Substances of Abuse and Hallucinogenic Activity: The Serotoninergic Pathway - Focus on Classical Hallucinogens and Entactogens

  • Matteo Lazzaretti
  • Gian Mario Mandolini
  • Alfredo Carlo Altamura
  • Paolo BrambillaEmail author


The chapter focuses on the mechanisms through which the serotoninergic system can induce hallucinations, altering sensory perceptive functions. The hallucinogenic activity of the serotoninergic receptors has been noticed since perceptual alterations induced by the consumption of some recreational drugs, such as LSD and ecstasy, were observed. Hallucinogenic effects and specific molecular mechanisms of action are discussed in this chapter. Hallucinogens and entactogens can both produce hallucinations through an increase of the serotoninergic pathway activity, which is thought to be one of the pathophysiological processes underlying positive symptoms. LSD and MDMA seem to act with a different molecular mechanism. The main molecular effect of classical hallucinogens consists of increasing 5-HT brain levels, since they act as 5-HT receptor agonists. 5-HT2A receptors, mainly localized in medial prefrontal cortex, thalamic reticular nucleus, locus coeruleus and raphe nucleus, seem to be the most important hallucinogenic target, even if it has been demonstrated that 5-HT2C receptors could also be required. Hallucinogens therefore alter ascending sensory information processed through the thalamus. This could be mediated through alterations in different systems leading to a sensorial information overload. Classical hallucinogens should be considered as potent modulators of cortex network activity through the augmented 5-HT2A agonist activity in the medial prefrontal cortex, the reduced inhibitory activity by thalamic reticular nucleus, the altered firing of raphe nucleus, and the increased activity in the locus coeruleus. Entactogens seem to act increasing intracellular and extracellular 5-HT levels by inhibiting the SERT activity, reversing its action through TAAR1 agonism, inhibiting VMAT2, and inhibiting the MAO enzymes. Entactogens also act on NET, and to a lesser extent on DAT. The hallucinogenic effect of entactogens is probably also due to a partial agonist activity on 5-HT2A activity.



This chapter was supported by a grant from the AIFA (Proposal AIFA-2016-02364852). pathway involved in substance-induced hallucinations.


  1. 1.
    Hoffer A, Osmond H, Smythies J. Schizophrenia: a new approach. II. Results of a year’s research. J Ment Sci. 1954;100:29–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Hollister LE. Drug-induced psychoses and schizophrenic reactions, a critical comparison. Ann N Y Acad Sci. 1962;96:80–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Hollister LE. Chemical psychoses: LSD and related drugs. Springfield, IL: Thomas; 1968.Google Scholar
  4. 4.
    Glennon RA. Classical drugs: an introductory overview. In: Lin GC, Glennon RA, editors. Hallucinogens: an update. Rockville, MD: National Institute on Drug Abuse; 1994.Google Scholar
  5. 5.
    Nichols DE, Glennon RA. Medicinal chemistry and structure-activity relationships of hallucinogens. In: Jacobs BL, editor. Hallucinogens: neurochemical, behavioral, and clinical perspectives. New York: Raven Press; 1984. p. 95–142.Google Scholar
  6. 6.
    Ludwig AM. Altered states of consciousness. Arch Gen Psychiatry. 1966;15:225–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Preller KH, Vollenweider FX. Phenomenology , structure, and dynamic of psychedelic states. Curr Top Behav Neurosci. 2018;36:221–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Díaz JL. Sacred plants and visionary consciousness. Phenomenol Cogn Sci. 2010;9(2):159–70.CrossRefGoogle Scholar
  9. 9.
    Schmid Y, Enzler F, Gasser P, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78:544–53.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Studerus E, Kometer M, Hasler F, et al. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011;25:1434–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Rolland B, Jardri R, Amad A, et al. Pharmacology of hallucinations: several mechanisms for one single symptom? BioMed Res Int. 2014;2014, Article ID 307106, 9 p.Google Scholar
  12. 12.
    Campbell RJ. Psychiatric dictionary. 6th ed. New York: Oxford University Press; 1989.Google Scholar
  13. 13.
    Anden NE, Corrodi H, Fuxe K, Hokfelt T. Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide. Br J Pharmacol. 1968;34:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Anden NE, Corrodi H, Fuxe K. Hallucinogenic drugs of the indolcalkylamine type and central monoamine neurons. J Pharmacol Exp Ther. 1971;179:236–49.PubMedGoogle Scholar
  15. 15.
    Randic M, Padjen A. Effect of N,N-dimethyltryptamine and D-lysergic acid diethylamide on the release of 5-hydroxyindoles in rat forebrain. Nature. 1971;230:532–3.PubMedCrossRefGoogle Scholar
  16. 16.
    Fuxe K, Holmstedt B, Jonsson G. Effects of 5-methoxy-N,N-dimethyltrypstamine on central monoamine neurons. Eur J Pharmacol. 1972;19:25–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Glennon RA, Young R, Rosecrans JA. Antagonism of the stimulus effects of the hallucinogen DOM and the purported serotonin agonist quipazine by 5-HT2 antagonists. Eur J Pharmacol. 1983;91:189–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Glennon RA, Titeler M, McKenney JD. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 1984;35:2505–11.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Colpaert FC, Janssen PA. A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharmacology. 1983;22:1001–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Colpaert FC, Niemegeers CJ, Janssen PA. A drug discrimination analysis of lysergic acid diethylamide (LSD): in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, an LSD-antagonist. J Pharmacol Exp Ther. 1982;221:206–14.PubMedGoogle Scholar
  21. 21.
    Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998;9:3897–902.PubMedCrossRefGoogle Scholar
  22. 22.
    Nichols D. Hallucinogens. Pharmacol Ther. 2004;101:131–81.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Gonzalez-Maeso J, Sealfon SC. Psychedelics and schizophrenia. Trends Neurosci. 2009;32:225–32.PubMedCrossRefGoogle Scholar
  24. 24.
    Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci. 2010;11(9):642–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Aghajanian GK, Marek GJ. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropsychopharmacology. 1997;36:589–99.Google Scholar
  26. 26.
    Aghajanian GK, Marek GJ. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res. 1999;825:161–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Marek GJ, Wright RA, Gewirtz JC, et al. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience. 2001;105:379–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Beique JC, Imad M, Mladenovic L, et al. Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci U S A. 2007;104:9870–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Puig MV, Celada P, az-Mataix L, et al. In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb Cortex. 2003;13:870–82.PubMedCrossRefGoogle Scholar
  30. 30.
    Gonzalez-Maeso J, et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–52.PubMedCrossRefGoogle Scholar
  31. 31.
    Marek GJ, Wright RA, Schoepp DD, et al. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther. 2000;292:76–87.PubMedGoogle Scholar
  32. 32.
    Moorman JM, Leslie RA. p-Chloroamphetamine induces c-fos in rat brain: a study of serotonin 2A/2C receptor function. Neuroscience. 1996;72:129–39.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Scruggs JL, Patel S, Bubser M, et al. DOI-induced activation of the cortex: dependence on 5-HT2A heteroceptors on thalamocortical glutamatergic neurons. J Neurosci. 2000;20:8846–52.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Pazos A, Probst A, Palacios JM. Serotonin receptors in the human brain: IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience. 1987;21:123–39.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Wong DF, Lever JR, Hartig PR, et al. Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-BR-LSD. Synapse. 1987;1:393–8.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Jakab RL, Goldman-Rakic PS. 5-HT2A serotonin in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci U S A. 1998;95:735–40.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Xia Z, Gray JA, Compton-Toth BA, et al. A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem. 2003;278:21901–8.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Celada P, Puig MV, Casanovas JM, et al. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci. 2001;21:9917–29.PubMedCrossRefGoogle Scholar
  39. 39.
    Vazquez-Borsetti P, Cortes R, Artigas F. Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex. 2009;19:1678–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Vollenweider FX, Vontobel P, Hell D, Leenders KL. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man—a PET study with [11C] raclopride. Neuropsychopharmacology. 1999;20:424–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Moreno JL, Holloway T, Albizu L, et al. Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptors agonists. Neurosci Lett. 2011;493:76–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Crick F. Function of the thalamic reticular complex: the searchlight hypothesis. Proc Natl Acad Sci U S A. 1984;81:4586–90.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Pinault D. The thalamic reticular nucleus: structure, function and concept. Brain Res Brain Res Rev. 2004;46:1–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Yingling CD, Skinner JE. Selective regulation of thalamic sensory relay nuclei by nucleus reticularis thalami. Electroencephalogr Clin Neurophysiol. 1976;41:476–82.PubMedCrossRefGoogle Scholar
  45. 45.
    Guillery RW, Sherman SM. Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system. Neuron. 2002;33:163–75.PubMedCrossRefGoogle Scholar
  46. 46.
    Guillery RW, Feig SL, Lozsadi DA. Paying attention to the thalamic reticular nucleus. Trends Neurosci. 1998;21:28–32.PubMedCrossRefGoogle Scholar
  47. 47.
    Golomb D, Ahissar E, Kleinfeld D. Coding of stimulus frequency by latency in thalamic networks through the interplay of GABAB-mediated feedback and stimulus shape. J Neurophysiol. 2006;95:1735–50.PubMedCrossRefGoogle Scholar
  48. 48.
    McAlonan K, Cavanaugh J, Wurtz RH. Attentional modulation of thalamic reticular neurons. J Neurosci. 2006;26:4444–50.PubMedCrossRefGoogle Scholar
  49. 49.
    McAlonan K, Cavanaugh J, Wurtz RH. Guarding the gateway to cortex with attention in visual thalamus. Nature. 2008;456:391–4.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yu XJ, Xu XX, He S, et al. Change detection by thalamic reticular neurons. Nat Neurosci. 2009;12:1165–70.PubMedCrossRefGoogle Scholar
  51. 51.
    Vollenweider FX, Geyer MA. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull. 2001;56:495–507.PubMedCrossRefGoogle Scholar
  52. 52.
    Nestler EJ, Alreja M, Aghajanian GK. Molecular control of locus coeruleus neurotransmission. Biol Psychiatry. 1999;46:1131–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Rasmussen K, Aghajanian GK. Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists. Brain Res. 1986;385:395–400.PubMedCrossRefGoogle Scholar
  54. 54.
    Chiang C, Aston-Jones G. A 5-hydroxytryptamine 2 agonist augments γ-aminobutyric acid and excitatory amino acid inputs to noradrenergic locus coeruleus neurons. Neuroscience. 1993;54:409–20.PubMedCrossRefGoogle Scholar
  55. 55.
    Rasmussen K, Glennon RA, Aghajanian GK. Phenethyl-amine hallucinogens in the locus coeruleus: potency of action correlates with rank order of 5-HT2 binding affinity. Eur J Pharmacol. 1986;132:79–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Marek GJ, Aghajanian GK. Indoleamine and the phenethylamine hallucinogens: mechanisms of psychotomimetic action. Drug Alcohol Depend. 1998;51:189–98.PubMedCrossRefGoogle Scholar
  57. 57.
    Araneda R, Andrade R. 5-Hydroxytryptamine 2 and 5-hydroxy-tryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience. 1991;40:399–412.PubMedCrossRefGoogle Scholar
  58. 58.
    Behrendt RP. Hallucinations: synchronization of thalamocortical gamma oscillations underconstrained by sensory input. Conscious Cogn. 2003;12:413–51.PubMedCrossRefGoogle Scholar
  59. 59.
    Tilakaratne N, Friedman E. Genomic responses to 5-HT1a or 5-HT2a2c receptor activation is differentially regulated in four regions of rat brain. Eur J Pharmacol. 1996;307:211–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Nichols CD, Sanders-Bush E. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology. 2002;26:634–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Leslie RA, Moorman JM, Coulson A, et al. Serotonin 2/1 C receptor activation causes a localized expression of the immediate-early gene c-fos in rat brain: evidence for involvement of dorsal raphe nucleus projection fibers. Neuroscience. 1993;53:457–63.PubMedCrossRefGoogle Scholar
  62. 62.
    Nichols CD, Garcia EE, Sanders-Bush E. Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration. Mol Brain Res. 2003;111:182–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Pazos A, Hoyer D, Palacios JM. The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur J Pharmacol. 1984;106:539–46.PubMedCrossRefGoogle Scholar
  64. 64.
    Titeler M, Lyon RA, Glennon RA. Radioligand binding evidence implicates the brain 5-HT 2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology. 1988;94:213–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Parker MA, Marona-Lewicka D, Lucaites VL, et al. A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor. J Med Chem. 1998;41:5148–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, et al. Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. J Med Chem. 2001;44:1003–10.PubMedCrossRefGoogle Scholar
  67. 67.
    Burris KD, Breeding M, Sanders-Bush E. (+) Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist. J Pharmacol Exp Ther. 1991;258:891–6.PubMedGoogle Scholar
  68. 68.
    Fiorella D, Rabin RA, Winter JC. Role of 5-HT 2A and 5-HT 2C receptors in the stimulus effects of hallucinogenic drugs II: reassessment of LSD false positives. Psychopharmacology. 1995;121:357–63.PubMedCrossRefGoogle Scholar
  69. 69.
    Sanders-Bush E. Neurochemical evidence that hallucinogenic drugs are 5-HT1C receptor agonists: what next? NIDA Res Monogr. 1994;146:203–13.PubMedGoogle Scholar
  70. 70.
    Glennon RA, Hauck AE. Mechanistic studies on DOM as a discriminative stimulus. Pharmacol Biochem Behav. 1985;23:937–41.PubMedCrossRefGoogle Scholar
  71. 71.
    Glennon RA. Do hallucinogens act as 5-HT2 agonists or antagonists? Neuropsychopharmacology. 1990;56:509–17.Google Scholar
  72. 72.
    Nichols DE. Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs. 1986;18:305–13.PubMedCrossRefGoogle Scholar
  73. 73.
    Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci. 2014;9:1645–52.PubMedCrossRefGoogle Scholar
  74. 74.
    Carvalho M, Carmo H, Costa VM, et al. Toxicity of amphetamines: an update. Arch Toxicol. 2012;86:1167–231.PubMedCrossRefGoogle Scholar
  75. 75.
    Kleven MS, Seiden LS. Methamphetamine-induced neurotoxicity: structure activity relationships. Ann N Y Acad Sci. 1992;654:292–301.PubMedCrossRefGoogle Scholar
  76. 76.
    Freudenmann RW, Öxler F, Bernschneider-Reif S. The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction. 2006;101:1241–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Rugani F, Bacciardi S, Rovai L, et al. Symptomatological features of patients with and without ecstasy use during their first psychotic episode. Int J Environ Res Public Health. 2012;9:2283–92.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    United Nations Office on Drugs and Crime UNODC World Drug Report. United Nations publication, Sales No. E16XI7. 2016.Google Scholar
  79. 79.
    Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. Can Med Assoc J. 2001;165:917–28.Google Scholar
  80. 80.
    Parrott AC. Human psychopharmacology of ecstasy (MDMA): a review of 15 years of empirical research. Hum Psychopharmacol Clin Exp. 2001;16:557–77.CrossRefGoogle Scholar
  81. 81.
    Schifano F. Chronic atypical psychosis associated with MDMA. Lancet. 1991;338:1335.PubMedCrossRefGoogle Scholar
  82. 82.
    Cohen RS, Cocores J. Neuropsychiatric manifestations following the use of 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”). Prog Neuro-Psychopharmacol Biol Psychiatry. 1997;21:727–34.CrossRefGoogle Scholar
  83. 83.
    Keenan E, Gervin M, Dorman A, O'Connor JJ. Psychosis and recreational use of MDMA (“Ecstasy”). Ir J Psychol Med. 1993;10:162–3.CrossRefGoogle Scholar
  84. 84.
    Boné PI, Ramos GP, Villalba YP, et al. Persisting and late onset psychotic disorder due to consumption of ecstasy (MDMA). Actas Esp Psiquiatr. 1999;28:61–5.Google Scholar
  85. 85.
    Landabaso MA, Iraurgi I, Jiménez-Lerma JM, et al. Ecstasy-induced psychotic disorder: six-month follow-up study. Eur Addict Res. 2002;8:133–40.PubMedCrossRefGoogle Scholar
  86. 86.
    Potash MN, Gordon KA, Conrad KL. Persistent psychosis and medical complications after a single ingestion of MDMA “Ecstasy”: a case report and review of the literature. Psychiatry. 2009;6:40.PubMedGoogle Scholar
  87. 87.
    Brown C, Osterloh J. Multiple severe complications from recreational ingestion of MDMA ('Ecstasy'). JAMA. 1987;258:780–1.PubMedCrossRefGoogle Scholar
  88. 88.
    Creighton FJ, Black DL, Hyde CE. 'Ecstasy' psychosis and flashbacks. Br J Psychiatry. 1991;159:713–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Vollenweider FX. Brain mechanisms of hallucinogens and entactogens. Dialogues Clin Neurosci. 2001;3:265–80.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Davison D, Parrott AC. Ecstasy (MDMA) in recreational users: self-reported psychological and physiological effects. Hum Psychopharmacol Clin Exp. 1997;12:221–6.CrossRefGoogle Scholar
  91. 91.
    Oliveri M, Calvo G. Increased visual cortical excitability in ecstasy users: a transcranial magnetic stimulation study. J Neurol Neurosurg Psychiatry. 2003;74:1136–8.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Hanck L, Schellekens AF. Hallucinogen persisting perception disorder after ecstasy use. Ned Tijdschr Geneeskd. 2012;157:A5649.Google Scholar
  93. 93.
    Robbins TW, Everitt BJ. Drug addiction: bad habits add up. Nature. 1999;398:567–70.PubMedCrossRefGoogle Scholar
  94. 94.
    Parrott AC, Sisk E, Turner JJD. Psychobiological problems in heavy ‘ecstasy’(MDMA) polydrug users. Drug Alcohol Depend. 2000;60:105–10.PubMedGoogle Scholar
  95. 95.
    Green AR, Cross AJ, Goodwin GM. Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”). Psychopharmacology. 1995;119:247–60.PubMedCrossRefGoogle Scholar
  96. 96.
    Koch S, Galloway MP. MDMA induced dopamine release in vivo: role of endogenous serotonin. J Neural Transm. 1997;104:135–46.PubMedCrossRefGoogle Scholar
  97. 97.
    O'Loinsigh ED, Boland G, Kelly JP, et al. Behavioural, hyperthermic and neurotoxic effects of 3,4-methylenedioxymethamphetamine analogues in the Wistar rat. Prog Neuro-Psychopharmacol Biol Psychiatry. 2001;25:621–38.CrossRefGoogle Scholar
  98. 98.
    Mechan AO, Esteban B, O'Shea E, et al. The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats. Br J Pharmacol. 2002;135:170–80.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Verrico CD, Miller GM, Madras BK. MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology. 2007;189:489–503.PubMedCrossRefGoogle Scholar
  100. 100.
    Rothman RB, Baumann MH. Monoamine transporters and psychostimulant drugs. Eur J Pharmacol. 2003;479:23–40.PubMedCrossRefGoogle Scholar
  101. 101.
    Clauwaert KM, Van Bocxlaer JF, Els A, et al. Determination of the designer drugs 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyethylamphetamine, and 3,4-methylenedioxyamphetamine with HPLC and fluorescence detection in whole blood, serum, vitreous humor, and urine. Clin Chem. 2000;46:1968–77.PubMedGoogle Scholar
  102. 102.
    Green AR, Mechan AO, Elliott JM, et al. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev. 2003;55:463–508.PubMedCrossRefGoogle Scholar
  103. 103.
    de Win MM, Jager G, Booij J, Reneman L, et al. Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users. Brain. 2008;131:2936–45.PubMedCrossRefGoogle Scholar
  104. 104.
    Parrott AC. MDMA and 5-HT neurotoxicity: the empirical evidence for its adverse effects in humans—no need for translation. Br J Pharmacol. 2012;166:1518–20.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Meyer JS. 3,4-Methylenedioxymethamphetamine (MDMA): current perspectives. Subst Abuse Rehabil. 2013;4:83–99.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Berger UV, Gu XF, Azmitia EC. The substituted amphetamines 3, 4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur J Pharmacol. 1992;215:153–60.PubMedCrossRefGoogle Scholar
  107. 107.
    Mørland J. Toxicity of drug abuse—amphetamine designer drugs (ecstasy): mental effects and consequences of single dose use. Toxicol Lett. 2000;112:147–52.PubMedCrossRefGoogle Scholar
  108. 108.
    Gudelsky GA, Nash JF. Carrier-mediated release of serotonin by 3,4-methylenedioxymethamphetamine: implications for serotonin-dopamine interactions. J Neurochem. 1996;66:243–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Tao R, Shokry IM, Callanan JJ, et al. Mechanisms and environmental factors underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats. Psychopharmacology. 2015;232:1245–60.PubMedCrossRefGoogle Scholar
  110. 110.
    Hagino Y, Takamatsu Y, Yamamoto H, et al. Effects of MDMA on extracellular dopamine and serotonin levels in mice lacking dopamine and/or serotonin transporters. Curr Neuropharmacol. 2011;9:91–5.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Liechti ME, Baumann C, Gamm A, Vollenweider FX. Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology. 2000a;22:513–21.PubMedCrossRefGoogle Scholar
  112. 112.
    Liechti ME, Saur MR, Gamma A, et al. Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT2 antagonist ketanserin in healthy humans. Neuropsychopharmacology. 2000b;23:396–404.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M. Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors. Psychopharmacology. 1998;136:409–14.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Kometer M, Schmidt A, Jäncke L, et al. Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci. 2013;33:10544–51.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Sadzot B, Baraban JM, Glennon RA, et al. Hallucinogenic drug interactions at human brain 5-HT 2 receptors: implications for treating LSD-induced hallucinogenesis. Psychopharmacology. 1989;98:495–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Mlinar B, Mascalchi S, Morini R, et al. MDMA induces EPSP-spike potentiation in rat ventral hippocampus in vitro via serotonin and noradrenaline release and coactivation of 5-HT4 and β1 receptors. Neuropsychopharmacology. 2008;33:1464–75.PubMedCrossRefGoogle Scholar
  117. 117.
    Oleskevich S, Descarries L. Quantified distribution of the serotonin innervation in adult rat hippocampus. Neuroscience. 1990;34:19–33.PubMedCrossRefGoogle Scholar
  118. 118.
    Oleskevich S, Descarries L, Lacaille JC. Quantified distribution of the noradrenaline innervation in the hippocampus of adult rat. J Neurosci. 1989;9:3803–15.PubMedCrossRefGoogle Scholar
  119. 119.
    Hensler JG. Serotonergic modulation of the limbic system. Neurosci Biobehav Rev. 2006;30:203–14.PubMedCrossRefGoogle Scholar
  120. 120.
    Gamma A, Buck A, Berthold T, et al. 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H215O]-PET in healthy humans. Neuropsychopharmacology. 2000;23:388–95.PubMedCrossRefGoogle Scholar
  121. 121.
    Litjens RP, Brunt TM, Alderliefste GJ, et al. Hallucinogen persisting perception disorder and the serotonergic system: a comprehensive review including new MDMA-related clinical cases. Eur Neuropsychopharmacol. 2014;24:1309–23.PubMedCrossRefGoogle Scholar
  122. 122.
    Greene SL, Dargan PI, O’Connor N, et al. Multiple toxicity from 3, 4-methylenedioxymethamphetamine (“ecstasy”). Am J Emerg Med. 2003;21:121–4.PubMedCrossRefGoogle Scholar
  123. 123.
    Segura M, Farré M, Pichini S, et al. Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans. Clin Pharmacokinet. 2005;44:649–60.PubMedCrossRefGoogle Scholar
  124. 124.
    Roiser JP, Cook LJ, Cooper JD, et al. Association of a functional polymorphism in the serotonin transporter gene with abnormal emotional processing in ecstasy users. Am J Psychiatr. 2005;162:609–12.PubMedCrossRefGoogle Scholar
  125. 125.
    Roiser JP, Rogers RD, Cook LJ, et al. The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls. Psychopharmacology. 2006;188:213–27.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Matteo Lazzaretti
    • 1
  • Gian Mario Mandolini
    • 1
  • Alfredo Carlo Altamura
    • 1
  • Paolo Brambilla
    • 1
    • 2
    Email author
  1. 1.Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly
  2. 2.Department of Psychiatry and Behavioural NeurosciencesUniversity of Texas at HoustonHoustonUSA

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