Post-Traumatic Stress Disorder (PTSD) continues to represent a significant and complex public health challenge, affecting approximately 12 million adults in the United States alone. The disorder’s prevalence spans 4% to 8% of the general population, with this figure looming even higher—up to 30%—within military personnel and veterans. A particularly troubling aspect of PTSD is its frequent comorbidity with alcohol use disorder (AUD) and chronic pain, conditions which not only coexist but also exacerbate one another, leading to worsening clinical outcomes and complicating treatment protocols. Indeed, roughly 63% of veterans diagnosed with PTSD report concomitant AUD and/or chronic pain, underscoring the urgent need for therapeutic strategies that address this triad holistically.
Despite advances in psychiatric medicine, there remains a glaring void in pharmacological interventions that effectively target PTSD when it occurs alongside alcohol misuse and chronic pain. Current treatment regimens often involve polypharmacy—multiple medications administered simultaneously—which can increase the risk of adverse side effects, reduce patient compliance, and ultimately yield suboptimal efficacy. Existing drugs frequently fail to provide relief across all these interlinked symptoms, highlighting a critical gap in care for patients grappling with this constellation of disorders. This therapeutic impasse has driven researchers toward novel compounds that modulate central nervous system pathways implicated in both stress and addiction.
In a pioneering set of experimental investigations, scientists from Florida Atlantic University’s Charles E. Schmidt College of Medicine joined forces with the University of Oklahoma College of Pharmacy to explore the efficacy of PPL-138, a novel opioid partial agonist, as a potential unified treatment option. This compound exerts its pharmacological actions by selectively modulating opioid receptors—specifically targeting the nuanced balance between agonism and antagonism in these receptors, which play a pivotal role in the reward and stress pathways of the brain. Through this targeted approach, researchers hypothesized that PPL-138 could attenuate the intertwined symptoms of PTSD, anxiety, chronic pain, and problematic alcohol consumption.
The intellectual property rights for PPL-138 are held by Phoenix PharmaLabs, Inc., now actively engaged in propelling this promising candidate through the stages of clinical trials. Preclinical examination of the drug’s effects involved two complementary studies employing rat models, recognized for their translational relevance in mimicking human PTSD-like behaviors and associated comorbidities. The University of Oklahoma’s study primarily evaluated whether prolonged administration of PPL-138 could alleviate PTSD-related symptom clusters arising from chronic traumatic stress. Parallel research conducted at Florida Atlantic University scrutinized how trauma-induced anxiety modulates alcohol consumption behaviors, employing differential grouping of rats based on susceptibility to trauma and stress resilience.
The findings, published in the British Journal of Pharmacology, present compelling evidence that PPL-138 produces significant reductions in anxiety-like behaviors, pain sensitivity, and alcohol intake—but crucially, these effects were confined to rats that developed PTSD-like phenotypes. Notably, the drug exhibited specificity by diminishing alcohol self-administration exclusively in animals with trauma-related anxiety markers, without impacting rats categorized as resilient or unstressed. This selective efficacy points to a mechanism that targets neural substrates underlying the pathological intersection of stress and addiction, positioning PPL-138 as a transformative candidate in psychopharmacology.
Delving deeper into sex-specific responses revealed intriguing differences consistent with established human epidemiological patterns. Female rats demonstrated a marked decrease in alcohol consumption when treated with PPL-138, even in the absence of escalated drinking behavior, suggesting that anxiety rather than the quantity of alcohol intake may be the dominant driver of alcohol use in females. Conversely, male rats exhibited more pronounced drinking escalation post-trauma, with PPL-138 effectively reducing intake principally among those exhibiting signs of anxiety. These nuanced sex differences highlight the necessity to tailor pharmacotherapies with attention to biological sex as a critical moderating factor.
Further validation that PPL-138’s behavioral effects were not confounded by sedation or motor impairment came from activity assays. Neither locomotion nor general activity levels were diminished in treated rats, with movement remaining stable in males and slightly increased in females. This specificity excludes non-selective suppression as the underlying cause of reduced alcohol consumption, strengthening the argument that PPL-138 acts on discrete neurobiological circuits linked to trauma-related anxiety and addiction pathways without generalized CNS depression.
According to Dr. Andrea Cippitelli, lead author and assistant professor in the Department of Biomedical Science at the FAU Schmidt College of Medicine, these experimental results herald a major advance toward integrated therapeutic options. The ability of a single compound to concurrently mitigate the core overlapping symptoms of PTSD, chronic pain, and alcohol misuse could revolutionize clinical management, especially considering the current fragmentation of care and high rates of treatment resistance. Dr. Cippitelli emphasizes the potential of PPL-138 to fill the unmet medical need for efficacious, safer pharmacotherapies that serve this vulnerable population.
Beyond its promise as a dual-action agent, PPL-138 embodies a broader scientific strategy targeting the endogenous opioid system’s role in stress modulation and addictive behaviors. By functioning as a partial agonist, the compound finely tunes receptor activity, avoiding the pitfalls of full agonists such as tolerance, dependence, and respiratory depression while retaining therapeutic benefit. This pharmacodynamic profile aligns with emerging paradigms in neuropsychopharmacology, prioritizing receptor subtype selectivity and balanced modulatory approaches to optimize efficacy and safety.
The collaborative nature of this work, involving experts across disciplines and institutions, reflects the complexity of addressing intertwined neuropsychiatric disorders. Contributions from pharmacologists, neuroscientists, and behavioral scientists culminated in a robust experimental framework capable of dissecting the multifaceted interactions between trauma, anxiety, and substance use. Furthermore, the support of the U.S. Department of Defense’s Health Affairs Office through its Alcohol and Substance Use Research Program underscores the strategic importance of developing interventions aimed at military populations disproportionately burdened by these conditions.
As the research progresses toward clinical validation, future directions will likely involve phase 1 and 2 trials to examine safety, tolerability, and initial efficacy of PPL-138 in human subjects, with particular attention to individuals exhibiting comorbid PTSD and AUD. The incorporation of biomarker assessments and stratification by sex will be critical to parsing the drug’s mechanistic impact and optimizing personalized treatment paradigms. If successful, PPL-138 could inaugurate a new era in the pharmacological management of overlapping psychiatric and pain disorders—offering hope to millions worldwide.
In summary, this innovative research not only illuminates a promising candidate for tackling the intertwined burdens of PTSD, anxiety, chronic pain, and alcohol misuse but also exemplifies how precise targeting of neural systems implicated in addiction and stress resilience can yield nuanced therapeutics. By transcending the piecemeal approach of symptom-by-symptom treatment, PPL-138 paves the way for a more integrated, effective, and safer strategy—one that could ultimately transform outcomes for patients who have long been marginalized by existing therapeutic limitations.
Subject of Research: Animals
Article Title: The opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder
News Publication Date: 9-Aug-2025
Web References:
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.70151
References:
Cippitelli, A. et al. The opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder. British Journal of Pharmacology, 2025.
Image Credits:
Florida Atlantic University
Keywords:
Anxiety disorders, Chronic pain, Alcohol abuse, Pharmacology, Drug targets, Neuropharmacology, Post traumatic stress disorder, Research and development, Clinical psychology, Psychiatric disorders, Neuroses, Behavioral psychology
