Treatment-Resistant Depression (TRD)Depressive DisordersAnxiety Disorders5-MeO-DMT

5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

This review (2023) of 5-MeO-DMT, a tryptamine with unique antidepressant potential, notes its distinct effects compared to typical psychedelics. It draws parallels between 5-MeO-DMT's effects and epileptiform activity, particularly through 5-HT1A receptor interactions, suggesting its therapeutic action may resemble electroconvulsive therapy (ECT).

Authors

  • Otto Simonsson
  • Peter Hendricks
  • Robin Carhart-Harris

Published

Psychopharmacology
meta Study

Abstract

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mecha-nism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by reviewing aberrant 5-HT1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT1A receptor agonist properties-and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform activity, suggesting a similarity to electroconvulsive therapy. It is also noted that “reactivations,” the sudden re-experiencing of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms in research settings and among naturalistic users are warranted.

Available with Blossom Pro

Research Summary of '5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?'

Introduction

5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is a tryptamine found in several plants and in the secretions of the Incilius alvarius toad that is most commonly vaporised and inhaled in naturalistic spiritual and recreational contexts. Dourron and colleagues situate 5-MeO-DMT as an "atypical" psychedelic because, unlike classic psychedelics whose actions are largely attributed to 5-HT2A receptor agonism, the compound shows comparatively low affinity at 5-HT2A (reported Ki ~907 nM) and much higher affinity at 5-HT1A (reported Ki ~3.0 nM). Interest in 5-MeO-DMT has grown because short inhaled sessions (15–30 minutes) could offer a more scalable therapeutic model than longer-acting agents such as psilocybin, and early naturalistic and open-label data suggest potential anxiolytic and antidepressant effects, including in treatment‑resistant depression. This review paper aims to delineate how 5-MeO-DMT's pharmacology, acute and post-acute phenomenology, and adverse-event profile may differ from typical psychedelics, and to propose a novel hypothesis: some of 5-MeO-DMT's distinctive effects and its relatively frequent reports of post-acute "reactivations" might reflect transient epileptiform activity, particularly in medial temporal lobe regions where 5-HT1A receptors are relatively concentrated. The authors argue that clarifying these potential mechanisms is important both for safety monitoring and for optimising therapeutic development, and they call for targeted preclinical and human research to test their proposal.

Expert Research Summaries

Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.

See Pro PlansAlready have an account? Sign in

Study Details

References (51)

Papers cited by this study that are also in Blossom

The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms

Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)

Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin

Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)

Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study

Barsuglia, J. P., Davis, A. K., Palmer, R. et al. · Frontiers in Psychology (2018)

Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

Becker, A. M., Holze, F., Grandinett, T. et al. · Clinical Pharmacology and Therapeutics (2021)

Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

Cameron, L. P., Benson, C. J., Dunlap, L. E. · ACS Chemical Neuroscience (2018)

Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences

Carbonaro, T. M., Bradstreet, M. P., Barrett, F. S. et al. · Journal of Psychopharmacology (2016)

Serotonin and brain function: a tale of two receptors

Carhart-Harris, R. L., Nutt, D. J. · Journal of Psychopharmacology (2017)

A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: results from a randomized, controlled laboratory study

Dakwar, E., Nunes, E. V., Hart, C. L. et al. · Neuropharmacology (2018)

72 cited
The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption

Davis, A. K., Barsuglia, J. P., Lancelotta, R. et al. · Journal of Psychopharmacology (2018)

Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effects

Davis, A. K., Clifton, J. M., Weaver, E. G. et al. · Journal of Psychopharmacology (2020)

Show all 51 references
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety

Davis, A. K., So, S., Lancelotta, R. et al. · The American Journal of Drug and Alcohol Abuse (2019)

113 cited
Self-Entropic Broadening Theory: Toward a New Understanding of Self and Behavior Change Informed by Psychedelics and Psychosis

Dourron, H. M., Strauss, C., Hendricks, P. S. · Pharmacological Reviews (2022)

A narrative synthesis of research with 5-MeO-DMT

Ermakova, A. O., Dunbar, F., Rucker, J. et al. · Journal of Psychopharmacology (2021)

Flashbacks and HPPD: A Clinical-oriented Concise Review

Lerner, A. G. · The Israel Journal of Psychiatry and Related Sciences; Jerusalem (2014)

Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences

Gashi, L., Sandberg, S., Pedersen, W. · International Journal of Drug Policy (2021)

Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life

Goodwin, G. M. · Journal of Affective Disorders (2023)

Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers

Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A. et al. · Pharmacopsychiatry (2005)

187 cited
Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Holze, F., Ley, L., Müller, F. et al. · Neuropsychopharmacology (2022)

169 cited
Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)

214 cited
Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function

Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)

Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review

Knight, G., Rucker, J., Cleare, A. J. et al. · Frontiers in Psychiatry (2022)

Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects

Lancelotta, R., Davis, A. K. · Journal of Psychoactive Drugs (2020)

Phenomenology and Content of the Inhaled N, N-Dimethyltryptamine (N, N-DMT) Experience

Lawrence, D. W., Carhart-Harris, R. L., Griffiths, R. R. et al. · Research Square (2022)

Does getting high hurt? Characterization of cases of LSD and psilocybin-containing mushroom exposures to national poison centers between 2000 and 2016

Leonard, J. B., Klein-Schwartz, W. · Journal of Psychopharmacology (2018)

53 cited
Alterations of consciousness and mystical-type experiences after acute LSD in humans

Liechti, M. E., Dolder, P. C., Schmid, Y. · Psychopharmacology (2016)

190 cited
A Single Dose of 5-MeO-DMT Stimulates Cell Proliferation, Neuronal Survivability, Morphological and Functional Changes in Adult Mice Ventral Dentate Gyrus

Lima da Cruz, R. V., Moulin, T. C., Petiz, L. L. et al. · Frontiers in Molecular Neuroscience (2018)

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)

Psychedelics, meditation, and self-consciousness

Milliere, R., Carhart-Harris, R. L., Roseman, L. et al. · Frontiers in Psychology (2018)

Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants

Müller, F., Holze, F., Becker, A. M. et al. · Psychopharmacology (2022)

Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports

Nayak, S., Gukasyan, N., Barrett, F. S. et al. · Pharmacopsychiatry (2021)

Psychedelics

Nichols, D. E. · Pharmacological Reviews (2016)

Tripping on nothing: placebo psychedelics and contextual factors

Olson, J. A., Suissa-Rocheleau, L., Lifshitz, M. et al. · Psychopharmacology (2020)

The adverse events of ibogaine in humans: an updated systematic review of the literature (2015-2020)

Ona, G., Rocha, J. M., Bouso, J. C. et al. · Psychopharmacology (2021)

Reactivations after 5-methoxy-N,N-dimethyltryptamine use in naturalistic settings: An initial exploratory analysis of the phenomenon’s predictors and its emotional valence

Ortiz Bernal, A. M., Raison, C. L., Lancelotta, R. et al. · Frontiers in Psychiatry (2022)

Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience

Peill, J. M., Trinci, K. E., Kettner, H. et al. · Journal of Psychopharmacology (2022)

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

Pokorny, T., Preller, K. H., Kraehenmann, R. et al. · European Neuropsychopharmacology (2016)

103 cited
Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)

A phase 1, dose-ranging study to assess safety and psychoactive effects of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in healthy volunteers

Reckweg, J., Mason, N. L., van Leeuwen, C. et al. · Frontiers in Pharmacology (2021)

The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)

Reckweg, J., Uthaug, M. V., Szabo, A. et al. · Journal of Neurochemistry (2022)

A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression

Reckweg, J., van Leeuwen, C., Theunissen, E. L. et al. · Frontiers in Psychiatry (2023)

62 cited
Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)

Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial

Rothberg, R. L., Azhari, N., Haug, N. A. et al. · Journal of Psychopharmacology (2020)

Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions

Shen, H. W., Jiang, X. L., Winter, J. C. et al. · Current Drug Metabolism (2010)

Psychometric evaluation of the altered states of consciousness rating scale (OAV)

Studerus, E., Gamma, A., Vollenweider, F. X. · PLOS ONE (2010)

Toxicities Associated With NBOMe Ingestion-A Novel Class of Potent Hallucinogens: A Review of the Literature

Suzuki, J., Dekker, M. A., Valenti, E. S. et al. · Psychosomatics (2014)

DMT models the near-death experience

Timmermann, C., Roseman, L., Williams, L. et al. · Frontiers in Psychology (2018)

Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment

Uthaug, M. V., Lancelotta, R., Szabo, A. et al. · Psychopharmacology (2019)

86 cited
A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms

Uthaug, M. V., Lancelotta, R., van Oorsouw, K. et al. · Psychopharmacology (2019)

145 cited
On Perception and Consciousness in HPPD: A Systematic Review

Ermentrout, G. B., Vis, P. J., Goudriaan, A. E. et al. · Frontiers in Neuroscience (2021)

Safety pharmacology of acute MDMA administration in healthy subjects

Vizeli, P., Liechti, M. E. · Journal of Psychopharmacology (2017)

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants

Vogt, S. B., Ley, L., Erne, L. et al. · Translational Psychiatry (2023)

64 cited

Cited By (2)

Papers in Blossom that reference this study

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

Aarrestad, I. K., Cameron, L. P., Fenton, E. M. et al. · Nature Neuroscience (2025)

Complex slow waves in the human brain under 5-MeO-DMT

Blackburne, G., Mcalpine, R. G., Fabus, M. et al. · Cell Reports (2025)

Your Personal Research Library

Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.

See Pro PlansSign in
5-MeO-DMT: An atypical psychedelic with unique... — Research Summary & Context | Blossom