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Review article: Biomedical intelligence

Vol. 149 No. 3940 (2019)

Acute effects of lysergic acid diethylamide (LSD) on resting brain function

  • Felix Müller
  • Stefan Borgwardt
Cite this as:
Swiss Med Wkly. 2019;149:w20124


Lysergic acid diethylamide (LSD) is a potent hallucinogenic substance that was extensively investigated by psychiatrists during the 1950s and 1960s. Researchers were interested in the unique effects induced by this substance, some of which resemble symptoms seen in schizophrenia. Moreover, during that period LSD was studied and used for the treatment of several mental disorders such as depression, anxiety, addiction and personality disorders. Despite this long history of research, how LSD induces its specific effects on a neuronal level has been relatively unclear. In recent years there has been a revival of research in hallucinogenic drugs and their possible clinical applications. These contemporary studies in the UK and Switzerland include neuroimaging studies using functional magnetic resonance imaging (fMRI). In this review, we collect and interpret these recent neuroimaging findings. Overall, previous results across studies indicate that LSD administration is associated with extensive alterations in functional brain connectivity, measuring the correlated activities between different brain regions. The studies mostly reported increases in connectivity between regions and, more specifically, consistently found increased connectivity within the thalamocortical system. These latter observations are in agreement with models proposing that hallucinogenic drugs exert their effects by inhibiting cerebral filtering of external and internal data. However, studies also face several limitations, including potential biases of neuroimaging measurements.


  1. Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78(8):544–53. doi:.
  2. Preller KH, Burt JB, Ji JL, Schleifer CH, Adkinson BD, Stämpfli P, et al. Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. eLife. 2018;7:e35082. doi:.
  3. Liechti ME. Modern Clinical Research on LSD. Neuropsychopharmacology. 2017;42(11):2114–27. doi:.
  4. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264–355. doi:.
  5. Carhart-Harris RL, Muthukumaraswamy S, Roseman L, Kaelen M, Droog W, Murphy K, et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci USA. 2016;113(17):4853–8. doi:.
  6. Preller KH, Razi A, Zeidman P, Stämpfli P, Friston KJ, Vollenweider FX. Effective connectivity changes in LSD-induced altered states of consciousness in humans. Proc Natl Acad Sci USA. 2019;116(7):2743–8. doi:.
  7. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 2015;29(1):57–68. doi:.
  8. Müller F, Lenz C, Dolder P, Lang U, Schmidt A, Liechti M, et al. Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr Scand. 2017 a;136(6):648–57. doi:.
  9. Mueller F, Lenz C, Dolder PC, Harder S, Schmid Y, Lang UE, et al. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl Psychiatry. 2017 b;7(4):e1084. doi:.
  10. Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Stämpfli P, et al. The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Curr Biol. 2017;27(3):451–7. doi:.
  11. Schmidt A, Müller F, Lenz C, Dolder PC, Schmid Y, Zanchi D, et al. Acute LSD effects on response inhibition neural networks. Psychol Med. 2018;48(9):1464–73. doi:.
  12. Tahedl M, Levine SM, Greenlee MW, Weissert R, Schwarzbach JV. Functional Connectivity in Multiple Sclerosis: Recent Findings and Future Directions. Front Neurol. 2018;9:828. doi:.
  13. Collin G, Hulshoff Pol HE, Haijma SV, Cahn W, Kahn RS, van den Heuvel MP. Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings. Front Psychiatry. 2011;2:73. doi:.
  14. Dolder PC, Schmid Y, Müller F, Borgwardt S, Liechti ME. LSD acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. 2016;41(11):2638–46. doi:.
  15. Tagliazucchi E, Roseman L, Kaelen M, Orban C, Muthukumaraswamy SD, Murphy K, et al. Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution. Curr Biol. 2016;26(8):1043–50. doi:.
  16. Müller F, Dolder PCPC, Schmidt A, Liechti MEME, Borgwardt S. Altered network hub connectivity after acute LSD administration. Neuroimage Clin. 2018;18:694–701. doi:.
  17. Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, et al. Correspondence of the brain’s functional architecture during activation and rest. Proc Natl Acad Sci USA. 2009;106(31):13040–5. doi:.
  18. Roseman L, Leech R, Feilding A, Nutt DJ, Carhart-Harris RL. The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Front Hum Neurosci. 2014;8:204. doi:.
  19. Klaassens BL, van Gorsel HC, Khalili-Mahani N, van der Grond J, Wyman BT, Whitcher B, et al. Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity. Neuroimage. 2015;122:440–50. doi:.
  20. Murphy K, Birn RM, Handwerker DA, Jones TB, Bandettini PA. The impact of global signal regression on resting state correlations: are anti-correlated networks introduced? Neuroimage. 2009;44(3):893–905. doi:.
  21. Power JD, Mitra A, Laumann TO, Snyder AZ, Schlaggar BL, Petersen SE. Methods to detect, characterize, and remove motion artifact in resting state fMRI. Neuroimage. 2014;84:320–41. doi:.
  22. Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26(8):1327–37. doi:.
  23. Hollister LE, Hartman AM. Mescaline, lysergic acid diethylamide and psilocybin comparison of clinical syndromes, effects on color perception and biochemical measures. Compr Psychiatry. 1962;3(4):235–41. doi:.
  24. Hollister LE, Sjoberg BM. Clinical syndromes and biochemical alterations following mescaline, lysergic acid diethylamide, psilocybin and combination of the three psychotomimetic drugs. Compr Psychiatry. 1964;5(3):170–8. doi:.
  25. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology. 1997;16(5):357–72. doi:.
  26. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29(3):289–99. doi:.
  27. Griffiths R. Overview of the Johns Hopkins psilocybin research project. Interdisciplinary Conference on Psychedelics Research. Amsterdam, June 3–5, 2016.
  28. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 2014;28(11):983–92. doi:.
  29. Nichols DE, Johnson MW, Nichols CD. Psychedelics as Medicines: An Emerging New Paradigm. Clin Pharmacol Ther. 2017;101(2):209–19. doi:.
  30. Froese T, Leenen I, Palenicek T. A role for enhanced functions of sleep in psychedelic therapy? Adapt Behav. 2018;26(3):129–35. doi:.
  31. Sampedro F, de la Fuente Revenga M, Valle M, Roberto N, Domínguez-Clavé E, Elices M, et al. Assessing the psychedelic “after-glow” in ayahuasca users: Post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Int J Neuropsychopharmacol. 2017;20(9):698–711. doi:.
  32. Kuypers KPC. Out of the box: A psychedelic model to study the creative mind. Med Hypotheses. 2018;115:13–6. doi:.
  33. Geyer MA, Vollenweider FX. Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci. 2008;29(9):445–53. doi:.
  34. Jones E. The Thalamus, Second edition. New York: Cambridge University Press; 2007.
  35. Parent A, Hazrati LN. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Brain Res Rev. 1995;20(1):91–127. doi:.
  36. van den Heuvel MP, Sporns O. Rich-club organization of the human connectome. J Neurosci. 2011;31(44):15775–86. doi:.
  37. Saalmann YB. Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition. Front Syst Neurosci. 2014;8:83. doi:.
  38. Malekmohammadi M, Elias WJ, Pouratian N. Human thalamus regulates cortical activity via spatially specific and structurally constrained phase-amplitude coupling. Cereb Cortex. 2015;25(6):1618–28. doi:.
  39. Huxley A. The doors of perception. In: The Doors of Perception and Heaven and Hell. London: Chatto and Windus; 1954.
  40. Grof S. Realms of the Human Unconscious: Observations from LSD Research. New York: Viking Press; 1975.
  41. Khalili-Mahani N, Chang C, van Osch MJ, Veer IM, van Buchem MA, Dahan A, et al. The impact of “physiological correction” on functional connectivity analysis of pharmacological resting state fMRI. Neuroimage. 2013;65:499–510. doi:.
  42. Wise RG, Tracey I. The role of fMRI in drug discovery. J Magn Reson Imaging. 2006;23(6):862–76. doi:.
  43. Tylš F, Páleníček T, Horáček J. Psilocybin--summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014;24(3):342–56. doi:.
  44. Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603–20. doi:.
  45. Fantegrossi WE, Murnane KS, Reissig CJ. The behavioral pharmacology of hallucinogens. Biochem Pharmacol. 2008;75(1):17–33. doi:.
  46. Cooper R. Diagnostic and Statistical Manual of Mental Disorders (DSM). Knowl Organ. 2018. doi:.
  47. Orsolini L, Papanti GD, De Berardis D, Guirguis A, Corkery JM, Schifano F. The “Endless Trip” among the NPS users: Psychopathology and psychopharmacology in the Hallucinogen-persisting perception disorder. A systematic review. Front Psychiatry. 2017;8:240. doi:.
  48. Halpern JH, Pope HG, Jr. Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend. 2003;69(2):109–19. doi:.
  49. Strassman RJ. Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis. 1984;172(10):577–95. doi:.
  50. Hendricks PS, Thorne CB, Clark CB, Coombs DW, Johnson MW. Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population. J Psychopharmacol. 2015;29(3):280–8. doi:.
  51. Johansen PO, Krebs TS. Psychedelics not linked to mental health problems or suicidal behavior: a population study. J Psychopharmacol. 2015;29(3):270–9. doi:.
  52. Cohen S. Lysergic acid diethylamide: side effects and complications. J Nerv Ment Dis. 1960;130(1):30–40. doi:.
  53. Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011;25(11):1434–52. doi:.