Abstract
The aim of the present chapter is to shed light on different aspects related to synaptic dopamine and clinical effects of 3,4-methylenedioxymethamphetamine (MDMA). MDMA is a psychoactive stimulant abused by young people worldwide. Numerous studies demonstrated circulating catecholamine concentrations increase after MDMA administration, indicating sympathetic system activation modulating psychomotor and neuroendocrine function.
Its mechanism of action at synaptic terminals of the dopaminergic system is strongly similar to a cocaine-like effect attributable to an inhibition of the plasma membrane transporters for dopamine (DAT) and to an increased extracellular concentration of serotonin (5-HT). Clinical and preclinical studies have investigated the effects of repeated MDMA exposure. It produces neuroadaptive responses at both serotoninergic and dopaminergic level coherently with the development and maintenance of MDMA self-administration in some experimental animals and the development of a substance misuse in some humans. More systematic investigation in humans should be assessed, focusing on interindividual variables in MDMA pharmacokinetics-pharmacodynamics to better understand its acute specific pharmacological effects and toxicity.
Despite its misuse, there is a great enthusiasm from clinicians who see the potential role of MDMA as a powerful addition to psychotherapy for the treatment of post-traumatic stress disorder (PTSD), as well as a potential primary treatment for social dysfunction occurring in a wide range of other neuropsychiatric disorders (social anxiety, autism, schizophrenia, and alcohol use disorders).
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Abbreviations
- 5-HT:
-
5-hydroxytryptamine or serotonin
- BP:
-
Blood pressure
- CNS:
-
Central Nervous System
- CPP:
-
Conditioned place preference
- CYP2D6:
-
Cytochrome P450
- DA:
-
Dopamine
- DAT:
-
Dopamine transporter
- DhβE:
-
Dihydroβerythroidine
- FDA:
-
Food and Drug Administration
- H:
-
Histamine
- HR:
-
Heart rate
- LSD:
-
Lysergic Acid Diethylamide
- M:
-
Muscarine
- MAO:
-
Monoamine oxidase
- MDA:
-
3,4-methylenedioxyamphetamine
- MDE:
-
3,4-methylenedioxyethylamphetamine
- MDMA:
-
3,4-methylenedioxymethamphetamine
- MLA:
-
Methyllycaconitine
- MMDA:
-
3-methoxy-4,5-methylenedioxyamphetamine
- nAChRs:
-
Nicotinic receptors
- NE:
-
Norepinephrine
- PTSD:
-
Post-traumatic stress disorder
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- SERT:
-
Serotonin transporter
- SNpc:
-
Substantia Nigra pars compacta
- SSRI:
-
Selective serotonin reuptake inhibitor
- T:
-
Temperature
- VMAT:
-
Vesicular monoamine transporter
- VTA:
-
Ventral Tegmental Area
References
Abdallah CG, Averill LA, Akiki TJ, Raza M, Averill CL, Gomaa H, Adikey A, Krystal JH (2019) The neurobiology and pharmacotherapy of posttraumatic stress disorder. Annu Rev Pharmacol Toxicol 6(59):171–189. https://doi.org/10.1146/annurev-pharmtox-010818-021701. Epub 2018 Sep 14. PMID: 30216745; PMCID: PMC6326888
Anderson GM, Braun G, Braun N, Nichols DE, Shulgin AT (1978) Absolute configuration and psychotomimetic activity. In: Barnett G, Trsic M, Willet R (eds) Quantitative structure activity relationship of analgesics, narcotic antagonists, and hallucinogens, NIDA research monograph 22. NIDA, Rockville
Bahji A, Forsyth A, Groll D, Hawken ER (2020) Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: a systematic review and meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry 10(96):109735. https://doi.org/10.1016/j.pnpbp.2019.109735
Bristol Imperial MDMA in Alcoholism Study (2020). https://clinicaltrials.gov/ct2/show/NCT04158778?term=mdma&cond=Alcohol+Use+Disorder&draw=2&rank=1)
Cami J, Farré M, Mas M, Roset PN, Poudevida S, Mas A, San L, De La Torre R (2000) Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): psychomotor performance and subjective effects. J Clin Psychopharmacol 20
Ciudad-Roberts A, Camarasa J, Pubill D, Escubedo E (2013) Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 1(44):201–209. https://doi.org/10.1016/j.pnpbp.2013.02.013. Epub 2013 Mar 4. PMID: 23466442
Cole JC, Sumnall HR (2003) Altered states: the clinical effects of ecstasy. Pharmacol Ther 98(1):35–58. https://doi.org/10.1016/s0163-7258(03)00003-2. PMID: 12667887
De Gregorio D, Aguilar-Valles A, Preller KH, Heifets BD, Hibicke M, Mitchell J, Gobbi G (2020) Hallucinogens in mental health: preclinical and clinical studies on LSD, psilocybin, MDMA, and ketamine. J Neurosci 41(5):891–900. https://doi.org/10.1523/JNEUROSCI.1659-20.2020
De la Torre R, Farré M, Ortuño J et al (2000a) Non-linear pharmacokinetics of MDMA (“ecstasy”) in humans. Br J Clin Pharmacol 49:104–109
De la Torre R, Farré M, Roset PN et al (2000b) Pharmacology of MDMA in humans. Ann N Y Acad Sci 914:225–237
De la Torre R, Farré M, Roset PN, Pizarro N, Abanades S, Segura M, Segura J, Camí J (2004) Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 26(2):137–144. https://doi.org/10.1097/00007691-200404000-00009. PMID: 15228154
Drug Enforcement Administration (1984) Schedules of controlled substances proposed placement of 3,4-methylenedioxymethamphetamine in schedule I. Fed Regis 49:30210
Eisner B (1994) Ecstasy: the MDMA story (expanded), 2nd edn. Ronin Publishing, Berkeley
European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) European Drug Report 2019: Trends and Developments
Faillace LA, Szára S (1968) Hallucinogenic drugs: influence of mental set and setting. Dis Nerv Syst 29:124–126
Federici M, Sebastianelli L, Natoli S, Bernardi G, Mercuri NB (2007) Electrophysiologic changes in ventral midbrain dopaminergic neurons resulting from (+/−) -3,4-Methylenedioxymethamphetamine (MDMA—“ecstasy”). Biol Psychiatry 62:680–686
Federici M, Latagliata EC, Ledonne A, Rizzo FR, Feligioni M, Sulzer D, Dunn M, Sames D, Gu H, Nisticò R, Puglisi-Allegra S, Mercuri NB (2014) Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate. J Biol Chem 289:264–274
Fisk JE, Montgomery C, Wareing M, Murphy PN (2006) The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic? Hum Psychopharmacol 21(6):355–366. https://doi.org/10.1002/hup.777. PMID: 16915582
Fornai F, Gesi M, Lenzi P, Ferrucci M, Pellegrini A, Ruggieri S, Casini A, Paparelli A (2002) Striatal postsynaptic ultrastructural alterations following methylenedioxymethamphetamine administration. Ann N Y Acad Sci 965:381–398
Freedman DX (1968) On the use and abuse of LSD. Arch Gen Psychiatry 18:330–347
Garcia-Rates S, Camarasa J, Escubedo E, Pubill D (2007) Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation. Toxicol Appl Pharmacol 223:195–205
Gervin M, Hughes R, Bamford L, Smyth BP, Keenan E (2001) Heroin smoking by "chasing the dragon" in young opiate users in Ireland: stability and associations with use to "come down" off "ecstasy". J Subst Abus Treat 20(4):297–300. https://doi.org/10.1016/s0740-5472(01)00174-x. PMID: 11672646
Gifford AN, Minabe Y, Toor A, Wang RY, Ashby CR Jr (1996) Examination of the action of 3,4-methylenedioxymethamphetamine on rat A10 dopamine neurons. Synapse 23:52–57
Green AR, Mechan AO, Martin A et al (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508
Grinspoon L, Bakalar JB (1986) Can drugs be used to enhance the psychotherapeutic process? Am J Psychother 40(3):393–404
Heifets BD, Malenka RC (2016) MDMA as a probe and treatment for social Behaviors. Cell 166(2):269–272. https://doi.org/10.1016/j.cell.2016.06.045. PMID: 27419864
Heifets BD, Salgado JS, Taylor MD, Hoerbelt P, Cardozo Pinto DF, Steinberg EE, Walsh JJ, Sze JY, Malenka RC (2019) Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Sci Transl Med 11(522):eaaw6435. https://doi.org/10.1126/scitranslmed.aaw6435. PMID: 31826983; PMCID: PMC7123941
Hoegberg LCG, Christiansen C, Soe J, Telving R, Andreasen MF, Staerk D, Christrup LL, Kongstad KT (2018) Recreational drug use at a major music festival: trend analysis of anonymised pooled urine. Clin Toxicol (Phila) 56(4):245–255. https://doi.org/10.1080/15563650.2017.1360496
Kahn DE, Ferraro (2012) N, Benveniste RJ. 2012. 3 cases of primary intracranial hemorrhage associated with "Molly", a purified form of 3,4-methylenedioxymethamphetamine(MDMA). J Neurol Sci 323(1–2):257–260
Kalant H (2001) The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ 165(7):917–928. PMID: 11599334; PMCID: PMC81503
Kalivas PW, O'Brien C (2008) Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 33(1):166–180. https://doi.org/10.1038/sj.npp.1301564. Epub 2007 Sep 5. PMID: 17805308
Kamilar-Britt P, Bedi G (2015) The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals. Neurosci Biobehav Rev 57:433–446. https://doi.org/10.1016/j.neubiorev.2015.08.016. Epub 2015 Sep 25. PMID: 26408071; PMCID: PMC4678620
Karuppagounder SS, Bhattacharya D, Ahuja M, Suppiranmaniam V, Deruiter J, Clark R, Dhanasekaran M (2014) Elucidating the neurotoxic effects of MDMA and its analogs. Life Sci 101(1–2):37–42
Lee GY, Gong GW, Vrodos N et al (2003) 'Ecstasy'-induced subarachnoid haemorrhage: an underreported neurological complication? J Clin Neurosci 10:705–707
Liechti ME, Gamma A, Vollenweider FX (2001) Gender differences in the subjective effects of MDMA. Psychopharmacology 154(2):161–168. https://doi.org/10.1007/s002130000648. PMID: 11314678
Llabrés S, Garcia-Ratés S, Cristobaal-Lecina E, Riera A, Borrell JI, Camarasa J, Pubill D, Luque JF, Escubedo E (2014) Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies. Eur J Med Chem 81:35–46
Lyles J, Cadet JL (2003) Methylenedioxymethamphetamine (MDMA, ecstasy) neurotoxicity: cellular and molecular mechanisms. Brain Res Rev 42:155–168
Martins SS, Storr CL, Alexandre PK, Chilcoat HD (2008) Adolescent ecstasy and other drug use in the National Survey of parents and youth: the role of sensation-seeking, parental monitoring and peer's drug use. Addict Behav 33(7):919–933. https://doi.org/10.1016/j.addbeh.2008.02.010
Mas M, Farré M, De La Torre R, Roset PN, Ortuño J, Segura J, Camí J (1999) Cardiovascular and neuroendocrine effects, and pharmacokinetics of MDMA in humans. J Pharmacol Exp Ther 290:136–145
Mithoefer M (2013) MDMA-assisted psychotherapy: how different is it from other psychotherapy? MAPS News-Lett 23:10–14
Mohamed WM, Ben Hamida S, Cassel JC, de Vasconcelos AP, Jones BC (2011) MDMA: interactions with other psychoactive drugs. Pharmacol Biochem Behav 99(4):759–774. https://doi.org/10.1016/j.pbb.2011.06.032. Epub 2011 Jul 5. PMID: 21756931
Montastruc F, Montastruc G, Vigreux P et al (2012) Valvular heart disease in a patient taking 3,4- methylenedioxymethamphetamine (MDMA, 'Ecstasy'). Br J Clin Pharmacol 2012(74):547–548
Morton J (2005) Ecstasy: pharmacology and neurotoxicity. Curr Opin Pharmacol 5:79–86
Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (2020). https://clinicaltrials.gov/ct2/show/NCT03537014?term=MDMA+%22Phase+3%22&cond=PTSD&draw=2&rank=1
Mushanyu J, Nyabadza F, Muchatibaya G, Stewart AG (2017) On the role of imitation on adolescence methamphetamine abuse dynamics. Acta Biotheor 65(1):37–61. https://doi.org/10.1007/s10441-016-9302-3. Epub 2016 Dec 18. PMID: 27990591
Naranjo C (1973) The healing journey. Pantheon Books, New York
Newton DF, Naiberg MR, Goldstein BI (2015) Oxidative stress and cognition amongst adults without dementia or stroke: implications for mechanistic and therapeutic research in psychiatric disorders. Psychiatry Res 227(2–3):127–134. https://doi.org/10.1016/j.psychres.2015.03.038. Epub 2015 Apr 8. PMID: 25892258
Osmond H (1957) A review of the clinical effects of psychotomimetic agents. Ann N Y Acad Sci 66(3):418–434
Panos JJ, Baker LE (2010) An in vivo microdialysis assessment of concurrent MDMA and cocaine administration in Sprague-Dawley rats. Psychopharmacology 209(1):95–102. https://doi.org/10.1007/s00213-009-1774-2. Epub 2010 Jan 30. PMID: 20112010
Pantoni MM, Kim JL, Van Alstyne KR, Anagnostaras SG (2022) MDMA and memory, addiction, and depression: dose-effect analysis. Psychopharmacology (Berl) 239(3):935–949. https://doi.org/10.1007/s00213-022-06086-9. Epub 2022 Feb 18. PMID: 35179622; PMCID: PMC8891111
Papaseit E, Pérez-Mañá C, Torrens M, Farré A, Poyatos L, Hladun O, Sanvisens A, Muga R, Farré M (2020) MDMA interactions with pharmaceuticals and drugs of abuse. Expert Opin Drug Metab Toxicol 16(5):357–369. https://doi.org/10.1080/17425255.2020.1749262. Epub 2020 Apr 12. PMID: 32228243
Parrott AC (2004) Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology 173(3–4):234–241. https://doi.org/10.1007/s00213-003-1712-7
Pifl C, Nagy G, Berenyi S, Kattinger A, Reither H, Antus S (2005) Pharmacological characterization of ecstasy synthesis byproducts with recombinant human monoamine transporters. J Pharmacol Exp Ther 314:346–354
Pubill D, Garcia-Ratés S, Camarasa J, Escubedo E (2013) 3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors. Neurotoxicology 35:41–49
Rice ME, Cragg SJ (2004) Nicotine amplifies reward-related dopamine signals in striatum. Nature Neurosci 7(6):583–584
Rizzo FR, Federici M, Mercuri NB (2018) 3,4-Methylenedioxymethamphetamine (MDMA) alters synaptic dopamine release in the dorsal striatum through nicotinic receptors and DAT inhibition. Neuroscience 1(377):69–76. https://doi.org/10.1016/j.neuroscience.2018.02.037. Epub 2018 Mar 3. PMID: 29510210
Rothman RB, Baumann MH, Dersch CM et al (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41
Scarponi M, Bernardi G, Mercuri NB (1999) Electrophysiological evidence for a reciprocal interaction between amphetamine and cocaine-related drugs on rat midbrain dopaminergic neurons. Eur J Neurosci 11:593–598
Schenk S, Highgate Q (2021) Methylenedioxymethamphetamine (MDMA): serotonergic and dopaminergic mechanisms related to its use and misuse. J Neurochem 157(5):1714–1724. https://doi.org/10.1111/jnc.15348. Epub 2021 Mar 25. PMID: 33711169
Schenk S, Newcombe D (2018) Methylenedioxymethamphetamine (MDMA) in psychiatry: pros, cons, and suggestions. J Clin Psychopharmacol 38(6):632–638. https://doi.org/10.1097/JCP.0000000000000962. PMID: 30303861
Schilt T, Koeter MW, Smal JP, Gouwetor MN, van den Brink W, Schmand B (2010) Long-term neuropsychological effects of ecstasy in middle-aged ecstasy/polydrug users. Psychopharmacology 207(4):583–591. https://doi.org/10.1007/s00213-009-1688-z. Epub 2009 Oct 13. PMID: 19823808
Sevak RJ, Vansickel AR, Stoops WW, Glaser PE, Hays LR, Rush CR (2011) Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. J Clin Psychopharmacol 31:470–480. https://doi.org/10.1097/JCP.0b013e318221b2db
Shulgin A, Shulgin A (1991) PIHKAL: a chemical love story. Transform Press, Berkeley
Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75:406–433
United Nations Office on drugs and crime (UNDOC). World Drug Report 2019. Available from: https://wdr.unodc.org/wdr2019/index.html
van Amsterdam J, Pennings E, van den Brink W (2020) Fatal and non-fatal health incidents related to recreational ecstasy use. J Psychopharmacol (Oxford, England) 34(6):591–599. https://doi.org/10.1177/0269881119897559
White SR, Obradovic T, Imel KM, Wheaton MJ (1996) The effects of methylenedioxymethamphetamine (MDMA, “ecstasy”) on monoaminergic neurotransmission in the central nervous system. Prog Neurobiol 49:455–479
Wish ED, Fitzelle DB, O'Grady KE, Hsu MH, Arria AM (2006) Evidence for significant polydrug use among ecstasy-using college students. J Am Coll Heal 55(2):99–104. https://doi.org/10.3200/JACH.55.2.99-104. PMID: 17017306; PMCID: PMC3005618
Yamamoto BK, Nash JF, Gudelsky GA (1995) Modulation of methylenedioxymethamphetamine- induced striatal dopamine release by the interaction between serotonin and gamma-aminobutyric acid in the substantia nigra. J Pharmacol Exp Ther 273:1063–1070
Zhang H, Sulzer D (2004) Frequency-dependent modulation of dopamine release by nicotine. Nat Neurosci 7:581–582
Zhou FM, Liang Y, Dani JA (2001) Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 4(12):1224–1229. https://doi.org/10.1038/nn769. PMID: 11713470
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Rizzo, F.R., Bruno, A., Federici, M., Mercuri, N.B. (2022). 3,4-Methylenedioxymethamphetamine (MDMA) and Synaptic Dopamine. In: Patel, V.B., Preedy, V.R. (eds) Handbook of Substance Misuse and Addictions. Springer, Cham. https://doi.org/10.1007/978-3-030-67928-6_116-1
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