Serotonin toxicity of serotonergic psychedelics
Abstract
Rationale In recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents.Objectives A critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies.Results True ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity.Conclusions Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Psilocybin shows a lower risk of serotonin toxicity compared to other psychedelics.
“Regarding possible serotonin toxicity, psilocybin shows a lower risk compared to other psychedelics. 41”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [41]
Cites
2 retracted
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05249-5 · Cited by 359 · see citing works
RetractedFeduccia, A. A., Jerome, L., Mithoefer, M. C., & Holland, J. (2021) · Psychopharmacology · doi:10.1007/s00213-020-05710-w · Cited by 40 · see citing works
RetractedBoyer, E. W., & Shannon, M. (2005) · New England Journal of Medicine · doi:10.1056/nejmra041867 · Cited by 1,821 · see citing works
Nichols, D. E. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011478 · Cited by 1,762 · see citing works
Sternbach, H. A. (1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.6.705 · Cited by 1,349 · see citing works
Nichols, D. E. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2003.11.002 · Cited by 1,211 · see citing works
Dunkley, E. J. C., Isbister, G. K., Sibbritt, D. W., Dawson, A. H., & Whyte, I. M. (2003) · QJM · doi:10.1093/qjmed/hcg109 · Cited by 1,032 · see citing works
The neurobiology of psychedelic drugs: implications for the treatment of mood disorders
Vollenweider, F. X., & Kometer, M. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2884 · Cited by 723 · see citing works
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881110378371 · Cited by 674 · see citing works
Shulgin, A. T., & Shulgin, A. (1991) · Cited by 668 · see citing works
Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity
Gillman, P. K. (2005) · British Journal of Anaesthesia · doi:10.1093/bja/aei210 · Cited by 399 · see citing works
Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens
Rickli, A., Moning, O. D., Hoener, M. C., & Liechti, M. E. (2016) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2016.05.001 · Cited by 379 · see citing works
Kehr, J., Ichinose, F., Yoshitake, S., Goiny, M., Sievertsson, T., Nyberg, F., & Yoshitake, T. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01499.x · Cited by 312 · see citing works
Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions
Scotton, W. J., Hill, L. J., Williams, A. C., & Barnes, N. M. (2019) · International Journal of Tryptophan Research · doi:10.1177/1178646919873925 · Cited by 267 · see citing works
Gudelsky, G. A., & Nash, J. F. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66010243.x · Cited by 252 · see citing works
Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids.
Gable, R. S. (2007) · Addiction · doi:10.1111/j.1360-0443.2006.01652.x · Cited by 244 · see citing works
Modern clinical research on LSD
Liechti, M. E. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.86 · Cited by 236 · see citing works
Rickli, A., Luethi, D., Reinisch, J., Buchy, D., Hoener, M. C., & Liechti, M. E. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.08.034 · Cited by 215 · see citing works
Shulgin, A. T., & Shulgin, A. (1997) · Cited by 198 · see citing works
Buckholtz, N. S., & Boggan, W. O. (1977) · Biochemical Pharmacology · doi:10.1016/0006-2952(77)90007-7 · Cited by 185 · see citing works
Shen, H.-W., Jiang, X.-L., C. Winter, J., & Yu, A.-M. (2010) · Current Drug Metabolism · doi:10.2174/138920010794233495 · Cited by 170 · see citing works
Kurrasch‐Orbaugh, D. M., Watts, V. J., Barker, E. L., & Nichols, D. E. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.042184 · Cited by 166 · see citing works
Bonson, K. R. (1996) · Neuropsychopharmacology · doi:10.1016/0893-133x(95)00145-4 · Cited by 157 · see citing works
Hysek, C. M., Simmler, L. D., Nicola, V. G., Vischer, N., Donzelli, M., Krähenbühl, S., Grouzmann, E., Huwyler, J., Hoener, M. C., & Liechti, M. E. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036476 · Cited by 157 · see citing works
Liechti, M. E., & Vollenweider, F. X. (2000) · Journal of Psychopharmacology · doi:10.1177/026988110001400313 · Cited by 144 · see citing works
Sklerov, J., Levine, B., Moore, K. A., King, T., & Fowler, D. (2005) · Journal of Analytical Toxicology · doi:10.1093/jat/29.8.838 · Cited by 144 · see citing works
Pharmahuasca: Human Pharmacology of Oral DMT Plus Harmine
Ott, J. (1999) · Journal of Psychoactive Drugs · doi:10.1080/02791072.1999.10471741 · Cited by 140 · see citing works
Callaway, J. C., & Grob, C. S. (1998) · Journal of Psychoactive Drugs · doi:10.1080/02791072.1998.10399712 · Cited by 137 · see citing works
Clinical Guidelines for the Treatment of Depressive Disorders VII. Comorbidity
Enns, M. W., Swenson, J. R., McIntyre, R. S., Swinson, R. P., Kennedy, S. H., & The CANMAT Depression Work Group (2001) · The Canadian Journal of Psychiatry · doi:10.1177/070674372001460101007 · Cited by 136 · see citing works
Triptans, Serotonin Agonists, and Serotonin Syndrome (Serotonin Toxicity): A Review
Gillman, P. K. (2009) · Headache The Journal of Head and Face Pain · doi:10.1111/j.1526-4610.2009.01575.x · Cited by 135 · see citing works
Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects
Dolder, P. C., Schmid, Y., Steuer, A. E., Kraemer, T., Rentsch, K. M., Hammann, F., & Liechti, M. E. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0513-9 · Cited by 133 · see citing works
Suzuki, J., Dekker, M. A., Valenti, E. S., Cruz, F. A., Correa, A. M., Poklis, J. L., & Poklis, A. (2014) · Psychosomatics · doi:10.1016/j.psym.2014.11.002 · Cited by 125 · see citing works
Hyperthermia in Psychostimulant Overdose
Callaway, C. W., & Clark, R. F. (1994) · Annals of Emergency Medicine · doi:10.1016/s0196-0644(94)70165-2 · Cited by 124 · see citing works
Over 30 million psychedelic users in the United States
Krebs, T. S., & Johansen, P.-Ø. (2013) · F1000Research · doi:10.12688/f1000research.2-98.v1 · Cited by 124 · see citing works
Monoamine Oxidase Inhibitor Poisoning Resulting from Internet Misinformation on Illicit Substances
Brush, D. E., Bird, S. B., & Boyer, E. W. (2004) · Journal of Toxicology Clinical Toxicology · doi:10.1081/clt-120030949 · Cited by 120 · see citing works
Death following ingestion of MDMA (ecstasy) and moclobemide
Vuori, E., Henry, J. A., Ojanperä, I. A., Nieminen, R., Savolainen, T., Wahlsten, P., & Jäntti, M. (2003) · Addiction · doi:10.1046/j.1360-0443.2003.00292.x · Cited by 114 · see citing works
Chemistry and Structure–Activity Relationships of Psychedelics
Nichols, D. E. (2017) · Current topics in behavioral neurosciences · doi:10.1007/7854_2017_475 · Cited by 114 · see citing works
Tancer, M., & Johanson, C.-E. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0576-z · Cited by 113 · see citing works
Farré, M., Abanades, S., Roset, P. N., Peiró, A. M., Torrens, M., O'Mathúna, B., Segura, M., & de la Torre, R. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.129056 · Cited by 113 · see citing works
Pharmacological profile of mephedrone analogs and related new psychoactive substances
Luethi, D., Kolaczynska, K. E., Docci, L., Krähenbühl, S., Hoener, M. C., & Liechti, M. E. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.07.026 · Cited by 106 · see citing works
Dantrolene in the treatment of MDMA-related hyperpyrexia: a systematic review
Grunau, B. E., Wiens, M. O., & Brubacher, J. R. (2010) · Canadian Journal of Emergency Medicine · doi:10.1017/s1481803500012598 · Cited by 104 · see citing works
MDMA and temperature: A review of the thermal effects of ‘Ecstasy’ in humans
Parrott, A. C. (2011) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2011.08.012 · Cited by 89 · see citing works
Nichols, D. E., & Grob, C. S. (2018) · Forensic Science International · doi:10.1016/j.forsciint.2018.01.006 · Cited by 89 · see citing works
Leonard, J. B., Anderson, B. D., & Klein‐Schwartz, W. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881118793086 · Cited by 89 · see citing works
Effect fingerprinting of new psychoactive substances (NPS): What can we learn from in vitro data?
Hondebrink, L., Zwartsen, A., & Westerink, R. H. S. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.022 · Cited by 80 · see citing works
Deconstructing Ecstasy: The Politics Of Mdma Research
Grob, C. S. (2000) · Addiction Research & Theory · doi:10.3109/16066350008998989 · Cited by 79 · see citing works
Coma, Hyperthermia, and Bleeding Associated with Massive LSD Overdose a Report of Eight Cases
Klock, J., Boerner, U., & Becker, C. E. (1975) · Clinical Toxicology · doi:10.3109/15563657508988063 · Cited by 78 · see citing works
Bonson, K. R., & Murphy, D. L. (1995) · Behavioural Brain Research · doi:10.1016/0166-4328(96)00102-7 · Cited by 76 · see citing works
Psilocybin-Assisted Therapy: A Review of a Novel Treatment for Psychiatric Disorders
Thomas, K., Malcolm, B., & Lastra, D. (2017) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2017.1320734 · Cited by 75 · see citing works
Self-citationNeuroleptic malignant syndrome and serotonin syndrome
Tormoehlen, L. M., & Rusyniak, D. E. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64074-1.00039-2 · Cited by 61 · see citing works
Parrott, A. C. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01941.x · Cited by 51 · see citing works
Rapid detection of NBOME's and other NPS on blotter papers by direct ATR-FTIR spectrometry
Neto, J. C. (2015) · Forensic Science International · doi:10.1016/j.forsciint.2015.04.025 · Cited by 50 · see citing works
Drug-Induced Serotonin Syndrome
Bartlett, D. (2017) · Critical Care Nurse · doi:10.4037/ccn2017169 · Cited by 50 · see citing works
Ayahuasca Exposure: Descriptive Analysis of Calls to US Poison Control Centers from 2005 to 2015
Heise, C. W., & Brooks, D. E. (2016) · Journal of Medical Toxicology · doi:10.1007/s13181-016-0593-1 · Cited by 48 · see citing works
Serotonin toxicity involving MDMA (ecstasy) and moclobemide
Pilgrim, J. L., Gerostamoulos, D., Woodford, N. W. F., & Drummer, O. H. (2011) · Forensic Science International · doi:10.1016/j.forsciint.2011.04.008 · Cited by 45 · see citing works
Controversies in Serotonin Syndrome Diagnosis and Management: A Review
Uddin, M. F. (2017) · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · doi:10.7860/jcdr/2017/29473.10696 · Cited by 40 · see citing works
Extreme Hyperthermia After LSD Ingestion
Friedman, S. A. (1971) · JAMA · doi:10.1001/jama.1971.03190110067020 · Cited by 36 · see citing works
Mescaline: the chemistry and pharmacology of its analogs.
Shulgin, A. T. (1973) · PubMed · Cited by 34 · see citing works
Batisse, A., Grégoire, M., Marillier, M., et al. (2016) · L Encéphale · doi:10.1016/j.encep.2015.09.002 · Cited by 33 · see citing works
MDMA and Seizures: A Dangerous Liaison?
Giorgi, F. S., Lazzeri, G., Natale, G., Iudice, A., Ruggieri, S. A., Paparelli, A., Murri, L., & Fornai, F. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1369.035 · Cited by 32 · see citing works
Bruggisser, M., Bodmer, M., Wilks, M. F., Kupferschmidt, H., & Liechti, M. E. (2010) · Swiss Medical Weekly · doi:10.4414/smw.2010.13115 · Cited by 31 · see citing works
In Vitro Screening of Psychoactive Drugs by [35S]GTP.GAMMA.S Binding in Rat Brain Membranes
Nonaka, R., Nagai, F., Ogata, A., & Satoh, K. (2007) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.30.2328 · Cited by 30 · see citing works
Jiang, X.-L., Shen, H.-W., Mager, D. E., & Yu, A. (2013) · Drug Metabolism and Disposition · doi:10.1124/dmd.112.050724 · Cited by 29 · see citing works
Ayahuasca: An ancient sacrament for treatment of contemporary psychiatric illness?
Malcolm, B., & Lee, K. C. (2017) · Mental Health Clinician · doi:10.9740/mhc.2017.01.039 · Cited by 29 · see citing works
Self-citationEffects of "Ecstasy" Blocked by Serotonin Reuptake Inhibitors
Stein, D. J., & Rink, J. (1999) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v60n0711a · Cited by 24 · see citing works
Cactus alkaloids. XXXVI. Mescaline and related compounds from Trichocereus peruvianus.
Jh, P., Jl, M., Rw, K., et al. (1978) · PubMed · Cited by 19 · see citing works
Analysis of 25 C NBOMe in Seized Blotters by HPTLC and GC–MS
Duffau, B. E., Camargo, C., Kogan, M. J., et al. (2016) · Journal of Chromatographic Science · doi:10.1093/chromsci/bmw095 · Cited by 19 · see citing works
Culbertson, V. L., Rahman, S. E., Bosen, G. C., Caylor, M. L., Echevarria, M. M., & Xu, D. Q. (2018) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.2163 · Cited by 19 · see citing works
McManus, D. J., Mousseau, D. D., Paetsch, P. R., et al. (1991) · Biological Psychiatry · doi:10.1016/0006-3223(91)90182-l · Cited by 17 · see citing works
The Spectrum Concept of Serotonin Toxicity
Gillman, P. K. (2004) · Pain Medicine · doi:10.1111/j.1526-4637.2004.04033.x · Cited by 16 · see citing works
Serotonin syndrome: a spectrum of toxicity
Ellahi, R. (2015) · BJPsych Advances · doi:10.1192/apt.bp.114.013037 · Cited by 15 · see citing works
“Much ado about nothing”: monoamine oxidase inhibitors, drug interactions, and dietary tyramine
Gillman, P. K. (2017) · CNS Spectrums · doi:10.1017/s1092852916000651 · Cited by 15 · see citing works
The risks of monoamine oxidase inhibitors in the treatment of bronchial asthma
Mathov, E. (1963) · Journal of Allergy · doi:10.1016/0021-8707(63)90089-3 · Cited by 14 · see citing works
Yu, C., Tran, H. T. N., Saber, Y., et al. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172912 · Cited by 13 · see citing works
Mirtazapine: Unable to Induce Serotonin Toxicity?
Gillman, P. K. (2003) · Clinical Neuropharmacology · doi:10.1097/00002826-200311000-00003 · Cited by 12 · see citing works
Bupropion, Bayesian Logic and Serotonin Toxicity
Gillman, P. K. (2010) · Journal of Medical Toxicology · doi:10.1007/s13181-010-0084-8 · Cited by 11 · see citing works
Schindler, E. A. D., Harvey, J. A., & Aloyo, V. J. (2012) · Brain Research · doi:10.1016/j.brainres.2012.10.057 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Becker, A. M., Holze, F., Grandinetti, T., Klaiber, A., Toedtli, V. E., Kolaczynska, K. E., Duthaler, U., Varghese, N., Eckert, A., Grünblatt, E., et al. (2022) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2487 · Cited by 184 · see citing works
Sloshower, J., Skosnik, P. D., Safi-Aghdam, H., Pathania, S., Syed, S., Pittman, B., & D’Souza, D. C. (2023) · Journal of Psychopharmacology · doi:10.1177/02698811231154852 · Cited by 165 · see citing works
Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review
Sarparast, A., Thomas, K., Malcolm, B., & Stauffer, C. S. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06083-y · Cited by 88 · see citing works
Self-citationBender, D., & Hellerstein, D. J. (2022) · Psychopharmacology · doi:10.1007/s00213-021-06049-6 · Cited by 88 · see citing works
Morton, E., Sakai, K., Ashtari, A., Pleet, M., Michalak, E. E., & Woolley, J. (2023) · Journal of Psychopharmacology · doi:10.1177/02698811221131997 · Cited by 78 · see citing works
Sloshower, J., Zeifman, R. J., Guss, J., Krause, R., Safi-Aghdam, H., Pathania, S., Pittman, B., & D’Souza, D. C. (2024) · Scientific Reports · doi:10.1038/s41598-024-58318-x · Cited by 65 · see citing works
“Since medications commonly used in this population (e.g., serotonergic antidepressants) can interfere with the effects of psilocybin 59 , participants were required to be off any conventional antidepressant or antipsychotic medications for at least 2 weeks prior to study enrollment (or four weeks…”
BackgroundCalder, A. E., Rausch, B., Liechti, M. E., Holze, F., & Hasler, G. (2024) · Journal of Psychopharmacology · doi:10.1177/02698811241278873 · Cited by 20 · see citing works
Scala, M., Fabbri, C., Fusar-Poli, P., Di Lorenzo, G., Ferrara, M., Amerio, A., Fusar-Poli, L., Pichiecchio, A., Asteggiano, C., Menchetti, M., et al. (2024) · CNS Spectrums · doi:10.1017/s1092852924002268 · Cited by 9 · see citing works
“41 Both psychedelic effects and serotonin syndrome are associated with an increase in 5-HT 2A neurotransmission 42,43 that is responsible for transient serotonin-related symptoms such as nausea, anxiety, hypertension, tachycardia, visual deficits, motor incoordination, and mild tremors, even at…”
- Authors
- Malcolm, B., & Thomas, K.
- Affiliations
- Touro University California (US)
- Corresponding author
- Malcolm, Benjamin
- Venue
- Psychopharmacology
- Published
- 2021-07-12
- Volume
- 239
- Issue
- 6
- Pages
- 1881-1891
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W3182695044
- Cited by
- 138
- References
- 77
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 44 · 2023: 34 · 2022: 17 · 2021: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- serotonin syndrome, serotonergic psychedelics, drug-drug interactions, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, psychedelic therapy, adverse drug reactions, hyperthermia, myoclonus, seizure activity
- MeSH terms
- Hallucinogens, Humans, Monoamine Oxidase Inhibitors, Serotonin, Selective Serotonin Reuptake Inhibitors, Serotonin Agents
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
