Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

Abstract

Background:

Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness.

Aims:

We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals.

Method:

Sixteen participants completed a pre-drug [¹¹C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models.

Results:

Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score.

Conclusion:

This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.

Keywords

Serotonin 2A receptor psilocybin subjective drug intensity psychedelics mystical type experience positron emission tomography

Get full access to this article

View all access options for this article.

References

Barrett

Griffiths

(2018) Classic hallucinogens and mystical experiences: Phenomenology and neural correlates. Curr Top Behav Neurosci 36: 393–430.

Barrett

Johnson

Griffiths

(2015) Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol 29: 1182–1190.

Beliveau

Ganz

Feng

, et al. (2017) A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci 37: 120–128.

Bogenschutz

Forcehimes

Pommy

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

Bonson

Buckholtz

Murphy

(1996) Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology 14: 425–436.

Brown

Nicholas

Cozzi

, et al. (2017) Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clin Pharmacokinet 56: 1543–1554.

Carhart-Harris

Bolstridge

Day

CMJ

, et al. (2018) Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology (Berl) 235: 399–408.

Carhart-Harris

Bolstridge

Rucker

, et al. (2016) Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry 3: 619–627.

Dolder

Schmid

Steuer

, et al. (2017) Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin Pharmacokinet 56: 1219–1230.

10.

Dos Santos

Hallak

JEC

(2020) Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms. Neurosci Biobehav Rev 108: 423–434.

11.

Erritzoe

Holst

Frokjaer

, et al. (2010) A nonlinear relationship between cerebral serotonin transporter and 5-HT(2A) receptor binding: An in vivo molecular imaging study in humans. J Neurosci 30: 3391–3397.

12.

Ettrup

da Cunha-Bang

McMahon

, et al. (2014) Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36. J Cereb Blood Flow Metab 34: 1188–1196.

13.

Ettrup

Svarer

McMahon

, et al. (2016) Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: Test–retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin. Neuroimage 130: 167–174.

14.

Fisher

Meltzer

Price

, et al. (2009) Medial prefrontal cortex 5-HT(2A) density is correlated with amygdala reactivity, response habituation, and functional coupling. Cereb Cortex 19: 2499–2507.

15.

Frokjaer

Mortensen

Nielsen

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

16.

Gonzalez-Maeso

Weisstaub

Zhou

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

17.

Gray

Roth

(2001) Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists. Brain Res Bull 56: 441–451.

18.

Greve

Svarer

Fisher

, et al. (2014) Cortical surface-based analysis reduces bias and variance in kinetic modeling of brain PET data. Neuroimage 92: 225–236.

19.

Griffiths

Johnson

Carducci

, 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.

20.

Griffiths

Johnson

Richards

, et al. (2011) Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects. Psychopharmacology (Berl) 218: 649–665.

21.

Griffiths

Richards

McCann

, et al. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 187: 268–283; discussion 284–292.

22.

Holze

Duthaler

Vizeli

, et al. (2019) Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects. Br J Clin Pharmacol 85: 1474–1483.

23.

Hrdina

(1993) Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT 2 receptors in rat brain: An autoradiographic study. Synapse 14: 324–331.

24.

Johnson

Garcia-Romeu

Cosimano

, et al. (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28: 983–992.

25.

Johnson

Griffiths

(2017) Potential therapeutic effects of psilocybin. Neurotherapeutics 14: 734–740.

26.

Johnson

Hendricks

Barrett

, et al. (2019) Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther 197: 83–102.

27.

Johnson

Richards

Griffiths

(2008) Human hallucinogen research: Guidelines for safety. J Psychopharmacol 22: 603–620.

28.

Kellar

Cascio

Butler

, et al. (1981) Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. Eur J Pharmacol 69: 515–518.

29.

Kometer

Schmidt

Bachmann

, et al. (2012) Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry 72: 898–906.

30.

MacLean

Johnson

Griffiths

(2011) Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol 25: 1453–1461.

31.

Madsen

Fisher

Burmester

, et al. (2019) Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol 44: 1328–1334.

32.

Madsen

Fisher

Stenbaek

, et al. (2020) A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding. Eur Neuropsychopharmacol 33: 71–80.

33.

Maslow

(1959) Cognition of being in the peak experiences. J Genet Psychol 94: 43–66.

34.

Monti

(2011) Serotonin control of sleep-wake behavior. Sleep Med Rev 15: 269–281.

35.

Moreno

Wiegand

Taitano

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

36.

Muggeo

(2003) Estimating regression models with unknown break-points. Stat Med 22: 3055–3071.

37.

Nichols

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

38.

Nielson

May

Forcehimes

, et al. (2018) The psychedelic debriefing in alcohol dependence treatment: Illustrating key change phenomena through qualitative content analysis of clinical sessions. Front Pharmacol 9: 132–132.

39.

Pahnke

(1963) Drugs and Mysticism. PhD Thesis, Harvard University, USA.

40.

Peroutka

Snyder

(1980) Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science 210: 88–90.

41.

Preller

Vollenweider

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

42.

Ross

Bossis

Guss

, 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.

43.

Sanders-Bush

Breeding

Knoth

, et al. (1989) Sertraline-induced desensitization of the serotonin 5HT-2 receptor transmembrane signaling system. Psychopharmacology (Berl) 99: 64–69.

44.

Sheehan

Lecrubier

Sheehan

, et al. (1998) The mini-international neuropsychiatric interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59: 22–33; quiz 34–57.

45.

Stolz

Marsden

Middlemiss

(1983) Effect of chronic antidepressant treatment and subsequent withdrawal on [3 H]-5-hydroxytryptamine and [3 H]-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour. Psychopharmacology (Berl) 80: 150–155.

46.

Studerus

Gamma

Kometer

, et al. (2012) Prediction of psilocybin response in healthy volunteers. PLoS ONE 7: e30800.

47.

Svarer

Madsen

Hasselbalch

, et al. (2005) MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 24: 969–979.

48.

Team R Core (2019) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna. Available at https://www.r-project.org/.

49.

Varnas

Halldin

Hall

(2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22: 246–260.

50.

Vollenweider

Vollenweider-Scherpenhuyzen

Babler

, et al. (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9: 3897–3902.

51.

Woods

Cherry

Mazziotta

(1992) Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 16: 620–633.

52.

Yatham

Liddle

Dennie

, et al. (1999) Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: A positron emission tomography study with fluorine-18–labeled setoperone. Arch Gen Psychiatry 56: 705–711.

53.

Zhang

Stackman

Jr (2015) The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 6: 225–225.