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

      case-report

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          Abstract

          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.

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          The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

          E Dunkley, R. Whyte, Geoffrey Isbister … (2003)
          There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. To improve the criteria for diagnosing clinically significant serotonin toxicity. Retrospective analysis of prospectively collected data We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.
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            Brain edema and breakdown of the blood-brain barrier during methamphetamine intoxication: critical role of brain hyperthermia.

            Eugene A. Kiyatkin, H Sharma, John P. Brown (2007)
            To clarify the role of brain temperature in permeability of the blood-brain barrier (BBB), rats were injected with methamphetamine (METH 9 mg/kg) at normal (23 degrees C) and warm (29 degrees C) environmental conditions and internal temperatures were monitored both centrally (nucleus accumbens, NAcc) and peripherally (skin and nonlocomotor muscle). Once NAcc temperatures peaked or reached 41.5 degrees C (a level suggesting possible lethality), animals were administered Evans blue dye (protein tracer that does not normally cross the BBB), rapidly anaesthetized, perfused and had their brains removed. All METH-treated animals showed brain and body hyperthermia associated with relative skin hypothermia, suggesting metabolic activation coupled with peripheral vasoconstriction. While METH-induced NAcc temperature elevation varied from 37.60 to 42.46 degrees C (or 1.2-5.1 degrees C above baseline), it was stronger at 29 degrees C (+4.13 degrees C) than 23 degrees C (+2.31 degrees C). Relative to control, METH-treated animals had significantly higher brain levels of water, Na(+), K(+) and Cl(-), suggesting brain edema, and intense immunostaining for albumin, indicating breakdown of the BBB. METH-treated animals also showed strong immunoreactivity for glial fibrillary acidic protein (GFAP), possibly suggesting acute abnormality or damage of astrocytes. METH-induced changes in brain water, albumin and GFAP correlated linearly with NAcc temperature (r = 0.93, 0.98 and 0.98, respectively), suggesting a key role of brain hyperthermia in BBB permeability, development of brain edema and subsequent functional and structural neural abnormalities. Therefore, along with a direct destructive action on neural cells and functions, brain hyperthermia, via breakdown of the BBB, may be crucial for both decompensation of brain functions and cell injury following acute METH intoxication, possibly contributing to neurodegeneration resulting from chronic drug use.
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              2C or not 2C: phenethylamine designer drug review.

              Be Vang Dean, Samuel Stellpflug, Aaron Burnett … (2013)
              New groups of synthetic "designer drugs" have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as "legal" highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy-N-methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.
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                Author and article information

                Contributors
                Wouter de Ruijter: w.de.ruijter@nwz.nl
                Journal
                Journal ID (nlm-ta): J Forensic Sci
                Journal ID (iso-abbrev): J. Forensic Sci
                Journal ID (doi): 10.1111/(ISSN)1556-4029
                Journal ID (publisher-id): JFO
                Title: Journal of Forensic Sciences
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0022-1198
                ISSN (Electronic): 1556-4029
                Publication date (Electronic): 23 October 2019
                Publication date (Print): November 2019
                Volume: 64
                Issue: 6 ( doiID: 10.1111/jfo.v64.6 )
                Pages: 1950-1952
                Affiliations
                [ 1 ] Department Intensive Care Northwest Clinics (Noordwest Ziekenhuisgroep) Postbus 501 1800 AM Alkmaar The Netherlands
                [ 2 ] Amsterdam University Medical Centre Meibergdreef 9 1105 AZ Amsterdam The Netherlands
                [ 3 ] Radboud Universiteit, Behavourial Science Institute Montessorilaan 3 6525 HR Nijmegen The Netherlands
                Author notes
                [*] [* ] Corresponding author: Wouter de Ruijter, M.D., Ph.D. E‐mail: w.de.ruijter@ 123456nwz.nl

                Article
                Publisher ID: JFO14214
                DOI: 10.1111/1556-4029.14214
                PMC ID: 6900031
                PubMed ID: 31643086
                SO-VID: e32e5efa-3e77-49b8-a92b-5e9925582ec3
                Copyright © © 2019 The Authors. Journal of Forensic Sciences published by Wiley Periodicals, Inc. on behalf of American Academy of Forensic Sciences
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 05 August 2019
                Date revision received : 26 September 2019
                Date accepted : 27 September 2019
                Page count
                Figures: 1, Tables: 0, Pages: 3, Words: 2321
                Categories
                Subject: Case Report
                Subject: Toxicology
                Subject: Case Reports
                Custom metadata
                source-schema-version-number 2.0
                cover-date November 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                Keywords: forensic science,2c‐b,intoxication,serotonin syndrome,designer drugs,phenethylamine
                Data availability:
                Keywords: forensic science, 2c‐b, intoxication, serotonin syndrome, designer drugs, phenethylamine

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