Next-Generation Adaptogens: Molecular Mechanisms, Bioactive Compounds and Human Health Relevance of Selected Botanicals and Fungi

Adaptogens are natural substances proposed to enhance non-specific resistance to stress and support physiological homeostasis. This review critically evaluates the phytochemistry, molecular mechanisms, human-health relevance, and translational evidence for seven proposed next-generation adaptogens: Lepidium meyenii, Astragalus membranaceus, Cordyceps militaris, Rhaponticum carthamoides, Gynostemma pentaphyllum, Centella asiatica, and Glycyrrhiza glabra. Evidence from mechanistic studies, clinical trials, systematic reviews, and meta-analyses was critically synthesised with emphasis on chemically characterised preparations, molecular target engagement, human exposure, and the distinction between preclinical and clinical evidence. The most consistently supported mechanisms include fatty acid amide hydrolase (FAAH) inhibition by maca macamides; telomerase- and senescence-related effects of Astragalus constituents; and AMP-activated protein kinase (AMPK)-centred metabolic regulation by cordycepin and gypenosides. Other relevant pathways include oestrogen receptor beta (ERβ)-related and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)-dependent anabolic signalling by phytoecdysteroids; brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB)-associated neuroplasticity and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent redox regulation by C. asiatica; and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inhibition by glycyrrhetinic acid. However, evidence strength differs markedly among species and outcomes, and many mechanisms remain predominantly preclinical. Clinical translation is further limited by extract variability, incomplete pharmacokinetic characterisation, uncertain bioavailability, and safety concerns. The next-generation adaptogen concept should therefore be regarded as a pathway-oriented framework whose validation requires standardised preparations, mechanism-aligned biomarkers, clinically relevant endpoints, and rigorous safety assessment.