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Background Non-disordered drug use is defined as using a substance in the past year without meeting two or more Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnostic criteria for a substance use disorder (SUD). Non-disordered drug use can have negative health consequences, including, but not limited to, an increased risk of drug (e.g., opioid, cannabis, synthetic cannabinoids, cocaine, and methamphetamine) overdose, brain damage due to hypoxia related to respiratory depression, cardiovascular complications, effects on maternal and infant health, infectious diseases, and soft-tissue damage and wounds. The Emergency Medical Services (EMS) reported more than 214,000 cases of non-fatal opioid-involved overdose (NFOO) in the U.S. from September 2022 to September 2023. One of the main complications of opioid overdose due to opioid-induced respiratory depression (OIRD) is hypoxia-related brain injuries. The average reported EMS response time is over 9 minutes, while brain damage due to lack of oxygen can start within 4 minutes of OIRD. Hypoxia-related brain injuries can result in various neurological problems, such as reduced motor skills, mental confusion, memory and cognitive impairment, involuntary movements, seizures, and brain swelling. Furthermore, people who have experienced NFOO have a 15.3 times higher risk of developing encephalopathy caused by hypoxic injury. Unlike hypoxia-related brain injuries caused by traumatic brain injuries, cardiac arrest, or stroke, there are currently no products approved by the U.S. Food and Drug Administration (FDA) specifically designed to prevent, diagnose, or treat brain injuries resulting from NFOO. Non-disordered cannabis and synthetic cannabinoid use can have negative consequences, including delirium, psychosis, anxiety, panic attacks, palpitations, paranoia, hallucinations, sleep disorders, cannabinoid hyperemesis syndrome, and fatal and non-fatal overdose. Long-term cannabis use can impair cognitive functions, such as decision-making, concept formation, and planning. Studies have shown that even non-disordered cannabis use by adolescents can affect brain development and increase the risk of cognitive impairment, poor educational outcomes, and adverse psychosocial events, such as major depression, suicidal ideation, and aggression. There are no FDA-approved products intended to prevent, diagnose, or treat cannabis-induced complications for either adults or adolescents. In 2020, over 5 million Americans reported using cocaine, and about 2.5 million reported using methamphetamine. Both drugs increase the risk of cardiovascular problems, especially strokes. People who use cocaine have a more than 6-fold higher risk of having a stroke within 24 hours of use. People who use methamphetamine have a 32% higher risk of cardiovascular disease overall and almost double the risk of strokes compared to the general population. There are several approaches to prevent and treat non-stimulant-induced cardiovascular diseases. However, no solutions presently exist for the prevention and therapy of stimulant-induced cardiovascular diseases. Similarly, non-disordered drug use during pregnancy can have severe health consequences. Opioid use during pregnancy can cause neonatal opioid withdrawal syndrome (NOWS) and preterm birth. Cannabis use during pregnancy can cause preterm birth, low birth weight, and long-term brain development problems that affect memory, learning, and behavior. Cocaine and methamphetamine use during pregnancy can cause spontaneous miscarriage, difficult delivery, and preterm labor. Exposure to cocaine and methamphetamine during fetal development can cause behavioral problems, language and memory problems, and deficits in information processing and sustained attention in newborns. These consequences can lead to increased morbidity and mortality, as well as long-term intellectual and developmental disabilities in newborns. Pharmacological treatments are limited to NOWS mitigation and implement opioids such as morphine, methadone, and buprenorphine. In addition, people who use drugs are at a higher risk of getting blood-borne infections, especially if they share needles or other injection equipment. The number of acute endocarditis and recurrent endocarditis cases has markedly increased among persons who inject drugs. Care for endocarditis typically consists of a course of antibiotics delivered by intravenous drip for several weeks, usually requiring hospitalization. Lack of access to healthcare due to stigma, discrimination, financial limitations, and reluctance to be hospitalized, often hinders people who use drugs from receiving proper medical treatment for endocarditis. New approaches to prevent and treat endocarditis in this population are needed. Moreover, emerging novel substances also cause severe health consequences. For example, xylazine is currently reported as an adulterant in an increasing number of illicit drug mixtures, especially in the Northeast region of the United States. Xylazine is a non-opioid sedative that is not approved for human use and has no known antidote. Injecting xylazine or xylazine-containing drugs can cause soft tissue injuries that may lead to wounds, abscesses, skin ulcers and limb amputation. In the areas with a high prevalence of the use of xylazine mixed with fentanyl or heroin, abscesses, and painful skin ulcers are often reported. Current treatment options for xylazine-induced soft tissue injuries are limited to the prevention of wound infections but are not preventing or treating soft tissue injuries. Research Objectives and Specific Areas of Interest This notice of funding opportunity (NOFO) invites applications for research and development activities to create commercially viable products to address the health consequences of non-disordered drug use. The scope of proposed projects may encompass FDA-regulated areas such as pharmacotherapeutics, including small molecules and biologics, or medical therapeutic and diagnostic devices, including software classified as a medical device. Small businesses that have already marketed products or are developing technologies for different indications and are interested in demonstrating the potential of their product to treat the health consequences of non-disordered drug use are particularly encouraged to apply. Specific proposed objectives will vary among applications. Appropriate goals include, but are not necessarily limited, to the following approaches: Prevent, diagnose, and treat: NFOO-induced hypoxia-related brain injuries; Stimulant-induced cardiovascular complications; The consequences of maternal drug exposure. Prevent and treat: Medical consequences of cannabis and synthetic cannabinoids use in adults; Medical consequences of cannabis and synthetic cannabinoids use in adolescents; Acute endocarditis caused by intravenous drug use; Xylazine-induced tissue injuries. FDA-regulated pharmacotherapeutics: For FDA-regulated pharmacotherapeutics, applicants should propose and conduct activities that will eventually lead to the filing of an Investigational New Drug (IND) application, as well as clinical studies to support the filing of either a New Drug Application (NDA) or a Biological License Application (BLA). FDA-regulated medical therapeutic and diagnostic devices, including software as a medical device: For applications proposing medical therapeutic and diagnostic devices, including software as a medical device, applicants should propose activities that will lead to the successful filing of an FDA premarket application for clearance/approval (e.g., 510(k), De Novo, or Premarket Approval application). Such activities include early engagement with the FDA Center of Devices and Radiological Health via the Pre-Submission Program to receive feedback on proposed intended use, preclinical testing, and study design protocols. Applications Not Responsive to this NOFO The following types of studies are not responsive to this NOFO and will not be reviewed: Applications focused solely on solutions for health consequences not related to non-disordered drug use. Applications focused solely on solutions for patients already diagnosed with SUD. Applications focusing solely on the health consequences of alcohol use. Applications pursuing pain as a sole focus without addressing non-disordered drug use. Applications that are considered incomplete to this NOFO Fast-track applications that do not include two separate sets of milestones, one set for Phase I and another set for Phase II, will also be considered incomplete and will be administratively withdrawn and not reviewed. The Small Business Technology Transfer (STTR) program is a phased program. An overall objective of the STTR program at NIH is to increase private sector commercialization of innovations derived from federally supported research and development. The main objective of the STTR Phase I is to establish the technical merit and feasibility of the proposed research and development efforts. In contrast, the STTR Phase II objective is to continue the R&D efforts to advance the technology toward ultimate commercialization. Beyond the scope of this NOFO, it is anticipated and encouraged that the outcomes of successful STTR projects will help attract strategic partners or investors to support the ultimate commercialization of the technology as a publicly available product or service. The following types of applications are accepted in response to this NOFO: Phase I. The objective of this phase is to establish the technical merit and feasibility of proposed research or R&D efforts and to determine the quality of performance of the prime applicant (small business concern or SBC) before providing further Federal support in Phase II. Fast Track. The NIH Fast Track process allows Phase 1 and Phase II grant applications to be submitted and reviewed together. It expedites award decisions and funding of STTR Phase II applications for scientifically meritorious projects with high commercialization potential. Importantly, before Fast Track Phase II can start, the National Institute on Drug Abuse (NIDA) conducts an administrative review and evaluates the achievement of the stated milestones. In addition to Approach and Investigator(s), Fast-Track milestones are assessed as Additional Review Criteria: Does the Phase I application specify milestones that should be achieved prior to initiating Phase II? The applicant’s failure to provide milestones and specific, measurable, achievable, relevant, and time-bound milestone deliverables may be sufficient reason for the peer review to exclude the application from the Fast Track review. Fast Track applicants must propose two separate sets of milestones associated with the specific, measurable, achievable, relevant, and time-bound milestone deliverables, one set for Phase I and another set for Phase II. It is essential to clearly state the go/no-go milestone decisions that will determine the transition to Phase II. Failure to adequately address these criteria may negatively affect the application’s impact score. Based on peer review recommendations, NIDA Program Officer may negotiate the Phase I milestones with the Fast Track potential awardees before they are included in the terms of the award. Special Considerations NIDA applicants are strongly encouraged to review the guidelines and adhere to the requirements applicable to their research listed in the Special Considerations for NIDA Funding Opportunities and Awards. Upon award, these considerations will be included in the Notice of Grant Award. See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.