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Introduction: Synthetic cannabinoids are currently the largest group of new psychoactive substances. Those that have been subjected to legal control are replaced by newer uncontrolled substances, which causes constant and dynamic changes to the drug market. Some of the most recent synthetic cannabinoids that have appeared on the "legal highs" market are AMB-FUBINACA and EMB-FUBINACA. Case history: A 27-year-old man was found dead on a bed in an apartment. At autopsy, congestion of internal organs, pulmonary oedema and left-sided pleural adhesions were found. The medical examiner concluded that the man died due to acute respiratory failure. The autopsy materials (blood, urine, liver, kidney, stomach, intestine, lung and brain) were collected for further toxicological analyses. Methods: The synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA were isolated from autopsy materials by precipitation with acetonitrile. The quantitative analyses were carried out by LC-MS/MS. Results: AMB-FUBINACA and EMB-FUBINACA were detected and quantified in all post-mortem materials except the blood. The determined concentrations of these compounds in solid tissues were in the range of 0.2-0.9 ng/g and 0.2-3.5 ng/g. The highest concentrations of AMB-FUBINACA and EMB-FUBINACA were revealed in the stomach content (5.8 and 36.2 ng/mL, respectively). Discussion: The presented case demonstrates that even in cases of fatalities, it is possible that the parent substance will not be present in the blood, while being present in other autopsy materials. The determined concentrations of the compounds may indicate oral administration of synthetic cannabinoids. It can also be assumed that AMB-FUBINACA and EMB-FUBINACA probably contributed to death. Conclusion: The presented case shows that synthetic cannabinoids can be undetected in the blood of even seriously or fatally intoxicated people. This situation means that the analysis of only blood samples may not confirm poisoning. The presented case also suggests that AMB-FUBINACA and EMB-FUBINACA use is dangerous to health and may lead to fatal intoxication.

We report a case of intoxication with a mixture of three synthetic cannabinoids and a synthetic cathinone, which have been disclosed by a highly sensitive progressing technology. A man was found dead, and his forensic autopsy was performed at our department. After further examinations of his specimens, EAM-2201 and α-PVP have been newly found in his lung. The concentrations of EAM-2201 have not been reported yet in any authentic human specimens although its existence (not quantified) in blood was reported in 2015. Therefore, a sensitive quantitation method of these compounds in blood and solid tissues has been devised using the sensitive instrument. The limits of detection of these compounds were in the range of 3-10 pg/ml with their quantification range of 10-1000 pg/ml in blood. The femoral vein blood levels of EAM-2201 and AB-PINACA were 56.6 ± 4.2 and 12.6 ± 0.1 pg/ml, respectively, and AB-FUBINACA could be detected but not quantifiable in the blood specimens; α-PVP could not be detected. The standard addition method was employed for the quantification of these compounds in the lung, liver and kidney specimens. The lung levels of EAM-2201, AB-PINACA, AB-FUBINACA and α-PVP were 348 ± 34, 355 ± 30, 124 ± 12 and 59.0 ± 7.4 pg/g, respectively. In conclusion, in this study, the concentrations of EAM-2201 in authentic human specimens including blood and solid tissues and those of AB-PINACA and AB-FUBINACA in solid tissue specimens were quantified for the first time to our knowledge., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: In 2014, the "European Monitoring Centre for Drugs and Drug Addiction" (EMCDDA) reported on 30 novel synthetic cannabinoids (SCs). Among these were indole- and indazole-based valine derivatives with a cyclohexylmethyl side chain (e.g., AB-CHMINACA and MDMB-CHMICA), which represent a new class of SCs., Methods: A prospective observational study of patients treated in emergency departments (EDs) after the intake of SCs was conducted. Clinical and laboratory data were combined and reported to a poison control centre. Serum and/or urine samples of ED patients were analyzed using LC-MS/MS., Results: Forty four patients (39 male, five female, 12-48 years) were included. AB-CHMINACA (MDMB-CHMICA) was identified in 20 (19) serum samples, and in 21 (25) urine samples, respectively. In 19 of the cases, more than one SC was present. Other psychoactive substances (mainly amfetamines) were identified in seven cases, but in five out of these in urine samples only. Based on the Poison Severity Score, severity of poisoning was minor (4), moderate (31) or severe (9). Most frequently reported neuropsychiatric symptoms were CNS-depression (n = 21, 61%), disorientation (n = 20, 45%), generalized seizures (n = 12, 27%), combativeness (n = 8, 18%) and extreme agitation (n = 7, 16%). Duration of symptoms lasting 24 hours or longer occurred in 15 cases (34%)., Discussion: The prevalence of certain neuropsychiatric symptoms was higher in our study than in former reports after the intake of SCs of the aminoalkylindole-type (first generation) SCs. In addition, severe poisoning and duration of symptoms were also higher., Conclusions: In this study, the valine derivative AB-CHMINACA and the tert-leucine derivative MDMB-CHMICA ("third generation of SCs") seem to be associated with more severe clinical toxicity than was previously reported in patients exposed to earlier generation SCs such as JWH-018. However, this observation needs to be confirmed with a larger cohort of patients with analytically confirmed abuse of third generation SCs. The rapid turnover of SCs on the drug market together with the occurrence of SCs such as AB-CHMINACA and MDMB-CHMICA is alarming, especially because of the unexpectedly high frequency of neuropsychiatric symptoms.

Synthetic cannabinoids (SC), are a novel class of designer drugs which emerged as a drug of abuse in the late 2000's. We report a case series of 6 patients who may have smoked a synthetic cannabinoid product in a remote wilderness setting. They presented with varying degrees of altered mental status, agitation, and seizures. Two were confirmed to have AB-PINACA, ADB-PINACA and their respective pentanoic acid metabolites in biological specimens via liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS). Both compounds had DEA Schedule I classification at the time of case presentation, and 22 SCs are currently temporary or permanent DEA Schedule I. More than 150 SCs are known to date, and new compounds are appearing at a rapid rate on darknet and surface web e-commerce websites, marketed as "research chemicals" or "legal highs." The scale and rapidity of SC evolution make legal control and analytical detection difficult. Nontargeted testing with liquid chromatography high resolution mass spectrometry (LC-HRMS), examining both parent compounds and metabolites, is the ideal method for novel SC identification and confirmation. Due to full agonism at the cannabinoid receptors CB1 and CB2, clinical effects are more severe than marijuana, which is a partial cannabinoid receptor agonist. They include agitated delirium, lethargy and coma, seizures, tachycardia, hypertension, and hallucinations, among other findings. Treatment is primarily symptomatic and aimed at airway protection and control of agitation and seizures. SCs do not appear to be abating anytime soon and require the cooperation of law enforcement, analytical scientists, and clinicians to adequately control. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.', (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Despite widespread use of diverse synthetic cannabinoid (sCB) compounds, the pathophysiology associated with intoxication with many sCB compounds, including AB-CHMINACA, is poorly understood, as is their metabolism and distribution into blood and organs., Case Details: A young man died shortly after ingesting an herb product containing sCB compounds. Toxicological analyses of blood samples revealed high levels of AB-CHMINACA (7.61 ± 0.59 ng/mL) and its metabolites (M2, 56.73 ± 4.16 ng/mL; M4, 2.29 ± 0.14 ng/mL) and trace amounts of 5-fluoro-AMB, FUB-PB-22, and AB-FUBINACA. The autopsy revealed severe pulmonary edema, and histology showed air bubbles in the alveolar effusion, suggesting rapid progression of edema. Low blood levels of N-terminal pro-brain natriuretic peptide excluded cardiogenic pulmonary edema. Histological examination revealed diffuse neuronal (brain) and myocardial (sub-endocardial) hyper-eosinophilia, indicating hypoxic encephalopathy and systemic hypoxemia, respectively., Conclusions: The findings show that AB-CHMINACA induced rapid progression of pulmonary edema resulting in hypoxic encephalopathy and systemic hypoxemia, possibly through severe seizures. The high blood ratio of the M2 metabolite to the parent compound, AB-CHMINACA, demonstrates rapid metabolism. This highlights the usefulness of quantification of M2 in diagnosing AB-CHMINACA intoxication.

Aim of the Study: The aim of this study was to develop and validate a method for the determination of the synthetic cannabinoid AB-CHMINACA in blood, followed by its verification in forensic toxicological practice., Material and Methods: The case of a 41-year-old man admitted to hospital because of scheduled cardiac surgery was discussed. The man died after 12 hours of hospitalization. Based on collected evidence, AB-CHMINACA poisoning was suspected. The identification and determination of AB-CHMINACA in the man's blood was performed by high-performance liquid chromatography coupled with tandem mass spectrometry using electrospray ionization (HPLC-ESI-MS-MS), after prior solid phase extraction., Results: The concentration of AB-CHMINACA determined in the man's blood sample was 0.5 ng/ml., Conclusions: In the interpretation of the case, it was concluded that AB-CHMINACA had no direct effect on the patient's death, the cause of which was ascertained as chronic heart failure secondary to aortic valve disease, decompensated by pneumonia. However, an indirect impact of side effects resulting from the use of synthetic cannabinoids cannot be ruled out. They might have exacerbated the man's disease process leading to sudden cardiac arrest caused by asystole.

We experienced an autopsy case in which the cause of death was judged as poisoning by multiple new psychoactive substances, including AB-CHMINACA, 5-fluoro-AMB and diphenidine [Forensic Toxicol. 33 (2015): 45-53]. Although unchanged AB-CHMINACA could be detected from 8 solid tissues, it could neither be detected from blood nor urine specimens. In this article, we obtained eight kinds of reference standards of AB-CHMINACA metabolites from a commercial source. The AB-CHMINACA metabolites from the urine specimen of the abuser were extracted by a modified QuEChERS method and analyzed by liquid chromatography-tandem mass spectrometry before and after hydrolysis with β-glucuronidase. Among the eight AB-CHMINACA metabolites tested, only 2 metabolites could be identified in the urine specimen of the deceased. After hydrolysis with β-glucuronidase, the concentrations of the two metabolites were not increased, suggesting that the metabolites were not in the conjugated forms. The metabolites detected were 4-hydroxycyclohexylmethyl AB-CHMINACA (M1), followed by N-[[1-(cyclohexylmethyl)-1H-indazol-3-yl]carbonyl]-l-valine (M3). Their concentrations were 52.8 ± 3.44 and 41.3 ± 5.04 ng/ml (n=10) for M1 and M3, respectively. Although there is one preceding report showing the estimations of metabolism of AB-CHMINACA without reference standards, this is the first report dealing with exact identification using reference standards, and quantification of M1 and M3 in an authentic urine specimen., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Compared to other calcium channel blockers (CCBs), overdose with dihydropyridine CCBs are considered relatively benign due to their vascular selectivity. Although not a sustained-release preparation, amlodipine's prolonged duration of effect is concerning following overdose. In addition, angiotensin II receptor blocker blunting of vasoconstrictive and sympathetic compensatory responses could exacerbate calcium channel blocker toxicity. We describe severe toxicity associated with an overdose of amlodipine and valsartan., Case Report: A 75-year-old woman presented to the ED 45 minutes after a witnessed suicidal ingestion of a "handful" of amlodipine and valsartan tablets. Hypotension, which appeared two hours after ingestion, was refractory to crystalloids and colloids, calcium gluconate, epinephrine, norepinephrine, phenylephrine, and vasopressin infusions. High-dose insulin euglycemia (HIE) therapy, and treatment with glucagon and naloxone were successful in improving her hemodynamic status. In this combined overdose, right heart catheterization demonstrated both negative inotropic effects and decreased systemic vascular resistance., Conclusion: Co-ingestion of amlodipine with valsartan produced profound toxicity. Early institution of HIE therapy may be beneficial to reverse these effects.

Introduction: Little data exist on potentially adverse valsartan ingestions reported to poison control centers., Methods: Using adult ingestions of valsartan reported to Texas poison control centers during 2000-2005, I determined the proportion of cases involving serious outcomes for selected variables and evaluated for statistical significance by calculating the rate ratio (RR) and 95% confidence interval (CI)., Results: Thirteen (7%) of 185 total cases involved serious outcomes. Serious outcomes were significantly more likely to occur with a maximum dose 320 mg (RR 9.06, CI 1.30-100.14) or 4 tablets (RR 9.00, CI 2.07-39.11) or where the circumstances of the exposures involved self-harm or malicious intent (RR 17.28, CI 4.98-67.13)., Conclusions: The severity of the medical outcome associated with adult valsartan ingestions depended on the dose and the circumstances of the ingestion. Such information is useful for creating triage guidelines for the management of adult valsartan ingestions.

Valsartan is a strong angiotensin receptor inhibitor specific for the angiotensin I receptor, which has been proven safe and well-tolerated in clinical trials. We were able to confirm its safety and tolerability in a case of high-dose exposure to valsartan with suicidal intention. A 25-year-old, fully conscious, female patient was brought to our hospital by relatives on July 24, 2001, at 9:15 p.m. following intake of a high dose of valsartan. It was established that she had taken 28 Diovan 80 mg tablets (2.24 g) 5 hours before admission to the hospital. Her clinical condition at the time of admission was good and did not deteriorate after admission. During the follow-up, her blood pressure never fell below 90/60 mmHg. The only complaint she had were painful muscle cramps which, with only supportive therapy, disappeared spontaneously over 2 days, and her blood pressure also returned to normal during this period. This report demonstrates the effect/side effect profile of valsartan when taken at a high dose, not achievable in a clinical trial.

A novel cause of mass extinction of fauna close to the (K/T) Boundary is suggested. A large amount of non-protein amino acids (AIB and ISOVAL) has been observed close to this event. It is speculated that these amino acids may be toxic and are responsible for the extinction. The toxicity level is estimated for this suggestion to be true and experimentalists are encouraged to test this level of toxicity for the amino acids.