A retrospective analysis of the "Neverending Trip" after administration of a potent full agonist of 5-HT2A receptor - 25I-NBOMe.

BACKGROUND: 5-HT2A receptor (e.g. 25I-NBOMe) agonists not only pose risks of acute intoxication but also long-term effects and significant adverse reactions, e.g. hallucinogen persisting perception disorder (HPPD), derealization, and depersonalization. AIMS: We evaluated the risk associated with single and repeated use of 25I-NBOMe. We aimed to identify factors that may increase the risk of HPPD, increase its severity and determine the time when the first symptoms appear. Herein, we report the first extensive evaluation of 25I-NBOMe-induced HPPD. METHOD: We assessed all reports (58) collected by The Pomeranian Pharmacovigilance Centre (PPC) from 2013 to 2020. RESULTS: The study included a total of 58 reports of adverse reactions caused by 25I-NBOMe. In the case of 15 reports (in patients aged 19-26 years), symptoms persisted many months after the discontinuation of 25I-NBOMe. The most common were: pseudohallucinations, bizarre delusions, derealizations and in some cases development or worsening of depression has been diagnosed. HPPD-like symptoms were most common in patients who took the drug regularly (i.e., several times a month). The risk of HPPD-like symptoms is higher in patients who have severe visual pseudohallucinations, severe bizarre delusions, derealization and/or depersonalization onset immediately after taking the drug. Recurrence of HPPD symptoms may be provoked by many factors, however, there is some cases there is no apparent reason. HPPD after 25I-NBOMe use can last from 2 months up to 2 years. In some patients, pharmacological treatment was necessary due to 25I-NBOMe-induced HPPD and depression. CONCLUSIONS: The study showed long-lasting effects after 25I-NBOMe administration and allowed for the determination of HPPD risk factors.

Acute Limb Ischemia after Intake of the Phenylethylamine Derivate NBOMe.

Objective: N-(2-methoxy) benzyl-phenethylamine (NBOMe) derivatives have a high affinity to the serotonin receptor 2A and emerged as new psychedelic agents. We report the case of a 30-year-old man admitted to the hospital because of acute ischemia of the left arm with clinical symptoms of pallor, pulselessness, paresthesia, and a motoric deficit. The patient had a history of schizophrenia and drug abuse and disclosed during the hospital stay the sublingual intake of a substance bought as 25I-NBOMe the night before the ischemic event. Methods: Routine clinical diagnostics including among others color-coded duplex sonography and computed tomography angiography (CTA) were performed. The remainder of the drugs was analyzed using high performance liquid chromatography. Results: Initial color-coded duplex sonography of the upper left limb showed pathological flow profiles of the axillary, brachial, ulnar, and radial artery with a reduced diameter of the ulnar (0.9 mm) and radial (1.1 mm) artery. In consequence, peripheral vasospasm, distal arterial thrombosis, or arterial embolization was anticipated. As therapeutic measures, the patient immediately received intravenous systemic vasodilators (alprostadil) and therapeutic anticoagulation with low molecular weight heparin. Instant symptom improvement was observed within the first day after therapy initiation. The subsequently performed CTA of the heart and left arm showed no signs of thrombotic material. Treatment was continued for five days and the patient was released thereafter having completely normalized perfusion in his left arm. Outpatient treatment was continued with calcium-channel blockers, as the patient had also displayed arterial hypertension. Drug analysis retrieved a composition of the isomers 25I-NBOMe, 25C-NBOMe, and 25H-NBOMe as well as traces of pentylon. Conclusion: NBOMe ingestion implicates the risk of peripheral vasospasms with severe, limb-threatening ischemia.

Unexpected Serotonin Syndrome, Epileptic Seizures, and Cerebral Edema Following 2,5-dimethoxy-4-bromophenethylamine Ingestion.

4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a designer drug. In Europe, 2C-B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4-methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C-B ingestion, confirmed by liquid chromatography-tandem mass spectrometry, in an 18-year-old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug-induced toxicity. This case showed that 2C-B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C-B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.

Seizures, Systemic Inflammatory Response, and Rhabdomyolysis Associated With Laboratory-Confirmed 2C-I and 25-I Exposure.

The 2C drugs are hallucinogenic phenethylamines. They and their n-benzyloxymethyl analogs have become popular as "legal highs," and significant toxicity has been attributed to their use. We report on a case of seizures, systemic inflammatory response, and rhabdomyolysis associated with laboratory-confirmed 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine exposure. A 17-year-old male teenager developed seizures after taking "2 strips of acid." The seizures resolved with midazolam, but he became apneic and was intubated. His head computed tomography was unremarkable. Initial creatinine level was 1.5 mg/dL, with a creatine kinase of 112 U/L. His urine immunoassay drug screen was negative. He was extubated within 12 hours but had elevated temperatures for 48 hours. He was treated with antibiotics, but no source of infection was identified. His creatinine level peaked at 2.46 mg/dL. His creatine kinase peaked 72 hours later at 14579 U/L. He was treated with intravenous fluids and did not require renal replacement therapy. He recovered fully and was discharged after 5 days. Serum and urine samples were tested using liquid chromatography time-of-flight mass spectrometry. We detected 4-iodo-2,5-dimethoxyphenethylamine and 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine in both serum and urine. No other substances were detected. The 2C drugs and their n-benzyloxymethyl analogs are potent serotonergic agents. Their use has been associated with multiple adverse effects including seizures, rhabdomyolysis, and death. They should be considered in differential diagnosis for drug-induced seizures and as a cause for systemic inflammatory response. This case highlights the significant toxicity seen with these compounds.

Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens.

Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT2A-binding affinity and hallucinogenic potency. N-benzylphenethylamines ("NBOMes") such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) show subnanomolar affinity for the 5-HT2A receptor and are reportedly highly potent in humans. Several NBOMEs have been available from online vendors since 2010, resulting in numerous cases of toxicity and multiple fatalities. This chapter reviews the structure-activity relationships, behavioral pharmacology, metabolism, and toxicity of members of the NBOMe hallucinogen class. Based on a review of 51 cases of NBOMe toxicity reported in the literature, it appears that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction.

Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions.

BACKGROUND: 2C-B (Nexus) is one of the most widespread novel psychoactive substances. There is limited information about its pharmacological properties, and few studies in humans concern its acute and chronic effects. 2C-B has been classified as a stimulant, hallucinogen, entactogen, and/or empathogen. OBJECTIVES: To evaluate the emotional, subjective, and cardiovascular effects of 2C-B. METHODS: Twenty healthy recreational 2C-B users (12 women) self-administered a 20 mg dose of 2C-B. Evaluations included emotional (IAPS, FERT, and speech), subjective (visual analog scales, ARCI, VESSPA, HRS, and POMS questionnaires), and cardiovascular effects (blood pressure and heart rate). Results. Positive subjective effects predominated with a reduction of anger under the influence of 2C-B. It did, however, increase reactivity to negative emotional stimuli and decrease the ability to recognize expressions of happiness. Augmented emotionality in speech could be appreciated by others. 2C-B induced euphoria and well-being, changes in perceptions, and slight hallucinogenic states. Mild sympathetic actions were observed. CONCLUSIONS: The specific profile that 2C-B exerts on emotions suggests its classification as an entactogen with psychedelic properties.

Pharmacokinetics, pharmacodynamics and toxicology of new psychoactive substances (NPS): 2C-B, 4-fluoroamphetamine and benzofurans.

BACKGROUND: Recently, the number of new psychoactive substances (NPS) appearing on the illicit drug market has shown a marked increase. Although many users perceive the risk of using NPS as medium or low, these substances can pose a serious health risk and several NPS have been implicated in drug-related deaths. In Europe, frequently detected NPS are 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-fluoroamphetamine (4-FA) and benzofurans (5-(2-aminopropyl)benzofuran (5-APB) or 6-(2-aminopropyl)benzofuran (6-APB)). However, little is known about the health risks of these specific NPS. METHODS: In this paper, existing literature on the pharmacokinetics and pharmacodynamics of 2C-B, 4-FA and benzofurans (5-APB/6-APB) was reviewed. RESULTS: Our review showed that the clinical effects of 2C-B, 4-FA and benzofurans (5-APB/6-APB) are comparable with common illicit drugs like amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Therefore, NPS toxicity can be handled by existing treatment guidelines that are based on clinical effects instead of the specific drug involved. Even so, information on the health risks of these substances is limited to a number of case reports that are complicated by confounders such as analytical difficulties, mislabelling of drugs, concomitant exposures and interindividual differences. CONCLUSION: To aid in early legislation, data on clinical effects from poisons centres and user fora should be combined with (in vitro) screening methods and collaboration on an (inter)national level is essential. As a result, potentially hazardous NPS could be detected more quickly, thereby protecting public health.

Cerebral vasculopathy after 4-bromo-2,5-dimethoxyphenethylamine ingestion.

BACKGROUND: 4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a designer-drug variant of 3,4-methylenedioxymethamphetamine (ecstasy) whose recreational use has increased significantly over the last 10 years. Neurologic consequences of 2C-B usage are currently unknown. CASE REPORT: A 43-year-old woman experienced severe headaches within 48 hours of taking liquid 2C-B, after which time she developed progressive encephalopathy and quadraparesis, which did not improve over several months. MRA and cerebral angiogram imaging demonstrated profound vascular abnormalities of large, medium, and small-caliber vessels with subsequent watershed infarction. Brain biopsy and cerebrospinal fluid studies ruled out an inflammatory process. CONCLUSIONS: This case demonstrates an idiosyncratic and devastating neurologic response to 2C-B, a recreational drug whose popularity has increased with widespread availability of online guides for its synthesis.

Morbidity involving the hallucinogenic designer amines MDA and 2C-I.

A case is presented of a 39-year-old woman who suffered severe debilitation because of a hemorrhagic stroke in the context of substance abuse. The patient presented to the emergency room with rapidly diminishing mental status, hypertension, and vasoconstriction; her friends provided a history of ingestion of cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and 2C-I, a novel designer amine. A multi-targeted LC-MS/MS method for sympathomimetic amines and related drugs in urine detected and quantified 2C-I and MDA, while ruling out MDMA. The cause of the stroke was determined to be an underlying cerebrovascular abnormality called Moyamoya, secondary to substance abuse. In clinical laboratories, gas chromatography-mass spectrometry or liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmation of a positive amphetamine immunoassay is usually directed only towards amphetamine, methamphetamine, MDMA and MDA. This report demonstrates the utility of testing for a wider menu of compounds using LC-MS/MS in order to better characterize the prevalence and toxicities of novel amines such as 2C-I.