The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management.

The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H₂O₂ and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors 6 (IC₅₀ 0.54 μM, Ki 1.60 μM) and 7 (IC₅₀ 0.23 μM, K_i 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury.