N,N-Dimethylpentylone–an emerging NPS stimulant of concern in the United States

Abstract

The objective of this study is to inform forensic toxicologists about the rise and proliferation of the new synthetic stimulant N,N-dimethylpentylone in postmortem investigations. For the majority of 2020 and 2021, eutylone was the dominant synthetic stimulant and the primary novel psychoactive substance (NPS) sold as “ecstasy”, “molly”, or “MDMA.” In September 2021, eutylone was recommended for international control, which created a shift internationally in the NPS stimulant drug market. After this notice of international control, eutylone positivity began to decline and identifications of the new synthetic stimulant N,N-dimethylpentylone began to increase. Synthetic stimulants have been deemed a risk to public health and with possible adverse effects including hallucinations, hyperthermia, arrythmias, and serotonin syndrome, which can lead to death. Beginning in Q4 2021, our laboratory initiated surveillance efforts to track the emergence and proliferation of N,N-dimethylpentylone, in addition to assessment of its associated harms and impacts. In collaboration between the CFSRE and NMS Labs, authentic toxicology samples were comprehensively tested for N,N-dimethylpentylone, other NPS, and commonly encountered drugs. Blood and urine samples were prepared using a single-step basic liquid-liquid extraction. Screening analysis was conducted using a Sciex TripleTOF® 5600+ liquid chromatograph time-of-flight mass spectrometer (LC-QTOF-MS). When possible, quantitative confirmations were performed using the method of standard addition with analysis via a Waters TQ-S Micro liquid chromatograph tandem quadrupole mass spectrometer (LC-QQQ-MS). By LC-QTOF-MS, N,N-dimethylpentylone was distinguishable from its isomers using retention time and/or fragment spectrum. By LC-QQQ-MS, a specialized method was developed to chromatographically separate all known isomers. Basic demographic and case information were available for select cases in collaboration with medical examiner offices. N,N-Dimethylpentylone was confirmed in 32 cases, including postmortem ( n = 26), DUID ( n = 1), and unknown ( n = 5) cases which were collected between August 2021 to March 2022. Cases originated from nine states, primarily Florida ( n = 17) and the Mid-Atlantic region of the United States ( n = 13). Individuals were largely male (62%), and age ranged between 27 to 52 years old. To date, N,N-dimethylpentylone was quantitated in five postmortem cases with concentrations ranging from 33 to 970 ng/mL (mean: 270 ± 400 ng/mL, median: 87 ng/mL). In addition, pentylone was confirmed in all five cases, affirming that this drug is a primary metabolite of N,N-dimethylpentylone. Pentylone concentrations ranged from 10 to 420 ng/mL (mean: 120 ± 170 ng/mL, median: 37 ng/mL). Notable drugs identified alongside N,N-dimethylpentylone in the 32 total cases were pentylone ( n = 23), fentanyl or other opioids ( n = 13), methamphetamine ( n = 11), and eutylone ( n = 5). In eight cases, there were no other drugs of interest identified with N,N-dimethylpentylone. N,N-Dimethylpentylone was first identified in a toxicology sample in the USA in Q3 2021. N,N-Dimethylpentylone is increasingly being identified in forensic toxicology samples, rising in positivity from 0% in Q3 2021 to 1.5% in Q1 2022, while eutylone fell from 9.2% to 2.5%. Concentrations observed in blood were high and consistent with other NPS stimulants reported. Laboratories may misidentify N,N-dimethylpentylone as N-ethylpentylone due to their isomeric relationship; however, it has been our experience that concurrent identification of pentylone may give a stronger indication that N,N-dimethylpentylone is present. This is due to the fact that pentylone is a metabolite of N,N-dimethylpentylone, and is not a metabolite of N-ethylpentylone. N,N-Dimethylpentylone is an increasingly prevalent synthetic stimulant being identified in forensic cases in the United States and around the world. Continued awareness about the emergence of new stimulants after international control is imperative as positivity will vary as previously prevalent drugs fade and new drug emerge. Undoubtedly, the emergence of N,N-dimethylpentylone depicts a shift in the international NPS market of stimulants.