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The Analytical Zen Podcast
Biography and Research: See Orcid.org/0000-0001-8344-6582 (presenting 100+ academic works)
Dr. Geraldine M. Dowling SFHEA is an accomplished professional with over 20 years experience in forensic, analytical toxicology, food safety, drug residue testing, method validation, ISO17025 laboratory accreditation and more than 10 years experience in academia as an educator. She is an internationally recognised researcher. She is a Senior Fellow of the Higher Education Academy (SFHEA), awarded for excellence in teaching/research/leadership within higher education reflecting extensive experience and significant contributions to improving educational practices, research, mentoring professionals and enhancing the overall quality of teaching and learning in academic settings and in industry.
She is the creator and host of The Analytical Zen Podcast, an educational series designed to make complex scientific concepts accessible to both students and the general public (available on Spotify etc).
Dr. Dowling is currently elected Vice Chair (past Treasurer) of the United Kingdom and Ireland Association of Forensic Toxicologists (body represents forensic toxicology professionals in England, Ireland, Wales, Northern Ireland, Scotland and the Channel Islands). She is the International Association of Forensic Toxicologists elected regional representative for Ireland, a member of the Society of Forensic Toxicologists in America and elected member of the London Toxicology Group Committee. She has extensive experience in working/training professional staff and students in ISO17025 accredited national government laboratories in Ireland, including The State Laboratory, Teagasc, The National Dairy Science Laboratory, The Irish Equine Centre and The Marine Institute. She is a Principal Investigator supervising postgraduate students (PhD/MSc). Her research interests focus on analytical chemistry, lab accreditation, forensic science, forensic/clinical toxicology, metabolomics, medicine, flavoromics, food safety and education pedagogies.
Dr. Dowling was invited to give her expertise to a Irish Government working group titled the “Emerging Drug Trends and Drug Checking Working Group.” This government-supported initiative aim was to introduce safer, more informed approaches particularly through harm-reduction strategies rather than punitive or enforcement only methods.
Dr. Dowling is a contributing author, reviewer and editor across selected international journals eg Drug Testing and Analysis, Journal of Analytical Toxicology, Forensic Science Review, Journal of Forensic Research, Frontiers in Molecular Physiology etc. In addition, she has written, edited/co-authored four books.
Dr. Dowling is the Editor-in-Chief of The IACFT Journal, the official publication of the International Alliance of Clinical and Forensic Toxicologists (ISSN: 3088-6600), as well as the Editor-in-Chief of the Science Undergraduate Research Experience Journal (ISSN: 2990-8167).
She is a Honorary Professor at Kingston University, London UK, a Visiting Senior Lecturer at King’s College London, UK and an Honorary Senior Lecturer at the Cameron Forensic Medical Sciences Unit, Queen Mary University of London, UK. She formerly served as an Adjunct Assistant Professor at Trinity College Dublin's School of Medicine and as a visiting scholar at the National University of La Plata, Argentina.
Dr. Dowling’s work has had a lasting impact, with government agencies such as Ireland’s Marine Institute using her methods in aquaculture monitoring since 2006 and internationally the U.S. FDA adopting her research for monitoring non-steroidal anti-inflammatory drugs since 2011. This research continues to be applied and is still in use in 2025.
Please see Linkedln profile:
www.linkedin.com/in/geraldine-dowling-msc-pgdip-phd-sfhea-2b66b835
The Analytical Zen Podcast
Inside Synthetic Cathinones
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In this episode of The Analytical Zen Podcast, Dr. Simona Pichini guides us through the complex and fast-evolving world of synthetic cathinones. Dr. Pichini is an Italian pharmacotoxicologist and Acting Director of the National Centre on Addiction and Doping at the Italian National Institute of Health. She is a leading expert in the pharmacokinetics and toxicology of drugs of abuse, new psychoactive substances, doping agents and alcohol biomarkers across all age groups. With a PhD in Clinical Pharmacology and more than 400 scientific publications (H-index: 56) and her work bridges analytical science with clinical outcomes. Dr. Pichini also advises national helplines, contributes to Italy’s Early Warning System on NPS, and serves as a scientific expert for the EU Drugs Agency. She is a member of the editorial boards of Therapeutic Drug Monitoring and the Journal of Pharmaceutical and Biomedical Analysis. An active member of the International Association of Forensic Toxicologists (TIAFT) since 2004, she received the TIAFT Achievement Award in 2010 becoming the first woman ever to do so and she currently serves as Secretary of the Association. She also co-organized the TIAFT 2023 meeting in Rome, Italy.
Host Intro And Guest Bio
SPEAKER_01I'm your host, Geraldine M. Dowling. What should you expect in the Analytical SEM podcast? Well, we'll dive into cutting-edge research and topics that inspire curiosity, the latest in forensic and clinical toxicology pursuits, and engaging conversations and perspectives from disciplines outside of these fields. We're thrilled to have Dr. Simona Picchini as our guest on the Analytical Zen podcast. Dr. Picchini is an Italian pharmaco toxicologist at the Italian National Institute of Health, where she serves as acting director of the National Centre on Addiction and Doping. She's a recognized expert in pharmacinetics and toxicokinetics of classical drugs of abuse, new psychoactive substances, and doping agents, analysing both conventional and alternative biological matrices. She is regarded as an authority on ethanol exposure biomarkers in newborns, children, adult and pregnant women linking biomarker monitoring with clinical outcomes. Dr. Bikini holds a master's degree in pharmaceutical chemistry and technology from the Sapienza University of Rome 1986 Comlade, a master's degree in pharmacy from the Sapienza University of Rome 1987 Comlade, and a PhD in clinical pharmacology from the Università Autinoma de Barcelona in 2005 Com Laude. She's the author of more than 400 scientific publications with a H index of 56, as well as book chapters and technical reports. She also serves as a technical and scientific advisor for Italy's national helplines on alcohol, drugs of abuse, tobacco use, doping, and gambling. In addition, she contributes to the Italian National Early Warning System on New Psychoactive Substances and acts as a scientific expert at the European Union Drugs Agency or UDA. Dr. Bicchini is a member of the editorial boards of therapeutic drug monitoring and the Journal of Pharmaceutical and Biomedical Analysis. An active member of the International Association of Forensic Toxicologists or TIAFT since 2004, she received the Tiaft Achievement Award in 2010, the first woman ever to do so, and currently she is the Secretary of the Association. She also co-organized the Tiaft 2023 meeting in Rome, Italy. I'd like to welcome Simona to the Analytical Zen podcast.
SPEAKER_00Good morning, Geraldine, and thank you. It's a pleasure to be here with you and to have been invited.
Scope Of Addictions And Today’s Focus
SPEAKER_01Simona, tell us a little bit about your background and where you work, etc.
Natural Khat Roots And Core Chemistry
SPEAKER_00Well, I work at the National Institute of Health in Rome, Italy, and I'm now the head of the National Center on Addiction and Doping. I would say addictions, because we started with drugs of abuse, but now we also deal with other addictions. For example, the technological ones, gambling, gaming, alcohol, tobacco smoke. So we covered with our research and our monitoring information and information all types of addiction. And regarding this, today I'll be guiding you through a journey into one of the most challenging and rapidly evolving families of new psychoactive substances, which are synthetic catenons. The talk brings together our research findings, clinical experiences, and broader epidemiological data from Italy and Europe, offering an integrated view of their chemistry, pharmacology, toxicology, and public health relevance. Let's start from the beginning with the natural roots of these compounds. Catinons originate from kata edulis, better known as cat, a shrub native of East Africa and the Arabian Peninsula. For centuries, people have chewed its leaves for dissimulating effects in a way similar to how coca leaves are used in South America. The main psychoactive components are cateen and cationine, the latter often described as a natural amphetamine. Chemically, it is a beta ketoamphetamine. Mechanistically, cationone increases dopamine levels in the central nervous system by inhibiting its reuptake or stimulating its release at catecholaminergic synapses. When natural cation and its plant sources became controlled, clandestine chemists began to modify its chemical backbone, giving rise to synthetic catinons, now a major subgroup within the new psychoactive substances, also called NPS.
SPEAKER_01What are the main structural modifications that distinguish synthetic cations from the natural compound and how do these affect their pharmacology?
Structural Tweaks And Transporter Targets
Pharmacodynamics Across DAT, NET, SERT
Field PK Studies And Matrices
Oral Vs Intranasal Kinetics
SPEAKER_00Well, clandestine chemists introduce substitution at the four key positions of the cation scaffold. They might have alkyl chains, introduce pyrolidinic ring, perform allogenation or modify the aromatic ring. These small structural changes profoundly alter lipophilicity, steric bulk, and electronic properties, influencing how the molecule interacts with monamine transporter. As a result, we can observe major differences in potency, selectivity, and duration of action. In short, a tiny substitution can shift the cation from behaving like a dopamine, preferring stimulant, to an entactogen-like substance or even to a long-acting pyrolidinophenon with high abuse potential. From a pharmacodynamic standpoint, synthetic catons primarily act as monamine transporter inhibitors. Inhibition of the dopamine transporter called DAT is linked to euphoria, reinforcement, and sometimes psychotic symptoms. Norepinephrine transporter called NET inhibition causes psychostimulation and cardiovascular stimulation. Serotonin transported called CERT inhibition contributes to entactogenic and psychotrophic effects, but also increases the risk of hyperthermia and hyponatremia. Depending on the chemical substitution, some cationons act more like classic stimulants such as amphetamine, while others resemble MDMA or even produce mixed, unpredictable profiles. Now, moving from the chemistry to pharmacokinetics, our research team, in collaboration with colleagues from the Autonomous University of Barcelona in Spain, conducted several in vitro studies on healthy volunteers. These participants self-administered their own doses of substances like alpha pyrovalerophenon, for chlorometcatinon, Nethyl hexidron, Netylpentadron, and methylon in realistic nightlife setting, and then self-collected biological samples, such as urine, oral fluid, and sweat over several hours. I mean none of invasive biological matrixes, so no blood. Using advanced analytical techniques we own in our laboratories, for example, ultra-high performance liquid chromatography coupled to high resolution mass spectrometry or gas chromatography coupled to tandem mass spectrometry, we tracked both parent compounds and newly discovered metabolites.
SPEAKER_01What are the key pharmacinetic differences observed between oral and intranasal administration?
Variability And Co‑Factors In Metabolism
SPEAKER_00Well, for orally administered four chloromet cationon as an example, the maximum concentration in oral fluid was around six micrograms per milliliter, with the time peaks, the so-called T max, of about three hours. In contrast, when other cationons such as N etylpentadron or L ethyl Exadron were taken internatally, peak concentration was slightly lower, ranging from one to four micrograms per milliliter, but they appeared much faster, typically within one hour. So, generally speaking, intranasal administration produces quicker effects, but not necessarily higher concentrations. For alpha pirovalerophenon administered nasally at two different doses, 10 and 20 milligrams, we found median salivaris C max of about one nanogram per milliliter for both doses and a T max around 40 minutes, followed by a rapid decline within five hours. Interestingly, we observed a double peak in the pharmacokinetics, I mean in the substance disposition, most likely due to vocal contamination from snorting. Overall, the absorption and elimination patterns vary not only by compound, but also by root, dose, and individual metabolism.
SPEAKER_01Why is there such a high individual variability in absorption and metabolism of these drugs, Simona?
SPEAKER_00Well, the differences stem from multiple factors. Root-related artifacts such as vocal contamination are one source. Biological diversity, including variation in hepatic enzymes like the CYPS or UGTS, also plays a major role. Additionally, co-administered substances, hydration, food intake, or even sweeting physiology can influence excretion. We observed, for instance, that alpha pirovalerophenon was detectable in sweat for all low doses users, but in fewer cases at higher doses, highlighting that physiology and environmental significantly impact the results.
SPEAKER_01A central pharmacological question is: how do the pharmacodynamics of synthetic cathanomes compare with classical stimulants like amphetamine or ecstasy or MDMA?
Clinical Toxicity And Red Flags
SPEAKER_00Functionally, both act on the same transporters: dopamine, norepinephrine, or noreadrenaline in the European language, and serotonine, but with different selectivity profiles. Some cationons strongly prefer dopamine transporter and norepinephrine transporter, leading to amphetamine-like stimulation and euphoria, while others show more balanced or serotonin transported dominant profiles, resulting in MDMA-like empathy and mood elevation. This wide pharmacological spectrum explains the diversity of effects and also why user may not know exactly what to expect. I have to add that synthetic catenons act on the same transporters of cocaine, so sometimes they resemble the effects of cocaine. Now, moving to the toxicological and clinical domain. Our studies and case series have documented a wide range of adverse effects associated with synthetic catenons. Neuropsychiatric symptoms are common: anxiety, paranoia, psychosis, aggression, and confusion, along with autonomic effects such as tachycardia, hypertension, and hyperthermia. Many patients also show bruxism, agitation, and violent behavior. Simona, which symptoms tend to predict severe or even fatal outcomes? Well, severe agitation, delirium, and psychosis are the red flags, especially when combined with hyperthermia, metabolic acidosis, or cardiovascular collapse. In the most serious intoxication, these symptoms can progress to common or multi-organ failure. Alarmingly, fatalities have been reported even at concentrations commonly found in regular consumers, particularly involving compounds like MDPHP.
SPEAKER_01Of course, the monotoxicological interpretation becomes much harder when more than one substance is involved. So, how does polydrug use complicate toxicological interpretation?
Polydrug Use And Interpretation
Two Case Studies: Neonate And Chemsex
SPEAKER_00In many cases, catinons are consumed along with other stimulants or miss sold as MDMA. This overlap creates synergistic or unpredictable toxic effects. For instance, stimulants combined with antidepressants can intensify serotonin toxicity or hyperthermia. On the analytical side, overlapping metabolites make it difficult to attribute a finding to one parent compound or to another. In postmortem cases, redistribution and the presence of multiple substances father, blur, causality. Altogether, polydrug use remains one of the most persistent challenges for both clinicians and forensic scientists. I have to add that synthetic catenons often are found in post-mortem biological fluids together with classical drugs, cocaine, heroin. And let me, for example, share two clinical cases that illustrate the real-world impact of synthetic cationons use. The first involved a newborn suffering from withdrawal symptom after birth. It was a case from 2014, our first case in my laboratory, and the samples came from Barcelona, Spain. The mother, undergoing methadone therapy, had also chronically consumed for metyl at cationone during pregnancy, the so-called FOR-MEC. The infant displayed tremors, irritability, and feeding difficulties. Toxicological analysis confirmed exposure to both methadone and for MEC, even detecting the cation in the baby's hair. This case provided direct evidence that synthetic cationons can cross placenta and induce fetal dependence. It highlights the urgent need for prenatal toxicology screening and neonatal care protocols tailored to NPS exposure. For instance, when we find a baby with neonatal withdrawal syndrome, but we don't find any classical drugs of abuse in urine screening, for example, we can look for new psychoactive substances. Another case, a second case, occurred in a chemsex context, because indeed synthetic catadons are often used in chemsex situations. A middle-aged man died of cardiac arrest after consuming 4MEC and gamma butyrocton GBL. The stimulant depressant combination created a dangerous pharmacological mismatch. While 4MEC increased earth rate and psychomotor activity, GBL suppressed respiration. Postmortem analysis confirmed both substances. This case underscored the lethal potential of synthetic cationons when used in high-risk recreational settings and the importance of arm reduction strategies.
SPEAKER_01Simona, why are synthetic cationons particularly prevalent in Italy? And how have trends evolved in recent years?
Prevalence In Italy And EU Trends
SPEAKER_00Across Europe, cationons account for 86% of all NPS seizures. The most monitored class of NPS is that of synthetic and semi-synthetic cannabinoids. But in Italy, synthetic catadons are the most frequently identified NPS, surpassing synthetic cannabinoids. Between 2016 and 2024, 39 new cathinons were identified for the first time in Italy, with a notable spike in 2024. This reflects both increased trafficking and improved analytical detection. We found MDPHP, 3CMC, the chlorometcathinone, or nor etylpentadron, among the most commonly sazed, often sold as powder tablets or MDMA adulterants.
Surveillance, Methods, And Matrices
SPEAKER_01What are the most effective strategies for regulators and laboratories to keep pace with such rapid developments?
Biomarkers And Lab Differentiation
SPEAKER_00Well, the key is the continuous analytical surveillance. In my center, we manage the national early warning system on drugs. So for us, analytical surveillance is very important. Combining targeted and untargeted workflows using high-resolution mass spectrometry allows rapid detection of both known and novel analogs. Sharing new spectral data and reference standards among laboratories is essential, moreover. Early warning systems, interlaboratory collaboration, and blanket scheduling can help close legal loofalls. On a practical side, analyzing multiple biological matrixes, urine, oral fluid, sweat, and hair provides more complete pictures of both recent and long-term exposure. Each matrix offers unique advantages. Oral fluid reflects acute intake. Uine captures short-term elimination. Sweat can indicate cumulative exposure, and hair reveals chronic patterns. And please note that none of these matrixes are invasive ones. This multimatrix approach is especially valuable in clinical settings, forensic investigation and prenatal toxicology. Training clinicians and forensic professionals to recognize caffeinonic related symptoms is equally essential. Many cases present with agitation, confusion, or cardiovascular instability that might be misattributed to other substances. Early recognition can improve outcomes and guide appropriate interventions. Finally, integrating wastewater epidemiology with the analysis of wastewater not only in Italy but all across Europe, and seizure profiling helps identify emerging substances and shifting consumption trends, these two act as real-time indicators, allowing public health authorities to respond proactively.
SPEAKER_01Before we close, two final questions often come up in professional discussions. What are the most promising biomarkers for detecting synthetic cationone exposure in clinical settings, Simona? Okay.
SPEAKER_00Biomarker in orafluid and sweat, especially parent compounds and glucuronidated metabolites, are proving useful for real-time detection using a known invasive biological matrix. Air analysis also offers retrospective insight into chronic use. However, due to rapid metabolism and structural diversity, no single biomarker is sufficient. A panel approach combining multiple metabolites and matrixes is currently the most reliable strategy.
SPEAKER_01How can forensic laboratories differentiate between structurally similar pathodons in poor smortan samples?
Key Takeaways, Team Thanks, Closing
SPEAKER_00This remains a major challenge. High resolution mass spectrometry and antioselective chromatography and metabolite profiling are essential tools. Differentiating positional isomers or analogs often requires reference standards and collaborative databases. In complex cases, combining toxicological data with circumstantial evidence such as says substances or user history can help clarify attribution. To conclude, synthetic catons represent a dynamic, complex, and high risk segment of the drug market. The chemistry evolves faster than most regulatory frameworks can adapt. Their clinical toxicity can be unpredictable, and their prevalence in Europe, particularly in Italy, remains substantial. Combining analytical vigilance, toxicological research, and public health intervention is the only effective way forward. And please, Geraldine, let me acknowledge my team, my colleagues, Silvia Graziano, Maria Rosaria Vary, Anna Giulia Ditrana, Nunzia La Maida, Valeria Quilina, and in Spain, Esther Papasate, Clara Perez Magna, and Majifar Re, the only man, for their collaboration.
SPEAKER_01And Simona, before we conclude, is there anything else you'd like to share with our listeners?
SPEAKER_00Well, first of all, I would like to thank you, Geraldine, for your kind invitation to speak and to share scientific insight from the south of Europe to the north of Europe to Ireland. The key message to take home is the importance of harmonizing the way we understand, address, and prevent the issue of psychoactive substances across Europe. Once again, thank you, Geraldine, for this opportunity.
SPEAKER_01And to our listeners, thank you for tuning in to another episode of the Analytical Zen Podcast. Be sure to join us next time and stay curious.