13 Nov Synthetic Stimulants
Novel Psychoactive Substances (NPS) are a diverse group of synthetic substances created to mimic the effects of scheduled or illicit drugs; however, they may vary widely in both toxicity and potency from the drugs they are intended to mimic. Synthetic stimulants, along with synthetic cannabinoids, are NPS for which traditional toxicology testing is widely available. However, it is important to know what compounds are in circulation in the illicit drug supply when evaluating a test menu, as a single synthetic stimulant’s availability typically rises and falls over time in response to regulation and is replaced with new compounds.1-3
The most common type of synthetic stimulants in circulation today are cathinones, so they are the focus of this update. They are derivatives of the naturally occurring compound cathinone, which is the primary psychoactive component of khat. They are “euphoric stimulants,” meaning they have a short duration of physical and psychological effects like more common stimulants such as amphetamine. Synthetic cathinones first appeared in the early 2000s and were sold as “bath salts” but have also been erroneously labeled as incense, plant food, or jewelry cleaner and are typically labeled “Not for human consumption” to avoid regulation. The top reasons users choose synthetic cathinones include availability, affordability,4 and avoidance of legal ramifications.5 They are often sold as MDMA or may be incorporated into other drug products when more common stimulants are in short supply.6-9 However, synthetic stimulants can be much more potent than the drugs they are intended to mimic. Adverse effects can include agitation, combative violent behavior, tachycardia and hypertension, hallucinations, paranoia, confusion, vomiting, hyperthermia, seizures, and death.10,11 Single-patient case reports have also reported hyperpyrexia, seizures, hyponatremia, rhabdomyolysis, myocarditis, metabolic acidosis, and death.12-20 In a case series of three reported deaths from methylone (synthetic cathinone) intoxication, all patients had hyperpyrexia and seizures, with metabolic acidosis, disseminated intravascular coagulation, and acute renal failure.12,21
As classes of drugs become regulated, new derivatives appear to market to evade the law.2,3,22 Piperazines are a class of synthetic stimulants that share the abuse and dependence potential of dextroamphetamine, cocaine, LSD, and MDMA. As expected, they also cause psychoactive and sympathomimetic-like symptoms. In some cases, they have been found to cause severe complications and death.23 Piperazines have also been found to be combined with legal and illegal substances including synthetic cannabinoids, cathinones, and herbal products.24 Effective toxicology screening techniques continue to be needed to identify and limit the use of synthetic stimulant drugs.25
Testing menus that are not routinely updated may be searching for compounds that are not in circulation. As an illustration, Aegis’ testing trends for select synthetic cathinones are shown below. In Figure 1, a rise in eutylone samples from 2020 to 2021 is followed by a sharp decline. The peak detection of eutylone in 2021 coincides with the appearance of pentylone, which was later determined to be present as a metabolite of a new cathinone, N,N-dimethylpentylone. Pentylone and N,N-dimethylpentylone are the most common cathinones detected currently, but their detection may have reached a peak in mid-2023, as the number of positive samples decreased in Q3 2023.
On a different scale, Figure 2 shows N-cyclohexyl methylone, which is one of the emerging cathinones that may replace the most detected cathinones from Figure 1. It was first detected in Q2 2022 and is on a general upward trend. Figure 2 also illustrates the rise and decline of butylone from its peak in Q3 2021. As butylone began to decline, a slight increase in alpha-PiHP detections began, although it has declined somewhat since the peak in Q2 2022. The declines in butylone and alpha-PiHP also closely coincide with the sharp increases in pentylone and N,N-dimethylpentylone detection previously illustrated in Figure 1.
Laboratories’ test menus are developed at a fixed point in time to reflect drug trends at the time of development. As illustrated above, these trends change and regular updates to testing menus are as important, or possibly more important, than having a test offering at all. Updates can greatly reduce the likelihood of false-negative results and undetected drug use. Most importantly, when evaluating test menus, clinicians should have an awareness of what drugs are in circulation in their area to determine if test coverage is adequate.
Aegis’ Synthetic Stimulant Test Menu (as of 11/1/2023)
|
2-Fluoromethamphetamine** |
Butylone* |
N-ethyl Heptedrone* |
|
3/4-Fluoromethamphetamine** |
Chloro-N,N-DMC* |
N-ethyl Hexedrone* |
|
3/4-Methylmethcathinone* |
Dimethylone* |
N-ethyl Pentedrone* |
|
3,4-DMMA** |
Eutylone* |
N-propyl Butylone* |
|
4F-3-methyl-alpha-PVP* |
MBZP** |
NM N-cyclohexyl Methylone* |
|
4-Fluoromethylphenidate** |
MDPHP** |
N,N-dimethyl Pentylone* |
|
Alpha-D2PV* |
Methylenedioxy-PV8* |
Pentylone* |
|
Alpha-PiHP* |
N-butyl-Hexedrone* |
TFMPP**
|
|
Alpha-PHP* |
N-cyclohexyl Butylone* |
|
|
Benzylone* |
N-cyclohexyl Methylone* |
|
*Denotes synthetic cathinone
**Non-cathinone stimulant
NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.
References:
1. Michienzi AE, Borek HA. Emerging Agents of Substance Use/Misuse. Emerg Med Clin North Am. 2022 May;40(2):265-281. doi: 10.1016/j.emc.2022.01.001. Epub 2022 Apr 5. PMID: 35461623.
2. Pulver B, Riedel J, Westphal F, Luhn S, Schönberger T, Schäper J, Auwärter V, Luf A, Pütz M. A new synthetic cathinone: 3,4-EtPV or 3,4-Pr-PipVP? An unsuccessful attempt to circumvent the German legislation on new psychoactive substances. Drug Test Anal. 2023 Jan;15(1):84-96. doi: 10.1002/dta.3371. Epub 2022 Oct 26. PMID: 36136085.
3. Fogarty MF, Krotulski AJ, Papsun DM, Walton SE, Lamb M, Truver MT, Chronister CW, Goldberger BA, Logan BK. N, N-Dimethylpentylone (Dipentylone)-A New Synthetic Cathinone Identified in a Postmortem Forensic Toxicology Case Series. J Anal Toxicol. 2023 Jun 17:bkad037. doi: 10.1093/jat/bkad037. Epub ahead of print. PMID: 37329303.
4. Sutherland R, Bruno R, Peacock A, et al. Motivations for new psychoactive substance use among regular psychostimulant users in Australia. Int J Drug Policy. 2017;43:23-32. doi:10.1016/j.drugpo.2016.12.021
5. Riley AL, Nelson KH, To P, et al. Abuse potential and toxicity of the synthetic cathinones (i.e., “Bath salts”). Neurosci Biobehav Rev. 2020;110:150-173. doi:10.1016/j.neubiorev.2018.07.015
6. National Drug Threat Assessment 2019. US Department of Justice Drug Enforcement Administration. Dec 2019; DEA-DCT-DIR-007-20. https://www.dea.gov/sites/default/files/2020-01/2019-NDTA-final-01-14-2020_Low_Web-DIR-007-20_2019.pdf.
7. Oliver CF, Palamar JJ, Salomone A, et al. Synthetic cathinone adulteration of illegal drugs. Psychopharmacology (Berl). 2019;236(3):869-879. doi:10.1007/s00213-018-5066-6
8. European Monitoring Centre for Drugs and Drug Addiction. EU Drug Markets Report 2019. https://www.emcdda.europa.eu/system/files/publications/12078/20192630_TD0319332ENN_PDF.pdf
9. Gomila Muñiz I, Lendoiro E, de-Castro-Ríos A, Elorza Guerrero MÁ, Puiguriguer Ferrando J, Sahuquillo Frias L, Sanchís Cortés P, Barceló Martín B. Detection of unsuspected cathinone and piperazine-type drugs in urine samples positive for methamphetamine and amphetamine collected in emergency departments. Emergencias. 2022 Jun;34(3):174-180. English, Spanish. PMID: 35736521.
10. Marinetti LJ, Antonides HM. Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol. 2013;37(3):135-146. doi:10.1093/jat/bks136
11. Tamama K. Synthetic drugs of abuse. Adv Clin Chem. 2021;103:191-214. doi:10.1016/bs.acc.2020.10.001
12. Capriola M. Synthetic cathinone abuse. Clin Pharmacol. 2013;5:109-115. Published 2013 Jul 2. doi:10.2147/CPAA.S42832
13. Sauer C, Hoffmann K, Schimmel U, Peters FT. Acute poisoning involving the pyrrolidinophenone-type designer drug 4′-methyl-alpha-pyrrolidinohexanophenone (MPHP). Forensic Sci Int. 2011;208(1-3):e20-e25. doi:10.1016/j.forsciint.2011.02.026
14. Borek HA, Holstege CP. Hyperthermia and multiorgan failure after abuse of “bath salts” containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med. 2012;60(1):103-105. doi:10.1016/j.annemergmed.2012.01.005
15. Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, O’Riordan JI. A harmless high?. Lancet. 2010;376(9742):742. doi:10.1016/S0140-6736(10)60891-4
16. Murray BL, Murphy CM, Beuhler MC. Death following recreational use of designer drug “bath salts” containing 3,4-Methylenedioxypyrovalerone (MDPV). J Med Toxicol. 2012;8(1):69-75. doi:10.1007/s13181-011-0196-9
17. Daziani G, Lo Faro AF, Montana V, et al. Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review. Int J Mol Sci. 2023;24(7):6230. Published 2023 Mar 25. doi:10.3390/ijms24076230
18. Lee PY, Hsu CC, Chan CH. Synthetic Cathinone-Induced Myocarditis and Psychosis: A Case Report. J Addict Med. 2023 Mar-Apr 01;17(2):e135-e137. doi: 10.1097/ADM.0000000000001056. Epub 2022 Aug 24. PMID: 36001046.
19. Hobbs JM, DeRienz RT, Baker DD, Shuttleworth MR, Pandey M. Fatal Intoxication by the Novel Cathinone 4-Fluoro-3-methyl-a-PVP. J Anal Toxicol. 2022 Mar 21;46(3):e101-e104. doi: 10.1093/jat/bkac003. PMID: 35020879.
20. Wachholz P, Celinski R, Bujak-Gizycka B, Skowronek R, Pawlas N. A fatal case of poisoning with a cathinone derivative: a-PiHP and its postmortem distribution in body fluids and organ tissues. J Anal Toxicol. 2023 Jul 22;47(6):547-551. doi: 10.1093/jat/bkad026. PMID: 37130049; PMCID: PMC10362950.
21. Pearson JM, Hargraves TL, Hair LS, et al. Three fatal intoxications due to methylone. J Anal Toxicol. 2012;36(6):444-451. doi:10.1093/jat/bks043
22. Arbo MD, Bastos ML, Carmo HF. Piperazine compounds as drugs of abuse. Drug Alcohol Depend. 2012;122(3):174-185. doi:10.1016/j.drugalcdep.2011.10.007
23. Lee H, Wang GY, Curley LE, Kydd RR, Kirk IJ, Russell BR. Investigation of the effects of ‘piperazine-containing party pills’ and dexamphetamine on interhemispheric communication using electroencephalography. Psychopharmacology (Berl). 2016;233(15-16):2869-2877. doi:10.1007/s00213-016-4335-5
24. Tabarra I, Soares S, Rosado T, et al. Novel synthetic opioids – toxicological aspects and analysis. Forensic Sci Res. 2019;4(2):111-140. Published 2019 Jul 3. doi:10.1080/20961790.2019.1588933
25. Gilani F. Novel psychoactive substances: the rising wave of ‘legal highs’. Br J Gen Pract. 2016;66(642):8-9. doi:10.3399/bjgp16X683053
