Background/Objectives: The microbiota-gut-brain axis (MGBA) modifies central nervous system (CNS) pharmacotherapy by influencing the biopharmaceutics, pharmacokinetics (PK), and pharmacodynamics (PD) of drugs, while CNS drugs reciprocally reshape the MGBA. This review examines these interactions and their clinical relevance, explicitly grading the strength of the evidence. Methods: This narrative, mechanistically oriented review focuses on four oral drugs representing distinct mechanistic archetypes: levodopa/carbidopa (biopharmaceutical-dominant), olanzapine (PK-dominant), sertraline (PD-dominant), and amitriptyline (mixed). PubMed/MEDLINE, Google Scholar, and Google were searched up to 1 September 2026; of approximately 260 records screened, 64 were cited. No PRISMA reporting or dual screening was performed. Findings were assigned to five evidence tiers (L1-L5) and classified as associative or causal. Results: For levodopa/carbidopa, fecal tyrosine decarboxylase (tdc) gene abundance correlates with daily dose requirement (human observational), and Helicobacter pylori eradication or treatment of small intestinal bacterial overgrowth improves levodopa exposure or motor outcomes (human interventional). For olanzapine, microbiota depletion increased bioavailability ~1.8-fold in rats (single study), and microbiome-dependent weight gain is causal in rodents, whereas human data are phenomenological only. For sertraline, antimicrobial activity and fecal depletion are demonstrated in vitro; the pharmacodynamic blockade derives from fluoxetine models. For amitriptyline, antimicrobial and anticholinergic effects are preclinical, and the ATLANTIS trial demonstrates efficacy in irritable bowel syndrome without measuring the microbiome. Conclusions: The microbiome is a measurable modifier of CNS drug fate, but few interactions are clinically actionable. Progress requires prospective trials with standardized MGBA biomarkers, microbiome-informed PK/PD models, and independent replication.
