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Self-transcendence is an ambiguous construct without consensual meaning, yet many claim that it relates to, or even causes, beneficial outcomes. Few discuss its potential deleterious side effects, choosing to focus primarily on positive effects. However, anything with sufficient potency to heal may have unintended side effects, especially when it leads beyond a transitory state to becoming an enduring trait, such as when self-transcendence (ST) becomes persistent self-transcendence (PST). With PST, evidence is overviewed here, along with two illustrative case reports, that people can suffer emotional difficulties, motivation changes, loss of self-reflexivity, anhedonia, dissociation, depersonalization, memory problems, and other psychological concerns. This is discussed in terms of the disruption of the sense of self, which ordinarily serves as an integrative center for the person that conveys a sense of agency. Possible neurobiological and sociocultural effects of PST are also discussed, with a focus on its role on narrative memory as the construction of self-concept. Evidence has also been accumulating on problematic side effects of meditation and mindfulness, techniques commonly presented as paths to PST. Given that PST is often presented as a pinnacle of human development and spiritual attainment, seekers of PST, psychologists, and other mental health professionals are urged to become informed about its possible side effects, and view this phenomenon in a more balanced way.