The Protective Properties of Natural Products Against Neurotoxicity Induced by Stimulant, Hallucinogenic, and Opioid CNS Agents

Abstract

Context: CNS-active agents (stimulants, hallucinogens, and opioids) pose a risk of neurotoxicity and may contribute to progressive neuronal damage and neurodegeneration. Several mechanisms are associated with cellular injury induced by CNS-active drugs, including oxidative stress due to excessive production of reactive oxygen species, neuroinflammation driven by microglial overactivation, mitochondrial dysfunction, impaired calcium homeostasis, and activation of apoptotic and necrotic cell-death pathways. Substantial evidence supports the potential of natural products from plant and dietary/endogenous sources as neuroprotective agents. Evidence Acquisition: This review summarizes preclinical (in vitro and in vivo) and clinical studies published in PubMed, Scopus, and Web of Science (2000 - 2025) that evaluated the neuroprotective properties of natural products derived from plants and other dietary or endogenous sources. Results: These biologically active compounds exert antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects through multiple mechanisms, including scavenging of reactive oxygen species; suppressing pro-inflammatory cytokines (e.g., TNF-α and IL-1β) and microglial hyperactivation; inhibiting caspase-mediated apoptosis; supporting mitochondrial function; activating pro-survival signaling pathways (e.g., the PI3K/Akt pathway); and inducing antioxidant-response genes through Nrf2-mediated transcriptional activation. Conclusions: Natural neuroprotective agents, particularly plant-derived compounds, have demonstrated promising preclinical neuroprotective effects against neurotoxicity induced by CNS agents. However, the current evidence indicates preclinical potential rather than established therapeutic efficacy. Well-designed clinical trials are required to determine their safety, optimal dosing, delivery methods, and therapeutic value before they can be considered for clinical use.