CoChat
Sign Up
Cited by 739Neurotransmitter Receptor Influence on BehaviorPsychedelics and Drug StudiesTreatment of Major Depression

The DOI matches its Crossref record; 541 of the 541 references it cites were found in a registry or an index.

Serotonin and brain function: a tale of two receptors

Open access
Carhart-Harris, RL, Nutt, DJ·2017·Journal of Psychopharmacology
DOI 10.1177/0269881117725915PMC PMC5606297
Open this paper in CoChat — free accountOpen PDF

Abstract

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1177/0269881117725915

Cites

541 of 541 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1. Regional distribution of serotonin 1A (left) and 2A receptors (right) in healthy volunteers as measured using PET imaging and radioligands selective for the 5-HT 1A and 2A receptors. Pathway 1 refers to the ‘passive coping’ pathway hypothesised to be mediated by 5-HT1AR signalling and concerned with passive endurance, and ‘pathway 2’ refers to the ‘active coping’ pathway hypothesised to be mediated by 5-HT2AR signalling and concerned with an active change in outlook and/or behaviour. Images reproduced from (Beliveau et al., 2016) with permission. Note: The dense expression of the 5-HT1AR in medial temporal lobe regions and particularly the hippocampus is not clearly evident in the relevant maps shown here (left) but can be seen in values presented in the paper itself, as well as others (Pazos and Palacios, 1985; Pazos et al., 1987).
Figure 1. Regional distribution of serotonin 1A (left) and 2A receptors (right) in healthy volunteers as measured using PET imaging and radioligands selective for the 5-HT 1A and 2A receptors. Pathway 1 refers to the ‘passive coping’ pathway hypothesised to be mediated by 5-HT1AR signalling and concerned with passive endurance, and ‘pathway 2’ refers to the ‘active coping’ pathway hypothesised to be mediated by 5-HT2AR signalling and concerned with an active change in outlook and/or behaviour. Images reproduced from (Beliveau et al., 2016) with permission. Note: The dense expression of the 5-HT1AR in medial temporal lobe regions and particularly the hippocampus is not clearly evident in the relevant maps shown here (left) but can be seen in values presented in the paper itself, as well as others (Pazos and Palacios, 1985; Pazos et al., 1987).CC BY · PubMed Central
Figure 2. Extra-pharmacological (EP) model of drug action. This model is intended to provide a comprehensive account of the action of psychoactive drugs that takes into account important extra-pharmacological components such as trait, pre-state, dosage and environmental factors and how these interact with a given drug’s specific pharmacology to predict the quality of the acute ‘intoxicated’ or ‘medicated’ state and subsequent longer-term outcomes. The model is conceived with acute dosing in mind; however, it could also be adapted and applied to chronic dosing regimens.
Figure 2. Extra-pharmacological (EP) model of drug action. This model is intended to provide a comprehensive account of the action of psychoactive drugs that takes into account important extra-pharmacological components such as trait, pre-state, dosage and environmental factors and how these interact with a given drug’s specific pharmacology to predict the quality of the acute ‘intoxicated’ or ‘medicated’ state and subsequent longer-term outcomes. The model is conceived with acute dosing in mind; however, it could also be adapted and applied to chronic dosing regimens.CC BY · PubMed Central
Figure 3. A two-part or ‘bipartite’ model of brain serotonin function. Model proposes that brain serotonin mediates adaptive responses to adversity via two distinct mechanisms: one mediated by postsynaptic 5-HT1AR signalling in aid of stress moderation (pathway 1) and the other mediated by 5-HT2AR signalling is aid of more substantial adaptive changes (pathway 2). SSRIs and other conventional antidepressant medications work on and can enhance pathway 1, whereas pathway 2 can be enhanced by 5-HT2AR agonist psychedelic drugs such as psilocybin. Note: it is hypothesised that active coping can be most effectively implemented if the window of plasticity afforded by 5-HT2AR agonism is complemented by supportive psychotherapy that promotes a willingness to confront and work through sources of stress (Watts et al., 2017). Illustrations by Samantha Strong (S.L.Strong1@bradford.ac.uk).
Figure 3. A two-part or ‘bipartite’ model of brain serotonin function. Model proposes that brain serotonin mediates adaptive responses to adversity via two distinct mechanisms: one mediated by postsynaptic 5-HT1AR signalling in aid of stress moderation (pathway 1) and the other mediated by 5-HT2AR signalling is aid of more substantial adaptive changes (pathway 2). SSRIs and other conventional antidepressant medications work on and can enhance pathway 1, whereas pathway 2 can be enhanced by 5-HT2AR agonist psychedelic drugs such as psilocybin. Note: it is hypothesised that active coping can be most effectively implemented if the window of plasticity afforded by 5-HT2AR agonism is complemented by supportive psychotherapy that promotes a willingness to confront and work through sources of stress (Watts et al., 2017). Illustrations by Samantha Strong (S.L.Strong1@bradford.ac.uk).CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Items 201–400 of 541

Research works printed but not linked: 48

  1. Anisman H, 2008, Journal of Psychiatry & Neuroscience: JPN, 33, 131
  2. Atasoy SR R, 2017, In preparation
  3. Bradbury S, 2013, Addict Biol
  4. Bremner JD, 1984, J Clin Psychiatry, 45, 414
  5. Bressa GM, 1987, Int J Clin Pharmacol Res, 7, 111
  6. Brown GL, 1990, J Clin Psychiatry, 31
  7. Busch AK, 1950, Dis Nerv Syst, 11, 241
  8. Carhart-Harris RL, 2016, Psychol Med, 1
  9. Celada P, 2004, J Psychiatry Neurosci: JPN, 29, 252
  10. Cohen JY, 2015, Elife, 4
  11. Coppen AJ, 1969, Int Psychiatry Clin, 6, 53
  12. Dayan P, 2015, Elife, 4
  13. Friston KJ, 1991, Ciba Found Symp, 163, 76
  14. Gaddum JH, 1953, J Physiol, 121
  15. Gouzoulis E, 1994, Der Nervenarzt, 65, 198
  16. Gray JA, 1983, Encephale, 9, 161B
  17. Gregoire C, 2016, The Huffinton Post
  18. Grof S, 1975, Realms of Human Unconscious: Observations from LSD Research
  19. Harvey JA, 1975, Fed Proc, 34, 1796
  20. Hess SM, 1961, Arch Int Pharmacodyn Ther, 134, 89
  21. Johnson MW, 2016, Am J Drug Alcohol Abuse, 1
  22. Jorgensen LM, 2016, J Cereb Blood Flow Metab
  23. Knorr UB, 2012, Dan Med J, 59, B4426
  24. Lerner GA, 2015, Isr J Psychiatry Relat Sci, 52, 67
  25. Lord L, 2017, In preparation
  26. Lucki I, 1991, J Clin Psychiatry, 24
  27. Meana JJ, 2013, Bas Clin Pharmacol Toxicol, 113, 6
  28. Nour MM, 2017, J Psychoactive Drugs
  29. Olivier B, 1990, Prog Clin Biol Res, 361, 203
  30. Ott U, 2006, Hypnosis and Consciousness States: The Cognitive Neuroscience Perspective, 257
  31. Pare CM, 1965, Lancet, 1, 923
  32. Plaznik A, 1994, Pol J Pharmacol, 46, 473
  33. Preller KH, 2016, ECNP abstract, 003
  34. Roseman L, 2017, Psychopharmacology
  35. Russ SL, 2017, Theory, Res Practice, 4, 38
  36. Sandison RA, 1964, Nurs Times, 60, 529
  37. Schwartenbeck P, 2014, Cereb Cortex
  38. Sessa B, 2016, Neurosci Lett
  39. 10.1002/1098-2396(20001215)38:4<460::AID-SYN11>3.0.CO;2-D · DOI
  40. Soubrie P, 1986, J Pharmacol, 17, 107
  41. Strassman R, 2000, DMT: The Spirit Molecul : A Doctor’s Revolutionary Research into the Biology of Near-death and Mystical Experiences
  42. Waldman A, 2017, A Really Good Day: How Microdosing made a Mega Difference in my Mood, My Marriage, and My Life
  43. Watts R, 2017, J Humanist Psychol, 1
  44. Weber ET, 2010, Front Neurosci, 4
  45. Wise CD, 1970, Dis Nerv Syst, 31, 34
  46. Yoshinaga N, 2013, BMJ Open, 3
  47. Zhou JS, 2008, Zhong Nan Da Xue Xue Bao Yi Xue Ban, 33, 305
  48. Zis AP, 1992, Neuropsychopharmacology, 7, 189

Cited by

Sorted by citations

See all 739

Related

See all

Metadata

Authors
Carhart-Harris, R., & Nutt, D.
Affiliations
Psychedelic Research Group, Neuropsychopharmacology Unit, Centre for Psychiatry, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Venue
Journal of Psychopharmacology
Publisher
SAGE Publications
Published
2017-08-31
Volume
31
Issue
9
Pages
1091-1120
ISSN
  • 0269-8811 (ISSN-L)
  • 1461-7285
DOI
10.1177/0269881117725915
PMC
PMC5606297
OpenAlex
W2753654430
Cited by
739
References
541
Citations by year
2026: 80 · 2025: 99 · 2024: 131 · 2023: 85 · 2022: 79 · 2021: 98 · 2020: 81 · 2019: 45 · 2018: 36 · 2017: 4
FWCI
5.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Psychopharmacology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
Medical Research Council (MR/J00460X/1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords
serotonin, 5-HT1A receptor, 5-HT2A receptor, serotonergic neurotransmission, stress coping, passive coping, active coping, neuroplasticity, adversity, selective serotonin reuptake inhibitors, psychedelics, 5-HT2A receptor agonists, antidepressants, serotonergic system
MeSH terms
Animals, Antidepressive Agents, Brain, Hallucinogens, Humans, Synaptic Transmission, Serotonin, Selective Serotonin Reuptake Inhibitors, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT2A

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review