Serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses. Compounds with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access. One short-acting psychedelic is 5-MeO-DMT, which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies. However, relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects. Here we characterized the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice. We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation. However, unlike psilocybin, 5-MeO-DMT did not affect the size of dendritic spines. These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin.
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The data that support the findings and the code used to analyze the data in this study are available at https://github.com/Kwan-Lab.
The data that support the findings and the code used to analyze the data in this study are available at https://github.com/Kwan-Lab.
Vollenweider FX, Preller KH. Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 2020;21:611–24.
Nutt D, Erritzoe D, Carhart-Harris R. Psychedelic psychiatry’s brave new World. Cell 2020;181:24–8.
Johnson MW, Griffiths RR. Potential therapeutic effects of psilocybin. Neurotherapeutics 2017;14:734–40.
Kelmendi B, Kaye AP, Pittenger C, Kwan AC. Psychedelics. Curr Biol. 2022;32:R63–R67.
Kwan AC, Olson DE, Preller KH, Roth BL. The neural basis of psychedelic action. Nat Neurosci. 2022;25:1407–19.
Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384:1402–11.
Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry. 2021;78:481–9.
Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. Lancet Psychiatry. 2016;3:619–27.
Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacol (Berl). 2004;172:145–56.
Reckweg J, Mason NL, van Leeuwen C, Toennes SW, Terwey TH, Ramaekers JG. 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. Front Pharm. 2021;12:760671.
Shulgin A, Shulgin A. TiHKAL: The Continuation. Transform Press: Berkeley, CA; 2002.
Davis AK, Barsuglia JP, Lancelotta R, Grant RM, Renn E. The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption. J Psychopharmacol. 2018;32:779–92.
Barsuglia J, Davis AK, Palmer R, Lancelotta R, Windham-Herman AM, Peterson K, et al. Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study. Front Psychol. 2018;9:2459.
Davis AK, So S, Lancelotta R, Barsuglia JP, Griffiths RR. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety. Am J Drug Alcohol Abus. 2019;45:161–9.
Uthaug MV, Lancelotta R, van Oorsouw K, Kuypers KPC, Mason N, Rak J, et al. 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. Psychopharmacol (Berl). 2019;236:2653–66.
Ermakova AO, Dunbar F, Rucker J, Johnson MW. A narrative synthesis of research with 5-MeO-DMT. J Psychopharmacol. 2021. 2698811211050543.
Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, et al. The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). J Neurochem. 2022;162:128–46.
Winter JC, Filipink RA, Timineri D, Helsley SE, Rabin RA. The paradox of 5-methoxy-N,N-dimethyltryptamine: An indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors. Pharmacol Biochem Behav. 2000;65:75–82.
Shen HW, Jiang XL, Winter JC, Yu AM. Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Curr Drug Metab. 2010;11:659–66.
Ray TS. Psychedelics and the human receptorome. PLoS One. 2010;5:e9019.
Savalia NK, Shao LX, Kwan AC. A dendrite-focused framework for understanding the actions of ketamine and psychedelics. Trends Neurosci. 2021;44:260–75.
Carhart-Harris RL, Nutt DJ. Serotonin and brain function: A tale of two receptors. J Psychopharmacol. 2017;31:1091–120.
Halberstadt AL, Koedood L, Powell SB, Geyer MA. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice. J Psychopharmacol. 2011;25:1548–61.
Dunlap LE, Azinfar A, Ly C, Cameron LP, Viswanathan J, Tombari RJ, et al. Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies. J Med Chem. 2020;63:1142–55.
Cameron LP, Patel SD, Vargas MV, Barragan EV, Saeger HN, Warren HT, et al. 5-HT2ARs mediate therapeutic behavioral effects of psychedelic tryptamines. ACS Chem Neurosci. 2023;14:351–58.
de Montigny C, Aghajanian GK. Preferential Action of 5-Methoxytryptamine and 5-Methoxydimethyltryptamine on Presynaptic Serotonin Receptors - Comparative Iontophoretic Study with Lsd and Serotonin. Neuropharmacology 1977;16:811–8.
Trulson ME, Jacobs BL. Effects of 5-methoxy-N,N-dimethyltryptamine on behavior and raphe unit activity in freely moving cats. Eur J Pharm. 1979;54:43–50.
Winne J, Boerner BC, Malfatti T, Brisa E, Doerl J, Nogueira I, et al. Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT. Exp Neurol. 2020;326:113175.
Lima da Cruz RV, Moulin TC, Petiz LL, Leao RN. A Single Dose of 5-MeO-DMT stimulates cell proliferation, neuronal survivability, morphological and functional changes in adult mice ventral dentate gyrus. Front Mol Neurosci. 2018;11:312.
Dakic V, Minardi Nascimento J, Costa Sartore R, Maciel RM, de Araujo DB, Ribeiro S, et al. Short-term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Sci Rep. 2017;7:12863.
Riga MS, Soria G, Tudela R, Artigas F, Celada P. The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs. Int J Neuropsychopharmacol. 2014;17:1269–82.
Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529.
Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006;26:7870–4.
Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex. 2006;16:313–20.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959–64.
Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro 2016;3:ENEURO.0133–15.2016.
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61.
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:eaat8078.
Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–44.e4.
Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics promote structural and functional neural plasticity. Cell Rep. 2018;23:3170–82.
Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P. Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci USA. 2009;106:19575–80.
Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci USA. 2021;118:e2022489118.
Raval NR, Johansen A, Donovan LL, Ros NF, Ozenne B, Hansen HD, et al. A single dose of psilocybin increases synaptic density and decreases 5-HT2A receptor density in the pig brain. Int J Mol Sci. 2021;22:835.
de la Fuente Revenga M, Zhu B, Guevara CA, Naler LB, Saunders JM, Zhou Z, et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 2021;37:109836.
Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021;589:474–79.
Sherwood AM, Claveau R, Lancelotta R, Kaylo KW, Lenoch K. Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use. ACS Omega. 2020;5:32067–75.
Halberstadt AL, Geyer MA. Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacol (Berl). 2013;227:727–39.
de la Fuente Revenga M, Vohra HZ, Gonzalez-Maeso J. Automated quantification of head-twitch response in mice via ear tag reporter coupled with biphasic detection. J Neurosci Methods. 2020;334:108595.
Castellucci GA, Calbick D, McCormick D. The temporal organization of mouse ultrasonic vocalizations. PLoS One. 2018;13:e0199929.
Fonseca AH, Santana GM, Bosque Ortiz GM, Bampi S, Dietrich MO. Analysis of ultrasonic vocalizations from mice using computer vision and machine learning. Elife. 2021;10:e59161.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.
Thevenaz P, Ruttimann UE, Unser M. A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process. 1998;7:27–41.
McKinney W. Data structures for statistical computing in Python. Proc. of the 9th Python in Science Conf. 2010;445:51–6.
Virtanen P, Gommers R, Oliphant TE, Haberland M, Reddy T, Cournapeau D, et al. SciPy 1.0: Fundamental algorithms for scientific computing in Python. Nat Methods. 2020;17:261–72.
Waskom M. seaborn: statistical data visualization. Journal of Open Source Software. 2021;6:3021.
Corne SJ, Pickering RW. A possible correlation between drug-induced hallucinations in man and a behavioural response in mice. Psychopharmacologia (Berl). 1967;11:65–78.
Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology 2020;167:107933.
Schmitz GP, Jain MK, Slocum ST, Roth BL. 5-HT2A SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics. ACS Chem Neurosci. 2022;13:2386–98.
Holy TE, Guo Z. Ultrasonic songs of male mice. PLoS Biol. 2005;3:e386.
Neunuebel JP, Taylor AL, Arthur BJ, Egnor SE. Female mice ultrasonically interact with males during courtship displays. Elife. 2015;4:e06203.
Davoudian PA, Shao LX, Kwan AC. Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin. ACS Chem Neurosci. 2023;14:468–80.
Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11:72.
Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 2000;28:41–51.
Holtmaat A, Bonhoeffer T, Chow DK, Chuckowree J, De Paola V, Hofer SB, et al. Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat Protoc. 2009;4:1128–44.
Yanni PA, Lindsley TA. Ethanol inhibits development of dendrites and synapses in rat hippocampal pyramidal neuron cultures. Brain Res Dev Brain Res. 2000;120:233–43.
Munoz-Cuevas FJ, Athilingam J, Piscopo D, Wilbrecht L. Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference. Nat Neurosci. 2013;16:1367–9.
Kasai H, Matsuzaki M, Noguchi J, Yasumatsu N, Nakahara H. Structure–stability–function relationships of dendritic spines. Trends Neurosci. 2003;26:360–8.
Holler S, Kostinger G, Martin KAC, Schuhknecht GFP, Stratford KJ. Structure and function of a neocortical synapse. Nature 2021;591:111–16.
Jurgens U. Neural pathways underlying vocal control. Neurosci Biobehav Rev. 2002;26:235–58.
Tschida K, Michael V, Takatoh J, Han BX, Zhao S, Sakurai K, et al. A Specialized Neural Circuit Gates Social Vocalizations in the Mouse. Neuron 2019;103:459–72.e4.
Lefler Y, Campagner D, Branco T. The role of the periaqueductal gray in escape behavior. Curr Opin Neurobiol. 2020;60:115–21.
Fish EW, Sekinda M, Ferrari PF, Dirks A, Miczek KA. Distress vocalizations in maternally separated mouse pups: modulation via 5-HT(1A), 5-HT(1B) and GABA(A) receptors. Psychopharmacol (Berl). 2000;149:277–85.
Takahashi A, Yap JJ, Bohager DZ, Faccidomo S, Clayton T, Cook JM, et al. Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups. Psychopharmacol (Berl). 2009;204:61–71.
Budylin T, Guariglia SR, Duran LI, Behring BM, Shaikh Z, Neuwirth LS, et al. Ultrasonic vocalization sex differences in 5-HT(1A)-R deficient mouse pups: Predictive phenotypes associated with later-life anxiety-like behaviors. Behav Brain Res. 2019;373:112062.
Cao D, Yu J, Wang H, Luo Z, Liu X, He L, et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science 2022;375:403–11.
Kaplan AL, Confair DN, Kim K, Barros-Alvarez X, Rodriguiz RM, Yang Y, et al. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity. Nature. 2022;610:582–91.
We thank Ling-Xiao Shao for advice on imaging, Neil Savalia for advice on statistical analyses, Gregg Castellucci and Katherine Tschida for advice on measuring ultrasonic vocalizations, Antonio Fonseca for advice on the VocalMat software, and Janghoo Lim for loaning equipment for recording ultrasonic vocalizations. 5-MeO-DMT-succinate was generously provided by Usona Institute’s Investigational Drug & Material Supply Program; the Usona Institute IDMSP is supported by Alexander Sherwood, Robert Kargbo, and Kristi Kaylo in Madison, WI. The behavioral experiments were supported by the Yale Program in Psychedelic Science, NIH/NIMH grant R01MH121848 (A.C.K.), NIH/NIMH grant R01MH128217 (A.C.K.), One Mind – COMPASS Rising Star Award (A.C.K.), and NIH/NIGMS medical scientist training grant T32GM007205 (P.A.D.). The imaging experiments were supported by a sponsored research project from Freedom Biosciences (C.P., S.J.J.), NIH/NINDS training grant T32NS041228 (C.L.), China Scholarship Council-Yale World Scholars Fellowship (H.W.), and NIH/NIMH training grant T32MH019961 (S.J.J.).
ACK is a member of the Scientific Advisory Board of Empyrean Neuroscience and Freedom Biosciences. ACK has consulted for Biohaven Pharmaceuticals. No-cost compounds were provided to ACK for research by Usona Institute. CP has served as a consultant in the past year for Biohaven Pharmaceuticals, Teva Pharmaceuticals, and Brainsway Therapeutics and has performed research under contract with Biohaven and with Blackthorn Therapeutics, Ltd., on unrelated projects. CP and APK have performed research under contract with Transcend Therapeutics on unrelated projects. CP and SJJ have a sponsored research agreement with Freedom Biosciences. The sponsor of this research was not involved in the analyses or writing of the manuscript. The duties had no influence on the content of this article. The remaining authors have nothing to disclose.
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Jefferson, S.J., Gregg, I., Dibbs, M. et al. 5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice. Neuropsychopharmacol. 48, 1257–1266 (2023). https://doi.org/10.1038/s41386-023-01572-w
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