Trip killers: Addressing a critical knowledge gap in psychedelic research

Psychedelic drugs are increasingly under investigation as potential therapeutic agents for mental health conditions and are being increasingly used recreationally. Psychedelic use may result in an episode of intense psychological distress, commonly referred to as a "bad trip." Bad trips represent a potentially volatile, erratic, and dangerous situation, which may, in extreme cases, require presentation to accident and emergency departments and psychiatric hospital admission. Managing such cases requires careful consideration, with priority given to non-pharmacological strategies. When these measures prove insufficient, an alternative approach may be necessary, one that can effectively attenuate or terminate the psychedelic state and restore psychological stability. Despite clinical relevance, there is no systematic evaluation of pharmacological interventions to terminate such experiences. This review identifies and critically appraises candidate medications with potential utility as abortive agents, including serotonin antagonists, drugs for psychosis, and select drugs for anxiety and depression. We review these agents, their mechanisms of action, pharmacokinetics, safety profiles, and applicability in acute care settings. Binding strength at the molecular level, potency to functionally block receptor-mediated effects, and lack of side effects are key considerations. We conclude by proposing a provisional framework for the pharmacologic management of adverse psychedelic experiences and highlight key priorities for future research.