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Clinical and Forensic Toxicology: The Latest Updates

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 83716

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Prof. Dr. Francesco P. Busardó

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Department of Excellence of Biomedical Sciences and Public Health, University Politecnica delle Marche, 60121 Ancona, Italy
Interests: toxicology; forensic toxicology; drugs of abuse; legal medicine; hepatotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Within the field of analytical toxicology, there are two distinct disciplines involved in the testing of human biological matrices and non-biological specimens: clinical and forensic toxicology.

The difference between both specialties lies in the final use of the obtained results. In clinical toxicology, analytical results support clinical management, selection of an appropriate treatment, diagnosis, prognosis, and eventual disclosure of drug intoxication in the emergency room. In addition, drugs of abuse testing in maintenance treatments is also an area of special interest. In forensic toxicology, the obtained results have medico-legal implications related to eventual drug contribution to death or to possible impairment or to behavioral changes linked to a crime.

There are numerous areas of mutual interest between clinical and forensic toxicology. Indeed, most of the advances in the clinical setting come from investigation in forensic laboratories. Owing to those advances, the number of detectable pharmacological and psychoactive substances and/or metabolites and the number of conventional and non-conventional biological matrices to be investigated is continuously increasing. Furthermore, technological innovations in the field of sample pre-treatment and in the instrumental methodologies has improved levels of precision, accuracy, sensitivity, and specificity of quali-quantitative analyses in both disciplines.

The aim of this Special Issue is to collect original and review articles to provide the latest updates in the field of clinical and forensic toxicology.

Suggested topics include, but are not limited to:

Determination of cannabinoids in biological matrices for clinical (medical cannabis) and forensic (recreational cannabis) purposes
Development and validation of analytical methods for the identification and quantification of New Psychoactive Substances (NPS) in conventional and non-conventional biological matrices.
Studies and updated reviews on drugs of abuse-related toxicity, acute intoxications, and fatalities.
Metabolic pathways of new synthetic opioids, their potency, and studies of incubation with human hepatocytes to simulate in vivo metabolism.

Prof. Dr. Francesco P. Busardó
Guest Editor

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Keywords

Clinical toxicology
Forensic toxicology
Drugs of abuse
Acute intoxications
Fatalities
New Psychoactive Substances (NPS)
Liquid chromatography-high resolution mass spectrometry (LC-HRMS/MS)
Liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Gas chromatography-tandem mass spectrometry (GC-MS) and Gas chromatography-tandem mass spectrometry (GC-MS/MS)
NPS-related toxicity

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Published Papers (11 papers)

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22 pages, 2342 KiB

Open AccessEditor’s ChoiceArticle

A Quantitative LC–MS/MS Method for the Detection of 16 Synthetic Cathinones and 10 Metabolites and Its Application to Suspicious Clinical and Forensic Urine Samples

by Abdulaziz A. Aldubayyan, Erika Castrignanò, Simon Elliott and Vincenzo Abbate

Pharmaceuticals 2022, 15(5), 510; https://doi.org/10.3390/ph15050510 - 22 Apr 2022

Cited by 11 | Viewed by 4569

Abstract

Background: Synthetic cathinones currently represent one of the most predominant (sub)-classes of new psychoactive substance (NPS) in illicit drug markets. Despite the increased concerns caused by the constant introduction of new analogues, these drugs are not commonly assayed in routine drug testing procedures and may not be detected in standard screening procedures. This study presents a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the detection and quantification of 16 synthetic cathinones and 10 metabolites in human urine. Methods: The method was validated for all analytes using published guidelines. The evaluated parameters achieved acceptable values according to the set criteria. Potential abuse of synthetic cathinones was investigated in suspicious urine samples from Saudi Arabia originating from workplace drug testing, pre-employment and Accident & Emergency (A&E). Such samples generated a presumptive positive immunoassay for amphetamine; however, they yielded a negative LC–MS/MS confirmation for this analyte, following the recommended cutoff values of Substance of Abuse and Mental Health Services Administration (SAMHSA) guidelines. Results: 5.8% of the analyzed samples were found to contain at least one target analyte, namely mephedrone and N-ethylpentylone, as well as their dihydro-metabolites. The results also revealed polydrug use with the synthetic cathinones being present together with other classical stimulant drugs. Conclusions: This is the first report of NPS use in Saudi Arabia with respect to designer stimulant drugs. Confirmatory urine analyses for suspicious stimulant use should extend beyond classical stimulants to cover a broad range of NPSs and their metabolites in order to report any otherwise potentially undetected/new analyte. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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13 pages, 291 KiB

Open AccessArticle

Prevalence of Licit and Illicit Drugs Use during Pregnancy in Mexican Women

by Larissa-María Gómez-Ruiz, Emilia Marchei, Maria Concetta Rotolo, Pietro Brunetti, Giulio Mannocchi, Aracely Acosta-López, Ruth-Yesica Ramos-Gutiérrez, Mary-Buhya Varela-Busaka, Simona Pichini and Oscar Garcia-Algar

Pharmaceuticals 2022, 15(3), 382; https://doi.org/10.3390/ph15030382 - 21 Mar 2022

Cited by 10 | Viewed by 3350

Abstract

For the first time, the present study employed hair testing to investigate the prevalence of classical drugs of abuse and new psychoactive substances use during gestation in a cohort of 300 Mexican pregnant women. An interview was conducted to collect data on sociodemographic aspects of the patients, and a 9 cm-long hair strand was taken from the back of the head of each mother one month after delivery. A validated ultra-high-performance liquid chromatography–high-resolution mass spectrometry method was used for the screening of classic drugs, new psychoactive substances, and medications in maternal hair. Out of 300 examined hair samples from pregnant women, 127 (42.3%) resulted positive for psychoactive substances: 45 (35.4%) for cannabis only, 24 (18.9%) for methamphetamine only, 13 (10.2%) for cocaine only, 1 (0.3%) for heroin, 1 for N-N-dimethyltryptamine (0.3%), 1 for ketamine (0.8%), and 35 (16.3%) for more than one psychoactive substance. Furthermore, seven samples (2.3%) resulted positive for new psychoactive substances (NPS): two samples for synthetic cannabinoids, two for synthetic cathinones, and three for nor-fentanyl, and 3.3% of women hair resulted positive for anticonvulsant, antidepressant, and antipsychotic medications. Finally, 83 women hair samples (27.7%) tested positive for nicotine. Nonsteroidal anti-inflammatory drugs (NSAIDs) and other painkillers (60.0%), medications for the treatment of nausea and vomiting (12.3%), antihistamines (8.7%) and nasal/sinus decongestants (6.7%), cough suppressants (5.0%), and bronchodilator agents (5.0%) were also detected in pregnant women hair. The gestational use of psychoactive substances and exposure to tobacco smoke, assessed by hair testing, were associated with a significantly younger age and with a low education grade of the mothers (p < 0.005). This study provides a significant preliminary indication of the under-reported gestational consumption of licit and illicit psychoactive and pharmacologically active drugs in a Mexican environment, showing the value of toxicological and forensic analyses in the global effort to determine the health risks caused by classic drugs and new psychoactive substances during pregnancy. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

19 pages, 3465 KiB

Open AccessArticle

The Psychonauts’ Benzodiazepines; Quantitative Structure-Activity Relationship (QSAR) Analysis and Docking Prediction of Their Biological Activity

by Valeria Catalani, Michelle Botha, John Martin Corkery, Amira Guirguis, Alessandro Vento, Norbert Scherbaum and Fabrizio Schifano

Pharmaceuticals 2021, 14(8), 720; https://doi.org/10.3390/ph14080720 - 26 Jul 2021

Cited by 13 | Viewed by 5180

Abstract

Designer benzodiazepines (DBZDs) represent a serious health concern and are increasingly reported in polydrug consumption-related fatalities. When new DBZDs are identified, very limited information is available on their pharmacodynamics. Here, computational models (i.e., quantitative structure-activity relationship/QSAR and Molecular Docking) were used to analyse DBZDs identified online by an automated web crawler (NPSfinder^®) and to predict their possible activity/affinity on the gamma-aminobutyric acid A receptors (GABA-ARs). The computational software MOE was used to calculate 2D QSAR models, perform docking studies on crystallised GABA-A receptors (6HUO, 6HUP) and generate pharmacophore queries from the docking conformational results. 101 DBZDs were identified online by NPSfinder^®. The validated QSAR model predicted high biological activity values for 41% of these DBDZs. These predictions were supported by the docking studies (good binding affinity) and the pharmacophore modelling confirmed the importance of the presence and location of hydrophobic and polar functions identified by QSAR. This study confirms once again the importance of web-based analysis in the assessment of drug scenarios (DBZDs), and how computational models could be used to acquire fast and reliable information on biological activity for index novel DBZDs, as preliminary data for further investigations. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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13 pages, 1572 KiB

Open AccessArticle

Analysis of Cannabinoids Concentration in Cannabis Oil Galenic Preparations: Harmonization between Three Laboratories in Northern Italy

by Alice Palermiti, Alessia Cafaro, Sebastiano Barco, Paolo Bucchioni, Paolo Franceschini, Jessica Cusato, Amedeo De Nicolò, Alessandra Manca, Elisa Delia De Vivo, Eleonora Russo, Francesco Cecchi, Federica Pigliasco, Flavia Lillo, Gino Tripodi, Antonio D’Avolio and Giuliana Cangemi

Pharmaceuticals 2021, 14(5), 462; https://doi.org/10.3390/ph14050462 - 14 May 2021

Cited by 12 | Viewed by 3350

Abstract

Medical cannabis is increasingly being used in the treatment and support of several diseases and syndromes. The quantitative determination of active ingredients (delta-9 tetrahydrocannabinol, THC, and cannabidiol, CBD) in galenic oily preparations is prescribed by law for each produced batch. The aim of this work is to describe the organization of the titration activity centralized at three regional reference laboratories in Northern Italy. Pre-analytical, analytical, and post-analytical phases have been defined in order to guarantee high quality standards. A cross-validation between laboratories allowed for the definition of the procedures that guarantee the interchangeability between reference laboratories. The risk management protocol adopted can be useful for others who need to undertake this activity. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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20 pages, 1198 KiB

Open AccessArticle

The Interest of a Systematic Toxicological Analysis Combined with Forensic Advice to Improve the Judicial Investigation and Final Judgment in Drug Facilitated Sexual Assault Cases

by Sarah M. R. Wille, Karolien Van Dijck, Antje Van Assche, Vincent Di Fazio, Maria del Mar Ramiréz-Fernandéz, Vanessa Vanvooren and Nele Samyn

Pharmaceuticals 2021, 14(5), 432; https://doi.org/10.3390/ph14050432 - 4 May 2021

Cited by 12 | Viewed by 3964

Abstract

The conviction rate in drug facilitated sexual assault (DFSA) cases is known to be very low. In addition, the potential impact of toxicological results on the case is often not well understood by the judicial authorities. The aims of this study were (1) to obtain more knowledge concerning the prevalence of incapacitating substances in DFSA cases, (2) to create a more efficient DFSA analysis strategy taking background information into account, and (3) to evaluate the potential impact of systematic toxicological analysis (STA) on the final judicial outcome. This small-scale epidemiological study (n = 79) demonstrates that ‘commonly-used’ illicit drugs, psychoactive medicines and ethanol are more prevalent in DFSA cases in contrast to the highly mediatized date rape drugs. Additionally, via case examples, the interest of performing STA—to prove incapacitation of the victim—in judicial procedures with mutual-consent discussions has been demonstrated as it led to increased convictions. However, more attention has to be paid to ensure a short sampling delay and to get more accurate information from the medical treatment of the alleged victim. This will improve the interpretation of the toxicological analysis and thus its applicability in a DFSA case. The future is multi-disciplinary and will certainly lead to an efficient and more cost-effective DFSA approach in which STA can impact the final judgment. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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13 pages, 949 KiB

Open AccessArticle

Cannabis-Based Oral Formulations for Medical Purposes: Preparation, Quality and Stability

by Francesca Baratta, Marco Simiele, Irene Pignata, Lorenzo Ravetto Enri, Antonio D’Avolio, Riccardo Torta, Anna De Luca, Massimo Collino and Paola Brusa

Pharmaceuticals 2021, 14(2), 171; https://doi.org/10.3390/ph14020171 - 22 Feb 2021

Cited by 14 | Viewed by 6124

Abstract

Current legislation in Italy provides that medical Cannabis may be administered orally or by inhalation. One of the fundamental criteria for the administration of oral formulations is that they deliver a known consistent quantity of the active ingredients to ensure uniform therapies leading to the optimisation of the risks/benefits. In 2018, our group developed an improved Cannabis oil extraction technique. The objective of the present work was to carry out a stability study for the oil extracts obtained by this method. Furthermore, in order to facilitate the consumption of the prescribed medical Cannabis therapy by patients, a standard procedure was defined for the preparation of a single-dose preparation for oral use (hard capsules) containing the oil extract; thereafter, the quality and stability were evaluated. The hard capsules loaded with the oil extract were analysed and found to be uniform in content. The encapsulation process did not alter the quantity of the active molecule present in the oil. The stability tests yielded excellent results. Since the capsule dosage form is easily transported and administered, has pleasant organoleptic properties and is stable at room temperature for extended periods of time, this would facilitate the adherence to therapy by patients in treatment. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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13 pages, 1013 KiB

Open AccessArticle

Acute Pharmacological Effects of Oral and Intranasal Mephedrone: An Observational Study in Humans

by Esther Papaseit, Eulalia Olesti, Clara Pérez-Mañá, Marta Torrens, Francina Fonseca, Marc Grifell, Mireia Ventura, Rafael de la Torre and Magí Farré

Pharmaceuticals 2021, 14(2), 100; https://doi.org/10.3390/ph14020100 - 28 Jan 2021

Cited by 15 | Viewed by 5724

Abstract

Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of mephedrone, orally (n = 5, 100–200 mg; mean 150 mg) or intranasally (n = 5, 50–100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of mephedrone in oral fluid and also the total amount of mephedrone and metabolites in urine showed that concentrations of mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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Review

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27 pages, 10159 KiB

Open AccessReview

Pharmacological and Toxicological Effects of Phytocannabinoids and Recreational Synthetic Cannabinoids: Increasing Risk of Public Health

by Vidyasagar Naik Bukke, Moola Archana, Rosanna Villani, Gaetano Serviddio and Tommaso Cassano

Pharmaceuticals 2021, 14(10), 965; https://doi.org/10.3390/ph14100965 - 24 Sep 2021

Cited by 27 | Viewed by 5847

Abstract

Synthetic Cannabinoids (CBs) are a novel class of psychoactive substances that have rapidly evolved around the world with the addition of diverse structural modifications to existing molecules which produce new structural analogues that can be associated with serious adverse health effects. Synthetic CBs represent the largest class of drugs detected by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) with a total of 207 substances identified from 2008 to October 2020, and 9 compounds being reported for the first time. Synthetic CBs are sprayed on natural harmless herbs with an aim to mimic the euphoric effect of Cannabis. They are sold under different brand names including Black mamba, spice, K2, Bombay Blue, etc. As these synthetic CBs act as full agonists at the CB receptors, they are much more potent than natural Cannabis and have been increasingly associated with acute to chronic intoxications and death. Due to their potential toxicity and abuse, the US government has listed some synthetic CBs under schedule 1 classification. The present review aims to provide a focused overview of the literature concerning the development of synthetic CBs, their abuse, and potential toxicological effects including renal toxicity, respiratory depression, hyperemesis syndrome, cardiovascular effects, and a range of effects on brain function. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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46 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

by Pietro Brunetti, Raffaele Giorgetti, Adriano Tagliabracci, Marilyn A. Huestis and Francesco Paolo Busardò

Pharmaceuticals 2021, 14(6), 560; https://doi.org/10.3390/ph14060560 - 11 Jun 2021

Cited by 44 | Viewed by 17655

Abstract

The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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64 pages, 4355 KiB

Open AccessReview

Human Poisoning from Poisonous Higher Fungi: Focus on Analytical Toxicology and Case Reports in Forensic Toxicology

by Estelle Flament, Jérôme Guitton, Jean-Michel Gaulier and Yvan Gaillard

Pharmaceuticals 2020, 13(12), 454; https://doi.org/10.3390/ph13120454 - 11 Dec 2020

Cited by 21 | Viewed by 7124

Abstract

Several families of higher fungi contain mycotoxins that cause serious or even fatal poisoning when consumed by humans. The aim of this review is to inventory, from an analytical point of view, poisoning cases linked with certain significantly toxic mycotoxins: orellanine, α- and β-amanitin, muscarine, ibotenic acid and muscimol, and gyromitrin. Clinicians are calling for the cases to be documented by toxicological analysis. This document is therefore a review of poisoning cases involving these mycotoxins reported in the literature and carries out an inventory of the analytical techniques available for their identification and quantification. It seems indeed that these poisonings are only rarely documented by toxicological analysis, due mainly to a lack of analytical methods in biological matrices. There are many reasons for this issue: the numerous varieties of mushroom involved, mycotoxins with different chemical structures, a lack of knowledge about distribution and metabolism. To sum up, we are faced with (i) obstacles to the documentation and interpretation of fatal (or non-fatal) poisoning cases and (ii) a real need for analytical methods of identifying and quantifying these mycotoxins (and their metabolites) in biological matrices. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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51 pages, 882 KiB

Open AccessFeature PaperReview

Pharmacology of Herbal Sexual Enhancers: A Review of Psychiatric and Neurological Adverse Effects

by Pietro Brunetti, Alfredo Fabrizio Lo Faro, Anastasio Tini, Francesco Paolo Busardò and Jeremy Carlier

Pharmaceuticals 2020, 13(10), 309; https://doi.org/10.3390/ph13100309 - 14 Oct 2020

Cited by 14 | Viewed by 18391

Abstract

Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

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