Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238

Fogarty, Melissa F; Vandeputte, Marthe M.; Krotulski, Alex J; Papsun, Donna M; Walton, Sara E.; Stove, Christophe; Logan, Bari M.

doi:10.1007/s00204-022-03257-7

Cited by 17 publications

(26 citation statements)

References 13 publications

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“…Cases were reported between January 2020 and December 2021 (collection dates for 7 studied specimens were before 2020); cases reported herein complement previously reported case series by the authors. 90,107,109,115,121 Table 2 shows the number of detections for each NSO, as well as mean, median, and range of quantitative results.…”

Section: Resultsmentioning

confidence: 99%

Proliferation of Novel Synthetic Opioids in Postmortem Investigations After Core-Structure Scheduling for Fentanyl-Related Substances

Papsun

Krotulski²,

Logan

2022

Am J Forensic Med Pathol

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New generations of novel synthetic opioids (NSOs) have emerged to fill a void in the illicit drug markets left by the decline in popularity of fentanyl analogs subsequent to core-structure scheduling of fentanyl-related substances in the United States and China. These new opioids include members of the 2-benzyl benzimidazole (eg, isotonitazene, metonitazene, N-pyrrolidino etonitazene, protonitazene, etodesnitazene), benzimidazolone (eg, brorphine), and cinnamylpiperazine (eg, AP-238, 2-methyl AP-237) subclasses. Novel synthetic opioids continue to be detected in opioid-related fatal overdoses, demonstrating the harms associated with exposure to these drugs. Between January 2020 and December 2021, 384 casework blood samples were reported by our laboratory to contain 1 or more of the prior listed 8 NSOs. Isotonitazene (n = 144), metonitazene (n = 122), and brorphine (n = 91) were the 3 most prevalent substances, with positivity for isotonitazene and brorphine peaking just before the announcement of emergency scheduling. These NSOs have been documented as significant drivers of drug mortality, and this case series described here highlights the challenges medical examiners and coroners face in staying current with emerging drugs. Challenges include regional differences, rapid turnover, short lifecycles, variable toxicology testing, and difficulty in assessing individual drug toxicity in polydrug cases.

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Section: Resultsmentioning

confidence: 99%

Proliferation of Novel Synthetic Opioids in Postmortem Investigations After Core-Structure Scheduling for Fentanyl-Related Substances

Papsun

Krotulski²,

Logan

2022

Am J Forensic Med Pathol

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“…The compound recently re‐emerged on the market, likely in response to the Chinese inclusion of all fentanyl‐related drugs within the list of controlled narcotics, 19 leading to a shift towards more varied chemical structures of synthetic opioids. The scientific knowledge regarding bucinnazine and its effects in humans is still very limited 17,20–22 . AP‐237 was classified as an NSO due to its potential for abuse, and even though its analgesic effect is thought to be approximately 1/3 compared to morphine, it seems to be one of the more potent piperazine type opioids 15,18 .…”

Section: Resultsmentioning

confidence: 99%

“…The scientific knowledge regarding bucinnazine and its effects in humans is still very limited. 17 , 20 , 21 , 22 AP‐237 was classified as an NSO due to its potential for abuse, and even though its analgesic effect is thought to be approximately 1/3 compared to morphine, it seems to be one of the more potent piperazine type opioids. 15 , 18 The efficacy (EC 50 ) at the μ opioid receptor was estimated in vitro in the range of 3 × 10 4 to 8 × 10 3 nM, but results remained ambiguous.…”

Section: Resultsmentioning

confidence: 99%

“…Although the concentrations here reported should be taken only as rough approximations and a precise quantification was beyond the scope of our analysis, 5F‐ADB and AP‐237 might be regarded as unintentionally applied impurities, although this cannot be deducted from the available results. However, the hypothesis of impurities appears likely with respect to the relative potencies of the compounds, on the basis of which an effective dose of AP‐237 can be expected above 10 mg, 20 , 22 whereas the cannabinoids are believed to produce strong effects from doses as low as 2–4 mg for JWH‐018, 23 , 24 and probably less than 1 mg for more potent compounds like MDMB‐4en‐PINACA. Moreover, due to the preparation methods for papers illicitly infused with SCs, the drug concentrations might vary widely from one area to another, 4 , 7 so that it is possible that the compounds here detected were more concentrated in some areas.…”

Section: Resultsmentioning

confidence: 99%

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Detection of AP‐237 and synthetic cannabinoids on an infused letter sent to a German prisoner

Giorgetti

Brunetti

Pelotti

et al. 2022

Drug Testing and Analysis

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In the past years, new psychoactive substances (NPS) started circulating in prisons, leading to health risks and challenges for the criminal justice system. Seizures of papers and cards impregnated with synthetic cannabinoid (SCs) have been reported.In November 2021, a letter suspected to be drug-infused was sent from a German prison to this laboratory. Toxicological analyses were performed by means of gas chromatography-mass spectrometry (GC-MS) for drug screening and liquid chromatography-tandem mass spectrometry (LC-MS/MS) as well as highperformance (HP) LC with diode-array detection (DAD) for semi-quantification of the compounds. The novel synthetic opioid (NSO) AP-237 was detected on the letter, with an estimated concentration of 1.2 μg/cm 2 , together with the SCs MDMB-4en-PINACA (77 μg/cm 2 ) and 5F-ADB (6.5 μg/cm 2 ). To the best of the authors' knowledge, this is the first time an NSO was detected on a drug-infused paper seized in a prison. Highly potent NSOs could easily be dissolved in organic solvents to produce

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“…In the first three quarters of 2021, 18 cases involving 2-methyl AP-237 were reported by CFSRE, and four also included the designer benzodiazepine, etizolam [13][14][15]. Fogarty et al reported four postmortem cases between February 2020 and April 2021 involving 2-methyl AP-237 with blood concentrations ranging from 820 to 5800 ng/mL and a mean concentration of 2280 ng/mL [16]. A clinical case was also received during this time involving an emergency department admission blood concentration of 21 ng/mL [16].…”

Section: Introductionmentioning

confidence: 99%

Fatal intoxication involving 2‐methyl AP‐237

Truver,

Crosby,

Gillette

et al. 2023

Journal of Forensic Sciences

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Novel synthetic opioids contribute considerably to the opioid epidemic, especially with the frequent emergence of structurally similar compounds. This case report describes a fatal intoxication involving 2‐methyl AP‐237. A 54‐year‐old Caucasian male was found deceased from an apparent drug overdose. A plastic container labeled “2MAP” and a cut straw were found in the decedent's backpack at the scene. A white substance found in the container tested positive for fentanyl by field testing. According to his medical history, the decedent was treated for a drug overdose 3 years prior to his death. With no diagnostic findings at autopsy, the case was submitted for toxicological analysis. An unknown substance was detected in peripheral blood and urine using gas chromatography with nitrogen phosphorous detection (GC‐NPD). Further testing was conducted using gas chromatography–mass spectrometry (GC–MS) and liquid chromatography‐quadrupole‐time‐of‐flight mass spectrometry (LC‐QTOF‐MS) which confirmed the presence of 2‐methyl AP‐237 and potential metabolites in blood and urine. Quantitation by GC‐NPD revealed concentrations of 2‐methyl AP‐237 in blood and urine at 480 ng/mL and 4200 ng/mL, respectively. The toxicological analysis also identified and quantitated alprazolam in the blood at 55 ng/mL. Additionally, the metabolism of 2‐methyl AP‐237 was investigated and three hydroxylated metabolites were identified in peripheral blood and urine. Limited literature is available for the detection and quantitation of 2‐methyl AP‐237 in postmortem specimens. Given the toxicological findings with unremarkable autopsy findings, this case is an example of a fatal intoxication involving 2‐methyl AP‐237.

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Toxicological and pharmacological characterization of novel cinnamylpiperazine synthetic opioids in humans and in vitro including 2-methyl AP-237 and AP-238

Cited by 17 publications

References 13 publications

Proliferation of Novel Synthetic Opioids in Postmortem Investigations After Core-Structure Scheduling for Fentanyl-Related Substances

Proliferation of Novel Synthetic Opioids in Postmortem Investigations After Core-Structure Scheduling for Fentanyl-Related Substances

Detection of AP‐237 and synthetic cannabinoids on an infused letter sent to a German prisoner

Fatal intoxication involving 2‐methyl AP‐237

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