Public Alerts

The objective of this announcement is to notify public health and safety, clinicians, law enforcement, first responders, medical examiners and coroners, forensic and clinical laboratory personnel, and all other related communities about new information surrounding new generation synthetic opioids in clinical settings after suspected opioid overdoses and presentation to emergency departments, including: metonitazene, N-piperidinyl etonitazene, isotonitazene, and brorphine.

Drug use can lead to adverse events and overdose scenarios where individuals present to emergency departments for clinical evaluation and/or treatment. The culprit can be traditional drugs (e.g., heroin, fentanyl, cocaine, methamphetamine) or novel psychoactive substances (NPS); however, proper drug testing methodologies must be employed for accurate identification and characterization. A partnership between the American College of Medical Toxicology (ACMT) and the Center for Forensic Science Research and Education (CFSRE) was established to comprehensively assess the role and prevalence of synthetic opioids and other drugs among suspected overdose events in the United States. Patients with a suspected opioid overdose presented to an emergency department at a participating site within ACMT’s Toxicology Investigators Consortium (ToxIC). Residual, discarded biological samples were obtained for testing against an expansive library of drugs and other substances.
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Cayman Chemical and NPS Discovery at the Center for Forensic Science Research and Education (CFSRE) have developed new, more appropriate names to address the newly emergent “MDA-19” and its related analogues following the systematic convention typically used for synthetic cannabinoid nomenclature.

Synthetic cannabinoids represent a vastly diverse sub-class of novel psychoactive substances (NPS). The turnover of this sub-class is largely linked to drug scheduling actions and, like other sub-classes of NPS, new drugs were historically produced via slight tweaks to the molecular structure. In May 2021, China announced new legislation to control synthetic cannabinoids as a class using commonly encountered structural backbones. This has resulted in the emergence of new generations of synthetic cannabinoids with core components that were previously unencountered and/or not well characterized. An example is “MDA-19” and its related analogues. “MDA-19” is a CB2 agonist and was studied, like many synthetic cannabinoids, under legitimate research for pharmaceutical purposes. Similar to JWH-018 and other early synthetic cannabinoids, naming conventions utilizing the initials of a researcher or organization are not ideal and may be misleading (e.g., the abbreviation “MDA” is also used for the stimulant drug methylenedioxyamphetamine). A well-accepted systematic naming convention exists for synthetic cannabinoids and should be applied, where appropriate, to avoid any confusion or mischaracterization.
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N-Pyrrolidino etonitazene (etonitazepyne) is a new high potency synthetic opioid bearing structural resemblance to etonitazene, a synthetic opioid that is nationally and internationally controlled. N-Pyrrolidino etonitazene is dissimilar in structure to other synthetic opioids typically encountered in forensic casework (e.g., fentanyl). Unlike the 2-benzylbenzimidazole analogues that were first synthesized and reported in the literature in the 1950s (e.g., metonitazene, isotonitazene), N-pyrrolidino etonitazene does not appear in prior literature or patents. Recent in vitro pharmacological data suggest that this new opioid exhibits potency similar to etonitazene (~20x more potent than fentanyl). N-Pyrrolidino etonitazene was first reported by NPS Discovery in May 2021 following initial detection in a toxicology case. To date, eight blood specimens associated with postmortem death investigations in the U.S. have contained N-pyrrolidino etonitazene; additional confirmations are pending. The toxicity of N-pyrrolidino etonitazene has not been examined or reported but recent association with death among people who use drugs leads professionals to believe this synthetic opioid retains the potential to cause widespread harm and is of public health concern. Identifications of N-pyrrolidino etonitazene have also been reported recently from agencies in Europe.
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Tramadol is a synthetic opioid analgesic approved in 1995 by the United States Food and Drug Administration (FDA) for moderate to moderately severe pain. Its mechanism of action involves opioid and non-opioid pharmacological activities. Tramadol is a μ-opioid receptor agonist, producing opioid-like effects of analgesia, and respiratory and CNS depression. It also acts as a serotonin and norepinephrine reuptake inhibitor, which can cause excitatory neurological effects. Tramadol is metabolized by CYP2D6 to O-desmethyltramadol, an active metabolite that is more potent and has a longer half-life than the parent drug. Tramadol is approximately equipotent to its structural analog codeine. In 2014, the FDA classified tramadol as a schedule IV controlled substance due to its potential for abuse. Tramadol is available as immediate-release and extended-release tablets. Trade names include ConZip®, Ultram®, Ultracet®, Ryzolt®, and Rybix ODT®.
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Dipyrone is a non-opioid analgesic with antipyretic activity, which was developed by the German company Hoechst AG in 1920 with mass production starting in 1922. It is a pro-drug, which is rapidly metabolized after oral administration to active pyrazolone compounds. Dipyrone is also know under different generic names such as metamizole, noramidopyrine, and others. Dipyrone was sold as an over-the-counter (OTC) analgesic until the 1970s, at which time it was banned in several countries, including the United States, several European nations, Japan, and Australia following reports of users developing agranulocytosis, occasionally resulting in death. The safety of the drug is still controversial, resulting in varying levels of restriction and regulation worldwide. Dipyrone is still available, however, by prescription and OTC in many countries in Europe, South America, and Asia.
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The objective of this report is to provide guidance in developing an appropriate analytical scope of testing for novel psychoactive substances (NPS) in the United States based on current trends and intelligence. This report is based on information available in Q1 2021 and is subject to change along with the drug market.

NPS Discovery and the SOFT Designer Drugs Committee have established the below recommendations for NPS scope based on information from extensive collaborations, partnerships, and initiatives which yield national perspectives. Suggested cut-off concentrations or reporting limits (in ng/mL) are listed for each NPS. These values were categorized (i.e., <1, 1-10, and >10 ng/mL) and determined based on currently available quantitative data and/or comparison to structurally similar NPS within the given sub-class.
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Phenacetin, a pain-relieving and fever-reducing drug, was discovered as an analgesic in 1887. It was one of the first synthetic fever reducers on the market and one of the first non-opioid analgesics without anti-inflammatory properties. Due to its hazardous side effects, including carcinogenic and kidney-damaging properties, the Food and Drug Administration (FDA) ordered its withdrawal from drug markets in 1983. Since being withdrawn phenacetin has become a common adulterant of illicit substances. In a 9-year longitudinal study of cocaine powders in the Netherlands, the percentage of samples containing phenacetin increased from 1.6 to 40.6 with a peak of 48% in 2006. Additionally, phenacetin was the most frequently identified adulterant in the samples.
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4F-MDMB-BICA was first identified in the United States (U.S.) in plant-like material seized by law enforcement in May 2020 and soon after in toxicology casework in July 2020, with concurrent emergence in European countries. 4F-MDMB-BICA is structurally similar to the synthetic cannabinoid 4F-MDMB-BINACA, differing by an indole vs. indazole core, respectively. 4F-MDMB-BICA is an activator of the cannabinoid receptor system and its toxicity can be demonstrated through medicolegal death investigations paired with comprehensive toxicology findings. In the U.S., 4F-MDMB-BICA has been identified in at least 26 toxicology cases associated with postmortem (PM) and driving under the influence of drugs (DUID) investigations. In Europe, 4F-MDMB-BICA has been identified in several countries, including Hungary, the United Kingdom, Belgium, and Slovenia. Eleven deaths were attributed to the use of 4F-MDMB-BICA in Hungary between May and August 2020.
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Metonitazene is a potent synthetic opioid bearing structural resemblance to etonitazene, a synthetic opioid that is nationally and internationally controlled. Metonitazene is dissimilar in structure to other synthetic opioids typically encountered in forensic casework (e.g. fentanyl analogues). Metonitazene and similar analogues (e.g. etonitazene, isotonitazene) were first synthesized and reported in the literature in the 1950s. Pharmacological data suggest that this group of synthetic opioids have potency similar to or greater than fentanyl. Metonitazene was first reported by NPS Discovery after detection in a seized drug powder in July 2020. To date, metonitazene has been identified in eight blood specimens associated with postmortem death investigations in the U.S.
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Fluorofentanyl was identified as early as 2016 in the U.S. and Europe, but overall detections remained low until recent months. Positivity of para-fluorofentanyl began increasing in Q3 2020 and within a few months this fentanyl analogue has been identified in 16 forensic cases. para-Fluorofentanyl is commonly found in combination with fentanyl, but the concentration ratio between these two substances varies (0.003 to 26); para-fluorofentanyl is the primary synthetic opioid in multiple cases. para-Fluorofentanyl is a potent synthetic opioid with reported potency similar to fentanyl.
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