Clinical and Toxicological Profile of NBOMes: A Systematic Review.

BACKGROUND: NBOMes are a new class of potent hallucinogens widely present in illicit drugs. Little is known about this class of drugs, regarding its detection and clinical manifestations of intoxication. OBJECTIVE: This study aims to enhance care involving NBOMes by reviewing the literature on their clinical manifestations and laboratorydetection. METHODS: A systematic review was performed on the clinical manifestations and laboratory tests of NBOMEs ingestion. Embase, Pubmed, PsycINFO, and Cochrane databases were employed in this analysis. RESULTS: Forty-five articles met the inclusion criteria out of the 2814 nonduplicated studies on the theme. Seventy case reports of intoxication were found in the analyzed articles (64.3% were men and 11.4% were women, mean age of 22.5). The technique most employed for NBOMes identification was chromatography of blood, urine, and oral fluids. Moreover, the studies identified 13 chemical structures differentfrom the NBOMes on their toxicological analyses.According to these studies, most of these drugs were ingested orally-nasal use was the second preferred administration route, followed by intravenous administration. CONCLUSION: Better identification of the clinicalmanifestations and laboratory profile of NBOMes is crucial to the recognition of intoxication as well as to its effective treatment.

Novel psychoactive substances. / Nye psykoaktive stoffer.

There has been a significant increase in the number of new intoxicants on the illegal drugs market globally, also in Norway. The substances are given the name NPS: Novel Psychoactive Substances, and are mainly sold over the Internet. Uncertain dosage of potent substances entails a risk of accidental overdose, and therefore serious intoxication and death. In this article we provide an overview of current knowledge with regard to these substances.

Toxicities associated with NBOMe ingestion-a novel class of potent hallucinogens: a review of the literature.

BACKGROUND: A new class of synthetic hallucinogens called NBOMe has emerged as drugs of abuse. OBJECTIVE: Our aim was to conduct a systematic review of published reports of toxicities associated with NBOMe ingestion. METHODS: We searched PubMed for relevant English-language citations that described adverse effects from analytically confirmed human NBOMe ingestion. Demographic and clinical data were extracted. RESULTS: A total of 10 citations met the criteria for inclusion, representing 20 individual patients. 25I-NBOMe was the most common analogue identified, followed by 25B-NBOMe and 25C-NBOMe. Fatalities were reported in 3 (15%) cases. Of all the patients, 7 (35%) were discharged after a period of observation, whereas 8 (40.0%) required admission to an intensive care unit. The most common adverse effects were agitation (85.0%), tachycardia (85.0%), and hypertension (65.0%). Seizures were reported in 8 (40.0%) patients. The most common abnormalities reported on laboratory tests were elevated level of creatinine kinase (45.0%), leukocytosis (25.0%), and hyperglycemia (20.0%). CONCLUSION: NBOMe ingestion is associated with severe adverse effects. Clinicians need to have a high index of suspicion for NBOMe ingestion in patients reporting the recent use of hallucinogens.

Pathological findings in 2 cases of fatal 25I-NBOMe toxicity.

The research compound 25I-NBOMe, also known as CIMBI-5 or INBMeO, was created in academic laboratories as a potent serotonin 2A receptor agonist. Because of its high affinity and ambiguous legal status, recreational drug enthusiasts have used this compound as a powerful alternative to other hallucinogenic drugs such as lysergic acid diethylamide. We report 2 deaths after 25I-NBOMe ingestion by decedents who attended separate "rave" parties. The first case involved a 21-year-old male who admitted taking "acid" to his friend. A sudden violent rage caused him to flail about, and he subsequently became unresponsive. The postmortem examination revealed numerous external injuries that were consistent with physical aggression. The second case involved a 15-year-old female who was socializing outside a rave party, became ill, and rapidly deteriorated as her friend transported her to the hospital. The postmortem assessment was similar to the first case in that external contusions featured prominently. Comprehensive toxicology screens in both cases revealed only evidence of marijuana use. A deeper analysis using time-of-flight mass spectrometry revealed the presence of 25I-NBOMe, which was further confirmed by tandem-mass spectrometry. The behavior and injuries in these cases reveal a consistent pattern preceding fatal 25I-NBOMe toxicity.

Severe methemoglobinemia and hemolytic anemia from aniline purchased as 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a recreational drug, on the Internet - Oregon, 2011.

In August 2011, two men in Oregon drank a liquid they believed to be 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a psychoactive stimulant used as a recreational drug, after purchasing it on the Internet. Fifteen minutes after ingestion, the men became cyanotic and subsequently were treated for refractory methemoglobinemia and hemolytic anemia. The Oregon Poison Center, Oregon Public Health Division, Drug Enforcement Administration (DEA), and Food and Drug Administration (FDA) jointly investigated to determine the cause of the poisoning and identify other cases. The Oregon Poison Center and Oregon Public Health Division promptly alerted health-care providers and public health agencies and searched for additional cases. DEA confiscated all product remaining in the men's possession, and FDA identified the substance as aniline, an industrial solvent known to cause methemoglobinemia. One patient reported purchasing the substance from the Internet site of a Chinese chemical company. No additional cases were identified by investigators. Purchase of chemicals from unregulated Internet sources poses a serious risk to purchasers from product contamination and substitution.

Fatalities related to new psychoactive substances in Singapore-A case series.

The use of New Psychoactive Substances (NPS) has become a serious global issue with increasing number of reports of their toxicities and fatalities. Likewise, in Singapore, the number of exhibits containing NPS detected had increased 80% from 2011 to 2014. This is a case series of the first four autopsy cases of fatalities due to or related to the use of NPS in Singapore. In one case, we present the first reported case of death due directly to ADB-FUBINACA toxicity (post-mortem blood concentration of 56ng/ml). Another case was due to 25B-NBOMe toxicity (post-mortem blood concentration of 10ng/ml) while the last two cases were deaths related to 5-Fluoro ADB, where the metabolites of the drug were detected.

NBOMe hallucinogenic drug exposures reported to the Danish Poison Information Centre.

INTRODUCTION: N-benzylmethoxy (NBOMe) is a new class of hallucinogenic designer drugs sold on cheap blotter papers. They are potent 5-hydroxytryptamine-2A-receptor agonists, and since their recent entry into the drug market there have been worldwide reports of severe intoxications and even fatalities. This study reviews suspected NBOMe drug exposures reported to the Danish Poison Information Centre (DPIC). METHODS: Data from the DPIC database were extracted, including all enquiries with NBOMe exposures reported from 1 January 2013 to 30 June 2016. The following data were extracted: age, sex, date of exposure, risk assessment, co-exposures, geography and reported symptoms. RESULTS: A total of 43 cases were identified: one in 2013, five in 2014, 32 in 2015 and five in the first six months of 2016. The mean patient age was 21 years (range: 15-34 years) with 32 (74%) male and 11 (26%) female patients. The patients most frequently presented with hallucinations/psychosis (n = 18), tachycardia (n = 18) and agitation (n = 15). A total of 16 patients were admitted with co-exposures to other drugs such as alcohol (n = 9), cannabis (n = 7), amphetamine (n = 5) cocaine (n = 3), benzodiazepines (n = 1) and 3,4-methylenedioxymethamphetamine (n = 1). The cases were distributed evenly across the entire country with only ten cases having a postal address in one of the three major cities of Denmark. CONCLUSIONS: This study has shown a steep and sudden rise in reported NBOMe exposures in Denmark within 3-4 years. Geographical data demonstrate an even distribution throughout the country. However, our results also suggest that the use has started to decline. FUNDING: none. TRIAL REGISTRATION: This study was approved by the Danish Data Protection Agency. (BFH-2016-070/04985).

Mistaking 2C-P for 2C-B: What a Difference a Letter Makes.

2,5-Dimethoxy-4(n)-propylphenethylamine (2C-P) is a synthetic phenethylamine derivative belonging to the large family of the so-called 2C drugs. These compounds can differ significantly in receptor affinity, potency and duration of action, and an important structural difference is the ligand in the 4 position of the phenyl ring, such as propyl in 2C-P or bromine in 2,5-dimethoxy-4-bromophenethylamine (2C-B). The 2C drugs are known for their hallucinogenic properties. We present a case of a 19-year-old male admitted to the emergency department with severe hallucinations, mydriasis, tachycardia, agitation and confusion following the use of a substance sold as 2C-B. By using liquid chromatography-mass spectrometry, the more potent substance 2C-P was detected and quantified. On the basis of two blood sample concentrations, the estimated elimination half-life was 19 h. This case report illustrates and discusses the differences in potency and duration of action of 2C drugs.

Emerging drugs of abuse.

Several new and emerging substances are being diverted for abuse. Most of these emerging abused substances do not cause traditional drug screens to turn positive. The health effects of these substances have not yet been fully elucidated. Health care providers should be aware of the existence of these new abused substances.

Fatal Intoxications with 25B-NBOMe and 25I-NBOMe in Indiana During 2014.

Over the last few years, NBOMe substances have been used either as a legal alternative to lysergic acid diethylamide (LSD) or sold surreptitiously as LSD to unknown users. These NBOMe substances have been detected in blotter papers, powders, capsules and liquids. We report the deaths of two teenage male subjects that were related to 25B-NBOMe and 25I-NBOMe in Indiana during 2014. Samples were extracted via a solvent protein precipitation with acetonitrile and analyzed via ultra-performance liquid chromatography with tandem mass spectrometry. For these two cases, we describe the NBOMe instrumental analysis, toxicological results for postmortem heart blood and urine specimens and the relevant case history and pathological findings at autopsy. In the first case, 25B-NBOMe was detected in postmortem heart blood at 1.59 ng/mL; in the second case, 25I-NBOMe was detected in postmortem heart blood at 19.8 ng/mL. We also review relevant published casework from clinical toxicology and postmortem toxicology in which analytically confirmed 25B-NBOMe and 25I-NBOMe were determined to be causative agents in intoxications or deaths.

[Fatal intoxication with the new designer drug 25C-NBOMe]. / Fatalt forløb efter intoksikation med det nye designerdrug 25C-NBOMe.

This is a case report of a 22-year-old man, who snorted the content of three capsules of the new designer drug 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine). 1-2 hours after the intake he became unconscious with generalized seizures, so he was intubated prehospitally and brought to the local hospital. At admission he had acute renal failure and was severely metabolic acidotic with potassium 8.6 mmol/l, lactate 28 mmol/l and pH 6.69. Despite maximal therapy he died ten hours after admission. 25C-NBOMe is currently legal in most parts of the world, and fatal intoxication with the drug has not yet been described in Scandinavia.

A fatal poisoning involving 25C-NBOMe.

This paper reports on a fatal overdose case involving the potent hallucinogenic drug 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine). In the present case, a young male was hospitalized after the recreational use of this potent drug. He died at the hospital at approximately 12h after ingestion, with preceding signs of serotonin toxicity. Medico-legal autopsy was performed on the deceased, during which time peripheral whole blood, urine, vitreous humor, liver and gastric content samples were submitted for toxicological examination. Further, whole blood collected at the hospital at 2-4h following ingestion of the drug was analyzed. 25C-NBOMe and a demethylated and glucuronidated metabolite of 25C-NBOMe were identified in the urine and blood samples using ultra-performance liquid chromatography with high-resolution time-of-flight mass spectrometry (UPLC-HRTOF-MS). Subsequently, 25C-NBOMe was quantified in the peripheral whole blood (0.60µg/kg), urine (2.93µg/kg), vitreous humor (0.33µg/kg), liver (0.82µg/kg) and gastric content (0.32µg total) samples collected during autopsy and in the ante-mortem whole blood (0.81µg/kg) by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). The autopsy findings were consistent with acute poisoning. Based on the toxicological findings, the cause of death was determined to be a fatal overdose of 25C-NBOMe in combination with amphetamine intake. To our knowledge, the present paper reports the first quantification of 25C-NBOMe in biological specimens from a fatal intoxication case.

Recreational phenethylamine poisonings reported to a French poison control center.

OBJECTIVES: Over the last decade, use of phenethylamines has become increasingly prevalent. This study aimed to describe typical aspects of phenethylamine poisoning in order to better inform patient care. METHODS: Phenethylamine poisoning cases reported to the Poison Control Center of Angers, France, from January, 2007 to December, 2013 were examined. Clinical findings were examined in 105 patients, including phenethylamine used, symptoms and final outcome. Patients were predominantly male (80%), with mean age 26±8 years. RESULTS: MDMA (38%), amphetamine (18%) and methamphetamine (14%) were the most commonly reported. Synthetic cathinones (10%) and the 2C series (7%) were also found. Substances most commonly associated with phenethylamine poisoning were cannabis (27%), ethanol (20%) and cocaine (9%). The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. Of the cases, the Poison Severity Score was: null or low, 66%, moderate, 21%, severe or fatal, 13%. Of the patients, 77% received hospital care and 12.4% were admitted to an intensive care unit. Analytical confirmations were obtained for all severe cases. While 93% of patients recovered, there were 5 deaths and 2 patients presented with neurological sequelae. CONCLUSIONS: Phenethylamine poisonings may be severe in young and healthy individuals. Physicians, toxicologists and analysts should be aware of new phenethylamine consumption trends in order to inform management of patient care and to contribute to a more responsive drug policy.

Prevalence of use and acute toxicity associated with the use of NBOMe drugs.

INTRODUCTION: The 25X-NBOMe series are N-2-methoxybenzyl analogues of the respective 2C-X substituted phenethylamine and include 25B-N(BOMe)2, 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25E-NBOMe, 25G-NBOMe, 25H-NBOMe, 25I-NBOMe, 25N-NBOMe and 25iP-NBOMe. There are reports of their use as novel psychoactive substances and associated acute toxicity from Europe, the United States and elsewhere over the last five years. This review will discuss the epidemiology of use and pattern of acute toxicity associated with use of these compounds. METHODS: A PubMed search was performed using the search terms 'NBOMe', '25B-N(BOMe)2', '25B-NBOMe', '25C-NBOMe', '25D-NBOMe', '25E-NBOMe', '25G-NBOMe', '25H-NBOMe', '25I-NBOMe', '25N-NBOMe' and '25iP-NBOMe' covering the years 1966-2014. In addition, abstracts from the 2010-2014 congresses of the European Association of Poisons Centres and Clinical Toxicologists and the 2010-2013 North American Congress of Clinical Toxicology were reviewed using these search terms. Further information was obtained from the European Information System and Database on New Drugs co-ordinated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). PREVALENCE OF USE: There are no national or international surveys collecting data on the prevalence of use of NBOMe drugs. The only information on prevalence of use is from two sub-population surveys of individuals who frequent nightclubs. Of 22,289 respondents of the 2013 Global Drugs Survey, 582 (2.6%) had previously used an NBOMe; the most commonly used NBOMe was 25I-NBOMe (442 respondents, 2.0% of whole cohort and 75.9% of those who had used an NBOMe). In a survey of 397 clubbers in London nightclubs in 2013, 11.8% had heard of the NBOMe drugs (compared with 96.0% for mephedrone), and 4.8% had ever used an NBOMe (compared with 76.6% for mephedrone). ACUTE TOXICITY: There were 29 published cases in the literature of acute toxicity associated with the use of an NBOMe: 25I-NBOMe - 23 cases; 25B-NBOMe - 3 cases; 25C-NBOMe - 3 cases. Commonly reported features include tachycardia (96.6%), hypertension (62.0%), agitation/aggression (48.2%), seizures (37.9%) and hyperthermia (27.6%). Five patients were reported to have developed acute kidney injury. There were an additional 25 reports of acute toxicity related to the use of 25I-NBOMe reported to the EMCDDA. The pattern of toxicity in these cases is similar to that seen in the published cases. NBOMe-related deaths. 25I-NBOMe has been detected in eight fatalities; in one of these, 25C-NBOMe was also detected. The role of the NBOMe drugs in these deaths has not been determined in all cases. CONCLUSIONS: Currently, there is evidence suggesting limited use of the NBOMe class of drugs as novel psychoactive substances compared with that of classical recreational drugs and other novel psychoactive substances such as mephedrone.

NBOMe and 2C substitute phenylethylamine exposures reported to the National Poison Data System.

BACKGROUND: Hallucinogenic designer drugs, especially NBOMe and the 2C substitute phenylethylamine series, have been increasing ubiquitous in past years. The purpose of this study is to characterize and compare clinical features of NBOMe and 2C exposures in humans. METHOD: This is a retrospective cohort study of all single agent exposures to NBOMe and 2C substitute phenylethlamine reported to the National Poison Data System (NPDS) from 1st September 2012 to 30th September 2014. RESULTS: Over the study period, there were a total 341 cases including 148 NBOMe exposures and 193 2C exposures. The majority cases involved men (73.9%); median age was 18 years (Interquartile-range, 16-21). Similar clinical effects were reported in both groups including tachycardia (45.2%), agitation/irritable (44.3%), hallucination/delusion (32.0%), confusion (19.1%) and hypertension (18.5%). There were higher incidences of hallucination/delusion, single episode seizure and benzodiazepine administration in NBOMe exposures (40.5%, 8.8% and 50.0%respectively) than those of 2C exposures (25.4%, 3.1%, and 32.6% respectively). There were 2.3% death; no difference between two groups. DISCUSSION: The higher rate of symptoms in NBOMe is consistent with the higher 5HT2A agonistic effects of NBOMe described in both molecular and animal studies. CONCLUSION: Common clinical effects of NBOMe and 2C exposures were tachycardia, agitation/irritable, hallucination/delusion, confusion, and hypertension. There were higher incidences of hallucination/delusion, single episode seizure and benzodiazepine administration in NBOMe.

Evolution of the NBOMes: 25C- and 25B- Sold as 25I-NBOMe.

INTRODUCTION: The NBOMes (N-benzyl-oxy-methyl derivatives of known 2C phenylethylamines) are a new and growing class of potent synthetic stimulants. Case reports provide the bulk of available safety and clinical data for clinicians. We report two cases of NBOMe intoxication with 25C-NBOMe (the first lab-confirmed US case) and 25B-NBOMe, respectively, both confirmed via triple quadrapole mass spectrometry. CASE REPORTS: Case 1: A 16-year-old girl had a generalized seizure after reported use of 25I-NBOMe. She presented with altered mental status, lower extremity rigidity, and elevated CPK (6042 U/L). Despite treatment with benzodiazepines, her lower extremity rigidity persisted and CPK peaked at 47,906 U/L. She was discharged on hospital day 8. Serum and urine specimens confirmed presence of 25C-NBOMe. Case 2: A 15-year-old boy developed bizarre behavior after reported use of 25I-NBOMe. In the ED, he had two generalized seizures and persistent muscle rigidity. CPK peaked at 429 U/L. Seizures were managed with benzodiazepines, and he was discharged within 24 h. Serum specimens revealed 25B-NBOMe. DISCUSSION: NBOMes are amphetamine derivatives and highly potent 5-HT(2A) receptor agonists. Clinical manifestations are a product of enhanced central sympathetic and serotonergic tone. We report two cases of NBOMe intoxication in patients who believed they used 25I-NBOME, while lab confirmation proved otherwise. Whether unique clinical manifestations are specific to the NBOMe variant, dose, route of administration, or other factors is unknown. Laboratory confirmation may play a role in identifying unexpected NBOMe variants, while contributing to the epidemiologic data on these novel substances.

Postmortem identification and quantitation of 2,5-dimethoxy-4-n-propylthiophenethylamine using GC-MSD and GC-NPD.

2,5-Dimethoxy-4-n-propylthiophenethylamine (2C-T-7) has structural and pharmacodynamic similarities to methylenedioxymethamphetamine (MDMA). This compound was initially identified from a routine screening procedure in postmortem urine from a 20-year-old male that died in a local emergency room after reportedly insufflating 35 mg. This report describes the development of a quantitative method for 2C-T-7. A number of method parameters were studied including internal standard selection, liquid-liquid extraction scheme, and drug stability in preserved refrigerated blood. The adopted method for blood and urine involves the addition of trimethoxyamphetamine (TMA) as internal standard, alkalinization with ammonium hydroxide, and liquid-liquid extraction with n-chlorobutane. To facilitate recovery from liver, a 1:4 aqueous homogenate was pretreated with dilute perchloric acid, centrifuged, and the supernatant was extracted as previously described. In each case, 0.1% hydrochloric acid in methanol was added during the final concentration step to prevent loss of drug caused by evaporation. Samples were analyzed by gas chromatography with nitrogen-phosphorus detection (GC-NPD) and electron ionization GC-mass spectrometry (MS) utilizing selected ion monitoring. For the GC-MS analysis, the characteristic ions monitored for 2C-T-7 were m/z 226, 255, and 183 and for TMA, m/z 182. The limits of detection and quantitation in blood were 6.0 and 15.6 ng/mL, respectively, by both GC-NPD and GC-MS. The results from the postmortem case were as follows: heart blood, 57 ng/mL; femoral blood, 100 ng/mL; urine, 1120 ng/mL; and liver, 854 ng/g.

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions.

The use of mushrooms containing the hallucinogenic substance psilocybin for intentional intoxication is relatively common. Occasionally, this results in adverse reactions with typical tachycardia that is not evidently caused by psilocybin. This study demonstrates the presence of phenylethylamine in the species Psilocybe semilanceata using gas chromatography-mass spectrometry and shows that the amount of this substance may vary much more than that of psilocybin. The highest amount of phenylethylamine (146 microg/g wet weight) was observed in mushrooms from a case of three young men hospitalized because of adverse reactions. Comparison of the symptoms observed in clinical cases of magic mushroom intoxication with those after intake of pure psilocybin or phenylethylamine suggests that phenylethylamine might have a role in the development of adverse reactions to Psilocybe mushroom intake.

Quantitative determination of amphetamine and alpha-phenylethylamine enantiomers in judicial samples using capillary gas chromatography.

alpha-Phenylethylamine was recently reported by us in various samples seized from the illicit drug circuit. At first, alpha-phenylethylamine was identified in powders that generally contained amphetamine and caffeine. Then, a couple, who were known drug users, was found dead in their apartment. Urine samples from both victims contained large amounts of amphetamine and alpha-phenylethylamine. All of the positive samples were re-examined with gas chromatography to determine the chirality of the detected drug or drugs. The homochiral derivatizing reagent N-trifluoroacetyl-L-prolyl chloride was used to convert the drug enantiomers into their corresponding diastereomeric derivatives. These derivatives were separated on an achiral stationary phase and detected using either flame ionization detection (FID) or on-line Fourier-transform infrared spectrometry (FTIR) for quantitative or qualitative purposes, respectively. Excellent separation was realized between all diastereomeric derivatives, and interference of excess, nonvolatile derivatizing reagent was reduced to a minimum. All powder samples consisted of racemic mixtures for alpha-phenylethylamine and for amphetamine. The urine samples also contained both enantiomers of alpha-phenyl ethylamine and amphetamine, albeit in varying proportions. These findings again substantiate the synthetic origin of alpha-phenylethylamine, attributing its presence in the urine of both victims to intentional or accidental intake. The disproportionate isomeric composition found in the urine samples confirms previous reports of a stereoselective metabolism for amphetamine enantiomers and suggests a similar pharmacokinetic profile for alpha-phenylethylamine.

Adverse effects of the use of unusual phenethylamine compounds sold as illicit amphetamine.

A 40-year-old man, who had regularly taken illicit amphetamine by intra-nasal inhalation for several years without ill effects, was admitted to hospital with signs of massive adrenergic overstimulation shortly after inhaling material which he had purchased in the belief that it was amphetamine. The administration of the beta-blocker practolol produced a paradoxical increase in blood pressure. After his discharge from hospital he suffered disabling feelings of anxiety for several weeks. Analysis of a sample of the material showed it to contain p-methyl amphetamine and N, p-dimethyl amphetamine.