Pharmacokinetics of Psychoactive Substances: Molecular and Forensic Aspects

Dear Colleagues,

We invite researchers to contribute with their scientific works to this Special Issue, aiming to advance our understanding of the pharmacokinetics of psychoactive substances and their implications in clinical and forensic settings.

The field of psychoactive substances and their pharmacokinetics represents a critical area of study in both clinical and forensic contexts. Recent evidence highlights the necessity of standardizing investigations related to drug-related fatalities and intoxications across different jurisdictions and laboratories worldwide.

Thus, prevention and intervention in the consumption of psychoactive substances (e.g., opioids, central nervous system stimulants or depressants, ethanol, hallucinogens, Cannabis derivatives, dissociative substances, and inhalants) in labor activity should be considered as an investment of organizations and not as a cost, in view of the professional, personal, and family advantages for workers and employers, with a potential impact on productivity, security, health, and quality of life at work.

Mechanisms of action for synthetic cathinones involve interactions with dopamine, serotonin and norepinephrine transporters with varying affinities and selectivities. This has been shown in in vitro studies, including human cell lines and preclinical models of ring substituted cathinones, such as methylone, which act as transporter substrates that increase the release of dopamine, serotonin, and norepinephrine. Substances possessing a pyrrolidine ring, as in α-PVP (α-pyrrolidinopentiophenone), act as transport blockers (reuptake inhibitors) at the dopamine transporter. Increasing the length of the α-carbon chain increases the affinity and potency at the dopamine transporter. Compounds with a higher potency at the dopamine transporter, includincludeding α-pyrrolidinophenones and 4-fluoroamphetamine (4-FA), exhibit stimulant properties similar to methamphetamine while cathinones that have similar potencies at dopamine and serotonin transporters, or higher potency at the serotonin transporter, may have more empathogenic activity (e.g., ethylone).

Some of the direct neurotoxicity effects are hyperthermia and neuroinflammation. 

These substances present unique challenges for detection and analysis, requiring sophisticated analytical techniques and continuous updates to existing methodologies. The complexity of modern drug abuse is further complicated by polydrug use and the increasing prevalence of synthetic compounds, making traditional screening methods insufficient when used alone.Forensic toxicology plays a pivotal role in determining both the cause and manner of death in cases of suspected drug intoxication, serving crucial public health and social functions. While death scene investigation provides valuable context, it must be complemented by comprehensive toxicological analysis. Modern toxicology laboratories employ advanced techniques to identify and quantify drugs in biological samples, supporting the work of forensic pathologists and medical examiners. However, the quality of forensic diagnosis varies significantly across regions and countries, influenced by factors such as technical capabilities, personnel expertise, and available resources.The NPS phenomenon represents a particularly challenging aspect of contemporary drug abuse, with new molecules continuously entering the illicit market in response to international regulations. Synthetic cannabinoid receptor agonists (SCRAs) remain the most prevalent class of these substances, while novel opioid receptor agonists emerge as an increasing concern. These developments pose significant challenges for health professionals and toxicologists, requiring constant vigilance and adaptation of analytical methods.The pharmacokinetic profiles of these substances are often complex and poorly understood, necessitating extensive research to elucidate their metabolism, distribution, and elimination patterns. This knowledge is crucial for developing effective detection methods and understanding their toxic effects. The interaction between different substances in cases of polydrug use further complicates the analytical and interpretative aspects of toxicological investigations.In conclusion, this Special Issue presents current research and comprehensive reviews addressing various aspects of drug abuse, NPS challenges, toxicity profiles, and pharmacokinetic characteristics. The collected works emphasize the importance of continued scientific investigation in this rapidly evolving field, aiming to enhance our understanding and improve both clinical and forensic practices. The findings underscore the need for standardized methodologies, international collaboration, and ongoing adaptation to emerging challenges in psychoactive substance analysis and interpretation. 

This Special Issue is supervised by Prof. Angelo Montana, Prof. Fabrizio Lo faro and assisted by Dr. Davide Radaelli (Department of Legal Medicine, University of Trieste).

Best whises,
Prof. Dr. Angelo Montana
Dr. Fabrizio Lo Faro
Guest Editors

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• psychoactive substances
• pharmacokinetics
• forensic Toxicology
• forensic pathology
• toxicological biomarkers
• cerebral damage
• in vitro, in vivo, and in silico models
• new Psychoactive Substances (NPS)
• new synthetic opioids
• liquid chromatography-high resolution mass spectrometry (LC-HRMS/MS)
• liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography
• tandem mass spectrometry (GC-MS/MS)