The Clinical Toxicology of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B): The Severity of Poisoning After Exposure to Low to Moderate and High Doses.

STUDY OBJECTIVE: We studied the severity of poisoning after exposure to low to moderate and high doses of 4-bromo-2,5-dimethoxyphenethylamine (2C-B). METHODS: Patients for whom the Dutch Poisons Information Centre was consulted for 2C-B exposure from 2016 to 2018 were included in a prospective cohort study. Data were collected through telephone interviews with the physician or patient. Patients were categorized according to the reported 2C-B dose: low to moderate (up to 20 mg), high (greater than 20 mg), or unknown. Presence of 2C-B was analyzed in leftover drug and biological samples with liquid/gas chromatography-mass spectrometry. The severity of poisoning was graded with the Poisoning Severity Score. RESULTS: We included 59 patients, of whom 32 could be followed up. Low to moderate 2C-B doses were reported by 9 patients (28%), high doses by 17 (53%), and unknown doses by 6 (19%). Poisoning was moderate in the majority of patients in both the low- to moderate-dose and high-dose groups. Frequently reported symptoms included mydriasis, agitation or aggression, hallucinations, confusion, anxiety, hypertension, and tachycardia. The presence of 2C-B was confirmed in 5 patients in urine (n=3) or drug samples (n=4). CONCLUSION: In this study, most 2C-B poisonings resulted in moderate toxicity even at high reported doses up to 192 mg. No severe cases were observed. The clinical course was usually short-lived (up to 24 hours) and typically involved hallucinations in addition to mild somatic effects.

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.

Severe poisoning after self-reported use of 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, a novel substituted amphetamine: a case series.

Significant toxicity from amphetamine and cathinone derivatives is being increasingly reported. We describe a series of self-reported exposures to 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25-I-NBOME or 25-I), a novel amphetamine derivative. Ten patients with an average age of 17 years presented to local emergency departments (EDs) in our community after ingestion and/or insufflation of a drug referred to as "25-I." Of 10 patients, 6 reported taking 25-I alone; other substances included ethanol; 2,5-dimethoxy-4-ethylphenethylamine; marijuana; and ketamine. Most common effects included tachycardia (90%), hypertension (70%), agitation (60%), and hallucinations (50%). The average heart rate was 123 beats per minute. Two patients were found in status epilepticus, and another was found unresponsive. One patient who had a seizure had multiple, discrete intraparenchymal hemorrhages and acute kidney injury. Six patients were admitted to the intensive care unit, two were treated in the ED and released, and 1 each was admitted to psychiatry or managed in a clinical decision unit and subsequently discharged. Three patients required emergent intubation, and all admitted patients (7/10) were given intravenous benzodiazepines for sedation. Urine and blood specimens were obtained from 1 patient, which showed analytic confirmation of 25-I. In addition to sympathomimetic effects, methoxy and other substituent groups impart serotonergic effects, resulting in hallucinogenic properties. 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine appears to be extremely potent with a reported "dose" of 500 µg resulting in increased potential for inadvertent overdose. This case series describes significant morbidity in a local cluster of young patients after self-reported use of 25-I, a newly identified drug of abuse.

The electric Kool-Aid NBOMe test: LC-TOF/MS confirmed 2C-C-NBOMe (25C) intoxication at Burning Man.

Designer drugs are constantly evolving, with the NBOMe derivatives of the 2C class of phenethylamines recently emerging in the US market. Cases of 2C-I-NBOMe toxicity have recently been reported in the literature. No reports to date describe the clinical effects 2C-C-NBOMe toxicity.

"My friend said it was good LSD": a suicide attempt following analytically confirmed 25I-NBOMe ingestion.

A new class of synthetic hallucinogens called NBOMe has emerged, and reports of adverse effects are beginning to appear. We report on a case of a suicide attempt after LSD ingestion which was analytically determined to be 25I-NBOMe instead. Clinicians need to have a high index of suspicion for possible NBOMe ingestion in patients reporting the recent use of LSD or other hallucinogens.

Severe clinical toxicity caused by 25I-NBOMe confirmed analytically using LC-MS-MS method.

Rhabdomyolysis is a relatively rare, but potentially serious complication of various diseases. Muscular injury and resultant release of electrolytes, myoglobin and other enzymatic proteins e.g. creatine kinase (CK) into circulation may result in multi-organ failure requiring an extensive treatment. Non-traumatic causes of rhabdomyolysis, like poisonings, appear to be much more frequent than traumatic causes. We present the case of a patient who developed exceptionally massive rhabdomyolysis, with CK up to 516 455 U/l, after ingestion of a relatively small dose of a novel psychoactive substance known as "Alice in Wonderland". Laboratory quantification was performed using a validated LC-MS/MS method in a whole blood sample.

Bad trip due to 25I-NBOMe: a case report from the EU project SPICE II plus.

OBJECTIVE: The potent hallucinogenic drug 25I-NBOMe has recently emerged on the drug market. We present a case with analytically confirmed 25I-NBOMe intoxication from the prospective study "SPICE II Plus". CASE REPORT: Because of a severe headache a 42-year-old man took one sip of a pediatric analgesic syrup, which had been refilled with a self-made solution of 25I-NBOMe in ethanol. Thirty minutes later restlessness occurred. On arrival in the emergency department mydriasis, strong sweating, disorientation, and agitation were noticed. Within short time the patient developed severe agitation, coenesthesia, and complex hallucinations. In blood serum samples obtained at admission revealed the presence of 25I-NBOMe (34 ng/mL), 2C-I (12 ng/mL) and 25I-NBOH (<1 ng/mL) (LC-ESI-MS/MS). The presumed analgesic syrup contained 25I-NBOMe (2800 µg/mL), and besides ethanol no other compounds were detected. After six hours, the symptoms resolved without further complications. CONCLUSIONS: This is a unique case of an analytically confirmed, accidental ingestion of 25I-NBOMe in a drug naïve adult. The finding of 2C-I in the serum sample 50 minutes after intake indicates a fast metabolic breakdown of 25I-NBOMe due to first-pass metabolism.

Retrospective Demonstration of 25I-NBOMe Acute Poisoning Using Hair Analysis.

BACKGROUND: The abuse of new psychoactive substances or NPS has been dramatically increasing all around the world since the last half of the year 2000 and has become a serious public health problem. NPS are a challenge for the worldwide forensic community due to the difficulties to accurately document the cases. The N-benzylmethoxy (NBOMe) group is a new class of hallucinogenic designer drugs and has gained importance in recent years. 25I-NBOMe (2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)- methyl]ethanamine) is an analog of the 2C series of psychedelic phenethylamine drugs that contain an N-methoxybenzyl substituent, which significantly affects their pharmacological activities. It is a potent agonist of 5-HTA receptors and a severe hallucinogenic drug, with numerous irreversible psychedelic effects which can last from 5 to 10 hours. It is consumed most often in the form of drops or blotters by the transmucosal, sublingual or intranasal routes. The active dosage is very low, supposed to be less than 100 µg. The literature is poor in reporting cases where 25I-NBOMe was identified. Only very few clinical cases of over dosages were published, suggesting a low prevalence of this compound. METHODS: We present a retrospective demonstration of 25I-NBOMe acute poisoning with dramatic outcome, using hair analysis. Two hair strands, measuring 9.5 cm, were collected 6.5 months after drug consumption during a forensic clinical evaluation of brain dysfunctions after cardiorespiratory arrest and were analyzed by ultra-high performance liquid chromatography system coupled to a tandem mass spectrometry (UPLC-MS/MS) and using two specific transitions: m/z 428.1 > 121.2 (quantification) and 428.1 > 90.6 (confirmation). Hair strands were segmented to determine the historic pattern of drug use and differentiate a single exposure from a chronic exposure. The hair test result for 25I-NBOMe was the following: not detected (0-2 cm), not detected (2-4 cm), 1.0 pg/mg (4-6 cm), 4.9 pg/mg (6-8 cm) and not detected (8-9.5 cm). RESULT: The result of the segment 6-8 cm coincides with the date of consumption (calculated with a hair growth rate at 1 cm/month) and the low concentration detected in the segment 4-6 cm probably corresponds to the contribution of dormant hair. The toxicological significance of the measured concentrations is difficult to determine because this is the first case dealing with hair analysis for 25I-NBOMe. CONCLUSION: The use of hair analysis for NPS is still at the initial stages. In particular, little is known about the incorporation into the keratin matrix after intake and the correlation between dosage frequency of use, and hair concentrations. Under these circumstances, NPS hair analysis should be cautiously interpreted by experienced forensic toxicologist.

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.

A Case Review of the First Analytically Confirmed 25I-NBOMe-Related Death in Washington State.

This case was submitted to the Washington State Patrol Toxicology Laboratory in September 2014. A 15-year-old male went to a party where he ingested 25I-NBOMe and mushrooms. A short time later, he started to vomit and began seizing until he eventually passed out. Resuscitation efforts were made, but were unsuccessful. He was transported to a local hospital, where he died three days later of multi-system organ failure following cardiopulmonary arrest. The hospital admission samples were negative for ethanol and basic drugs and their metabolites. The hospital serum confirmed positive for delta-9-tetrahydrocannabinol (THC) and carboxy-THC at 4.1 and 83 ng/mL, respectively. On the basis of the case history, the hospital blood and urine were sent to NMS Labs for NBOMe and psilocin confirmation. The blood was positive for 25I-NBOMe, and the urine was positive for 25C-, 25H- and 25I-NBOMe, as well as, psilocin. Antemortem and postmortem blood were also sent to AIT Laboratories for NBOMe confirmation. The antemortem blood confirmed positive for 25I-NBOMe with a concentration of 0.76 ng/mL. The manner of death was ruled an accident as a result of combined 25I-NBOMe and psilocin intoxication.

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.

25I-NBOMe related death in Australia: a case report.

We present a toxicologically confirmed 25I-NBOMe related death from Australia. 25I-NBOMe is a synthetic new psychoactive substance (NPS), which is a derivative of the 2C-X series of phenethylamines. NBOMe compounds have hallucinogenic and stimulant properties and are potent agonists of the human 5HT2A receptor. They have been associated with severe toxicity and fatalities. No case reports on deaths related to 25I-NBOMe toxicity from Australia have been published thus far. Very limited toxicological data is available in the current literature. The decedent in the presented case had a post mortem aortic non-preserved blood concentration of 25I-NBOMe of approximately 28 µg/L, a concentration that appears to be much higher than those previously reported in non-fatal cases of toxicity and analytically confirmed 25I-NBOMe related fatalities. The publication of new data is essential in improving knowledge and awareness amongst the forensic community regarding emerging psychoactive substances, such as the NBOMe compounds.

Identification of Metabolite Biomarkers of the Designer Hallucinogen 25I-NBOMe in Mouse Hepatic Microsomal Preparations and Human Urine Samples Associated with Clinical Intoxication.

'NBOMe' (dimethoxyphenyl-N-[(2-methoxyphenyl)methyl]ethanamine) derivatives are a new class of designer hallucinogenic drugs widely available on the Internet. Currently, 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) is the most popular abused derivative in the USA. There are little published data on the absorption, metabolism and elimination of 25I-NBOMe, or any of the other NBOMe derivatives. Therefore, there are no definitive metabolite biomarkers. We present the identification of fifteen 25I-NBOMe metabolites in phase I and II mouse hepatic microsomal preparations, and analysis of two human urine samples from 25I-NBOMe-intoxicated patients to test the utility of these metabolites as biomarkers of 25I-NBOMe use. The synthesis of two major urinary metabolites, 2-iodo-4-methoxy-5-[2-[(2-methoxyphenyl) methylamino]ethyl]phenol (2-O-desmethyl-5-I-NBOMe, M5) and 5-iodo-4-methoxy-2-[2-[(2-methoxyphenyl)methylamino]ethyl]phenol (5-O-desmethyl-2-I-NBOMe), is also presented. Seven phase II glucuronidated metabolites of the O-desmethyl or the hydroxylated phase I metabolites were identified. One human urine sample contained 25I-NBOMe as well as all 15 metabolites identified in mouse hepatic microsomal preparations. Another human urine sample contained no parent 25I-NBOMe, but was found to contain three O-desmethyl metabolites. We recommend ß-glucuronidase enzymatic hydrolysis of urine prior to 25I-NBOMe screening and the use of M5 as the primary biomarker in drug testing.

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.

NBOMe designer drug exposures reported to Texas poison centers.

Use of 2-methoxybenzyl analogues of 2C-X phenethylamines (NBOMe) is increasing in the United States. Twenty-five NBOMe exposures reported to Texas poison centers during 2012-2013 were identified; 76% involved 25I-NBOMe, 12% involved 25C-NBOMe, and 12% involved an unknown NBOMe. Eighty-eight percent of the patients were men; mean age was 17 years (range, 14-25 years). The exposure route was 72% from ingestion alone, 12% from inhalation alone, 4% from ingestion and inhalation, and 12% from an unknown route. The most common clinical effects were tachycardia (52%), agitation (48%), hallucinations (32%), hypertension (32%), confusion (24%), and mydriasis (20%). Two patients died.