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CONTEXT: Although epidemiological studies have reported protective effects of religion and spirituality on mental health, it is unknown whether spirituality can be used as an intervention to improve psychological well-being. OBJECTIVE: To evaluate the efficacy of a home study-based spirituality program on mood disturbance in emotionally distressed patients. DESIGN, SETTING, AND PARTICIPANTS: A non-blinded, randomized, wait list-controlled trial of 165 individuals with mood disturbance [score of >40 on the Profile of Mood States (POMS)] were recruited from primary care clinics in a Canadian city between August 2000 and March 2001. INTERVENTIONS: Participants were randomized to a spirituality group (an 8-week audiotaped spirituality home-study program), a mindfulness meditation-based stress reduction group (attendance at facilitated classes for 8 weeks), or a wait-list control group (no intervention for 12 weeks). MAIN OUTCOME MEASURES: Primary outcomes were mood disturbance, measured using POMS, and quality of life, measured using the SF-36, a short-form health survey with 36 questions. The POMS and the SF-36 were completed at baseline, at 8 weeks, and at 12 weeks. RESULTS: At the end of the 8-week intervention period, the mean POMS score improvement was -43.1 (-45.7%) for the spirituality group, -22.6 (-26.3%) for the meditation group, and -10.3 (11.3%) for the control group (P<.001 for spirituality vs control group; P=.034 for spirituality vs meditation group). Mean improvement in the SF-36 mental component summary score was 14.4 (48.6%) for the spirituality group, 7.1 (22.3%) for the meditation group, and 4.7 (16.1%) for the control group (P<.001 for spirituality vs control group; P=.029 for spirituality vs meditation group). At 12 weeks, POMS and SF-36 scores remained significantly different from baseline for the spirituality group.