FAU study explores how a new drug may help treat PTSD and its common companions

About 12 million adults in the United States are affected by PTSD, impacting between 4% and 8% of the adult population – and up to 30% of military personnel and veterans. Strikingly, 63% of veterans with post-traumatic stress disorder also suffer from alcohol use disorder (AUD) and/or chronic pain. These conditions frequently overlap, with individuals who have AUD or chronic pain often also experiencing PTSD.

When these disorders co-occur, they tend to worsen one another, making effective treatment significantly more challenging. Currently, no approved medications effectively treat PTSD and AUD together, and many available drugs come with serious side effects or limited results.

Researchers from Florida Atlantic University's Charles E. Schmidt College of Medicine, in collaboration with the University of Oklahoma College of Pharmacy, conducted two complementary studies in rats to explore how a new drug, PPL-138, might help treat PTSD and its common companions – anxiety, chronic pain, and AUD. A type of opioid partial agonist, PPL-138 works by targeting specific opioid receptors in the brain.

Intellectual property related to PPL-138 is owned by Phoenix PharmaLabs, Inc. The company is in the process of advancing PPL-138 through clinical trials.

The first study, carried out at the University of Oklahoma, looked at whether long-term treatment with PPL-138 could reduce PTSD-related symptoms in chronic traumatic stress. The second study, conducted at FAU, focused on the relationship between trauma, anxiety and alcohol use, and researchers divided rats into different groups. 

Results, published in the British Journal of Pharmacology, provide promising evidence that PPL-138 could become a valuable treatment for PTSD and alcohol misuse – particularly when symptoms are rooted in anxiety. By targeting a brain system involved in both stress and addiction, researchers believe PPL-138 may one day offer a much-needed breakthrough for those struggling with these life-altering conditions.

Findings show that PPL-138 significantly reduced anxiety-like behavior, pain responses, and alcohol consumption – but only in rats that developed PTSD-like symptoms. In both male and female rats, the drug selectively reduced alcohol use in those that also showed signs of trauma-related anxiety, without affecting those that were resilient or not stressed.

Our results show that PPL-138 not only reduces trauma-related anxiety and pain, but also selectively curbs alcohol use in rats most vulnerable to stress-induced drinking. This kind of targeted treatment could transform how we manage PTSD and its comorbidities – especially for the large number of patients who currently fall through the cracks of existing therapies."

Andrea Cippitelli, Ph.D., lead author and assistant professor, Department of Biomedical Science within the Schmidt College of Medicine and member of the FAU Stiles-Nicholson Brain Institute

The study findings also emphasize the need to consider sex differences in both the causes and treatment of these overlapping conditions. Among female rats, PPL-138 reduced alcohol intake in those exhibiting anxiety, even if their drinking had not escalated. This indicates that anxiety alone may be a primary factor driving alcohol use in females. 

"Anxious male rats were twice as likely as females to increase their alcohol intake following trauma, while nearly all female rats with more alcohol intake also displayed clear signs of anxiety," said Cippitelli. "This mirrors well-documented patterns in humans, where women are more prone to anxiety-related disorders like PTSD and often use alcohol to cope with emotional distress, whereas men typically engage in heavier, more generalized drinking."

Importantly, the effects of PPL-138 were not due to sedation or reduced activity. The compound did not alter movement or alcohol consumption in rats with anxiety-related behaviors or traumatic stress. In fact, movement levels remained unchanged in male rats and slightly increased in females – supporting the idea that the drug acts specifically on stress- and anxiety-related behaviors, rather than causing general suppression or sedation.

"This research represents a much-needed step toward helping both civilians and veterans living with the invisible wounds of trauma," said Cippitelli. "In our preclinical studies, PPL-138 shows strong potential as a single therapy for the overlapping symptoms of PTSD, chronic pain, and alcohol misuse – offering a potentially safer and more effective alternative to current multi-drug approaches."

Study co-authors are Yong Zhang, Ph.D., University of Oklahoma College of Pharmacy; Kyle Kealoha, a Ph.D. student in the FAU Department of Biomedical Science; Ali Idriss, former research lab technician, FAU Department of Biomedical Science; Panini S. Patankar, M.D., University of Oklahoma College of Pharmacy; Benjamin Carper, RTI International, Research Triangle Park; Lawrence Toll, Ph.D., a professor of biomedical science, Schmidt College of Medicine and a member of the FAU Stiles-Nicolson Brain Institute; and Kelly M. Standifer, Ph.D., University of Oklahoma College of Pharmacy.

This work was supported by the U.S. Office of the Assistant Secretary of Defense for Health Affairs through the Alcohol and Substance Use Research Program.