Ketamine commonly and rapidly induces a variety of dissociative and other altered states of consciousness (ASCs), some of which are associated with particular affective states and ketamine’s therapeutic effects. To unpack how specific ketamine-induced nonordinary states influence affective states, it is critical to understand the neural mechanisms that underlie these effects. In this chapter, we describe a randomized, placebo-controlled study in nonclinical (healthy) participants (NCT03475277) that revealed affective brain states are dependent upon specific aspects of ASCs. Notably, dissociative depersonalization negatively mediated or suppressed the effect of ketamine on right anterior insula reactivity to threat stimuli, potentially reflecting relief from negative affective states. Conversely, dissociative amnesia positively mediated or enhanced the effect of ketamine on right anterior insula reactivity, suggesting an exacerbation of negative affect. These findings in nonclinical participants provide insights into the potential neural mechanisms underlying ketamine’s therapeutic action. The chapter discusses the implications of these results for optimizing and personalizing ketamine’s use in depression treatment if replicated in depressed individuals. Our work highlights the potential for early prediction of treatment response and the importance of considering specific components of the dissociative experience in clinical applications.