms of concern and their acute responses to treatment interventions.\\u003csup\\u003e\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e. The VAS scales were re-assessed following a 30 min resting condition and 30 min exercise condition (Fig.\\u0026nbsp;1).\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eBlood sample for circulating ECS markers\\u003c/strong\\u003e\\u003c/p\\u003e\\u003cp\\u003eBlood samples were taken directly after baseline data collection, after the 30 min resting condition and after the 30 min exercise condition (Fig.\\u0026nbsp;1). The baseline data collection concluded with the first of three blood samples being taken. All blood samples were collected by a trained professional into 10 mL heparinised tubes. A small cannula was inserted in the non-dominant arm and then removed at the end of the session.\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eResting condition (control, 30 min)\\u003c/em\\u003e:\\u003c/p\\u003e\\u003cp\\u003eImmediately after the baseline data collection, participants were instructed to quietly rest (seated or lying down) in a quiet space with the option of reading a book or magazine of their choice for a 30-minute period. Mobile phones were placed on silent and out of reach of the participant. Heart rate and oxygen saturation (SpO\\u003csub\\u003e2\\u003c/sub\\u003e) were collected at the beginning of the resting condition and at 1 min intervals thereafter, while blood pressure was collected at the beginning of the seated rest condition and at 5 min intervals thereafter. The VAS scales were collected immediately after the final round of observations (i.e. heart rate, SpO\\u003csub\\u003e2\\u003c/sub\\u003e and blood pressure) followed by the second blood sample.\\u003c/p\\u003e\\u003cp\\u003e\\u003cem\\u003eExercise condition (30 min)\\u003c/em\\u003e:\\u003c/p\\u003e\\u003cp\\u003eImmediately following the 30 min resting condition, the participant was asked to transfer to the exercise equipment; time taken to transfer was recorded. The participant was familiarised with the exercise equipment (i.e. Precor treadmill or Precor upright cycle or Monark RT2 recumbent cycle ergometer). Participants were required to achieve a moderate intensity heart rate (i.e. 64–76% of age-predicted maximal heart rate (HR\\u003csub\\u003emax\\u003c/sub\\u003e=208 – (0.7 × age)) \\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e after a 5 min warm-up and then maintain this HR intensity range (64–76% of HR\\u003csub\\u003emax\\u003c/sub\\u003e) for the next 20 minutes. Participants were then instructed to perform a 5-min cool-down with the aim of reducing heart rate to \\u0026lt; 60% HR\\u003csub\\u003emax\\u003c/sub\\u003e. Treadmill speed/grade and cycle resistance were adjusted as required by the lead exercise physiologist (S.K.). Heart rate and SpO2 were collected at 1 min intervals throughout the exercise condition via iHealth pulse oximeter, while blood pressure (via manual Welsh Allyn DS66 trigger aneroid sphygmomanometer) and rating of perceived exertion (RPE) were recorded every 5 minutes. Recommended criteria for prematurely terminating the exercise condition was adhered to, as defined by the American College of Sports Medicine.\\u003csup\\u003e\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e At the end of the exercise bout, the VAS scales were re-assessed, followed by a third blood sample.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eRunner’s High\\u003c/strong\\u003e\\u003c/p\\u003e\\u003cp\\u003eafter the completion of the exercise bout, participants were asked “Did you experience a \\u003cem\\u003eRunner’s high\\u003c/em\\u003e” (Yes / No / I don’t know), as implemented in a previous trial.\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eBlood samples and assays\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eBlood samples were immediately centrifuged under refrigeration (4°C) for 10 min at 2000g, and the plasma separated into aliquots before freezing at -80 \\u003csup\\u003eo\\u003c/sup\\u003eC. Heparinized plasma were stored until the end of the study and then analyzed at the National Institute of Complementary Medicine, Westmead, NSW. ECS markers, including endocannabinoids (i.e. AEA, 2-AG, 1-AG) and related biogenic lipids (i.e. PEA, OEA and SEA), were separated from plasma by a modified QuEChERS system and were quantified by subsequent LC-MS/MS analysis. The method and validation are fully described in Appendix A.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eAdverse events\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eAdverse events were monitored throughout the present study, according to standard procedures.\\u003csup\\u003e\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eStatistical analyses\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eStatistical analyses were carried out using IBM SPSS Statistics Version 30.0.0 (IBM Corporation, Armonk, USA). All data were inspected visually and statistically for normality. Non-normally distributed variables were log-transformed prior to entry into linear models or analyzed using a nonparametric test (e.g. independent-samples median test). Main effects for time and group x time on dependent variables (i.e. baseline vs. post rest; post rest vs. post exercise) were evaluated using a general linear model (repeated measures). Normally distributed variables were described using mean ± SD and non-normally distributed data using median and ranges. Between group differences on continuous variables were evaluated using an independent samples T-test. Pearson and Spearman correlation coefficient was used to evaluate relationships between changes in circulating ECS markers and changes in affective states from rest to exercise. Statistical significance was set at p \\u0026lt; 0.05. Effect sizes were reported as partial eta-squared (h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u003c/sup\\u003e).\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eParticipant flow\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA participant flow diagram is presented in the Supplementary material. \\u0026nbsp; In brief, 33 cancer patients and 22 healthy controls were reviewed; 10 participants per group were enrolled, consented and completed all study procedures. \\u0026nbsp;Participant characteristics are presented in Table 1. \\u0026nbsp;There were no significant differences between groups in terms of age, sex and BMI. \\u0026nbsp;Three healthy controls reported meeting exercise guidelines for both aerobic and resistance training, while three cancer patients reported sufficient aerobic exercise only and one healthy control reported sufficient resistance training only. \\u003ca href=\\\"#_ENREF_22\\\" title=\\\"American College of Sports Medicine, 2022 #144\\\"\\u003e\\u003csup\\u003e22\\u003c/sup\\u003e\\u003c/a\\u003e Nine healthy controls (90%) and three cancer patients (30%) currently consumed alcohol and only one cancer patient of was a current smoker. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAll cancer patients (n=10) had an ECOG score of 0 indicating \\u0026lsquo;fully active, without restriction\\u0026rsquo;. \\u0026nbsp;The ESAS-17 survey indicated low symptom burden with median scores across 17 domains ranging from 0-3 (out of a maximum score of 10). \\u0026nbsp;Two patients with the highest symptom burden scored \\u0026sup3;5/10 on only 4 of 17 scales. \\u0026nbsp; All patients (n=10) scored in the \\u0026lsquo;normal\\u0026rsquo; range for HADS-Depression, while nine patients scored \\u0026lsquo;normal\\u0026rsquo; and one patient scored \\u0026lsquo;borderline\\u0026rsquo; for HADS-Anxiety. \\u0026nbsp; The majority of patients had gastrointestinal cancer (7/10, 70%) and were treated with a fluorouracil-centred chemotherapy regimen (Table 1). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResting and exercise data\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMean systolic and diastolic blood pressure and\\u0026nbsp;SpO\\u003csub\\u003e2\\u0026nbsp;\\u003c/sub\\u003ewere also not significantly different between groups during the resting or exercise condition. \\u0026nbsp;However, mean resting heart rate was significantly elevated in the cancer patients (75\\u0026plusmn;12 beats/min) during versus the healthy controls (61\\u0026plusmn;11 beats/min; p=0.02). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThree participants (one healthy control and two cancer patients) selected the treadmill as their preferred modality while all other participants selected the upright cycle. \\u0026nbsp;Mean heart rate achieved during the training period (20 min) were 75\\u0026plusmn;3% and 75\\u0026plusmn;5% of age-predicted maximal heart rate for the cancer patients and healthy controls, respectively. \\u0026nbsp;There were no significant differences in mean RPE or mean training intensity (expressed as %HR\\u003csub\\u003emax\\u003c/sub\\u003e) between groups. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAdverse events\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll participants completed the exercise protocol without adverse reactions and no adverse events were reported subsequent to the completion of all study protocols. \\u0026nbsp;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCirculating ECS markers\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNotably, the cancer patients had lower levels of circulating AEA, OEA and log SEA versus the healthy controls at all timepoints (Table 2; Figure 2). \\u0026nbsp;These differences were significant (p\\u0026lt;0.05) with the exception of one trend in AEA post exercise (p=0.06) There were also trends toward lower PEA in the cancer patients after the resting condition (p=0.07). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eResting condition:\\u003c/em\\u003e\\u0026nbsp; Circulating ECS markers did not change from baseline to after the resting condition with the exception AEA, which decreased significantly in the cancer patients versus the healthy controls (h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e= 0.25; p=0.03; Table 2; Figure 1a). \\u0026nbsp;There was also a trend toward reduced log 2-AG (p=0.09) and log SEA (p=0.06) in the total cohort after the resting condition. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eExercise condition:\\u0026nbsp;\\u003c/em\\u003eCirculating AEA (p=0.013;\\u0026nbsp;h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.29), log 1-AG (p=0.048;\\u0026nbsp;h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.20), OEA (p\\u0026lt;0.001;\\u0026nbsp;h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.59), PEA (p=0.004;\\u0026nbsp;h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.37) and log SEA (p=0.006;\\u0026nbsp;h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.35) all significantly increased with a large effect size after the exercise condition in the total cohort (time effect), while log 2-AG did not change (Table 2; Figure 1a-f). \\u0026nbsp; \\u0026nbsp;There were no significant between group (group x time) interaction effects for any circulating ECS marker. \\u0026nbsp;However, trends toward a larger increase of log 1-AG in the cancer patients (p=0.073) and a larger increase of OEA in the healthy controls (p=0.056) were detected (Table 1). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAffective states \\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNo significant differences were noted between groups on any VAS outcome at any timepoint, indicating a low symptom burden reported by the cancer patients. \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eResting condition:\\u003c/em\\u003e Sadness decreased in the total cohort over time (p=0.02) with no other VAS changes noted after the resting condition. \\u0026nbsp;\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eExercise condition:\\u003c/em\\u003e\\u0026nbsp; Happiness increased in the total cohort (p=0.02; h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.30) with no other VAS changes noted after the exercise condition.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eExperience of a \\u003cem\\u003eRunner\\u0026rsquo;s high\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eUpon completion of the exercise condition, five of 10 participants in each group (50%) responded \\u0026lsquo;yes\\u0026rsquo; to: \\u0026ldquo;Did you experience a \\u003cem\\u003eRunner\\u0026rsquo;s high?\\u003c/em\\u003e\\u0026rdquo; \\u0026nbsp; Two cancer patients and three healthy controls replied \\u0026lsquo;no\\u0026rsquo;, while the remaining patients replied \\u0026lsquo;don\\u0026rsquo;t know\\u0026rsquo;. \\u0026nbsp;Those who responded \\u0026lsquo;yes\\u0026rsquo; to experiencing a \\u003cem\\u003eRunner\\u0026rsquo;s high\\u0026nbsp;\\u003c/em\\u003edid not experience a significantly greater response of any circulating ECS marker after exercise versus those who responded \\u0026lsquo;no\\u0026rsquo; (all p\\u0026sup3;0.21).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRelationships between ECS and affective states changes with exercise\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNo associations were detected between changes in any affective state (VAS) scale and changes in circulating ECS outcomes from rest to exercise.\\u003c/p\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eThis pilot study compared the effect of acute, moderate-intensity aerobic exercise on circulating ECS markers and mood responses between cancer patients receiving chemotherapy and their apparently healthy peers. There were several key findings. In the total cohort, exercise significantly and with a large effect increased circulating endocannabinoids AEA and 1-AG, and endocannabinoid-like lipid mediators (i.e. OEA, PEA and SEA) with no change in 2-AG (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e; Fig.\\u0026nbsp;2a-f). The cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers across all timepoints indicating potential ECS dysfunction (Fig.\\u0026nbsp;2). Of the 10 affective states, only Happiness increased in the total cohort after exercise (p\\u0026thinsp;=\\u0026thinsp;0.023) while 50% of participants (5 per group) reported experiencing a \\u003cem\\u003eRunner\\u0026rsquo;s high.\\u003c/em\\u003e Changes in ECS markers were not associated with changes in affective states.\\u003c/p\\u003e\\u003cp\\u003eOur findings for core endocannabinoids, AEA and 2-AG, align with the evidence base.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e In healthy adults, acute moderate-intensity aerobic exercise has consistently increased circulating AEA, while the effect on 2-AG is equivocal with 59.1% of studies reporting no change and 40.9% of studies reporting an increase according to systematic review data.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e In the present study, the AEA response to exercise in cancer patients were not different to those experienced by their healthy peers. However, AEA remained at significantly lower or trending toward lower (p\\u0026thinsp;=\\u0026thinsp;0.06), concentrations across all timepoints in the cancer patients (Fig.\\u0026nbsp;2a). Sailler \\u003cem\\u003eet al.\\u003c/em\\u003e\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e have documented lower plasma AEA (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) coupled with higher plasma 2-AG (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) in cancer patients with localised disease versus age- and sex-matched controls. However, AEA levels were elevated in patients with metastatic disesase.\\u003csup\\u003e\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u003c/sup\\u003e Moreover, a separate study noted two-fold higher concentrations of circulating AEA and 2-AG in patients with cancer cachexia (BMI\\u0026thinsp;\\u0026lt;\\u0026thinsp;20kg/m\\u003csup\\u003e2\\u003c/sup\\u003e) versus age and sex-matched peers (both p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001).\\u003csup\\u003e28\\u003c/sup\\u003e Both endocannabinoids were positively correlated with C-reactive protein (CRP) (both p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.002),\\u003csup\\u003e28\\u003c/sup\\u003e a powerful predictor of cancer progression and mortality.\\u003csup\\u003e\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u003c/sup\\u003e Our findings add support for investigating the clinical significance of circulating AEA and 2-AG in cancer progression, and the anti-cancer (risk reduction) effects of acute and chronic exercise on these biomarkers.\\u003c/p\\u003e\\u003cp\\u003eOur 1-AG data is unique to the exercise literature. The exercise condition significantly increased 1-AG in the total cohort (p\\u0026thinsp;=\\u0026thinsp;0.048) driven largely by an increase in the cancer group with a trend toward a group x time interaction effect (Fig.\\u0026nbsp;2e; p\\u0026thinsp;=\\u0026thinsp;0.073). This effect was also seen to a lesser degree in 2-AG (Fig.\\u0026nbsp;2d; p\\u0026thinsp;=\\u0026thinsp;0.15). 2-AG is considered to be the less thermodynamically stable monoacyl glycerol isomer, which is susceptible to rapid non-enymatic isomerisazation (acyl migration) in protic solvents to form 1-AG.\\u003csup\\u003e\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e\\u003c/sup\\u003e 1-AG is considered an endocannabinoid due to its affinity for the CB\\u003csub\\u003e1\\u003c/sub\\u003e receptor, although it is reportedly far less potent than 2-AG.\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e However, previous studies of acute exercise in humans have not reported whether or not they achieved chromatographic resolution of 1-AG from 2-AG.\\u003csup\\u003e\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e Such studies may have potentially reported 2-AG as the sum of both markers. Alternatively, 1-AG may have been disregarded by other studies, due to the common but not universal perception that is predominately formed \\u003cem\\u003eex vivo\\u003c/em\\u003e artefactually.\\u003csup\\u003e\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e\\u003c/sup\\u003e Additional research is required to provide transparant reporting on both 1-AG and 2-AG, as to clarify the effects of acute exercise and the clinical implications of these effects.\\u003c/p\\u003e\\u003cp\\u003eThe exercise condition significantly increased OEA (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001; h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.59), PEA (p\\u0026thinsp;=\\u0026thinsp;0.004; h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.37) and log SEA (p\\u0026thinsp;=\\u0026thinsp;0.006; h\\u003csub\\u003ep\\u003c/sub\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e=0.35) with a large effect in the total cohort. These signalling lipids have endocannabinoid-like structure and function\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e are classified as N-acylethanolamines (NAEs), like AEA.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e However, OEA, PEA and SEA have no affinity for CB\\u003csub\\u003e1\\u003c/sub\\u003e and CB\\u003csub\\u003e2\\u003c/sub\\u003e receptors and rather activate other G-protein coupled receptors, and ion channel and nuclear receptors.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e Bioactivity of these NAEs includes anti-inflammatory, neuroprotective, anorectic and analgesic effects.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e There is evidence that OEA\\u003csup\\u003e\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR35 CR36 CR37\\\" citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e\\u003c/sup\\u003e and/or PEA,\\u003csup\\u003e\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR35\\\" citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u003c/sup\\u003e can be increased with prescribed, moderate-intensity aerobic exercise in healthy adults and those with mental health conditions including major depressive- and post-traumatic stress disorders. By contrast, self-selected intensities\\u003csup\\u003e\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e\\u003c/sup\\u003e and non-conventional exercise modalities (e.g. arm cycling)\\u003csup\\u003e\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e\\u003c/sup\\u003e have shown no effect on OEA, PEA or SEA, while acute resistance training has been shown to significantly decrease OEA and PEA.\\u003csup\\u003e\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e\\u003c/sup\\u003e Like AEA, our data showed that OEA and SEA levels were significantly lower in the cancer patients versus healthy controls across all timepoints (Fig.\\u0026nbsp;2b,c,f). The significance of these findings is unclear. Hay \\u003cem\\u003eet al.\\u003c/em\\u003e\\u003csup\\u003e\\u003cem\\u003e\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e\\u003c/em\\u003e\\u003c/sup\\u003e noted that circulating OEA was significantly elevated in dogs with multicentric lymphoma versus their healthy controls. Additional research on the clinical significance and exercise effects on these NAEs is needed in humans.\\u003c/p\\u003e\\u003cp\\u003eAEA, widely known as \\u003cem\\u003ethe bliss molecule\\u003c/em\\u003e, is considered a tonic neuromodulator as it continuously signals in the basal state and according to preclinical studies has been shown to elicit analgesic, anxiolytic and anti-depressant effects.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e Studies in adult cohorts have shown that exercise-induced increases in circulating AEA correlate with increased vigor,\\u003csup\\u003e\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e and reduced state anxiety, depression and fatigue,\\u003csup\\u003e\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e\\u003c/sup\\u003e however such associations have not been consistent.\\u003csup\\u003e\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e\\u003c/sup\\u003e While the total cohort did experience an improvement in Happiness (p\\u0026thinsp;=\\u0026thinsp;0.023), we found no evidence that exercise-induced increases in AEA or other ECS marker were associated with affective state responses or the experience of \\u003cem\\u003ethe Runner\\u0026rsquo;s high\\u003c/em\\u003e. There may be multiple reasons for these findings including low statistical power (sample size) and/or the measurements utilized. VAS are an adequate method to assess acute changes in affective state responses, including changes in euphoria in exercise studies.\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e However, the cancer patients in our study reported a low symptom burden, i.e. no difference in any VAS outcome versus the healthy controls. We cannot deduce whether this low symptom burden was accurate, or the result of study participation, e.g. the Hawthorne effect.\\u003csup\\u003e\\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e\\u003c/sup\\u003e It is possible that scales other than VAS might have been more appropriate and responsive to change in the cohort we studied. For example, in a study of advanced cancer patients, the VAS scale was less preferred for reporting symptoms versus the Numerical Rating Scale and Categorial Response Scale.\\u003csup\\u003e\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003eEndocannabinoids (e.g. AEA and 2-AG) readily cross the blood-brain barrier and researchers have posited that they may play a mechanistic role in the subjective experience of exercise-induced euphoria in humans.\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e\\u003c/sup\\u003e However, to date, there is no direct evidence that acute increases in peripheral endocannabinoids correlate with or directly contribute to ECS responses within the central nervous system. It could be that such effects are mutually exclusive, and that circulating ECS markers play a key role in mediating the normal sympathetic nervous system response to moderate-intensity exercise (i.e. along with pro-inflammatory markers such as CRP and interleukin-6 and \\u0026minus;\\u0026thinsp;10) rather than mediating affective states.\\u003csup\\u003e\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e\\u003c/sup\\u003e These are areas for future exploration.\\u003csup\\u003e\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\u003cp\\u003eIn the resting condition, AEA decreased significantly while PEA tended to decrease in the cancer patients versus the healthy controls, while log 2-AG and log SEA tended to decrease in the total cohort. We were unable to determine if the resting condition induced a relaxation effect. Sadness significantly decreased in the total cohort after the resting condition (p\\u0026thinsp;=\\u0026thinsp;0.02), but no other VAS scale changed. To our knowledge, there has been no formal investigation of the acute effect of meditation or other relaxation therapies on circulating ECS markers and this remains an avenue for further scientific inquiry.\\u003c/p\\u003e\\u003cp\\u003eThe main limitations of this study include the small sample size (low statistical power) and that we did not utilize a randomised, double-blind, cross-over study design, which is the gold standard for this type of investigation. Accordingly, we cannot rule that the ECS changes in our study were not influenced by factors such as circadian rhythm.\\u003csup\\u003e\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e\\u003c/sup\\u003e Future trials should aim to address such limitations.\\u003c/p\\u003e\\u003cp\\u003eIn summary, this study has demonstrated that acute, moderate-intensity aerobic exercise can significantly increase a number of circulating ECS markers in cancer patients and healthy adults including AEA, 1-AG, OEA, PEA and SEA). However, the cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers across all timepoints indicating potential ECS dysfunction. Of 10 affective states, only Happiness increased in the total cohort after exercise (p\\u0026thinsp;=\\u0026thinsp;0.023). There was no correlation found between changes in circulating biomarkers and changes in affective states. Additional research is required to investigate the effect of various modalities and dosages of acute and chronic exercise on ECS markers and the clinical interpretation of these adaptations across a number of cancer populations.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eConflicts of interest/competing interests\\u003c/h2\\u003e\\u003cp\\u003eAll authors declare they have no competing interests.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eFunding information\\u003c/h2\\u003e\\u003cp\\u003eThis research was supported by a research grant from the SurFebruary Fund.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eBSC is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. BSC, JL, SK, JS, and ML conceived and designed the study. SK, JL, JS, AG, SW, MH contributed to participant recruitment, data collection and data entry. Blood samples were analysed by ML and DH. BSC performed the statistical analyses and drafted the manuscript. All authors interpreted the data, revised the draft and have read and approved the final version of the manuscript.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eData will be made available on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eCormie P, Atkinson M, Bucci L, et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. \\u003cem\\u003eMed J Aust.\\u003c/em\\u003e May 7 2018.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCheema BS, Kilbreath SL, Fahey PP, Delaney GP, Atlantis E. Safety and efficacy of progressive resistance training in breast cancer: a systematic review and meta-analysis. \\u003cem\\u003eBreast cancer research and treatment.\\u003c/em\\u003e 2014;148(2):249\\u0026ndash;268.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eTarasenko Y, Chen C, Schoenberg N. Self-Reported Physical Activity Levels of Older Cancer Survivors: Results from the 2014 National Health Interview Survey. \\u003cem\\u003eJournal of the American Geriatrics Society.\\u003c/em\\u003e 2017/02// 2017;65(2):e39-e44.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eClifford BK, Mizrahi D, Sandler CX, et al. Barriers and facilitators of exercise experienced by cancer survivors: a mixed methods systematic review. \\u003cem\\u003eSupport Care Cancer.\\u003c/em\\u003e Mar 2018;26(3):685\\u0026ndash;700.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCormie P, Zopf EM, Zhang X, Schmitz KH. 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Endocannabinoids and exercise. \\u003cem\\u003eBr J Sports Med.\\u003c/em\\u003e Oct 2004;38(5):536\\u0026ndash;541.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCerqueira \\u0026Eacute;, Marinho DA, Neiva HP, Louren\\u0026ccedil;o O. Inflammatory Effects of High and Moderate Intensity Exercise-A Systematic Review. \\u003cem\\u003eFront Physiol.\\u003c/em\\u003e 2019;10:1550.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eVaughn LK, Denning G, Stuhr KL, de Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm? \\u003cem\\u003eBr J Pharmacol.\\u003c/em\\u003e Jun 2010;160(3):530\\u0026ndash;543.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003ch2\\u003eTable 1: Characteristics of the healthy control and cancer patient groups\\u003c/h2\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"529\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eCharacteristic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHealthy Control Group (n=10)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCancer Patient Group (n=10)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eAge (y)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e54.3 \\u0026plusmn; 15.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e54.0 \\u0026plusmn; 15.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eWomen:Men\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e6:4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e6:4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eBody weight (kg)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e72.1 \\u0026plusmn; 13.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e70.1 \\u0026plusmn; 16.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eHeight (cm)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e171.9 \\u0026plusmn; 7.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e169.9\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;6.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eBody Mass Index (kg/m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e24.2 \\u0026plusmn; 2.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e23.9\\u0026nbsp;\\u0026plusmn;\\u0026nbsp;4.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eLifestyle habits (n):\\u003c/p\\u003e\\n \\u003cp\\u003e-Moderate-intensity aerobic exercise \\u0026gt;150min/wk\\u003c/p\\u003e\\n \\u003cp\\u003e-Resistance training \\u0026gt;2 sessions/wk\\u003c/p\\u003e\\n \\u003cp\\u003e-Current smoker\\u003c/p\\u003e\\n \\u003cp\\u003e-Current alcohol intake\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003eCancer Type\\u003csup\\u003e\\u0026nbsp;\\u003c/sup\\u003e(n):\\u003c/p\\u003e\\n \\u003cp\\u003e- Pancreatic\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e- Colorectal\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e- Periampullary\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e- Gastro-esophageal\\u003c/p\\u003e\\n \\u003cp\\u003e- Biliary tract\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e- Breast\\u003c/p\\u003e\\n \\u003cp\\u003e- Ovarian\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003eN/A\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003cp\\u003e2\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 265px;\\\"\\u003e\\n \\u003cp\\u003eChemotherapy protocol (n)\\u003c/p\\u003e\\n \\u003cp\\u003e- FOLFIRINOX\\u003c/p\\u003e\\n \\u003cp\\u003e- FOLFOX\\u003c/p\\u003e\\n \\u003cp\\u003e- FOLFIRI\\u003c/p\\u003e\\n \\u003cp\\u003e- Cisplatin and gemcitabine\\u003c/p\\u003e\\n \\u003cp\\u003e- Oxaliplatin and capecitabine\\u003c/p\\u003e\\n \\u003cp\\u003e- TCHP\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 123px;\\\"\\u003e\\n \\u003cp\\u003eN/A\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 142px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003cp\\u003e3\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u0026nbsp;\\u003c/p\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eContinuous variables reported according to mean \\u0026plusmn; standard deviation\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eFOLFIRINOX: folic acid, fluorouracil, irinotecan, oxaliplatin; FOLFOX: folinic acid, fluorouracil, oxaliplatin; FOLFIRI: folic acid, fluorouracil, irinotecan; TCHP: docetaxel, carboplatin, trastuzumab, pertuzumab\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 2:\\u003c/strong\\u003e\\u0026nbsp; Summary of outcome measures and effects of the exercise condition\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" align=\\\"left\\\" width=\\\"983\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd rowspan=\\\"2\\\" style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"3\\\" style=\\\"width: 290px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHealthy Control Group\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"4\\\" style=\\\"width: 296px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCancer Patient Group\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 217px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eExercise Effects\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBaseline\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePost Rest\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePost Exercise\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBaseline\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePost Rest\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePost Exercise\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTime\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e(p-value)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eGroup x Time\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e(p-value)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eCirculating ECS markers\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;AEA (ng/mL)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.274 \\u0026plusmn; 0.064\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.281 \\u0026plusmn; 0.086\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.380 \\u0026plusmn; 0.205\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.195 \\u0026plusmn; 0.077\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.158 \\u0026plusmn; 0.070\\u003csup\\u003e\\u0026dagger;*\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.229 \\u0026plusmn; 0.125\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.013\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.66\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Log 2-AG\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.383 \\u0026plusmn; 0.270\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.271 \\u0026plusmn; 0.241\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.264 \\u0026plusmn; 0.257\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.308 \\u0026plusmn; 0.277\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.215 \\u0026plusmn; 0.336\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.344 \\u0026plusmn; 0.319\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.19\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Log 1-AG\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.335 \\u0026plusmn; 0.261\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.247 \\u0026plusmn; 0.295\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.255 \\u0026plusmn; 0.255\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.232 \\u0026plusmn; 0.344\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.222 \\u0026plusmn; 0.340\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.388 \\u0026plusmn; 0.317\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.048\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.073\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;OEA (ng/mL)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.66 \\u0026plusmn; 0.54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.71 \\u0026plusmn; 0.68\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e2.54 \\u0026plusmn; 1.17\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.04 \\u0026plusmn; 0.36\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.02 \\u0026plusmn; 0.39\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.37 \\u0026plusmn; 0.53\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.056\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;PEA (ng/mL)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.37 \\u0026plusmn; 0.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.40 \\u0026plusmn; 0.44\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.57 \\u0026plusmn; 0.49\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.14 \\u0026plusmn; 0.39\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.07 \\u0026plusmn; 0.33\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.28 \\u0026plusmn; 0.43\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.004\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.70\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Log-SEA\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.174 \\u0026plusmn; 0.253\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.222 \\u0026plusmn; 0.273\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.154 \\u0026plusmn; 0.316\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.441 \\u0026plusmn; 0.135\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.472 \\u0026plusmn; 0.139\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e-0.393 \\u0026plusmn; 0.116\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.006\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.82\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eVisual Analog Scales (0-100)\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Pain\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1 (0-24)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e3 (0-9)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e7 (0-35)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e3.5 (0-12)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e2.5 (0-21)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.87\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e1.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Nausea\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-9)\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-5)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e3.5 (0-43)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e5 (0-25)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e3 (0-24)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.88\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Anger\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-10)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-1)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e1.5 (0-26)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-13)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.5 (0-4)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.92\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.58\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Sadness\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e7 (0-19)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-4)\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-3)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e10 (0-37)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-15)\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0 (0-15)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.64\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e1.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Happiness\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e72 \\u0026plusmn; 13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e71 \\u0026plusmn; 23\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e78 \\u0026plusmn; 14\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e68 \\u0026plusmn; 18\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e72 \\u0026plusmn; 16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e78 \\u0026plusmn; 8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.023\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.37\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Energy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e59 \\u0026plusmn; 20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e62 \\u0026plusmn; 20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e75 \\u0026plusmn; 20\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e56 \\u0026plusmn; 15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e62 \\u0026plusmn; 12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e65\\u0026plusmn;15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.25\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.43\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003eFatigue\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e14.5 (0-70)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e30 (0-72)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e22 (0-74)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e25.5 (0-63)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e23 (0-58)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e28 (0-63)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.87\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e1.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Anxiety\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e15.5 (0-50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e7.5 (0-37)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"2\\\" style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e9 (0-100)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.5 (0-67)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e3 (0-50)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 98px;\\\"\\u003e\\n \\u003cp\\u003e0.5 (0-34)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e0.41\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 109px;\\\"\\u003e\\n \\u003cp\\u003e1.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 180px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;Euphoria\\u003c/p\\u003e\\n 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presented as mean \\u003cu\\u003e+\\u003c/u\\u003e standard deviation except 8 of 10 visual analog scales (i.e. pain, nausea, anger, sadness, fatigue, anxiety, euphoria, depression) with non-parametric distribution, which are presented as median (range).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003csup\\u003e*\\u003c/sup\\u003e\\u003c/strong\\u003eSignificant group x time effect for the resting condition\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003eSignificant time effect for the resting condition\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003eSignificantly lower versus healthy control group at corresponding timepoint\\u0026nbsp;\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"supportive-care-in-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"jscc\",\"sideBox\":\"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)\",\"snPcode\":\"520\",\"submissionUrl\":\"https://submission.nature.com/new-submission/520/3\",\"title\":\"Supportive Care in Cancer\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"oncology, exercise physiologist, cannabis, health, runner’s high, quality of life, rehabilitation, therapy, training\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7028112/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7028112/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003ePurpose\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo investigate endocannabinoid system (ECS) and affective state responses to acute aerobic exercise in adult cancer patients versus their healthy peers.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eParticipants engaged in 30 min of quiet rest followed by 30 min exercise. Exercise involved 5-min warm-up/cool-down procedures and 20 min of moderate-intensity training (64–76% of age-predicted maximal heart rate) on treadmill or cycle. Blood samples and 10 Visual Analog Scales (VAS) were collected before and after rest each condition. Participants were also asked after exercise: ‘Did you experience a \\u003cem\\u003eRunner’s high.\\u003c/em\\u003e’ Blood samples were analysed for endocannabinoids: N-arachidonoylethanolamine (AEA; anandamide), 2-arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), and mediators: palmitoylethanolamide (PEA), oleoylethanolamide (OEA), and stearoylethanolamide (SEA).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eCancer patients had lower circulating AEA, OEA and log SEA versus controls across all timepoints (all p \\u0026lt; 0.06). In the total cohort, exercise increased AEA, log 1-AG, OEA, PEA and log SEA (all p = 0.05) while log 2-AG did not change. Of 10 VAS scales, only \\u003cem\\u003eHappiness\\u003c/em\\u003e increased with exercise in the total cohort (p = 0.02). There were no group x time effects or associations between ECS and VAS responses to exercise. Five patients per group (50%) reported experiencing a \\u003cem\\u003eRunner’s high\\u003c/em\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eExercise increased endocannabinoid and endocannabinoid-like lipid mediators in the total cohort. However, cancer patients exhibited lower AEA, OEA and SEA concentrations versus their peers indicating potential ECS dysfunction. Additional research is required to investigate the effect of various modalities and dosages of exercise on ECS markers and the clinical interpretation of these adaptations across a range of cancer populations.\\u003c/p\\u003e\\n\\u003cp\\u003eAustralian New Zealand Clinical Trials Registry #: ACTRN12623000193673\\u003c/p\\u003e\",\"manuscriptTitle\":\"Endocannabinoid system and mood responses to acute aerobic exercise in adult cancer patients versus healthy controls\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-30 09:40:09\",\"doi\":\"10.21203/rs.3.rs-7028112/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-10-17T04:21:28+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"200463844762506238021824699298518239890\",\"date\":\"2025-09-25T21:59:12+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-09-23T16:55:40+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"133866455692053788266546596635523359287\",\"date\":\"2025-09-19T15:11:06+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-09-19T03:10:39+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-08-10T22:29:03+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-07-04T12:25:29+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Supportive Care in Cancer\",\"date\":\"2025-07-02T10:03:57+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"supportive-care-in-cancer\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"jscc\",\"sideBox\":\"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)\",\"snPcode\":\"520\",\"submissionUrl\":\"https://submission.nature.com/new-submission/520/3\",\"title\":\"Supportive Care in Cancer\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"6a8c03cc-b8a6-4ace-8cdd-762e7cfb2e9a\",\"owner\":[],\"postedDate\":\"September 30th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-08T16:11:42+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-7028112\",\"link\":\"https://doi.org/10.1007/s00520-025-10221-5\",\"journal\":{\"identity\":\"supportive-care-in-cancer\",\"isVorOnly\":false,\"title\":\"Supportive Care in Cancer\"},\"publishedOn\":\"2025-12-02 15:57:56\",\"publishedOnDateReadable\":\"December 2nd, 2025\"},\"versionCreatedAt\":\"2025-09-30 09:40:09\",\"video\":\"\",\"vorDoi\":\"10.1007/s00520-025-10221-5\",\"vorDoiUrl\":\"https://doi.org/10.1007/s00520-025-10221-5\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7028112\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7028112\",\"identity\":\"rs-7028112\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}