# Evaluation of the drug-drug interactions of fentanyl with stimulants in the context of overdose

> **NIH NIH U01** · CLEAR SCIENTIFIC, LLC · 2021 · $114,933

## Abstract

Project Summary/Abstract
CDC data show that between 2013 and 2020 fentanyl-linked deaths have increased 10-fold and are now twice
those involving heroin. Fentanyl and fentanyl analogues (F/FA) are commonly found in seizure of stimulants
and “club drugs.” Compounding this crisis is the concurrent use of F/FA with stimulants, particularly
methamphetamine and cocaine, driving the so-called 4th wave of the opioid crisis. Illicitly manufactured fentanyl,
heroin, cocaine, or methamphetamine (alone or in combination) were involved in nearly 85% of drug overdose
deaths in 24 states and the District of Columbia during January-June 2019. Unfortunately, there is limited
understanding of the drug-drug interactions and physiological consequences of F/FA co-intoxication with a
stimulant, and there are no targeted therapies. Co-intoxication manifests in a complex continuum of clinical
presentation due to different effect sites and drug-drug interactions, which can intensify or mask symptoms.
Some symptoms include opioid-induced respiratory depression and muscle rigidity, and stimulant-induced
increases in blood pressure and heart rate. The primary opioid reversal agent, naloxone, a µ-opioid receptor
(MOR) antagonist, as a solo therapeutic, may provoke acute opioid withdrawal exacerbated by unopposed
stimulant effects; naloxone's short duration of action may also result in re-narcotization.
It is crucial to understand the drug-drug interactions in opioid-stimulant co-use. In addition, a single therapeutic
that reverses the adverse effects of both co-intoxicants, simultaneously, through enhanced pharmacokinetic
clearance would be highly beneficial. Our drug candidate, CS-1103, currently being studied as reversal agent for
methamphetamine, also holds promise for treatment of opioid-stimulant co-intoxication. To better understand
the in vivo physiologic and pharmacologic impact of F/FA-stimulant co-intoxication and to provide a foundation
for CS-1103, and its use in conjunction with naloxone, we will undertake the following Aims in rodent studies of
opioid intoxication: Aim 1 will determine the physiological and pharmacological effects of fentanyl-
methamphetamine co-intoxication in awake, behaving rats. We will administer fentanyl and
methamphetamine at various ratios, dose levels, and length of time between opioid and stimulant dosing. We
will quantify effects on breathing, metabolism, hemodynamics, intoxicant pharmacokinetics, muscle rigidity,
and sedation/immobility. These studies will provide a better understanding of the complex interaction between
fentanyl and methamphetamine, to guide future therapies. Aim 2 will determine the physiological and
pharmacological effects of fentanyl-methamphetamine co-intoxication reversal by CS-1103 in
awake, behaving rats. We will identify doses of CS-1103 alone (and also in conjunction with naloxone)
required to normalize intoxicant-induced effects identified in Aim 1. These studies will clarify the safety,
efficacy, optimu...

## Key facts

- **NIH application ID:** 10433799
- **Project number:** 3U01DA053054-02S1
- **Recipient organization:** CLEAR SCIENTIFIC, LLC
- **Principal Investigator:** Xinhua Li
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $114,933
- **Award type:** 3
- **Project period:** 2020-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433799

## Citation

> US National Institutes of Health, RePORTER application 10433799, Evaluation of the drug-drug interactions of fentanyl with stimulants in the context of overdose (3U01DA053054-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433799. Licensed CC0.

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