These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.

Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing.

Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.

Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin.

Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy.

References

Avants, BB, Tustison, N, Song, G ( 2008 ) Advanced normalization tools (ANTS) . Insight J 2: 1 – 35 .

Google Scholar

Beck, A, Steer, R, Garbin, M ( 1988 ) Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation . Clin Psychol Rev 8: 77 – 100 .

Google Scholar Crossref | ISI

Berman, MG, Peltier, S, Nee, DE, et al . ( 2011 ) Depression, rumination and the default network . Soc Cogn Affect Neurosci 6: 548 – 555 .

Google Scholar Crossref | Medline | ISI

Bogenschutz, MP, Forcehimes, AA, Pommy, JA, et al . ( 2015 ) Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study . J Psychopharmacol 29: 289 – 299 .

Google Scholar SAGE Journals | ISI

Button, KS, Ioannidis, JP, Mokrysz, C, et al . ( 2013 ) Power failure: Why small sample size undermines the reliability of neuroscience . Nat Rev Neurosci 14: 365 – 376 .

Google Scholar Crossref | Medline | ISI

Carhart-Harris, RL ( 2019 ) How do psychedelics work? Curr Opin Psychiatry 32: 16 – 21 .

Google Scholar Crossref | Medline

Carhart-Harris, RL, Bolstridge, M, Day, CMJ, et al . ( 2018 a) Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up . Psychopharmacology (Berl) 235: 399 – 408 .

Google Scholar Crossref | Medline

Carhart-Harris, RL, Bolstridge, M, Rucker, J, et al . ( 2016 a) Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study . Lancet Psychiatry 3: 619 – 627 .

Google Scholar Crossref | Medline | ISI

Carhart-Harris, RL, Erritzoe, D, Haijen, E, et al . ( 2018 b) Psychedelics and connectedness . Psychopharmacology (Berl) 235: 547 – 550 .

Google Scholar Crossref | Medline

Carhart-Harris, RL, Erritzoe, D, Williams, T, et al . ( 2012 ) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin . Proc Natl Acad Sci USA 109: 2138 – 2143 .

Google Scholar Crossref | Medline | ISI

Carhart-Harris, RL, Murphy, K, Leech, R, et al . ( 2015 ) The effects of acutely administered 3,4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labeling and blood oxygen level-dependent resting state functional connectivity . Biol Psychiatry 78: 554 – 562 .

Google Scholar Crossref | Medline

Carhart-Harris, RL, Muthukumaraswamy, S, Roseman, L, et al . ( 2016 b) Neural correlates of the LSD experience revealed by multimodal neuroimaging . Proc Natl Acad Sci USA 113: 4853 – 4858 .

Google Scholar Crossref | Medline | ISI

Carhart-Harris, RL, Nutt, DJ ( 2017 ) Serotonin and brain function: A tale of two receptors . J Psychopharmacol 31: 1091 – 1120 .

Google Scholar SAGE Journals | ISI

Carhart-Harris, RL, Roseman, L, Bolstridge, M, et al . ( 2017 ) Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms . Sci Rep 7: 13187 .

Google Scholar Crossref | Medline

Carhart-Harris, RL, Roseman, L, Haijen, E, et al . ( 2018 c) Psychedelics and the essential importance of context . J Psychopharmacol 269881118754710.

Google Scholar SAGE Journals

Carhart-Harris, RL, Roseman, L, Haijen, E, et al . ( 2018 d) Psychedelics and the essential importance of context . J Psychopharmacol 32: 725 – 731 .

Google Scholar SAGE Journals | ISI

Cavanna, AE, Trimble, MR ( 2006 ) The precuneus: A review of its functional anatomy and behavioural correlates . Brain 129: 564 – 583 .

Google Scholar Crossref | Medline | ISI

Cooney, RE, Joormann, J, Eugene, F, et al . ( 2010 ) Neural correlates of rumination in depression . Cogn Affect Behav Neurosci 10: 470 – 478 .

Google Scholar Crossref | Medline | ISI

Cox, RW ( 1996 ) AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages . Comput Biomed Res 29: 162 – 173 .

Google Scholar Crossref | Medline

Cunningham, WA, Van Bavel, JJ, Johnsen, IR ( 2008 ) Affective flexibility: Evaluative processing goals shape amygdala activity . Psychol Sci 19: 152 – 160 .

Google Scholar SAGE Journals | ISI

Dale, AM, Fischl, B, Sereno, MI ( 1999 ) Cortical surface-based analysis. I. Segmentation and surface reconstruction . Neuroimage 9: 179 – 194 .

Google Scholar Crossref | Medline | ISI

Dannlowski, U, Ohrmann, P, Konrad, C, et al . ( 2009 ) Reduced amygdala-prefrontal coupling in major depression: Association with MAOA genotype and illness severity . Int J Neuropsychopharmacol 12: 11 – 22 .

Google Scholar Crossref | Medline | ISI

Drevets, WC, Videen, TO, Price, JL, et al . ( 1992 ) A functional anatomical study of unipolar depression . J Neurosci 12: 3628 – 3641 .

Google Scholar Crossref | Medline | ISI

Engel, K, Bandelow, B, Gruber, O, et al . ( 2009 ) Neuroimaging in anxiety disorders . J Neural Transm (Vienna) 116: 703 – 716 .

Google Scholar Crossref | Medline | ISI

Frassle, S, Lomakina, EI, Razi, A, et al . ( 2017 ) Regression DCM for fMRI . Neuroimage 155: 406 – 421 .

Google Scholar Crossref | Medline

Fusar-Poli, P, Placentino, A, Carletti, F, et al . ( 2009 ) Functional atlas of emotional faces processing: A voxel-based meta-analysis of 105 functional magnetic resonance imaging studies . J Psychiatry Neurosci 34: 418 – 432 .

Google Scholar Medline | ISI

Gasser, P, Holstein, D, Michel, Y, et al . ( 2014 ) Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases . J Nerv Ment Dis 202: 513 – 520 .

Google Scholar Crossref | Medline | ISI

Godlewska, BR, Norbury, R, Selvaraj, S, et al . ( 2012 ) Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients . Psychol Med 42: 2609 – 2617 .

Google Scholar Crossref | Medline

Goeleven, E, De Raedt, R, Leyman, L, et al . ( 2008 ) The Karolinska directed emotional faces: A validation study . Cognit Emot 22: 1094 – 1118 .

Google Scholar Crossref | ISI

Goodwin, GM, Price, J, De Bodinat, C, et al . ( 2017 ) Emotional blunting with antidepressant treatments: A survey among depressed patients . J Affect Disord 221: 31 – 35 .

Google Scholar Crossref | Medline

Gordon, JA, Hen, R. ( 2004 ) The serotonergic system and anxiety . Neuromolecular Med 5: 27 – 40 .

Google Scholar Crossref | Medline | ISI

Griffiths, RR, Johnson, MW, Carducci, MA, et al . ( 2016 ) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial . J Psychopharmacol 30: 1181 – 1197 .

Google Scholar SAGE Journals | ISI

Grimm, O, Kraehenmann, R, Preller, KH, et al . ( 2018 ) Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination . Eur Neuropsychopharmacol 28: 691 – 700 .

Google Scholar Crossref | Medline

Grob, CS, Danforth, AL, Chopra, GS, et al . ( 2011 ) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer . Arch Gen Psychiatry 68: 71 – 78 .

Google Scholar Crossref | Medline

Hamilton, JP, Farmer, M, Fogelman, P, et al . ( 2015 ) Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience . Biol Psychiatry 78: 224 – 230 .

Google Scholar Crossref | Medline

Hamilton, M ( 1960 ) A rating scale for depression . J Neurol Neurosurg Psychiatry 23: 56 – 62 .

Google Scholar Crossref | Medline | ISI

Hariri, AR, Bookheimer, SY, Mazziotta, JC ( 2000 ) Modulating emotional responses: Effects of a neocortical network on the limbic system . Neuroreport 11: 43 – 48 .

Google Scholar Crossref | Medline | ISI

Harmer, CJ, Duman, RS, Cowen, PJ ( 2017 ) How do antidepressants work? New perspectives for refining future treatments . Lancet Psychiatry 4: 409 – 418 .

Google Scholar Crossref | Medline

Harmer, CJ, Goodwin, GM, Cowen, PJ ( 2009 a) Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action . Br J Psychiatry 195: 102 – 108 .

Google Scholar Crossref | Medline | ISI

Harmer, CJ, O’Sullivan, U, Favaron, E, et al . ( 2009 b) Effect of acute antidepressant administration on negative affective bias in depressed patients . Am J Psychiatry 166: 1178 – 1184 .

Google Scholar Crossref | Medline | ISI

Harmer, CJ, Shelley, NC, Cowen, PJ, et al . ( 2004 ) Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition . Am J Psychiatry 161: 1256 – 1263 .

Google Scholar Crossref | Medline | ISI

Hassabis, D, Kumaran, D, Maguire, EA ( 2007 ) Using imagination to understand the neural basis of episodic memory . J Neurosci 27: 14365 – 14374 .

Google Scholar Crossref | Medline | ISI

Hayley, S, Litteljohn, D ( 2013 ) Neuroplasticity and the next wave of antidepressant strategies . Front Cell Neurosci 7: 218 .

Google Scholar Crossref | Medline | ISI

Johnson, MW, Garcia-Romeu, A, Griffiths, RR ( 2017 ) Long-term follow-up of psilocybin-facilitated smoking cessation . Am J Drug Alcohol Abuse 43: 55 – 60 .

Google Scholar Crossref | Medline | ISI

Jonassen, R, Chelnokova, O, Harmer, C, et al . ( 2015 ) A single dose of antidepressant alters eye-gaze patterns across face stimuli in healthy women . Psychopharmacology (Berl) 232: 953 – 958 .

Google Scholar Crossref | Medline

Koenigs, M, Grafman, J ( 2009 ) Posttraumatic stress disorder: The role of medial prefrontal cortex and amygdala . Neuroscientist 15: 540 – 548 .

Google Scholar SAGE Journals | ISI

Kong, L, Chen, K, Tang, Y, et al . ( 2013 ) Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder . J Psychiatry Neurosci 38: 417 – 422 .

Google Scholar Crossref | Medline

Lebedev, AV, Lovden, M, Rosenthal, G, et al . ( 2015 ) Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin . Hum Brain Mapp 36: 3137 – 3153 .

Google Scholar Crossref | Medline | ISI

Ma, Y ( 2015 ) Neuropsychological mechanism underlying antidepressant effect: A systematic meta-analysis . Mol Psychiatry 20: 311 – 319 .

Google Scholar Crossref | Medline

Madsen, MK, Fisher, PM, Burmester, D, et al . ( 2019 ) Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels . Neuropsychopharmacology 44: 1328 – 1334 .

Google Scholar Crossref | Medline

Majic, T, Schmidt, TT, Gallinat, J ( 2015 ) Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? J Psychopharmacol 29: 241 – 253 .

Google Scholar SAGE Journals | ISI

Moreno, FA, Wiegand, CB, Taitano, EK, et al . ( 2006 ) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder . J Clin Psychiatry 67: 1735 – 1740 .

Google Scholar Crossref | Medline | ISI

Morris, JS, Friston, KJ, Buchel, C, et al . ( 1998 ) A neuromodulatory role for the human amygdala in processing emotional facial expressions . Brain 121: 47 – 57 .

Google Scholar Crossref | Medline | ISI

Moses-Kolko, EL, Perlman, SB, Wisner, KL, et al . ( 2010 ) Abnormally reduced dorsomedial prefrontal cortical activity and effective connectivity with amygdala in response to negative emotional faces in postpartum depression . Am J Psychiatry 167: 1373 – 1380 .

Google Scholar Crossref | Medline

Muthukumaraswamy, SD, Carhart-Harris, RL, Moran, RJ, et al . ( 2013 ) Broadband cortical desynchronization underlies the human psychedelic state . J Neurosci 33: 15171 – 15183 .

Google Scholar Crossref | Medline | ISI

Nichols, DE ( 2016 ) Psychedelics . Pharmacol Rev 68: 264 – 355 .

Google Scholar Crossref | Medline | ISI

Nolen-Hoeksema, S ( 1991 ) Responses to depression and their effects on the duration of depressive episodes . J Abnorm Psychol 100: 569 – 582 .

Google Scholar Crossref | Medline | ISI

O’Reilly, JX, Woolrich, MW, Behrens, TE, et al . ( 2012 ) Tools of the trade: Psychophysiological interactions and functional connectivity . Soc Cogn Affect Neurosci 7: 604 – 609 .

Google Scholar Crossref | Medline | ISI

Osorio Fde, L, Sanches, RF, Macedo, LR, et al . ( 2015 ) Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A preliminary report . Rev Bras Psiquiatr 37: 13 – 20 .

Google Scholar Crossref | Medline | ISI

Preller, KH, Vollenweider, FX ( 2018 ) Phenomenology, structure, and dynamic of psychedelic states . Curr Top Behav Neurosci 36: 221 – 256 .

Google Scholar Crossref | Medline

Ramasubbu, R, Konduru, N, Cortese, F, et al . ( 2014 ) Reduced intrinsic connectivity of amygdala in adults with major depressive disorder . Front Psychiatry 5: 17 .

Google Scholar Crossref | Medline | ISI

Riedel, M, Moller, HJ, Obermeier, M, et al . ( 2010 ) Response and remission criteria in major depression: A validation of current practice . J Psychiatr Res 44: 1063 – 1068 .

Google Scholar Crossref | Medline | ISI

Robinson, OJ, Krimsky, M, Lieberman, L, et al . ( 2016 ) Anxiety-potentiated amygdala-medial frontal coupling and attentional control . Transl Psychiatry 6: e833 .

Google Scholar Crossref | Medline

Roseman, L, Demetriou, L, Wall, MB, et al . ( 2018 ) Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression . Neuropharmacology 142: 263 – 269 .

Google Scholar Crossref | Medline

Roseman, L, Leech, R, Feilding, A, et al . ( 2014 ) The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers . Front Hum Neurosci 8: 204 .

Google Scholar Crossref | Medline | ISI

Roseman, L, Nutt, DJ, Carhart-Harris, RL ( 2017 ) Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression . Front Pharmacol 8: 974 .

Google Scholar Crossref | Medline

Rosenkranz, JA, Moore, H, Grace, AA ( 2003 ) The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli . J Neurosci 23: 11054 – 11064 .

Google Scholar Crossref | Medline | ISI

Ross, S, Bossis, A, Guss, J, et al . ( 2016 ) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial . J Psychopharmacol 30: 1165 – 1180 .

Google Scholar SAGE Journals | ISI

Rush, AJ, Trivedi, MH, Ibrahim, HM, et al . ( 2003 ) The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric evaluation in patients with chronic major depression . Biol Psychiatry 54: 573 – 583 .

Google Scholar Crossref | Medline | ISI

Sampedro, F, de la Fuente Revenga, M, Valle, M, et al . ( 2017 ) Assessing the psychedelic ‘after-glow’ in ayahuasca users: Post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities . Int J Neuropsychopharmacol 20: 698 – 711 .

Google Scholar Crossref | Medline

Siegel, JS, Power, JD, Dubis, JW, et al . ( 2014 ) Statistical improvements in functional magnetic resonance imaging analyses produced by censoring high-motion data points . Hum Brain Mapp 35: 1981 – 1996 .

Google Scholar Crossref | Medline

Smith, SM, Jenkinson, M, Woolrich, MW, et al . ( 2004 ) Advances in functional and structural MR image analysis and implementation as FSL . Neuroimage 23( Suppl 1 ): S208 – S219 .

Google Scholar Crossref | Medline | ISI

Somerville, LH, Kim, H, Johnstone, T, et al . ( 2004 ) Human amygdala responses during presentation of happy and neutral faces: Correlations with state anxiety . Biol Psychiatry 55: 897 – 903 .

Google Scholar Crossref | Medline | ISI

Spielberger, CD, Gorsuch, RL, Lushene, R, et al . ( 1983 ) Manual for the State-Trait Anxiety Inventory. Palo Alto, CA : Consulting Psychologists Press .

Google Scholar

Stevens, JS, Jovanovic, T, Fani, N, et al . ( 2013 ) Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder . J Psychiatr Res 47: 1469 – 1478 .

Google Scholar Crossref | Medline | ISI

Stroud, JB, Freeman, TP, Leech, R, et al . ( 2018 ) Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression . Psychopharmacology (Berl) 235: 459 – 466 .

Google Scholar Crossref | Medline

Studerus, E, Gamma, A, Kometer, M, et al . ( 2012 ) Prediction of psilocybin response in healthy volunteers . PLoS One 7: e30800 .

Google Scholar Crossref | Medline | ISI

Treynor, W, Gonzalez, R, Nolen-Hoeksema, S. ( 2003 ) Rumination reconsidered: A psychometric analysis . Cogn Ther Res 27: 247 – 259 .

Google Scholar Crossref | ISI

Utevsky, AV, Smith, DV, Huettel, SA ( 2014 ) Precuneus is a functional core of the default-mode network . J Neurosci 34: 932 – 940 .

Google Scholar Crossref | Medline | ISI

Vuilleumier, P, Pourtois, G ( 2007 ) Distributed and interactive brain mechanisms during emotion face perception: Evidence from functional neuroimaging . Neuropsychologia 45: 174 – 194 .

Google Scholar Crossref | Medline | ISI