A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders

Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)1A and 5-HT2A/C receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and Κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents.