Philippe A. Melas

Why are some people more biologically vulnerable to addiction, anxiety and relapse, while others seem more resilient? And how can this knowledge help us develop better, more mechanism-informed treatments? These questions drive my research at Karolinska Institutet.

My name is Philippe A. Melas, and I am an independent principal investigator/PI and Docent at the Department of Clinical Neuroscience and the Centre for Psychiatry Research. My research focuses on the molecular biology of addiction, with alcohol use disorder as the main starting point. I am especially interested in why addiction so often overlaps with anxiety, stress sensitivity, and other psychiatric or substance-related problems.

My academic journey began in Greece, where I studied Molecular Biology and Genetics. I later moved to Sweden and completed my PhD at Karolinska Institutet, focusing on genetic and epigenetic mechanisms in psychiatric disorders. During my postdoctoral years at Columbia University in New York, my research moved deeper into addiction neuroscience and into the question of how repeated substance use, stress and biological vulnerability can leave long-lasting molecular traces in the brain.

Since returning to Karolinska Institutet, I have built an independent, externally funded research program that starts from human biology and follows the most promising clues into experimental models. We combine human genetics, postmortem brain tissue, stem-cell-derived neurons, animal models, RNA biology, proteomics and computational drug discovery. The aim is not only to describe what is altered in the addicted brain, but to understand which mechanisms may be possible to target in future treatments.

Alcohol use disorder as a window into addiction biology

Alcohol use disorder is the main focus of my current research, but the questions are broader. Many people with alcohol problems also experience anxiety, depression, nicotine use or other substance use. This makes alcohol use disorder an important clinical problem in its own right, but also a useful model for studying shared mechanisms of addiction and psychiatric vulnerability. My research asks why some individuals remain vulnerable to craving, negative emotions and relapse, and whether molecular changes in the brain can help explain this vulnerability.

From genetic risk to RNA regulation in alcohol use disorder

Human genetic studies have identified many DNA regions linked to alcohol-related and psychiatric traits. The next challenge is to understand what these signals actually do in the brain. One genetic signal that has become central to my work lies near FTO, a gene involved in regulating chemical marks on RNA. RNA helps cells use genetic information, and changes in RNA regulation may help explain how inherited risk becomes long-lasting brain change. In our human genetic work, we have also found that FTO-related variation may influence problematic alcohol use indirectly through neuroticism, a trait related to negative emotions, anxiety and stress sensitivity. This supports the idea that addiction biology cannot be fully separated from emotional and psychiatric vulnerability.

A surprising role for circular RNAs in alcohol dependence

One of our most intriguing findings comes from the amygdala, a brain region important for stress and emotional learning. When we studied RNA regulation in alcohol dependence, the strongest signal was not in ordinary messenger RNAs, as one might expect, but in circular RNAs: unusually stable RNA molecules that are abundant in the brain and still poorly understood. Several of these circular RNAs came from FKBP5, a gene involved in the body’s stress response. This has opened a new research direction linking FTO, RNA regulation, circular RNAs and stress biology. We are now testing this pathway in human stem-cell-derived neurons and animal models to understand whether it contributes to alcohol-related brain changes. At the same time, we are asking whether this biology can be used therapeutically. Because FTO is an enzyme, it may be possible to influence this pathway pharmacologically. We are therefore studying whether FTO-modulating compounds can affect alcohol-related molecular changes and reduce alcohol intake in models of dependence.

Human brain proteomics and drug repurposing

In parallel, we use a complementary route to search for new treatment ideas directly from the human brain. We study postmortem brain tissue from people with alcohol use disorder and look for molecular patterns that may reveal what has changed in the disease state. In particular, we use proteomics to study proteins, the working molecules of the cell and the targets of most medications. These human brain signatures are then used for drug repurposing, where we ask whether existing or experimentally characterized compounds could counteract addiction-related molecular changes. In this way, the FTO/circular RNA work and the proteomics work are connected by the same translational goal: to move from human molecular findings toward experimentally testable treatment strategies for alcohol use disorder.

Toward broader substance use disorder research

Although alcohol use disorder is my main research platform, many of the mechanisms we study may be relevant to other substance use disorders. Craving, relapse, stress sensitivity and loss of control are shared across several forms of addiction, and many people use more than one substance. A long-term goal of my research is therefore to understand which molecular mechanisms are alcohol-specific and which reflect broader addiction vulnerability. This knowledge may eventually help guide more precise treatment strategies across alcohol, nicotine, cannabis, opioid and stimulant use disorders.

Funding and scientific development

I am deeply grateful to the funders who have made my research possible. As principal investigator, I have received project support from the Swedish Research Council, the Swedish Brain Foundation, the Alcohol Research Council of the Swedish Alcohol Retailing Monopoly, Karolinska Institutet, the Åke Wiberg Foundation, the Petrus and Augusta Hedlund Foundation, the Magnus Bergvall Foundation, the Royal Physiographic Society in Lund, the Sigurd and Elsa Golje Memorial Foundation, the Lars Hierta Memorial Foundation, the Loo and Hans Osterman Foundation, the Längmanska Foundation, and other private foundations.

This support has been essential for building an independent research program in molecular psychiatry and addiction neuroscience. It has allowed me to pursue new ideas, develop international collaborations and take steps from molecular discovery toward treatment-oriented research. Earlier doctoral and postdoctoral fellowships from the Swedish Research Council, the Sweden-America Foundation, the Royal Physiographic Society in Lund, the Fernström Foundation, Karolinska Institutet and the Bodossaki Foundation were equally important in shaping my scientific path.

As Docent in experimental psychiatry at Karolinska Institutet, teaching and supervision are central parts of my academic work. My teaching focuses mainly on psychiatric genetics, addiction genetics, and molecular mechanisms in psychiatry, with the goal of making complex biological concepts accessible and relevant to students, clinicians and early-career researchers. I strive to create an active learning environment where students are encouraged to ask questions, connect molecular concepts to real psychiatric and clinical problems, and think critically about how genetic and biological findings should be interpreted. I am actively involved in the Research School for Clinicians in Psychiatry, organized by Karolinska Institutet and Region Stockholm, where I co-lead the Psychiatric Genetics week. This teaching is especially meaningful to me because it brings together clinicians and researchers around questions that are directly relevant to psychiatric care and future research. I also supervise students and early-career researchers in projects related to molecular psychiatry and translational neuroscience. Through my teaching and supervision, I work to connect genetics, neuroscience and clinical psychiatry in a way that helps students understand not only the methods, but also why they matter for mental health research.

Supervision to doctoral degree

• Wenjie Cai, 2026
• Buse Bektash, 2024-
• Miranda Stiernborg, Exploring the gut microbiome in ADHD and schizophrenia spectrum disorder, 2024
• Yabin Wei, Novel mechanisms in depression: Focus on telomere biology and epigenetic regulation, 2015