Standard pharmacotherapy for mental disorders, including depression and anxiety, is supported by extensive clinical validation and international treatment guidelines. However, it is frequently associated with limitations such as adverse side effects, low patient adherence, and the risk of relapse. Conventional approaches rely primarily on antidepressants, anxiolytics, mood stabilizers, neuroleptics, and stimulants, which modulate monoaminergic, GABAergic, and dopaminergic neurotransmission. Recently, preclinical and emerging clinical studies have suggested that selected natural substances-specifically mushroom-derived compounds and well-established medicinal plants-may offer complementary therapeutic pathways. This narrative review critically evaluates the pharmacological efficacy, mechanisms of action, and safety profiles of selected natural compounds, including psilocybin-related tryptamines, Hericium erinaceus, ibotenic acid/muscimol from Amanita muscaria, ergothioneine, as well as notable botanical agents (e.g., Hypericum perforatum, Valeriana officinalis). We systematically distinguish between robust human clinical data (e.g., psilocybin-assisted therapy) and preliminary in vitro/in vivo findings. Particular attention is paid to their neurotrophic, anti-inflammatory, and neuromodulatory properties, while emphasizing substantial safety concerns, including intoxication risks associated with isoxazole derivatives, and potentially severe cytochrome P450-mediated drug-drug interactions. Ultimately, while certain natural compounds show promise as adjunctive interventions, most remain strictly investigational and cannot replace evidence-based conventional pharmacotherapy without further long-term, large-scale randomized controlled trials.
