The document reports on a study that examined the effects of compassion meditation training on inflammatory, neuroendocrine, and behavioral responses to psychosocial stress. The study found that participants randomized to 6 weeks of compassion meditation training showed reduced IL-6 levels, cortisol levels, and mood disturbance in response to a social stress test, compared to a control group. Greater engagement in meditation practice was associated with smaller stress responses.

1. Raison et al . Trend Immun, 27:24-31, 2006 Chronic Stress, Depression and the Stress System IFN-a HPA Axis Decreased cortisol Resistance to cortisol Loss of circadian variation ANS Increased SNS Decreased cholinergic Reduced HRV

2. HPA Axis Increased activity Develop resistance Loss of circadian variation ANS Increased SNS Decreased cholinergic Reduced HRV Raison et al . Trend Immun, 27:24-31, 2006 Pathways Linking Stress, Inflammation and Depression IFN-a

3. HPA Axis Increased activity Develop resistance Loss of circadian variation ANS Increased SNS Decreased cholinergic Reduced HRV Raison et al . Trend Immun, 27:24-31, 2006 Pathways Linking Stress, Inflammation and Depression Increased Inflammation

4. Inflammation as a Link Between Stress, Depression and Illness DIABETES CARDIOVASCULAR CANCER DEMENTIA

5. SSRI Pretreatment Reduces IFN-alpha- Induced Depression Weeks on IFN-alpha 0 2 4 6 8 10 12 0 20 40 60 80 100 Placebo Musselman et al., New England Journal of Medicine, 344:961-966, 2001. Survival Free of Major Depression (%)

6. *-the majority of the depressed patients in this sample also endorsed significant early life stress as measured by the CTQ Pace et al., Am J Psychiatry , 2006. Plasma IL-6, pg/ ml 0 1 2 3 4 5 6 -15 0 15 30 Major Depression (n = 14) Control (n = 13) TSST * Plasma IL-6, pg/ ml 0 1 2 3 4 5 6 -15 0 15 30 45 60 75 90 STRESS Time (min) Psychosocial Stress Activates Inflammation: Effect of Depression *Between group comparison, p < 0.05 +Within group comparison vs. 0 min time pt, p < 0.05 Health Men WITH early trauma/neglect and major depression (n = 14) Health Men WITHOUT early trauma/neglect or major depression (n = 13) *Between group comparison, p < 0.05 +Within group comparison vs. 0 min time pt, p < 0.05 + + + + * + + *

7. Positive Social Connectivity Associated with Reduced Inflammation Loucks EB et al. J Biosoc Sci 2006

8. Compassion Meditation Protocol Developed by LTN, PhD Active Compassion for Others The meditation training culminates in the generation of active compassion: practices introduced to develop a determination to work actively to alleviate the suffering of others. When this training is successful, this state of mind becomes ingrained and spontaneous. Week 6 Wishing and Aspirational Compassion Using the concepts of appreciation and empathy as a starting point, the meditator will be guided toward the first stages of compassion: the wish that all beings might be happy and free of suffering, and the aspiration to help them achieve that. Week 5 Developing Affection and Empathy Techniques will be presented for developing undifferentiated affection for others, based on the many ways that others benefit us each day. The meditators will be introduced to the concept of empathy for others: identifying with their happiness and suffering alike. Week 4 Cultivating Equanimity and Appreciation Introducing practices designed to challenge unexamined thoughts and feelings determining categories of friend, enemy and stranger; introducing the perspective that all persons are all alike in wanting to be happy, and appreciating others for the ways they benefit us. Week 3 Developing Compassion for Oneself through Mindfulness of Sensations, Feelings and Emotions Introduction of techniques to develop awareness of how thoughts and actions contribute to subjective experiences of happiness or suffering, and techniques to increase identification of habitual, conditioned reactions. Week 2 Developing Attention and Stability of Mind Introduction of basic meditation techniques for focusing attention for increasingly longer periods of time. These techniques are included in the practice of all subsequent compassion meditation components. Week 1

9. Freshman College Students males/females Compassion Meditation Group Health Discussion Control Group intervention 6 Weeks intervention Psychosocial Stress Test

10. Effect of Compassion Meditation on Inflammatory, Neuroendocrine and Behavioral Responses to Psychosocial Stress STUDY HYPOTHESES: Randomization to six weeks of training in compassion meditation will reduce interleukin (IL)-6, cortisol and behavioral distress responses to a standardized laboratory psychosocial stressor (Trier Social Stress Test [TSST]) in medically-healthy young adults when compared to randomization to a health discussion control group. 1. In participants randomized to compassion meditation training, amount of meditation practice during the study will be associated with inflammatory, neuroendocrine and behavioral responses to the TSST. 2.

11. Time (min) TSST a plasma cortisol, µg/ dl 0 7.5 10.0 12.5 15.0 17.5 log plasma IL-6, pg/ ml -1.5 -1.0 -0.5 0 0.5 b Time (min) TSST Time (min) TSST POMS - Total Mood Distribution Score -5 0 5 10 15 c Effect of Compassion Meditation on Inflammatory, Neuroendocrine and Behavioral Responses to Psychosocial Stress Pace et al., PNE 2008 d Control Compassion meditation 0 15 30 45 60 75 90 0 15 30 45 60 75 90 Control Compassion meditation 0 15 30 45 60 75 90

12. Average meditation session per week Compassion Meditation Group (n = 33) Distribution of Meditation Practice Exposure in Compassion Group

13. -2.0 -1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0 2 3 4 5 6 7 Average meditation sessions per week Log MAXIMAL I L-6 Post-stressor 8 9 1 POMS - Total Mood Score (post-stressor) -20 -15 -10 -5 0 5 10 15 20 25 30 2 3 4 5 6 7 Average meditation sessions per week 8 9 1 Evidence for a “Dose-Response” Relationship Between Amount of Meditation Practice and IL-6 and POMS Responses to the TSST Pace et al., PNE 2008 r p = 0.46, p<0.01 r p = 0.39, p<0.05

14. TSST Increasing inflammation Effect of Meditation Practice on IL-6 Responses to the TSST when Compared to Control Subjects TSST log plasma IL-6, pg/ ml Time (min) -1.5 -1 -0.5 0 0.5 0 15 30 45 60 75 90 Control (n = 28) Compassion meditation (n = 16) (high practice) Compassion meditation (n = 17) (low practice) Compassion meditation (n = 33)

15. STRESSOR Effect of Meditation Practice on Distress Responses to the TSST when Compared to Control Subjects Increasing Distress -5 0 5 10 15 POMS - Total Mood Distribution Score -15 0 15 30 Time (min) Compassion meditation (n = 16) (high practice) Compassion meditation (n = 17) (low practice) Control (n = 28)

16. Increased Engagement With Meditation Practice Reduced Behavioral And Physiological Stress Responses Reduced Behavioral And Physiological Stress Responses Increased Engagement With Meditation Practice Increased Engagement With Meditation Practice Reduced Behavioral And Physiological Stress Responses

17. Randomized to Compassion Meditation High Practice Time Group Post-training TSST Low Practice Time Group Post-training TSST Randomized to Compassion Meditation High Practice Time Group Pre-training TSST Low Practice Time Group Pre-training TSST 6 Weeks intervention TSST TSST 6 Weeks intervention

18. TSST prior to meditation training TSST after meditation training 0.5 0 -0.5 -1.0 -1.5 0 30 60 45 75 90 15 TSST 0.5 0 -0.5 -1.0 -1.5 0 30 60 45 75 90 15 TSST log plasma IL-6, pg/ml log plasma IL-6, pg/ml low practice high practice Time (min) Time (min) 18 12 10 8 0 0 30 60 45 75 90 15 TSST 16 14 18 12 10 8 0 0 30 60 45 75 90 15 TSST 16 14 plasma cortisol, µg/ml plasma cortisol, µg/ml Time (min) Time (min) IL-6 Cortisol

19. 25 10 5 0 -5 0 30 60 45 75 90 15 TSST 20 15 25 10 5 0 -5 0 30 60 45 75 90 15 TSST 20 15 POMS - total mood distribution score POMS - total mood distribution score Time (min) Time (min) TSST prior to meditation training TSST after meditation training POMS Total Distress