Neuro-regulatory drug discovery (NRGDD): a neural-circuit framework for systemic therapeutic modulation

Drug discovery has long treated the brain as a passive target or a site of symptom control, not as a regulatory organ that drives systemic therapeutic responses. Discrete neural circuits directly and measurably control immune activation, inflammatory signaling, metabolic regulation, hormone release, and cardiovascular function. This evidence is substantial. Its therapeutic potential remains largely untapped. This article introduces Neuro-Regulatory Drug Discovery (NRGDD), a formalized drug-discovery framework that organizes and operationalizes principles drawn from neuroimmunology, bioelectronic medicine, autonomic pharmacology, and systems pharmacology into a causally structured development logic. While individual elements of this approach exist within established fields, no prior framework has combined circuit-specific eligibility criteria, causal disruption requirements, peripheral biomarker validation standards, and regulatory development strategy within a unified discovery model. NRGDD is distinguished from adjacent fields not by the novelty of its biological substrate but by the specificity and enforceability of its operational requirements. Under NRGDD, therapeutic activity is initiated through a defined neural circuit and confirmed through measurable changes in peripheral biomarkers. The framework specifies criteria for circuit selection, causal proof, biomarker validation, and regulatory strategy. The core hypothesis is that drugs or devices targeting specific neural regulatory circuits will produce consistent, measurable downstream changes in peripheral biomarkers. These changes can guide drug development, reduce clinical failures, and support effects that persist beyond the dosing period. Device-based neuromodulation is primarily used to identify and validate druggable circuits, not as the primary therapeutic goal. Clinical support comes from vagus nerve stimulation (VNS) trials in rheumatoid arthritis (RA), pyridostigmine treatment in COVID-19, and nicotine patch therapy in ulcerative colitis.