Key Dates

Related Announcements

• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required). See NOFO PA-20-194.
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
• May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required). See NOFO PA-20-196.
• May 5, 2020 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed). See NOFO PA-20-200.

Issued by

National Institute on Drug Abuse (NIDA)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to encourage research on the prevalence and consequences of xylazine use and the treatment of xylazine use and overdose alone or in combination with other drugs.

Background

Xylazine is an alpha-2 adrenergic receptor agonist with sedative and analgesic properties that is FDA-approved for veterinary use. Xylazine overdose induces sedation and can lead to respiratory depression especially when used with opioids. There are no FDA-approved agents to treat xylazine overdose in humans, although veterinary adrenergic antagonists have been used for emergency treatment of accidental xylazine injection.

Xylazine is increasingly becoming identified in unregulated drug supplies. A May 2023 DEA (NFLIS) publication reported that in 2015 xylazine was identified in 149 items, but this increased to 10361 items in 2022. There is a strong association between the use of xylazine and opioids and/or stimulants. Between 2021 and 2022, 80% of fentanyl/fentalog -positive drug paraphernalia seized in Maryland tested positive for xylazine. Concurrently, the presence of xylazine in drug overdose and withdrawal-related toxicology samples is also increasing. The CDC reported that in 2019, xylazine was involved in overdose deaths in 25 out of 38 states, reflecting its perfusion through unregulated US drug supplies. In December 2022, the FDA issued an alert addressing potential life-threatening effects associated with xylazine-adulterated drugs. These effects include CNS and respiratory depression, hypotension, and bradycardia. In April 2023, the U.S. Executive Administration declared xylazine an emerging threat .

Little is known about the medical consequences of using xylazine-adulterated drugs, although reports suggest that chronic use can produce severe skin lesions. The cause of these ulcers and abscesses is unclear, but they may be due to vasoconstriction or adrenergic dysregulation of insulin control. It is therefore unknown whether xylazine use poses equal risks to all, or whether diabetic patients are more vulnerable.

Xylazine-adulterated drugs may impact the likelihood and severity of drug overdose. It is unknown whether long-term exposure to xylazine increases the risk of developing substance-use disorders (SUDs) or how it affects opioid/stimulant overdose and withdrawal syndromes. Therapeutic protocols for SUDs may need to be developed or adapted to optimally treat xylazine positive patients.

Areas of Interest include (but are not limited to) :

Basic Research

• alpha-2 adrenergic and mu opioid receptors bidirectionally regulate each other. In cells that naturally express both receptor types, what are the specific interactive effects of fentanyl and xylazine?
• What are the combined effects of xylazine and stimulants/opioids on noradrenergic homeostasis?
• What is the impact of xylazine adulterated opioids/stimulants on glycemic regulation?

Preclinical Behavioral Pharmacology

• What is the impact of xylazine on the abuse potential of opioids and stimulants?
• How does xylazine affect the onset and outcome of opioids/stimulant overdose?
• How does xylazine affect dependence development and withdrawal syndromes?

Clinical Characteristics

• What are the clinical manifestations of acute overdose and chronic use of xylazine? Which organ systems are affected by chronic xylazine use?
• How are the risks of drug overdose (opioids, stimulants, other drugs) modified by the presence of xylazine?
• What are the risks of xylazine overdose, and how are they modified by concomitant medications?
• How does xylazine affect withdrawal syndromes and the progression of SUDs development?

Pharmacological Interventions

• What are the most appropriate approaches for treating overdoses involving xylazine? How does xylazine impact SUD treatment - acutely (e.g., first contact with treatment providers) and during recovery?
• How should the medical consequences of xylazine use be treated?
• Are there consequences associated with abrupt transition from xylazine-adulterated drugs to medications to treat SUDs (MSUDs)?
• Are there drug-drug interactions between xylazine and MSUDs, such as other alpha -2 adrenergic agonists or opioid agonists/antagonists?

Epidemiology

• Which unregulated drugs are most likely to be adulterated with xylazine and is this changing geographically over time?
• Is the relative proportion/dose of xylazine changing over time?
• Are the risks and sequalae of xylazine use the same in different demographic populations?
• What are the psychosocial consequences of xylazine use?
• Are other alpha-2 adrenergic adulterants emerging and is their use differentiated by illicit drug type?

Application and Submission Information

This notice applies to due dates on or after October 16, 2023 and subsequent receipt dates through January 8, 202 5.

Submit applications for this initiative using one of the following notice of funding opportunity (NOFO) or any reissues of these announcements through the expiration date of this notice.

• PA-20-200 (R03) NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed).
• PA-20-194 (R21) NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required).
• PA-20-195 (R21) NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed).
• PA-20-19 6 (R21) NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required).

All instructions in the SF424 (R&R) Application Guide and the NOFO used for submission must be followed.

• For funding consideration, applicants must include NOT-DA-24-009 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed notice of funding opportunity.

Scientific/Research Contact(s)

Jana Drgonova, PhD
Division of Therapeutics and Medical Consequences
National Institute on Drug Abuse (NIDA)
Email: jana.drgonova@nih.gov
Telephone: 301-827-5933

Aidan Hampson, PhD
Division of Therapeutics and Medical Consequences
National Institute on Drug Abuse (NIDA)
Email: aidan.hampson@nih.gov
Telephone: 301-827-5925