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5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride
Abstract
The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.
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“Comparison of the two scans revealed a global 20% decline in [11C]-raclopride (41) binding in the striatum, which is similar to the displacements evoked by amphetamine or other strong releasers of dopamine.”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [96]
In the citing paper
“Furthermore, the decline in the ventral striatum correlated with individual ratings for euphoria and depersonalization.”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [96]
In the citing paper
“The other explanation of psychedelics' ability to facilitate altered states of consciousness characterized by heightened introspection and diminished ego boundaries is their influence on 5-HT1A [64] and 5-HT2B [65], and interacting with the dopaminergic [66] and glutamatergic systems [67].”
From Mindfulness meditation and psychedelics: potential synergies and commonalities (2023) · cites this paper as [66]
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“Indeed, the administration of psilocybin to healthy human volunteers, decreased the binding of the dopamine D2 antagonist [ (11)C] raclopride in both caudate nucleus and putamen (Vollenweider et al., 1999).”
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Self-citationEffect of Psilocybin on Empathy and Moral Decision-Making
Pokorny, T., Preller, K. H., Kometer, M., Dziobek, I., & Vollenweider, F. X. (2017) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx047 · Cited by 197
“Although psilocybin also has downstream effects on the dopamine system (Vollenweider et al., 1998; Vollenweider et al., 1999; Halberstadt and Geyer, 2011), an involvement of the dopamine system in the current results is unlikely since administration of the dopamine reuptake inhibitor methylphenidate did not lead to in…”
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Vollenweider, F., Csomor, P., Knappe, B., Geyer, M., & Quednow, B. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301324 · Cited by 159
“Moreover, we previously reported that the 5-HT releasing agent MDMAF which indirectly stimulates both 5-HT 2A and 5-HT 1A receptorsFalso increases PPI at long (120 ms) but not short ISI (30 ms) in healthy human volunteers and disrupts PPI in rats (Vollenweider et al, 1999a).”
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“These techniques, used in combination with administration of pharmacological compounds that target non-dopaminergic neurotransmitter systems, have allowed examination of the neuropharmacology of DA release in the human brain (Breier et al., 1998; Brody et al., 2004; Dewey et al., 1993; Vollenweider et al., 1999), and…”
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“Previous research has shown a relationship between 5-HT2A receptor activity and goal directed behavior likely due to indirect modulation of DA release (Vollenweider et al. 1999; Sakashita,et al. 2015; Dalley et al. 2002; Boureau and Dayan 2011).”
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BackgroundSelf-citationMolecular Mechanisms of Psilocybin and Implications for the Treatment of Depression
Ling, S., Ceban, F., Lui, L. M. W., Lee, Y., Teopiz, K. M., Rodrigues, N. B., Lipsitz, O., Gill, H., Subramaniapillai, M., Mansur, R. B., et al. (2022) · CNS Drugs · doi:10.1007/s40263-021-00877-y · Cited by 127
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“Psilocybin also increases striatal dopamine concentrations, but haloperidol (an antagonist of D2, D3, and D4 receptors) decreases the euphoria and depersonalization effects of psilocybin by only 30%,([41]) and actually increases its psychotomimetic effects,([35])”
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“Recent behavioral and neuroimaging studies demonstrated that psychedelics produce their psychological effects primarily via agonist action at 5-HT2A receptors in the brain [15, 16], although modulatory downstream effects upon the gamma-aminobutyric acid (GABA)ergic [17], dopaminergic [18] and glutamatergic [17] system…”
Self-citationThe role of the extrapersonal brain systems in religious activity
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“…Swiss group used PET to analyze the effects of silocybin [0.25 mg/kg, oral] on the binding of [11C]raclopride o D2-dopamine receptors in the striatum of seven healthy ale volunteers [age: 27 ± 2.3 years] (Vollenweider et al., 1999). silocybin was administered 80 min before [11C]raclopride injecion.”
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“Effective doses of psilocybin significantly decreased [11C]raclopride binding in the striatum, which is indicative for an increase in endogenous dopamine levels in this brain structure (Vollenweider et al. 1999).”
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BackgroundPsilocybin modulates functional connectivity of the amygdala during emotional face discrimination
Grimm, O., Krähenmann, R., Preller, K. H., Seifritz, E., & Vollenweider, F. X. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.03.016 · Cited by 96
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“Moreover, psilocybin has been found to increase striatal dopamine concentrations Frontiers in Psychology | www.frontiersin.org 10 September 2021 | Volume 12 | Article 729425 in humans, a mechanism partly underlying euphoria and depersonalization phenomena (Vollenweider et al., 1999).”
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“, psilocybin, seem to disrupt the 5-HT1A/2A balance (Vollenweider et al. 1999) by driving 5-HT2A activity, resulting in excessive neuronal output contributing to extremes of disinhibition, disorganization, and loss of self-control.”
BackgroundSex differences and serotonergic mechanisms in the behavioural effects of psilocin
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“In line with this, psilocin has been shown to induce dopamine release in the striatum in humans (Vollenweider et al., 1999) and, more recently, also in the nucleus accumbens of male Wistar rats, although only with a very high dose of 10 mg/kg of psilocin (Sakashita et al., 2015).”
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Neural Mechanisms and Psychology of Psychedelic Ego Dissolution
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Therapeutic Applications of Classic Hallucinogens
Bogenschutz, M. P., & Ross, S. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_464 · Cited by 92
Heterogeneous Effects of Alcohol on Dopamine Release in the Striatum: A PET Study
Yoder, K. K., Constantinescu, C. C., Kareken, D. A., Normandin, M. D., Cheng, T., O’Connor, S., & Morris, E. D. (2007) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2007.00390.x · Cited by 85
“…increases in DA levels and the subjective effects of the drugs, including methylphenidate (Volkow et al., 1999), amphetamine (Abi-Dargham et al., 2003; Drevets et al., 2001; Martinez et al., 2003; Oswald et al., 2005), nicotine (Barrett et al., 2004), and psilocybin (Vollenweider et al., 1999).”
BackgroundBailer, U. F., Frank, G., Price, J. C., MELTZER, C. C., Becker, C. R., Mathis, C. A., Wagner, A., Barbarich-Marsteller, N. C., Bloss, C. S., Putnam, K. T., et al. (2012) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2012.06.010 · Cited by 82
“In support of this idea, agents that are relatively 5-HT specific, such as psilocybin (Vollenweider et al., 1999), fenfluramine (Smith et al., 1997), and citalopram (Tiihonen et al., 1996) alter [ 11 C]raclopride binding.”
A triple-network organization for the mouse brain
Mandino, F., Vrooman, R. M., Foo, H. E., Yeow, L. Y., Bolton, T. A. W., Salvan, P., Teoh, C. L., Lee, C. Y., Beauchamp, A., Luo, S. X., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01298-5 · Cited by 87
Sakashita, Y., Abe, K., Katagiri, N., Kambe, T., Saitoh, T., Utsunomiya, I., Horiguchi, Y., & Taguchi, K. (2015) · Biological ^|^ Pharmaceutical Bulletin · doi:10.1248/bpb.b14-00315 · Cited by 81
Sekssaoui, M., Bockaert, J., Marin, P., & Bécamel, C. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01794-6 · Cited by 84
“S5D, E and Table 1).”
Alterations of dopamine and serotonin transmission in schizophrenia
Remington, G. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)00906-0 · Cited by 83
“A second PET study involving psilocybin reported decreased [11C]raclopride binding in both the caudate and the putamen (19 and 20%, respectively), but this compound has mixed 5-HT1A and 5-HT2A agonist properties (Vollenweider et al., 1999).”
BackgroundThe neuroscientific study of spiritual practices
Newberg, A. B. (2014) · Frontiers in Psychology · doi:10.3389/fpsyg.2014.00215 · Cited by 90
“Some neuroimaging studies exploring hallucinogenic agents have already been performed (Vollenweider et al., 1997, 1999, 2000), but a more extensive study of such agents, particularly in relation to religious and spiritual experiences is required.”
BackgroundAbnormal Striatal Dopamine Transmission in Schizophrenia
Brunelin, J., Fecteau, S., & Suaud-Chagny, M. (2013) · Current Medicinal Chemistry · doi:10.2174/0929867311320030011 · Cited by 90
STEEVES, T., & FOX, S. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(08)00924-2 · Cited by 79
Romeo, B., Hermand, M., Pétillion, A., Karila, L., & Benyamina, A. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.03.002 · Cited by 76
“, 2015), but also in the ventral striatum in humans (Vollenweider, 1999).”
BackgroundCerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome
Haugbøl, S., Pinborg, L. H., Regeur, L., Hansen, E. S., Bolwig, T. G., Nielsen, F. Å., Svarer, C., Skovgaard, L. T., & Knudsen, G. M. (2006) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145706006559 · Cited by 75
Fungal Hallucinogens Psilocin, Ibotenic Acid, and Muscimol
Stebelska, K. (2013) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0b013e31828741a5 · Cited by 76
Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review
Divito, A. J., & Leger, R. F. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-06009-x · Cited by 78
Treatment-resistant depression: molecular mechanisms and management
Kajumba, M. M., Kakooza‐Mwesige, A., Nakasujja, N., Attix, D. K., & Canli, T. (2024) · Molecular Biomedicine · doi:10.1186/s43556-024-00205-y · Cited by 93
Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines
Winter, J. C. (2009) · Psychopharmacology · doi:10.1007/s00213-008-1356-8 · Cited by 65
“Finally, I will attempt no further definition of hallucinogen beyond saying that if a chemical mimics in human subjects the subjective effects of LSD or a tryptamine such as psilocybin or a phenethylamine such as mescaline, then it is a hallucinogen.”
BackgroundPsilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy
Dodd, S., Norman, T. R., Eyre, H. A., Stahl, S. M., Phillips, A., Carvalho, A. F., & Berk, M. (2023) · CNS Spectrums · doi:10.1017/s1092852922000888 · Cited by 73
“42 Dopamine increases were correlated with euphoria and depersonalisation.”
Cumming, P. D., Rosa‐Neto, P., Watanabe, H., Smith, D. F., Bender, D., Clarke, P. B. S., & GJEDDE, A. H. (2003) · NeuroImage · doi:10.1016/s1053-8119(03)00079-x · Cited by 68
Psychedelic therapy's transdiagnostic effects: A research domain criteria (RDoC) perspective
Kelly, J. R., Gillan, C. M., Prenderville, J., Kelly, C., Harkin, A., Clarke, G., & O'Keane, V. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.800072 · Cited by 69
“A Positron emission tomography (PET) study in healthy humans showed that psilocybin increased striatal dopamine concentrations, and this increase correlated with euphoria and depersonalization phenomena (211), whereas the mixed 5-HT2/D2 antagonist risperidone attenuated the effects of psilocybin (212).”
BackgroundWienberg, M., Glenthoj, B., Jensen, K., & Oranje, B. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881109102606 · Cited by 68
Winkelman, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.619890 · Cited by 55
“Psilocybin increases striatal dopamine concentrations (Vollenweider et al., 1999), an area of the brain mediating rewards from social interactions.”
BackgroundPsilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse
Meinhardt, M. W., Güngör, C., Skorodumov, I., Mertens, L. J., & Spanagel, R. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0694-z · Cited by 65
Mertens, L. J., & Preller, K. H. (2021) · Pharmacopsychiatry · doi:10.1055/a-1341-1907 · Cited by 65
“Evidence is mostly derived from preclinical studies, but one human positron emission tomography (PET) trial also revealed increased striatal dopamine levels following a psilocybin dose [93].”
BackgroundPsilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat
Jefsen, O. H., Højgaard, K., Christiansen, S. L., Elfving, B., Nutt, D., Wegener, G., & Müller, H. K. (2019) · Acta Neuropsychiatrica · doi:10.1017/neu.2019.15 · Cited by 64
“35 mg/kg) have also been found to increase dopamine levels in ventral striatum (NAc and olfactory tuberculum) in human PET studies (Vollenweider et al., 1999).”
BackgroundInfluential5-HT2A and muscarinic receptors in schizophrenia: a postmortem study
Matsumoto, I., Inoue, Y., Iwazaki, T., Pavey, G., & Dean, B. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2004.12.059 · Cited by 62
Kuroki, T., Meltzer, H., & Ichikawa, J. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02516-2 · Cited by 55
Leger, R. F., & Unterwald, E. M. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211044688 · Cited by 61
“They also have direct or indirect interactions with dopamine transmission (Nichols et al., 2017; Vollenweider et al., 1999; Watts et al., 1995).”
BackgroundThe Effect of Psilocin on Memory Acquisition, Retrieval, and Consolidation in the Rat
Rambousek, L., Páleníček, T., Valeš, K., & Stuchlík, A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00180 · Cited by 54
“BEHAVIORAL NEUROSCIENCE ORIGINAL RESEARCH ARTICLE published: 16 May 2014 doi: 10.3389/fnbeh.2014.00180 The effect of psilocin on memory acquisition, retrieval, and consolidation in the rat”
BackgroundInfluentialSerotonergic Hallucinogens and Emerging Targets for Addiction Pharmacotherapies
Ross, S. (2012) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2012.04.002 · Cited by 54
Grandjean, J., Buehlmann, D., Buerge, M., Sigrist, H., Seifritz, E., Vollenweider, F. X., Pryce, C. R., & Rudin, M. (2020) · NeuroImage · doi:10.1016/j.neuroimage.2020.117456 · Cited by 57
Self-citationPáleníček, T., Fujáková, M., Brunovský, M., Horáček, J., Gorman, I., Balı́ková, M., Rambousek, L., Syslová, K., Kačer, P., Zach, P., et al. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2797-7 · Cited by 52
Horsley, R. R., Páleníček, T., Kolin, J., & Valeš, K. (2018) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000394 · Cited by 52
A neurobiological perspective on social influence: Serotonin and social adaptation
Duerler, P., Vollenweider, F. X., & Preller, K. H. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15607 · Cited by 52
“In human and rodent studies Psi also showed downstream effects on the DA level in the VS in humans (Puig et al., 2003; Vollenweider, 1999; Vollenweider & Kometer, 2010).”
BackgroundSelf-citation
Metadata
- Authors
- Vollenweider, F.
- Affiliations
- University Hospital Zurich (CH)
- Corresponding author
- Vollenweider, F
- Venue
- Neuropsychopharmacology
- Published
- 1999-05
- Volume
- 20
- Issue
- 5
- Pages
- 424-433
- ISSN
- 0893-133X (ISSN-L)
- OpenAlex
- W1986425243
- Cited by
- 305
- References
- 73
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 28 · 2023: 28 · 2022: 20 · 2021: 18 · 2020: 19 · 2019: 6 · 2018: 13 · 2017: 7 · 2016: 14 · 2015: 7 · 2014: 6 · 2013: 9 · 2012: 11
- FWCI
- 8.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- psilocybin, psychosis, serotonin, dopamine release, dopamine D2 receptor, [11C]raclopride, striatum, caudate nucleus, putamen, 5-HT2A receptor, 5-HT1A receptor, serotonin-dopamine interaction, hallucinations, depersonalization, schizophrenia
- MeSH terms
- Adult, Basal Ganglia, Dopamine, Hallucinogens, Humans, Male, Psilocybin, Psychometrics, Psychoses, Substance-Induced, Salicylamides, Serotonin, Tomography, Emission-Computed, Antipsychotic Agents, Dopamine Antagonists, Raclopride
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