The forgotten psychedelic: Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin
Using 7T resting-state fMRI in a double-blind, placebo-controlled crossover study, the authors show that acute 2C-B and psilocybin both reduce intra-network static connectivity while increasing between-network and subcortical–cortical coupling and brain complexity, but 2C-B causes less between-network desynchronisation and relative elevations in transmodal connectivity compared with psilocybin. These spatially divergent effects align with monoaminergic transporter and serotonergic receptor distributions and link transmodal-axis desynchronisation to behavioural measures, highlighting 2C-B as a distinct tool for psychedelic neuroscience and potential pharmacotherapies.
Authors
- Johannes Ramaekers
- Nathalie Mason
- Paolo Mallaroni
Published
Abstract
As psychedelic-assisted psychotherapy gains momentum, clinical investigation of next-generation psychedelics may lead to novel compounds tailored for specific populations. 2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenethylamine reported to produce less dysphoria and subjective impairment than the psychedelic tryptamine psilocybin. Despite its popularity among recreational users and distinct pharmacodynamics, the neural correlates of 2C-B remain unexplored. Using 7 T resting-state functional MRI in 22 healthy volunteers, we mapped out the acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin and placebo across spatiotemporal benchmarks of functional brain organisation. In a within-subjects, double-blind, placebo-controlled crossover design, we evaluated the neuropharmacological and neurobehavioural correlates of an array of connectivity measures - including static (sFC) and global connectivity (gFC), dynamic connectivity variability (dFC), and spontaneous brain complexity. Compared to placebo, 2C-B and psilocybin selectively reduced intranetwork sFC, while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B exhibited less pronounced reductions in between-network dFC but elicited elevations in transmodal sFC. Both compounds yielded spatially divergent increases in gFC yet produced similar increases in brain complexity. Using PET density modelling, the spatial distribution of neural effects aligned with documented differences in monoaminergic transporter and serotonergic receptor binding affinity beyond 5-HT2A, highlighting the role of pharmacology in shaping functional dynamics. Lastly, we show behavioural markers of psychedelic effects are reflected by the decoupling of the transmodal axis of functional brain organisation. Together, our findings highlight 2C-B as a useful new addition to the study of psychedelic neuroscience and may motivate new pharmacotherapy strategies.
Research Summary of 'The forgotten psychedelic: Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin'
Blossom's Take
This study reports on the brain (neurological) effects of both 2C-B and psilocybin in healthy volunteers. Several other papers have been written about this trial, and we first reported these results in 2024, when the preprint was published.
Introduction
As clinical interest in psychedelic-assisted psychotherapy grows, there is increasing motivation to characterise next-generation compounds that may offer improved tolerability profiles for specific patient populations. 2C-B (2,5-dimethoxy-4-bromophenethylamine) is a phenethylamine psychedelic reported by recreational users to produce less dysphoria and cognitive impairment than classical tryptamine psychedelics such as psilocybin, despite broadly comparable subjective effects at matched doses. Its neural correlates had not previously been characterised in humans. This study mapped the acute effects of 2C-B and psilocybin on functional brain organisation using 7T resting-state fMRI in healthy volunteers, benchmarking findings against established neuroimaging signatures of psychedelic action and examining the relationship between brain changes, pharmacological receptor maps, and subjective experience.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Mallaroni, P., Singleton, P., Mason, N. L., Satterthwaite, T. D., & Ramaekers, J. G. The forgotten psychedelic: Spatiotemporal mapping of brain organisation following the administration of 2C-B and psilocybin.
References (38)
Papers cited by this study that are also in Blossom
Daws, R. E., Timmermann, C., Giribaldi, B. et al. · Nature Medicine (2022)
Linguiti, S., Vogel, J. W., Sydnor, V. J. et al. · Neuroscience and Biobehavioral Reviews (2023)
Girn, M., Rosas, F. E., Daws, R. E. et al. · Trends in Cognitive Sciences (2023)
Kwan, A. C., Olson, D. E., Preller, K. H. et al. · Nature Medicine (2022)
Wall, M. B., Harding, R., Zafar, R. et al. · Molecular Psychiatry (2023)
Sessa, B., Fischer, F. M. · Drug Science Policy and Law (2015)
Mallaroni, P., Mason, N. L., Reckweg, J. T. et al. · Clinical Pharmacology and Therapeutics (2023)
Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)
Rickli, A., Luethi, D., Reinisch, J. et al. · Neuropharmacology (2015)
Ray, T. S. · PLOS ONE (2010)
Show all 38 referencesShow fewer
Liechti, M. E., Baumann, C., Gamma, A. et al. · Neuropsychopharmacology (2000)
Deco, G., Cruzat, J., Cabral, J. et al. · Current Biology (2018)
Singleton, S. P., Luppi, A. I., Carhart-Harris, R. L. et al. · Nature Communications (2022)
Pokorny, T., Preller, K. H., Kraehenmann, R. et al. · European Neuropsychopharmacology (2016)
McCulloch, D. E-W., Knudsen, G. M., Barrett, F. S. et al. · Neuroscience and Biobehavioral Reviews (2022)
McCulloch, D. E-W., Olsen, A. S., Ozenne, B. et al. · MedRvix (2023)
Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)
Nour, M. R., Evans, J., Nutt, D. J. et al. · Frontiers in Human Neuroscience (2016)
Timmermann, C., Roseman, L., Haridas, S. et al. · PNAS (2023)
Doss, M. K., Považan, M., Rosenberg, M. D. et al. · Translational Psychiatry (2021)
Doss, M. K., May, D. G., Johnson, M. W. et al. · Scientific Reports (2020)
Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)
Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)
Holze, F., Dolder, P. C., Ley, L. et al. · Neuropsychopharmacology (2020)
Girn, M., Roseman, L., Bernhardt, B. et al. · NeuroImage (2022)
Roseman, L., Leech, R., Feilding, A. et al. · Frontiers in Human Neuroscience (2014)
Tagliazucchi, E., Roseman, L., Kaelen, M. et al. · Current Biology (2016)
Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)
Lord, L. D., Expert, P., Atasoy, S. et al. · NeuroImage (2019)
Mortaheb, S., Fort, L. D., Mason, N. L. et al. · Biological Psychiatry (2023)
Carhart-Harris, R. L., Friston, K. J. · Pharmacological Reviews (2019)
Vollenweider, F. X., Preller, K. H. · Nature Reviews Neuroscience (2020)
Ort, A., Smallridge, J. W., Sarasso, S. et al. · iScience (2023)
Mediano, P. A. M., Rosas, F. E., Timmermann, C. et al. · ACS Chemical Neuroscience (2024)
Juliani, A., Chelu, V., Graesser, L. et al. · Biorxiv (2024)
Mallaroni, P., Mason, N. L., Kloft, L. et al. · NeuroImage (2024)
Tolle, H. M., Farah, J. C., Mallaroni, P. et al. · Network Neuroscience (2024)
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