Designer drug- Trifluoromethylphenylpiperazine derivatives (TFMPP) - A future potential peril towards modern society

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Muralikrishnan Dhanasekaran Mohammed Majrashi Darshini Desai Sindhu Ramesh Manoj Govindarajulu Mohammed Almaghrabi Jack Deruiter C. Randall Clark Vishnu Suppiramaniam Muralikrishnan Dhanasekaran

Abstract

“Designer drugs” (referred as synthetic drugs, research drugs/chemicals) are synthesized by drug dealers and chemists illicitly to elicit euphoric and psychostimulatory actions.  These drugs are structural congeners of illegal and/or banned abusive substances and exhibit pharmacological effects similar to their parent drug.  Moreover, due to its designed structural difference to circumvent drug laws, these can be currently obtained legitimately and readily in common stores and through internet.  Alarmingly, several designer drugs are significantly toxic and perilous as compared to their corresponding street drug. Piperazine derivatives have been designed by substituting various chemical groups to the basic piperazine moiety to have a stimulatory effect. Various drugs with piperazine structural moieties are Benzylpiperazine-(BZP), 2C-B-BZP, CDPP, DBZP, MBZP, mCPP, MCDZP, MeOPP, pCPP, pFPP, and Trifluoromethylphenylpiperazine-(TFMPP). The most commonly abused piperazine derivatives are BZP, TFMPP and mCPP.  But, there are few articles that have revealed the prevalence and toxic actions of TFMPP.  Hence, in this review, we focus on pharmacodynamic, pharmacokinetic and toxic effects of TFMPP.  Similar to other stimulants, TFMPP also increases the monoaminergic neurotransmission. Interestingly, TFMPP principally affects the serotonergic neurotransmission. TFMPP displays significant agonistic activity towards 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C receptors, except the 5-HT2A receptor, where it acts as a weak partial agonist or antagonist. On the other hand, TFMPP has insignificant affinity towards 5-HT3 receptor. It also affects release of acetylcholine and the release and uptake of monoaminergic neurotransmitters (dopamine, norepinephrine). Due to the specific effects of TFMPP on serotonergic neurotransmission, it induces hallucination, psychotropic effect, anxiety, nociceptic effect, hypothermia, hypotension, and bradycardia. Furthermore, it has a great impact on various behavioral activities such as aggression, avoidance, anxiety, sexual activities, feeding and accommodation. Conversely, if suitable prophylactic and therapeutic measures are not considered immediately, TFMPP can be an impending danger for the global health care.

Article Details

How to Cite
DHANASEKARAN, Muralikrishnan et al. Designer drug- Trifluoromethylphenylpiperazine derivatives (TFMPP) - A future potential peril towards modern society. Medical Research Archives, [S.l.], v. 5, n. 8, aug. 2017. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/1190>. Date accessed: 20 apr. 2024.
Keywords
Trifluoromethylphenylpiperazine (TFMPP), Designer Drugs, Substances of Abuse, Psychostimulatory substances, Serotonergic neurotransmission
Section
Review Articles

References

References:
1. Crocq M-A. Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues Clin Neurosci. 2007;9(4):355–61.
2. Gerritsen J. Host defence mechanisms of the respiratory system. Paediatr Respir Rev [Internet]. 2000 Jun;1(2):128–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12531105
3. Hübner M. Zwischen Alkohol und Abstinenz : Trinksitten und Alkoholfrage im deutschen Proletariat bis 1914. Dietz; 1988. 223 p.
4. Gao H, Qi M, Zhang Q. Response inhibition is more effortful than response activation: behavioral and electrophysiological evidence. Neuroreport. 2017 Mar;
5. Tscharke BJ, Chen C, Gerber JP, White JM. Temporal trends in drug use in {Adelaide}, {South} {Australia} by wastewater analysis. Sci Total Environ [Internet]. 2016 Sep;565:384–91. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0048969716308853
6. Tang MHY, Ching CK, Tse ML, Ng C, Lee C, Chong YK, et al. Surveillance of emerging drugs of abuse in {Hong} {Kong}: validation of an analytical tool. Hong Kong Med J = Xianggang Yi Xue Za Zhi. 2015 Apr;21(2):114–23.
7. Maciów-Głąb M, Rojek S, Kula K, Kłys M. "New designer drugs" in aspects of forensic toxicology. Arch Med sa̧dowej i Kryminol [Internet]. [cited 2016 May 26];64(1):20–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25184424
8. Elliott S, Evans J. A 3-year review of new psychoactive substances in casework. Forensic Sci Int [Internet]. 2014 Oct [cited 2016 May 26];243:55–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24810679
9. Chen C, Kostakis C, Irvine RJ, White JM. Increases in use of novel synthetic stimulant are not directly linked to decreased use of 3,4-methylenedioxy-{N}-methylamphetamine ({MDMA}). Forensic Sci Int. 2013 Sep;231(1–3):278–83.
10. Young SA, Thrimawithana TR, Antia U, Fredatovich JD, Na Y, Neale PT, et al. Pharmaceutical quality of "party pills" raises additional safety concerns in the use of illicit recreational drugs. N Z Med J [Internet]. 2013 Jun 14 [cited 2016 May 26];126(1376):61–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23822962
11. Sheridan J, Dong CY, Butler R, Barnes J. The impact of {New} {Zealand}’s 2008 prohibition of piperazine-based party pills on young people’s substance use: results of a longitudinal, web-based study. Int J Drug Policy. 2013 Sep;24(5):412–22.
12. Zuba D, Byrska B. Prevalence and co-existence of active components of “legal highs”. Drug Test Anal [Internet]. 2013 Jun;5(6):420–9. Available from: http://doi.wiley.com/10.1002/dta.1365
13. World Health Organization. WHO expert committee on drug dependence. World Health Organ Tech Rep Ser [Internet]. 2012 [cited 2016 May 26];(973):1–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24547667
14. Arbo MD, Bastos ML, Carmo HF. Piperazine compounds as drugs of abuse. Drug Alcohol Depend [Internet]. 2012 May 1 [cited 2016 May 26];122(3):174–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22071119
15. Maskell PD, Paoli GD, Seetohul LN, Pounder DJ. Phenazepam is currently being misused in the {UK}. BMJ [Internet]. 2011 Jul;343(jul05 3):d4207--d4207. Available from: http://www.bmj.com/cgi/doi/10.1136/bmj.d4207
16. Poon WT, Lai CF, Lui MC, Chan AYW, Mak TWL. Piperazines: a new class of drug of abuse has landed in {Hong} {Kong}. Hong Kong Med J = Xianggang Yi Xue Za Zhi. 2010 Feb;16(1):76–7.
17. Wilkins C, Sweetsur P. Differences in harm from legal BZP/TFMPP party pills between North Island and South Island users in New Zealand: a case of effective industry self-regulation? Int J Drug Policy [Internet]. 2010 Jan [cited 2016 May 26];21(1):86–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19359158
18. Wilkins C, Sweetsur P, Girling M. Patterns of benzylpiperazine/trifluoromethylphenylpiperazine party pill use and adverse effects in a population sample in New Zealand. Drug Alcohol Rev [Internet]. 2008 Nov [cited 2016 May 26];27(6):633–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19378447
19. Elliott S, Smith C. Investigation of the first deaths in the United Kingdom involving the detection and quantitation of the piperazines BZP and 3-TFMPP. J Anal Toxicol [Internet]. 2008 Mar [cited 2016 May 26];32(2):172–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18334102
20. de Boer D, Bosman IJ, Hidvégi E, Manzoni C, Benkö AA, dos Reys LJ, et al. Piperazine-like compounds: a new group of designer drugs-of-abuse on the European market. Forensic Sci Int [Internet]. 2001 Sep 15 [cited 2016 May 26];121(1–2):47–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11516887
21. Lin JC, Jan RK, Kydd RR, Russell BR. Subjective effects in humans following administration of party pill drugs BZP and TFMPP alone and in combination. Drug Test Anal [Internet]. 2011 Sep [cited 2016 May 26];3(9):582–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21538945
22. Lin JC, Jan RK, Lee H, Jensen M-A, Kydd RR, Russell BR. Determining the subjective and physiological effects of BZP combined with TFMPP in human males. Psychopharmacology (Berl) [Internet]. 2011 Apr [cited 2016 May 26];214(3):761–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21060995
23. Sánchez C, Arnt J, Moltzen EK. The antiaggressive potency of (-)-penbutolol involves both 5-{HT}1A and 5-{HT}1B receptors and beta-adrenoceptors. Eur J Pharmacol. 1996 Feb;297(1–2):1–8.
24. Oliver JM, Klocek J, Wells A. Depressed and anxious moods mediate relations among perceived socialization, self-focused attention, and dysfunctional attitudes. J Clin Psychol. 1995 Nov;51(6):726–39.
25. Rowland NE, Robertson K, Lo J, Rema E. Cross tolerance between anorectic action and induction of {Fos}-ir with dexfenfluramine and 5HT1B/2C agonists in rats. Psychopharmacology (Berl). 2001 Jun;156(1):108–14.
26. Rowland NE, Marshall M, Roth JD. Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats. Psychopharmacology (Berl). 2000 Mar;149(1):77–83.
27. Tokumo K, Tamura N, Hirai T, Nishio H. Effects of ({Z})-3-hexenol, a major component of green odor, on anxiety-related behavior of the mouse in an elevated plus-maze test and biogenic amines and their metabolites in the brain. Behav Brain Res. 2006 Jan;166(2):247–52.
28. Stewart BR, Jenner P, Marsden CD. Induction of purposeless chewing behaviour in rats by 5-{HT} agonist drugs. Eur J Pharmacol. 1989 Mar;162(1):101–7.
29. Liminga U, Johnson AE, Andrén PE, Gunne LM. Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat. Pharmacol Biochem Behav. 1993 Oct;46(2):427–33.
30. Yarosh HL, Katz EB, Coop A, Fantegrossi WE. MDMA-like behavioral effects of N-substituted piperazines in the mouse. Pharmacol Biochem Behav [Internet]. 2007 Nov [cited 2016 May 26];88(1):18–27. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17651790
31. Fantegrossi WE, Winger G, Woods JH, Woolverton WL, Coop A. Reinforcing and discriminative stimulus effects of 1-benzylpiperazine and trifluoromethylphenylpiperazine in rhesus monkeys. Drug Alcohol Depend. 2005 Feb;77(2):161–8.
32. Maj J, Bijak M, Dziedzicka-Wasylewska M, Rogoz R, Rogóz Z, Skuza G, et al. The effects of paroxetine given repeatedly on the 5-{HT} receptor subpopulations in the rat brain. Psychopharmacology (Berl). 1996 Sep;127(1):73–82.
33. Chojnacka-Wójcik E. Modulation of the 5-{HT}1C receptor-mediated behavior by 5-{HT}2, but not 5-{HT}1A, receptor activation. Pol J Pharmacol Pharm. 1992 Oct;44(5):427–36.
34. Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ, et al. Modulation of 5-{HT}(2A) receptor-mediated head-twitch behaviour in the rat by 5-{HT}(2C) receptor agonists. Pharmacol Biochem Behav. 2001 Aug;69(3–4):643–52.
35. Darmani NA, Martin BR, Glennon RA. Withdrawal from chronic treatment with (+/-)-{DOI} causes super-sensitivity to 5-{HT}2 receptor-induced head-twitch behaviour in mice. Eur J Pharmacol. 1990 Sep;186(1):115–8.
36. Herndon JL, Pierson ME, Glennon RA. Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine. Pharmacol Biochem Behav [Internet]. 1992 Nov [cited 2016 May 26];43(3):739–48. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1333084
37. Grant KA, Colombo G. Discriminative stimulus effects of ethanol: effect of training dose on the substitution of {N}-methyl-{D}-aspartate antagonists. J Pharmacol Exp Ther. 1993 Mar;264(3):1241–7.
38. Kant GJ, Meininger GR, Maughan KR, Wright WL, Robinson TN, Neely TM. Effects of the serotonin receptor agonists 8-{OH}-{DPAT} and {TFMPP} on learning as assessed using a novel water maze. Pharmacol Biochem Behav. 1996 Feb;53(2):385–90.
39. Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry. 1998 Aug;44(3):151–62.
40. Meneses A. Involvement of 5-{HT}(2A/2B/2C) receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol. 2002 Dec;22(5–6):675–88.
41. De Vry J, Schreiber R, Daschke A, Jentzsch KR. Effects of serotonin 5-{HT}(1/2) receptor agonists in a limited-access operant food intake paradigm in the rat. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2003 Oct;13(5):337–45.
42. McKearney JW. Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, {MK}-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine. Pharmacol Biochem Behav. 1990 Jan;35(1):181–5.
43. Lucion AB, De Almeida RM, De Marques AA. Influence of the mother on development of aggressive behavior in male rats. Physiol Behav. 1994 Apr;55(4):685–9.
44. Frances H, Monier C, Debray M. Behavioral effect of beta-blocking drugs resulting from the stimulation or the blockade of serotonergic 5-{HT}1B receptors. Pharmacol Biochem Behav. 1994 Aug;48(4):965–9.
45. Mørk A, Geisler A. 5-{Hydroxytryptamine} receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat. Eur J Pharmacol. 1990 Jan;175(3):237–44.
46. Lecci A, Borsini F, Mancinelli A, D’Aranno V, Stasi MA, Volterra G, et al. Effect of serotoninergic drugs on stress-induced hyperthermia ({SIH}) in mice. J Neural Transm Gen Sect. 1990;82(3):219–30.
47. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. ENGLAND; 1999 Feb;66(2):137–47.
48. Pickard GE, Weber ET, Scott PA, Riberdy AF, Rea MA. 5HT1B receptor agonists inhibit light-induced phase shifts of behavioral circadian rhythms and expression of the immediate-early gene c-fos in the suprachiasmatic nucleus. J Neurosci Off J Soc Neurosci. 1996 Dec;16(24):8208–20.
49. Hernandez EJ, Williams PA, Dudek FE. Effects of fluoxetine and {TFMPP} on spontaneous seizures in rats with pilocarpine-induced epilepsy. Epilepsia. 2002 Nov;43(11):1337–45.
50. Przegaliński E, Baran L, Siwanowicz J. Role of 5-hydroxytryptamine receptor subtypes in the 1-[3-(trifluoromethyl)phenyl] piperazine-induced increase in threshold for maximal electroconvulsions in mice. Epilepsia. 1994 Aug;35(4):889–94.
51. Crick H, Manuel NA, Wallis DI. A novel 5-{HT} receptor or a combination of 5-{HT} receptor subtypes may mediate depression of a spinal monosynaptic reflex in vitro. Neuropharmacology. 1994 Jul;33(7):897–904.
52. Cohen ML, Fuller RW, Kurz KD. {LY}53857, a selective and potent serotonergic (5-{HT}2) receptor antagonist, does not lower blood pressure in the spontaneously hypertensive rat. J Pharmacol Exp Ther. 1983 Nov;227(2):327–32.
53. Brown CM, Kilpatrick AT, Martin A, Spedding M. Cerebral ischaemia reduces the density of 5-{HT}2 binding sites in the frontal cortex of the gerbil. Neuropharmacology. 1988 Aug;27(8):831–6.
54. McKenney JD, Glennon RA. TFMPP may produce its stimulus effects via a 5-HT1B mechanism. Pharmacol Biochem Behav [Internet]. 1986 Jan [cited 2016 May 26];24(1):43–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3945665
55. Thompson I, Williams G, Caldwell B, Aldington S, Dickson S, Lucas N, et al. Randomised double-blind, placebo-controlled trial of the effects of the “party pills” BZP/TFMPP alone and in combination with alcohol. J Psychopharmacol [Internet]. 2010 Sep [cited 2016 May 26];24(9):1299–308. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19329546
56. Schep LJ, Slaughter RJ, Vale JA, Beasley DMG, Gee P. The clinical toxicology of the designer "party pills" benzylpiperazine and trifluoromethylphenylpiperazine. Clin Toxicol (Phila) [Internet]. 2011 Mar [cited 2016 May 26];49(3):131–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21495881
57. Di Sciullo A, Bluet-Pajot MT, Mounier F, Oliver C, Schmidt B, Kordon C. Changes in anterior pituitary hormone levels after serotonin 1A receptor stimulation. Endocrinology. 1990 Aug;127(2):567–72.
58. Rouru J, Pesonen U, Isaksson K, Huupponen R, Koulu M. Effect of chronic treatment with {TFMPP}, a 5-{HT}1 receptor agonist, on food intake, weight gain, plasma insulin and neuropeptide {mRNA} expression in obese {Zucker} rats. Eur J Pharmacol. 1993 Apr;234(2–3):191–8.
59. Kitchener SJ, Dourish CT. An examination of the behavioural specificity of hypophagia induced by 5-{HT}1B, 5-{HT}1C and 5-{HT}2 receptor agonists using the post-prandial satiety sequence in rats. Psychopharmacology (Berl). 1994 Jan;113(3–4):369–77.
60. Kennett GA, Whitton P, Shah K, Curzon G. Anxiogenic-like effects of {mCPP} and {TFMPP} in animal models are opposed by 5-{HT}1C receptor antagonists. Eur J Pharmacol. 1989 May;164(3):445–54.
61. Roudebush RE, Bryant HU. Pharmacologic manipulation of a four day murine delayed type hypersensitivity model. Agents Actions. 1993 Jan;38(1–2):116–21.
62. Aiello-Zaldivar M, Luine V, Frankfurt M. 5,7-{DHT} facilitated lordosis: effects of 5-{HT} agonists. Neuroreport. 1992 Jun;3(6):542–4.
63. Krantic S, Robitaille Y, Quirion R. Deficits in the somatostatin {SS}1 receptor sub-type in frontal and temporal cortices in {Alzheimer}’s disease. Brain Res. 1992 Feb;573(2):299–304.
64. Rea MA, Pickard GE. A 5-{HT}(1B) receptor agonist inhibits light-induced suppression of pineal melatonin production. Brain Res. 2000 Mar;858(2):424–8.
65. Heidenreich BA, Napier TC. Effects of serotonergic 5-{HT}1A and 5-{HT}1B ligands on ventral pallidal neuronal activity. Neuroreport. 2000 Sep;11(13):2849–53.
66. Sawynok J, Reid A. Neurotoxin-induced lesions to central serotonergic, noradrenergic and dopaminergic systems modify caffeine-induced antinociception in the formalin test and locomotor stimulation in rats. J Pharmacol Exp Ther. 1996 May;277(2):646–53.
67. Waldmeier PC, Williams M, Baumann PA, Bischoff S, Sills MA, Neale RF. Interactions of isamoltane ({CGP} 361A), an anxiolytic phenoxypropanolamine derivative, with 5-{HT}1 receptor subtypes in the rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1988 Jun;337(6):609–20.
68. Robertson DW, Bloomquist W, Wong DT, Cohen ML. mCPP but not TFMPP is an antagonist at cardiac 5HT3 receptors. Life Sci. 1992; 50(8): 599-605.
69. Lee H, Wang GY, Curley LE, Sollers JJ, Kydd RR, Kirk IJ, et al. Acute effects of BZP, TFMPP and the combination of BZP and TFMPP in comparison to dexamphetamine on an auditory oddball task using electroencephalography: a single-dose study. Psychopharmacology (Berl) [Internet]. 2016 Mar [cited 2016 May 26];233(5):863–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26630992
70. Edwards E, Whitaker-Azmitia PM, Harkins K. 5-{HT}1A and 5-{HT}1B agonists play a differential role on the respiratory frequency in rats. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 1990 Apr;3(2):129–36.
71. King KA, Holtman JR. Characterization of the effects of activation of ventral medullary serotonin receptor subtypes on cardiovascular activity and respiratory motor outflow to the diaphragm and larynx. J Pharmacol Exp Ther. 1990 Feb;252(2):665–74.
72. Curley LE, Kydd RR, Kirk IJ, Russell BR. Differential responses to anticipation of reward after an acute dose of the designer drugs benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) alone and in combination using functional magnetic resonance imaging (fMRI). Psychopharmacology (Berl) [Internet]. 2013 Oct [cited 2016 May 26];229(4):673–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23666554
73. Hayes ES, Adaikan PG. The effects of 5HT(1) agonists on erection in rats in vivo and rabbit corpus cavernosum in vitro. Int J Impot Res. 2002 Aug;14(4):205–12.
74. Pastel RH, Fernstrom JD. Short-term effects of fluoxetine and trifluoromethylphenylpiperazine on electroencephalographic sleep in the rat. Brain Res. 1987 Dec;436(1):92–102.
75. Matsumoto RR, Hussong MJ, Truong DD. Effects of selective serotonergic ligands on posthypoxic audiogenic myoclonus. Mov Disord Off J Mov Disord Soc. 1995 Sep;10(5):615–21.
76. da Silva D, Silva MJ, Moreira P, Martins MJ, Valente MJ, Carvalho F, et al. In vitro hepatotoxicity of “{Legal} {X}”: the combination of 1-benzylpiperazine ({BZP}) and 1-(m-trifluoromethylphenyl)piperazine ({TFMPP}) triggers oxidative stress, mitochondrial impairment and apoptosis. Arch Toxicol. 2017 Mar;91(3):1413–30.
77. Antia U, Tingle MD, Russell BR. Validation of an {LC}-{MS} {Method} for the {Detection} and {Quantification} of {BZP} and {TFMPP} and their {Hydroxylated} {Metabolites} in {Human} {Plasma} and its {Application} to the {Pharmacokinetic} {Study} of {TFMPP} in {Humans}*. J Forensic Sci [Internet]. 2010 Sep;55(5):1311–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20533987
78. Antia U, Tingle MD, Russell BR. Metabolic interactions with piperazine-based “party pill” drugs. J Pharm Pharmacol [Internet]. 2009 Jul [cited 2016 May 26];61(7):877–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19589229
79. Antia U, Lee HS, Kydd RR, Tingle MD, Russell BR. Pharmacokinetics of “party pill” drug N-benzylpiperazine (BZP) in healthy human participants. Forensic Sci Int [Internet]. 2009 Apr 15 [cited 2016 May 26];186(1–3):63–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19261399
80. Chou K. Distribution of BZP and TFMPP. University of Auckland; 2008.
81. Baumann MH, Clark RD, Budzynski AG, Partilla JS, Blough BE, Rothman RB. N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or “Ecstasy”). Neuropsychopharmacology [Internet]. 2005 Mar [cited 2016 May 26];30(3):550–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15496938
82. Walsh I, Wasserman GS, Mestad P, Lanman RC. Near-fatal caffeine intoxication treated with peritoneal dialysis. Pediatr Emerg Care. 1987 Dec;3(4):244–9.
83. Holmgren P, Nordén-Pettersson L, Ahlner J. Caffeine fatalities--four case reports. Forensic Sci Int [Internet]. 2004 Jan 6 [cited 2017 Mar 10];139(1):71–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14687776
84. Kerrigan S, Lindsey T. Fatal caffeine overdose: Two case reports. Forensic Sci Int [Internet]. 2005 Oct 4 [cited 2017 Mar 10];153(1):67–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15935584
85. Staack RF, Fritschi G, Maurer HH. New designer drug 1-(3-trifluoromethylphenyl) piperazine ({TFMPP}): gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry studies on its phase {I} and {II} metabolism and on its toxicological detection in rat urine. J mass Spectrom JMS. 2003 Sep;38(9):971–81.
86. Peters FT, Schaefer S, Staack RF, Kraemer T, Maurer HH. Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry. J mass Spectrom JMS. 2003 Jun;38(6):659–76.
87. Staack RF, Maurer HH. Metabolism of designer drugs of abuse. Curr Drug Metab [Internet]. 2005 Jun [cited 2016 May 26];6(3):259–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15975043
88. Staack RF, Paul LD, Springer D, Kraemer T, Maurer HH. Cytochrome {P}450 dependent metabolism of the new designer drug 1-(3-trifluoromethylphenyl)piperazine ({TFMPP}). {In} vivo studies in {Wistar} and {Dark} {Agouti} rats as well as in vitro studies in human liver microsomes. Biochem Pharmacol. 2004 Jan;67(2):235–44.
89. Fuller RW, Snoddy HD, Mason NR, Hemrick-Luecke SK, Clemens JA. Substituted piperazines as central serotonin agonists: comparative specificity of the postsynaptic actions of quipazine and m-trifluoromethylphenylpiperazine. J Pharmacol Exp Ther. 1981 Sep;218(3):636–41.
90. Toomey RE, Horng JS, Hemrick-Luecke SK, Fuller RW. alpha 2 {Adrenoreceptor} affinity of some inhibitors of norepinephrine {N}-methyltransferase. Life Sci [Internet]. 1981 Dec;29(24):2467–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6119595
91. Hashimoto K, Ohno N, Murakami K, Kageyama J, Aoki Y, Takahara J. The effect of serotonin agonist 1-(trifluoromethylphenyl)-piperazine on corticotropin releasing factor and arginine vasopressin in rat hypothalamic nuclei. Endocrinol Jpn. 1982 Jun;29(3):383–8.
92. Pettibone DJ, Williams M. Serotonin-releasing effects of substituted piperazines in vitro. Biochem Pharmacol. 1984 May;33(9):1531–5.
93. Glennon RA, Titeler M, McKenney JD. Evidence for 5-{HT}2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984 Dec;35(25):2505–11.
94. Brady LS, Barrett JE. Effects of serotonin receptor agonists and antagonists on schedule-controlled behavior of squirrel monkeys. J Pharmacol Exp Ther. 1985 Nov;235(2):436–41.
95. Cunningham KA, Appel JB. Possible 5-hydroxytryptamine1 (5-{HT}1) receptor involvement in the stimulus properties of 1-(m-trifluoromethylphenyl)piperazine ({TFMPP}). J Pharmacol Exp Ther. 1986 May;237(2):369–77.
96. Sprouse JS, Aghajanian GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-{HT}1A and 5-{HT}1B agonists. Synapse. 1987;1(1):3–9.
97. Dabire H, Cherqui C, Fournier B, Schmitt H. Comparison of effects of some 5-{HT}1 agonists on blood pressure and heart rate of normotensive anaesthetized rats. Eur J Pharmacol. 1987 Aug;140(3):259–66.
98. Glennon RA, Pierson ME, McKenney JD. Stimulus generalization of 1-(3-trifluoromethylphenyl)piperazine ({TFMPP}) to propranolol, pindolol, and mesulergine. Pharmacol Biochem Behav. 1988 Jan;29(1):197–9.
99. Murakami H, Sano M, Tsukimura T, Yamazaki A. The relaxation induced by indole and nonindole 5-{HT} agonists in the molluscan smooth muscle. Comp Biochem Physiol C. 1988;90(1):249–55.
100. Titeler M, Lyon RA, Davis KH, Glennon RA. Selectivity of serotonergic drugs for multiple brain serotonin receptors. Role of [3H]-4-bromo-2,5-dimethoxyphenylisopropylamine ([3H]DOB), a 5-HT2 agonist radioligand. Biochem Pharmacol [Internet]. 1987 Oct 1 [cited 2017 Mar 10];36(19):3265–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3663239
101. Maj J, Chojnacka-Wójcik E, Kłodzińska A, Dereń A, Moryl E. Hypothermia induced by m-trifluoromethylphenylpiperazine or m-chlorophenylpiperazine: an effect mediated by 5-{HT}1B receptors? J Neural Transm. 1988;73(1):43–55.
102. Frances H. Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP). Pharmacol Biochem Behav [Internet]. 1988 Sep [cited 2016 May 26];31(1):37–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3252258
103. McKearney JW. Apparent antinociceptive properties of piperazine-type serotonin agonists: trifluoromethylphenylpiperazine, chlorophenylpiperazine, and {MK}-212. Pharmacol Biochem Behav. 1989 Mar;32(3):657–60.
104. Berlyne GM. Pseudoxanthoma elasticum. Lancet (London, England). 1960 Jan;1(7115):77–80.
105. Glickman SE, Sroges RW. Curiosity in zoo animals. Behaviour. 1966;26(1):151–88.
106. Welker WI, Benjamin RM, Miles RC, Woolsey CN. Motor effects of stimulation of cerebral cortex of squirrel monkey ({Saimiri} sciureus). J Neurophysiol. 1957 Jul;20(4):347–64.
107. MONTGOMERY KC, MONKMAN JA. The relation between fear and exploratory behavior. J Comp Physiol Psychol [Internet]. 1955 Apr;48(2):132–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14367588
108. Greenberg R. The role of neophobia and neophilia in the development of innovative behaviour of birds [Internet]. 2003 [cited 2017 Mar 10]. Available from: https://philpapers.org/rec/GRETRO-19
109. Hughes RN. Neotic preferences in laboratory rodents: issues, assessment and substrates. Neurosci Biobehav Rev. 2007;31(3):441–64.
110. Bardo MT, Donohew RL, Harrington NG. Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res [Internet]. 1996 May;77(1–2):23–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8762157
111. Hall CS. Emotional behavior in rats. Part I. Defecation and urination as measures of individual differences in emotionality. J. Comp. Physiol. Psychol. 1934;18:385–403.
112. Crawley JN. Cholecystokinin potentiation of dopamine-mediated behaviors in the nucleus accumbens. Ann N Y Acad Sci. 1985;448:283–92.
113. Gharbawie OA, Whishaw IQ. Parallel stages of learning and recovery of skilled reaching after motor cortex stroke: “oppositions” organize normal and compensatory movements. Behav Brain Res. 2006 Dec;175(2):249–62.
114. Kłodzińska A, Jaros T, Chojnacka-Wójcik E, Maj J. Exploratory hypoactivity induced by m-trifluoromethylphenylpiperazine ({TFMPP}) and m-chlorophenylpiperazine (m-{CPP}). J Neural Transm Park Dis Dement Sect. 1989;1(3):207–18.
115. Alhaider AA, Ageel AM, Ginawi OT. The quipazine- and {TFMPP}-increased conditioned avoidance response in rats: role of 5HT1C/5-{HT}2 receptors. Neuropharmacology. 1993 Dec;32(12):1427–32.
116. Bobker DH, Williams JT. Serotonin agonists inhibit synaptic potentials in the rat locus ceruleus in vitro via 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors. J Pharmacol Exp Ther [Internet]. American Society for Pharmacology and Experimental Therapeutics; 1989 Jul [cited 2017 Mar 10];250(1):37–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2526217
117. Dolzhenko AT, Komissarov I V, Kharin NA. The comparative effect of serotonin agonists on the presynaptic and somatodendritic autoreceptors of serotoninergic neurons. Biull Eksp Biol Med [Internet]. 1989 Dec [cited 2017 Mar 10];108(12):684–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2634439
118. Bolanos F, Fillion G. Minaprine antagonises the serotonergic inhibitory effect of trifluoromethylphenylpiperazine (TFMPP) on acetylcholine release. Eur J Pharmacol [Internet]. 1989 Sep 1 [cited 2017 Mar 10];168(1):87–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2583235
119. Benloucif S, Galloway MP. Facilitation of dopamine release in vivo by serotonin agonists: studies with microdialysis. Eur J Pharmacol. 1991 Jul;200(1):1–8.
120. Elverfors A, Nissbrandt H. Effects of d-amphetamine on dopaminergic neurotransmission; a comparison between the substantia nigra and the striatum. Neuropharmacology. 1992 Jul;31(7):661–70.
121. Prisco S, Esposito E. Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. Br J Pharmacol [Internet]. Blackwell Publishing Ltd; 1995 Sep [cited 2017 Mar 10];116(2):1923–31. Available from: http://doi.wiley.com/10.1111/j.1476-5381.1995.tb16684.x
122. Hemrick-Luecke SK, Fuller RW. Decreased hypothalamic epinephrine concentration by quipazine and other serotonin agonists in rats. Biochem Pharmacol. 1995 Jan;49(3):323–7.
123. Olivier B, Mos J. Rodent models of aggressive behavior and serotonergic drugs. Prog Neuropsychopharmacol Biol Psychiatry [Internet]. 1992 [cited 2017 Mar 10];16(6):847–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1513929
124. Cooper SJ, Barber DJ. Evidence for serotonergic involvement in saccharin preference in a two-choice test in rehydrating rats. Pharmacol Biochem Behav. 1994 Mar;47(3):541–6.
125. Zhang L, Dyer DC. Characterization of 5-hydroxytryptamine receptors on isolated ovine uterine artery in late pregnancy. J Pharmacol Exp Ther [Internet]. 1990 Jun [cited 2017 Mar 10];253(3):1236–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2359025
126. O’Gara BA, Illuzzi FA, Chung M, Portnoy AD, Fraga K, Frieman VB. Serotonin induces four pharmacologically separable contractile responses in the pharynx of the leech {Hirudo} medicinalis. Gen Pharmacol. 1999 Jun;32(6):669–81.
127. Hutson PH, Donohoe TP, Curzon G. Infusion of the 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia. Psychopharmacology (Berl) [Internet]. 1988 [cited 2017 Mar 10];95(4):550–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3145525
128. Fernández-Guasti A, Escalante A, Agmo A. Inhibitory action of various 5-HT1B receptor agonists on rat masculine sexual behaviour. Pharmacol Biochem Behav [Internet]. 1989 Dec [cited 2017 Mar 10];34(4):811–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2623035
129. Berendsen HH, Jenck F, Broekkamp CL. Involvement of 5-HT1C-receptors in drug-induced penile erections in rats. Psychopharmacology (Berl) [Internet]. 1990 [cited 2017 Mar 10];101(1):57–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2343074
130. Chaouloff F, Laude D, Baudrie V. Effects of the 5-HT1C/5-5-HT2 receptor agonists DOI and alpha-methyl-5-HT on plasma glucose and insulin levels in the rat. Eur J Pharmacol [Internet]. 1990 Oct 23 [cited 2017 Mar 10];187(3):435–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2127400
131. Poland RE, Frazer A. Corticosterone and prolactin response to TFMPP in rats during repeated antidepressant administration. J Pharm Pharmacol [Internet]. 1991 Jan [cited 2017 Mar 10];43(1):54–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1676062
132. da Silva D, Silva MJ, Moreira P, Martins MJ, Valente MJ, Carvalho F, et al. In vitro hepatotoxicity of “{Legal} {X}”: the combination of 1-benzylpiperazine ({BZP}) and 1-(m-trifluoromethylphenyl)piperazine ({TFMPP}) triggers oxidative stress, mitochondrial impairment and apoptosis. Arch Toxicol [Internet]. 2017 Mar;91(3):1413–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27358233
133. Dias-da-Silva D, Arbo MD, Valente MJ, Bastos ML, Carmo H. Hepatotoxicity of piperazine designer drugs: Comparison of different in vitro models. Toxicol In Vitro [Internet]. 2015 Aug [cited 2016 May 26];29(5):987–96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25863214
134. Arbo BD, Andrade S, Osterkamp G, Gomez R, Ribeiro MFM. Effect of low doses of progesterone in the expression of the {GABA}({A}) receptor α4 subunit and procaspase-3 in the hypothalamus of female rats. Endocrine. 2014 Aug;46(3):561–7.
135. Arbo MD, Silva R, Barbosa DJ, Dias da Silva D, Silva SP, Teixeira JP, et al. In vitro neurotoxicity evaluation of piperazine designer drugs in differentiated human neuroblastoma SH-SY5Y cells. J Appl Toxicol [Internet]. 2016 Jan [cited 2016 May 26];36(1):121–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25900438
136. Hondebrink L, Hermans EJP, Schmeink S, van Kleef RGDM, Meulenbelt J, Westerink RHS. Structure-dependent inhibition of the human α1β2γ2 GABAA receptor by piperazine derivatives: A novel mode of action. Neurotoxicology [Internet]. 2015 Dec [cited 2017 Mar 10];51:1–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26344803
137. Beckett NM, Cresswell SL, Grice DI, Carter JF. Isotopic profiling of seized benzylpiperazine and trifluoromethylphenylpiperazine tablets using δ13C and δ15N stable isotopes. Sci Justice J Forensic Sci Soc. 2015 Jan;55(1):51–6.
138. Stojanovska N, Kelly T, Tahtouh M, Beavis A, Fu S. Analysis of amphetamine-type substances and piperazine analogues using desorption electrospray ionisation mass spectrometry. Rapid Commun mass Spectrom RCM. 2014 Apr;28(7):731–40.
139. Siroká J, Polesel DN, Costa JL, Lanaro R, Tavares MFM, Polášek M. Separation and determination of chlorophenylpiperazine isomers in confiscated pills by capillary electrophoresis. J Pharm Biomed Anal. 2013 Oct;84:140–7.
140. Johnson RD, Botch-Jones SR. The stability of four designer drugs: {MDPV}, mephedrone, {BZP} and {TFMPP} in three biological matrices under various storage conditions. J Anal Toxicol. 2013 Mar;37(2):51–5.
141. Zuba D, Byrska B. Prevalence and co-existence of active components of “legal highs.” Drug Test Anal. 2013 Jun;5(6):420–9.
142. Rust KY, Baumgartner MR, Dally AM, Kraemer T. Prevalence of new psychoactive substances: A retrospective study in hair. Drug Test Anal [Internet]. 2012 Jun [cited 2016 May 26];4(6):402–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22522922
143. Moreno IED, da Fonseca BM, Barroso M, Costa S, Queiroz JA, Gallardo E. Determination of piperazine-type stimulants in human urine by means of microextraction in packed sorbent and high performance liquid chromatography-diode array detection. J Pharm Biomed Anal. 2012 Mar;61:93–9.
144. Elie L, Baron M, Croxton R, Elie M. Microcrystalline identification of selected designer drugs. Forensic Sci Int. 2012 Jan;214(1–3):182–8.
145. Bell C, George C, Kicman AT, Traynor A. Development of a rapid {LC}-{MS}/{MS} method for direct urinalysis of designer drugs. Drug Test Anal. 2011 Aug;3(7–8):496–504.
146. Wada M, Yamahara K, Ikeda R, Kikura-Hanajiri R, Kuroda N, Nakashima K. Simultaneous determination of {N}-benzylpiperazine and 1-(3-trifluoromethylphenyl)piperazine in rat plasma by {HPLC}-fluorescence detection and its application to monitoring of these drugs. Biomed Chromatogr BMC. 2012 Jan;26(1):21–5.
147. Wada M, Abe K, Ikeda R, Kikura-Hanajiri R, Kuroda N, Nakashima K. {HPLC} determination of methylphenidate and its metabolite, ritalinic acid, by high-performance liquid chromatography with peroxyoxalate chemiluminescence detection. Anal Bioanal Chem. 2011 Apr;400(2):387–93.
148. Moreno IED, da Fonseca BM, Magalhães AR, Geraldes VS, Queiroz JA, Barroso M, et al. Rapid determination of piperazine-type stimulants in human urine by microextraction in packed sorbent after method optimization using a multivariate approach. J Chromatogr A. 2012 Jan;1222:116–20.
149. Wohlfarth A, Weinmann W, Dresen S. {LC}-{MS}/{MS} screening method for designer amphetamines, tryptamines, and piperazines in serum. Anal Bioanal Chem. 2010 Apr;396(7):2403–14.
150. Dickson AJ, Vorce SP, Holler JM, Lyons TP. Detection of 1-benzylpiperazine, 1-(3-trifluoromethylphenyl)-piperazine, and 1-(3-chlorophenyl)-piperazine in 3,4-methylenedioxymethamphetamine-positive urine samples. J Anal Toxicol [Internet]. 2010 Oct [cited 2016 May 26];34(8):464–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21819791
151. Maher HM, Awad T, Clark CR. Differentiation of the regioisomeric 2-, 3-, and 4-trifluoromethylphenylpiperazines ({TFMPP}) by {GC}-{IRD} and {GC}-{MS}. Forensic Sci Int. 2009 Jul;188(1–3):31–9.
152. Vorce SP, Holler JM, Levine B, Past MR. Detection of 1-benzylpiperazine and 1-(3-trifluoromethylphenyl)-piperazine in urine analysis specimens using {GC}-{MS} and {LC}-{ESI}-{MS}. J Anal Toxicol. 2008 Aug;32(6):444–50.
153. Tsutsumi H, Katagi M, Miki A, Shima N, Kamata T, Nishikawa M, et al. Development of simultaneous gas chromatography-mass spectrometric and liquid chromatography-electrospray ionization mass spectrometric determination method for the new designer drugs, {N}-benzylpiperazine ({BZP}), 1-(3-trifluoromethylphenyl)piperazine ({T. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 May;819(2):315–22.
154. Bishop SC, McCord BR, Gratz SR, Loeliger JR, Witkowski MR. Simultaneous separation of different types of amphetamine and piperazine designer drugs by capillary electrophoresis with a chiral selector. J Forensic Sci. 2005 Mar;50(2):326–35.
155. Maher HM, Awad T, DeRuiter J, Clark CR. {GC}-{IRD} methods for the identification of some tertiary amines related to {MDMA}. Forensic Sci Int. 2010 Jun;199(1–3):18–28.