Mazindol ER Shows Promising Dual Action Against Fentanyl Addiction in Preclinical Studies
Key Insights
NLS Pharmaceutics' preclinical study demonstrates Mazindol ER (search) significantly reduces both fentanyl's rewarding effects and withdrawal symptoms in rodent models, suggesting potential as a novel non-opioid treatment for opioid addiction (search).
The drug's multi-receptor mechanism targets partial mu-opioid receptor (search) agonism, 5-HT1A receptor (search) activation, and orexin-2 receptor (search) modulation, offering a unique approach compared to traditional addiction treatments.
These findings will be presented at the 2025 ASCP Annual Meeting in Arizona, with researchers highlighting Mazindol's potential advantages over conventional ADHD (search) medications that show limited efficacy for opioid dependence.
NLS Pharmaceutics Ltd. (NASDAQ: NLSP) will present new preclinical data showing that its investigational drug Mazindol ER (search) significantly reduces both the rewarding effects of fentanyl and the severity of withdrawal symptoms in animal models. The findings will be presented at the 2025 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP) in Scottsdale, Arizona, on May 29, 2025.
The Swiss clinical-stage biopharmaceutical company, which focuses on central nervous system (CNS) disorders, collaborated with Key-Obs SAS (search) and other European academic institutions on the preclinical study designated KO-943. The research utilized validated rodent models to evaluate Mazindol's potential as a treatment for fentanyl dependence.
Dual Mechanism Against Fentanyl Addiction
The study employed two distinct experimental models to assess Mazindol's efficacy. In the first experiment using C57BL/6J mice, Mazindol at 0.5 mg/kg significantly reduced fentanyl-induced conditioned place preference (CPP), effectively neutralizing the behavioral reward effects typically associated with fentanyl exposure.
The second experiment, conducted in Sprague-Dawley rats, demonstrated that Mazindol administered at doses of 0.5 and 1.0 mg/kg dose-dependently reduced fentanyl withdrawal symptoms. These symptoms included agitation, salivation, and motor disturbances, as measured by the Gellert-Holtzman scale, a standardized assessment tool for opioid withdrawal severity.
Dr. Jean-Charles Bizot, Director of Research at Key-Obs SAS (search) and lead investigator of Study KO-943, emphasized the significance of these findings: "The study results show that Mazindol produced robust effects on both reward and withdrawal symptoms, demonstrating its potential as a non-opioid therapeutic candidate option for fentanyl dependence. The data support further exploration in clinical models, particularly given the multi-receptor activity of Mazindol."
Novel Multi-Target Mechanism of Action
What distinguishes Mazindol from other potential treatments is its unique pharmacological profile. Dr. Eric Konofal, MD, PhD, Chief Scientific Officer of NLS Pharmaceutics, explained: "These data suggest the potential of a multiple-target profile for Mazindol to address opioid addiction (search) through a novel mechanism of action. By targeting partial mu-opioid receptor (search) agonist activity, strong 5-HT1A receptor (search) agonist activity, and orexin-2 receptor (search) modulation, Mazindol may offer a unique, multi-modal strategy to reduce opioid reward and withdrawal symptoms."
This multi-receptor approach differs significantly from traditional addiction treatments, which often target single pathways. The findings are supported by results from both reward and withdrawal animal models, including the CPP paradigm in mice and naloxone-precipitated withdrawal in rats.
Implications for ADHD and CNS Disorder Treatment
The research has broader implications beyond addiction medicine. Standard stimulant and non-stimulant medications approved for attention-deficit/hyperactivity disorder (ADHD (search)) have shown no significant efficacy in addressing opioid withdrawal or reward. Mazindol's ability to reduce both in fentanyl-exposed animals suggests it may offer advantages over conventional treatments.
This aligns with clinical observations that differentiate the pharmacodynamic profile of Mazindol from traditional monoaminergic agents, as discussed in comparative studies such as Wigal et al., CNS Drugs (2018). NLS Pharmaceutics' pipeline includes drug candidates for ADHD (search), narcolepsy (search), hypersomnia (search), and substance use disorders, with a focus on repurposed and reformulated compounds.
Path Forward to Clinical Validation
While the preclinical results are promising, Dr. Konofal emphasized that "clinical trials, including the planned NLS-6002 study, are needed to validate these results in humans." The company plans to advance Mazindol ER (search) into human studies to further evaluate its potential as a treatment for fentanyl and other opioid dependencies.
The opioid crisis continues to pose significant public health challenges globally, with synthetic opioids like fentanyl driving overdose deaths in many regions. Novel non-opioid approaches to treating addiction are urgently needed, as current therapies have limitations in efficacy and accessibility.
The ASCP Annual Meeting, recognized as one of the world's premier scientific events for advancing neuropsychopharmacology and psychiatry, provides an important platform for NLS to present these findings to leading clinicians, researchers, and innovators in the field of CNS therapeutics.
NLS Pharmaceutics' poster, titled "Evaluating the Effects of Mazindol on Fentanyl Reward and Dependence in C57BL/6J Mice and Sprague-Dawley Rats (Study KO-943)," will be presented during the poster session on May 29, 2025, from 11:15 AM to 1:00 PM at the Fairmont Scottsdale Princess in Scottsdale, Arizona.