{"id":{"repo_id":"cadiz","oai_identifier":"oai:rodin.uca.es:10498/39607"},"canonical_url":"https://search.dev.ndltd.org/etd/cadiz/oai:rodin.uca.es:10498/39607","repository":{"repo_id":"cadiz","name":"Universidad de Cadiz","base_url":"https://rodin.uca.es/oai/request"},"display":{"title":"Physical fitness and exercise as modulators of the endocannabinoid system in adults with mild-to-moderate depression the sonrie study","abstract":"The endocannabinoid system (ES) is a lipid-based signaling network involved in multiple physiological processes including mood regulation, stress response, and neuroplasticity. The primary and most well studied endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These components, along with associated analogues interact with CB1 and CB2 receptors. CB1 receptors are abundant in the central nervous system and implicated in cognitive, emotional, and motor functions, whereas CB2 receptors are mainly associated with immune regulation. Depression is a complex, heterogeneous disorder with multifactorial etiology, ranging from genetic vulnerabilities to environmental stressors. Diagnostic criteria include persistent mood alterations and cognitive-somatic symptoms, with considerable variability across individuals. Pathophysiological hypotheses highlight disruptions in neuroendocrine and plasticity-related mechanisms, including ES dysregulation. Preclinical and clinical studies suggest that ES signaling pathway impairment, particularly CB1 receptor dysfunction and altered endocannabinoid tone contribute to depressive symptoms. Notably, AEA and 2-AG appear to exert complementary, stress-buffering roles. Physical exercise has emerged as a promising non-pharmacological strategy to the depression treatment. Acute exercise, especially at moderate-to-high intensities, appear to elevate AEA and 2-AG. However, the effects of chronic exercise on ES are inconsistent. Importantly, while exercise-induced changes in eCBs ligands are documented, the relationship between physical fitness (e.g., cardiorespiratory and muscular fitness) and eCBs remains unclear. Given that fitness reflects sustained physiological adaptations, it may independently modulate ES activity, offering a novel perspective in understanding and treating depressive disorders. Thus, the main aim of the present Doctoral Thesis is to clarify the extent to which physical exercise behavior and the physical-fitness adaptations it elicits modulate circulating endocannabinoid biomarkers in adults with depressive disorders, and to determine whether an internet-delivered psycho-physical program can leverage this pathway to improve fitness and biological profiles. The results in Study I confirmed that moderate-intensity aerobic and high-load resistance exercise reliably increases AEA, with less consistent effects on 2-AG, while supramaximal intensities may attenuate the eCB response. Chronic exercise appears to normalize eCB dysregulation in stressrelated conditions. Study II we found that higher fitness levels were inversely associated with baseline plasma eCBs and their analogues. Study III showed that a structured psycho-physical intervention enhanced cardiorespiratory fitness and induced directional changes in ES, with partial retention of benefits during followup. These findings demonstrate that physical exercise behavior and fitness modulate the ES in individuals with depression and support the role of eCBs as promising biomarkers of psychophysiological health. Moreover, internetdelivered interventions represent a feasible, non-pharmacological strategy to target ES dysfunction in depression.","abstract_html":"The endocannabinoid system (ES) is a lipid-based signaling network involved in multiple physiological processes including mood regulation, stress response, and neuroplasticity. The primary and most well studied endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These components, along with associated analogues interact with CB1 and CB2 receptors. CB1 receptors are abundant in the central nervous system and implicated in cognitive, emotional, and motor functions, whereas CB2 receptors are mainly associated with immune regulation. Depression is a complex, heterogeneous disorder with multifactorial etiology, ranging from genetic vulnerabilities to environmental stressors. Diagnostic criteria include persistent mood alterations and cognitive-somatic symptoms, with considerable variability across individuals. Pathophysiological hypotheses highlight disruptions in neuroendocrine and plasticity-related mechanisms, including ES dysregulation. Preclinical and clinical studies suggest that ES signaling pathway impairment, particularly CB1 receptor dysfunction and altered endocannabinoid tone contribute to depressive symptoms. Notably, AEA and 2-AG appear to exert complementary, stress-buffering roles. Physical exercise has emerged as a promising non-pharmacological strategy to the depression treatment. Acute exercise, especially at moderate-to-high intensities, appear to elevate AEA and 2-AG. However, the effects of chronic exercise on ES are inconsistent. Importantly, while exercise-induced changes in eCBs ligands are documented, the relationship between physical fitness (e.g., cardiorespiratory and muscular fitness) and eCBs remains unclear. Given that fitness reflects sustained physiological adaptations, it may independently modulate ES activity, offering a novel perspective in understanding and treating depressive disorders. Thus, the main aim of the present Doctoral Thesis is to clarify the extent to which physical exercise behavior and the physical-fitness adaptations it elicits modulate circulating endocannabinoid biomarkers in adults with depressive disorders, and to determine whether an internet-delivered psycho-physical program can leverage this pathway to improve fitness and biological profiles. The results in Study I confirmed that moderate-intensity aerobic and high-load resistance exercise reliably increases AEA, with less consistent effects on 2-AG, while supramaximal intensities may attenuate the eCB response. Chronic exercise appears to normalize eCB dysregulation in stressrelated conditions. Study II we found that higher fitness levels were inversely associated with baseline plasma eCBs and their analogues. Study III showed that a structured psycho-physical intervention enhanced cardiorespiratory fitness and induced directional changes in ES, with partial retention of benefits during followup. These findings demonstrate that physical exercise behavior and fitness modulate the ES in individuals with depression and support the role of eCBs as promising biomarkers of psychophysiological health. Moreover, internetdelivered interventions represent a feasible, non-pharmacological strategy to target ES dysfunction in depression.","abstract_has_math":false,"creators":["Ruiz Muñoz, Manuel"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Rosety Rodríguez, Miguel Ángel","España Romero, Vanesa"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025","date_published":"2025","updated_at":"2026-07-24T01:29:24Z","subjects":[],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/10498/39607","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Rosety Rodríguez, Miguel Ángel","España Romero, Vanesa"]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Didáctica de la Educación Física, Plástica y Musical"]},{"key":"dc:creator","label":"Author","values":["Ruiz Muñoz, Manuel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-05-15T12:40:43Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-05-15T12:40:43Z"]},{"key":"dc:date.issued","label":"Date","values":["2025"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10498/39607"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The endocannabinoid system (ES) is a lipid-based signaling network involved in multiple physiological processes including mood regulation, stress response, and neuroplasticity. The primary and most well studied endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These components, along with associated analogues interact with CB1 and CB2 receptors. CB1 receptors are abundant in the central nervous system and implicated in cognitive, emotional, and motor functions, whereas CB2 receptors are mainly associated with immune regulation. Depression is a complex, heterogeneous disorder with multifactorial etiology, ranging from genetic vulnerabilities to environmental stressors. Diagnostic criteria include persistent mood alterations and cognitive-somatic symptoms, with considerable variability across individuals. Pathophysiological hypotheses highlight disruptions in neuroendocrine and plasticity-related mechanisms, including ES dysregulation. Preclinical and clinical studies suggest that ES signaling pathway impairment, particularly CB1 receptor dysfunction and altered endocannabinoid tone contribute to depressive symptoms. Notably, AEA and 2-AG appear to exert complementary, stress-buffering roles. Physical exercise has emerged as a promising non-pharmacological strategy to the depression treatment. Acute exercise, especially at moderate-to-high intensities, appear to elevate AEA and 2-AG. However, the effects of chronic exercise on ES are inconsistent. Importantly, while exercise-induced changes in eCBs ligands are documented, the relationship between physical fitness (e.g., cardiorespiratory and muscular fitness) and eCBs remains unclear. Given that fitness reflects sustained physiological adaptations, it may independently modulate ES activity, offering a novel perspective in understanding and treating depressive disorders. Thus, the main aim of the present Doctoral Thesis is to clarify the extent to which physical exercise behavior and the physical-fitness adaptations it elicits modulate circulating endocannabinoid biomarkers in adults with depressive disorders, and to determine whether an internet-delivered psycho-physical program can leverage this pathway to improve fitness and biological profiles. The results in Study I confirmed that moderate-intensity aerobic and high-load resistance exercise reliably increases AEA, with less consistent effects on 2-AG, while supramaximal intensities may attenuate the eCB response. Chronic exercise appears to normalize eCB dysregulation in stressrelated conditions. Study II we found that higher fitness levels were inversely associated with baseline plasma eCBs and their analogues. Study III showed that a structured psycho-physical intervention enhanced cardiorespiratory fitness and induced directional changes in ES, with partial retention of benefits during followup. These findings demonstrate that physical exercise behavior and fitness modulate the ES in individuals with depression and support the role of eCBs as promising biomarkers of psychophysiological health. Moreover, internetdelivered interventions represent a feasible, non-pharmacological strategy to target ES dysfunction in depression.","El sistema endocannabinoide (SE) es una red de señalización basada en lípidos que participa en múltiples procesos fisiológicos, incluyendo la regulación del estado de ánimo, la respuesta al estrés y la neuroplasticidad. Los ligandos endógenos primarios y más estudiados son la anandamida (AEA) y el 2- araquidonilglicerol (2-AG). Estos componentes, junto con otros análogos relacionados, interactúan con los receptores CB1 y CB2. Los receptores CB1 son abundantes en el sistema nervioso central y están implicados en funciones cognitivas, emocionales y motoras, mientras que los receptores CB2 se asocian principalmente con la regulación inmunológica. La depresión es un trastorno complejo y heterogéneo, con una etiología multifactorial que abarca desde vulnerabilidades genéticas hasta aspectos ambientales o sociodemográficos. Los criterios diagnósticos incluyen alteraciones persistentes del estado de ánimo y síntomas cognitivo-somáticos, con una notable variabilidad entre individuos. Las hipótesis fisiopatológicas destacan disrupciones en mecanismos neuroendocrinos y relacionados con la plasticidad, incluyendo una disfunción del SE. Los estudios preclínicos y clínicos sugieren que una alteración en la vía de señalización del SE, especialmente una disfunción del receptor CB1 y un tono endocannabinoide alterado, contribuyen a los síntomas depresivos. Es relevante señalar que AEA y 2-AG parecen ejercer funciones complementarias en la amortiguación del estrés. El ejercicio físico ha emergido como una estrategia no farmacológica prometedora para el tratamiento de la depresión. En respuesta aguda al ejercicio, especialmente a intensidades moderadas o altas, parece elevar los niveles de AEA y 2-AG. Sin embargo, los efectos crónicos del ejercicio sobre el SE son inconsistentes. Es importante destacar que, si bien se han documentado cambios inducidos por el ejercicio en los ligandos endocannabinoides, la relación entre la condición física (por ejemplo, la capacidad cardiorrespiratoria y la fuerza muscular) y los endocannabinoides aún no está clara. Dado que la condición física refleja adaptaciones fisiológicas sostenidas, podría modular de forma independiente la actividad del SE, ofreciendo una nueva perspectiva para comprender y tratar los trastornos depresivos. Por tanto, el objetivo principal de esta Tesis Doctoral fue esclarecer en qué medida el ejercicio físico y las adaptaciones en la condición física que este induce modulan la concentración de los biomarcadores del SE en adultos con trastornos depresivos, y determinar si un programa psicofísico administrado por internet puede activar esta vía para mejorar la condición física y los perfiles biológicos. Los resultados del Estudio I confirman que el ejercicio aeróbico de intensidad moderada y el entrenamiento de fuerza con cargas altas incrementan de forma consistente los niveles de AEA, con efectos menos consistentes sobre el 2-AG, mientras que las intensidades submáximas podrían atenuar la respuesta endocannabinoide. El ejercicio crónico parece normalizar la disfunción del SE en condiciones relacionadas con el estrés. En el Estudio II observamos que mayores niveles de condición física se asociaban inversamente con los niveles basales de endocannabinoides plasmáticos y sus análogos. El Estudio III demostramos que una intervención psicofísica estructurada mejoró la condición cardiorrespiratoria e indujo cambios en el SE, con una retención parcial de los beneficios durante el seguimiento. Estos hallazgos demuestran que tanto el ejercicio físico como la condición física modulan el SE en personas con depresión, y respaldan el papel de los endocannabinoides como biomarcadores prometedores de salud psicofisiológica. Además, las intervenciones administradas por internet representan una estrategia no farmacológica viable para abordar la disfunción del SE en la depresión."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Physical fitness and exercise as modulators of the endocannabinoid system in adults with mild-to-moderate depression the sonrie study"]}]}],"canonical_facts":{"dc:contributor.advisor":["Rosety Rodríguez, Miguel Ángel","España Romero, Vanesa"],"dc:contributor.other":["Didáctica de la Educación Física, Plástica y Musical"],"dc:creator":["Ruiz Muñoz, Manuel"],"dc:date.accessioned":["2026-05-15T12:40:43Z"],"dc:date.available":["2026-05-15T12:40:43Z"],"dc:date.issued":["2025"],"dc:description.abstract":["The endocannabinoid system (ES) is a lipid-based signaling network involved in multiple physiological processes including mood regulation, stress response, and neuroplasticity. The primary and most well studied endogenous ligands are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These components, along with associated analogues interact with CB1 and CB2 receptors. CB1 receptors are abundant in the central nervous system and implicated in cognitive, emotional, and motor functions, whereas CB2 receptors are mainly associated with immune regulation. Depression is a complex, heterogeneous disorder with multifactorial etiology, ranging from genetic vulnerabilities to environmental stressors. Diagnostic criteria include persistent mood alterations and cognitive-somatic symptoms, with considerable variability across individuals. Pathophysiological hypotheses highlight disruptions in neuroendocrine and plasticity-related mechanisms, including ES dysregulation. Preclinical and clinical studies suggest that ES signaling pathway impairment, particularly CB1 receptor dysfunction and altered endocannabinoid tone contribute to depressive symptoms. Notably, AEA and 2-AG appear to exert complementary, stress-buffering roles. Physical exercise has emerged as a promising non-pharmacological strategy to the depression treatment. Acute exercise, especially at moderate-to-high intensities, appear to elevate AEA and 2-AG. However, the effects of chronic exercise on ES are inconsistent. Importantly, while exercise-induced changes in eCBs ligands are documented, the relationship between physical fitness (e.g., cardiorespiratory and muscular fitness) and eCBs remains unclear. Given that fitness reflects sustained physiological adaptations, it may independently modulate ES activity, offering a novel perspective in understanding and treating depressive disorders. Thus, the main aim of the present Doctoral Thesis is to clarify the extent to which physical exercise behavior and the physical-fitness adaptations it elicits modulate circulating endocannabinoid biomarkers in adults with depressive disorders, and to determine whether an internet-delivered psycho-physical program can leverage this pathway to improve fitness and biological profiles. The results in Study I confirmed that moderate-intensity aerobic and high-load resistance exercise reliably increases AEA, with less consistent effects on 2-AG, while supramaximal intensities may attenuate the eCB response. Chronic exercise appears to normalize eCB dysregulation in stressrelated conditions. Study II we found that higher fitness levels were inversely associated with baseline plasma eCBs and their analogues. Study III showed that a structured psycho-physical intervention enhanced cardiorespiratory fitness and induced directional changes in ES, with partial retention of benefits during followup. These findings demonstrate that physical exercise behavior and fitness modulate the ES in individuals with depression and support the role of eCBs as promising biomarkers of psychophysiological health. Moreover, internetdelivered interventions represent a feasible, non-pharmacological strategy to target ES dysfunction in depression.","El sistema endocannabinoide (SE) es una red de señalización basada en lípidos que participa en múltiples procesos fisiológicos, incluyendo la regulación del estado de ánimo, la respuesta al estrés y la neuroplasticidad. Los ligandos endógenos primarios y más estudiados son la anandamida (AEA) y el 2- araquidonilglicerol (2-AG). Estos componentes, junto con otros análogos relacionados, interactúan con los receptores CB1 y CB2. Los receptores CB1 son abundantes en el sistema nervioso central y están implicados en funciones cognitivas, emocionales y motoras, mientras que los receptores CB2 se asocian principalmente con la regulación inmunológica. La depresión es un trastorno complejo y heterogéneo, con una etiología multifactorial que abarca desde vulnerabilidades genéticas hasta aspectos ambientales o sociodemográficos. Los criterios diagnósticos incluyen alteraciones persistentes del estado de ánimo y síntomas cognitivo-somáticos, con una notable variabilidad entre individuos. Las hipótesis fisiopatológicas destacan disrupciones en mecanismos neuroendocrinos y relacionados con la plasticidad, incluyendo una disfunción del SE. Los estudios preclínicos y clínicos sugieren que una alteración en la vía de señalización del SE, especialmente una disfunción del receptor CB1 y un tono endocannabinoide alterado, contribuyen a los síntomas depresivos. Es relevante señalar que AEA y 2-AG parecen ejercer funciones complementarias en la amortiguación del estrés. El ejercicio físico ha emergido como una estrategia no farmacológica prometedora para el tratamiento de la depresión. En respuesta aguda al ejercicio, especialmente a intensidades moderadas o altas, parece elevar los niveles de AEA y 2-AG. Sin embargo, los efectos crónicos del ejercicio sobre el SE son inconsistentes. Es importante destacar que, si bien se han documentado cambios inducidos por el ejercicio en los ligandos endocannabinoides, la relación entre la condición física (por ejemplo, la capacidad cardiorrespiratoria y la fuerza muscular) y los endocannabinoides aún no está clara. Dado que la condición física refleja adaptaciones fisiológicas sostenidas, podría modular de forma independiente la actividad del SE, ofreciendo una nueva perspectiva para comprender y tratar los trastornos depresivos. Por tanto, el objetivo principal de esta Tesis Doctoral fue esclarecer en qué medida el ejercicio físico y las adaptaciones en la condición física que este induce modulan la concentración de los biomarcadores del SE en adultos con trastornos depresivos, y determinar si un programa psicofísico administrado por internet puede activar esta vía para mejorar la condición física y los perfiles biológicos. Los resultados del Estudio I confirman que el ejercicio aeróbico de intensidad moderada y el entrenamiento de fuerza con cargas altas incrementan de forma consistente los niveles de AEA, con efectos menos consistentes sobre el 2-AG, mientras que las intensidades submáximas podrían atenuar la respuesta endocannabinoide. El ejercicio crónico parece normalizar la disfunción del SE en condiciones relacionadas con el estrés. En el Estudio II observamos que mayores niveles de condición física se asociaban inversamente con los niveles basales de endocannabinoides plasmáticos y sus análogos. El Estudio III demostramos que una intervención psicofísica estructurada mejoró la condición cardiorrespiratoria e indujo cambios en el SE, con una retención parcial de los beneficios durante el seguimiento. Estos hallazgos demuestran que tanto el ejercicio físico como la condición física modulan el SE en personas con depresión, y respaldan el papel de los endocannabinoides como biomarcadores prometedores de salud psicofisiológica. Además, las intervenciones administradas por internet representan una estrategia no farmacológica viable para abordar la disfunción del SE en la depresión."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://hdl.handle.net/10498/39607"],"dc:language.iso":["eng"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 Internacional"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:title":["Physical fitness and exercise as modulators of the endocannabinoid system in adults with mild-to-moderate depression the sonrie study"],"dc:type":["doctoral thesis"]},"updated_at":"2026-07-24T01:29:24Z"}