Bioelectrical and Neurochemical Modulation by Peganum harmala: A Narrative Review of its Role in Neural Hyperactivity, Stress Circuitry, and Cortical Excitability

Neuropsychiatric and neurodegenerative conditions are widespread across the globe, frequently linked to disturbances in monoaminergic transmission, increased cortical excitability, and maladaptive responses to stress. Existing pharmacological treatments are often hindered by delayed onset of action, limited effectiveness, and adverse side effects. This narrative review provides a critical examination of the neurochemical and electrophysiological characteristics of Peganum harmala L. (Syrian rue), highlighting its potential as a versatile botanical option for managing Central Nervous System (CNS) disorders. A comprehensive literature review was performed utilizing databases such as PubMed, Scopus, and Web of Science until 2025. This search included preclinical studies, mechanistic investigations, and toxicological assessments concerning key alkaloids from P. harmala (harmine, harmaline, tetrahydroharmine, vasicine). Only studies published in English that reported pharmacological or electrophysiological findings were considered. The β-carboline alkaloids found in P. harmala function as reversible inhibitors of MAO-A, leading to increased levels of serotonin, dopamine, and norepinephrine. Harmine has been shown to enhance BDNF expression while also exhibiting antioxidant properties. On an electrophysiological level, harmaline modifies thalamocortical rhythms and EEG patterns, affecting cortical excitability. In animal models, it demonstrates anxiolytic, antidepressant, and neuroprotective effects; however, at high doses it can provoke proconvulsant activity and serotonergic toxicity. Its role in modulating stress through HPA axis downregulation and amygdala-hippocampal plasticity further emphasizes its significance in psychiatry. Conclusion: Peganum harmala presents a distinctive dual mechanism-both biochemical and bioelectrical-that positions it as a potential treatment for mood disorders, seizures, and stress-related conditions. However, successful clinical application will require standardized formulations along with studies focusing on dosage safety and controlled trials to confirm effectiveness while minimizing neurotoxicity.