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Nowadays, synthetic cathinones (SCs) is the second more representative subclass of New Psychoactive Substances, accounting for 104 analogues in the illegal market. Since its first report in 2011, α-pyrrolidinovalerophenone (α-PVP) gained popularity among drug users, provoking an increased number of intoxications. Nonetheless, pharmacokinetics data is still limited in the literature. An observational non-controlled naturalistic study on 8 healthy volunteers was conducted to assess the α-PVP and β-OH-α-PVP concentrations in OF and urine, after snorting 10 mg or 20 mg of α-PVP. A multi-analytical approach based on GC-EI-MS/MS and LC-HESI-HRMS/MS was developed and fully validated for the analytes quantification, while four untargeted LC-HESI-HRMS/MS methods in full-MS and ddMS 2 were set up for unknown metabolites characterization in urine samples assisted by a dedicated data mining software. In OF, α-PVP reached a mean C max of 762 ± 323 ng/mL at 1 h after 10 mg administration, while a C max of 2,900 ± 1,373 ng/mL at 47 min after 20 mg dose. In urine, a total α-PVP mean amount of 179.2 ± 94.9 µg was accumulated after 10 mg dose, (27.2 ± 9.8 µg between 0-2 h and 152.0 ± 98.2 µg between 2-5 h), while a total amount of 122.9 ± 44.0 µg, of (36.2 ± 16.5 and 86.7 ± 28.3 µg between 0-2 and 2-5 h, respectively) was detected after 20 mg dose. Among the 10 identified metabolites, β-OH-α-PVP was a minor metabolite (total amount: 56.4 ± 27.1 and 69.1 ± 38.1 µg after 10 mg and 20 mg). The N-butanoic acid metabolite was the most abundant, detected also as glucuronide. In conclusion, α-PVP showed a later time peak than non-pyrrolidine SCs, with comparable C max. The pyrrolidine ring oxidative opening produced the most abundant urinary metabolite, independently from the dose., Competing Interests: Declarations. Competing Interest: All the authors declare no competing interest for this research., (© 2025. The Author(s).)

Cannabidiol (CBD), the main non-intoxicating compound in cannabis, has been hypothesized to reduce the adverse effects of Δ 9 -tetrahydrocannabinol (THC), the main psychoactive and analgesic component of cannabis. This clinical trial investigated the hypothesis that CBD counteracts the adverse effects of THC and thereby potentially improves the tolerability of cannabis as an analgesic. A randomized, double-blind, placebo-controlled, five-way cross-over trial was performed in 37 healthy volunteers. On each visit, a double-placebo, THC 9 mg with placebo CBD, or THC 9 mg with 10, 30, or 450 mg CBD was administered orally. Psychoactive and analgesic effects were quantified using standardized test batteries. Pharmacokinetic sampling was performed. Data were analyzed using mixed-effects model. Co-administration of 450 mg CBD did not reduce, but instead significantly increased subjective, psychomotor, cognitive, and autonomous effects of THC (e.g., VAS "Feeling High" by 60.5% (95% CI: 12.7%, 128.5%, P < 0.01)), whereas THC effects with 10 and 30 mg CBD were not significantly different from THC alone. CBD did not significantly enhance THC analgesia at any dose level. Administration of 450 mg CBD significantly increased AUC last of THC (AUC last ratio: 2.18, 95% CI: 1.54, 3.08, P < 0.0001) and 11-OH-THC (AUC last ratio: 6.24, 95% CI: 4.27, 9.12, P < 0.0001) compared with THC alone, and 30 mg CBD significantly increased AUC last of 11-OH-THC (AUC last ratio: 1.89, 95% CI: 1.30, 2.77, P = 0.0013), and of THC (AUC last ratio: 1.44, 95% CI: 1.01, 2.04, P = 0.0446). Present findings do not support the use of CBD to reduce adverse effects of oral THC or enhance THC analgesia., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Synthetic cathinones are the second largest group of new psychoactive substances (NPS) monitored by the European Monitoring Centre for Drugs and Drug Addiction. Although 3-methylmethcathinone (3-MMC, C 11 H 15 NO) is legally banned in many countries, it is readily available for purchase online and on the street. Due to the scarcity of information regarding the pharmacokinetic and toxicological profile of 3-MMC, understanding its biotransformation pathways is crucial in determining its potential toxicity in humans and in the development of analytical methods for screening of human matrices. To gain more insight, Phase I and Phase II in vitro biotransformation of 3-MMC was investigated using human liver microsomes and human liver cytosol. Suspect and non-target screening approaches were employed to identify metabolites. To confirm in vitro results in an in vivo setting, human matrices (i.e., plasma, urine, saliva and hair) positive for 3-MMC (n=31) were screened. In total three biotransformation products were identified in vitro: C 11 H 15 NO 2 (a hydroxylated derivate), C 11 H 17 NO (a keto-reduced derivate) and C 10 H 13 NO (an N-desmethyl derivate). All three were confirmed as human metabolites in respectively 16 %, 52 % and 42 % of the analysed human samples. In total, 61 % of the analysed samples were positive for at least one of the three metabolites. Interestingly, three urine samples were positive for all three metabolites. The presence of 3-MMC in saliva and hair indicates its potential applicability in specific settings, e.g., roadside testing or chronic consumption analysis. To our knowledge, C 11 H 17 NO was not detected before in vivo. Although some of these metabolites have been previously suggested in vitro or in a single post mortem case report, a wide in vivo confirmation including the screening of four different human matrices was performed for the first time. These metabolites could serve as potential human biomarkers to monitor human 3-MMC consumption effectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Response rate to treatment is generally not as high as expected in psychiatric disorders. The lack of clinical improvement under a well-conducted treatment, that complies with guidelines, may be the consequence of genetic abnormalities that impact the metabolizing pathways of the drug. Genetic polymorphism of metabolizing enzymes is frequent in the population and has been proven to have a clinical impact. It may also be the consequence of environmental or organic factors that interact with the pharmacokinetic pathways (absorption, distribution, metabolizing, excretion) of the drug. These intrinsic and extrinsic factors will lead to inter- and intraindividual fluctuations in plasma drug concentrations. Therapeutic drug monitoring permits to measure plasma drug concentrations in order to adapt psychopharmacotherapy individually. In some cases, it can be coupled to pharmacogenetic testings. This review presents recent literature and guidelines on the subject. Eventually, there is a focus made on the French-speaking part of Belgium where neither therapeutic drug monitoring, nor pharmacogenetics testing, are used frequently in clinical practice. Some challenges are to be addressed to implement these techniques in Belgium.

N-ethylhexedrone (NEH) is a new cathinone derivative with, currently, low toxicokinetic and toxicodynamic knowledge. We present three documented clinical cases of NEH intoxication with plasma and urine concentrations. A thorough search for metabolites was performed. The three patients were admitted to the emergency department, and two out of the three were hospitalized for an extended period. While recovering from the drug effects, 12-24 h after nasal intake of New Psychoactive Substance (NPS), the patients described the following disorders: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing and loss of consciousness. NEH was identified in all samples by liquid chromatography-high resolution mass spectrometry (LC-HRMS), and quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Quantitative analysis showed decreasing concentrations over time: for Case 1, from 97.2 (Day 1, D1) to 0.7 (Day 7, D7) µg/L for plasma, and from 724 (D1) to 0.5 (D7) µg/L for urine. NEH concentration of 7.9 µg/L was found in the plasma collected at admission for Case 2. For Case 3, concentrations ranging from 49 (D1) to 1.8 (D7) µg/L in plasma, and from 327.3 (Day 6, D6) to 116.8 (D7) µg/L in urine were found. NEH was no longer detected in the urine sample at Day 10. Elimination half-life was estimated at 19, and 28 hours in Patients 1 and 3, respectively. Four metabolites were identified in blood and urine: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH and hydroxy-NEH. The cases presented highlight the long detectable lifetime of NEH. Characterization of the metabolites will allow better identification of the consumption of this drug. Serious adverse events can be observed after NEH consumption, as two out of the three patients required intubation and ventilation. A syndrome of inappropriate antidiuretic hormone secretion (SIADH) was also diagnosed. Two out of the three cases are notable because of the number of samples collected and because NEH was the only drug of abuse detected., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Introduction Since the last edition of the Black Book, several innovative agents have been approved or are poised to be approved in the coming year. These include novel antidepressants, the first muscarine agonist for the treatment of schizophrenia, the first psychedelic which may be approved for the treatment of PTSD (Post Traumatic Stress Disorder), and the first disease modifying drug for the treatment of Alzheimer's disease. Three new antidepressants have come to the market in the past 18 months. The first of those, Auvelity, the combination of bupropion and dextromethorphan, takes advantage of a pharmacokinetic and pharmacodynamic synergism between the two drugs. 85 Dextromethorphan has several pharmacodynamic properties including actions on the NMDA receptor and the Sigma 1 receptor, adding to the indirect norepinephrine agonist properties of bupropion. How Dextromethorphan is rapidly metabolized via the CYP2D6 isoenzyme to dextrophan that may have mu opioid agonist properties. The combination with bupropion, a CYP2D6 inhibitor, inhibits the metabolism of dextromethorphan allowing for more consistent therapeutic levels. The combination of dextromethorphan 45 mg twice per day and bupropion SR 105 mg twice daily appears to be more effective than an equivalent dose of bupropion alone both in speeding up antidepressant response and achieving remission. However, it's not clear at this time how the combination would compare with a more typical dose of bupropion of 300-450 milligrams a day range. The phase III program for Auvelity, showed that the drug was well tolerated with the most common side effects being dizziness, headache, and dry mouth. 86 Another novel antidepressant agent approved in 2023 is zuranolone (Zurzuvae). Zuranolone is an oral analog of IV brexanalone, and like brexanolone, was approved for the treatment of post-partum depression. 83 The advantages of zuranolone over brexanalone are many. While brexanolone is a 60-hour intravenous infusion that must be administered in a health care facility, zuranolone is a once/day oral medication that is usually taken at home. Like brexanolone, and unlike most antidepressants, zuranolone has a short course of treatment, lasting just 14 days. Zuranolone's, as does brexanolone, is thought to act primarily as allosteric modulator of the GABA-a receptors. Despite only 14 days of treatment, zuranolone produced in depression in post-partum patients a clinically and significantly meaningful improvement at day 15 and continued to day 45 or 1 month past the end of treatment. Zuranolone is a schedule IV drug. The most common side effect in clinical trials was somnolence with 36% of participants reporting this side effect vs only 6% of those on placebo. 84 Other common side effects included dizziness, diarrhea and fatigue. While the FDA declined to approve zuranolone as monotherapy or as an adjunctive treatment to standard antidepressants in major depression itself, there are positive studies in non-post-partum major depression albeit with smaller effect sizes and less consistent duration of activity. It is likely that zuranolone will continue to be studied in other depressive syndromes such as depression with anxious distress. The third "new" antidepressant approved late 2023 was gepirone (Exxua). Gepirone is not exactly a new or novel antidepressant and originally sought approval in the US about 20 years ago. 88 There had been two positive studies of gepirone during the original NDA application but also a number of failed, negative, or non-informative studies as well. Thus, the FDA declined to originally approve the drug. However, failed and negative trials are common with antidepressants and after much internal debate, the FDA ultimately agreed to approve the drug based on the positive trials and a relatively favorable side effect profile. Gepirone, like buspirone, is a partial agonist of the 5HT1a receptor and a 5HT2 antagonist. As such, gepirone does not tend to be associated with sexual side effects, weight gain, or sedation. The most common side effects are dizziness, nausea, and insomnia which tend to improve in many patients over time. Second generation antipsychotics (SGAs) continue to be the only class of agents [other than esketamine (Spravato)] approved in adjunctive treatment of resistant major depression. In addition to olanzapine (combined with fluoxetine; Symbyax), aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti), cariprazine (Vraylar) became the latest SGA to be approved in 2022. 90 Adjunctive cariprazine at 1.5 mg daily was significantly more effective than adjunctive placebo in patients with MDD who had failed to achieve an adequate response with an antidepressant alone after 6 weeks of treatment. Interestingly, a 3 mg dose of cariprazine was less consistently effective. 91 The major advantage of cariprazine over some of the other approved adjunctive SGA's is easy dosing, with the starting 1.5 mg dose being the optimal therapeutic dose for most people, and a lower metabolic side effect burden with most subjects having limited or no weight gain in short term trials. The most common side effect were akathisia/restlessness, fatigue, and nausea. Lumateperone (Caplyta) is also has positive phase III data in the adjunctive treatment of major depression and is expective file for approval in late 2024. Another recent major development in psychopharmacology is the reemergence of psychedelics in the treatment of psychiatric disorders. The first of these is MDMA (phenethylamine 3,4-methylenedioxymethamphetamine) assisted psychotherapy for the treatment of PTSD. A New Drug Application (NDA) was accepted by the FDA for MDMA in the treatment of PTSD in late 2023. 87 Because the drug is being fast tracked as a "breakthrough" treatment by the FDA, it was expected to see approval in the summer of 2024. The phase II and III data for MDMA assisted psychotherapy in the treatment of PTSD have been quite consistent and impressive. However, independent reviews have pointed to significant deficiencies in these studies including the bias introduced because of functional unblinding; virtually all patients in psychedelic studies can guess whether they got the active drug or placebo. The functional unblinding, the lack of standardization of adjunctive psychotherapy as well as the abuse potential of MDMA, may delay an FDA approval. The typical regimen in these trials included 3 preparatory psychotherapy sessions followed by once/month dosing sessions (lasting about 8 hours) and using doses of 120-160 mg in a split dose. There were typically 3 monthly dosing sessions, each followed by 3 integrative psychotherapy sessions to help subjects process and understand their experiences during the dosing sessions. In the most recent phase 3 trials, over 70% of subjects no longer met criteria for PTDS compared to 46% of those treated with psychotherapy and placebo alone. 89 The only approved medications for treating PTSD are two SSRIs, paroxetine and sertraline. These drugs effect only some dimensions of PTSD with only 20-30% achieving a remission level response with these drugs. Thus, MDMA assisted psychotherapy appears to achieve much higher levels of remission and response than has been true for the SSRIs. Since MDMA is not taken continuously, side effects from MDMA tend to be short lived. Side effects have included muscle tightness, nausea, diminished appetite, excessive sweating, feeling cold and dizziness among others. Since MDMA is currently a schedule I drug, it is likely that a rigorous Risk Evaluation Mitigation (REMs) program will be put in place and a limited number of centers and clinicians will be designated to perform MDMA assisted psychotherapy for PTSD. In addition to MDMA, psilocybin-assisted psychotherapy is in phase 3 trials for treating resistant depression but unlikely to be available before late 2025 at the earliest. An argument can be made that there has not been a truly novel antipsychotic since the introduction of clozapine in the US in 1990. All first-generation antipsychotics have been dopamine 2 antagonists and second-generation drugs have involved some ratio of 5HT2 antagonism to D2 blockade. In 2023, the FDA accepted the application of xenomaline/tropsium (KarXT) which may become the first muscarinic M1M4 agonist approved for the treatment of schizophrenia. 82,83 Tropsium is added as a muscarine antagonist to block the peripheral cholinergic effects of a muscarine agonist. Xenomaline/tropsium appears to be effective in treating both positive and negative symptoms of schizophrenia. In a phase 3 study of 407 patients with schizophrenia, xenomaline/tropsium at doses of xenomaline/50 mg/tropsium 20 mg twice daily up to 125 mg/30 mg twice daily was significantly more effective than placebo in treating both and negative symptoms over 5 weeks of treatment. As would be expected, the side effect profile of xenomaline/tropsium is very different that all currently available antipsychotics. There is no risk of EPS as it is not a dopamine antagonist, and xenomaline/tropsium is not associated with significant metabolic effects. The side effects are cholinergic in nature and include constipation, dry mouth, and nausea. A decision is expected in September of 2024. The year 2023 also saw the approval of the first disease modifying drug in the treatment of Alzheimer's disease, lecanemab (Lequembi). While acetylcholinesterase inhibitors and memantine have been available for decades, these drugs modestly improve cognition in Alzheimer's disease patients and do not alter the progressive course of the illness. Lecanemab is an IV monoclonal antibody that targets the removal of beta-amyloid in the brain as well proto-fibrils that are also known to be toxic to neuronal tissue. When given early in the course of the illness, patients treated with Lecanemab showed 27% less decline on some measures of cognition and function than did patients treated with a placebo over 18 months (about 1 and a half years). It is not known whether treatment for longer than 18 months would show lesser or greater decline over time. However, there are simulation studies that suggest that Lecanemab may modestly reduce the number of patients who progress to severe Alzheimer's disease and require institutional care. The standard dose is 10 mg/kg given via IV over one hour every 2 weeks for 18 months. Lecanemab is typically administered in an infusion center so that side effects can be monitored. The most serious side effects of Lecanemab are amyloid related imaging abnormalities (ARIA) that are associated with brain edema and microhemorrhages. ARIA can occur in up to 15% of patients. More common side effects are headache and nausea. While it remains to be seen how useful these new agents will be in clinical practice, they do represent an approach to treating neuropsychiatric disorders that are a notable departure from the pharmacotherapy of the past half century. It seems likely that some patients who have not been able to respond to or tolerate traditional pharmacotherapy will find hope in these new medications., (Copyright © 1964–2024 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Synthetic cathinones represent one of the largest and most abused new psychoactive substance classes, and have been involved in numerous intoxications and fatalities worldwide. Methcathinone analogues like 3-methylmethcathinone (3-MMC), 3-chloromethcathinone (3-CMC), and 4-CMC currently constitute most of synthetic cathinone seizures in Europe. Documenting their consumption in clinical/forensic casework is therefore essential to tackle this trend. Targeting metabolite markers is a go-to to document consumption in analytical toxicology, and metabolite profiling is crucial to support investigations. We sought to identify 3-CMC, 4-CMC, and 4-bromomethcathinone (4-BMC) human metabolites. The substances were incubated with human hepatocytes; incubates were screened by liquid chromatography-high-resolution tandem mass spectrometry and data were mined with Compound Discoverer (Themo Scientific). 3-CMC-positive blood, urine, and oral fluid and 4-CMC-positive urine and saliva from clinical/forensic casework were analyzed. Analyses were supported by metabolite predictions with GLORYx freeware. Twelve, ten, and ten metabolites were identified for 3-CMC, 4-CMC, and 4-BMC, respectively, with similar transformations occurring for the three cathinones. Major reactions included ketoreduction and N-demethylation. Surprisingly, predominant metabolites were produced by combination of N-demethylation and ω-carboxylation (main metabolite in 3-CMC-positive urine), and combination of β-ketoreduction, oxidative deamination, and O-glucuronidation (main metabolite in 4-CMC-positive urine). These latter metabolites were detected in negative-ionization mode only and their non-conjugated form was not detected after glucuronide hydrolysis; this metabolic pathway was never reported for any methcathinone analogue susceptible to undergo the same transformations. These results support the need for comprehensive screening strategies in metabolite identification studies, to avoid overlooking significant metabolites and major markers of consumption., (© 2024. The Author(s).)

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Introduction: There is a large body of preclinical data implicating that grapefruit juice (GJ) inhibits many CYP 450 isoforms. The potential of GJ-to-drug is of high relevance to clinical psychiatry, because a wide range of psychotropic medicines undergo CYP 450 metabolism and P-gp transport., Areas Covered: Relevant data were identified by searching the electronic databases up to February 2024. This work constitutes a summary of preclinical and clinical data on GJ impact on CYP 450 metabolism, P-glycoprotein, and organic anion-transporting polypeptides (OATPs), with focus on studies that assessed GJ-to-psychotropic drug interactions. Additionally, an unpublished case series of nine patients is provided., Expert Opinion: The impact of GJ on CYP 3A4 appears to be the critical mechanism for the majority of GJ-to-psychopharmacotherapy interactions described in human studies or case reports. However, there are studies and cases of patients clearly showing that this is not the only route explaining the GJ effect, and at times, this particular is of no relevance and that other CYP 450 isoforms as well as drug transporting proteins might be involved. The risk of GJ-to-psychotropic drugs needs to be further evaluated in a 'real-world' setting and apply not only measures of pharmacokinetics but also treatment effectiveness and safety.

Background: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective., Methods: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated., Results: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity., Conclusions: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

(-)-Δ 9 -Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. In humans, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and nonpsychoactive circulating metabolites of THC, respectively. Whether these cannabinoids are substrates or inhibitors of human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) is unknown. Previous animal studies suggest that THC and its metabolites could be substrates of these transporters. Therefore, we performed Transwell, cellular accumulation, and vesicular transport assays, at pharmacologically relevant concentrations of these cannabinoids, using Madin-Darby canine kidney (MDCK) II cells or plasma membrane vesicles overexpressing human P-gp or BCRP. Neither THC nor 11-OH-THC was found to be a substrate or inhibitor of P-gp or BCRP. The efflux ratio of THC-COOH in MDCKII-BCRP cells was 1.6, which was significantly decreased to 1.0 by the BCRP inhibitor Ko143. Likewise, cellular accumulation of THC-COOH was significantly increased 1.6-fold in the presence versus absence of Ko143. THC-COOH also significantly inhibited BCRP-mediated transport of Lucifer yellow, a BCRP substrate; however, THC-COOH was neither a substrate nor an inhibitor of P-gp. Collectively, these results indicate that THC and 11-OH-THC are not substrates or inhibitors (at pharmacologically relevant concentrations) of either P-gp or BCRP. THC-COOH is a weak substrate and inhibitor of BCRP, but not of P-gp. Accordingly, we predict that P-gp/BCRP will not modulate the disposition of these cannabinoids in humans. In addition, use of these cannabinoids will not result in P-gp- or BCRP-based drug interactions. SIGNIFICANCE STATEMENT: This study systematically investigated whether Δ 9 -tetrahydrocannabinol (THC) and its major metabolites, 11-hydroxy-THC and 11-nor-9-carboxy-THC, are substrates and/or inhibitors of human P-gp and BCRP at pharmacologically relevant concentrations. The results obtained are highly valuable for mechanistic understanding and prediction of the roles of P-gp and BCRP in determining the human pharmacokinetics, tissue distribution, and drug interactions of cannabinoids., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Bariatric surgical procedures are being commonly performed increasingly, and many surgical candidates are concomitantly taking psychotropic medication. This paper aims to elucidate issues when prescribing psychiatric medication in this setting of substantial anatomical and physiological change., Method: A hand search of the literature to assess the current understanding of effects of various bariatric procedures on the bioavailability of psychotropic medication., Results: Predominantly malabsorptive bariatric procedures may reduce bioavailability of some but not all commonly used psychiatric medications. There is minimal information about the effects of the most commonly performed surgery, vertical sleeve gastrectomy. Lithium prescription and monitoring requires caution., Conclusions: There is limited guidance for prescription for psychotropic medication in the bariatric surgery patient group, and vigilance for unexpected adverse effects or altered efficacy is warranted.

Background: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness., Aims: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals., Method: Sixteen participants completed a pre-drug [ 11 C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models., Results: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score., Conclusion: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Background: Feedback evaluation of actions and error response detection are critical for optimizing behavioral adaptation. Oxytocin can facilitate learning following social feedback but whether its effects vary as a function of feedback valence remains unclear., Aims: The present study aimed to investigate whether oxytocin would influence responses to positive and negative feedback differentially or equivalently., Methods: The present study employed a randomized, double-blind, placebo controlled within-subject design to investigate whether intranasal oxytocin (24 IU) influenced behavioral and evoked electrophysiological potential responses to positive or negative feedback in a probabilistic learning task., Results: Results showed that oxytocin facilitated learning and this effect was maintained in the absence of feedback. Using novel stimulus pairings, we found that oxytocin abolished bias towards learning more from negative feedback under placebo by increasing accuracy for positively reinforced stimuli. Oxytocin also decreased the feedback-related negativity difference (negative minus positive feedback) during learning, further suggesting that it rendered the evaluation of positive and negative feedback more equivalent. Additionally, post-learning oxytocin attenuated error-related negativity amplitudes but increased the late error positivity, suggesting that it may lower conflict detection between actual errors and expected correct responses at an early stage of processing but at a later stage increase error awareness and motivation for avoiding them., Conclusions: Oxytocin facilitates learning and subsequent performance by rendering the impact of positive relative to negative feedback more equivalent and also by reducing conflict detection and increasing error awareness, which may be beneficial for behavioral adaption.

Literature regarding the clinical use of psychotropic drugs in exotic animals remains scarce. Psychotropic drugs acting on serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid pathways work by decreasing fear and anxiety, reactivity, and hypervigilance, and by improving impulse control. They are indicated for some cases of aggression, self-mutilation, and compulsive and anxiety disorders, including feather-damaging behavior. Side effects are rarely seen when dosages are appropriately adjusted to the individual, starting with a low dose and slowly titrating to effect. Several drug interactions exist between psychotropic drugs and other classes. Psychotropic drugs cannot be used to replace appropriate environmental conditions in exotic animals. before "Side effects"., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The human gut microbiome plays a key role in host physiology in health and disease. There is a growing emphasis on the bidirectional interaction between various medications and the gut microbiome. Here, we will first review how drugs can affect microbiome composition and how the microbiome can alter the pharmacodynamics and potentially pharmacokinetics of psychotropic medications. We will take into consideration different classes of psychotropics, including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine, and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for future drug discovery in psychiatry which will need to consider the host microbiome as a major potential target., (© 2021 S. Karger AG, Basel.)

Oral cannabis products (a.k.a. "edibles") have increased in popularity in recent years. Most prior controlled pharmacokinetic evaluations of cannabis have focused on smoked cannabis and included males who were frequent cannabis users. In this study, 17 healthy adults (8 females), with no cannabis use in at least the past 2 months, completed 4 double-blind outpatient sessions where they consumed cannabis brownies containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10, 25 or 50 mg. Whole blood and oral fluid specimens were collected at baseline and for 8 h post-brownie ingestion. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to measure THC and relevant metabolites. In whole blood, concentrations of THC and 11-hydroxy-THC (11-OH-THC) peaked 1.5-2 h after brownie consumption, decreased steadily thereafter, and typically returned to baseline within 8 h. Blood concentrations for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) and THCCOOH-glucuronide were higher than THC and 11-OH-THC and these metabolites were often still detected 8 h post-brownie consumption. Women displayed higher peak concentrations for THC and all metabolites in whole blood compared to men, at least partially owing to their lower body weight/body mass index. Detection of THC in oral fluid was immediate and appeared to reflect the degree of cannabis deposition in the oral cavity, not levels of THC circulating in the blood. THC concentrations were substantially higher in oral fluid than in blood; the opposite trend was observed for THCCOOH. Agreement between ELISA and LC-MS-MS results was high (i.e., over 90%) for blood THCCOOH and oral fluid THC but comparatively low for oral fluid THCCOOH (i.e., 67%). Following oral consumption of cannabis, THC was detected in blood much later, and at far lower peak concentrations, compared to what has been observed with inhaled cannabis. These results are important given the widespread use of toxicological testing to detect recent use of cannabis and/or to identify cannabis intoxication., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known., Areas Covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated., Expert Opinion: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159.

The 2019-20 coronavirus pandemic (SARS-CoV-2; severe acute respiratory syndrome coronavirus 2) has dramatic consequences on populations in terms of morbidity and mortality and in social terms, the general confinement of almost half of the world's population being a situation unprecedented in history, which is difficult today to measure the impact at the individual and collective levels. More specifically, it affects people with various risk factors, which are more frequent in patients suffering from psychiatric disorders. Psychiatrists need to know: (i) how to identify, the risks associated with the prescription of psychotropic drugs and which can prove to be counterproductive in their association with COVID-19 (coronavirus disease 2019), (ii) how to assess in terms of benefit/risk ratio, the implication of any hasty and brutal modification on psychotropic drugs that can induce confusion for a differential diagnosis with the evolution of COVID-19. We carried out a review of the literature aimed at assessing the specific benefit/risk ratio of psychotropic treatments in patients suffering from COVID-19. Clinically, symptoms suggestive of COVID-19 (fever, cough, dyspnea, digestive signs) can be caused by various psychotropic drugs and require vigilance to avoid false negatives and false positives. In infected patients, psychotropic drugs should be used with caution, especially in the elderly, considering the pulmonary risk. Lithium and Clozapine, which are the reference drugs in bipolar disorder and resistant schizophrenia, warrant specific attention. For these two treatments the possibility of a reduction in the dosage - in case of minimal infectious signs and in a situation, which does not allow rapid control - should ideally be considered taking into account the clinical response (even biological; plasma concentrations) observed in the face of previous dose reductions. Tobacco is well identified for its effects as an inducer of CYP1A2 enzyme. In a COVID+ patient, the consequences of an abrupt cessation of smoking, particularly related with the appearance of respiratory symptoms (cough, dyspnea), must therefore be anticipated for patients receiving psychotropics metabolized by CYP1A2. Plasma concentrations of these drugs are expected to decrease and can be related to an increase risk of relapse. The symptomatic treatments used in COVID-19 have frequent interactions with the most used psychotropics. If there is no curative treatment for infection to SARS-CoV-2, the interactions of the various molecules currently tested with several classes of psychotropic drugs (antidepressants, antipsychotics) are important to consider because of the risk of changes in cardiac conduction. Specific knowledge on COVID-19 remains poor today, but we must recommend rigor in this context in the use of psychotropic drugs, to avoid adding, in patients suffering from psychiatric disorders, potentially vulnerable in the epidemic context, an iatrogenic risk or loss of efficiency., (Copyright © 2020 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

N-Ethylpentylone (NEP) is one of the most confiscated synthetic cathinones in the world. However, its pharmacology and pharmacokinetics remain largely unknown. In this study, the pharmacokentics of NEP in rat nucleus accumbens (NAc) was assessed via brain microdialysis after the intraperitoneal (ip) administration of NEP (20 or 50 mg/kg). The concentrations of dopamine (DA) and serotonin (5-HT) and their metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and 5-hydroxyindoleacetic acid (5-HIAA), were simultaneously monitored to elucidate the pharmacological effect of NEP. In addition, the plasma levels of NEP were also assessed. The pharmacokinetics of NEP showed a dose-related pattern, with NEP rapidly passing through the blood-brain barrier and reaching a maximum concentration (C max ) at approximately 40-minutes postdose. Approximately 4% of plasma NEP was distributed to the NAc, and considering a homogeneous brain distribution, over 90% of plasma NEP was potentially distributed to the brain. High values of area under curve (AUC) and mean residence time (MRT) of NEP were observed in both the NAc and plasma, indicating large and long-lasting effects. NEP elicited dose-related increases in microdialysate DA and 5-HT and increased the concentration of 3-MT in a dose-related manner. However, the rate of DA converted into 3-MT was unaffected. NEP had a negative effect on the rates of which DA and 5-HT were transformed into DOPAC and 5-HIAA, respectively. In summary, NEP rapidly entered the NAc and showed a long-lasting effect. In addition, DA increased more significantly than 5-HT, indicating a large potential for NEP abuse., (© 2019 Society for the Study of Addiction.)

Background: The systematic reviews and meta-analyses performed until now did not provide the adequate picture of actual knowledge in the field of neuropsychiatric symptoms treatment using psychotropic cannabinoids in patients with Alzheimer disease (AD)., The Study Question: Which is the level of evidence, from quantitative and qualitative point of view, concerning the efficacy and safety of the treatment with psychotropic cannabinoids of neuropsychiatric symptoms in AD?, Study Design: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Google Scholar Data, and Clinicaltrials.gov were searched for randomized clinical trials with cannabinoids in Alzheimer dementia agitation and aggression., Measures and Outcomes: The rationale, the objectives, and the methods used for searching the trials have been established according to PRISMA Criteria 2009., Results: The total number of patients in the 9 publications evaluated in this study, which included data from 6 clinical trials, was 422 patients-treatments, where treatment was a psychoactive cannabinoid or placebo, some of them obtained by multiplying selected patients with the number of cannabinoid treatments in the crossover studies. There are multiple sources of bias in the analyzed studies; 2 elements have prevented conclusive results. One element was polypragmazia, a major role being played by the use of psychotropic drugs other than cannabinoids, in an effort to reduce agitation and aggressive behavior. The second one was the large number of concomitant symptoms, for example, pain (commonly causing anxiety and agitation)., Conclusions: No clear conclusion can be drawn on the effectiveness of psychoactive cannabinoids in the treatment of psychiatric manifestations, in particular agitation and aggression, in AD. In the future, large randomized controlled trial with adequate designs, without crossover and for longer duration, adapted to cannabinoid pharmacokinetics, is required to establish the real efficacy and safety of these drugs in aggressive and/or agitated patients with AD.

Background: THC can be measured in blood up to a month after last intake in heavy cannabis users. The cognitive deficits during abstinence have been hypothesized to be at least in part due to residual THC in brain. To which extent THC accumulation will occur after occasional cannabis use has gained limited attention. We aimed to predict THC-levels between smoking sessions in non-daily as well as daily cannabis users and to compare these predictions with published THC levels., Methods: Predictions were based on pharmacokinetic principles on drug accumulation after repeated dosing, applied to different cannabis smoking patterns, using data from a three-compartment model for THC pharmacokinetics and results on the terminal elimination half-life of THC in humans. We searched the literature for THC measurements which could be compared with these predictions. We found no such results from controlled studies of long-term repeated cannabis consumption of known THC amounts. Thirteen published studies contained, however, enough information on cannabis use and results from THC-measurements to make tentative comparisons with the predictions., Results: The predictions of THC-plasma levels present after different cannabis smoking patterns assuming terminal elimination half-lives of THC of 21.5 h or longer, had some support in published THC levels measured in individuals self-reporting their cannabis consumption. We found no consistent discrepancies between the predictions and reported THC plasma levels after non-daily or daily cannabis use. The predictions indicate that THC might be present in plasma between smoking sessions above usual analytical limits when smoking every third and second day, and at lower levels after once weekly smoking., Conclusions: The study indicates that THC might be present continuously even in non-daily smokers at low levels, even if the smoking occasions are separated by a week. This is different from alcohol, where ethanol has disappeared after a day. From a toxicological point of view the persistance of THC in the brain, raises questions whether this should be given more attention as with other toxicological thinking where long-term presence of bioactive substances gives rise to concern. There are some uncertainties in this analysis, and controlled studies on THC-accumulation accompanying different use patterns seem warranted., Competing Interests: Declaration of Competing Interest JM has received remuneration from the Norwegian Department of Transportation, from Norwegian courts and police for reports on THC pharmacokinetics and effects related to driving behaviour. JGB does not have any conflicts of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

3,4-Dimethylmethcathinone (3,4-DMMC) is a new psychoactive substance whose recreational use and trade have recently increased. Given the absence of information on the toxicokinetics of 3,4-DMMC, the present work aimed at validating a GC-MS methodology for the drug quantification in biological matrices, and further characterizing its biodistribution in Wistar rats. The method was validated based on the evaluation of the drug stability, limit of detection and quantification, linearity, selectivity, precision, accuracy and recovery. To characterize biodistribution, Wistar rats were administered with 20 or 40 mg/Kg of 3,4-DMMC i.p.. After 1 h or 24 h, rats were anaesthetized, euthanized and blood, brain, liver, heart, kidneys, lungs, spleen, urine (only at 24 h), and a portion of gut, muscle and adipose tissue were collected for analysis. After 1 h, 3,4-DMMC was present in all analysed matrices, and the presence of two metabolites was further detected in all of them. The drug accumulation was higher in kidneys, lungs, spleen and brain. After 24 h, 3,4-DMMC was only present in urine, along with five metabolites. All metabolites were tentatively identified. Through elucidation of the most appropriate analytical matrices and the metabolites that may have the largest detection windows, these data are expected to assist in future clinical and forensic investigations., (Copyright © 2019. Published by Elsevier B.V.)

Drug interaction databases are important tools in today's clinical decision support. However, there is great variation with regard to classification and presentation of interactions among databases. The present study aimed to investigate consensus among databases with regard to combinations of psychotropics. A database integrated in Norwegian computerised clinical decision support systems and three international recommended subscription databases were compared. Combinations of psychotropics (two or more) prescribed to patients 65 years or older on a single day from three nursing homes in Bergen, Norway 16 years apart (2000 and 2016) were studied. The databases were compared in a common analysis with the following questions: interaction (no, not contraindicated or contraindicated), type (pharmacodynamic or pharmacokinetic), the total number of interactions, and the first ranked interaction among several in each patient. Consensus among the four drug interaction databases was associated with pharmacokinetic interactions involving mainly older psychotropics in the common analysis. The qualities that best characterised interactions with consensus was primarily the evidence including a description of manageability. There was a surprising lack of consensus with regard to contraindicated interactions, even when older psychotropics were involved. Lack of consensus decreased with the number of psychotropics in the combinations. This was mainly because the highest ranked interactions in the respective databases involved different drugs. We propose evidence and manageability as core factors when ranking and presenting interactions in clinical decision support., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Pharmacogenomic testing in clinical psychiatry has grown at an accelerated pace in the last few years and is poised to grow even further. Despite robust evidence lacking regarding efficacy in clinical use, there continues to be growing interest to use it to make treatment decisions. We intend this article to be a primer for a clinician wishing to understand the biological bases, evidence for benefits, and pitfalls in clinical decision-making. Using clinical vignettes, we elucidate these headings in addition to providing a perspective on current relevance, what can be communicated to patients, and future research directions. Overall, the evidence for pharmacogenomic testing in psychiatry demonstrates strong analytical validity, modest clinical validity, and virtually no evidence to support clinical use. There is definitely a need for more double-blinded randomized controlled trials to assess the use of pharmacogenomic testing in clinical decision-making and care, and until this is done, they could perhaps have an adjunct role in clinical decision-making but minimal use in leading the initial treatment plan.

Many clients do not take their medications as prescribed. One of the reasons may be the common adverse drug effects and drug-drug interactions of certain medications. This article reviews adverse drug effects (including less serious side effects), the pharmacokinetics and pharmacodynamics involved in adverse effects, and the pharmacokinetics of drug interactions. For medications to be effective in treating mental disorders, nurses need to carefully assess clients and their motivations for taking medications, routinely inquire about when and how they are taking their prescriptions, any adverse effects they are experiencing, and how they are managing common, less severe adverse effects. [Journal of Psychosocial Nursing and Mental Health Services, 58(2), 9-13.]., (Copyright 2020, SLACK Incorporated.)

Purpose: The purpose of this short overview is to summarize and discuss the English-written and PubMed-listed review articles and original studies published between January 2015 and April 2019 on the use of metabolomics techniques for investigating the metabolism of new psychoactive substances (NPS). First, a brief introduction is given on the metabolism of NPS and metabolomics techniques in general. Afterward, the selected original studies are summarized and discussed. Finally, a section dedicated to the studies on NPS beyond metabolism using metabolomics techniques is provided. Thereafter, both sections are concluded and perspectives are given., Methods: PubMed was searched for English-written literature published between January 1, 2015 and April 1, 2019., Results: The present short overview found that the current use of metabolomics techniques in investigating the metabolism of NPS is rather limited, but these techniques can support and facilitate traditional metabolism studies., Conclusions: Thus, there may be a certain potential for using metabolomics techniques in the field of NPS research, but a great challenge remains to thoroughly adopt the existing metabolomics methods.

Background: NPS belonging to the benzodiazepine (BZD) class, e.g., 'legal/designer BZDs'/'research chemicals', have recently emerged in the drug (mainly online/virtual) market., Objective: While certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians'/public health knowledge/awareness, to incentive harm reduction strategies., Method: A comprehensive overview was carried out by using the EMCDDA/EDND database regularly monitored by our research team, by specifically looking at the 'new BZDs' so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilingual qualitative netnographic study was conducted to obtain further clinical/pharmacological/ toxicological data, including psychonauts' online trip reports., Results: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably administered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds., Conclusion: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the US, the use of synthetic opioids (e.g. fentanyl and derivatives) has become an increasing health issue with thousands of overdose deaths being observed since 2013. With the high mortality rate associated with these substances, postmortem analyses and interpretation of synthetic opioids has become extremely important. However, due to the novelty of these compounds, the available data are limited and provides challenges to toxicologists. The objectives of this study were (1) to develop and validate analytical methods for the determination of synthetic opioids in vitreous humor and brain, and (2) to investigate the postmortem distribution of new synthetic opioids in blood, vitreous humor, and brain tissue. Vitreous humor (0.5mL) and brain tissue (5g) homogenized in water (diluted 1:3, w/w) were extracted by mixed mode cation exchange-reversed phase solid phase extraction. Extracts were analyzed by liquid chromatography tandem mass spectrometry (LC-MSMS). The chromatographic separation was performed by reversed-phase with 0.1% formic acid in water and in acetonitrile as mobile phases in gradient mode, with a total run time of 21min. Data were acquired with ESI+ in dynamic multiple reaction mode (dMRM), monitoring 2 transitions per compound. The methods were succesfully validated following SWGTOX guidelines, with limits of quantification of 0.1ng/mL in vitreous humor and 0.1ng/g in brain. Fifty-eight authentic case samples from the New York City Office of the Chief Medical Examiner (NYC-OCME) were analyzed to assess the distribution and detectability of synthetic opioids in these postmortem samples. Of the fifteen synthetic opioids included in the method, six synthetic opioids and metabolites (4-ANPP, acetylfentanyl, fentanyl, furanylfentanyl, norfentanyl, U-47700) were detected in the authentic cases. Concentrations for most analytes were within the 0.1 to 100ng/mL or ng/g calibration range across all three matrices, with only concentrations from acetylfentanyl and U-47700 exceeding 100ng/mL or ng/g. The highest concentrations were observed in brain (except norfentanyl), followed by blood and vitreous humor. Most analytes were detected in all three matrices in a given case. This was followed by detection of an analyte in combinations of brain and another matrix or brain only. Through the case analyses, vitreous humor and brain demonstrated to be viable alternatives to blood when performing postmortem analyses of synthetic opioids. Brain exhibited a higher detectability for most analytes when compared to blood and vitreous humor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Polypharmacy is associated with delirium, but the mechanisms for this connection are unclear. Our goal was to determine the frequency of supratherapeutic psychotropic drug levels (SPDLs) in older hospitalized patients and if it is associated with the duration of emergency department (ED) delirium., Design: Secondary analysis of a prospective cohort study., Setting: Tertiary care academic medical center., Participants: ED patients 65 years or older who were admitted to the hospital., Measurements: Delirium was assessed in the ED and during the first 7 days of hospitalization using the modified Brief Confusion Assessment Method. Drug concentrations were determined in serum samples collected at enrollment via a novel platform based on liquid chromatography-tandem mass spectrometry capable of identifying and quantitating 78 clinically approved medications including opioids, benzodiazepines, antidepressants, antipsychotics, and amphetamines. Patients with serum psychotropic drug concentrations above established reference ranges were considered supratherapeutic and have a SPDL. We performed proportional odds logistic regression to determine if SPDLs were associated with ED delirium duration adjusted for confounders. Medical record review was performed to determine if the doses of medications associated with SPDLs were adjusted at hospital discharge., Results: A total of 158 patients were enrolled; of these, 66 were delirious in the ED. SPDLs were present in 11 (17%) of the delirious and 4 (4%) of the non-delirious ED patients. SPDLs were significantly associated with longer ED delirium duration (adjusted proportional odds ratio = 6.0; 95% confidence interval = 2.1-17.3) after adjusting for confounders. Of the 15 medications associated with SPDLs, 9 (60%) were prescribed at the same or higher doses at the time of hospital discharge., Conclusion: SPDLs significantly increased the odds of prolonged ED delirium episodes. Approximately half of the medications associated with SPDLs were continued after hospital discharge at the same or higher doses. J Am Geriatr Soc 67:2387-2392, 2019., (© 2019 The American Geriatrics Society.)

Hypericum perforatum L. (St. John's wort) is used to treat mild-to-moderate depression. Its potential safety risks are pharmacokinetic drug interactions via cytochrome P450 (CYP) enzymes and P-glycoprotein, presumably caused by hyperforin. In a phase I, open-label, nonrandomized, single-sequence study, the low-hyperforin Hypericum extract Ze 117 was investigated using a drug cocktail in 20 healthy volunteers. No pharmacokinetic interactions of Ze 117 were observed for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein. Area under the curve (AUC) and peak plasma concentration (C max ) of the used probe drugs showed 90% confidence intervals (CIs) of the geometric mean ratios of the drugs taken together with Ze 117 vs. probe drug alone, well within the predefined bioequivalence range of 80-125%. Though Ze 117 did not induce dextromethorphan metabolism by CYP2D6, it weakly increased dextromethorphan AUC ratio (mean 147.99, 95% CI 126.32-173.39) but not the corresponding metabolic ratio. Ze 117 does not show clinically relevant pharmacokinetic interactions with important CYPs and P-glycoprotein., (© 2019 Max Zeller & Söhne AG. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The abuse of new psychoactive substances (NPS) has been increasing dramatically since the late 2000s worldwide. Between 2009 and 2017, a total of 803 individual NPS were reported to the United Nations Office of Drugs and Crime by 111 countries and territories. Although the most popular compounds are synthetic cannabinomimetics and psychostimulatory derivatives of cathinone (so-called β-keto-amphetamines), novel benzodiazepines have recently emerged on the recreational drug market. The misuse/abuse of "designer benzodiazepines" (DBZD), a common name for the benzodiazepine class NPS, has become an increasing problem in many countries. The DBZD group includes pharmaceutical drug candidates that have never been approved for medical use, compounds that were synthesized by a simple structural modification of a registered drug, and some active metabolites of registered benzodiazepines. This survey presents members of the DBZD group, describes the epidemiological trends and clinical effects associated with DBZD use, and discusses available data on their metabolism. Special emphasis is given to cases of intoxications involving these compounds., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The paucity of novel drugs for neuropsychiatric indications contrasts with the remarkable recent advances in neuroscience research. We have identified 5 challenges the field needs to address and recommend potential solutions. First, we need to drive discovery efforts based on human data. Second, we need to think more carefully about animal models, embracing them as tools to test pathophysiological alterations. Third, we need to develop strategies to select more homogenous groups of patients in our clinical trials. Fourth, we need to develop and validate translational biomarkers, which can be used for pharmacodynamic assessments as well as for patient selection. Fifth, we need to adopt more reliable and objective measures to capture clinical efficacy. The tools that will allow these solutions to be implemented may already be in place but not routinely adopted or are still being developed. Overall, a change in mindset to adopt science- and data-driven paths is needed., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

The widespread diffusion of new psychoactive substances, requires a continuous update and development of new methods able to identify and quantify these new molecules in biological matrices. In this study an analytical method for the determination of two new benzodifuranyl derivatives, 1-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)propan-2-amine and 2-(2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-4-yl)ethanamine, in rat plasma was developed. A solid phase extraction using C18 cartridges was carried out obtaining good recoveries with low matrix effect. Quantification was performed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Separation was carried out on a C18 reverse phase column with water/methanol containing 0.1% of formic acid as mobile phase. These conditions allowed to achieve adequate separation, resolution and signal-to-noise ratio for analytes and internal standard. Calibration curves were linear over the concentration range from 10 to 400 ng/ml with correlation coefficients that exceeded 0.995. Obtained precision, accuracy and recovery showed good reproducibility and selectivity. Finally, the validation method was successfully applied to an in vivo study in order to evaluate the pharmacokinetic profile of these new amphetamines., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Currently, an unprecedented number of individuals can legally access cannabis. Vaporization is increasingly popular as a method to self-administer cannabis, partly due to perception of reduced harm compared with smoking. Few controlled laboratory studies of cannabis have used vaporization as a delivery method or evaluated the acute effects of cannabis among infrequent cannabis users. This study compared the concentrations of cannabinoids in whole blood and oral fluid after administration of smoked and vaporized cannabis in healthy adults who were infrequent users of cannabis. Seventeen healthy adults, with no past-month cannabis use, self-administered smoked or vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10 and 25 mg in six double-blind outpatient sessions. Whole blood and oral fluid specimens were obtained at baseline and for 8 h after cannabis administration. Cannabinoid concentrations were assessed with enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) methods. Sensitivity, specificity and agreement between ELISA and LC-MS-MS results were assessed. Subjective, cognitive performance and cardiovascular effects were assessed. The highest concentrations of cannabinoids in both whole blood and oral fluid were typically observed at the first time point (+10 min) after drug administration. In blood, THC, 11-OH-THC, THCCOOH and THCCOOH-glucuronide concentrations were dose-dependent for both methods of administration, but higher following vaporization compared with smoking. THC was detected longer in oral fluid compared to blood and THCCOOH detection in oral fluid was rare and highly erratic. For whole blood, greater detection sensitivity for ELISA testing was observed in vaporized conditions. Conversely, for oral fluid, greater sensitivity was observed in smoked sessions. Blood and/or oral fluid cannabinoid concentrations were weakly to moderately correlated with pharmacodynamic outcomes. Cannabis pharmacokinetics vary by method of inhalation and biological matrix being tested. Vaporization appears to be a more efficient method of delivery compared with smoking., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

We present a novel multiplex assay for the simultaneous detection of 12 polymorphisms within the UGT1A9 sequence, which codes for enzymes involved in phase II biotransformation. The assay combines a multiplexed amplification step with single-base extension sequencing. The method described here is fast, cost-effective, and easy-to-use, combining the relevant features of screening methods for research and diagnostics in pharmacogenetics. To validate the assay, we tested reproducibility and sensitivity and analysed allele frequencies of 110 Caucasian individuals. Furthermore, we describe combining genetic information of individuals consuming Cannabis sativa products with respective plasma concentrations of a metabolite.

Marijuana use by pregnant women is increasing. To predict developmental risk to the fetus/neonate from such use, in utero fetal exposure to (-)-∆ 9 -tetrahydrocannabinol (THC), the main psychoactive cannabinoid in marijuana and its active psychoactive metabolite, 11-hydroxy-∆ 9 -tetrahydrocannabinol (11-OH-THC), needs to be determined. Since such measurement is not possible, physiologically based pharmacokinetic (PBPK) modeling and simulation can provide an alternative method to estimate fetal exposure to cannabinoids. To do so, pharmacokinetic parameters for the disposition of THC and 11-OH-THC need to be elucidated. Here, we report a first step to estimate these parameters, namely, those related to maternal metabolism of THC/11-OH-THC in human liver microsomes (HLMs) at plasma concentrations observed after smoking marijuana. Using recombinant cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes, CYP1A1, 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 3A7, and UGT1A9 and UGT2B7 were found to be involved in the disposition of THC/11-OH-THC. Using pooled HLMs, the fraction metabolized ( f m ) by relevant enzymes was measured using selective enzyme inhibitors, and then adjusted for enzyme cross-inhibition. As previously reported, CYP2C9 was the major enzyme responsible for depletion of THC and formation of 11-OH-THC with f m values of 0.82 ± 0.08 and 0.99 ± 0.10, respectively (mean ± S.D.), while CYP2D6 and CYP2C19 were minor contributors. 11-OH-THC was depleted by UGT and P450 enzymes with f m values of 0.60 ± 0.05 and 0.40 ± 0.05, respectively (mean ± S.D.), with UGT2B7, UGT1A9, CYP2C9, and CYP3A4 as contributors. These mechanistic data represent the first set of drug-dependent parameters necessary to predict maternal-fetal cannabinoid exposure during pregnancy using PBPK modeling., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: The common practice of switching between branded (reference) medications and their corresponding generic products, between generic products, or even from a generic product to a branded medication during the treatment of central nervous system (CNS) disorders may compromise efficacy and/or tolerability., Methods: We assessed the published literature from March 1, 2010 through June 30, 2017 via PubMed using the MeSH term 'generics, drugs' alone and in combination with class-specific terms (e.g., 'anticonvulsants', 'mood stabilisers'), for studies detailing outcomes following product switches., Results: Although some studies comparing the initiation of reference versus generic drugs suggest equivalence between products, several studies detailing a switch between reference and generic products describe reductions in efficacy, reduced medication adherence and persistence, and increased overall health care resource utilization and costs associated with generic substitution., Conclusion: When product switches are considered, they should only proceed with the full knowledge of both patient and provider.

This column is the third in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first column in this series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs and how to recognize such DDIs, and strategies for avoiding them. The second column in the series further discussed strategies for avoiding and/or minimizing adverse outcomes from DDIs. This third column deals with pharmacokinetic considerations concerning DDIs in psychiatric practice. Specifically, this column discusses the 2 major types of pharmacokinetically mediated DDIs: those mediated by cytochrome P450 (CYP) enzymes and those mediated by transport proteins. The role of each of these regulatory proteins in the pharmacokinetics of drugs is reviewed as well as how genetically determined variation in the functional activity of these regulatory proteins can alter the accumulation of a drug in the body (ie, via CYP enzymes) and in specific compartments of the body (ie, via transport proteins), either increasing or decreasing their accumulation leading to either reduced efficacy or increased toxicity. This column further explains how coprescribed drugs can also affect the functional integrity of these regulatory proteins and lead to differences from usual in the accumulation of drugs dependent on the activity of these CYP enzymes and drug transporters. This phenomenon is known as phenoconversion in which a patient can functionally change from his or her genetic status, for example, having extensive or normal metabolism, to having poor or slow metabolism and hence greater accumulation than would be expected based on the patient's genotype.

Since 2008 there has been an onslaught of new drugs in the illicit marketplace. Often referred to as "research chemicals," "designer drugs," or "novel psychoactive substances" (NPS), these substances are used for their pharmacological effects which are often similar to more widely known drugs such as ecstasy or heroin. In some cases users specifically seek out these new chemicals, in other cases they are simply purchasing what they believe to be their normal drug of choice from a dealer, but the product is not what it is purported to be. Implementation of national and international systems to monitor the appearance of new compounds enables laboratories to be prepared with validated tests to detect them in biological specimens. The most common classes of NPS are synthetic cannabinoids, novel opioids, novel benzodiazepines, stimulants, and hallucinogens. Within these groups the compounds may be drugs that were originally synthesized for research purposes during the pursuit of new therapeutic agents such as the synthetic cannabinoid JWH-018 and the designer opioid U47700. Others like etizolam are compounds used in other countries but not commonly seen in the USA. Some are drugs synthesized specifically to circumvent legal controls. In all cases, these compounds present a unique challenge to forensic toxicology laboratories which must quickly develop and validate analytical methods for the identification and quantification in biological matrices.This chapter is a condensed and updated version of an article originally published in Clinical and Forensic Toxicology News.

Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules and lipophilic properties. Lipophilicity of drug candidate can affect both the pharmacokinetic and pharmacodynamics properties, in particular, the ability of a molecule to cross the cell membrane. Among the new methods for determination of the lipophilicity of compounds, micellar electrokinetic chromatography (MEKC) is considered to be an appropriate one for bioactive molecules, as it closely mimics the physiological conditions. In this paper MEKC was used for the estimation of the lipophilicity of 24 derivatives of 8-alkoxy-7H-purine-2,6-dione, designed and synthesized as potential antidepressant/anxiolytic and antipsychotic agents. The results of experimental method were compared with calculated in silico parameters (AlogPs and milogP by Virtual Computational Laboratory website, log P Pallas by Pallas 3.1, Mlog P by Marvin, log P ChemS by ChemSketch, log P ChemDraw by ChemBioUltra) using Principal Component Analysis (PCA) method. Finally, using estimated log P values for selected compounds ligand - lipophilicity efficiency (LLE), per cent efficiency index (PEI), and binding efficiency index (BEI) parameters were calculated. Applied MEKC procedure could be used for selection of potential lead structure in a group of 7H-purine-2,6-dione derivatives., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rationale: A series of studies conducted approximately 40 years ago demonstrated an acute bronchodilator effect of smoked cannabis in healthy adults and adults with asthma. However, the acute effects of vaporized cannabis on airway function in adults with advanced chronic obstructive pulmonary disease (COPD) remain unknown., Objectives: To test the hypothesis that inhaled vaporized cannabis would alleviate exertional breathlessness and improve exercise endurance by enhancing static and dynamic airway function in COPD., Methods: In a randomized controlled trial of 16 adults with advanced COPD (forced expiratory volume in 1 second [FEV 1 ], mean ± SD: 36 ± 11% predicted), we compared the acute effect of 35 mg of inhaled vaporized cannabis (18.2% Δ 9 -tetrahydrocannabinol, <0.1% cannabidiol) versus 35 mg of a placebo control cannabis (CTRL; 0.33% Δ 9 -tetrahydrocannabinol, <0.99% cannabidiol) on physiological and perceptual responses during cardiopulmonary cycle endurance exercise testing; spirometry and impulse oscillometry at rest; and cognitive function, psychoactivity, and mood., Results: Compared with CTRL, cannabis had no effect on breathlessness intensity ratings during exercise at isotime (cannabis, 2.7 ± 1.2 Borg units vs. CTRL, 2.6 ± 1.3 Borg units); exercise endurance time (cannabis, 3.8 ± 1.9 min vs. CTRL, 4.2 ± 1.9 min); cardiac, metabolic, gas exchange, ventilatory, breathing pattern, and/or operating lung volume parameters at rest and during exercise; spirometry and impulse oscillometry-derived pulmonary function test parameters at rest; and cognitive function, psychoactivity, and mood., Conclusions: Single-dose inhalation of vaporized cannabis had no clinically meaningful positive or negative effect on airway function, exertional breathlessness, and exercise endurance in adults with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT03060993).

Introduction: Most direct-acting antivirals (DAAs) and psychotropic drugs are metabolized by or induct/inhibit CYP enzymes and drug transporters. Although they are frequently coadministered, the drug-drug interactions (DDIs) have been little studied. Therefore, the aim of this review is to describe the interactions between the approved DAA or combination regimens and the main psychoactive substances, including legal and illegal drugs of abuse. Areas covered: We performed a literature search on PubMed database on drug interactions with the currently available antivirals for hepatitis C and a review of the information on pharmacokinetics, metabolism, and drug interactions from www.hep-druginteractions.org and from all the Summary of Product Characteristics (SmPC). This review covers the DDI between the DAA regimens approved, such as simeprevir and sofosbuvir, paritaprevir, glecaprevir, voxilaprevir, ombitasvir, ledipasvir, daclatasvir and sofosbuvir, elbasvir and grazoprevir, sofosbuvir and velpatasvir, glecaprevir/pibrentasvir, sofosbuvir and velpatasvir, and main psychotropic agents. Expert Commentary: DAA regimens based on sofosbuvir combination usually have less DDI than protease inhibitor-based regimens. Among protease inhibitors regimens, new combinations, such as glecaprevir/elbasvir and grazoprevir/elbasvir, seemed to have less DDI than the combination POrD (paritaprevir/ombitasvir/ritonavir/dasabuvir). However, the analysis of each interaction is theoretical and further interaction studies would be necessary to confirm actual effect.

4-Hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET) is a new psychoactive substance (NPS) of the chemical class of tryptamines. It shows structural similarities to the endogenous neurotransmitter serotonin, and is a serotonergic hallucinogen, affecting emotional, motoric, and cognitive functions. The knowledge about its biotransformation is mandatory to confirm the abuse of the substance by urine analysis in forensic cases. Therefore, phase I metabolites were generated by the use of the pooled human liver microsomes (pHLM) in vitro model and analyzed by high-performance liquid chromatography high-resolution tandem mass spectrometry with information-dependent acquisition (HPLC-IDA-HR-MS/MS). Furthermore, three authentic urine samples was analyzed and results were compared: 12 different in vitro and 4 in vivo metabolites were found. The predominant biotransformation steps observed in vitro were mono- or dihydroxylation of 4-HO-MET, besides demethylation, demethylation in combination with monohydroxylation, formation of a carboxylic acid, deethylation, and oxidative deamination. In vivo, monohydroxylation, and glucuronidation were detected. A metabolic pathway based on these results was proposed. For the analysis of urine samples in forensic cases, the N-oxide metabolite and the HO-alkyl metabolite are recommended as target compounds, besides the glucuronides of 4-HO-MET and the parent compound 4-HO-MET itself., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This review discusses common mental health disorders and their associations with cardiovascular disease risks. Commonly found mental health disorders include depression, anxiety, and personality types. The link between depression and cardiovascular disease mortality has been established. Depression is also common in patients with heart failure. In addition to discussing psychological disorders, a review of psychotropic drugs is also included. Drugs are described for therapy for depression and anxiety, as well as associations with cardiovascular drug-drug interactions. Drug-drug interactions are more common and potentially dangerous in elderly patients, in whom the conditions often coexist. The most common drug-drug interactions involve the P450 system of enzymes., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)