AshwagandhavsNAC (N-Acetyl Cysteine)

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.

NAC provides cysteine, the rate-limiting substrate for glutathione (GSH) synthesis via gamma-glutamylcysteine ligase (GCLC) and glutathione synthetase (GSS). GSH is the primary intracellular antioxidant, essential for GPx and GST-mediated detoxification of reactive oxygen species in neurons. NAC also modulates glutamate via the cystine-glutamate antiporter (System Xc-, composed of xCT and 4F2hc) — NAC is deacetylated to cysteine, which exchanges for glutamate; the increased extracellular cystine is reduced to cysteine intracellularly, while the exchange increases extrasynaptic glutamate, which activates inhibitory mGlu2/3 autoreceptors on presynaptic terminals, reducing excessive glutamatergic signaling and compulsive behaviors. This glutamate modulation is the basis for psychiatric applications (OCD, addiction). NAC may also directly modulate NMDA receptors via redox sites.