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The neurobiology of psychedelic drugs: implications for the treatment of mood disorders


After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

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Figure 1: Activation of the prefrontal network and glutamate release by psychedelics.
Figure 2: Brain activity patterns in psychedelic-induced states of consciousness.


  1. 1

    Hofmann, A. & Schultes, R. E. Plants of the Gods (McGraw-Hill Book Company, Maidenhead, UK, 1979).

    Google Scholar 

  2. 2

    Hofmann, A. in Chemical Constitution and Pharmacodynamic Actions (ed. Burger, A.) 169–235 (M.Dekker, New York, 1968).

    Google Scholar 

  3. 3

    Domino, E. F., Kamenka, J. M. & Gneste, P. The joint French–US seminar on phencyclidine and related arylcyclohexylamines. Trends Pharmacol. Sci. 9, 363–367 (1983).

    Google Scholar 

  4. 4

    Hasler, F., Grimberg, U., Benz, M. A., Huber, T. & Vollenweider, F. X. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology 172, 145–156 (2004).

    CAS  Google Scholar 

  5. 5

    Dittrich, A. in 50 Years of LSD. Current Status and Perspectives of Hallucinogens (eds Pletscher, A. & Ladewig, D.) 101–118 (Parthenon, New York, 1994).

    Google Scholar 

  6. 6

    Fischer, R., Marks, P. A., Hill, R. M. & Rockey, M. A. Personality structure as the main determinant of drug induced (model) psychoses. Nature 218, 296–298 (1968).

    CAS  Google Scholar 

  7. 7

    Leuner, H. Die Experimentelle Psychose (Springer, Berlin Göttingen Heidelberg, 1962).

    Google Scholar 

  8. 8

    Hoch, P. H., Cattell, J. P. & Pennes, H. H. Effects of mescaline and lysergic acid (d-LSD-25). Am. J. Psychiatry 108, 579–584 (1952).

    CAS  Google Scholar 

  9. 9

    Chapman, J. The early symptoms of schizophrenia. Br. J. Psychiatry 112, 225–251 (1966).

    CAS  Google Scholar 

  10. 10

    Gouzoulis-Mayfrank, E. et al. Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study. Eur. Psychiatry 13, 399–406 (1998).

    CAS  Google Scholar 

  11. 11

    Geyer, M. A. & Vollenweider, F. X. Serotonin research: contributions to understanding psychoses. Trends Pharmacol. Sci. 29, 445–453 (2008).

    CAS  Google Scholar 

  12. 12

    Nichols, D. E. Hallucinogens. Pharmacol. Ther. 101, 131–181 (2004).

    CAS  Google Scholar 

  13. 13

    Krystal, J. H. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Arch. Gen. Psychiatry 51, 199–214 (1994).

    CAS  PubMed  Google Scholar 

  14. 14

    Anis, N. A., Berry, S. C., Burton, N. R. & Lodge, D. The dissociative anesthetics, ketamine and phencyclidine selective reduce excitation of central mammalian neurons by N-methyl-D-aspartate. Br. J. Pharmacol. 79, 565–575 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Sandison, R. A. Psychological aspects of the LSD treatment of neuroses. J. Ment Sci. 100, 508–515 (1954).

    CAS  Google Scholar 

  16. 16

    Schmiege, G. R. Jr. LSD as a therapeutic tool. J. Med. Soc. N.J. 60, 203–207 (1963).

    Google Scholar 

  17. 17

    Malleson, N. Acute adverse reactions to LSD in clinical and experimental use in the United Kingdom. Br. J. Psychiatry 118, 229–230 (1971).

    CAS  Google Scholar 

  18. 18

    Hoffer, A. in The Uses and Implications of Hallucinogenic Drugs (eds Aaronson, B. & Osmond, H.) 357–366 (Hogarth Press, London, 1970).

    Google Scholar 

  19. 19

    Abramson, H. The use of LSD in Psychotherapy and Alcoholism (Bobbs-Merrill, New York, 1967).

    Google Scholar 

  20. 20

    Kast, E. in LSD: The Consciousness Expanding Drug (ed. Solomon, D.) 241–256 (G.P. Putman, New York, 1964).

    Google Scholar 

  21. 21

    Pahnke, W. N., Kurland, A. A., Goodman, L. E. & Richards, W. A. LSD-assisted psychotherapy with terminal cancer patients. Curr. Psychiatr. Ther. 9, 144–152 (1969).

    CAS  Google Scholar 

  22. 22

    Leuner, H. in 50 Years of LSD: Current Status and Perspectives of Hallucinogen Research (eds Pletscher, A. & Ladewig, D.) 175–189 (Parthenon, New York, 1994).

    Google Scholar 

  23. 23

    Kurland, A. A., Unger, S., Shaffer, J. W. & Savage, C. Psychedelic therapy utilizing LSD in the treatment of the alcoholic patient: a preliminary report. Am. J. Psychiatry 123, 1202–1209 (1967).

    CAS  Google Scholar 

  24. 24

    Skolnick, P., Popik, P. & Trullas, R. Glutamate-based antidepressants: 20 years on. Trends Pharmacol. Sci. 30, 563–569 (2009).

    CAS  Google Scholar 

  25. 25

    Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000).

    CAS  Google Scholar 

  26. 26

    Zarate, C. A. Jr et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006).

    CAS  Google Scholar 

  27. 27

    Phelps, L. E. et al. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol. Psychiatry 65, 181–184 (2009).

    CAS  Google Scholar 

  28. 28

    Price, R. B., Nock, M. K., Charney, D. S. & Mathew, S. J. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry 66, 522–526 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Aan het Rot, M. et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol. Psychiatry 67, 139–145 (2010).

    CAS  Google Scholar 

  30. 30

    Mathew, S. J. et al. Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int. J. Neuropsychopharmacol. 13, 71–82 (2010).

    CAS  Google Scholar 

  31. 31

    Holsboer, F. How can we realize the promise of personalized antidepressant medicines? Nature Rev. Neurosci. 9, 638–646 (2008).

    CAS  Google Scholar 

  32. 32

    Salvadore, G. et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology 35, 1415–1422 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Salvadore, G. et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol. Psychiatry 65, 289–295 (2009).

    CAS  Google Scholar 

  34. 34

    Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Rev. Drug Discov. 7, 426–437 (2008).

    CAS  Google Scholar 

  35. 35

    Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Rev. Neurosci. 8, 413–426 (2007).

    CAS  Google Scholar 

  36. 36

    Krupitsky, E. et al. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J. Subst. Abuse Treatment 23, 273–283 (2002).

    Google Scholar 

  37. 37

    Moreno, F. A., Wiegand, C. B., Taitano, E. K. & Delgado, P. L. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J. Clin. Psychiatry 67, 1735–1740 (2006).

    CAS  Google Scholar 

  38. 38

    Brandrup, E. & Vanggaard, T. LSD treatment in a severe case of compulsive neurosis. Acta Psychiatr. Scand. 55, 127–141 (1977).

    CAS  Google Scholar 

  39. 39

    Leonard, H. L. & Rapoport, J. L. Relief of obsessive–compulsive symptoms by LSD and psilocin. Am. J. Psychiatry 144, 1239–1240 (1987).

    CAS  Google Scholar 

  40. 40

    Moreno, F. A. & Delgado, P. L. Hallucinogen-induced relief of obsessions and compulsions. Am. J. Psychiatry 154, 1037–1038 (1997).

    CAS  Google Scholar 

  41. 41

    Sewell, R. A., Halpern, J. H. & Pope, H. G. Jr. Response of cluster headache to psilocybin and LSD. Neurology 66, 1920–1922 (2006).

    Google Scholar 

  42. 42

    Gonzalez-Maeso, J. & Sealfon, S. C. Agonist-trafficking and hallucinogens. Curr. Med. Chem. 16, 1017–1027 (2009).

    CAS  Google Scholar 

  43. 43

    Winter, J. C. Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines. Psychopharmacology (Berlin) 203, 251–263 (2009).

    CAS  Google Scholar 

  44. 44

    Large, C. H. Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J. Psychopharmacol. 21, 283–301 (2007).

    CAS  Google Scholar 

  45. 45

    Quirk, M. C., Sosulski, D. L., Feierstein, C. E., Uchida, N. & Mainen, Z. F. A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration. Front. Syst. Neurosci. 3, 13 (2009).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    DeRubeis, R. J., Siegle, G. J. & Hollon, S. D. Cognitive therapy versus medication for depression: treatment outcomes and neural mechanisms. Nature Rev. Neurosci. 9, 788–796 (2008).

    CAS  Google Scholar 

  47. 47

    Clark, L., Chamberlain, S. R. & Sahakian, B. J. Neurocognitive mechanisms in depression: implications for treatment. Annu. Rev. Neurosci. 32, 57–74 (2009).

    CAS  Google Scholar 

  48. 48

    Geyer, M. A., Nichols, D. E. & Vollenweider, F. X. in Encyclopedia of Neuroscience (ed. Squire, L. R.) 741–748 (Academic Press, Oxford, 2009).

    Google Scholar 

  49. 49

    Marona-Lewicka, D., Thisted, R. A. & Nichols, D. E. Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacologia (Berlin) 180, 427–435 (2005).

    CAS  Google Scholar 

  50. 50

    Glennon, R. A., Titeler, M. & McKenney, J. D. Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci. 35, 2505–2511 (1984).

    CAS  Google Scholar 

  51. 51

    Aghajanian, G. K. & Marek, G. J. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropsychopharmacology 36, 589–599 (1997).

    CAS  Google Scholar 

  52. 52

    Aghajanian, G. K. & Marek, G. J. Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res. 825, 161–171 (1999).

    CAS  Google Scholar 

  53. 53

    Wing, L. L., Tapson, G. S. & Geyer, M. A. 5HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology 100, 417–425 (1990).

    CAS  Google Scholar 

  54. 54

    Sipes, T. E. & Geyer, M. A. DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT2A and not by 5-HT2C receptors. Behav. Pharmacol. 6, 839–842 (1995).

    CAS  Google Scholar 

  55. 55

    Gonzalez-Maeso, J. et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53, 439–452 (2007).

    CAS  Google Scholar 

  56. 56

    Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A., Vogel, H. & Hell, D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9, 3897–3902 (1998).

    CAS  Google Scholar 

  57. 57

    Schmid, C. L., Raehal, K. M. & Bohn, L. M. Agonist-directed signaling of the serotonin 2A receptor depends on b-arrestin-2 interactions in vivo. Proc. Natl Acad. Sci. USA 105, 1079–1084 (2008).

    CAS  Google Scholar 

  58. 58

    Puig, M. V., Celada, P., az-Mataix, L. & Artigas, F. 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 13, 870–882 (2003).

    Google Scholar 

  59. 59

    Beique, J. C., Imad, M., Mladenovic, L., Gingrich, J. A. & Andrade, R. Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc. Natl Acad. Sci. USA 104, 9870–9875 (2007).

    Google Scholar 

  60. 60

    Aghajanian, G. K. & Marek, G. J. Serotonin and hallucinogens. Neuropsychopharmacology 21, 16S–23S (1999).

    CAS  Google Scholar 

  61. 61

    Marek, G. J., Wright, R. A., Gewirtz, J. C. & Schoepp, D. D. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105, 379–392 (2001).

    CAS  Google Scholar 

  62. 62

    Aghajanian, G. K. Modeling 'psychosis' in vitro by inducing disordered neuronal network activity in cortical brain slices. Psychopharmacology (Berlin) 206, 575–585 (2009).

    CAS  Google Scholar 

  63. 63

    Zhang, C. & Marek, G. J. AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 62–71 (2008).

    Google Scholar 

  64. 64

    Benneyworth, M. A. et al. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol. Pharmacol. 72, 477–484 (2007).

    CAS  Google Scholar 

  65. 65

    Lambe, E. K. & Aghajanian, G. K. Hallucinogen-induced UP states in the brain slice of rat prefrontal cortex: role of glutamate spillover and NR2B-NMDA receptors. Neuropsychopharmacology 31, 1682–1689 (2006).

    CAS  Google Scholar 

  66. 66

    Celada, P., Puig, M. V., Casanovas, J. M., Guillazo, G. & Artigas, F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J. Neurosci. 21, 9917–9929 (2001).

    CAS  Google Scholar 

  67. 67

    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 19, 1678–1686 (2009).

    Google Scholar 

  68. 68

    Vollenweider, F. X., Vontobel, P., Hell, D. & Leenders, K. L. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man: A PET study with [11C]raclopride. Neuropsychopharmacology 20, 424–433 (1999).

    CAS  Google Scholar 

  69. 69

    Jones, K. A. et al. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc. Natl Acad. Sci. USA 106, 19575–19580 (2009).

    CAS  Google Scholar 

  70. 70

    Buckholtz, N. S., Zhou, D. F., Freedman, D. X. & Potter, W. Z. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharmacology 3, 137–148 (1990).

    CAS  Google Scholar 

  71. 71

    Gresch, P. J., Smith, R. L., Barrett, R. J. & Sanders-Bush, E. Behavioral tolerance to lysergic acid diethylamide is associated with reduced serotonin-2A receptor signaling in rat cortex. Neuropsychopharmacology 30, 1693–1702 (2005).

    CAS  Google Scholar 

  72. 72

    Shelton, R. C., Sanders-Bush, E., Manier, D. H. & Lewis, D. A. Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase, A. Neuroscience 158, 1406–1415 (2008).

    Google Scholar 

  73. 73

    Bhagwagar, Z. et al. Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11C]MDL 100,907. Am. J. Psychiatry 163, 1580–1587 (2006).

    Google Scholar 

  74. 74

    Meyer, J. H. et al. Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am. J. Psychiatry 160, 90–99 (2003).

    Google Scholar 

  75. 75

    Sibille, E. et al. Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice. Mol. Pharmacol. 52, 1056–1063 (1997).

    CAS  Google Scholar 

  76. 76

    Yamauchi, M., Miyara, T., Matsushima, T. & Imanishi, T. Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors. Brain Res. 1067, 164–169 (2006).

    CAS  Google Scholar 

  77. 77

    Gomez-Gil, E. et al. Decrease of the platelet 5-HT2A receptor function by long-term imipramine treatment in endogenous depression. Hum. Psychopharmacol. 19, 251–258 (2004).

    CAS  Google Scholar 

  78. 78

    Cohen, H. Anxiolytic effect and memory improvement in rats by antisense oligodeoxynucleotide to 5-hydroxytryptamine-2A precursor protein. Depress. Anxiety. 22, 84–93 (2005).

    CAS  Google Scholar 

  79. 79

    Weisstaub, N. V. et al. Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313, 536–540 (2006).

    CAS  PubMed  Google Scholar 

  80. 80

    Anisman, H., Merali, Z. & Stead, J. D. Experiential and genetic contributions to depressive- and anxiety-like disorders: clinical and experimental studies. Neurosci. Biobehav. Rev. 32, 1185–1206 (2008).

    CAS  Google Scholar 

  81. 81

    Lukkes, J., Vuong, S., Scholl, J., Oliver, H. & Forster, G. Corticotropin-releasing factor receptor antagonism within the dorsal raphe nucleus reduces social anxiety-like behavior after early-life social isolation. J. Neurosci. 29, 9955–9960 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Reul, J. M. & Holsboer, F. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr. Opin. Pharmacol. 2, 23–33 (2002).

    CAS  Google Scholar 

  83. 83

    Magalhaes, A. C. et al. CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nature Neurosci. 13, 622–629 (2010).

    CAS  Google Scholar 

  84. 84

    Frokjaer, V. G. et al. Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biol. Psychiatry 63, 569–576 (2008).

    CAS  Google Scholar 

  85. 85

    Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neurosci. 8, 365–371 (2005).

    CAS  Google Scholar 

  86. 86

    Kupers, R. et al. A PET [18F]altanserin study of 5-HT12A receptor binding in the human brain and responses to painful heat stimulation. Neuroimage 44, 1001–1007 (2009).

    Google Scholar 

  87. 87

    Oye, I., Paulsen, O. & Maurset, A. Effects of ketamine on sensory perception: Evidence for a role of N-methyl-D-aspartate receptors. J. Pharmac. Exp. Ther. 260, 1209–1213 (1992).

    CAS  Google Scholar 

  88. 88

    Moghaddam, B., Adams, B., Verma, A. & Daly, D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17, 2921–2927 (1997).

    CAS  Google Scholar 

  89. 89

    Lopez-Gil, X. et al. Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology 32, 2087–2097 (2007).

    CAS  Google Scholar 

  90. 90

    Jackson, M. E., Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc. Natl Acad. Sci. USA 101, 8467–8472 (2004).

    CAS  Google Scholar 

  91. 91

    Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Jodo, E. et al. Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway. Cereb. Cortex 15, 663–669 (2005).

    Google Scholar 

  93. 93

    Moghaddam, B. & Adams, B. W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352 (1998).

    CAS  Google Scholar 

  94. 94

    Preskorn, S. H. et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 28, 631–637 (2008).

    CAS  Google Scholar 

  95. 95

    Maeng, S. et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349–352 (2008).

    CAS  Google Scholar 

  96. 96

    Anand, A. et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Arch. Gen. Psychiatry 57, 270–276 (2000).

    CAS  Google Scholar 

  97. 97

    Jentsch, J. D., Tran, A., Taylor, J. R. & Roth, R. H. Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence. Psychopharmacology (Berlin) 138, 89–95 (1998).

    CAS  Google Scholar 

  98. 98

    Breier, A. et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects — application of a novel PET approach. Synapse 29, 142–147 (1998).

    CAS  Google Scholar 

  99. 99

    Vollenweider, F. X., Vontobel, P., Leenders, K. L. & Hell, D. Effects of S-ketamine on striatal dopamine release: a [11C] raclopride PET study of a model psychosis in humans. J. Psych. Res. 34, 35–43 (2000).

    CAS  Google Scholar 

  100. 100

    Krystal, J. H. et al. Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology 145, 193–204 (1999).

    CAS  Google Scholar 

  101. 101

    Varty, G. B., Bakshi, V. P. & Geyer, M. A. M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in sprague-dawley and wistar rats. Neuropsychopharmacology 20, 311–321 (1999).

    CAS  Google Scholar 

  102. 102

    Snigdha, S. et al. Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. J. Pharmacol. Exp. Ther. 332, 622–631 (2010).

    CAS  Google Scholar 

  103. 103

    Scruggs, J. L., Schmidt, D. & Deutch, A. Y. The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci. Lett. 346, 137–140 (2003).

    CAS  Google Scholar 

  104. 104

    Muschamp, J. W., Regina, M. J., Hull, E. M., Winter, J. C. & Rabin, R. A. Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res. 1023, 134–140 (2004).

    CAS  Google Scholar 

  105. 105

    Kargieman, L., Santana, N., Mengod, G., Celada, P. & Artigas, F. Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine. Proc. Natl Acad. Sci. USA 104, 14843–14848 (2007).

    CAS  Google Scholar 

  106. 106

    Shi, W. X. & Zhang, X. X. Dendritic glutamate-induced bursting in the prefrontal cortex: further characterization and effects of phencyclidine. J. Pharmacol. Exp. Ther. 305, 680–687 (2003).

    CAS  Google Scholar 

  107. 107

    Vollenweider, F. X. et al. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [F-18]-fluorodeoxyglocose (FDG). Eur. Neuropsychopharmacol. 7, 9–24 (1997).

    CAS  Google Scholar 

  108. 108

    Vollenweider, F. X. et al. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16, 357–372 (1997).

    CAS  Google Scholar 

  109. 109

    Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D. & Angst, J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers measured by FDG-PET. Eur. Neuropsychopharmacol. 7, 25–38 (1997).

    CAS  Google Scholar 

  110. 110

    Schreckenberger, M. et al. The psilocybin psychosis as a model psychosis paradigma for acute schizophrenia: a PET study with 18-FDG. Eur. J. Nucl. Med. 25, 877 (1998).

    Google Scholar 

  111. 111

    Gouzoulis-Mayfrank, E. et al. Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and D-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 20, 565–581 (1999).

    CAS  Google Scholar 

  112. 112

    Walter, M. et al. The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch. Gen. Psychiatry 66, 478–486 (2009).

    CAS  Google Scholar 

  113. 113

    Hasler, G. et al. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch. Gen. Psychiatry 64, 193–200 (2007).

    CAS  Google Scholar 

  114. 114

    Bishop, S. J. Trait anxiety and impoverished prefrontal control of attention. Nature Neurosci. 12, 92–98 (2009).

    CAS  Google Scholar 

  115. 115

    Bishop, S. J. Neural mechanisms underlying selective attention to threat. Ann. NY Acad. Sci. 1129, 141–152 (2008).

    Google Scholar 

  116. 116

    Johnstone, T., van Reekum, C. M., Urry, H. L., Kalin, N. H. & Davidson, R. J. Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J. Neurosci. 27, 8877–8884 (2007).

    CAS  Google Scholar 

  117. 117

    Chen, C. H. et al. Functional coupling of the amygdala in depressed patients treated with antidepressant medication. Neuropsychopharmacology 33, 1909–1918 (2008).

    CAS  Google Scholar 

  118. 118

    Fu, C. H. et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study. Arch. Gen. Psychiatry 61, 877–889 (2004).

    PubMed  Google Scholar 

  119. 119

    Sheline, Y. I. et al. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol. Psychiatry 50, 651–658 (2001).

    CAS  Google Scholar 

  120. 120

    Martinowich, K., Manji, H. & Lu, B. New insights into BDNF function in depression and anxiety. Nature Neurosci. 10, 1089–1093 (2007).

    CAS  Google Scholar 

  121. 121

    Krystal, J. H. et al. Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug Discov. Today 14, 690–697 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Machado-Vieira, R., Salvadore, G., DiazGranados, N. & Zarate, C. A. Jr. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol. Ther. 123, 143–150 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Vaidya, V. A., Marek, G. J., Aghajanian, G. K. & Duman, R. S. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 17, 2785–2795 (1997).

    CAS  Google Scholar 

  124. 124

    Cavus, I. & Duman, R. S. Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol. Psychiatry 54, 59–69 (2003).

    CAS  Google Scholar 

  125. 125

    Garcia, L. S. et al. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 450–455 (2009).

    CAS  Google Scholar 

  126. 126

    Studerus, E., Kometer, M., Hasler, F. & Vollenweider, F. X. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J. Psychopharmacology (in the press).

  127. 127

    Perry, E. B. Jr et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology (Berlin) 192, 253–260 (2007).

    CAS  Google Scholar 

  128. 128

    Savage, C., Savage, E., Fadiman, J. & Harman, W. W. LSD: Therapeutic effects of the psychedelic experience. Psychol. Rep. 14, 111–120 (1964).

    Google Scholar 

  129. 129

    Pahnke, W. N., Kurland, A. A., Unger, S., Savage, C. & Grof, S. The experimental use of psychedelic (LSD) psychotherapy. JAMA 212, 1856–1863 (1970).

    CAS  Google Scholar 

  130. 130

    Kurland, A. A., Grof, S. & Panke, W. N. G. L. E. LSD in the treatment of alcoholics. Pharmakopsychiatr. Neuropsychopharmakol. 4, 83–94 (1971).

    Google Scholar 

  131. 131

    Griffiths, R. R., Richards, W., Johnson, M., McCann, U. & Jesse, R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J. Psychopharmacol. 22, 621–632 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Griffiths, R. R., Richards, W. A., McCann, U. & Jesse, R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berlin) 187, 268–283 (2006).

    CAS  Google Scholar 

  133. 133

    Dittrich, A. The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry 31, 80–84 (1998).

    Google Scholar 

  134. 134

    Vollenweider, F. X. Advances and pathophysiological models of hallucinogen drug actions in humans: a preamble to schizophrenia research. Pharmacopsychiatry 31, 92–103 (1998).

    CAS  Google Scholar 

  135. 135

    Fischer, R. A cartography of the ecstatic and meditative states. Science 174, 897–904 (1971).

    CAS  Google Scholar 

  136. 136

    Osmond, H. A review of the clinical effects of psychotomimetic agents. Ann. NY Acad. Sci. 66, 418–434 (1957).

    CAS  Google Scholar 

  137. 137

    Kurland, A. A. LSD in the supportive care of the terminally ill cancer patient. J. Psychoactive Drugs 17, 279–290 (1985).

    CAS  Google Scholar 

  138. 138

    Abramson, H. A. The Use of LSD in Psychotherapy and Alcoholism (Bobbs-Merrill, Indianapolis, 1967).

    Google Scholar 

  139. 139

    Hollister, L. E., Shelton, J. & Krieger, G. A controlled comparison of lysergic acid diethylamide (LSD) and dextroamphetmine in alcoholics. Am. J. Psychiatry 125, 1352–1357 (1969).

    CAS  Google Scholar 

  140. 140

    Savage, C. & McCabe, O. L. Residential psychedelic (LSD) therapy for the narcotic addict. A controlled study. Arch. Gen. Psychiatry 28, 808–814 (1973).

    CAS  Google Scholar 

  141. 141

    Grof, S., Goodman, L. E., Richards, W. A. & Kurland, A. A. LSD-assisted psychotherapy in patients with terminal cancer. Int. Pharmacopsychiatry 8, 129–144 (1973).

    CAS  Google Scholar 

  142. 142

    Pahnke, W. N. Psychedelic drugs and mystical experience. Int. Psychiatry Clin. 5, 149–162 (1969).

    CAS  Google Scholar 

  143. 143

    Grinspoon, L. & Bakalar, J. B. Psychedelic Drugs Reconsidered (Basic Books., New York, 1979).

    Google Scholar 

  144. 144

    Crocket, R., Sandison, R. A. & Walk, A. in Proc. R. Med–Psychol. Assoc. (Lewis & Co., London, 1963).

    Google Scholar 

  145. 145

    Leuner H. in Ethnopsychotherapie (eds Dittrich, A. & Scharfetter, C.) 151–161 (Enke, Stuttgard, 1987)

    Google Scholar 

  146. 146

    Geert-Jorgensen, E. Further observations regarding hallucinogenic treatment. Acta Psychiatr. Scand. 203 (Suppl.), 195–200 (1968).

    CAS  Google Scholar 

  147. 147

    Khorramzadeh, E. & Lotfy, A. O. The use of ketamine in psychiatry. Psychosomatics 14, 344–346 (1973).

    CAS  Google Scholar 

  148. 148

    Mascher, E. in Neuro-Psychopharmacology (eds Brill, H., Cole, J. O., Denker, P., Hippins, H. & Bradley, P. B.) 441–444 (Excerpta-Medica, Amsterdam, 2010).

    Google Scholar 

  149. 149

    Vollenweider, F. X. Brain mechanisms of hallucinogens and entactogens. Dialogues Clin. Neurosci. 3, 265–279 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors would like to acknowledge the financial support of the Swiss Neuromatrix Foundation (to F.X.V. and M.K.), and of the Heffter Research Institute (to F.X.V.). The authors thank D. Nichols for critical comments on the manuscript.

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Cluster period

A period of time during which cluster headache attacks occur regularly.


Two stereoisomeric molecules that are mirror images of each other and are not superimposable.

Existentially oriented psychotherapy

A form of therapy that emphasizes the development of a sense of self-direction through choice and of awareness in resolving existential conflicts (such as the inevitability of death, isolation and meaninglessness).


A former term for a category of mental disorders characterized by anxiety and a sense of distress. This category includes disorders now classified as mood disorders, anxiety disorders, dissociative disorders, sexual disorders and somatoform disorders.

Psychoanalytically oriented psychotherapy

A therapy based on Freudian psychoanalysis in which unconscious conflicts that are thought to cause the patient's symptoms are brought into consciousness to create insight for the resolution of the problems.


In Freudian psychoanalytic theory this term describes a psychological strategy to cope with reality by means of a temporary reversion of the ego to an earlier stage of development.


A drug used to treat amyotrophic lateral sclerosis and that has NMDA (N-methyl-D-aspartate) receptor blocking properties similar to those of ketamine.

Schedule 1

A legislative category containing controlled drugs that have a high potential for abuse, a lack of accepted safety and no currently accepted medical use in treatments.

Selective serotonin reuptake inhibitors

A class of compounds typically used as antidepressants.


The motivation to realize all of one's potential.

Structure–activity relationship

(Often abbreviated to SAR.) This is the relationship between the chemical structure of a molecule and its biological activity.


A phenomenon in psychoanalysis characterized by unconscious redirection of feelings or desires from one person to another.

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Vollenweider, F., Kometer, M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11, 642–651 (2010).

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