AshwagandhavsTianeptine

Ashwagandha's withanolide compounds (withaferin A, withanolide A, withanone) modulate the hypothalamic-pituitary-adrenal (HPA) axis, reducing corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) signaling, thereby lowering cortisol production by 25-30% in stressed individuals. It acts as a GABA-A receptor positive allosteric modulator at the benzodiazepine site, producing anxiolytic effects without sedation. Ashwagandha inhibits acetylcholinesterase (AChE), raising acetylcholine levels in the hippocampus and cortex. The withanolides have anti-inflammatory properties via inhibition of NF-κB and COX-2, and antioxidant effects that reduce neuroinflammation and oxidative stress. It may support neurogenesis through upregulation of BDNF and its receptor TrkB, and modulation of the PI3K/Akt pathway.

Tianeptine is a full agonist at mu-opioid (MOR) and delta-opioid (DOR) receptors, mediating both its antidepressant/anxiolytic effects and abuse potential at high doses. Paradoxically, it enhances serotonin reuptake via SERT—opposite to SSRIs—yet still produces antidepressant effects, possibly through opioid-mediated mood regulation. Tianeptine modulates glutamatergic signaling by reversing stress-induced downregulation of AMPA receptor subunits (GluA1/GluA2) and restoring synaptic plasticity. In the hippocampus and amygdala, it prevents stress-induced dendritic atrophy, spine loss, and CA3 pyramidal cell damage—likely through opioid receptor activation and downstream HPA axis effects. It increases BDNF levels and promotes neurogenesis. The combination of opioid agonism, glutamate normalization, and neuroplasticity enhancement underlies its unique profile.