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NIH/NIMH Therapeutics Discovery Research

NIMH supports early-stage therapeutic discovery and development, through first-in-human and early efficacy trials for mental disorders. This web page details the range of NIMH programs and resources related to therapeutic discovery and development, as well as complementary programs available through broader NIH efforts.

NIMH Drug and Device Development Pipeline
NIMH-specific Resource    
Multiple NIH Institutes/Centers
Target ID

Target ID: Identification of molecules that play a role in a disease processes.

Assay Development

Assay Development: Development of an experimentally controlled biochemical or biological system used for the quantitative analysis of test samples.


HTS: High throughput screening - a method in which a large number of assays (1000-1M) are performed and assessed in a relatively short time period, using automated technologies.

Hit to Lead

Hit to Lead: Progression from discovery of a compound whose activity exceeds a predefined threshold, to the identification of a compound within a series with sufficient pharmacological and biological characteristics to progress to a full drug development program.

Lead Optimization

Lead Optimization: Process in which the drug-like properties of an initial lead or lead series are improved and compounds with favorable chemical, pharmacological, and toxicological profiles are identified for progression to the clinic.


Pre-Clinical: Testing of compounds in experimental systems for their biological and toxic effects and potential clinical applications.

Phase I

Phase I: Assessment of drug safety and tolerability. Drugs are tested in a small group of healthy volunteers to determine the drug's activity. Related “first-in-human” studies may also assess target engagement and pharmacological effects.

Phase II

Phase II: Typically double-blinded, placebo-controlled studies designed to continue Phase I safety assessments, to determine how well the drug works in patients, and to identify the optimal dose to be used in Phase III clinical trials.


Provides screening of novel psychoactive compounds for pharmacological and functional activity at cloned human or rodent CNS receptors, channels, and transporters. Assays also available for bioavailability predictions and cardiovascular toxicity predictions.

Synthesizes and distributes novel research chemicals, psychoactive drugs, and compounds including support for radiochemistry, and limited medicinal chemistry and GMP synthesis.


Provides toxicology and safety assessment of promising, target-selective compounds for use as imaging ligands in human studies. The program also provides limited ADME toxicology, and PK support for early drug and ligand discovery.


Supports the identification and evaluation of neurophysiological measures as potential assays that bridge between preclinical and first in human studies in treatment development research.


Supports experimental medicine-based first-in-human and proof-of-concept studies of novel mechanism of action investigational drugs or devices to attract private funding for further clinical development as FDA-approved treatments. Also supports testing of novel drugs for use in pediatric populations with psychiatric disorders.


Supports pilot testing of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support “go/no-go” decisions about further development or testing of the intervention.

Small Business Program SBIR & STTR

Supports small businesses/biotechnology companies in the development of high throughput tools for compound screening, target identification, novel technologies for evaluating compounds in clinical trials, and drug discovery/development.

National Cooperative Drug Discovery and Development Groups (NCDDG) ( U19, U01)

Advancing the discovery, preclinical development, and proof of concept testing of new candidate medications to treat mental disorders or drug or alcohol addiction, and to develop novel ligands as tools to further characterize existing or to validate new drug targets.

Supports development of novel, robust analytical platforms, using in vitro assays to measure neurobiological endpoints and build a pipeline to be used in the context of target identification and drug discovery.


Bridging Interventional Development Gaps: provides access to government-funded contract resources for generating data and clinical material that investigators need to file an IND application with the FDA.

Development of Assays for High-Throughput Screening for Use in Probe and Pre-therapeutic Discovery
( R01, R21)

Supports development of assays for specific biological targets and disease mechanisms with intent to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads.

Drug Discovery for Nervous System Disorders ( R01, R21)

Supports studies aimed at translating basic science findings into the conceptualization, discovery, and preclinical evaluation of innovative therapeutics for nervous system disorders, with the goal of accelerating the development of new treatments.

The NIH Clinical Collection is a plated array of approximately 450 small molecules that have a history of use in human clinical trials.

Discovery of in vivo ( R01) and cell-based ( R21) Chemical Probes

Supports optimization of hits using integrated biological and chemical examination of structure activity relationships to develop novel in vivo chemical probes.

The Network bridges the gap in drug development between academic and industry research, offering researchers a “virtual pharma” to develop promising hit compounds from chemical optimization through Phase I clinical testing.


PubChem is a component of the NIH Molecular Libraries Roadmap Initiative. It provides information on the biological activities of small molecules. PubChem is organized as three linked databases within the NCBI’s Entrez information retrieval system.


The program creates a drug development pipeline within the NIH to stimulate research collaborations with academic scientists, non-profit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses.


Strategic Plan


Extramural Divisions Supporting Therapeutics Research and Trials

Information Relevant to Therapeutics Discovery FOAs

  • Discovery of in vivo Chemical Probes for Novel Brain Targets: PAR-17-336 (R01)
  • Discovery of Cell-based Chemical Probes for Novel Brain Targets: PAR-17-335 (R21)
  • Novel Assays to Address Translational Gaps in Treatment Development (UG2/UH3): PAR-16-065
  • Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders: PAR-18-227
  • National Cooperative Drug Discovery and Development Groups (NCDDG): PAR-18-230 (U01) and PAR-18-231 (U19)
  • Drug Discovery for Nervous System Disorders: PAR-16-041 (R01); PAR-16-042 (R21)
    • Lead Compound Report Card (PDF file): Use this form to summarize the characteristics of a lead compound you are studying and the desired characteristics of a therapeutic candidate, to track progress through the lead optimization process.
    • Sample Drug Development Testing Funnel (PDF file): A graphical illustration of the comprehensive series of assays used for lead optimization and candidate selection.
  • National Cooperative Reprogrammed Cell Research Groups (NCRCRG) to Study Mental Illness: PAR-18-230 (U01); PAR-18-231 (U19)
  • ChemNavigator allows investigators to search a database of commercially available drug discovery screening compounds. It includes a new Semi-Custom Synthesis Online Request System (SCOSRS) option that links investigators with companies capable of synthesizing specific compounds at reasonable costs.
  • Rigor and Reproducibility: Information to assist the extramural community in addressing rigor and transparency in NIH grant applications and progress reports
  • Research Domain Criteria (RDoC) Project: A description of the RDoC project, workshop proceedings, current Requests for Applications (RFAs), and additional information.

Additional Funding Announcements and Notices Relevant to Therapeutics Discovery

  • NIMH Clinical Trials Funding Opportunity Announcements