Background: Despite increasing cannabis use among the general population, very little data exists on potential harms associated with use. In randomized controlled trials examining the effect of THC-based pharmaceuticals on the management of pain, adverse events included dizziness, sedation, confusion, loss of balance, nausea, vomiting, and hallucination. These side effects suggest that cannabis used in combination with opioids—which also cause, dizziness, sedation, confusion, respiratory depression, nausea, vomiting and constipation—may be particularly harmful. Older Veterans, and those with underlying respiratory and cardiac conditions, may be at higher risk of adverse effects from combined opioid and cannabis use. On the other hand, several ecological studies suggest that state-based recreational legalization may be associated with a decrease in opioid related deaths. Thus, it is plausible that cannabis use, by reducing the use of opioids, reduces respiratory depression and the risk of overdose. However, ecological studies examining the effect of legalization on opioid related deaths do not inform our understanding of the effects of combined use of cannabis and opioids on individual health. Understanding the effects of the combined use of cannabis and opioids on individual patient outcomes is critically important. No evidence base is currently available to inform VA guidelines on cannabis use among chronic pain patients who receive opiates. Significance: Although cannabis use is common among Veterans with chronic pain, the risk or benefits of cannabis use among Veterans on long-term opioid therapy (LTOT) is unknown. This proposal is directly responsive to research gaps identified by VA practice guidelines and the HSR&D priority area focused on “Studying safety and efficacy issues related to long-term opioid therapy among aging Veterans and Veterans with mental health (non-pain) conditions”. Our proposal is also responsive to the HSR&D priority area: “Assessing the feasibility of LTOT cohort studies using data-mining strategies.” Innovation: To address the gaps in the literature on the potential harms (or benefits) of cannabis use among patients on long-term opioid therapy, we propose an innovative approach to cohort construction using a combination of urine drug screen data, text processing algorithms (developed by our team), and national VA and Medicare data to categorize exposure status (concomitant cannabis plus opioid vs. opioid without cannabis) to address the following aims: Specific Aims: Aim 1: To examine the association of cannabis use on the outcome of all-cause mortality among Veterans ≥18 years-old who use long-term opioids. Aim 2: To examine the association of cannabis use on the primary outcome of all-cause mortality and the secondary outcomes of hospitalization among Veterans ≥65 years-old on LTOT with chronic obstructive lung disease, congestive heart failure or sleep apnea. Aim 3: To examine the association of cannabis on th...