Novel Psychoactive Substance Use and Psychological Trauma: A Multimethodological Analysis.

BACKGROUND: Authors discuss the connections between novel psychoactive substance (NPS) use and psychological trauma. The transition from classical substances to NPS, a paradigm change, poses a challenge for the treatment systems. Objective: Research evidence suggests difficulties in emotion regulation and trauma-related NPS-use. Authors explore some demographic and psychopathological characteristics related to such findings and examine the connections between emotion regulation deficiency and the choice of substance. METHOD: This study uses a methodological triangulation of a biologically identified sample to confirm NPS use, a survey method to describe users' socioeconomic characteristics, and Minnesota Multiphasic Personality Inventory (MMPI-2) subscales to study dysfunctions in emotion regulation. RESULTS: Participants (77 patients) were mainly polydrug users. The transgenerational transfer of substance use was a salient feature, but material deprivation was not characteristic of the entire sample. NPS use was not connected to certain psychopathological characteristics the way classical substance use was. More than half of the respondents had elevated scores on MMPI-2 Demoralization (RCd) and Dysfunctional Negative Emotions (RC7) scales. Nearly half of them also scored high on Neuroticism/Negative Emotionality (NEGE). CONCLUSIONS: Results suggest that NPS use in the context of polydrug use is connected to psychological trauma and emotion regulation deficiency, but the MMPI-2 scales to assess emotional dysfunctions are not connected to a particular type of NPS.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

N-desethyl isotonitazene detected in polydrug users admitted to hospital in Birmingham, United Kingdom.

INTRODUCTION: Nitazenes are potent synthetic opioids and N-desethyl isotonitazene, a metabolite of isotonitazene, has emerged as a drug in its own right. METHODS: This is an observational case series of patients with suspected or declared substance use who were admitted to hospitals in the Sandwell and West Birmingham National Health Service Trust between July and October 2023. All patients were found on toxicological screening to have been exposed to N-desethyl isotonitazene. RESULTS: Twenty presentations involving 19 patients who tested positive for N-desethyl isotonitazene were included in the study. In 19 presentations, multiple substances were detected on toxicological screening. The number of patients testing positive for other substances were: 19 for cocaine and its main metabolite benzoylecgonine, 13 for morphine, 11 for the heroin-specific metabolite 6-monoacetylmorphine, ten for xylazine, eight for gabapentinoids (pregabalin and/or gabapentin), seven for methadone and/or the metabolite, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, six for benzodiazepines and five for the synthetic cannabinoid MDMB-4en-PINACA. Only one patient had no other substances detected apart from N-desethyl isotonitazene. This patient presented with coma, miosis, bradypnoea and hypercapnia and responded to naloxone. In this cohort, the median concentration of N-desethyl isotonitazene was 1.53 µg/L (n = 14; range 0.59-5.48) in whole blood and 27.75 µg/L (n = 16; range 0.51-91.53) in urine. DISCUSSION: The majority of the patients in this cohort presented with features typical of an opioid overdose, which is unsurprising as they were all experienced users of diamorphine. Although these features are also consistent with the known effects of N-desethyl isotonitazene, in only one case is it possible to attribute the patient's features to N-desethyl isotonitazene toxicity alone. CONCLUSIONS: This case series highlights the need for toxicovigilance in the illicit drug market as patterns of substance misuse evolve and novel psychoactive substances continue to emerge.

Mitragyna speciosa (Kratom) poisoning: Findings from ten cases.

Kratom is a mixture of compounds that are present in the leaves of the tropical tree Mitragyna speciosa. It is used as a psychoactive agent with both opiate and stimulant-like effects. In this case series we describe the signs, symptoms, and the management of kratom overdose in the prehospital setting and in intensive care. We retrospectively searched for cases in the Czech Republic. Over 36 months we found 10 cases of kratom poisoning, which healthcare records were analyzed and reported as per CARE guidelines. The dominant symptoms in our series were neurological and included quantitative (n = 9) or qualitative (n = 4) disorder of consciousness. Signs and symptoms of vegetative instability [hypertension (n = 3) and tachycardia (n = 3) vs. bradycardia/cardiac arrest (n = 2), mydriasis (n = 2) vs. miosis (n = 3)] were noticed. Prompt response to naloxone in two cases and lack of response in one patient were observed. All patients survived and the effect of intoxication wore off within two days. Kratom overdose toxidrome is variable and, in keeping with its receptor physiology, consists of signs and symptoms of opioid-like overdose, sympathetic overactivation and serotonin-like syndrome. Naloxone can help to avoid intubation in some cases.

Delta-8 tetrahydrocannabinol: a scoping review and commentary.

BACKGROUND AND AIMS: Delta-8 tetrahydrocannabinol (THC) is a psychoactive substance from the Cannabis plant that has been rising in popularity in the United States since the 2018 US Farm Bill implicitly legalized it. This study reviewed research from peer-reviewed and non-peer-reviewed (e.g. anecdotal and news) reports related to delta-8 THC to summarize current knowledge and implications for public health and safety. METHODS: A scoping review was conducted using PubMed, Scopus, Google Scholar and Google as search engines, leading to the identification of 103 documents that were summarized. The themes that emerged were (1) legality, (2) use (popularity, motives, psychoactivity/potency, benefits/consequences), (3) synthesis (byproducts, laboratory testing) and (4) retail (availability, price, packaging, youth-oriented marketing). A second author independently coded 20% of the documents, which verified the categorization of articles by these emergent themes. RESULTS: Most research used animal/cell models or focused upon ways to identify the chemical structure of delta-8 THC in various products. Findings suggest that people often use delta-8 THC as a substitute for other substances. Anecdotally, delta-8 THC is a less potent psychoactive than delta-9 THC; however, several negative consequences have been reported. There is no federal age restriction for purchase/possession of delta-8 THC products. Delta-8 THC is readily accessible on-line, is typically less expensive than delta-9 THC and is often marketed in ways that would seemingly appeal to children. There are no regulations on synthesis, resulting in products being contaminated and/or yielding inconsistent effects. There have been thousands of calls to US poison control centers due to accidental delta-8 THC exposure among minors. CONCLUSIONS: Most research on delta-8 THC is largely anecdotal, not peer-reviewed and does not involve human subjects. Future research should examine delta-8 THC use using nationally representative samples to more clearly understand the prevalence and consequences of use. Laws are needed to mitigate the risks of using delta-8 THC, particularly quality control of synthesis and minimum purchase age.

A case of fatal multidrug intoxication involving flualprazolam: distribution in body fluids and solid tissues.

PURPOSE: Designer benzodiazepines (DBZDs) increasingly emerged on the novel psychoactive substance (NPS) market in the last few years. They are usually sold as readily available alternatives to prescription benzodiazepines (BZDs) or added to counterfeit medicines. BZDs are generally considered relatively safe drugs due to the low risk of serious acute adverse effects in mono-intoxication, though e.g., alprazolam seems to display an elevated risk of respiratory depression. Here we report on a fatal intoxication involving the novel DBZD flualprazolam. METHODS: A complete postmortem examination was performed. General unknown screenings and analysis of drugs of abuse were performed on postmortem samples by immunoassay, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. The standard addition method was employed to quantify flualprazolam in postmortem blood and tissues. Finally, a toxicological significance score (TSS) was assigned. RESULTS: Flualprazolam was detected in heart serum (25.4 ng/mL) and peripheral blood (21.9 ng/mL) as well as in urine, stomach contents, brain, liver and kidney (65.2-323 ng/g). The cause of death was deemed as central nervous system (CNS) and respiratory depression with agonal aspiration of stomach contents, in the setting of a multiple drug intake. Given the concentration levels of the co-consumed CNS depressants, the contribution of flualprazolam to the death was considered likely (TSS of 3). CONCLUSIONS: Our results support that highly potent DBZDs like flualprazolam carry an elevated risk for unintended toxicity, especially in association with other CNS depressants. A multidisciplinary evaluation of fatalities remains mandatory, especially when pharmacological/toxicological data on intoxicating compounds are lacking. To our knowledge this is the first report of flualprazolam concentrations in solid tissues in human.

Pattern of novel psychoactive substance use among patients presented to the poison control centre of Ain Shams University Hospitals, Egypt: A cross-sectional study.

Background: Novel psychoactive substances (NPSs) are relatively new substances in the illicit drug market, not previously listed in the United Nations Office on Drugs and Crime (UNDOC). Strox and Voodoo are considered some of the most popular blends of NPS in the Egyptian drug market. Objectives: The current study was conducted to assess NPS's use pattern: Voodoo and Strox among acutely intoxicated patients presented to the poison control center of Ain Shams University Hospitals (PCC- ASUH). Methods: A single center based cross-sectional study was carried out in the PCC-ASUH among acutely intoxicated patients presenting to the emergency department (ED) over four months (from January-April 2019. using a previously adopted and validated Fahmy and El-Sherbini socioeconomic scale (SES). Data were presented as mean, median and range as appropriate. Both smoking and crowding indexes were calculated and presented as previously reported. Results: Fifty-one patients were presented to the ED of PCC-ASUH during the study period. A total of 96.1% (n = 49) were males. The mean age was 25 ± 7.5 years. The most common NPS used was Strox: 54.9% (n = 28), followed by Voodoo: 27.4% (n = 14). Neurological and gastrointestinal (GI) symptoms were the most frequent presentations. The most common motive behind NPS use was the desire to give a trial of new psychoactive substances. The mean SES score was 35.1 ± 13.17. Most patients have the preparatory as the highest education 36.0% (n = 18). Conclusions: NPS use is common among young males in preparatory education from different social classes, starting it most commonly as a means to experiencing a new high. Neurological and GI manifestations are the most common presenting symptoms of NPS intoxication.

The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides.

BACKGROUND: Novel psychedelics (NPs) are an expanding set of compounds, presenting new challenges for drug policy and opportunities for clinical research. Unlike their classical derivatives, little is known regarding their use profiles or their subjective effects. AIMS: The purpose of this study was to compile usage patterns and adverse event rates for individual NPs belonging to each of three main psychedelic structural families. Targeting the most widely used representatives for each class, we expanded on their phenomenological distinctions. METHODS: A two-part survey was employed. We investigated the prevalence of novel phenethylamines, tryptamine and lysergamides in NP users (N = 1180), contrasting the type and incidence of adverse events (AEs) using a set of logistic regressions. Honing in on 2-4-Bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) (48.6%), 1-propionyl-lysergic acid diethylamide (1P-LSD) (34.2%) and 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) (23.1%), we examined their phenomenological separability using a gradient boosting (XGBoost) supervised classifier. RESULTS: Novel phenethylamines had the highest prevalence of use (61.5%) seconded by tryptamines (43.8%) and lysergamides (42.9%). Usage patterns were identified for 32 different compounds, demonstrating variable dosages, durations and a common oral route of administration. Compared to phenethylamines, the odds for tryptamines and lysergamides users were significantly less for overall physical AEs. No significant differences in overall psychological AEs were found. Overall model area under the curve (AUC) stood at 0.79 with sensitivity (50.0%) and specificity (60.0%) for 2C-B ranking lowest. CONCLUSION: NP classes may hold distinct AE rates and phenomenology, the latter potentially clouded by the subjective nature of these experiences. Further targeted research is warranted.

Biomarkers of 4-hydroxy-N,N-methylpropyltryptamine (4-OH-MPT) intake identified from human hepatocyte incubations.

BACKGROUND: 4-Hydroxy-N,N-methylpropyltryptamine (4-OH-MPT) is a psychedelic tryptamine whose use is regulated in several countries. Due to unspecific effects, consumption can be ascertained only through toxicological analyses. However, the trace amounts of tryptamines are usually challenging to detect in biological samples. 4-OH-MPT metabolism was characterized to identify optimal metabolite markers of intake in clinical/forensic toxicology. RESEARCH DESIGN AND METHODS: 4-OH-MPT was incubated with 10-donor-pooled human hepatocytes to simulate in vivo conditions; samples were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and data were processed with Compound Discoverer from Thermo Scientific. LC-HRMS/MS and data mining were supported by in silico metabolite predictions (GLORYx). RESULTS: Three phase I and four phase II metabolites were identified, including N-oxidation and N-demethylation at the alkylamine chain, and O-glucuronidation and sulfation at the hydroxylindole core. CONCLUSIONS: 4-OH-MPT metabolic fate was consistent with the human metabolism of tryptamine analogues: we suggest 4-OH-MPT-N-oxide and 4-hydroxy-N,N-propyltryptamine (4-OH-PT) as metabolite biomarkers of 4-OH-MPT consumption after glucuronide/sulfate hydrolysis in biological samples to improve detection of 4-OH-MPT and phase I metabolites; 4-OH-MPT-glucuronide is suggested as an additional biomarker when hydrolysis is not performed. Further research on the metabolism of structural analogues is necessary to evaluate the specificity of 4-OH-MPT metabolite biomarkers.

Synthetic Cannabinoid-Related Deaths in England, 2012-2019.

Aim: To identify drug-related death trends associated with synthetic cannabinoid receptor agonists (SCRAs) reported to the National Programme on Substance Abuse Deaths (NPSAD) from England. Design: Case reports from NPSAD (England) where a SCRA was detected in post-mortem tissue(s) and/or implicated in the death were extracted, analyzed, and compared against non-SCRA-related deaths that occurred over the same time period (2012-2019). Findings: One hundred sixty-five death SCRA-related reports were extracted, with 18 different SCRAs detected. Following the first death in 2012, a subsequent sharp increase in reporting is evident. Acute SCRA use was the underlying cause of death in the majority of cases (75.8%) with cardiorespiratory complications the most frequently cited underlying physiological cause (13.4%). SCRA users were predominantly found dead (68.6%), with a large proportion of those witnessed becoming unresponsive described as suddenly collapsing (81.6%). Psychoactive polydrug use was detected in 90.3% of cases, with alcohol the most commonly co-detected (50.3%), followed by opioids (42.2%), benzodiazepines/Z-drugs (32.1%), stimulants (32.1%, [28.5% cocaine]), and cannabis (24.8%). Compared to all non-SCRA-related NPSAD deaths occurring over the same time period, SCRA-related decedents were more predominantly male (90.3% vs. 72.0%; p<0.01), and lived in more deprived areas (p<0.01). While a comparatively significant proportion of decedents were homeless (19.4% vs. 4.1%), living in a hostel (13.3% vs. 2.3%) or in prison (4.9% vs. 0.2%) at time of death (all p<0.01), the greatest majority of SCRA-related decedents were living in private residential accommodations (57.6%). Conclusions: This is the largest dataset regarding SCRA-related mortalities reported to date. Reporting of SCRA-related deaths in England have increased considerably, with polydrug use a specific concern. Lack of effective deterrents to SCRA use under current UK legislation, compounded by limited knowledge regarding the physiological impacts of SCRA consumption and their interaction with other co-administered substances are contributory factors to the occurrence of SCRA-related mortalities in an increasingly deprived demographic.

Mephentermine Misuse: An Impending Crisis among Sportspersons.

Mephentermine is a sympathomimetic amine, frequently used as a vasopressor. It is structurally comparable to amphetamines, and World Anti-Doping Agency has prohibited its use as a performance-enhancing drug. However, its illegal consumption by several sportspersons and those appearing for physical endurance tests is a growing concern for health-care professionals. We present a case of misuse of intravenous mephentermine by a young male who abruptly increased its amount a few days prior to the sports competition and developed acute psychosis. The case report highlights the need for strict regulations for procuring methamphetamine and effective treatment strategies for managing its misuse.

Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents.

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (Emax 12.5 mg/kg; i.p.) compared to methamphetamine (Emax 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC50 = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC50 > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.

Qua-Alluding to the Past: A Case of Methaqualone Analog Ingestion.

Methaqualone, known previously under the brand name Quaalude, is a Schedule I sedative hypnotic drug that may cause neurotoxicity in overdose, characterized by somnolence, hyperreflexia and muscular hyperactivity. We present a case of a 21-year-old male who reportedly ingested methaqualone in addition to insufflation of street cocaine. He subsequently developed hypoxia, hyperreflexia, myoclonus, and altered mental status. His laboratory results were notable for the presence of methemoglobinemia, which was most likely due to a cocaine contaminant. Laboratory analysis of the alleged methaqualone pills identified the substance as SL-164, a dichlorinated methaqualone analog. Urine toxicology results were positive for SL-164 (and presumed metabolites) as well as for cocaine and tetrahydrocannabinol metabolites. The patient was treated with supplemental oxygen and a benzodiazepine (lorazepam) and observed in the Emergency Department (ED) until his symptoms resolved. This case highlights current community access to methaqualone analogs. The case also focuses on laboratory techniques used to identify the methaqualone analog.

The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative.

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02-8.7 µM) and NET inhibitors (IC50 = 0.03-4.6 µM), and exhibited no SERT activity at concentrations < 10 µM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17-0.18 µM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264-356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.

Deaths from novel psychoactive substances in England, Wales and Northern Ireland: Evaluating the impact of the UK psychoactive substances act 2016.

BACKGROUND: 'Legal highs' began appearing in the UK in the mid-2000s. Whilst many of these substances were controlled under the 1971 Misuse of Drugs Act, novel compounds and new variants of controlled compounds were continuously being introduced to the recreational drug market. The Psychoactive Substances Act (PSA) was therefore implemented in 2016 as a blanket ban on all novel psychoactive substances (NPS). AIM: To evaluate the impact of the PSA on deaths following NPS use in England, Wales and Northern Ireland. METHODS: Cases reported to the National Programme on Substance Abuse Deaths where death had occurred 3 years pre- or post-implementation of the PSA were extracted. Cases with NPS detected at post-mortem were analysed and compared against cases non-NPS cases. RESULTS: 293 deaths with NPS detected were identified; 91 occurring before the PSA and 202 afterwards, indicating an 222.0% post-PSA increase. Contrastingly, non-NPS drug-related death case reporting increased by only 8.0%. Synthetic cannabinoid, anxiolytic/sedative and stimulant NPS were detected in the largest proportions of deaths pre-PSA; post-PSA stimulant NPS detections reduced whilst synthetic cannabinoid and anxiolytic/sedative detections increased.Post-PSA, average decedent age increased significantly (mean age pre-PSA 34.4 ± 10.8 vs post-PSA 38.3 ± 9.4), and they were significantly more likely to have been living in deprived areas (pre-PSA 50.0% vs post-PSA 65.9%). CONCLUSIONS: Reporting of deaths following NPS use has risen despite introduction of the PSA. Whilst deaths amongst younger individuals and those living in more affluent areas has reduced, additional approaches to prohibition are needed to curb their persistence in deprived demographics.

Naphyrone (naphthylpyrovalerone): Pharmacokinetics, behavioural effects and thermoregulation in Wistar rats.

Naphthylpyrovalerone (naphyrone) is a pyrovalerone cathinone that potently inhibits monoamine transporters and provides stimulatory-entactogenic effects. Little is known about the safety of naphyrone or its effects in vivo, and more research is needed to acquire knowledge about its fundamental effects on physiology and behaviour. Our objective was to investigate naphyrone's pharmacokinetics, acute toxicity, hyperthermic potential and stimulatory and psychotomimetic properties in vivo in male Wistar rats. Pharmacokinetics after 1 mg/kg subcutaneous (sc.) naphyrone were measured over 6 h in serum, the brain, liver and lungs. Rectal temperature (degree Celsius) was measured over 10 h in group-versus individually housed rats after 20 mg/kg sc. In the behavioural experiments, 5, 10 or 20 mg/kg of naphyrone was administered 15 or 60 min prior to testing. Stimulation was assessed in the open field, and sensorimotor processing in a prepulse inhibition (PPI) task. Peak concentrations of naphyrone in serum and tissue were reached at 30 min, with a long-lasting elevation in the brain/serum ratio, consistent with observations of lasting hyperlocomotion in the open field and modest increases in body temperature. Administration of 20 mg/kg transiently enhanced PPI. Naphyrone crosses the blood-brain barrier rapidly and is eliminated slowly, and its long-lasting effects correspond to its pharmacokinetics. No specific signs of acute toxicity were observed; therefore, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.

Synthetic cannabis: adverse events reported to the New Zealand Pharmacovigilance Centre.

INTRODUCTION: Synthetic Cannabinoid Receptor Agonists (SCRA) were legally available in New Zealand (NZ) prior to May 2014. During the period November 2012-November 2019, reports of adverse events associated with SCRA use from across the country were submitted to the New Zealand Pharmacovigilance Centre (NZPhvC). The purpose of this study was to investigate adverse reactions associated with SCRA reported to the NZPhvC. METHODS: The NZPhvC database was searched for adverse events involving SCRA. Cases were extracted and analysed for demographic information of users, reactions reported and SCRA involved. Summary statistics were performed using SAS 9.3. RESULTS: One hundred and thirteen cases were identified from 1 November 2012 to 31 November 2019, comprising 81 males (71.7%) and 32 females (28.3%), with a mean age of 28.4 ± 10.1 years. Ethnicity included European (51.3%, n = 58), Maori (39.8%, n = 45), Indian (1.8%, n = 2), and Polynesian (0.9%, n = 1). There were a total of 327 reactions recorded in these cases, and the majority were psychiatric (52%, n = 170), followed by nervous system (11%, n = 35), alimentary (7%, n = 24), and cardiovascular (7%, n = 23). Where the compounds could be identified, the majority of events involved AB-FUBINACA (n = 18), 5 F-PB-22 (n = 17), and PB-22 (n = 6). CONCLUSIONS: This study found that young, male and European populations frequently were involved in SCRA adverse events. A disproportionate number of Maori were present in this group. Psychiatric reactions were of clinical significance, and possibly correlated to the high potency and efficacy of SCRA compared to cannabis. Pharmacovigilance is a useful tool to measure and monitor illicit drug use, and with appropriate infrastructure and capacity has the potential to contribute to drug policy at a national level.

Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations.

For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto the market. However, the detection of SC metabolites is often critical in order to prove consumption in clinical and forensic settings. In this research, the metabolite profile of two pyrrolidinyl SCs, α-pyrrolidinohexaphenone (α-PHP) and 4''-fluoro-α-pyrrolidinovalerophenone (4F-α-PVP), were characterized to identify optimal intake markers. Experiments were conducted using pooled human hepatocyte incubations followed by liquid chromatography-high-resolution tandem mass spectrometry and data-mining software. We suggest α-PHP dihydroxy-pyrrolidinyl, α-PHP hexanol, α-PHP 2'-keto-pyrrolidinyl-hexanol, and α-PHP 2'-keto-pyrrolidinyl as markers of α-PHP use, and 4F-α-PVP dihydroxy-pyrrolidinyl, 4F-α-PVP hexanol, 4F-α-PVP 2'-keto-pyrrolidinyl-hexanol, and 4F-α-PVP 2'-keto-pyrrolidinyl as markers of 4F-α-PVP use. These results represent the first data available on 4F-α-PVP metabolism. The metabolic fate of α-PHP was previously studied using human liver microsomes and urine samples from α-PHP users. We identified an additional major metabolite (α-PHP dihydroxy-pyrrolidinyl) that might be crucial for documenting exposure to α-PHP. Further experiments with suitable analytical standards, which are yet to be synthesized, and authentic specimens should be conducted to confirm these results.

Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents.

BACKGROUND: Recently, the recreational use of substituted phenethylamines has grown rapidly. Among these are 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD). However, studies characterizing their abuse potential are still lacking. AIM: The purpose of this study was to investigate the abuse potential of MAL and BOD. METHODS: The psychostimulant, reinforcing, and rewarding properties of MAL and BOD were analyzed using locomotor sensitization, self-administration, and conditioned place preference tests. Dopamine antagonists (i.e. SCH23390, haloperidol) were administered during conditioned place preference to evaluate the involvement of the mesolimbic dopamine system. Furthermore, dopamine-related protein expression in the nucleus accumbens and the ventral tegmental area was measured along with dopamine concentrations in the nucleus accumbens. Electroencephalography was conducted to determine effects of MAL and BOD on brain wave activity. RESULTS: MAL induced psychostimulant effects and sensitization, while BOD induced locomotor depression in mice. Only MAL was self-administered by rats. Both drugs induced conditioned place preference in mice at different doses; dopamine receptor antagonists blocked MAL- and BOD-induced conditioned place preference. Both the compounds altered the expression of dopamine receptor D1 and D2 proteins in the nucleus accumbens and tyrosine hydroxylase (TH) and dopamine transporter in the ventral tegmental area, enhanced dopamine levels in the nucleus accumbens, and increased delta and gamma wave activities in the brain. CONCLUSIONS: MAL may induce abuse potential via the mesolimbic dopaminergic system and possibly accompanied by alterations in brain wave activity. Moreover, the lack of rewarding and reinforcing effects in BOD suggest that this drug may have little to no capability to engender compulsive behavior, though having found to induce alterations in dopaminergic system and brain wave activities.

The characteristics and outcomes of toxin-induced massive rhabdomyolysis.

OBJECTIVES: This study investigates common patterns in patients with exceptionally high creatine kinase (CK) levels to identify factors that could have contributed to the development of severe rhabdomyolysis in the studied cohort. MATERIAL AND METHODS: The authors present a retrospective analysis of patients with massive rhabdomyolysis (measured CK activity >50 000 U/l) caused by xenobiotics. The patients were selected from a group of 7708 patients treated at the Regional Toxicological Center. RESULTS: The most frequent causative agents were recreational drugs, sedatives and anti-epileptics. Six patients developed multi-organ failure, including 1 who died. Substance abuse disorder was diagnosed in 90% of the patients. Each patient had at least 1 contributory factor present (hypothermia, hyperthermia, injury, an episode of agitation, seizures, prolonged immobilization), and the median was 3 factors. Acute kidney injury was observed in 90% of the patients, and 70% needed renal replacement therapy due to acute renal failure, which meant a longer hospital stay. Creatinine concentration differences between days 2 and 1 of the presentation (Cdiff) correlated with the length of hospital stay (r = 0.73, p = 0.02). All patients with negative Cdiff values did not need dialysis. No patients experienced liver failure. CONCLUSIONS: Massive rhabdomyolysis seems to be the effect of coincidence of several factors rather than the myotoxic effect alone. A creatinine concentration difference between days 2 and 1 of hospitalization was a good prognostic factor for the need for further dialysis. Int J Occup Med Environ Health. 2020;33(5):661-73.