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 co-use with opioids or opioid/stimulant combinations. This NOSI also encourages research into how xylazine impacts treatment of opioid use disorders and overdose.

Background

Xylazine is an alpha-2 adrenergic receptor agonist with sedative and analgesic properties that is FDA-approved for veterinary use. Xylazine can be mixed (adulterated) with illegal drugs, such as fentanyl, heroin, cocaine, either to enhance drug effects or increase street value by increasing their weight. When used in combination with opioids/stimulants, xylazine is known to produce synergistic effects in analgesic activity and respiratory depression, as well as other deleterious effects, such as vascular constriction and severe skin lesions/infection. Whether and how xylazine adulteration affects the treatment of opioid overdose or opioid use disorder is not known. There are no FDA-approved agents to reverse xylazine effects in humans, although veterinary adrenergic antagonists have been used for emergency treatment of accidental xylazine injection.

Xylazine has been increasingly identified in unregulated drug supplies, although it is unclear to what degree users understand whether xylazine is present in their purchases, and whether they generally avoid it or seek out xylazine-adulterated products. A May 2023 DEA publication [National Forensic Lab Information System (NFLIS)] reported that xylazine was identified in 149 analyzed items in 2015, and that this increased to 10361 items in 2022. Today xylazine is commonly found in both opioids and opioid/stimulant combinations. For example, between 2021 and 2022, 80% of seized fentanyl/fentalog-positive drug paraphernalia seized in Maryland, tested positive for xylazine. Over the same period another report identified xylazine in samples from 25 of 39 states, with 96% of samples positive for fentanyl, but cocaine and/or methamphetamine was also identified in 45% and 34% of samples (respectively). The presence of xylazine in drug overdose and withdrawal-related toxicology samples is also increasing. In 2019, xylazine was found in 31% of heroin and/or fentanyl overdose deaths in Philadelphia, Pennsylvania. In that same year the CDC reported that xylazine was involved in overdose deaths in 25 out of 38 states, which reflects its increased presence in unregulated US drug supplies. In November 2022, the FDA alerted healthcare professionals that xylazine use may result in serious and life-threatening effects, which are difficult to distinguish from opioid overdoses . These symptoms include CNS and respiratory depression, hypotension, and bradycardia. Xylazine can also induce severe necrotic skin ulcerations--the cause of this is unclear. In April 2023, the White House's Office of National Drug Control Policy officially designated fentanyl mixed with xylazine as an emerging threat to the United States. This designation comes after a careful review of the impact of xylazine on the opioid crisis, including its growing role in overdose deaths in all regions of the United States.

Little is known about the medical consequences of using xylazine-adulterated drugs. It is unknown how xylazine induces skin necrosis, and whether its use poses equal risks to all individuals. It is also unknown whether/how xylazine-adulterated drugs impact the likelihood and severity of drug overdose and the risk of developing substance-use disorders (SUDs). Xylazine may also affect the clinical presentation of opioid withdrawal as adrenergic withdrawal somewhat resembles opioid withdrawal symptoms, and xylazine has a very short pharmacological half-life (in animals). Adrenergic therapies are used to treat opioid withdrawal syndrome, and so it is uncertain whether prolonged xylazine exposure will affect SUD treatment protocols and / or the therapeutics employed. For more information on current medical practices related to treatment of xylazine-exposed patients please review the presentations: Here.

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

Basic Research

• What are the receptor binding and cell signaling profiles of xylazine, and how do they compare to those of other alpha-2 adrenergic receptor agonists?
• What are the cellular and regional sites of action of xylazine, and how do they correlate with opioid receptors?
• How does xylazine interact with opioids at the biochemical, cellular, or circuit levels and how do these interactions affect the pharmacological actions of opioids (e.g., subjective effects, sedation, analgesia, respiratory depression)?
• What is the behavioral pharmacology of xylazine, and how does it affect drug use-related behaviors (e.g., drug-seeking, extinction, reinstatement of drug-seeking)?
• What are the acute and long-term effects of xylazine and xylazine/opioid combinations on cognitive function and social behavior, and what are the neurobiological bases of these effects?
• What are the mechanisms by which xylazine alone or in combination with opioids causes severe skin lesions/infection?
• Are any xylazine metabolites pharmacologically active? If so, how do they impact xylazine’s effects in the presence of opioids?
• Does xylazine alter the pharmacokinetic profiles of opioids?
• Does xylazine exert a synergistic effect with opioids? If so, what is the mechanism and do other alpha-2 adrenergic agonists act similarly?
• Are there sex, age, or genetic differences in the effects of xylazine or xylazine/opioid combinations?
• What is the impact of exposure to xylazine or xylazine/opioid combinations on pregnancy, pregnant individuals, and fetal and newborn health?
• What strategies, including drug discovery, can prevent or reverse the deleterious effects of xylazine when it is used alone or in combination with opioids?

Clinical Characteristics

• What are the clinical manifestations of acute and chronic use of xylazine? Which organ systems are affected by chronic xylazine use?
• How are the risks of opioid overdose modified by xylazine?
• Are there symptoms of xylazine overdose which differ from those associated with other adrenergic agonists like clonidine?
• Does xylazine have a withdrawal syndrome distinct from that of opioids? And how does xylazine affect opioid withdrawal syndrome, initiation of medications for opioid use disorder, and /or the progression of SUD development?

Pharmacological Interventions

• What are the most appropriate approaches for treating opioid/opioid+stimulant overdoses involving xylazine? How does xylazine impact SUD treatment - acutely (e.g., first contact with treatment providers) and during recovery from opioid use?
• Are there long-term unknown medical consequences of chronic xylazine exposure, and how should they be treated?
• Does xylazine affect the optimal timing or transition pattern from unregulated opioids to SUD medications?
• Are there drug-drug interactions between xylazine and medications typically used by SUD patients, including other alpha-2 adrenergic agonists, anti-retroviral drugs, or opioid receptors agonists/antagonists?

Epidemiology

• What are the patterns of use of xylazine adulterated drugs and are these changing geographically over time?
• Are the patterns, risks, and sequelae of xylazine use the same in different demographic populations?
• What are the factors that contribute to xylazine adulteration in the drug market, including source of the drug, geography, etc.?
• How can this knowledge be used to inform prevention opportunities?
• What are the health outcomes associated with use of drugs adulterated with xylazine, including fatal and non-fatal overdose, skin lesions, and psychosocial outcomes? How do these vary by population groups and/or drug combinations?
• What are the psychosocial consequences of xylazine in combination with other drugs?
• Are other alpha-2 adrenergic agonists (such as medetomidine) emerging, and is their use as adulterants 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, 2025.

Submit applications for this initiative using one of the following notices 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-20-196 (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-24-012 (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 contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

MeLisa Creamer, PhD MPH
Division of Epidemiology, Services and Prevention
National Institute on Drug Abuse (NIDA)
Email: MeLisa.creamer@nih.gov
Telephone: 301-402-1933

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

Hoang Le, PhD
Division of Neuroscience and Behavior
National Institute on Drug Abuse (NIDA)
Email: Hoang.le@nih.gov
Telephone: 301-451-8849