Deciphering endocannabinoid stress buffering in humans: Mechanistic and clinical investigations

In the face of major stressful life events, some individuals cope well whereas others go on to experience persistent physical and mental distress. How we react to and recover from stress depends on a complex interplay between environmental factors, social circumstances, biological vulnerability, and resilience factors. Research on animals and patient groups living under high loads of stress, for example due to post-traumatic stress disorder (PTSD), suggests that the intensity of a stress response and how quickly we recover relies in part on endocannabinoids—natural brain molecules that activate the same parts of the brain as cannabis. In this project, we will investigate how people’s ability to cope with acute and prolonged stress is related to their endocannabinoid levels. The overarching goal is to understand why some individuals are more resilient against stress than others. In one study, we are collect data from patients undergoing a stressful, yet very common life event: surgery. We measure perceived stress as well as mental and physical health from the period before the surgery to two years afterward, and test how these measures are related to levels of endocannabinoids and other stress hormones. In the second study, we use data from an experiment in which participants were exposed to psychosocial stress to investigate how endocannabinoid levels influence their stress responses and whether the stress itself can trigger the release of endocannabinoids. In the end, the overall goal of this research project is to assess whether measures of endocannabinoid levels can be used to assess the need for increased patient follow-up and help prevent poor health after major stressful life events.

In the face of major life stressors, some individuals cope well whereas others develop ill health and long-term adverse outcomes. Predicting who needs additional support in response to major life stressors is essential for targeted prevention and more efficient allocation of resources. The endocannabinoid system is emerging as a promising target for understanding vulnerability and resilience to stress. This system appears to buffer stress in two ways: by limiting the magnitude of the stress response, and by facilitating recovery after a stressful event. While the early findings are intriguing, they mainly stem from studies in rodents and small clinical groups with high stress burden. What role endocannabinoids have more globally for human resilience, health and well-being remains elusive. In this project we address this gap by leveraging comprehensive experimental and clinical data on two potent stress models: psychosocial stress and surgery. Drawing on these unique datasets, which combine experimental control with ecological validity, we will decipher how endocannabinoid levels influence people’s stress response and recovery across minutes, days, weeks and years. The project represents a novel directional shift for endocannabinoid research and will (i) determine the value of endocannabinoid levels as a biomarker to predict outcomes after surgery, (ii) quantify sex differences, (iii) assess endocannabinoid interplay with opioid analgesics, sex hormones and other stress markers (iv) spearhead open and reproducible science practices in endocannabinoid research, and (v) make this fine-grained and novel data available through an interactive web application. This project represents an ambitious effort to understand endocannabinoids’ role in stress resilience and will determine the value of endocannabinoids as a predictive biomarker and potential target for individualized treatment.