Pharmacopsychiatry 2021; 54(04): 176-190
DOI: 10.1055/a-1341-1907
Review

Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

Lea J. Mertens
1   Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Katrin H. Preller
2   Pharmaco-Neuroimaging and Cognitive-Emotional Processing, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Zurich, Switzerland
3   Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
› Author Affiliations

Abstract

Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.

In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.

While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.



Publication History

Received: 07 December 2020
Received: 07 September 2020

Accepted: 10 December 2020

Article published online:
20 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11: 642-651
  • 2 Nichols DE. Psychedelics. Pharmacol Rev 2016; 68: 264-355
  • 3 Rucker JJ, Jelen LA, Flynn S. et al. Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacology 2016; 30: 1220-1229
  • 4 Krebs TS, Johansen P. Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacology 2012; 26: 994-1002
  • 5 Bogenschutz MP, Ross S. Therapeutic applications of classic hallucinogens. Cur Top Behav Neurosci 2018; 36: 361-391
  • 6 Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000; 61: 4-6
  • 7 Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry 2017; 4: 409-418
  • 8 Yohn CN, Gergues MM, Samuels BA. The role of 5-HT receptors in depression. Mol Brain 2017; 10: 28
  • 9 Jans LA, Riedel WJ, Markus CR. et al. Serotonergic vulnerability and depression: assumptions, experimental evidence, and implications. Mol Psychiatry 2007; 12: 522-543
  • 10 Celada P, Puig M, Amargós-Bosch M. et al. The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neuroci 2004; 29: 252-265
  • 11 Gray JA, Roth BL. Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists. Brain Res Bull 2001; 56: 441-451
  • 12 Moravčíková L, Csatlósová K, Ďurišová B. et al. Role of serotonin-2A receptors in pathophysiology and treatment of depression. In: Guiard B, Di Giovanni G. 5-HT2A Receptors in the Central Nervous System. Cham, Switzerland: Humana Press. Springer International Publishing; 2018
  • 13 Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Mol Psychiatry 2007; 12: 331-359
  • 14 Fournier JC, DeRubeis RJ, Hollon SD. et al. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA 2010; 303: 47-53
  • 15 Kirsch I, Deacon BJ, Huedo-Medina TB. et al. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5: e45-e45
  • 16 Repo E, Kuikka JT, Bergström KA. et al. Dopamine transporter and D2-receptor density in late-onset alcoholism. Psychopharmacology 1999; 147: 314-318
  • 17 Volkow ND, Wang GJ, Fowler JS. et al. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 1996; 20: 1594-1598
  • 18 Matuskey D, Bhagwagar Z, Planeta B. et al. Reductions in brain 5-HT1B receptor availability in primarily cocaine-dependent humans. Biol Psychiatry 2014; 76: 816-822
  • 19 Heinz A, Higley JD, Gorey JG. et al. In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. Am J Psychiatry 1998; 155: 1023-1028
  • 20 Kaltenboeck A, Harmer C. The neuroscience of depressive disorders: A brief review of the past and some considerations about the future. Brain Neurosci Adv 2018; 2: 2398212818799269
  • 21 Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: A quantitative summary of four decades of research. Psychosom Med 2011; 73: 114-126
  • 22 Pariante CM, Lightman SL. The HPA axis in major depression: Classical theories and new developments. Trends Neurosci 2008; 31: 464-468
  • 23 Pittenger C, Duman RS. Stress, depression, and neuroplasticity: A convergence of mechanisms. Neuropsychopharmacology 2008; 33: 88-109
  • 24 Dwivedi Y, Rizavi HS, Conley RR. et al. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry 2003; 60: 804-815
  • 25 Molendijk ML, Spinhoven P, Polak M. et al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (n=9484). Mol Psychiatry 2014; 19: 791-800
  • 26 Bath KG, Lee FS. Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 2006; 6: 79-85
  • 27 Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry 2006; 59: 1116-1127
  • 28 Verduijn J, Milaneschi Y, Schoevers RA. et al. Pathophysiology of major depressive disorder: Mechanisms involved in etiology are not associated with clinical progression. Transl Psychiatry 2015; 5: e649
  • 29 Martinowich K, Lu B. Interaction between BDNF and serotonin: Role in mood disorders. Neuropsychopharmacology 2008; 33: 73-83
  • 30 Popoli M, Yan Z, McEwen BS. et al. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2011; 13: 22-37
  • 31 Castrén E. Neurotrophins and psychiatric disorders. In: Lewin GR, Carter BD. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag Publishing; 2014. 220. 461-479
  • 32 Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 2008; 1141: 105-130
  • 33 Barker JM, Taylor JR, De Vries TJ. et al. Brain-derived neurotrophic factor and addiction: pathological versus therapeutic effects on drug seeking. Brain Res 2015; 1628: 68-81
  • 34 Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci 2007; 8: 844-858
  • 35 Lüscher C. The emergence of a circuit model for addiction. Annu Rev Neurosci 2016; 39: 257-276
  • 36 Nestler EJ, Lüscher C. The molecular basis of drug addiction: Linking epigenetic to synaptic and circuit mechanisms. Neuron 2019; 102: 48-59
  • 37 Huys QJM, Deserno L, Obermayer K. et al. Model-free temporal-difference learning and dopamine in alcohol dependence: Examining concepts from theory and animals in human imaging. Biol Psychiatry Cogn Neurosci Neuroimaging 2016; 1: 401-410
  • 38 Hong H, Kim BS, Im HI. Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders. Int Neurourol J 2016; 20: 2-7
  • 39 Moylan S, Maes M, Wray NR. et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 2013; 18: 595-606
  • 40 Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171-186
  • 41 Dowlati Y, Herrmann N, Swardfager W. et al. A meta-analysis of cytokines in major depression. Biol Pychiatry 2010; 67: 446-457
  • 42 Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression. J Affect Disord 2012; 139: 230-239
  • 43 Zhao YN, Wang F, Fan YX. et al. Activated microglia are implicated in cognitive deficits, neuronal death, and successful recovery following intermittent ethanol exposure. Behav Brain Res 2013; 236: 270-282
  • 44 Sadasivan S, Pond BB, Pani AK. et al. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One 2012; 7: e33693
  • 45 Wang J, Qian W, Liu J. et al. Effect of methamphetamine on the microglial damage: role of potassium channel Kv1.3. PLoS One 2014; 9
  • 46 Bai S, Guo W, Feng Y. et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: A systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry 2020; 91: 21-32
  • 47 Chen ZY, Jing D, Bath KG. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140-143
  • 48 Lesch KP, Bengel D, Heils A. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527-1531
  • 49 Caspi A, Hariri AR, Holmes A. et al. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 2010; 167: 509-527
  • 50 Caspi A, Sugden K, Moffitt TE. et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386-389
  • 51 aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ 2009; 180: 305-313
  • 52 Murphy SE, Norbury R, Godlewska BR. et al. The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: A meta-analysis. Mol Psychiatry 2013; 18: 512-520
  • 53 Miller R, Wankerl M, Stalder T. et al. The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: A meta-analysis. Mol Psychiatry 2013; 18: 1018-1024
  • 54 Kendler KS, Kuhn JW, Vittum J. et al. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: A replication. Arch Gen Psychiatry 2005; 62: 529-535
  • 55 Seo MK, Ly NN, Lee CH. et al. Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus. Neuropharmacology 2016; 105: 388-397
  • 56 Tsankova N, Renthal W, Kumar A. et al. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007; 8: 355-367
  • 57 de Kloet ER, Joëls M, Holsboer F. Stress and the brain: From adaptation to disease. Nat Rev Neurosci 2005; 6: 463-475
  • 58 Kreek MJ, Nielsen DA, Butelman ER. et al. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005; 8: 1450-1457
  • 59 Li MD, Burmeister M. New insights into the genetics of addiction. Nat Rev Genet 2009; 10: 225-231
  • 60 Morozova TV, Mackay TF, Anholt RR. Genetics and genomics of alcohol sensitivity. Mol Genet Genomics 2014; 289: 253-269
  • 61 Cao J, Liu X, Han S. et al. Association of the HTR2A gene with alcohol and heroin abuse. Hum Genet 2014; 133: 357-365
  • 62 Nees F, Witt SH, Dinu-Biringer R. et al. BDNF Val66Met and reward-related brain function in adolescents: Role for early alcohol consumption. Alcohol 2015; 49: 103-110
  • 63 Hamilton PJ, Nestler EJ. Epigenetics and addiction. Curr Opin Neurobiol 2019; 59: 128-136
  • 64 Pierce RC, Fant B, Swinford-Jackson SE. et al. Environmental, genetic and epigenetic contributions to cocaine addiction. Neuropsychopharmacology 2018; 43: 1471-1480
  • 65 Nielsen DA, Utrankar A, Reyes JA. et al. Epigenetics of drug abuse: Predisposition or response. Pharmacogenomics 2012; 13: 1149-1160
  • 66 Cadet JL. Epigenetics of stress, addiction, and resilience: therapeutic implications. Mol Neurobiol 2016; 53: 545-560
  • 67 Beck AT. Depression. Harper and Row; New York: 1967
  • 68 Foland-Ross L, Gotlib I. Cognitive and Neural aspects of information processing in major depressive disorder: An integrative perspective. Front Psycholog 2012; 3: 489
  • 69 Roiser JP, Elliott R, Sahakian BJ. Cognitive mechanisms of treatment in depression. Neuropsychopharmacology 2012; 37: 117-136
  • 70 Mayberg HS. Modulating limbic-cortical circuits in depression: Targets of antidepressant treatments. Sem Clin Neuropsychiatry 2002; 7: 255-268
  • 71 Godlewska BR, Harmer CJ. Cognitive neuropsychological theory of antidepressant action: A modern-day approach to depression and its treatment. Psychopharmacology 2020; DOI: 10.1007/s00213-019-05448-0:.
  • 72 Ma Y. Neuropsychological mechanism underlying antidepressant effect: a systematic meta-analysis. Mol Psychiatry 2015; 20: 311-319
  • 73 Ng TH, Alloy LB, Smith DV. Meta-analysis of reward processing in major depressive disorder reveals distinct abnormalities within the reward circuit. Transl Psychiatry 2019; 9: 293
  • 74 Keren H, O’Callaghan G, Vidal-Ribas P. et al. Reward processing in depression: a conceptual and meta-analytic review across fMRI and EEG Studies. Am J Psychiatry 2018; 175: 1111-1120
  • 75 Wise T, Marwood L, Perkins AM. et al. Instability of default mode network connectivity in major depression: A two-sample confirmation study. Transl Psychiatry 2017; 7: e1105
  • 76 Kaiser RH, Andrews-Hanna JR, Wager TD. et al. Large-scale network dysfunction in major depressive disorder: A meta-analysis of resting-state functional connectivity. JAMA Psychiatry 2015; 72: 603-611
  • 77 Kupferberg A, Bicks L, Hasler G. Social functioning in major depressive disorder. Neurosci Biobehav Rev 2016; 69: 313-332
  • 78 Donges US, Kersting A, Dannlowski U. et al. Reduced awareness of others’ emotions in unipolar depressed patients. J Nerv Ment Dis 2005; 193: 331-337
  • 79 O’Connor L, Berry J, Lewis T. et al. Empathy and depression: the moral system on overdrive. In: Farrow T, Woodruff P. Empathy in Mental Illness. Cambridge: Cambrdige University Press; 2007: 49-75
  • 80 Hsu DT, Sanford BJ, Meyers KK. et al. It still hurts: Altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder. Mol Psychiatry 2015; 20: 193-200
  • 81 Volkow ND, Fowler JS, Wang GJ. The addicted human brain: Insights from imaging studies. J Clin Invest 2003; 111: 1444-1451
  • 82 Goldstein RZ, Alia-Klein N, Tomasi D. et al. Is decreased prefrontal cortical sensitivity to monetary reward associated with impaired motivation and self-control in cocaine addiction?. Am J Psychiatry 2007; 164: 43-51
  • 83 Patel KT, Stevens MC, Meda SA. et al. Robust changes in reward circuitry during reward loss in current and former cocaine users during performance of a monetary incentive delay task. Biol Psychiatry 2013; 74: 529-537
  • 84 Preller KH, Herdener M, Schilbach L. et al. Functional changes of the reward system underlie blunted response to social gaze in cocaine users. Proc Natl Acad Sci USA 2014; 111: 2842-2847
  • 85 Tobler PN, Preller KH, Campbell-Meiklejohn DK. et al. Shared neural basis of social and non-social reward deficits in chronic cocaine users. Soc Cogn Affect Neurosci 2016; 11: 1017-1025
  • 86 Pariyadath V, Gowin JL, Stein EA. Resting state functional connectivity analysis for addiction medicine: From individual loci to complex networks. Prog Brain Res 2016; 224: 155-173
  • 87 Quednow BB. Chapter 5: Social cognition in addiction. In: Verdejo-Garcia A. Cognition and Addiction. Academic Press; 2020: 63-78
  • 88 Eriksen L, Björnstad S, Götestam KG. Social skills training in groups for alcoholics: One-year treatment outcome for groups and individuals. Addict Behav 1986; 11: 309-329
  • 89 Zellner MR, Watt DF, Solms M. et al. Affective neuroscientific and neuropsychoanalytic approaches to two intractable psychiatric problems: Why depression feels so bad and what addicts really want. Neurosci Biobehav Rev 2011; 35: 2000-2008
  • 90 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: 3897-3902
  • 91 Madsen MK, Fisher PM, Burmester D. et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology 2019; 44: 1328-1334
  • 92 Pokorny T, Preller KH, Kraehenmann R. et al. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience. Eur Neuropsychopharmacology 2016; 26: 756-766
  • 93 Vollenweider FX, Vontobel P, Hell D. et al. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man—a PET study with [11C]raclopride. Neuropsychopharmacology 1999; 20: 424-433
  • 94 Johnson MW, MacLean KA, Reissig CJ. et al. Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug Alcohol Depend 2011; 115: 150-155
  • 95 Doss MK, May DG, Johnson MW. et al. The acute effects of the atypical dissociative hallucinogen salvinorin A on Functional connectivity in the human brain. Sci Rep 2020; 10: 16392-16392
  • 96 Yates M, Leake A, Candy JM. et al. 5HT2 receptor changes in major depression. Biol Psychiatry 1990; 27: 489-496
  • 97 Pandey GN, Dwivedi Y, Rizavi HS. et al. Higher expression of serotonin 5-HT(2A) receptors in the postmortem brains of teenage suicide victims. Am J Psychiatry 2002; 159: 419-429
  • 98 Shelton RC, Sanders-Bush E, Manier DH. et al. Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 2009; 158: 1406-1415
  • 99 Buckholtz NS, Zhou DF, Freedman DX. et al. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain. Neuropsychopharmacology 1990; 3: 137-148
  • 100 Madsen MK, Fisher PM, Stenbaek DS. et al. A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. Eur Neuropsychopharmacology 2020; 33: 71-80
  • 101 Martin DA, Nichols CD. The Effects of Hallucinogens on Gene Expression. Curr Top Behav Neurosci 2018; 36: 137-158
  • 102 Dolder PC, Grünblatt E, Müller F. et al. A Single dose of lsd does not alter gene expression of the serotonin 2A receptor gene (HTR2A) or early growth response genes (EGR1-3) in healthy subjects. Front Pharmacol 2017; 8: 423
  • 103 Nichols CD, Garcia EE, Sanders-Bush E. Dynamic changes in prefrontal cortex gene expression following lysergic acid diethylamide administration. Brain Res Mol Brain Res 2003; 111: 182-188
  • 104 Nichols CD, Sanders-Bush E. A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. Neuropsychopharmacology 2002; 26: 634-642
  • 105 Tilakaratne N, Friedman E. Genomic responses to 5-HT1A or 5-HT2A/2C receptor activation is differentially regulated in four regions of rat brain. Eur J Pharmacol 1996; 307: 211-217
  • 106 Vaidya VA, Marek GJ, Aghajanian GK. et al. 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 1997; 17: 2785-2795
  • 107 Schindler EAD, Wallace RM, Sloshower JA. et al. Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics. Front Pharmacol 2018; 9: 177
  • 108 Schmid Y, Enzler F, Gasser P. et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry 2015; 78: 544-553
  • 109 Hasler F, Grimberg U, Benz MA. et al. Acute psychological and physiological effects of psilocybin in healthy humans: A double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl) 2004; 172: 145-156
  • 110 Dos Santos RG, Grasa E, Valle M. et al. Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology (Berl) 2012; 219: 1039-1053
  • 111 Ly C, Greb AC, Cameron LP. et al. Psychedelics promote structural and functional neural plasticity. Cell Rep 2018; 23: 3170-3182
  • 112 Catlow BJ, Song S, Paredes DA. et al. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res 2013; 228: 481-491
  • 113 Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. Int Rev Psychiatry 2018; DOI: 10.1080/09540261.2018.1481827: 1-13
  • 114 Yu B, Becnel J, Zerfaoui M. et al. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther 2008; 327: 316-323
  • 115 Nau F, Yu B, Martin D. et al. Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo. PLoS One 2013; 8: e75426
  • 116 Kyzar EJ, Nichols CD, Gainetdinov RR. et al. Psychedelic drugs in biomedicine. Trends Pharmacol Sci 2017; 38: 992-1005
  • 117 Preller KH, Vollenweider FX. Modulation of social cognition via hallucinogens and “entactogens. Front Psychiatry 2019; 10: 881
  • 118 Griffiths RR, Johnson MW, Richards WA. et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol 2018; 32: 49-69
  • 119 Schmid Y, Liechti ME. Long-lasting subjective effects of LSD in normal subjects. Psychopharmacology (Berl) 2018; 235: 535-545
  • 120 Noorani T, Garcia-Romeu A, Swift TC. et al. Psychedelic therapy for smoking cessation: Qualitative analysis of participant accounts. J Psychopharmacol 2018; 32: 756-769
  • 121 Dolder PC, Schmid Y, Müller F. et al. LSD Acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology 2016; 41: 2638-2646
  • 122 Pokorny T, Preller KH, Kometer M. et al. Effect of psilocybin on empathy and moral decision-making. Int J Neuropsychopharmacol 2017; 20: 747-757
  • 123 Mason NL, Mischler E, Uthaug MV. et al. Sub-acute effects of psilocybin on empathy, creative thinking, and subjective well-being. J Psychoactive Drugs 2019; 51: 123-134
  • 124 Preller KH, Pokorny T, Hock A. et al. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing. Proc Natl Acad Sci USA 2016; 113: 5119-5124
  • 125 Preller KH, Vollenweider FX. Modulation of social cognition via hallucinogens and “entactogens”. Front Psychiatry 2019; 10: 881
  • 126 Gulliver D, Werry E, Reekie TA. et al. Targeting the oxytocin system: new pharmacotherapeutic approaches. Trends Pharmacol Sci 2019; 40: 22-37
  • 127 Kometer M, Schmidt A, Bachmann R. et al. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry 2012; 72: 898-906
  • 128 Bershad AK, Schepers ST, Bremmer MP. et al. Acute Subjective and behavioral effects of microdoses of lysergic acid diethylamide in healthy human volunteers. Biol Psychiatry 2019; 86: 792-800
  • 129 Schmidt A, Kometer M, Bachmann R. et al. The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. Psychopharmacology (Berl) 2013; 225: 227-239
  • 130 Mueller F, Lenz C, Dolder PC. et al. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl Psychiatry 2017; 7: e1084
  • 131 Kraehenmann R, Preller KH, Scheidegger M. et al. Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol Psychiatry 2015; 78: 572-581
  • 132 Kraehenmann R, Schmidt A, Friston K. et al. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. Neuroimage Clin 2016; 11: 53-60
  • 133 Grimm O, Kraehenmann R, Preller KH. et al. Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination. Eur Neuropsychopharmacology 2018; 28: 691-700
  • 134 Bershad AK, Preller KH, Lee R. et al. Preliminary report on the effects of a low dose of LSD on Resting-state amygdala functional connectivity. Biol Psychiatry Cogn Neurosci Neuroimaging 2020; 5: 461-467
  • 135 Barrett FS, Doss MK, Sepeda ND. et al. Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep 2020; 10: 2214
  • 136 Roseman L, Demetriou L, Wall MB. et al. Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology 2018; 142: 263-269
  • 137 Mertens LJ, Wall MB, Roseman L. et al. Therapeutic mechanisms of psilocybin: changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J Psychopharmacol 2020; 34: 167-180
  • 138 Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci 2020; 21: 611-624
  • 139 Carhart-Harris RL, Muthukumaraswamy S, Roseman L. et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci USA 2016; 113: 4853-4858
  • 140 Carhart-Harris RL, Erritzoe D, Williams T. et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA 2012; 109: 2138-2143
  • 141 Muthukumaraswamy SD, Carhart-Harris RL, Moran RJ. et al. Broadband cortical desynchronization underlies the human psychedelic state. J Neurosci 2013; 33: 15171-15183
  • 142 Müller F, Dolder PC, Schmidt A. et al. Altered network hub connectivity after acute LSD administration. Neuroimage Clin 2018; 18: 694-701
  • 143 Preller KH, Burt JB, Ji JL. 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
  • 144 Palhano-Fontes F, Andrade KC, Tofoli LF. et al. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One 2015; 10: e0118143
  • 145 Preller KH, Duerler P, Burt JB. et al. Psilocybin induces time-dependent changes in global functional connectivity. Biol Psychiatry 2020; 88: 197-207
  • 146 Roseman L, Nutt DJ, Carhart-Harris RL. Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol 2017; 8: 974
  • 147 Watts R, Day CM, Krzanowski J. et al. Patients’ Accounts of increased “connectedness” and “acceptance” after psilocybin for treatment-resistant depression. J Humanist Psychol 2017; 57: 520-564
  • 148 Griffiths R, Richards W, Johnson M. et al. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol 2008; 22: 621-632
  • 149 Watts R, Luoma JB. The use of the psychological flexibility model to support psychedelic assisted therapy. J Contextual. Behav Sci 2020; 15: 92-102
  • 150 Wolff M, Evens R, Mertens LJ. et al. Learning to let go: A cognitive-behavioral model of how psychedelic therapy promotes acceptance. Front Psychiatry 2020; 11: 5
  • 151 Carhart-Harris RL, Bolstridge M, Rucker J. et al. Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry 2016; 3: 619-627
  • 152 Grob CS, Danforth AL, Chopra GS. et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 2011; 68: 71-78
  • 153 Ross S, Bossis A, Guss J. et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. J Psychopharmacol 2016; 30: 1165-1180
  • 154 Johnson MW, Garcia-Romeu A, Cosimano MP. et al. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 2014; 28: 983-992
  • 155 Bogenschutz MP, Forcehimes AA, Pommy JA. et al. Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. J Psychopharmacol 2015; 29: 289-299
  • 156 Moreno FA, Wiegand CB, Taitano EK. et al. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 2006; 67: 1735-1740
  • 157 Gasser P, Holstein D, Michel Y. et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis 2014; 202: 513-520
  • 158 Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse 2017; 43: 55-60
  • 159 Carhart-Harris RL, Bolstridge M, Day CMJ. et al. Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology (Berl) 2018; 235: 399-408
  • 160 Osorio Fde L, Sanches RF, Macedo LR. et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A preliminary report. Rev Bras Psiquiatr 2015; 37: 13-20
  • 161 Palhano-Fontes F, Barreto D, Onias H. et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomized placebo-controlled trial. Psychological medicine 2019; 49: 655-663
  • 162 Griffiths RR, Johnson MW, Carducci MA. et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol 2016; 30: 1181-1197
  • 163 Olson JA, Suissa-Rocheleau L, Lifshitz M. et al. Tripping on nothing: Placebo psychedelics and contextual factors. Psychopharmacology 2020; 237: 1371-1382