Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

Simmler, Linda D.; Liechti, Matthias E.

doi:10.1007/164_2018_113

Linda D. Simmler¹² &
Matthias E. Liechti¹³

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 252))

3892 Accesses
32 Citations
1 Altmetric

Abstract

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Chapter: USD 29.95; Price excludes VAT (USA)

eBook: USD 139.00; Price excludes VAT (USA)

Hardcover Book: USD 179.99; Price excludes VAT (USA)

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

2-AI:: 2-Aminoindane
3-MMC:: 3-Methyl-N-methylcathinone
4-APB:: 4-(2-Aminopropyl)benzofuran
4-FA:: 4-Fluoroamphetamine
4-MA:: 4-Methylamphetamine
4-MTA:: 4-Methylthioamphetamine
5-APB:: 5-(2-Aminopropyl)benzofuran
5-APDB:: 5-(2-Aminopropyl)-2,3-dihydrobenzofuran
5-EAPB:: 5-(2-Ethylaminopropyl)benzofuran
5-IAI:: 5-Iodoaminoindan
5-IT, 5-API:: 5-(2-Aminopropyl)indole
5-MAPDB:: 1-(2,3-Dihydrobenzofuran-5-yl)-N-methylpropan-2-amine
6-APB:: 6-(2-Aminopropyl)benzofuran
6-APDB:: 6-(2-Aminopropyl)-2,3-dihydrobenzofuran
7-APB:: 7-(2-Aminopropyl)benzofuran
MBDB:: 3,4-Methylenedioxyphenyl-N-methyl-2-butanamine
MDA:: 3,4-Methylenedioxyamphetamine
MDAI:: 3,4-Methylenedioxyaminoindan
MDEA:: 3,4-Methylenedioxy-N-ethylamphetamine
MMAI:: 5-Methoxy-6-methyl-2-aminoindan
PMA:: para-Methoxyamphetamine
PMMA:: para-Methoxymethamphetamine

References

Adamowicz P, Zuba D, Byrska B (2014) Fatal intoxication with 3-methyl-N-methylcathinone (3-MMC) and 5-(2-aminopropyl)benzofuran (5-APB). Forensic Sci Int 245:126–132. https://doi.org/10.1016/j.forsciint.2014.10.016
Article CAS PubMed Google Scholar
Aerts LA, Mallaret M, Rigter H (2000) N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): its properties and possible risks. Addict Biol 5(3):269–282. https://doi.org/10.1111/j.1369-1600.2000.tb00191.x
Article CAS PubMed Google Scholar
Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113(2):296–320. https://doi.org/10.1016/j.pharmthera.2006.08.004
Article CAS PubMed Google Scholar
Bäckberg M, Beck O, Hulten P, Rosengren-Holmberg J, Helander A (2014) Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): a case series from the Swedish STRIDA project. Clin Toxicol (Phila) 52(6):618–624. https://doi.org/10.3109/15563650.2014.920088
Article CAS Google Scholar
Bauer CT, Banks ML, Blough BE, Negus SS (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168(4):850–862. https://doi.org/10.1111/j.1476-5381.2012.02214.x
Article CAS PubMed PubMed Central Google Scholar
Baumann MH, Wang X, Rothman RB (2007) 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology 189(4):407–424. https://doi.org/10.1007/s00213-006-0322-6
Article CAS PubMed Google Scholar
Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (2011) In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther 337(1):218–225. https://doi.org/10.1124/jpet.110.176271
Article CAS PubMed PubMed Central Google Scholar
Baumann MH, Ayestas MA Jr, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (2012) The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue. Neuropsychopharmacology 37(5):1192–1203. https://doi.org/10.1038/npp.2011.304
Article CAS PubMed Google Scholar
Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘bath salts’ products. Neuropsychopharmacology 38(4):552–562. https://doi.org/10.1038/npp.2012.204
Article CAS PubMed Google Scholar
Bershad AK, Miller MA, Baggott MJ, de Wit H (2016) The effects of MDMA on socio-emotional processing: does MDMA differ from other stimulants? J Psychopharmacol 30:1248–1258. https://doi.org/10.1177/0269881116663120
Article CAS PubMed Google Scholar
Blakely RD, Defelice LJ, Galli A (2005) Biogenic amine neurotransmitter transporters: just when you thought you knew them. Physiology 20:225–231. https://doi.org/10.1152/physiol.00013.2005
Article CAS PubMed Google Scholar
Blanckaert P, van Amsterdam J, Brunt T, van den Berg J, Van Durme F, Maudens K, van Bussel J (2013) 4-Methyl-amphetamine: a health threat for recreational amphetamine users. J Psychopharmacol 27(9):817–822. https://doi.org/10.1177/0269881113487950
Article CAS PubMed Google Scholar
Bonano JS, Glennon RA, De Felice LJ, Banks ML, Negus SS (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology 231(1):199–207. https://doi.org/10.1007/s00213-013-3223-5
Article CAS PubMed Google Scholar
Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (2009) The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A 106(47):20081–20086. https://doi.org/10.1073/pnas.0906522106
Article PubMed PubMed Central Google Scholar
Brandt SD, Braithwaite RA, Evans-Brown M, Kicman AT (2013) Aminoindane analogues. In: Dargan PI, Wood DM (eds) Novel psychoactive substances: classification, pharmacology and toxicology. Elsevier, London, pp 261–283. https://doi.org/10.1016/B978-0-12-415816-0.00011-0
Chapter Google Scholar
Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60(6):1181–1188. https://doi.org/10.1124/mol.60.6.1181
Article CAS PubMed Google Scholar
Carmo H, Remiao F, Carvalho F, Fernandes E, de Boer D, dos Reys LA, de Lourdes Bastos M (2003) 4-Methylthioamphetamine-induced hyperthermia in mice: influence of serotonergic and catecholaminergic pathways. Toxicol Appl Pharmacol 190(3):262–271
Article CAS PubMed Google Scholar
Colado MI, Granados R, O’Shea E, Esteban B, Green AR (1999) The acute effect in rats of 3,4-methylenedioxyethamphetamine (MDEA, “eve”) on body temperature and long term degeneration of 5-HT neurones in brain: a comparison with MDMA (“ecstasy”). Pharmacol Toxicol 84(6):261–266
Article CAS PubMed Google Scholar
Cole JC, Sumnall HR (2003) Altered states: the clinical effects of ecstasy. Pharmacol Ther 98(1):35–58
Article CAS PubMed Google Scholar
Corkery JM, Elliott S, Schifano F, Corazza O, Ghodse AH (2013) MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; ‘sparkle’; ‘mindy’) toxicity: a brief overview and update. Hum Psychopharmacol 28(4):345–355. https://doi.org/10.1002/hup.2298
Article CAS PubMed Google Scholar
Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104(7):1085–1099. https://doi.org/10.1111/j.1360-0443.2009.02564.x
Article PubMed Google Scholar
Daw ND, Kakade S, Dayan P (2002) Opponent interactions between serotonin and dopamine. Neural Netw 15(4–6):603–616. https://doi.org/10.1016/S0893-6080(02)00052-7
Article PubMed Google Scholar
Dawson P, Opacka-Juffry J, Moffatt JD, Daniju Y, Dutta N, Ramsey J, Davidson C (2014) The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat. Prog Neuro-Psychopharmacol Biol Psychiatry 48:57–63. https://doi.org/10.1016/j.pnpbp.2013.08.013
Article CAS Google Scholar
Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Coge F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ (2011) Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA). J Neurosci 31(47):16928–16940. https://doi.org/10.1523/JNEUROSCI.2502-11.2011
Article CAS PubMed Google Scholar
Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017) Pharmacokinetics and pharmacodynamics of lisdexamfetamine compared with D-amphetamine in healthy subjects. Front Pharmacol 8:617. https://doi.org/10.3389/fphar.2017.00617
Article CAS PubMed PubMed Central Google Scholar
Dukat M, Young R, Glennon RA (2002) Effect of PMA optical isomers and 4-MTA in PMMA-trained rats. Pharmacol Biochem Behav 72(1–2):299–305. https://doi.org/10.1016/S0091-3057(01)00776-6
Article CAS PubMed Google Scholar
Elliott S, Evans J (2014) A 3-year review of new psychoactive substances in casework. Forensic Sci Int 243:55–60. https://doi.org/10.1016/j.forsciint.2014.04.017
Article CAS PubMed Google Scholar
EMCDDA (2014) Report on the risk assessment of 5-(2-aminopropyl)indole in the framework of the Council Decision on new psychoactive substances, risk assessment. Publications Office of the European Union, Luxembourg. https://doi.org/10.2810/21296
Book Google Scholar
EMCDDA (2016) European drug report 2016. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Luxembourg. https://doi.org/10.2810/084165
Book Google Scholar
Eshleman AJ, Wolfrum KM, Reed JF, Kim SO, Swanson T, Johnson RA, Janowsky A (2017) Structure-activity relationships of substituted cathinones, with transporter binding, uptake, and release. J Pharmacol Exp Ther 360(1):33–47. https://doi.org/10.1124/jpet.116.236349
Article CAS PubMed PubMed Central Google Scholar
Gannon BM, Sulima A, Rice KC, Collins GT (2018) Inhibition of cocaine and 3,4-methylenedioxypyrovalerone (MDPV) self-administration by lorcaserin is mediated by 5-HT2C receptors in rats. J Pharmacol Exp Ther 364(2):359–366. https://doi.org/10.1124/jpet.117.246082
Article CAS PubMed PubMed Central Google Scholar
Gatch MB, Dolan SB, Forster MJ (2016) Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents. Behav Pharmacol 27(6):497–505. https://doi.org/10.1097/FBP.0000000000000237
Article CAS PubMed PubMed Central Google Scholar
Gillman PK (2005) Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95(4):434–441. https://doi.org/10.1093/bja/aei210
Article CAS PubMed Google Scholar
Glennon RA, Young R, Hauck AE, McKenney JD (1984) Structure-activity studies on amphetamine analogs using drug discrimination methodology. Pharmacol Biochem Behav 21(6):895–901
Article CAS PubMed Google Scholar
Glennon RA, Yousif M, Patrick G (1988) Stimulus properties of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs. Pharmacol Biochem Behav 29(3):443–449
Article CAS PubMed Google Scholar
Glennon RA, Young R, Dukat M, Chang-Fong J, El-Zahabi M (2007) N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce non-identical discriminative stimuli in rats. Pharmacol Biochem Behav 86(3):477–484. https://doi.org/10.1016/j.pbb.2007.01.007
Article CAS PubMed PubMed Central Google Scholar
Harro J (2015) Neuropsychiatric adverse effects of amphetamine and methamphetamine. Int Rev Neurobiol 120:179–204. https://doi.org/10.1016/bs.irn.2015.02.004
Article PubMed Google Scholar
Hartung TK, Schofield E, Short AI, Parr MJ, Henry JA (2002) Hyponatraemic states following 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) ingestion. QJM 95(7):431–437
Article CAS PubMed Google Scholar
Heal DJ, Smith SL, Gosden J, Nutt DJ (2013) Amphetamine, past and present – a pharmacological and clinical perspective. J Psychopharmacol 27(6):479–496. https://doi.org/10.1177/0269881113482532
Article CAS PubMed PubMed Central Google Scholar
Herraiz T, Brandt SD (2014) 5-(2-Aminopropyl)indole (5-IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO). Drug Test Anal 6(7–8):607–613. https://doi.org/10.1002/dta.1530
Article CAS PubMed Google Scholar
Hill SL, Thomas SH (2011) Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 49(8):705–719. https://doi.org/10.3109/15563650.2011.615318
Article CAS Google Scholar
Holden R, Jackson MA (1996) Near-fatal hyponatraemic coma due to vasopressin over-secretion after “ecstasy” (3,4-MDMA). Lancet 347(9007):1052
Article CAS PubMed Google Scholar
Hondebrink L, Nugteren-van Lonkhuyzen JJ, Rietjens SJ, Brunt TM, Venhuis B, Soerdjbalie-Maikoe V, Smink BE, van Riel A, de Vries I (2017) Fatalities, cerebral hemorrhage, and severe cardiovascular toxicity after exposure to the new psychoactive substance 4-fluoroamphetamine: a prospective cohort study. Ann Emerg Med. https://doi.org/10.1016/j.annemergmed.2017.07.482
Article PubMed Google Scholar
Horn AS, Snyder SH (1972) Steric requirements for catecholamine uptake by rat brain synaptosomes: studies with rigid analogs of amphetamine. J Pharmacol Exp Ther 180(3):523–530
CAS PubMed Google Scholar
Hysek CM, Vollenweider FX, Liechti ME (2010) Effects of a beta-blocker on the cardiovascular response to MDMA (ecstasy). Emerg Med J 27(8):586–589. https://doi.org/10.1136/emj.2009.079905
Article CAS PubMed Google Scholar
Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, Liechti ME (2011) The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (“ecstasy”) in humans. Clin Pharmacol Ther 90(2):246–255. https://doi.org/10.1038/clpt.2011.78
Article CAS PubMed Google Scholar
Hysek CM, Schmid Y, Rickli A, Simmler LD, Donzelli M, Grouzmann E, Liechti ME (2012a) Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans. Br J Pharmacol 166(8):2277–2288. https://doi.org/10.1111/j.1476-5381.2012.01936.x
Article CAS PubMed PubMed Central Google Scholar
Hysek CM, Brugger R, Simmler LD, Bruggisser M, Donzelli M, Grouzmann E, Hoener MC, Liechti ME (2012b) Effects of the alpha(2)-adrenergic agonist clonidine on the pharmacodynamics and pharmacokinetics of 3,4-methylenedioxymethamphetamine in healthy volunteers. J Pharmacol Exp Ther 340(2):286–294. https://doi.org/10.1124/jpet.111.188425
Article CAS PubMed Google Scholar
Hysek CM, Simmler LD, Nicola VG, Vischer N, Donzelli M, Krahenbuhl S, Grouzmann E, Huwyler J, Hoener MC, Liechti ME (2012c) Duloxetine inhibits effects of MDMA (“ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One 7(5):e36476. https://doi.org/10.1371/journal.pone.0036476
Article CAS PubMed PubMed Central Google Scholar
Hysek CM, Schmid Y, Simmler LD, Domes G, Heinrichs M, Eisenegger C, Preller KH, Quednow BB, Liechti ME (2014a) MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci 9(11):1645–1652. https://doi.org/10.1093/scan/nst161
Article PubMed Google Scholar
Hysek CM, Simmler LD, Schillinger N, Meyer N, Schmid Y, Donzelli M, Grouzmann E, Liechti ME (2014b) Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination. Int J Neuropsychopharmacol 17(3):371–381. https://doi.org/10.1017/S1461145713001132
Article CAS PubMed Google Scholar
Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (2013) Neurochemical profiles of some novel psychoactive substances. Eur J Pharmacol 700(1–3):147–151. https://doi.org/10.1016/j.ejphar.2012.12.006
Article CAS PubMed Google Scholar
Johnson MP, Conarty PF, Nichols DE (1991) [3H]monoamine releasing and uptake inhibition properties of 3,4-methylenedioxymethamphetamine and p-chloroamphetamine analogues. Eur J Pharmacol 200(1):9–16
Article CAS PubMed Google Scholar
Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, Yoshitake T (2011) Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats. Br J Pharmacol. https://doi.org/10.1111/j.1476-5381.2011.01499.x
Article CAS PubMed PubMed Central Google Scholar
Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3(8):760–773. https://doi.org/10.1016/S2215-0366(16)00104-8
Article PubMed PubMed Central Google Scholar
Liechti ME (2014) Effects of MDMA on body temperature in humans. Temperature (Austin) 1(3):192–200. https://doi.org/10.4161/23328940.2014.955433
Article Google Scholar
Liechti M (2015) Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly 145:w14043. https://doi.org/10.4414/smw.2015.14043
Article CAS PubMed Google Scholar
Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX (2000) Psychological and physiological effects of MDMA (“ecstasy”) after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology 23(4):396–404. https://doi.org/10.1016/S0893-133X(00)00126-3
Article CAS PubMed Google Scholar
Liechti ME, Gamma A, Vollenweider FX (2001) Gender differences in the subjective effects of MDMA. Psychopharmacology 154(2):161–168
Article CAS PubMed Google Scholar
Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (2008) Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther 324(3):948–956. https://doi.org/10.1124/jpet.107.132647
Article CAS PubMed Google Scholar
Linsen F, Koning RP, van Laar M, Niesink RJ, Koeter MW, Brunt TM (2015) 4-Fluoroamphetamine in the Netherlands: more than a one-night stand. Addiction 110(7):1138–1143. https://doi.org/10.1111/add.12932
Article PubMed Google Scholar
Luethi D, Kolaczynska KE, Docci L, Krahenbuhl S, Hoener MC, Liechti ME (2017) Pharmacological profile of mephedrone analogs and related new psychoactive substances. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2017.07.026
Article CAS PubMed Google Scholar
Lurie Y, Gopher A, Lavon O, Almog S, Sulimani L, Bentur Y (2012) Severe paramethoxymethamphetamine (PMMA) and paramethoxyamphetamine (PMA) outbreak in Israel. Clin Toxicol (Phila) 50(1):39–43. https://doi.org/10.3109/15563650.2011.635148
Article CAS Google Scholar
Luscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69(4):650–663. https://doi.org/10.1016/j.neuron.2011.01.017
Article CAS PubMed PubMed Central Google Scholar
Marusich JA, Antonazzo KR, Blough BE, Brandt SD, Kavanagh PV, Partilla JS, Baumann MH (2016) The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue. Neuropharmacology 101:68–75. https://doi.org/10.1016/j.neuropharm.2015.09.004
Article CAS PubMed Google Scholar
Mash DC, Duque L, Pablo J, Qin Y, Adi N, Hearn WL, Hyma BA, Karch SB, Druid H, Wetli CV (2009) Brain biomarkers for identifying excited delirium as a cause of sudden death. Forensic Sci Int 190(1–3):e13–e19. https://doi.org/10.1016/j.forsciint.2009.05.012
Article CAS PubMed Google Scholar
Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y (2014) 5-Hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis. Eur Neuropsychopharmacol 24(8):1362–1370. https://doi.org/10.1016/j.euroneuro.2014.04.009
Article CAS PubMed Google Scholar
McIntyre IM, Gary RD, Trochta A, Stolberg S, Stabley R (2015) Acute 5-(2-aminopropyl)benzofuran (5-APB) intoxication and fatality: a case report with postmortem concentrations. J Anal Toxicol 39(2):156–159. https://doi.org/10.1093/jat/bku131
Article CAS PubMed Google Scholar
Monte AP, Marona-Lewicka D, Cozzi NV, Nichols DE (1993) Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine. J Med Chem 36(23):3700–3706
Article CAS PubMed Google Scholar
Mrongovius RI, Bolt AG, Hellyer RO (1978) Comparison of the anorectic and motor activity effects of some aminoindanes, 2-aminotetralin and amphetamine in the rat. Clin Exp Pharmacol Physiol 5(6):635–640
Article CAS PubMed Google Scholar
Nichols DE (1986) Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs 18(4):305–313. https://doi.org/10.1080/02791072.1986.10472362
Article CAS PubMed Google Scholar
Nichols DE (2004) Hallucinogens. Pharmacol Ther 101(2):131–181. https://doi.org/10.1016/j.pharmthera.2003.11.002
Article CAS PubMed Google Scholar
Nichols DE (2017) Chemistry and structure-activity relationships of psychedelics. Curr Top Behav Neurosci. https://doi.org/10.1007/7854_2017_475
Google Scholar
Nichols DE, Brewster WK, Johnson MP, Oberlender R, Riggs RM (1990) Nonneurotoxic tetralin and indan analogues of 3,4-(methylenedioxy)amphetamine (MDA). J Med Chem 33(2):703–710
Article CAS PubMed Google Scholar
Nichols DE, Johnson MP, Oberlender R (1991) 5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine. Pharmacol Biochem Behav 38(1):135–139
Article CAS PubMed Google Scholar
Palenicek T, Lhotkova E, Zidkova M, Balikova M, Kuchar M, Himl M, Miksatkova P, Cegan M, Vales K, Tyls F, Horsley RR (2016) Emerging toxicity of 5,6-methylenedioxy-2-aminoindane (MDAI): pharmacokinetics, behaviour, thermoregulation and LD50 in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 69:49–59. https://doi.org/10.1016/j.pnpbp.2016.04.004
Article CAS Google Scholar
Pascoli V, Terrier J, Hiver A, Luscher C (2015) Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron. https://doi.org/10.1016/j.neuron.2015.10.017
Article CAS PubMed Google Scholar
Pei Y, Lee J, Leo D, Gainetdinov RR, Hoener MC, Canales JJ (2014) Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking. Neuropsychopharmacology 39(10):2299–2308. https://doi.org/10.1038/npp.2014.88
Article CAS PubMed PubMed Central Google Scholar
Pei Y, Mortas P, Hoener MC, Canales JJ (2015) Selective activation of the trace amine-associated receptor 1 decreases cocaine’s reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds. Prog Neuro-Psychopharmacol Biol Psychiatry 63:70–75. https://doi.org/10.1016/j.pnpbp.2015.05.014
Article CAS Google Scholar
Pinterova N, Horsley RR, Palenicek T (2017) Synthetic aminoindanes: a summary of existing knowledge. Front Psych 8:236. https://doi.org/10.3389/fpsyt.2017.00236
Article Google Scholar
Prosser JM, Nelson LS (2012) The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol 8(1):33–42. https://doi.org/10.1007/s13181-011-0193-z
Article PubMed Google Scholar
Rickli A, Hoener MC, Liechti ME (2015a) Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. Eur Neuropsychopharmacol 25(3):365–376. https://doi.org/10.1016/j.euroneuro.2014.12.012
Article CAS PubMed Google Scholar
Rickli A, Kopf S, Hoener MC, Liechti ME (2015b) Pharmacological profile of novel psychoactive benzofurans. Br J Pharmacol 172(13):3412–3425. https://doi.org/10.1111/bph.13128
Article CAS PubMed PubMed Central Google Scholar
Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME (2015c) Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology 99:546–553. https://doi.org/10.1016/j.neuropharm.2015.08.034
Article CAS PubMed Google Scholar
Roth BL (2007) Drugs and valvular heart disease. N Engl J Med 356(1):6–9. https://doi.org/10.1056/NEJMp068265
Article CAS PubMed Google Scholar
Rothman RB, Baumann MH (2006) Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs. Ann N Y Acad Sci 1074:245–260. https://doi.org/10.1196/annals.1369.064
Article CAS PubMed Google Scholar
Sainsbury PD, Kicman AT, Archer RP, King LA, Braithwaite RA (2011) Aminoindanes – the next wave of ‘legal highs’? Drug Test Anal 3(7–8):479–482. https://doi.org/10.1002/dta.318
Article CAS PubMed Google Scholar
Schindler CW, Thorndike EB, Goldberg SR, Lehner KR, Cozzi NV, Brandt SD, Baumann MH (2016) Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology 233(10):1981–1990. https://doi.org/10.1007/s00213-015-4057-0
Article CAS PubMed Google Scholar
Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB, Liechti ME (2014) Differential effects of MDMA and methylphenidate on social cognition. J Psychopharmacol 28(9):847–856. https://doi.org/10.1177/0269881114542454
Article CAS PubMed Google Scholar
Scorza C, Silveira R, Nichols DE, Reyes-Parada M (1999) Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action. Neuropharmacology 38(7):1055–1061
Article CAS PubMed Google Scholar
Simmler LD, Hysek CM, Liechti ME (2011) Sex differences in the effects of MDMA (ecstasy) on plasma copeptin in healthy subjects. J Clin Endocrinol Metab 96(9):2844–2850. https://doi.org/10.1210/jc.2011-1143
Article CAS PubMed Google Scholar
Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168(2):458–470. https://doi.org/10.1111/j.1476-5381.2012.02145.x
Article CAS PubMed Google Scholar
Simmler LD, Rickli A, Hoener MC, Liechti ME (2014a) Monoamine transporter and receptor interaction profiles of a new series of designer cathinones. Neuropharmacology 79:152–160. https://doi.org/10.1016/j.neuropharm.2013.11.008
Article CAS PubMed Google Scholar
Simmler LD, Rickli A, Schramm Y, Hoener MC, Liechti ME (2014b) Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives. Biochem Pharmacol 88(2):237–244. https://doi.org/10.1016/j.bcp.2014.01.024
Article CAS PubMed Google Scholar
Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (2016) In vitro characterization of psychoactive substances at rat, mouse, and human trace amine-associated receptor 1. J Pharmacol Exp Ther 357(1):134–144. https://doi.org/10.1124/jpet.115.229765
Article CAS PubMed Google Scholar
Simmler LD, Anacker AMJ, Levin MH, Vaswani NM, Gresch PJ, Nackenoff AG, Anastasio NC, Stutz SJ, Cunningham KA, Wang J, Zhang B, Henry LK, Stewart A, Veenstra-VanderWeele J, Blakely RD (2017) Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. Br J Pharmacol 174(16):2716–2738. https://doi.org/10.1111/bph.13899
Article CAS PubMed PubMed Central Google Scholar
Sprague JE, Brutcher RE, Mills EM, Caden D, Rusyniak DE (2004) Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced rhabdomyolysis with alpha1- plus beta3-adrenoreceptor antagonists. Br J Pharmacol 142(4):667–670. https://doi.org/10.1038/sj.bjp.0705823
Article CAS PubMed PubMed Central Google Scholar
Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69(4):628–649. https://doi.org/10.1016/j.neuron.2011.02.010
Article CAS PubMed PubMed Central Google Scholar
Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS, Banks ML (2016) Abuse-related neurochemical effects of para-substituted methcathinone analogs in rats: microdialysis studies of nucleus accumbens dopamine and serotonin. J Pharmacol Exp Ther 356(1):182–190. https://doi.org/10.1124/jpet.115.229559
Article CAS PubMed PubMed Central Google Scholar
Tessel RE, Rutledge CO (1976) Specificity of release of biogenic amines from isolated rat brain tissue as a function of the meta substituent of N-ethylamphetamine derivatives. J Pharmacol Exp Ther 197(2):253–262
CAS PubMed Google Scholar
Tessel RE, Woods JH (1975) Fenfluramine and N-ethyl amphetamine: comparison of the reinforcing and rate-decreasing actions in the rhesus monkey. Psychopharmacologia 43(3):239–244
Article CAS PubMed Google Scholar
Tessel RE, Woods JH, Counsell RE, Lu M (1975) Structure-activity relationships between meta-substituted N-ethylamphetamines and locomotor activity in mice. J Pharmacol Exp Ther 192(2):310–318
CAS PubMed Google Scholar
Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4(1):13–25. https://doi.org/10.1038/nrn1008
Article CAS PubMed Google Scholar
Verrico CD, Miller GM, Madras BK (2007) MDMA (ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology 189(4):489–503. https://doi.org/10.1007/s00213-005-0174-5
Article CAS PubMed Google Scholar
Vevelstad M, Oiestad EL, Middelkoop G, Hasvold I, Lilleng P, Delaveris GJ, Eggen T, Morland J, Arnestad M (2012) The PMMA epidemic in Norway: comparison of fatal and non-fatal intoxications. Forensic Sci Int 219(1–3):151–157. https://doi.org/10.1016/j.forsciint.2011.12.014
Article CAS PubMed Google Scholar
Vizeli P, Liechti ME (2017) Safety pharmacology of acute MDMA administration in healthy subjects. J Psychopharmacol 31(5):576–588. https://doi.org/10.1177/0269881117691569
Article CAS PubMed Google Scholar
Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005) Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther 313(2):848–854. https://doi.org/10.1124/jpet.104.080101
Article CAS PubMed Google Scholar
Welter-Luedeke J, Maurer HH (2016) New psychoactive substances: chemistry, pharmacology, metabolism, and detectability of amphetamine derivatives with modified ring systems. Ther Drug Monit 38(1):4–11. https://doi.org/10.1097/FTD.0000000000000240
Article CAS PubMed Google Scholar
Wijers CH, van Litsenburg RT, Hondebrink L, Niesink RJ, Croes EA (2017) Acute toxic effects related to 4-fluoroamphetamine. Lancet 389(10069):600. https://doi.org/10.1016/S0140-6736(17)30281-7
Article PubMed Google Scholar
Woolverton WL, English JA (1997) Effects of some phenylethylamines in rhesus monkeys trained to discriminate (+)-amphetamine from saline. Drug Alcohol Depend 44(2–3):79–85
Article CAS PubMed Google Scholar
Zwartsen A, Verboven AHA, van Kleef R, Wijnolts FMJ, Westerink RHS, Hondebrink L (2017) Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay. Toxicol In Vitro 45(Pt 1):60–71. https://doi.org/10.1016/j.tiv.2017.05.010
Article CAS PubMed Google Scholar

Download references

Acknowledgments

The authors would like to thank Dr. Patrick Burch for the design of Fig. 1. LDS is supported by the Swiss National Science Foundation (SNSF; PZ00P3_174178). MEL is supported by the Federal Office of Public Health (16.921318) and the SNSF (320030149493 and 320030_170249).

Author information

Authors and Affiliations

Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
Linda D. Simmler
Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland
Matthias E. Liechti

Authors

Linda D. Simmler
View author publications
You can also search for this author in PubMed Google Scholar
Matthias E. Liechti
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Linda D. Simmler or Matthias E. Liechti .

Editor information

Editors and Affiliations

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg (Saar), Germany
Hans H. Maurer
School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
Simon D. Brandt

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Cite this chapter

Simmler, L.D., Liechti, M.E. (2018). Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances. In: Maurer, H., Brandt, S. (eds) New Psychoactive Substances . Handbook of Experimental Pharmacology, vol 252. Springer, Cham. https://doi.org/10.1007/164_2018_113

Download citation

DOI: https://doi.org/10.1007/164_2018_113
Published: 10 April 2018
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-10560-0
Online ISBN: 978-3-030-10561-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

Publish with us

Policies and ethics