Psychedelics as anti-inflammatory agents
Abstract
Serotonin (5-hydroxytryptamine, 5-HT)2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.
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Other animal studies have proposed that psychedelics may elicit their antidepressant effect through anti-inflammatory processes, by inhibiting proinflammatory cytokines TNF-α and IL-6, which have been found to be associated with depression.
“Other animal studies have proposed that psychedelics may elicit their antidepressant effect through anti-inflammatory processes, by inhibiting proinflammatory cytokines TNF-α and IL-6, which have been found to be associated with depression [40].”
From The psychological processes of classic psychedelics in the treatment of depression: a systematic review protocol (2022) · cites this paper as [40]
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Are psychedelics the answer to chronic pain: A review of current literature
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Psychedelics for acquired brain injury: a review of molecular mechanisms and therapeutic potential
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Scoping Review: The Role of Psychedelics in the Management of Chronic Pain
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Psychedelics for Brain Injury: A Mini-Review
Khan, M., Carter, G. T., Aggarwal, S. K., & Holland, J. A. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.685085 · Cited by 37 · see citing works
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Trends in the Top-Cited Articles on Classic Psychedelics
Lawrence, D. W., Sharma, B., Griffiths, R. R., & Carhart-Harris, R. (2021) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2021.1874573 · Cited by 35 · see citing works
Psychedelics in neuroinflammation: Mechanisms and therapeutic potential
de Deus, J. L., Maia, J. M., Soriano, R. N., Amorim, M. R., & Branco, L. G. S. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111278 · Cited by 34 · see citing works
The Safety and Efficacy of Psychedelic-Assisted Therapies for Older Adults: Knowns and Unknowns
Johnston, C. B., Mangini, M., Grob, C. S., & Anderson, B. T. (2022) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2022.08.007 · Cited by 33 · see citing works
Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms
Garcia‐Romeu, A., Darcy, S., Jackson, H., White, T., & Rosenberg, P. B. (2021) · Current topics in behavioral neurosciences · doi:10.1007/7854_2021_267 · Cited by 31 · see citing works
Sinha, J. K., Trisal, A., Ghosh, S., Gupta, S., Singh, D. K. K., Han, S. S., Mahapatra, M., Abomughaid, M. M., Abomughayedh, A. M., Almutary, A. G., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102211 · Cited by 31 · see citing works
Pearson, C., Siegel, J. S., & Gold, J. A. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.120096 · Cited by 31 · see citing works
Are Psychedelic Medicines the Reset for Chronic Pain? Preliminary Findings and Research Needs
Zia, F., Baumann, M., Belouin, S., Dworkin, R., Ghauri, M. H., Hendricks, P. S., Henningfield, J., Lanier, R., Ross, S., & Berger, A. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109528 · Cited by 26 · see citing works
Psychedelic Cognition—The Unreached Frontier of Psychedelic Science
Bălăeţ, M. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.832375 · Cited by 30 · see citing works
Psychedelic control of neuroimmune interactions governing fear
Chung, E. N., Lee, J., Polonio, C. M., Choi, J., Akl, C. F., Kilian, M., Weiß, W. M., Gunner, G., Ye, M., Heo, T. H., et al. (2025) · Nature · doi:10.1038/s41586-025-08880-9 · Cited by 33 · see citing works
Beating pain with psychedelics: Matter over mind?
Elman, I., Pustilnik, A. C., & Borsook, D. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.12.005 · Cited by 28 · see citing works
Psychedelics and Anti-inflammatory Activity in Animal Models
Flanagan, T. W., & Nichols, C. D. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_367 · Cited by 29 · see citing works
Self-citationPsychedelics as preventive treatment in headache and chronic pain disorders
Schindler, E. A. D. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109166 · Cited by 29 · see citing works
Potential analgesic effects of psychedelics on select chronic pain conditions: A survey study
Cavarra, M., Mason, N. L., Kuypers, K. P. C., Bonnelle, V., Smith, W., Feilding, A., Kryskow, P., & Ramaekers, J. G. (2023) · European Journal of Pain · doi:10.1002/ejp.2171 · Cited by 29 · see citing works
A Comprehensive Review of the Current Status of the Cellular Neurobiology of Psychedelics
Banushi, B., & Polito, V. (2023) · Biology · doi:10.3390/biology12111380 · Cited by 25 · see citing works
Oña, G., Berrada, A., & Bouso, J. C. (2021) · Transcultural Psychiatry · doi:10.1177/13634615211038416 · Cited by 29 · see citing works
Psilocybin in Palliative Care: An Update
Whinkin, E., Opalka, M., Watters, C., Jaffe, A., & Aggarwal, S. K. (2023) · Current Geriatrics Reports · doi:10.1007/s13670-023-00383-7 · Cited by 27 · see citing works
The potential of psychedelics for the treatment of Alzheimer's disease and related dementias
Winkelman, M., Szabó, A., & Frecska, E. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.07.003 · Cited by 27 · see citing works
The DMT and Psilocin Treatment Changes CD11b+ Activated Microglia Immunological PhenotypePreprint
Kozłowska, U., Klimczak, A., Wiatr, K., & Figiel, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.07.434103 · Cited by 27 · see citing works
Glennon, R. A., & Dukat, M. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00157 · Cited by 26 · see citing works
Wiens, K. R., Brooks, N. A. H., Riar, I., Greuel, B. K., Lindhout, I. A., & Klegeris, A. (2024) · Molecules · doi:10.3390/molecules29215084 · Cited by 25 · see citing works
VanderZwaag, J., Halvorson, T., Dolhan, K., Šimončičová, E., Ben‐Azu, B., & Tremblay, M. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03772-0 · Cited by 26 · see citing works
Robinson, G. I., Li, D., Wang, B., Zahoruiko, Y., Gerasymchuk, M., Hudson, D., Kovalchuk, O., & Kovalchuk, I. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45080427 · Cited by 24 · see citing works
Dworkin, R. H., Anderson, B. T., Andrews, N., Edwards, R. R., Grob, C. S., Ross, S., Satterthwaite, T. D., & Strain, E. C. (2022) · Journal of Pain · doi:10.1016/j.jpain.2022.05.003 · Cited by 22 · see citing works
The illusion of knowledge in the emerging field of psychedelic research
Oña, G., Kohek, M., & Bouso, J. C. (2022) · New Ideas in Psychology · doi:10.1016/j.newideapsych.2022.100967 · Cited by 22 · see citing works
Bedside to bench: the outlook for psychedelic research
Acero, V. P., Cribas, E. S., Browne, K. D., Rivellini, O. M., Burrell, J. C., O’Donnell, J. C., Das, S., & Cullen, D. K. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1240295 · Cited by 22 · see citing works
Jensen, M. E., Stenbæk, D. S., Juul, T. S., Fisher, P. M., Ekstrøm, C. T., Knudsen, G. M., & Fink‐Jensen, A. (2022) · BMJ Open · doi:10.1136/bmjopen-2022-066019 · Cited by 22 · see citing works
Jones, G. M., Arias, D., & Nock, M. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-25658-5 · Cited by 21 · see citing works
Psilocybin and Eugenol Reduce Inflammation in Human 3D EpiIntestinal Tissue
Robinson, G. I., Li, D., Wang, B., Rahman, T., Gerasymchuk, M., Hudson, D., Kovalchuk, O., & Kovalchuk, I. (2023) · Life · doi:10.3390/life13122345 · Cited by 21 · see citing works
The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies
Low, Z. X. B., Ng, W. S., Lim, E. S. Y., Goh, B. H., & Kumari, Y. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111139 · Cited by 20 · see citing works
Jensen, M. E., Stenbæk, D. S., Messell, C., Poulsen, E. D., Varga, T. V., Fisher, P. M., Nielsen, M. K. K., Johansen, S. S., Volkow, N. D., Knudsen, G. M., et al. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811251319457 · Cited by 21 · see citing works
Laabi, S., LeMmon, C., Vogel, C., Chacon, M., & Jimenez, V. M. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114940 · Cited by 20 · see citing works
Flanagan, T. W., Foster, T. P., Galbato, T. E., Lum, P. Y., Louie, B., Song, G., Halberstadt, A. L., Billac, G. B., & Nichols, C. D. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.3c00297 · Cited by 20 · see citing works
Self-citationGermann, C. B. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.109406 · Cited by 20 · see citing works
Lysergic acid diethylamide induces increased signalling entropy in rats’ prefrontal cortex
Savino, A., & Nichols, C. D. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15534 · Cited by 19 · see citing works
Self-citationMacrodosing to microdosing with psychedelics: Clinical, social, and cultural perspectives
Kaypak, A. C., & Raz, A. (2022) · Transcultural Psychiatry · doi:10.1177/13634615221119386 · Cited by 19 · see citing works
The current state of ayahuasca research in animal models: A systematic review
Daldegan‐Bueno, D., Simionato, N. M., Favaro, V. M., & Maia, L. O. (2023) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2023.110738 · Cited by 20 · see citing works
Psychedelics in the Treatment of Headache and Chronic Pain Disorders
Schindler, E. A. D. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_365 · Cited by 19 · see citing works
Association between Lifetime Classic Psychedelic Use and Sick Leave in a Population-Based Sample
Mellner, C., Dahlén, M., & Simonsson, O. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph191811353 · Cited by 18 · see citing works
Deciphering psilocybin: Cytotoxicity, anti-inflammatory effects, and mechanistic insights
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Concurrent stress modulates the acute and post-acute effects of psilocybin in a sex-dependent manner
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Immune-brain plasticity underpins stress and affective behaviors
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Targeting inflammatory signaling in obsessive compulsive disorder: a promising approach
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Psilocybin as a novel treatment for chronic pain
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Psilocybin: From Psychiatric Pariah to Perceived Panacea
Fonzo, G. A., Wolfgang, A. S., Barksdale, B. R., Krystal, J. H., Carpenter, L. L., Kraguljac, N. V., Grzenda, A. L., McDonald, W. M., Widge, A. S., Rodríguez, C. I., et al. (2025) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230682 · Cited by 16 · see citing works
Rossi, G. N., Hallak, J. E. C., Baker, G. B., Dursun, S. M., & SANTOS, R. G. D. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-022-01460-2 · Cited by 16 · see citing works
Lyon, A. (2023) · doi:10.1093/oso/9780198843757.001.0001 · Cited by 17 · see citing works
Females in Psychedelic Research: A Perspective for Advancing Research and Practice
Cohen, Z. Z., & Blest‐Hopley, G. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.5c00255 · Cited by 15 · see citing works
- Authors
- Flanagan, T. W., & Nichols, C. D.
- Affiliations
- Louisiana State University Health Sciences Center New Orleans (US)
- Corresponding author
- Nichols, Charles D.
- ORCID
- Nichols, Charles D.
- Venue
- International Review of Psychiatry
- Publisher
- Informa UK Limited
- Published
- 2018-07-04
- Volume
- 30
- Issue
- 4
- Pages
- 363-375
- ISSN
- 0954-0261 (ISSN-L)
- 1369-1627
- OpenAlex
- W2886249511
- Cited by
- 267
- References
- 151
- Citations by year
- 2026: 37 · 2025: 46 · 2024: 39 · 2023: 54 · 2022: 38 · 2021: 32 · 2020: 15 · 2019: 5
- FWCI
- 15.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Review of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- psychedelics, 5-HT2A receptor agonists, anti-inflammatory activity, serotonin, psilocybin, inflammatory diseases, inflammatory signaling, depression, obsessive-compulsive disorder, addiction
- MeSH terms
- Amphetamines, Animals, Anti-Inflammatory Agents, Anxiety, Behavior, Animal, Depression, Hallucinogens, Humans, Obsessive-Compulsive Disorder, Psilocybin, Receptor, Serotonin, 5-HT2A
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