Pharmacokinetics and Pharmacodynamics of Psychoactive Substances: Clinical and Forensic Aspects

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (29 October 2021) | Viewed by 52397

Special Issue Editor


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Guest Editor
1. TOXRUN – Toxicology Research Unit, University Institute of Health Sciences, Advanced Polytechnic and University Cooperative (CESPU), CRL, 4585-116 Gandra, Portugal
2. Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
3. UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
4. MTG Research and Development Lab, 4200-604 Porto, Portugal
Interests: real-world evidence; implementation science; toxicology; forensic sciences; psychoactive substances; drugs; biomedical research; scientometrics; scientific medical writing; pedagogical Innovation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues

This Special Issue aims to cover, in a broad spectrum, the chemical structure, products available, pharmacokinetics, pharmacodynamics, metabolomics, clinical manifestations, diagnostics, and treatment of acute intoxications related to psychoactive substances in order to highlight their impact on public health. To better understand clinical and forensic effects, pharmacokinetics should be explored to find active and inactive metabolites and other biomarkers. Indeed, polymorphisms in genes encoding enzymes (e.g., CPY2B6) involved in metabolism or in target receptors may influence both drug efficacy and toxicity. Besides genetics, the extensive metabolism by P450 can cause important interactions when drugs are taken concomitantly. The identification of additional metabolites is also needed during drug development and for clinical and forensic toxicology, where specific metabolites are used to confirm xenobiotic exposure as potential biomarkers.

Prof. Ricardo Jorge Dinis-Oliveira
Guest Editor

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Keywords

  • psychoactive substances
  • toxicokinetics
  • toxicodynamics
  • toxicological analysis
  • interpretation of toxicological reports
  • antemortem toxicology
  • postmortem toxicology
  • clinical and forensic issues

Published Papers (7 papers)

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Research

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11 pages, 436 KiB  
Article
Poppers Use and High Methaemoglobinaemia: ‘Dangerous Liaisons’
by Malcolm Barrangou-Poueys-Darlas, Marie Gerardin, Sylvie Deheul, Marion Istvan, Marylène Guerlais, FAN, Pascale Jolliet, Thomas Dejoie and Caroline Victorri-Vigneau
Pharmaceuticals 2021, 14(10), 1061; https://doi.org/10.3390/ph14101061 - 19 Oct 2021
Cited by 4 | Viewed by 5961
Abstract
Poppers are legal and largely used in France despite severe side effects, such as methaemoglobinaemia (MetHbia). Our work aimed to assess the prevalence of poppers consumers among patients with a MetHbia higher than or equal to 5% in French university hospitals and its [...] Read more.
Poppers are legal and largely used in France despite severe side effects, such as methaemoglobinaemia (MetHbia). Our work aimed to assess the prevalence of poppers consumers among patients with a MetHbia higher than or equal to 5% in French university hospitals and its evolution before and after the legalization of poppers in France. We conducted a national multicentre observational retrospective study. All patients for whom at least one MetHbia measurement was performed from 2012 to 2017 in university hospitals where the French addictovigilance network (FAN) is implanted were included. For each MetHbia measurement exceeding or equal to 5%, a return to the clinical file was made by the FAN to assess poppers consumption. We calculated the prevalence of MetHbia exceeding or equal to 5% and 25% and the prevalence of poppers consumption before and after the legalization. A total of 239 (0.14%) patients had a MetHbia level exceeding or equal to 5% with 25 (10.46%) cases of poppers consumption. Poppers consumption represented 68.4% (13 out of 19) of cases with MetHbia greater than or equal to 25%. Poppers consumption among patients with MetHbia exceeding or equal to 5% increased after the legalization from 4.76% to 11.67% (prevalence ratio PR = 2.45, 95% CI = [0.98–8.37], p-value = 0.190). The proportion of patients with a MetHbia level of 25% or more increased after the legalization from 4.76% to 8.63% (PR = 1.81, 95% CI = [0.68–6.82], p-value = 0.374). The use of poppers is very frequently reported by patients with MetHbia greater than or equal to 25%. Full article
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21 pages, 2358 KiB  
Article
Pharmacokinetic Investigation of Commercially Available Edible Marijuana Products in Humans: Potential Influence of Body Composition and Influence on Glucose Control
by Taylor Russell Ewell, Kieran Shay Struebin Abbotts, Natasha N. Bondareva Williams, Hannah Michelle Butterklee, Matthew Charles Bomar, Kole Jerel Harms, Jordan Douglas Rebik, Sarah Margaret Mast, Natalie Akagi, Gregory P. Dooley and Christopher Bell
Pharmaceuticals 2021, 14(8), 817; https://doi.org/10.3390/ph14080817 - 20 Aug 2021
Cited by 9 | Viewed by 8274
Abstract
The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana [...] Read more.
The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana on glucose tolerance. Seven regular users of marijuana self-administered five edible products in a randomized crossover design; each product contained 10 mg of delta-9-tetrahydrocannabinol (THC). Thirty minutes following marijuana ingestion, participants imbibed a 75 g glucose beverage. Time-to-peak plasma THC concentration ranged between 35 and 90 min; maximal plasma THC concentration (Cmax) ranged between 3.2 and 5.5 ng/mL. Differences between products in plasma THC concentration during the first 20–30 min were detected (p = 0.019). Relations were identified between body composition and pharmacokinetic parameters for some products; however, none of these body composition characteristics were consistently related to pharmacokinetics across all five of the products. Edible marijuana had no effect on oral glucose tolerance compared with a marijuana-free control (Matsuda Index; p > 0.395). Commercially available edible marijuana products evoke different plasma THC concentrations shortly after ingestion, but do not appear to influence acute glucose regulation. These data may allow recreational marijuana users to make informed decisions pertaining to rates of edible marijuana ingestion and avoid overdose. Full article
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18 pages, 3789 KiB  
Article
Pharmacokinetic Properties of the Novel Synthetic Cannabinoid 5F-APINAC and Its Influence on Metabolites Associated with Neurotransmission in Rabbit Plasma
by Ksenia M. Shestakova, Natalia V. Mesonzhnik, Pavel A. Markin, Natalia E. Moskaleva, Andrey A. Nedorubov, Alex Brito, Elizaveta G. Appolonova, Roman M. Kuznetsov, Natalia L. Bochkareva, Alexey Kukharenko, Alexey V. Lyundup, Franco Tagliaro and Svetlana A. Appolonova
Pharmaceuticals 2021, 14(7), 668; https://doi.org/10.3390/ph14070668 - 13 Jul 2021
Cited by 3 | Viewed by 2293
Abstract
The strong psychoactive effects of synthetic cannabinoids raise the need for the deeper studying of their neurometabolic effects. The pharmacokinetic properties of 5F-APINAC and its influence on metabolomics profiles associated with neurotransmission were investigated in rabbit plasma. Twelve rabbits divided into three groups [...] Read more.
The strong psychoactive effects of synthetic cannabinoids raise the need for the deeper studying of their neurometabolic effects. The pharmacokinetic properties of 5F-APINAC and its influence on metabolomics profiles associated with neurotransmission were investigated in rabbit plasma. Twelve rabbits divided into three groups received 1-mL 5F-APINAC at 0.1, 1 and 2 mg/kg. The intervention groups were compared with the controls. Sampling was performed at nine time points (0–24 h). Ultra-high-performance liquid chromatography–tandem mass spectrometry was used. The pharmacokinetics were dose-dependent (higher curve at a higher dose) with a rapid biotransformation, followed by gradual elimination within 24 h. The tryptophan concentrations abruptly decreased (p < 0.05) in all tested groups, returning to the basal levels after 6 h. 5-hydroxylindole acetic acid increased (p < 0.05) in the controls, but this trend was absent in the treated groups. The aspartic acid concentrations were elevated (p < 0.001) in the treated groups. L-kynurenine was elevated (p < 0.01) in the intervention groups receiving 1 mg/kg to 2 mg/kg. Dose-dependent elevations (p < 0.01) were found for kynurenic acid, xanthurenic acid and quinolinic acid (p < 0.01), whereas the anthranilic acid trends were decreased (p < 0.01). The indole-3-propionic acid and indole-3-carboxaldehyde trends were elevated (p < 0.05), whereas the indole-3-lactic acid trajectories were decreased (p < 0.01) in the intervention groups. 5F-APINAC administration had a rapid biotransformation and gradual elimination. The metabolites related to the kynurenine and serotonergic system/serotonin pathways, aspartic acid innervation system and microbial tryptophan catabolism were altered. Full article
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19 pages, 1659 KiB  
Article
Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature
by Mafalda Campeão, Luciana Fernandes, Inês R. Pita, Cristina Lemos, Syed F. Ali, Félix Carvalho, Paulo Rodrigues-Santos, Carlos A. Fontes-Ribeiro, Edna Soares, Sofia D. Viana and Frederico C. Pereira
Pharmaceuticals 2021, 14(3), 271; https://doi.org/10.3390/ph14030271 - 16 Mar 2021
Cited by 2 | Viewed by 2687
Abstract
3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, [...] Read more.
3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions. Full article
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34 pages, 15246 KiB  
Article
Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats
by Joana Barbosa, Juliana Faria, Fernanda Garcez, Sandra Leal, Luís Pedro Afonso, Ana Vanessa Nascimento, Roxana Moreira, Frederico C. Pereira, Odília Queirós, Félix Carvalho and Ricardo Jorge Dinis-Oliveira
Pharmaceuticals 2021, 14(2), 97; https://doi.org/10.3390/ph14020097 - 27 Jan 2021
Cited by 12 | Viewed by 4875
Abstract
Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with [...] Read more.
Tramadol and tapentadol, two structurally related synthetic opioid analgesics, are widely prescribed due to the enhanced therapeutic profiles resulting from the synergistic combination between μ-opioid receptor (MOR) activation and monoamine reuptake inhibition. However, the number of adverse reactions has been growing along with their increasing use and misuse. The potential toxicological mechanisms for these drugs are not completely understood, especially for tapentadol, owing to its shorter market history. Therefore, in the present study, we aimed to comparatively assess the putative lung, cardiac, and brain cortex toxicological damage elicited by the repeated exposure to therapeutic doses of both prescription opioids. To this purpose, male Wistar rats were intraperitoneally injected with single daily doses of 10, 25, and 50 mg/kg tramadol or tapentadol, corresponding to a standard analgesic dose, an intermediate dose, and the maximum recommended daily dose, respectively, for 14 consecutive days. Such treatment was found to lead mainly to lipid peroxidation and inflammation in lung and brain cortex tissues, as shown through augmented thiobarbituric acid reactive substances (TBARS), as well as to increased serum inflammation biomarkers, such as C reactive protein (CRP) and tumor necrosis factor-α (TNF-α). Cardiomyocyte integrity was also shown to be affected, since both opioids incremented serum lactate dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) activities, while tapentadol was associated with increased serum creatine kinase muscle brain (CK-MB) isoform activity. In turn, the analysis of metabolic parameters in brain cortex tissue revealed increased lactate concentration upon exposure to both drugs, as well as augmented LDH and creatine kinase (CK) activities following tapentadol treatment. In addition, pneumo- and cardiotoxicity biomarkers were quantified at the gene level, while neurotoxicity biomarkers were quantified both at the gene and protein levels; changes in their expression correlate with the oxidative stress, inflammatory, metabolic, and histopathological changes that were detected. Hematoxylin and eosin (H & E) staining revealed several histopathological alterations, including alveolar collapse and destruction in lung sections, inflammatory infiltrates, altered cardiomyocytes and loss of striation in heart sections, degenerated neurons, and accumulation of glial and microglial cells in brain cortex sections. In turn, Masson’s trichrome staining confirmed fibrous tissue deposition in cardiac tissue. Taken as a whole, these results show that the repeated administration of both prescription opioids extends the dose range for which toxicological injury is observed to lower therapeutic doses. They also reinforce previous assumptions that tramadol and tapentadol are not devoid of toxicological risk even at clinical doses. Full article
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Review

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36 pages, 3531 KiB  
Review
Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects
by Andreia Machado Brito-da-Costa, Diana Dias-da-Silva, Nelson G. M. Gomes, Ricardo Jorge Dinis-Oliveira and Áurea Madureira-Carvalho
Pharmaceuticals 2021, 14(2), 116; https://doi.org/10.3390/ph14020116 - 03 Feb 2021
Cited by 13 | Viewed by 9807
Abstract
Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In [...] Read more.
Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the κ-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles. Full article
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36 pages, 2804 KiB  
Review
Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact
by Andreia Machado Brito-da-Costa, Diana Dias-da-Silva, Nelson G. M. Gomes, Ricardo Jorge Dinis-Oliveira and Áurea Madureira-Carvalho
Pharmaceuticals 2020, 13(11), 334; https://doi.org/10.3390/ph13110334 - 23 Oct 2020
Cited by 48 | Viewed by 16925
Abstract
Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. [...] Read more.
Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged. Full article
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