The unpaved road of ayahuasca, a psychoactive brew, as a treatment for neuropathic pain: A review of mechanistic insights and clinical prospects

Neuropathic pain (NP), a debilitating and chronic condition often accompanied by comorbid depression, presents significant therapeutic challenges. While conventional pharmacological treatments, though valuable, usually fall short in addressing their multifaceted nature, the pursuit of innovative solutions has led to the exploration of ayahuasca, a psychedelic brew originating from Amazonian plants, as a promising candidate. Recent investigations have unveiled its therapeutic potential in psychiatric disorders, particularly depression, characterized by notable alterations in mood-regulatory brain networks. In this narrative review, we explore ayahuasca's potential role in modulating neuropathic pain. Through the analysis of preclinical studies and functional MRI analyses, we aim to elucidate its influence on the affective-motivational component of pain perception and the complex immune modulation intrinsic to the pathophysiology of NP. Ayahuasca demonstrates the capacity to reduce activity within regions of the default mode network, closely linked with depression, thereby presenting a novel approach to addressing the interwoven complexities of chronic pain and mood disturbances. Furthermore, its potential to activate serotonin and sigma-1 receptors and modulate the immune/inflammatory response, including glial cells and the midbrain periaqueductal gray, a pivotal brain structure in the propagation and modulation of pain, provides valuable insights into its analgesic mechanisms. Despite these promising insights, we emphasize the imperative of rigorous research to establish the efficacy and safety, mechanisms of action, and long-term effects of ayahuasca therapy in the context of NP.