Psychedelic drug

{{Short description|Hallucinogenic class of psychoactive drug}} {{Redirect|Psychedelic|other uses|Psychedelic (disambiguation)}} {{broader|Hallucinogen}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug class | Name = Psychedelic | Image = File:Psilocybin, Kekulé, skeletal formula of canonical psilocybin.svg | ImageClass = skin-invert-image | Alt = | Caption = Chemical structure of psilocybin, the main active constituent of psilocybin-containing mushrooms and one of the most well-known serotonergic psychedelics. | Width = 200px | Pronounce = | Synonyms = Serotonergic psychedelic; Classical psychedelic; Classical hallucinogen; Serotonergic hallucinogen; Psychotomomimetic; Entheogen  | Use = Recreational, spiritual, medical, microdosing | ATC_prefix = | Mode_of_action = | Mechanism_of_action = Serotonin 5-HT2A receptor agonism | Biological_target = Serotonin 5-HT2A receptor | Chemical_class = Tryptamines; Phenethylamines; Lysergamides; Others  | Drugs.com =  | Consumer_Reports = | medicinenet = | rxlist = | rxlist_name =  | MeshID =  | legal_status = Variable }} {{Psychedelic sidebar}}

'''Psychedelics''' are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness".<ref name="Aghajanian, G 16S–23S">{{cite journal|author=Aghajanian, G|date=August 1999|title=Serotonin and Hallucinogens|journal=Neuropsychopharmacology|volume=21|issue=2|pages=16S–23S|doi=10.1016/S0893-133X(98)00135-3|pmid=10432484|doi-access=free}}</ref><ref name="psych-meditation-self">{{cite journal |last1=Millière |first1=Raphaël |last2=Carhart-Harris |first2=Robin L. |last3=Roseman |first3=Leor |last4=Trautwein |first4=Fynn-Mathis |last5=Berkovich-Ohana |first5=Aviva |title=Psychedelics, Meditation, and Self-Consciousness |journal=Frontiers in Psychology |date=2018 |volume=9 |article-number=1475 |doi=10.3389/fpsyg.2018.01475 |pmid=30245648 |pmc=6137697|doi-access=free }}</ref> Also referred to as '''classic hallucinogens''' or '''serotonergic hallucinogens''', the term ''psychedelic'' is sometimes used more broadly to include various other types of hallucinogens as well, such as those which are atypical or adjacent to psychedelia like ketamine and MDMA, respectively.<ref name="McClure 2022">{{cite journal |title=The promises and perils of psychedelic pharmacology for psychiatry |journal=Nature Reviews Drug Discovery |year=2022 |last1=McClure-Begley |first1=Tristan D. |last2=Roth |first2=Bryan L. |volume=21 |issue=6 |pages=463–473 |pmid=35301459 |doi=10.1038/s41573-022-00421-7 |s2cid=247521633 |url=https://www.nature.com/articles/s41573-022-00421-7 |access-date=2024-02-08 }}</ref>

Classic psychedelics generally cause specific psychological, visual, and auditory changes, and oftentimes a substantially altered state of consciousness.<ref name="Nichols2004" /><ref name="Nichols2016" /><ref name="dmt-nde"/><ref name="Griffiths">{{cite journal | title = Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance | journal = Psychopharmacology | date = 7 July 2006 | author = R. R. Griffiths |author2=W. A. Richards |author3=U. McCann |author4=R. Jesse | volume = 187 | issue = 3 | pages = 268–283| doi=10.1007/s00213-006-0457-5 | pmid=16826400| s2cid = 7845214 }}</ref> They have had the largest influence on science and culture, and include mescaline, LSD, psilocybin, and DMT.<ref>McKenna, Terence (1992). ''Food of the Gods: The Search for the Original Tree of Knowledge A Radical History of Plants, Drugs, and Human Evolution''</ref><ref>W. Davis (1996), ''One River: Explorations and Discoveries in the Amazon Rain Forest''. New York, Simon and Schuster, Inc. p. 120.</ref> There are a large number of both naturally occurring and synthetic serotonergic psychedelics.<ref name="KelmendiKayePittenger2022">{{cite journal | vauthors = Kelmendi B, Kaye AP, Pittenger C, Kwan AC | title = Psychedelics | journal = Curr Biol | volume = 32 | issue = 2 | pages = R63–R67 | date = January 2022 | pmid = 35077687 | pmc = 8830367 | doi = 10.1016/j.cub.2021.12.009 | bibcode = 2022CBio...32..R63K | url = https://alexkwanlab.org/wp-content/uploads/2022/01/kelmendiCurrBiol2022.pdf}}</ref><ref name="KwanOlsonPreller2022">{{cite journal | vauthors = Kwan AC, Olson DE, Preller KH, Roth BL | title = The neural basis of psychedelic action | journal = Nat Neurosci | volume = 25 | issue = 11 | pages = 1407–1419 | date = November 2022 | pmid = 36280799 | pmc = 9641582 | doi = 10.1038/s41593-022-01177-4 | url = https://alexkwanlab.org/wp-content/uploads/2022/11/kwanNatNeurosci2022.pdf}}</ref>

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides. They produce their psychedelic effects by binding to and activating a receptor in the brain called the serotonin 5-HT2A receptor, and hence are a type of serotonin 5-HT2A receptor agonist.<ref name="Aghajanian, G 16S–23S"/><ref name="psychedelicreview.com">{{Cite web|date=2020-10-05|title=Crystal Structure of LSD and 5-HT2AR Part 2: Binding Details and Future Psychedelic Research Paths|url=https://psychedelicreview.com/crystal-structure-of-lsd-and-5-ht2ar-part-2-binding-details-and-future-psychedelic-research-paths/|access-date=2021-02-12|website=Psychedelic Science Review|language=en-US}}</ref><ref name="Nichols2018" /><ref name="Nichols2016">{{Cite journal | last = Nichols | first = David E. | date = 2016 | title = Psychedelics | journal = Pharmacological Reviews | language = en | volume = 68 | issue = 2 | pages = 264–355 | doi = 10.1124/pr.115.011478 | issn = 0031-6997 | pmc = 4813425 | pmid = 26841800 }}</ref><ref name="McClure 2022" /> By activating serotonin 5-HT2A receptors,<ref>{{Cite book |date=11 November 2005 |title=Basic neurochemistry: Molecular, cellular and medical aspects |location=Amsterdam |publisher=Elsevier Science |last=Siegel|first=George J. |isbn=978-0-08-047207-2 |edition=7th |oclc=123438340}}</ref> they modulate the activity of key circuits in the brain involved with sensory perception and cognition. However, the exact nature of how psychedelics induce changes in perception and cognition via the serotonin 5-HT2A receptor is still unknown.<ref>{{Cite journal |last1=Smigielski |first1=Lukasz |last2=Scheidegger |first2=Milan |last3=Kometer |first3=Michael |last4=Vollenweider |first4=Franz X. |date=August 2019 |title=Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects |journal=NeuroImage |url= https://linkinghub.elsevier.com/retrieve/pii/S1053811919302952 |volume=196|pages=207–215|doi=10.1016/j.neuroimage.2019.04.009|pmid=30965131|s2cid=102487343}}</ref> The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation,<ref name="letheby-gerrans">{{cite journal |last1=Letheby |first1=Chris |last2=Gerrans |first2=Philip |title=Self unbound: ego dissolution in psychedelic experience |journal=Neuroscience of Consciousness |date=2017 |volume=3 |issue=1 |article-number=nix016 |doi=10.1093/nc/nix016 |pmid=30042848 |pmc=6007152 |quote=The connection with findings about PCC deactivation in 'effortless awareness' meditation is obvious, and bolstered by the finding that acute ayahuasca intoxication increases mindfulness-related capacities.}}</ref><ref name="psych-meditation-self"/> mystical experiences,<ref name="Griffiths"/><ref name="dmt-nde">{{cite journal |last1=Timmermann |first1=Christopher |last2=Roseman |first2=Leor |last3=Williams |first3=Luke |last4=Erritzoe |first4=David |last5=Martial |first5=Charlotte |last6=Cassol |first6=Héléna |last7=Laureys |first7=Steven |last8=Nutt |first8=David |last9=Carhart-Harris |first9=Robin |title=DMT Models the Near-Death Experience |journal=Frontiers in Psychology |date=2018 |volume=9 |article-number=1424 |doi=10.3389/fpsyg.2018.01424 |pmid=30174629 |pmc=6107838|doi-access=free }} </ref><ref> {{cite journal |title=Psychedelic Mystical Experiences Are Authentic |last=Van Eyghen |first=Hans |journal=Religions |date=2025 |volume=16 |issue=10 |page=1294 |doi=10.3390/rel16101294 |doi-access=free }} </ref> and near-death experiences,<ref name="dmt-nde"/> which also appear to be partially underpinned by altered default mode network (DMN) activity.<ref>{{Cite journal|last1=Brewer|first1=Judson A.|last2=Worhunsky|first2=Patrick D.|last3=Gray|first3=Jeremy R.|last4=Tang|first4=Yi-Yuan|last5=Weber|first5=Jochen|last6=Kober|first6=Hedy|date=2011-12-13|title=Meditation experience is associated with differences in default mode network activity and connectivity|journal=Proceedings of the National Academy of Sciences|volume=108|issue=50|pages=20254–20259|doi=10.1073/pnas.1112029108|pmc=3250176|pmid=22114193|bibcode=2011PNAS..10820254B|doi-access=free}}</ref><ref name="SiegelListonNicol2026">{{cite journal | vauthors = Siegel JS, Liston C, Nicol GE, Carhart-Harris RL, Bogenschutz MP | title = The science of psychedelic medicine | journal = Nat Med | volume = | issue = | pages = | date = February 2026 | pmid = 41652120 | doi = 10.1038/s41591-025-04194-5 | url = | quote = The majority of psychedelic clinical trials in recent years have used psilocybin. But a closer look reveals psychedelics to be a rich and growing class of compounds. There are at least six naturally occurring serotonergic psychedelic compounds, more than 100 psychedelic compounds currently under development by pharmaceutical companies157 and many additional synthetic compounds with documented psychedelic or hallucinogenic effects in humans—many first described and systematically cataloged in the PiHKAL and TiHKAL volumes158,159. AI-based tools for drug discovery (that is, AlphaFold2) suggest that the number of unique molecules with psychedelic 5-HT2A agonism could be over 100,000 (refs. 160,161). These compounds may differ not only in the profile of receptors that are co-activated, but also in the ways in which the 5-HT2A itself is engaged and activated162. The number of possible combinations between drug, dosing protocol and medical indication are limitless.}}</ref> The phenomenon of ego death is often described as a key feature of the psychedelic experience.<ref name="letheby-gerrans"/><ref name="psych-meditation-self"/><ref name="dmt-nde"/>

Many psychedelic drugs are illegal to possess without lawful authorisation, exemption or license worldwide under the UN conventions, with occasional exceptions for religious use or research contexts. Despite these controls, recreational use of psychedelics is common.<ref name="30-million">{{cite journal|author=Krebs, Teri S|author2=Johansen, Pål-Ørjan|date=28 March 2013|title=Over 30 million psychedelic users in the United States|journal=F1000Research|volume=2|page=98|doi=10.12688/f1000research.2-98.v1|pmc=3917651|pmid=24627778 |doi-access=free }}</ref><ref name="garcia-et-al">{{cite journal|author=Garcia-Romeu, Albert|author2=Kersgaard, Brennan|author3=Addy, Peter H.|date=August 2016|title=Clinical applications of hallucinogens: A review.|journal=Experimental and Clinical Psychopharmacology|volume=24|issue=4|pages=229–268|doi=10.1037/pha0000084|pmc=5001686|pmid=27454674}}</ref> There is also a long history of use of naturally occurring psychedelics as entheogens dating back thousands of years. Legal barriers have made the scientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologically safe and rarely lead to addiction.<ref name="canada-commission">{{cite book|last=Le Dain|first=Gerald|title=The Non-medical Use of Drugs: Interim Report of the Canadian Government's Commission of Inquiry|date=1971|page=106|quote=Physical dependence does not develop to LSD}}</ref><ref name="Ungless 2006">{{cite journal|author1=Lüscher, Christian|author2=Ungless, Mark A.|date=14 November 2006|title=The Mechanistic Classification of Addictive Drugs|journal=PLOS Medicine|volume=3|issue=11|article-number=e437|doi=10.1371/journal.pmed.0030437|pmc=1635740|pmid=17105338 |doi-access=free }}</ref> Psychedelic drugs are being studied for use in medicine, including treatment of depression, anxiety, addiction, post-traumatic stress disorder (PTSD), and other conditions.<ref name="SiegelListonNicol2026" /><ref name="Nichols2016"/> Although further research is needed, existing results suggest that psychedelics could be effective treatments for certain conditions.<ref name="SiegelListonNicol2026" /><ref name="bender-hellerstein-2022">{{cite journal |last1=Bender |first1=David |last2=Hellerstein |first2=David J. |title=Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research |journal=Psychopharmacology |date=2022 |volume=239 |issue=6 |pages=1907–1932 |doi=10.1007/s00213-021-06049-6 |pmid=35022823|s2cid=245906937 }}</ref><ref name="reiff-et-al-2020">{{cite journal | vauthors = Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, Kalin NH, McDonald WM | title = Psychedelics and Psychedelic-Assisted Psychotherapy | journal = The American Journal of Psychiatry | volume = 177 | issue = 5 | pages = 391–410 | date = May 2020 | pmid = 32098487 | doi = 10.1176/appi.ajp.2019.19010035 | s2cid = 211524704 }}</ref><ref name="tupper-et-al"/><ref name="garcia-et-al"/> A 2022 survey by YouGov found that 28% of Americans had used a psychedelic at some point in their life.<ref>{{cite web|last=Orth|first=Taylor|url=https://today.yougov.com/topics/lifestyle/articles-reports/2022/07/28/one-in-four-americans-have-tried-psychedelic-drugs|title=One in four Americans say they've tried at least one psychedelic drug|work=YouGov|date=July 28, 2022}}</ref>

==Examples== {{See also|List of psychedelic drugs|List of psychoactive plants|List of designer drugs}}

Some major examples of, and among the most well-known serotonergic psychedelics, include:<ref name="KelmendiKayePittenger2022" /><ref name="WalkerPullellaPiggott2023" /><ref name="Nichols2004" />

* '''LSD''' (lysergic acid diethylamide; lysergide) is a derivative of lysergic acid, which is obtained from the hydrolysis of ergotamine. Ergotamine is an alkaloid found in the fungus ''Claviceps purpurea'' (ergot), which primarily infects rye. LSD is both the prototypical psychedelic and the prototypical lysergamide. As a lysergamide, LSD contains both a tryptamine and phenethylamine group within its structure. Uniquely among psychedelics, LSD agonises dopamine receptors as well as serotonin receptors.<ref>{{Cite journal|date=1975-12-01|title=The dopamine receptor: Differential binding of d-LSD and related agents to agonist and antagonist states|url=https://www.sciencedirect.com/science/article/abs/pii/0024320575901186|journal=Life Sciences|language=en|volume=17|issue=11|pages=1715–1719|doi=10.1016/0024-3205(75)90118-6|issn=0024-3205|last1=Creese|first1=Ian|last2=Burt|first2=David R.|last3=Snyder|first3=Solomon H.|pmid=1207384}}</ref><ref>{{Cite journal|last1=Passie|first1=Torsten|last2=Seifert|first2=Juergen|last3=Schneider|first3=Udo|last4=Emrich|first4=Hinderk M.|date=October 2002|title=The pharmacology of psilocybin|url=http://doi.wiley.com/10.1080/1355621021000005937|journal=Addiction Biology|language=en|volume=7|issue=4|pages=357–364|doi=10.1080/1355621021000005937|pmid=14578010|s2cid=12656091}}</ref> Drugs like ALD-52 (1A-LSD), 1P-LSD, and 1V-LSD are prodrugs of LSD.<ref name="Ponce2024">{{cite journal | vauthors = Ponce JD | title = The use of prodrugs as drugs of abuse | journal = WIREs Forensic Science | volume = 6 | issue = 3 | date = 2024 | article-number = e1514 | doi = 10.1002/wfs2.1514 | issn = 2573-9468 | doi-access = free }}</ref><ref name="Elliott2020">{{cite journal | vauthors = Elliott SP, Holdbrook T, Brandt SD | title = Prodrugs of New Psychoactive Substances (NPS): A New Challenge | journal = Journal of Forensic Sciences | volume = 65 | issue = 3 | pages = 913–920 | date = May 2020 | pmid = 31943218 | doi = 10.1111/1556-4029.14268}}</ref>

* '''Psilocin''' (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid '''psilocybin''' (4-PO-DMT) and a substituted tryptamine, which is produced by hundreds of species of psilocybin-containing mushrooms. Of the classical psychedelics, psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences,<ref>{{Cite journal|last1=Griffiths|first1=R. R.|last2=Richards|first2=W. A.|last3=McCann|first3=U.|last4=Jesse|first4=R.|date=August 2006|title=Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance|url=https://link.springer.com/10.1007/s00213-006-0457-5|journal=Psychopharmacology|language=en|volume=187|issue=3|pages=268–283|doi=10.1007/s00213-006-0457-5|pmid=16826400|s2cid=7845214|issn=0033-3158}}</ref> although all psychedelics are capable of doing so to variable degrees. 4-AcO-DMT (''O''-acetylpsilocin or psilacetin) is a synthetic acetylated analogue of psilocin and is a prodrug of psilocin similarly to psilocybin.

* '''Mescaline''' (3,4,5-trimethoxyphenethylamine) is a phenethylamine alkaloid found in various species of cacti, the best-known of these being peyote (''Lophophora williamsii'') and the San Pedro cactus (''Echinopsis pachanoi'', syn. ''Trichocereus macrogonus'' var. ''pachanoi''). Mescaline has effects comparable to those of LSD and psilocybin.<ref>{{Cite book|last=Freye|first=E.|title=Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs: a comprehensive review on their mode of action, treatment of abuse and intoxication|date=2009|publisher=Springer|isbn=978-90-481-2448-0|location=Dordrecht|oclc=489218895}}</ref>{{page needed|date=January 2023}} Ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.<ref>{{Cite journal |last1=Bohn |first1=Arne |last2=Kiggen |first2=Michiel H. H. |last3=Uthaug |first3=Malin V. |last4=van Oorsouw |first4=Kim I. M. |last5=Ramaekers |first5=Johannes G. |last6=van Schie |first6=Hein T. |date=2022-12-05 |title=Altered States of Consciousness During Ceremonial San Pedro Use |url=https://www.tandfonline.com/doi/full/10.1080/10508619.2022.2139502 |journal=The International Journal for the Psychology of Religion |language=en |volume=33 |issue=4 |pages=309–331 |doi=10.1080/10508619.2022.2139502 |issn=1050-8619|hdl=2066/285968 |hdl-access=free }}</ref>

* '''DMT''' (''N'',''N''-dimethyltryptamine) is an indole alkaloid found in various species of plants.<ref name="TiHKAL1997" /> Traditionally, it is consumed by tribes in South America in the form of ayahuasca. A brew is used that consists of DMT-containing plants as well as plants containing monoamine oxidase inhibitors (MAOIs), like harmine and harmaline, which allows DMT to be consumed orally without being rendered inactive by monoamine oxidase (MAO) enzymes in the digestive system.<ref name="Riba 2003">{{Cite journal|last1=Riba|first1=Jordi|last2=Valle|first2=Marta|last3=Urbano|first3=Gloria|last4=Yritia|first4=Mercedes|last5=Morte|first5=Adelaida|last6=Barbanoj|first6=Manel J.|date=July 2003|title=Human Pharmacology of Ayahuasca: Subjective and Cardiovascular Effects, Monoamine Metabolite Excretion, and Pharmacokinetics|url=http://jpet.aspetjournals.org/lookup/doi/10.1124/jpet.103.049882|journal=Journal of Pharmacology and Experimental Therapeutics|language=en|volume=306|issue=1|pages=73–83|doi=10.1124/jpet.103.049882|pmid=12660312|s2cid=6147566|issn=0022-3565}}</ref> A pharmaceutical version of ayahuasca is called pharmahuasca.<ref>{{Cite journal |last1=Mueller |first1=Michael J. |last2=Aicher |first2=Helena D. |last3=Dornbierer |first3=Dario A. |last4=Marten |first4=Laurenz |last5=Suay |first5=Dila |last6=Meling |first6=Daniel |last7=Elsner |first7=Claudius |last8=Wicki |first8=Ilhui A. |last9=Müller |first9=Jovin |last10=Poetzsch |first10=Sandra N. |last11=Caflisch |first11=Luzia |last12=Hempe |first12=Alexandra |last13=Steinhart |first13=Camilla P. |last14=Puchkov |first14=Maxim |last15=Kost |first15=Jonas |date=2024-12-28 |title=Pharmacokinetics and pharmacodynamics of an innovative psychedelic N,N-dimethyltryptamine/harmine formulation in healthy participants: a randomized controlled trial |journal=The International Journal of Neuropsychopharmacology |volume=28 |issue=1 |article-number=pyaf001 |doi=10.1093/ijnp/pyaf001 |issn=1469-5111 |pmid=39774840|pmc=11770821 }}</ref> In the Western world, DMT is more commonly consumed via the vaporisation of freebase DMT. Whereas ayahuasca typically lasts for several hours, inhalation has an onset measured in seconds and has effects measured in minutes, being much more intense.<ref>{{Cite journal|last1=Haroz|first1=Rachel|last2=Greenberg|first2=Michael I.|date=November 2005|title=Emerging drugs of abuse|journal=The Medical Clinics of North America|volume=89|issue=6|pages=1259–1276|doi=10.1016/j.mcna.2005.06.008|issn=0025-7125|pmid=16227062}}</ref> Particularly in smoked or vaporised form, DMT has the ability to cause users to enter a hallucinatory realm fully detached from reality, being typically characterised by hyperbolic geometry, and described as defying visual or verbal description.<ref>{{Cite journal|last1=Strassman|first1=Ruck J.|last2=Qualls|first2=Clifford R.|last3=Uhlenhuth|first3=Eberhard H.|last4=Kellner|first4=Robert|date=1994-02-01|title=Dose-Response Study of N,N-Dimethyltryptamine in Humans: II. Subjective Effects and Preliminary Results of a New Rating Scale|journal=Archives of General Psychiatry|volume=51|issue=2|pages=98–108|doi=10.1001/archpsyc.1994.03950020022002|pmid=8297217|issn=0003-990X}}</ref> Users have also reported encountering and communicating with entities within this hallucinatory state.<ref>{{Cite journal|last1=Davis|first1=Alan K|last2=Clifton|first2=John M|last3=Weaver|first3=Eric G|last4=Hurwitz|first4=Ethan S|last5=Johnson|first5=Matthew W|last6=Griffiths|first6=Roland R|date=September 2020|title=Survey of entity encounter experiences occasioned by inhaled N,N -dimethyltryptamine: Phenomenology, interpretation, and enduring effects|journal=Journal of Psychopharmacology|language=en|volume=34|issue=9|pages=1008–1020|doi=10.1177/0269881120916143|pmid=32345112|issn=0269-8811|doi-access=free}}</ref> DMT is the archetypal substituted tryptamine, being the structural scaffold of psilocybin and, to a lesser extent, the lysergamides.

* '''5-MeO-DMT''' (5-methoxy-''N'',''N''-dimethyltryptamine; mebufotenin) is a naturally occurring substituted 5-methoxytryptamine which was first identified as having psychedelic effects in the 1960s.<ref name="ErmakovaDunbarRucker2022">{{cite journal | vauthors = Ermakova AO, Dunbar F, Rucker J, Johnson MW | title = A narrative synthesis of research with 5-MeO-DMT | journal = J Psychopharmacol | volume = 36 | issue = 3 | pages = 273–294 | date = March 2022 | pmid = 34666554 | doi = 10.1177/02698811211050543 | pmc = 8902691 }}</ref><ref name="ReckwegUthaugSzabo2022">{{cite journal | vauthors = Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG | title = The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) | journal = J Neurochem | volume = 162 | issue = 1 | pages = 128–146 | date = July 2022 | pmid = 35149998 | pmc = 9314805 | doi = 10.1111/jnc.15587 }}</ref><ref name="DourronNicholsSimonsson2023">{{cite journal | vauthors = Dourron HM, Nichols CD, Simonsson O, Bradley M, Carhart-Harris R, Hendricks PS | title = 5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk? | journal = Psychopharmacology (Berl) | volume = 242| issue = 7| pages = 1457–1479| date = December 2023 | pmid = 38072874 | doi = 10.1007/s00213-023-06517-1 | url = }}</ref><ref name="ShenJiangWinter2010">{{cite journal | vauthors = Shen HW, Jiang XL, Winter JC, Yu AM | title = Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions | journal = Curr Drug Metab | volume = 11 | issue = 8 | pages = 659–666 | date = October 2010 | pmid = 20942780 | pmc = 3028383 | doi = 10.2174/138920010794233495 }}</ref><ref name="TiHKAL1997" /><ref name="Shulgin1970">{{cite book | author = Alexander Shulgin | chapter = Chemistry and Structure-Activity Relationships of the Psychotomimetics | editor = D. H. Efron | title = Psychotomimetic Drugs | publisher = Raven Press | location = New York | pages = 21–41 | date = 1970 | url = https://www.erowid.org/library/books_online/psychotomimetic_drugs.pdf#page=23 }}</ref> It is found in certain hallucinogenic snuffs and in ''Incilius alvarius'' (''Bufo alvarius''; Colorado River toad) toad venom.<ref name="ErmakovaDunbarRucker2022" /><ref name="Delgrasso2024" /><ref name="BrimblecombePinder1975">{{cite book | vauthors = Brimblecombe RW, Pinder RM | chapter = Indolealkylamines and Related Compounds | pages = 98–144 | title = Hallucinogenic Agents | date = 1975 | publisher = Wright-Scientechnica | location = Bristol | isbn = 978-0-85608-011-1 | oclc = 2176880 | ol = OL4850660M | url = https://bitnest.netfirms.com/external/Books/978-0-85608-011-1}}</ref><ref name="Nelson1984">{{cite web | vauthors = Nelson K |others= Illustrated by Gail Patterson |title=Bufo alvarius: The Psychedelic Toad of the Sonoran Desert |url=https://www.erowid.org/archive/sonoran_desert_toad/almost.htm |date=1984|access-date=October 20, 2023 |website=Erowid}}</ref> 5-MeO-DMT is about 5- to 20-fold more potent by weight than DMT.<ref name="ShenJiangWinter2010" /><ref name="Hayes2025">{{cite journal | last=Hayes | first=Caroline | title=A Toad Less Traveled: Should 5-MeO-DMT Have a Role in Treating Depression? | journal=Psychedelic Medicine | date=14 April 2025 | issn=2831-4425 | doi=10.1089/psymed.2024.0049 | url=https://www.liebertpub.com/doi/10.1089/psymed.2024.0049 | access-date=6 May 2025 | article-number=psymed.2024.0049 | url-access=subscription }}</ref> It produces atypical psychedelic effects, including powerful experiences but a relative absence of visual effects, with these experiences often described as "whiteouts".<ref name="DourronNicholsSimonsson2023" /><ref name="ErmakovaDunbarRucker2022" /><ref name="Hayes2025" /> 5-MeO-DMT is usually smoked similarly to DMT and has been described as the "most powerful" known psychedelic or as the "Mount Everest" of psychedelics.<ref name="Delgrasso2024" /><ref name="Hayes2025" /> The atypical effects of 5-MeO-DMT are thought to be related to strong concomitant activity at the serotonin 5-HT1A receptor.<ref name="ErmakovaDunbarRucker2022" /><ref name="ReckwegUthaugSzabo2022" /><ref name="DourronNicholsSimonsson2023" /><ref name="TiHKAL1997" />

* '''2C-B''' (2,5-dimethoxy-4-bromophenethylamine) is a substituted phenethylamine first synthesized in 1974 by Alexander Shulgin.<ref name="PiHKAL1991" /> 2C-B has been described as both a psychedelic and a mild entactogen, with its psychedelic effects increasing and its entactogenic effects decreasing with dose.<ref name="LuethiLiechti2020" /><ref name="WillsErickson2012" /><ref name="GonzálezTorrensFarré2015" /><ref name="Oeri2021" /> 2C-B is the most well-known compound in the 2C family, their general structure being discovered as a result of modifying the structure of mescaline.<ref name="PiHKAL1991" />{{page needed|date=January 2023}} It is also the most widely used synthetic phenethylamine psychedelic.

MDMA ("ecstasy") is sometimes said to also have weak psychedelic effects, but it acts and is classified mainly as an entactogen rather than as a hallucinogen.<ref name="DunlapAndrewsOlson2018">{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = }}</ref> Certain closely related drugs like MDA and MMDA, while much less common, have greater psychedelic effects however.<ref name="PiHKAL1991">{{cite book |author1=Alexander T. Shulgin |title=PiHKAL: A Chemical Love Story |author2=Ann Shulgin |date=1991 |publisher=Transform Press |isbn=978-0-9630096-0-9 |edition=1st |location=Berkeley, CA |pages=503–506 |oclc=25627628}}</ref>

In addition to the above-listed psychedelics, there are hundreds of other much lesser-known psychedelic drugs.<ref name="SiegelListonNicol2026" /><ref name="PiHKAL1991" /><ref name="TiHKAL1997" /><ref name="CatalaniCorkeryGuirguis2021">{{cite journal | vauthors = Catalani V, Corkery JM, Guirguis A, Napoletano F, Arillotta D, Zangani C, Vento A, Schifano F | title = Psychonauts' psychedelics: A systematic, multilingual, web-crawling exercise | journal = Eur Neuropsychopharmacol | volume = 49 | issue = | pages = 69–92 | date = August 2021 | pmid = 33857740 | doi = 10.1016/j.euroneuro.2021.03.006 | url = }}</ref> Some research suggests that there may be more than 100,000 unique possible serotonergic psychedelics.<ref name="SiegelListonNicol2026" />

{{Gallery | title = | height = 200 | width = 200 | align = center | File:Synthetic mescaline powder i2001e0151 ccby3.jpg | Synthetic mescaline. This psychedelic was the first to be isolated.<ref>{{cite web|url=http://mescaline.com/exp|title=Peyote San Pedro Cactus – Shamanic Sacraments|work=D.M.Taylor}}</ref> | File:Three_psychedelic_drugs.png | From top to bottom: 2C-B pills, 4-HO-MET set in gelatine, and a strip of LSD tabs | File:N,N-DMT Freebase and Vape cartridge.jpg | Free base DMT extracted from ''Mimosa hostilis'' root bark (left); vape cartridge made with freebase DMT extract (right) }}

==Uses== ===Recreational=== {{Further|Recreational drug use#Hallucinogens}}

Recreational use of psychedelics has been common since the psychedelic era of the mid-1960s and continues to feature at festivals and events such as Burning Man.<ref name="30-million"/><ref name="garcia-et-al"/> A 2013 survey found that 13.4% of American adults had used a psychedelic at some point in their lives.<ref>{{cite journal|title=Psychedelics and Mental Health: A Population Study|journal=PLOS ONE|date=August 19, 2013|pmc=3747247|pmid=23976938|article-number=e63972|volume=8|issue=8|doi=10.1371/journal.pone.0063972|author=Krebs, Teri S.|author2=Johansen, Pål-Ørjan|bibcode=2013PLoSO...863972K|doi-access=free}}</ref>

A June 2024 report by the RAND Corporation indicated that psilocybin mushrooms are currently the most widely used psychedelic drug among U.S. adults. According to the RAND national survey, 3.1% of adults reported psilocybin use in the past year, while about 12% reported lifetime use. Similar lifetime prevalence was reported for LSD, whereas MDMA (ecstasy) showed lower lifetime use at 7.6%. Fewer than 1% of adults reported using any psychedelic in the past month.<ref>{{cite news |last=Goldman |first=Maya |url=https://www.axios.com/2024/06/27/psychedelics-mushrooms-rand |title=Mushrooms are the most commonly used psychedelic, study finds |work=Axios |date=2024-06-27 |access-date=2024-06-28 }}</ref>

A nationwide survey of 11,299 adults in Germany, published in 2025, found that 5.0% of respondents reported lifetime psychedelic use, with 0.7% reporting use within the past six months.<ref>{{cite journal|title=Population-based estimates of different dosage types of psychedelic use across socio-demographic groups in Germany|journal=Scientific Reports|date=May 29, 2025|volume=15|issue=18952|doi=10.1038/s41598-025-03873-0|author=Sattler, Sebastian|author2=Wood, Suzanne|author3=Petersen, Margit A.|author4=Seiffert, Fiona|author5=Mehlkop, Guido|article-number=18952|pmid=40442205 |pmc=12122786 |bibcode=2025NatSR..1518952S |doi-access=free}}</ref> Approximately 3% of respondents had used LSD, LSD analogues, psilocybin, or related substances at least once in their lifetime, and 0.5% had done so within the past six months. Lifetime prevalence of medium-to-high dosing (3.9%) was higher than microdosing (2.7%). Usage patterns varied by sociodemographic characteristics, including sex, age, residence, income, and marital status.

A number of frequently mentioned or traditional psychedelics such as ''ayahuasca'' (which contains DMT), San Pedro, peyote, and Peruvian torch (which all contain mescaline), psilocybin-containing mushrooms (which contain psilocin and psilocybin) and ''Tabernanthe iboga'' (which contains the unique hallucinogen ibogaine) all have a long and extensive history of spiritual, shamanic and traditional usage by indigenous peoples in various world regions, particularly in Latin America, but also Gabon, Africa in the case of iboga.<ref>{{cite book |last1=Carlini |first1=E. A. |last2=Maia |first2=Lucas O. |title=Plant Toxins |chapter=Plant and Fungal Hallucinogens as Toxic and Therapeutic Agents |series=Toxinology |date=2020 |pages=1–44 |doi=10.1007/978-94-007-6728-7_6-2 |chapter-url=https://link.springer.com/referenceworkentry/10.1007/978-94-007-6728-7_6-2 |access-date=23 February 2022 |publisher=Springer Netherlands |isbn=978-94-007-6728-7 |s2cid=239438352 |language=en}}</ref> Different countries and/or regions have come to be associated with traditional or spiritual use of particular psychedelics, such as the ancient and entheogenic use of psilocybe mushrooms by the native Mazatec people of Oaxaca, Mexico<ref>{{cite web |title=History of Psychedelics: How the Mazatec Tribe Brought Entheogens to the World |url=https://psychedelictimes.com/history-of-psychedelics-how-the-mazatec-tribe-brought-entheogens-to-the-world/ |website=Psychedelic Times |access-date=23 February 2022 |date=28 October 2015}}</ref> or the use of the ayahuasca brew in the Amazon basin, particularly in Peru for spiritual and physical healing as well as for religious festivals.<ref>{{Cite book|last=Ismael Eduardo Apud Peláez. |title=Ayahuasca: Between Cognition and Culture|date=2020|publisher=Publicacions Universitat Rovira i Virgili|isbn=978-84-8424-834-7|oclc=1229544084}}</ref> Peyote has also been used for several thousand years in the Rio Grande Valley in North America by native tribes as an entheogen.<ref>{{cite journal |last1=Prince |first1=Mark A. |last2=O'Donnell |first2=Maeve B. |last3=Stanley |first3=Linda R. |last4=Swaim |first4=Randall C. |title=Examination of Recreational and Spiritual Peyote Use Among American Indian Youth |journal=Journal of Studies on Alcohol and Drugs |date=May 2019 |volume=80 |issue=3 |pages=366–370 |doi=10.15288/jsad.2019.80.366 |pmid=31250802 |pmc=6614926 }}</ref> In the Andean region of South America, the San Pedro cactus (''Echinopsis pachanoi'') has a long history of use, possibly as a traditional medicine. Archaeological studies have found evidence of use going back two thousand years, to Moche culture,<ref>{{cite journal |vauthors=Bussmann RW, Sharon D |title=Traditional medicinal plant use in Northern Peru: tracking two thousand years of healing culture |journal=J Ethnobiol Ethnomed |volume=2 |issue=1 |article-number=47 |year=2006 |pmid=17090303 |pmc=1637095 |doi=10.1186/1746-4269-2-47 |doi-access=free }} </ref> Nazca culture,<ref>{{Cite journal |last1=Socha |first1=Dagmara M. |last2=Sykutera |first2=Marzena |last3=Orefici |first3=Giuseppe |date=2022-12-01 |title=Use of psychoactive and stimulant plants on the south coast of Peru from the Early Intermediate to Late Intermediate Period |journal=Journal of Archaeological Science |language=en |volume=148 |article-number=105688 |doi=10.1016/j.jas.2022.105688 |s2cid=252954052 |issn=0305-4403|doi-access=free |bibcode=2022JArSc.148j5688S }}</ref> and Chavín culture. Although authorities of the Roman Catholic church attempted to suppress its use after the Spanish conquest,<ref>{{cite book |last1=Larco |first1=Laura |title=Más allá de los encantos – Documentos sobre extirpación de idolatrías, Trujillo |chapter=Archivo Arquidiocesano de Trujillo Sección Idolatrías. (Años 1768–1771) |series=Travaux de l'IFEA |date=2008 |publisher=IFEA Instituto Francés de Estudios Andinos, Fondo Editorial de la Universidad Nacional Mayor de San Marcos |location=Lima |pages=67–87 |isbn=978-2-8218-4453-7 |url=https://books.openedition.org/ifea/4938 |access-date=April 9, 2020}}</ref> this failed, as shown by the Christian element in the common name "San Pedro cactus" – Saint Peter cactus. The name has its origin in the belief that just as St Peter holds the keys to heaven, the effects of the cactus allow users "to reach heaven while still on earth."<ref>{{Cite book |last=Anderson |first=Edward F. |year=2001 |title=The Cactus Family |location=Pentland, Oregon |publisher=Timber Press |isbn=978-0-88192-498-5 }} pp. 45–49.</ref> In 2022, the Peruvian Ministry of Culture declared the traditional use of San Pedro cactus in northern Peru as cultural heritage.<ref>{{Cite web |date=2022-11-17 |title=Declaran Patrimonio Cultural de la Nación a los conocimientos, saberes y usos del cactus San Pedro |url=https://elperuano.pe/noticia/197142-declaran-patrimonio-cultural-de-la-nacion-a-los-conocimientos-saberes-y-usos-del-cactus-san-pedro |access-date=2022-12-10 |website=elperuano.pe |language=es}}</ref>

Although people of Western culture have tended to use psychedelics for either psychotherapeutic or recreational reasons, most indigenous cultures, particularly in South America, have seemingly tended to use psychedelics for more supernatural reasons such as divination. This can often be related to "healing" or health as well but typically in the context of finding out what is wrong with the individual, such as using psychedelic states to "identify" a disease and/or its cause, locate lost objects, and identify a victim or even perpetrator of sorcery.<ref name="vice_4adngq">{{cite news |title= Psychedelics Weren't As Common in Ancient Cultures As We Think|url = https://www.vice.com/en/article/psychedelic-drug-use-in-ancient-indigenous-cultures/ |access-date=January 14, 2023 |work= Vice Media |publisher=Vice |date=December 10, 2020}}</ref> In some cultures and regions, even psychedelics themselves, such as ayahuasca and the psychedelic lichen of eastern Ecuador (''Dictyonema huaorani'') that supposedly contains both 5-MeO-DMT and psilocybin, have also been used by witches and sorcerers to conduct their malicious magic, similarly to nightshade deliriants like ''brugmansia'' and ''latua''.<ref name="vice_4adngq"/>{{citation needed|date=January 2023}}

===Medical=== {{Main|Psychedelic therapy}}

Psychedelic therapy (or psychedelic-assisted therapy) is the proposed use of psychedelic drugs to treat mental disorders.<ref>{{Cite journal |last1=Nutt |first1=David |last2=Spriggs |first2=Meg |last3=Erritzoe |first3=David |date=2023-02-01 |title=Psychedelics therapeutics: What we know, what we think, and what we need to research |journal=Neuropharmacology |volume=223 |article-number=109257 |doi=10.1016/j.neuropharm.2022.109257 |issn=0028-3908|doi-access=free |pmid=36179919 }}</ref> As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials.<ref name="marks-and-cohen-2021"/><ref name="pilecki-et-al-2021">{{cite journal |last1=Pilecki |first1=Brian |last2=Luoma |first2=Jason B. |last3=Bathje |first3=Geoff J. |last4=Rhea |first4=Joseph |last5=Narloch |first5=Vilmarie Fraguada |title=Ethical and legal issues in psychedelic harm reduction and integration therapy |journal=Harm Reduction Journal |date=2021 |volume=18 |issue=1 |page=40 |doi=10.1186/s12954-021-00489-1 |pmid=33827588 |pmc=8028769 |doi-access=free }}</ref> However, certain psychedelics like psilocybin and LSD are legally approved and/or used for treatment of conditions like treatment-resistant depression under special access programs in several countries including Australia, Switzerland, Canada, and Israel.<ref name="Langlitz2025">{{cite journal | last=Langlitz | first=Nicolas | title=Experiments in medicalization: psychedelic therapy in Switzerland and Australia | journal=BioSocieties | date=6 September 2025 | issn=1745-8552 | doi=10.1057/s41292-025-00369-y | url=https://link.springer.com/10.1057/s41292-025-00369-y | access-date=11 February 2026 | quote=Drawing on long-term ethnographic engagement with the psychedelic research community, [this article] presents two case studies: Switzerland's Limited Medical Use Program and Australia's Authorized Prescriber scheme. Both allow psychedelic therapies outside clinical trials, yet neither grants market access.}}</ref><ref name="NuttHuntSchlag2024">{{cite journal | vauthors = Nutt DJ, Hunt P, Schlag AK, Fitzgerald P | title = The Australia story: Current status and future challenges for the clinical applications of psychedelics | journal = Br J Pharmacol | volume = | issue = | pages = | date = December 2024 | pmid = 39701143 | doi = 10.1111/bph.17398 | url = | quote = [...] in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use of psilocybin for treatment-resistant depression and MDMA for PTSD to take effect from 1 July 2023. [...] compassionate use [of psychedelics] has been allowed in Switzerland for decades and more recently in Canada (TheraPsil, 2024) and Israel.}}</ref><ref name="AicherMüllerGasser2025">{{cite journal | vauthors = Aicher HD, Müller F, Gasser P | title = Further education in psychedelic-assisted therapy - experiences from Switzerland | journal = BMC Med Educ | volume = 25 | issue = 1 | page = 341 | date = March 2025 | pmid = 40045361 | pmc = 11881254 | doi = 10.1186/s12909-025-06871-y | doi-access = free| url = | quote = In Switzerland, MDMA, psilocybin, and LSD are applied in the framework of limited medical use as exceptional treatment options since 2014.}}</ref><ref name="LiechtiGasserAicher2025">{{cite journal | vauthors = Liechti ME, Gasser P, Aicher HD, Mueller F, Hawrot T, Schmid Y | title = Implementing psychedelic-assisted therapy: History and characteristics of the Swiss limited medical use program | journal = Neurosci Appl | volume = 4 | issue = | article-number = 105525 | date = 2025 | pmid = 40800003 | pmc = 12341733 | doi = 10.1016/j.nsa.2025.105525 | url = | quote = This article describes the Swiss limited access program for psychedelic/3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy. The Swiss Federal Office of Public Health can issue authorizations for the limited medical use of otherwise prohibited substances. To be eligible, patients suffer from a mostly incurable disease, the prohibited substance can alleviate the suffering, and there are no alternative treatments, or such treatments have already extensively been used with insufficient outcome. The current program started in 2014 with two physicians. In 2024, there were approximately 100 physicians who held authorizations to treat 723 patients with MDMA (245 patients), lysergic acid diethylamide (130 patients), or psilocybin (348 patients). [...]}}</ref>

The procedure for psychedelic therapy differs from that of therapies using conventional psychiatric medications. While conventional medications are usually taken without supervision at least once daily, in contemporary psychedelic therapy the drug is administered in a single session (or sometimes up to three sessions) in a therapeutic context.<ref name="nutt-et-al-2020">{{cite journal |last1=Nutt |first1=David |last2=Erritzoe |first2=David |last3=Carhart-Harris |first3=Robin |title=Psychedelic Psychiatry's Brave New World |journal=Cell |date=2020 |volume=181 |issue=1 |pages=24–28 |doi=10.1016/j.cell.2020.03.020 |pmid=32243793|s2cid=214753833 |doi-access=free }}</ref> The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards.<ref name="johnson-et-al-2008">{{cite journal |last1=Johnson |first1=M. W. |last2=Richards |first2=W. A. |last3=Griffiths |first3=R. R. |title=Human hallucinogen research: guidelines for safety |journal=Journal of Psychopharmacology |date=2008 |volume=22 |issue=6 |pages=603–620 |doi=10.1177/0269881108093587 |pmid=18593734 |pmc=3056407}}</ref><ref name="garcia-romeu-richards-2018">{{cite journal |last1=Garcia-Romeu |first1=Albert |last2=Richards |first2=William A. |title=Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions |journal=International Review of Psychiatry |date=2018 |volume=30 |issue=4 |pages=291–316 |doi=10.1080/09540261.2018.1486289 |pmid=30422079 |s2cid=53291327 |issn=0954-0261}}</ref><ref>{{Cite journal |last1=Bathje |first1=Geoff J. |last2=Majeski |first2=Eric |last3=Kudowor |first3=Mesphina |date=2022-08-04 |title=Psychedelic integration: An analysis of the concept and its practice |journal=Frontiers in Psychology |language=English |volume=13 |article-number=824077 |doi=10.3389/fpsyg.2022.824077 |doi-access=free |pmid=35992410 |pmc=9386447 |issn=1664-1078}}</ref> After ingesting the drug, the patient normally wears eyeshades and listens to music to facilitate focus on the psychedelic experience, with the therapeutic team interrupting only to provide reassurance if adverse effects such as anxiety or disorientation arise.<ref name="johnson-et-al-2008"/><ref name="garcia-romeu-richards-2018"/>

As of 2022, the body of high-quality evidence on psychedelic therapy remains relatively small and more, larger studies are needed to reliably show the effectiveness and safety of psychedelic therapy's various forms and applications.<ref name="bender-hellerstein-2022" /><ref name="reiff-et-al-2020" /> On the basis of favorable early results, ongoing research is examining proposed psychedelic therapies for conditions including major depressive disorder,<ref name="bender-hellerstein-2022" /><ref name="romeo-et-al-2020">{{cite journal |last1=Romeo |first1=Bruno |last2=Karila |first2=Laurent |last3=Martelli |first3=Catherine |last4=Benyamina |first4=Amine |title=Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis |journal=Journal of Psychopharmacology |date=2020 |volume=34 |issue=10 |pages=1079–1085 |doi=10.1177/0269881120919957 |pmid=32448048|s2cid=218873949 }}</ref> and anxiety and depression linked to terminal illness.<ref name="bender-hellerstein-2022" /><ref name="schimmel-et-al-2022">{{cite journal |last1=Schimmel |first1=Nina |last2=Breeksema |first2=Joost J. |last3=Smith-Apeldoorn |first3=Sanne Y. |last4=Veraart |first4=Jolien |last5=van den Brink |first5=Wim |last6=Schoevers |first6=Robert A. |title=Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review |journal=Psychopharmacology |date=2022 |volume=239 |issue=15–33 |pages=15–33 |doi=10.1007/s00213-021-06027-y |pmid=34812901|s2cid=244490236 |url=https://research.rug.nl/en/publications/d86d811c-a066-4d34-bc83-df904e91a765 }}</ref> The United States Food and Drug Administration has granted breakthrough therapy status, which expedites the assessment of promising drug therapies for potential approval, to psilocybin therapy for treatment-resistant depression and major depressive disorder.<ref name="marks-and-cohen-2021" />

It has been proposed that psychedelics used for therapeutic purposes may act as active "super placebos".<ref name="DupuisVeissière2022">{{cite journal | vauthors = Dupuis D, Veissière S | title = Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos? | journal = Transcult Psychiatry | volume = 59 | issue = 5 | pages = 571–578 | date = October 2022 | pmid = 36263513 | doi = 10.1177/13634615221131465 | url = }}</ref><ref name="vanElkYaden2022">{{cite journal | vauthors = van Elk M, Yaden DB | title = Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review | journal = Neurosci Biobehav Rev | volume = 140 | issue = | article-number = 104793 | date = September 2022 | pmid = 35878791 | doi = 10.1016/j.neubiorev.2022.104793 | url = | quote = In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility. | hdl = 1887/3515020 | hdl-access = free }}</ref><ref name="AnsariElliotHolmes2025">{{cite journal | last1=Ansari | first1=Mina | last2=Elliot | first2=Sophie I. | last3=Holmes | first3=Sophie E. | last4=Sanacora | first4=Gerard | title=Placebo Effects in the Treatment of Depression—Implications for the Psychedelic Renaissance | journal=Neurologic Clinics | date=2025 | volume=44 | issue=1 | pages=63–75 | doi=10.1016/j.ncl.2025.08.009 | pmid=41232997 | url=https://linkinghub.elsevier.com/retrieve/pii/S0733861925000593 | access-date=15 October 2025 }}</ref> On the other hand, the inverse placebo effect (or "knowcebo" effect) caused by blinding failure may create an illusion of large effect sizes with psychedelics.<ref name="AnsariElliottHolmes2026">{{cite journal | vauthors = Ansari M, Elliott SI, Holmes SE, Sanacora G | title = Placebo Effects in the Treatment of Depression-Implications for the Psychedelic Renaissance | journal = Neurol Clin | volume = 44 | issue = 1 | pages = 63–75 | date = February 2026 | pmid = 41232997 | doi = 10.1016/j.ncl.2025.08.009 | url = }}</ref><ref name="Hamzelou2026">{{cite web | last=Hamzelou | first=Jessica | title=Mind-altering substances are (still) falling short in clinical trials | website=MIT Technology Review | date=20 March 2026 | url=https://www.technologyreview.com/2026/03/20/1134419/psychedelics-overhyped-psilocybin-depression-placebo/ | access-date=20 March 2026 | quote=But with psychedelics, the difference between active drug and placebo is much greater. That’s partly because people who get the psychedelic drug know they’re getting it and are expecting the drug to improve their symptoms, [...] But it’s also partly because of the effect on those who know they’re not getting it. It’s pretty obvious when you’re getting a placebo, says Szigeti, and it can be disappointing. Scientists have long recognized the “nocebo” effect as placebo’s “evil twin”—essentially, when you expect to feel worse, you will. The disappointment of getting a placebo is slightly different, and Szigeti calls it the “knowcebo effect.” “It’s kind of like a negative psychedelic effect, because you have figured out that you’re taking the placebo,” he says. This phenomenon can distort the results of psychedelic drug trials. While a placebo in a traditional antidepressant drug trial improves symptoms by eight points, placebos in psychedelic trials improve symptoms by a mere four points, says Szigeti. If the active drug similarly improves symptoms by around 10 points, that makes it look as though the psychedelic is improving symptoms by around six points compared with a placebo. It “gives the illusion” of a huge effect, says Szigeti.}}</ref>

===Microdosing=== {{Main|Psychedelic microdosing}}

Psychedelic microdosing is the practice of using sub-threshold doses (microdoses) of psychedelics in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction.<ref>{{Cite journal |last=Fadiman |first=James |date=2016-01-01 |title= Microdose research: without approvals, control groups, double blinds, staff or funding |url= https://www.researchgate.net/publication/308138461 |journal=Psychedelic Press |volume=XV }}</ref><ref>{{cite web | first = Erin | last = Brodwin | date = 30 January 2017 | url = https://www.businessinsider.com/microdosing-lsd-effects-risks-2017-1 | title = The truth about 'microdosing,' which involves taking tiny amounts of psychedelics like LSD | work = Business Insider | access-date = 19 April 2017 }}</ref> The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.<ref>{{cite web | first = Henrik | last = Dahl | url = http://psypressuk.com/2015/07/07/a-brief-history-of-lsd-in-the-twenty-first-century/ | title = A Brief History of LSD in the Twenty-First Century | work = Psychedelic Press UK | date = 7 July 2015 | access-date = 19 April 2017 }}</ref><ref name="Webb_2019">{{cite journal | vauthors = Webb M, Copes H, Hendricks PS | title = Narrative identity, rationality, and microdosing classic psychedelics | journal = The International Journal on Drug Policy | volume = 70 | pages = 33–39 | date = August 2019 | pmid = 31071597 | doi = 10.1016/j.drugpo.2019.04.013 | s2cid = 149445841 }}</ref>

A 2022 study recognized signatures of psilocybin microdosing in natural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules.<ref>{{Cite web |last1=Chemistry |first1=University of |last2=Prague |first2=Technology |title=Recognizing signatures of psilocybin microdosing in natural language |url=https://medicalxpress.com/news/2022-09-signatures-psilocybin-microdosing-natural-language.html |access-date=2022-10-03 |website=medicalxpress.com |language=en}}</ref><ref>{{Cite journal |last1=Sanz |first1=Camila |last2=Cavanna |first2=Federico |last3=Muller |first3=Stephanie |last4=de la Fuente |first4=Laura |last5=Zamberlan |first5=Federico |last6=Palmucci |first6=Matías |last7=Janeckova |first7=Lucie |last8=Kuchar |first8=Martin |last9=Carrillo |first9=Facundo |last10=García |first10=Adolfo M. |last11=Pallavicini |first11=Carla |last12=Tagliazucchi |first12=Enzo |date=2022-09-01 |title=Natural language signatures of psilocybin microdosing |journal=Psychopharmacology |language=en |volume=239 |issue=9 |pages=2841–2852 |doi=10.1007/s00213-022-06170-0 |pmid=35676541 |s2cid=247067976 |issn=1432-2072 |url=https://research.tilburguniversity.edu/en/publications/8bb28b28-32bf-485a-bbd2-6c419fe3e654 }}</ref>

===Dosing=== The table below provides doses of major serotonergic psychedelics as well as the entactogen and mild psychedelic MDMA ("ecstasy") that have been determined on the basis of clinical studies.<ref name="HolzeSinghLiechti2024" /><ref name="LiechtiHolze2022" /><ref name="EngelThalBright2024" /><ref name="LeyHolzeArikci2023">{{cite journal | vauthors = Ley L, Holze F, Arikci D, Becker AM, Straumann I, Klaiber A, Coviello F, Dierbach S, Thomann J, Duthaler U, Luethi D, Varghese N, Eckert A, Liechti ME | title = Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants | journal = Neuropsychopharmacology | volume = 48 | issue = 11 | pages = 1659–1667 | date = October 2023 | pmid = 37231080 | pmc = 10517157 | doi = 10.1038/s41386-023-01607-2 | url = }}</ref><ref name="HolzeVizeliLey2021">{{cite journal | vauthors = Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, Duthaler U, Varghese N, Eckert A, Borgwardt S, Liechti ME | title = Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects | journal = Neuropsychopharmacology | volume = 46 | issue = 3 | pages = 537–544 | date = February 2021 | pmid = 33059356 | pmc = 8027607 | doi = 10.1038/s41386-020-00883-6 | url = }}</ref><ref name="HolzeBeckerKolaczynska2023" /><ref name="HolzeVizeliMüller2020">{{cite journal | vauthors = Holze F, Vizeli P, Müller F, Ley L, Duerig R, Varghese N, Eckert A, Borgwardt S, Liechti ME | title = Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects | journal = Neuropsychopharmacology | volume = 45 | issue = 3 | pages = 462–471 | date = February 2020 | pmid = 31733631 | pmc = 6969135 | doi = 10.1038/s41386-019-0569-3 | url = }}</ref> Other dosing schemes have also been reported.<ref name="EngelThalBright2024">{{cite journal | last1=Engel | first1=Liam B. | last2=Thal | first2=Sascha | last3=Bright | first3=Stephen J. | last4=Low | first4=Mitchell | title=Psychedelic trip sitting, dosages and intensities: Supplementing clinical studies with anecdotal reports | journal=Journal of Psychedelic Studies | date=17 July 2024 | issn=2559-9283 | doi=10.1556/2054.2024.00377 | doi-access=free | url=https://akjournals.com/downloadpdf/view/journals/2054/aop/article-10.1556-2054.2024.00377/article-10.1556-2054.2024.00377.pdf | access-date=15 March 2025 | page=}}</ref>

{| class="wikitable" |+ Doses of major serotonergic psychedelics and MDMA |- ! Psychedelic !! LSDa !! Psilocybin !! Mescalineb !! DMT ({{Abbr|i.v.|intravenous infusion}})c !! MDMAd |- | Subthreshold or microdoses || <10 μg || <2.5 mg || <75 mg || {{Abbr|N/A|Not applicable}} || {{Abbr|N/A|Not applicable}} |- | Low dose/minidose || 20–50 μg || 5–10 mg || 100–200 mg || 0.6 mg/min || 25–50 mg |- | Intermediate/good effect dose || 100 μg || 20 mg || 500 mg || 1.2 mg/min || 125–200 mg |- | High/ego-dissolution dose || 200 μg || 30–40 mg || 1,000 mg || 1.8 mg/min || {{Abbr|N/A|Not applicable}} |- class="sortbottom" | colspan="8" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' (1) All doses are for oral administration unless otherwise indicated. (2) For the psychedelics, doses are considered to be roughly equivalent in terms of peak or overall response. '''Footnotes:''' a = As LSD free base (100{{nbsp}}μg LSD base = 146{{nbsp}}μg LSD tartrate). b = As mescaline hydrochloride. c = As DMT fumarate given as constant infusions for >30{{nbsp}}minutes. d = As MDMA hydrochloride. '''Refs:''' <ref name="HolzeSinghLiechti2024" /><ref name="LiechtiHolze2022">{{cite book | vauthors = Liechti ME, Holze F | title = Disruptive Psychopharmacology | chapter = Dosing Psychedelics and MDMA | series = Curr Top Behav Neurosci | volume = 56 | pages = 3–21 | date = 2022 | pmid = 34734392 | doi = 10.1007/7854_2021_270 | isbn = 978-3-031-12183-8 | chapter-url = https://www.researchgate.net/publication/355943062}}</ref><ref name="LeyHolzeArikci2023" /><ref name="HolzeVizeliLey2021" /><ref name="HolzeBeckerKolaczynska2023" /><ref name="HolzeVizeliMüller2020" /> |}

In the case of dried psilocybin-containing mushrooms, microdoses are 0.1{{nbsp}}g to 0.3{{nbsp}}g and psychedelic doses are 1.0{{nbsp}}g to 3.5–5.0{{nbsp}}g.<ref name="KozlowskaNicholsWiatr2022">{{cite journal | vauthors = Kozlowska U, Nichols C, Wiatr K, Figiel M | title = From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders | journal = J Neurochem | volume = 162 | issue = 1 | pages = 89–108 | date = July 2022 | pmid = 34519052 | doi = 10.1111/jnc.15509 | url = | quote = One dosing method of psychedelics is the use of so called "microdoses"—very low concentrations of various psychedelics that do not reach the threshold of perceivable behavioral effects. This is usually 10% of active recreational doses (e.g., 10–15 µg of LSD, or 0.1–0.3 g of dry "magic mushrooms") taken up to three times per week.}}</ref><ref name="vanAmsterdamOpperhuizenvandenBrink2011">{{cite journal | vauthors = van Amsterdam J, Opperhuizen A, van den Brink W | title = Harm potential of magic mushroom use: a review | journal = Regul Toxicol Pharmacol | volume = 59 | issue = 3 | pages = 423–429 | date = April 2011 | pmid = 21256914 | doi = 10.1016/j.yrtph.2011.01.006 | url = https://psilosybiini.info/paperit/Harm%20potential%20of%20magic%20mushroom%20use,%20A%20review%20(van%20Amsterdam%20et%20al.,%202011).pdf }}</ref><ref name="LoweToyangSteele2021">{{cite journal | vauthors = Lowe H, Toyang N, Steele B, Valentine H, Grant J, Ali A, Ngwa W, Gordon L | title = The Therapeutic Potential of Psilocybin | journal = Molecules | volume = 26 | issue = 10 | date = May 2021 | page = 2948 | pmid = 34063505 | pmc = 8156539 | doi = 10.3390/molecules26102948 | doi-access = free | s2cid = 235227972 }}</ref> The preceding 1.0 to 5.0{{nbsp}}g range corresponds to psilocybin doses of about 10 to 50{{nbsp}}mg.<ref name="LoweToyangSteele2021" /> Psilocybin-containing mushrooms vary in their psilocybin and psilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content).<ref name="vanAmsterdamOpperhuizenvandenBrink2011" /><ref name="PepeHesamidelaCerda2023">{{cite journal | vauthors = Pepe M, Hesami M, de la Cerda KA, Perreault ML, Hsiang T, Jones AM | title = A journey with psychedelic mushrooms: From historical relevance to biology, cultivation, medicinal uses, biotechnology, and beyond | journal = Biotechnol Adv | volume = 69 | issue = | article-number = 108247 | date = December 2023 | pmid = 37659744 | doi = 10.1016/j.biotechadv.2023.108247 | url = }}</ref><ref name="TylšPáleníčekHoráček2014" /><ref name="LoweToyangSteele2021" /><ref name="Nichols2020">{{cite journal | vauthors = Nichols DE | title = Psilocybin: from ancient magic to modern medicine | journal = J Antibiot (Tokyo) | volume = 73 | issue = 10 | pages = 679–686 | date = October 2020 | pmid = 32398764 | doi = 10.1038/s41429-020-0311-8 | url = https://www.researchgate.net/publication/341321407 | quote = Total psilocybin and psilocin levels in species known to be used recreationally varied from 0.1% to nearly 2% by dry weight [8]. The medium oral dose of psilocybin is 4–8 mg, which elicits the same symptoms as the consumption of about 2 g of dried Psilocybe Mexicana [9].}}</ref><ref name="KurzbaumPáleníčekShrchaton2025">{{cite journal | last1=Kurzbaum | first1=Eyal | last2=Páleníček | first2=Tomáš | last3=Shrchaton | first3=Amiel | last4=Azerrad | first4=Sara | last5=Dekel | first5=Yaron | title=Exploring Psilocybe cubensis Strains: Cultivation Techniques, Psychoactive Compounds, Genetics and Research Gaps | journal=Journal of Fungi | volume=11 | issue=2 | date=28 January 2025 | issn=2309-608X | doi=10.3390/jof11020099 | doi-access=free | page=99 | pmid=39997393 | pmc=11856550 }}</ref><ref name="GoffSmithIslam2024">{{cite journal | vauthors = Goff R, Smith M, Islam S, Sisley S, Ferguson J, Kuzdzal S, Badal S, Kumar AB, Sreenivasan U, Schug KA | title = Determination of psilocybin and psilocin content in multiple Psilocybe cubensis mushroom strains using liquid chromatography - tandem mass spectrometry | journal = Anal Chim Acta | volume = 1288 | issue = | article-number = 342161 | date = February 2024 | pmid = 38220293 | doi = 10.1016/j.aca.2023.342161 | bibcode = 2024AcAC.128842161G | url = | quote = A method for clinical potency determination of psilocybin and psilocin in hallucinogenic mushroom species Psilocybe cubensis was developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Five strains of dried, intact mushrooms were obtained and analyzed: Blue Meanie, Creeper, B-Plus, Texas Yellow, and Thai Cubensis. [...] From most to least potent, the study found that the average total psilocybin and psilocin concentrations for the Creeper, Blue Meanie, B+, Texas Yellow, and Thai Cubensis strains were 1.36, 1.221, 1.134, 1.103, and 0.879 % (w/w), respectively.}}</ref><ref name="GotvaldováBorovičkaHájková2022">{{cite journal | vauthors = Gotvaldová K, Borovička J, Hájková K, Cihlářová P, Rockefeller A, Kuchař M | title = Extensive Collection of Psychotropic Mushrooms with Determination of Their Tryptamine Alkaloids | journal = Int J Mol Sci | volume = 23 | issue = 22 | date = November 2022 |article-number=14068 | pmid = 36430546 | pmc = 9693126 | doi = 10.3390/ijms232214068 | doi-access = free | url = }}</ref> Psilocybin and psilocin are similar in potency and dose but psilocin is about 1.4-fold more active, this being related to the difference in molecular weight between the two compounds.<ref name="TylšPáleníčekHoráček2014" /><ref name="Hofmann1968">{{cite book | author = Albert Hofmann | chapter = Psychotomimetic Agents | pages = 169–235 | veditors = Burger A | title = Drugs Affecting the Central Nervous System | volume = 2 | date = 1968 | publisher = M. Dekker | location = New York | oclc = 245452885 | ol = OL13539506M | chapter-url = https://archive.org/details/drugsaffectingce0000edit/page/169/mode/1up | url = https://books.google.com/books?id=o_GMwgEACAAJ | quote = Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs.}}</ref><ref name="WolbachMinerIsbell1962">{{cite journal | vauthors = Wolbach AB, Miner EJ, Isbell H | title = Comparison of psilocin with psilocybin, mescaline and LSD-25 | journal = Psychopharmacologia | volume = 3 | issue = 3| pages = 219–223 | date = 1962 | pmid = 14007905 | doi = 10.1007/BF00412109 | url = | quote = Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs.}}</ref>

Some psychedelics, such as 2C-B, 2C-E, 2C-P, methallylescaline (MAL), and 4-HO-DiPT among others, have been said to have steep dose–response curves, meaning that the difference in dose between a light experience and an overwhelming disconnection from reality can be small.<ref name="PiHKAL1991" />{{rp|506,518}}<ref name="TiHKAL1997">{{cite book | author1 = Alexander T. Shulgin | author2 = Ann Shulgin | title = TiHKAL: The Continuation | publisher = Transform Press | date = 1997 | edition = 1st | location = Berkeley, CA | isbn = 978-0-9630096-9-2 | oclc = 38503252 }}</ref>{{rp|467}} Conversely, 2C-D is described as having an unusually wide and gradual dose range.<ref name="PiHKAL1991" /><ref name="Hardison2007">{{cite journal | last=Hardison | first=Casey | title=A brief history and motivation of an entheogenic chemist | journal=Drugs and Alcohol Today | volume=7 | issue=2 | date=1 July 2007 | issn=1745-9265 | doi=10.1108/17459265200700013 | pages=26–31 | url=http://www.emerald.com/dat/article/7/2/26-31/102048 | quote=2C-D has a very gentle dose-response curve with a fantastically large range. 2C-D is what some have called a 'pharmacological tofu' (Shulgin & Shulgin, 1991).}}</ref>

===Durations=== The typical durations of major psychedelics are as follows:<ref name="HolzeSinghLiechti2024" /><ref name="PiHKAL1991" /><ref name="TiHKAL1997" /><ref name="BallentineFriedmanBzdok2022">{{cite journal | vauthors = Ballentine G, Friedman SF, Bzdok D | title = Trips and neurotransmitters: Discovering principled patterns across 6850 hallucinogenic experiences | journal = Sci Adv | volume = 8 | issue = 11 | article-number = eabl6989 | date = March 2022 | pmid = 35294242 | pmc = 8926331 | doi = 10.1126/sciadv.abl6989 | bibcode = 2022SciA....8L6989B }}</ref>

* Psilocybin oral: 5–6 hours<ref name="HolzeSinghLiechti2024" /><ref name="GeigerWurstDaniels2018" /> * LSD oral: 7–11 hours (dose-dependent)<ref name="HolzeSinghLiechti2024" /><ref name="LiechtiHolze2022" /> * Mescaline oral: 10–11 hours (range 6–14 hours) (dose-dependent)<ref name="HolzeSinghLiechti2024" /><ref name="KlaiberSchmidBecker2024">{{cite journal | vauthors = Klaiber A, Schmid Y, Becker AM, Straumann I, Erne L, Jelusic A, Thomann J, Luethi D, Liechti ME | title = Acute dose-dependent effects of mescaline in a double-blind placebo-controlled study in healthy subjects | journal = Transl Psychiatry | volume = 14 | issue = 1 | article-number = 395 | date = September 2024 | pmid = 39349427 | pmc = 11442856 | doi = 10.1038/s41398-024-03116-2 | url = }}</ref> * Dimethyltryptamine (DMT) inhaled: 5–20 minutes<ref name="CarbonaroGatch2016" /><ref name="RodriguesAlmeidaVieira-Coelho2019">{{cite journal | vauthors = Rodrigues AV, Almeida FJ, Vieira-Coelho MA | title = Dimethyltryptamine: Endogenous Role and Therapeutic Potential | journal = J Psychoactive Drugs | volume = 51 | issue = 4 | pages = 299–310 | date = 2019 | pmid = 31018803 | doi = 10.1080/02791072.2019.1602291 | hdl = 10216/114373 | url = | hdl-access = free }}</ref><ref name="BallentineFriedmanBzdok2022" /> * Ayahuasca (oral DMT with an {{Abbrlink|MAOI|monoamine oxidase inhibitor}}): 4–6 hours<ref name="CarbonaroGatch2016" /><ref name="EggerAicherCumming2024" /><ref name="Brito-da-CostaDias-da-SilvaGomes2020">{{cite journal | vauthors = Brito-da-Costa AM, Dias-da-Silva D, Gomes NG, Dinis-Oliveira RJ, Madureira-Carvalho Á | title = Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact | journal = Pharmaceuticals (Basel) | volume = 13 | issue = 11 | date = October 2020 | page = 334 | pmid = 33114119 | pmc = 7690791 | doi = 10.3390/ph13110334 | doi-access = free | url = }}</ref> * 5-MeO-DMT inhaled: 5–20 minutes<ref name="ReckwegUthaugSzabo2022" /><ref name="HolzeSinghLiechti2024" /><ref name="BallentineFriedmanBzdok2022" /> * 2C-B oral: 3–5 hours (range 2–8 hours)<ref name="HolzeArikciThomann2025">{{cite journal | vauthors=Holze F, Arikci D, Thomann J, Luethi D, Liechti ME | title=ACNP 64th Annual Meeting: Poster Abstracts P584-P872: P654. Pharmacokinetics and pharmacodynamics of oral 4-bromo-2,5-dimethoxyphenethylamine (2C-B) administration in healthy participants | journal=Neuropsychopharmacology | publisher=Nature Publishing Group | volume=51 | issue=1 | date=18 December 2025 | issn=1740-634X | doi=10.1038/s41386-025-02281-2 | pages=410–571 (448–449) | pmid=41507446 | pmc=12783840 | pmc-embargo-date=January 1, 2027 | url=https://www.nature.com/articles/s41386-025-02281-2}}</ref><ref name="BallentineFriedmanBzdok2022" /><ref name="PiHKAL1991" /><ref name="MallaroniMasonReckweg2023">{{cite journal | vauthors = Mallaroni P, Mason NL, Reckweg JT, Paci R, Ritscher S, Toennes SW, Theunissen EL, Kuypers KP, Ramaekers JG | title = Assessment of the Acute Effects of 2C-B vs. Psilocybin on Subjective Experience, Mood, and Cognition | journal = Clin Pharmacol Ther | volume = 114 | issue = 2 | pages = 423–433 | date = August 2023 | pmid = 37253161 | doi = 10.1002/cpt.2958 | url = }}</ref>

The shortest-acting oral psychedelics are the less-well-known ASR-3001 (5-MeO-iPALT) (1.5–2.5 hours)<ref name="MooreDaley2024">{{cite podcast | host = Joe Moore | date = 2 April 2024 | title = Shulgin Farm and the Future of Psychedelic Drug Development (Featuring: Paul F. Daley, Ph.D.) | url = https://psychedelicstoday.com/2024/04/02/shulgin-farm-and-the-future-of-psychedelic-drug-development/ | publisher = Psychedelics Today | time = 16:12–20:45 | quote=[ASR-3001] is a tryptamine that's orally active, fast-onset, the latent period before you start to feel effects is as little as 6 to 8 minutes, relatively short-acting, 90 minutes to two and a half hours, and satisfyingly internally psychedelic as opposed to entactogenic. [...]}}</ref><ref name="Goldstein2023">{{cite web | vauthors = Goldstein L | title=Pioneering Psychedelics Scientist Alexander "Sasha" Shulgin's Legacy Lives On Via New Compounds And Research | website=Benzinga | date=10 July 2023 | url=https://www.benzinga.com/markets/cannabis/23/07/33171977/pioneering-psychedelics-scientist-alexander-sasha-shulgins-legacy-lives-on-via-new-compounds-and | access-date=19 April 2025}}</ref> and 4-HO-DiPT (2–3 hours),<ref name="TiHKAL1997" /> while the longest-acting known psychedelic is 2C-G-5 (32–48 hours).<ref name="TrachselLehmannEnzensperger2013" /><ref name="PiHKAL1991" /> However, DOx psychedelics like DOM and the FLY psychedelic Bromo-DragonFLY (DOB-DFLY) reportedly may produce effects lasting for up to a few days at high doses.<ref name="CorazzaSchifanoFarre2011">{{cite journal | vauthors = Corazza O, Schifano F, Farre M, Deluca P, Davey Z, Torrens M, Demetrovics Z, Di Furia L, Flesland L, Siemann H, Skutle A, Van Der Kreeft P, Scherbaum N | title = Designer drugs on the internet: a phenomenon out-of-control? the emergence of hallucinogenic drug Bromo-Dragonfly | journal = Curr Clin Pharmacol | volume = 6 | issue = 2 | pages = 125–129 | date = May 2011 | pmid = 21592070 | doi = 10.2174/157488411796151129 | hdl = 2299/10464 | url = }}</ref><ref name="MallaroniMasonVinckenbosch2022">{{cite journal | vauthors = Mallaroni P, Mason NL, Vinckenbosch FR, Ramaekers JG | title = The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1783–1796 | date = June 2022 | pmid = 35487983 | doi = 10.1007/s00213-022-06142-4 | url = https://isomerdesign.com/bitnest/external/10.1007/s00213-022-06142-4}}</ref><ref name="HillThomas2011" /><ref name="Baggott2023" /><ref name="TroutDaley2024">{{cite journal | vauthors = Trout K, Daley PF | title = The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) | journal = Drug Test Anal | volume = 16 | issue = 12 | pages = 1496–1508 | date = December 2024 | pmid = 38419183 | doi = 10.1002/dta.3667 | url = https://shulginresearch.net/wp-content/uploads/2024/03/The-origin-of-25-dimethoxy-4-methylamphetamine-DOM-STP.-Trout.-Drug-Test.-Anal.-DOI-10.1002-dta.3667-2024.pdf}}</ref>

==Effects== ===Psychedelic effects=== {{Main|Psychedelic experience}}

Although several attempts have been made, starting in the 19th and 20th centuries, to define common phenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist.<ref>{{Cite book|last1=Preller|first1=Katrin H.|title=Behavioral Neurobiology of Psychedelic Drugs|last2=Vollenweider|first2=Franz X. |date=2016|publisher=Springer Berlin Heidelberg|isbn=978-3-662-55878-2|editor1=Adam L. Halberstadt |editor2=Franz X. Vollenweider |editor3=David E. Nichols |volume=36|location=Berlin, Heidelberg|pages=221–256|chapter=Phenomenology, Structure, and Dynamic of Psychedelic States |series=Current Topics in Behavioral Neurosciences|doi=10.1007/7854_2016_459|pmid=28025814}}</ref><ref name="swanson">{{Cite journal |last=Swanson|first=Link R.|date=2018-03-02|title=Unifying Theories of Psychedelic Drug Effects|journal=Frontiers in Pharmacology |volume=9 |article-number=172|doi=10.3389/fphar.2018.00172|pmid=29568270|pmc=5853825|issn=1663-9812|doi-access=free}}</ref> At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, pareidolia, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes or form constants are common as well. Higher doses often cause intense and fundamental alterations of sensory (notably visual) perception, such as synesthesia or the experience of additional spatial or temporal dimensions.<ref>{{cite journal|author1=Luke, David|title=Rock Art or Rorschach: Is there More to Entoptics than Meets the Eye?|journal=Time and Mind|date=28 November 2013|volume=3|issue=1|pages=9–28 |doi=10.2752/175169710x12549020810371|s2cid=144948636}}</ref> Tryptamines are well documented to cause classic psychedelic states, such as increased empathy, visual distortions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution or ego death with high enough dose, mystical, transpersonal and spiritual experiences, autonomous "entity" encounters, time distortion, closed eye hallucinations and complete detachment from reality with a high enough dose.<ref>{{Cite journal |last=Berry |first=Mark D.|date=July 2004|title=Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators |journal=Journal of Neurochemistry|volume=90|issue=2|pages=257–271|doi=10.1111/j.1471-4159.2004.02501.x |pmid=15228583 |s2cid=12126296 |issn=0022-3042|doi-access=free}}</ref> Luis Luna describes psychedelic experiences as having a distinctly gnosis-like quality, and says that they offer "learning experiences that elevate consciousness and can make a profound contribution to personal development."<ref name="luna-peru">{{cite journal |last1=Luna |first1=Luis Eduardo |title=The concept of plants as teachers among four mestizo shamans of Iquitos, northeastern Peru |journal=Journal of Ethnopharmacology |date=1984 |volume=11 |issue=2 |pages=135–156 |doi=10.1016/0378-8741(84)90036-9 |pmid=6492831 |url=http://home.iscte-iul.pt/~fgvs/Luna_plants.pdf |access-date=10 July 2020}}</ref> Czech psychiatrist Stanislav Grof studied the effects of psychedelics like LSD early in his career and said of the experience, that it commonly includes "complex revelatory insights into the nature of existence… typically accompanied by a sense of certainty that this knowledge is ultimately more relevant and 'real' than the perceptions and beliefs we share in everyday life."{{citation needed|date=January 2023}} Traditionally, the standard model for the subjective phenomenological effects of psychedelics has typically been based on LSD, with anything that is considered "psychedelic" evidently being compared to it and its specific effects.<ref name="Nichols2016" />

Good trips are reportedly deeply pleasurable, and typically involve intense joy or euphoria, a greater appreciation for life, reduced anxiety, a sense of spiritual enlightenment, and a sense of belonging or interconnectedness with the universe.<ref name="erowid-faq">{{cite web | vauthors = Honig D | url = https://www.erowid.org/chemicals/lsd/lsd_faq.shtml | title = Frequently Asked Questions | archive-url = https://web.archive.org/web/20160212232436/https://www.erowid.org/chemicals/lsd/lsd_faq.shtml | archive-date = 12 February 2016 | work = Erowid }}</ref><ref name="PMID6054248">{{cite journal | vauthors = McGlothlin W, Cohen S, McGlothlin MS | title = Long lasting effects of LSD on normals | journal = Archives of General Psychiatry | volume = 17 | issue = 5 | pages = 521–32 | date = November 1967 | pmid = 6054248 | doi = 10.1001/archpsyc.1967.01730290009002 | url = http://www.maps.org/w3pb/new/1967/1967_mcglothlin_4655_1.pdf | archive-url = https://web.archive.org/web/20110430020912/http://www.maps.org/w3pb/new/1967/1967_mcglothlin_4655_1.pdf | archive-date = April 30, 2011 }}</ref> Negative experiences, colloquially known as "bad trips," evoke an array of dark emotions, such as irrational fear, anxiety, panic, paranoia, dread, distrustfulness, hopelessness, and even suicidal ideation.<ref name="cdasa">{{cite web|url=http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-26.html#h-30 |title=Controlled Drugs and Substances Act |access-date=December 15, 2013 |publisher=Canadian Department of Justice |year=1996 |author=Canadian government |website=Justice Laws |archive-url=https://web.archive.org/web/20131215170432/http://laws-lois.justice.gc.ca/eng/acts/C-38.8/page-26.html |archive-date=December 15, 2013 }}</ref> While it is impossible to predict when a bad trip will occur, one's mood, surroundings, sleep, hydration, social setting, and other factors can be controlled (colloquially referred to as "set and setting") to minimize the risk of a bad trip.<ref name=MedlinePlus>{{citation|title=Substance use – LSD | vauthors = Rogge T |date=21 May 2014|access-date=14 July 2016|publisher=MedlinePlus, U.S. National Library of Medicine|url=https://medlineplus.gov/ency/patientinstructions/000795.htm|url-status=live|archive-url=https://web.archive.org/web/20160728004220/https://medlineplus.gov/ency/patientinstructions/000795.htm|archive-date=July 28, 2016|df=mdy-all}}</ref><ref name=CESAR>{{citation|title=LSD |author=CESAR |publisher=Center for Substance Abuse Research, University of Maryland |date=29 October 2013 |access-date=14 July 2016 |url=http://www.cesar.umd.edu/cesar/drugs/lsd.asp |archive-url=https://web.archive.org/web/20160715071823/http://www.cesar.umd.edu/cesar/drugs/lsd.asp |archive-date=July 15, 2016 }}</ref> The concept of "set and setting" also generally appears to be more applicable to psychedelics than to other types of hallucinogens such as deliriants, hypnotics and dissociative anesthetics.<ref>{{cite journal |last1=Garcia-Romeu |first1=Albert |last2=Kersgaard |first2=Brennan |last3=Addy |first3=Peter H. |title=Clinical applications of hallucinogens: A review. |journal=Experimental and Clinical Psychopharmacology |date=August 2016 |volume=24 |issue=4 |pages=229–268 |doi=10.1037/pha0000084|pmid=27454674 |pmc=5001686 }}</ref>

Psychedelics include naturally occurring tryptamines like psilocybin and DMT, the naturally occurring phenethylamine mescaline, and naturally occurring lysergamides like ergine (lysergic acid amide; LSA), as well as synthetic analogues and derivatives like LSD and 2C-B. Many of these psychedelics cause remarkably similar effects, despite their different chemical structures.{{Citation needed|date=April 2025}} However, many users anecdotally report that the three major families have subjectively different qualities in the "feel" of the experience, which are difficult to describe.{{Citation needed|date=April 2025}} There can also be very substantial differences between the drugs; for instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics.<ref name="Nichols2016"/><ref name="DourronNicholsSimonsson2023">{{cite journal | vauthors = Dourron HM, Nichols CD, Simonsson O, Bradley M, Carhart-Harris R, Hendricks PS | title = 5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk? | journal = Psychopharmacology (Berl) | volume = 242| issue = 7| pages = 1457–1479| date = December 2023 | pmid = 38072874 | doi = 10.1007/s00213-023-06517-1 | url = }}</ref> As additional examples, DiPT is said to primarily affect the auditory sense,<ref name="TittarelliMannocchiPantano2015">{{cite journal | vauthors = Tittarelli R, Mannocchi G, Pantano F, Romolo FS | title = Recreational use, analysis and toxicity of tryptamines | journal = Curr Neuropharmacol | volume = 13 | issue = 1 | pages = 26–46 | date = January 2015 | pmid = 26074742 | pmc = 4462041 | doi = 10.2174/1570159X13666141210222409 }}</ref><ref name="PiHKAL1991" /> 2C-T,<ref name="PiHKAL1991" /> 2C-T-17,<ref name="PiHKAL1991" /> MiPT,<ref name="TiHKAL1997" /> and ASR-3001 (5-MeO-iPALT)<ref name="Goldstein2023">{{cite web | vauthors = Goldstein L | title=Pioneering Psychedelics Scientist Alexander "Sasha" Shulgin's Legacy Lives On Via New Compounds And Research | website=Benzinga | date=10 July 2023 | url=https://www.benzinga.com/markets/cannabis/23/07/33171977/pioneering-psychedelics-scientist-alexander-sasha-shulgins-legacy-lives-on-via-new-compounds-and | access-date=19 April 2025}}</ref><ref name="Busby2023">{{cite web | vauthors = Busby M | title=The Heirs to a Vault of Novel Psychedelics Take a Trip Into the Unknown | website=DoubleBlind Mag | date=2 November 2023 | url=https://doubleblindmag.com/sasha-shulgin-legacy/ | access-date=19 April 2025}}</ref><ref name="Busby2025">{{cite web | vauthors = Busby M | title=What Happens When You Inherit 500 Psychedelic Compounds? | website=DoubleBlind Mag | date=30 March 2025 | url=https://doubleblindmag.com/what-happens-when-you-inherit-500-psychedelic-compounds/ | access-date=19 April 2025}}</ref> are said to produce psychedelic effects on thinking or "head space" with few or no visuals, and ''N''-methyltryptamine (NMT) is said to be a spatial psychedelic.<ref name="Nen2011">{{cite conference | author = Nen | title = Entheogenic effects of NMT from Acacia | conference = Entheogenesis Australis (EGA) Conference, Victoria, Australia, 2–5 December 2011 | date = 4 December 2011 | url = https://www.dmt-nexus.me/forum/default.aspx?g=posts&m=300323&%23post300323 | conference-url = https://web.archive.org/web/20120226052047/http://www.entheo.net/files/webfiles/ega11_program_v7.pdf}}</ref><ref name="Nen2013">{{cite conference | author = Nen | title = NMT: A Spatial Hallucinogen With Therapeutic Applications | conference = Breaking Convention: The Second Multidisciplinary Conference on Psychedelic Consciousness, University of Greenwich, London, 12–14 July 2013 | date = 13 July 2013 | url = https://www.youtube.com/watch?v=98WXxyb2u4A | conference-url = https://breakingconvention.co.uk/archive#conferenceArchive}}</ref>

The visuals of psychedelics have been reproduced, with these creations known as psychedelic replications.<ref name="Friedler2022">{{cite web | last=Friedler | first=Delilah | title=AI Can Now Generate DMT Visuals, Thanks To This Online Community | website=DoubleBlind Mag | date=15 June 2022 | url=https://doubleblindmag.com/ai-can-now-generate-dmt-visuals/ | access-date=15 March 2025}}</ref><ref name="Magee2023">{{cite web | last=Magee | first=Tamlin | title=DMT Users Are Using AI to Draw the Strange Beings They Meet While Tripping | website=VICE | date=24 April 2023 | url=https://www.vice.com/en/article/dmt-users-are-using-ai-to-draw-the-strange-beings-they-meet-while-tripping/ | access-date=15 March 2025}}</ref><ref name="Bilderbeck2022">{{cite web | last=Bilderbeck | first=Poppy | title=Video shows 'most accurate' representation of what psychedelic visuals look like | website=UNILAD | date=23 November 2022 | url=https://www.unilad.com/news/most-accurate-representation-psychedelic-visuals-20221123 | access-date=15 March 2025}}</ref><ref name="French2023">{{cite web | last=French | first=Kristen | title=What Hallucinogens Will Make You See | website=Nautilus | date=2 June 2023 | url=https://nautil.us/what-hallucinogens-will-make-you-see-308247/ | access-date=15 March 2025}}</ref><ref name="Rosa2022">{{cite web | last=Rosa | first=Tomáš | title=Jak člověk vidí svět pod vlivem halucinogenů? Vědkyně vytvořila přesná videa | trans-title=How does one see the world under the influence of hallucinogens? A scientist created accurate video | website=Deník.cz | date=25 November 2022 | url=https://www.denik.cz/veda/halucinogeny-drogy-uzivani-video.html?dop_source_zone_name=hpfeed.sznhp.box | language=cs | access-date=15 March 2025}}</ref>

Some rare individuals do not experience hallucinogenic effects with serotonergic psychedelics.<ref name="SpangemacherColmeneroScharf2024">{{cite journal | last1=Spangemacher | first1=M. | last2=Colmenero | first2=A.Y. Silva | last3=Scharf | first3=D.J. | last4=Brand | first4=M. | last5=Rohrmoser | first5=B. | last6=Kärtner | first6=L. | last7=Mertens | first7=L. | last8=Evens | first8=R. | last9=Gründer | first9=G. | last10=Wolff | first10=M. | title=Absence of psychedelic effects: case series and systematic literature review | journal=Neuroscience Applied | volume=3 | date=2024 | doi=10.1016/j.nsa.2024.104769 | doi-access=free | article-number=104769}}</ref>

===Other psychoactive effects=== Some psychedelics have been associated with other psychoactive effects in addition to their hallucinogenic effects.<ref name="Kuypers2024">{{cite book | last=Kuypers | first=Kim P. C. | title=Modern CNS Drug Discovery | chapter=Microdosing Psychedelics as a Promising New Pharmacotherapeutic | publisher=Springer Nature Switzerland | publication-place=Cham | date=2024 | isbn=978-3-031-61991-5 | doi=10.1007/978-3-031-61992-2_26 | chapter-url=https://link.springer.com/10.1007/978-3-031-61992-2_26 | access-date=28 May 2025 | pages=407–436 | quote=Interestingly, users sometimes attribute other effects to different psychedelics, in which LSD is more associated with cognitive and/or stimulant effects and psilocybin with emotional or well-being effects (Anderson et al. 2019b; Johnstad 2018). This stronger stimulant character of LSD compared to psilocybin was seen by some as an advantage while others experienced it as uncomfortable (Johnstad 2018). [...] Additionally, McGlothlin et al. (1967) showed that LSD (25 mcg) indeed induces stimulant effects, as the effects were similar to those of amphetamine (20 mg) (McGlothlin et al. 1967). Notwithstanding this does not confirm that psilocybin and LSD would have dissimilar effects; it rather supports the claims by users that LSD in low doses has stimulant effects (Johnstad 2018; Anderson et al. 2019a). [...] Decades earlier, Albert Hofmann, the "discoverer" of LSD and its hallucinogenic effects, mentioned that "very small doses, perhaps 25 micrograms," could be useful as an antidepressant (Ghose 2015; Horowitz 1976) or as a substitute for Ritalin (Fadiman 2017; Horowitz 1976).}}</ref><ref name="Baggott2023" /><ref name="PiHKAL1991" /> For example, psychedelics like LSD and DOM have been described as having mild stimulant and/or "psychic-energizing" (i.e., acute antidepressant) effects.<ref name="Kuypers2024" /><ref name="Baggott2023">{{cite journal | vauthors = Baggott MJ | title=Learning about STP: A Forgotten Psychedelic from the Summer of Love | journal=History of Pharmacy and Pharmaceuticals | volume=65 | issue=1 | date=1 October 2023 | issn=2694-3034 | doi=10.3368/hopp.65.1.93 | doi-access=free | pages=93–116 | url=https://hopp.uwpress.org/content/wphopp/65/1/93.full.pdf | access-date=26 January 2025 | quote=The Grateful Dead learned they could use small amounts as a stimulant, an effect they used extensively during the recording of the album Aoxomoxoa in 1968 and 1969.143 The use of lower doses of DOM echoed DOET's "psychic energizer" effects and may be the first documented use of subpsychedelic doses of a psychedelic for cognitive enhancement, a practice that is now called microdosing.144}}</ref> Some psychedelics and related drugs, like DOET (low doses), Ariadne, and ASR-2001 (2CB-5PrO), have been investigated specifically for such effects.<ref name="Baggott2023" /><ref name="PiHKAL1991" /><ref name="ShulginManningDaley2011-Ariadne">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter = #7. ARIADNE | pages = 7–9 | chapter-url = https://archive.org/details/shulgin-index-vol-1/page/7/mode/1up | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher = Transform Press | location = Berkeley, CA | volume = 1 | year = 2011 | isbn = 978-0-9630096-3-0 | oclc = 709667010}}</ref><ref name="CunninghamBockSerrano2023">{{cite journal | vauthors = Cunningham MJ, Bock HA, Serrano IC, Bechand B, Vidyadhara DJ, Bonniwell EM, Lankri D, Duggan P, Nazarova AL, Cao AB, Calkins MM, Khirsariya P, Hwu C, Katritch V, Chandra SS, McCorvy JD, Sames D | title = Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs | journal = ACS Chemical Neuroscience | volume = 14 | issue = 1 | pages = 119–135 | date = January 2023 | pmid = 36521179 | pmc = 10147382 | doi = 10.1021/acschemneuro.2c00597 }}</ref><ref name="Busby2023"/> 2C-B has been said to have mild entactogenic effects at low doses.<ref name="LuethiLiechti2020">{{cite journal | vauthors = Luethi D, Liechti ME | title = Designer drugs: mechanism of action and adverse effects | journal = Arch Toxicol | volume = 94 | issue = 4 | pages = 1085–1133 | date = April 2020 | pmid = 32249347 | pmc = 7225206 | doi = 10.1007/s00204-020-02693-7 | bibcode = 2020ArTox..94.1085L | quote = In one of the few clinical studies of a designer drug, 4-bromo-2,5-dimethoxyphenylethylamine (2C-B) was shown to induce euphoria, well-being, and changes in perception, and to have mild stimulant properties (Gonzalez et al. 2015). 2C-B may thus be classified as a psychedelic with entactogenic properties, an effect profile that is similar to various other phenethylamine psychedelics (Shulgin and Shulgin 1995).}}</ref><ref name="WillsErickson2012">{{cite book | vauthors = Wills B, Erickson T | chapter = Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives | editor-last=Barceloux | editor-first=Donald G. | title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants | publisher=Wiley | date=9 March 2012 | isbn=978-0-471-72760-6 | doi=10.1002/9781118105955.ch10 | pages=156–192 | quote=DOSE EFFECT: Anecdotal data suggests that recreational doses of 2C-B range from 4—30 mg with lower doses (4—10 mg) producing entactogenic effects, whereas high doses (10— 20 mg) cause psychedelic and sympathomimetic effects.}}</ref><ref name="GonzálezTorrensFarré2015">{{cite journal | vauthors = González D, Torrens M, Farré M | title = Acute Effects of the Novel Psychoactive Drug 2C-B on Emotions | journal = BioMed Research International | volume = 2015 |article-number=643878 | date = 2015-10-12 | pmid = 26543863 | doi = 10.1155/2015/643878 | pmc = 4620274 | doi-access = free }}</ref><ref name="Oeri2021" /> 5-MeO-DiPT and 5-MeO-MiPT have unique and unusual effects at typical doses including tactile and sexual enhancement, mild entactogenic effects, and only light hallucinogenic effects.<ref name="TiHKAL1997" /><ref name="PalamarAcosta2020">{{cite journal | vauthors = Palamar JJ, Acosta P | title = A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamines | journal = Hum Psychopharmacol | volume = 35 | issue = 1 | article-number = e2719 | date = January 2020 | pmid = 31909513 | pmc = 6995261 | doi = 10.1002/hup.2719 | url = }}</ref><ref name="ShulginCarter1980">{{cite journal | vauthors = Shulgin AT, Carter MF | title = N, N-Diisopropyltryptamine (DIPT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT). Two orally active tryptamine analogs with CNS activity | journal = Commun Psychopharmacol | volume = 4 | issue = 5 | pages = 363–369 | date = 1980 | pmid = 6949674 | doi = | url = https://bitnest.netfirms.com/external/Commun.Psychopharmacol/4.5.363}}</ref><ref name="Aragón2024">{{cite web | last=Aragón | first=Matthew | title=Meet Moxy: The Novel Psychedelic the DEA Tried To Ban | website=DoubleBlind Mag | date=9 January 2024 | url=https://doubleblindmag.com/what-is-moxy/ | access-date=8 October 2025}}</ref><ref name="Oeri2021" />

Some drugs, such as MDxx compounds like MDMA and MDA as well as α-alkyltryptamines like α-methyltryptamine (AMT), are entactogens and/or stimulants acting at monoamine transporters in addition to having varying degrees of psychedelic effects.<ref name="Oeri2021" /><ref name="DunlapAndrewsOlson2018" /><ref name="PiHKAL1991" />

===Psychedelic afterglows=== Psychedelics are associated with an afterglow, also known as positive subacute or post-experience effects, which may last days or even weeks after the psychedelic experience.<ref name="EvensSchmidtMajić2023">{{cite journal | vauthors = Evens R, Schmidt ME, Majić T, Schmidt TT | title = The psychedelic afterglow phenomenon: a systematic review of subacute effects of classic serotonergic psychedelics | journal = Ther Adv Psychopharmacol | volume = 13 | issue = | article-number = 20451253231172254 | date = 2023 | pmid = 37284524 | pmc = 10240558 | doi = 10.1177/20451253231172254 | url = }}</ref><ref name="MajićSchmidtGallinat2015" /><ref name="BasedowMajićHafiz2024">{{cite journal | vauthors = Basedow LA, Majić T, Hafiz NJ, Algharably EA, Kreutz R, Riemer TG | title = Cognitive functioning associated with acute and subacute effects of classic psychedelics and MDMA - a systematic review and meta-analysis | journal = Sci Rep | volume = 14 | issue = 1 | article-number = 14782 | date = June 2024 | pmid = 38926480 | pmc = 11208433 | doi = 10.1038/s41598-024-65391-9 | bibcode = 2024NatSR..1414782B | url = }}</ref><ref name="MajićSchmidtGröticke2025">{{cite journal | vauthors = Majić T, Schmidt TT, Gröticke A, Gasser P, Richards WA, Riemer TG, Evens R | title = The Afterglow Inventory (AGI): Validation of a new instrument for measuring subacute effects of classic serotonergic psychedelics | journal = J Psychopharmacol | volume = 39| issue = 5| pages = 474–488 | date = March 2025 | pmid = 40165350 | doi = 10.1177/02698811251326937 | pmc = 12099019 | url = }}</ref> These effects include reduction in psychopathology and increased well-being, mood, mindfulness, social functioning, spirituality, and executive functioning, and positive behavioral changes.<ref name="EvensSchmidtMajić2023" /> They also include mixed changes in personality, values, attitudes, creativity, and flexibility, as well as adverse effects like headaches, sleep disturbances, and sometimes increased psychological distress.<ref name="EvensSchmidtMajić2023" /> The afterglow period has been associated with changes in brain function, neuroplasticity, and immune system function.<ref name="BasedowMajićHafiz2024" /><ref name="ChisamoreKaczmarekLe2024" /><ref name="Kinderlehrer2025">{{cite journal | vauthors = Kinderlehrer DA | title = Mushrooms, Microdosing, and Mental Illness: The Effect of Psilocybin on Neurotransmitters, Neuroinflammation, and Neuroplasticity | journal = Neuropsychiatr Dis Treat | volume = 21 | issue = | pages = 141–155 | date = 2025 | pmid = 39897712 | pmc = 11787777 | doi = 10.2147/NDT.S500337 | doi-access = free | url = | quote = Mason et al studied the immune status of healthy humans after administration of oral psilocybin compared with placebo, and found an immediate reduction in the plasma concentration of TNF-α in the treatment group.Citation106 Although there was no immediate change in IL-6 and CRP, at seven days these levels were reduced while TNF-α concentrations had returned to baseline. They also documented an association between the degree of reduction of IL-6 and CRP and the positive effect on the participants' mood and social activity.}}</ref><ref name="MasonSzaboKuypers2023">{{cite journal | vauthors = Mason NL, Szabo A, Kuypers KP, Mallaroni PA, de la Torre Fornell R, Reckweg JT, Tse DH, Hutten NR, Feilding A, Ramaekers JG | title = Psilocybin induces acute and persisting alterations in immune status in healthy volunteers: An experimental, placebo-controlled study | journal = Brain Behav Immun | volume = 114 | issue = | pages = 299–310 | date = November 2023 | pmid = 37689275 | doi = 10.1016/j.bbi.2023.09.004 | url = | doi-access = free }}</ref> Both psychological and pharmacological effects may be involved in the afterglow phenomenon.<ref name="MajićSchmidtGallinat2015">{{cite journal | vauthors = Majić T, Schmidt TT, Gallinat J | title = Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences? | journal = J Psychopharmacol | volume = 29 | issue = 3 | pages = 241–253 | date = March 2015 | pmid = 25670401 | doi = 10.1177/0269881114568040 | url = }}</ref>

In 1898, the English writer and intellectual Havelock Ellis reported a heightened perceptual sensitivity to "the more delicate phenomena of light and shade and color" for a prolonged period of time after his exposure to mescaline.<ref name="Hanson2013">{{cite news |last1=Hanson |first1=Dirk |title=When the Trip Never Ends |url=https://dana.org/article/when-the-trip-never-ends/ |work=Dana Foundation |date=29 April 2013 }}</ref> The term "psychedelic afterglow" was first formally coined in the 1960s.<ref name="EvensSchmidtMajić2023" /> Albert Hofmann, the discoverer of LSD, said the following about the aftermath of his first full LSD experience in his 1980 book ''LSD: My Problem Child'':<ref name="Hofmann2013">{{cite book |last1=Hofmann |first1=Albert |title=LSD: My Problem Child |date=2013 |orig-date=1980|publisher=OUP Oxford |isbn=978-0-19-963941-0 |page=22|url=https://books.google.com/books?id=glPNoC2N-IgC&pg=PA22}}</ref>

{{Blockquote | text = Exhausted, I then slept, to awake next morning refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity, which persisted for the entire day. }}

During a speech on his 100th birthday in 2006, Hofmann additionally said of LSD:<ref>{{cite magazine |url=https://www.wired.com/science/discoveries/news/2006/01/70015?currentPage=2 |title=LSD: The Geek's Wonder Drug? |magazine=Wired |date=16 January 2006 |access-date=29 April 2008}}</ref>

{{Blockquote | text = It gave me an inner joy, an open mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation... I think that in human evolution it has never been as necessary to have this substance LSD. It is just a tool to turn us into what we are supposed to be. }}

==Contraindications== {{See also|Psilocybin#Contraindications}}

==Adverse effects== {{See also|Risks of psychedelic drugs|Bad trip|Trip sitter}}

Psychedelic drugs are addictive psychologically, with little to no physical addiction in classical psychedelics.<ref name="canada-commission"/><ref name="Ungless 2006"/><ref name="Nichols2016"/>

Risks do exist during an unsupervised psychedelic experience, however; Ira Byock wrote in 2018 in the ''Journal of Palliative Medicine'' that psilocybin is safe when administered to a properly screened patient and supervised by a qualified professional with appropriate set and setting. However, he called for an "abundance of caution" because in the absence of these conditions a range of negative reactions is possible, including "fear, a prolonged sense of dread, or full panic." He notes that driving or even walking in public can be dangerous during a psychedelic experience because of impaired hand-eye coordination and fine motor control.<ref name="byock-2018">{{cite journal |last1=Byock |first1=Ira |author-link1=Ira Byock |title=Taking Psychedelics Seriously |journal=Journal of Palliative Medicine |date=2018 |volume=21 |issue=4 |pages=417–421 |doi=10.1089/jpm.2017.0684 |pmid=29356590 |pmc=5867510}}</ref> In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.<ref name="Nichols2016"/>

A significant risk involves extended difficulties and persistent mental health effects following the acute experience.<ref name="EvansExtended">{{cite journal|title=Extended difficulties following the use of psychedelic drugs: A mixed methods study|first1=Jules|last1=Evans|first2=Oliver C.|last2=Robinson|first3=Eirini Ketzitzidou|last3=Argyri|first4=Shayam|last4=Suseelan|first5=Ashleigh|last5=Murphy-Beiner|first6=Rosalind|last6=McAlpine|first7=David|last7=Luke|first8=Katrina|last8=Michelle|first9=Ed|last9=Prideaux|date=October 24, 2023|journal=PLOS ONE|volume=18|issue=10|article-number=e0293349|doi=10.1371/journal.pone.0293349|doi-access=free |pmid=37874826|pmc=10597511 |bibcode=2023PLoSO..1893349E }}</ref> A 2023 international survey found 14% of respondents felt more anxious for an extended period following ingestion.<ref name="EvansExtended"/> In one survey<ref>{{cite journal |last1=Simonsson |first1=Otto |last2=Hendricks |first2=Peter S. |last3=Chambers |first3=Richards |last4=Osika |first4=Walter |last5=Goldberg |first5=Simon B. |title=Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics |journal=Journal of Affective Disorders |date=1 April 2023 |volume=326 |pages=105–110 |doi=10.1016/j.jad.2023.01.073 |pmid=36720405 |pmc=9974873 }}</ref>, 9% of users reported functional impairment lasting at least 24 hours beyond the trip itself. In another survey of 608 people who all reported post-psychedelic difficulties, one third of the dataset said the difficulties lasted longer than a year, and one fifth said the difficulties lasted longer than three years. The most commonly-reported post-psychedelic difficulties in that study were anxiety, feeling traumatized by the experience or uncovering earlier trauma, social isolation, derealization/depersonalization, visual distortions and existential confusion.<ref name="Argyri">{{cite journal |last1=Argyri |first1=Eirini K. |last2=Evans |first2=Jules |last3=Luke |first3=David |last4=Michael |last5=Michelle |first5=Katrina |last6=Rohani-Shukla |first6=Cyrus |last7=Suseelan |first7=Shayam |last8=Prideaux |first8=Ed |last9=McAlpine |first9=Rosalind |last10=Murphy-Beiner |first10=Ashleigh |last11=Robinson |first11=Oliver C. |title=Navigating groundlessness: An interview study on dealing with ontological shock and existential distress following psychedelic experiences |journal=PLOS ONE |date=5 May 2025 |volume=20 |issue=5 |article-number=e0322501 |doi=10.1371/journal.pone.0322501 |pmid=40323979 |pmc=12052184 |bibcode=2025PLoSO..2022501A |doi-access=free }}</ref> Most people recover from these difficulties with the help of accurate information<ref>{{cite web |title=Difficulties after psychedelics |url=https://challengingpsychedelicexperiences.com/symptoms/ |website=Challenging Psychedelic Experiences |access-date=11 December 2025}}</ref>, social support, and therapy.

Psilocybin-induced states of mind share features with states experienced in psychosis, and while a causal relationship between psilocybin and the onset of psychosis has not been established as of 2011, researchers have called for investigation of the relationship.<ref name="van-amsterdam-et-al">{{cite journal |last1=van Amsterdam |first1=Jan |last2=Opperhuizen |first2=Antoon |last3=van den Brink |first3=Wim |date=2011 |title=Harm potential of magic mushroom use: A review |journal=Regulatory Toxicology and Pharmacology |volume=59 |issue=3 |pages=423–429 |doi=10.1016/j.yrtph.2011.01.006 |pmid=21256914}}</ref> Many of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context.<ref>{{Cite journal|last1=Schlag|first1=Anne K|last2=Aday|first2=Jacob|last3=Salam|first3=Iram|last4=Neill|first4=Jo C|last5=Nutt|first5=David J|date=2022-02-02|title=Adverse effects of psychedelics: From anecdotes and misinformation to systematic science|journal=Journal of Psychopharmacology|volume=36|issue=3|pages=258–272|doi=10.1177/02698811211069100|pmid=35107059|pmc=8905125|issn=0269-8811}}</ref> A population study on associations between psychedelic use and mental illness published in 2013 found no evidence that psychedelic use was associated with increased prevalence of any mental illness.<ref>{{cite journal|author1=Krebs, Teri S.|author2=Johansen, Pål-Ørjan|author3=Lu, Lin|title=Psychedelics and Mental Health: A Population Study|journal=PLOS ONE|date=19 August 2013|volume=8|issue=8|article-number=e63972|doi=10.1371/journal.pone.0063972|pmid=23976938|pmc=3747247|bibcode=2013PLoSO...863972K|doi-access=free}}</ref> In any case, induction of psychosis has been associated with psychedelics in small percentages of individuals, and the rates appear to be higher in people with schizophrenia.<ref name="SabéSulstarovaGlangetas2024">{{cite journal | vauthors = Sabé M, Sulstarova A, Glangetas A, De Pieri M, Mallet L, Curtis L, Richard-Lepouriel H, Penzenstadler L, Seragnoli F, Thorens G, Zullino D, Preller K, Böge K, Leucht S, Correll CU, Solmi M, Kaiser S, Kirschner M | title = Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies | journal = Mol Psychiatry | volume = 30| issue = 3| pages = 1223–1255| date = November 2024 | pmid = 39592825 | doi = 10.1038/s41380-024-02800-5 | url = | doi-access = free | pmc = 11835720 }}</ref>

Using psychedelics poses certain risks of re-experiencing of the drug's effects, including flashbacks and hallucinogen persisting perception disorder (HPPD).<ref name="van-amsterdam-et-al" /> These non-psychotic effects are poorly studied, but the permanent symptoms (also called "endless trip") are considered to be rare.<ref>{{cite journal |last1=Baggott |first1=M. J. |last2=Coyle |first2=J. R. |last3=Erowid |first3=E. |last4=Erowid |first4=F. |last5=Robertson |first5=L. C. |date=1 March 2011 |title=Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire |journal=Drug and Alcohol Dependence |volume=114 |issue=1 |pages=61–67 |doi=10.1016/j.drugalcdep.2010.09.006 |pmid=21035275}}</ref>

Psychedelics can induce hypomania or mania in people with bipolar disorder.<ref name="EskinaziNasserdineCusin2026">{{cite journal | vauthors = Eskinazi M, Nasserdine R, Cusin RM, Baniotoupoulos P, Saccaro LF, De Pieri M, Corino T, Seragnoli F, Briefer JF, Aboulafia Brakha T, Richard-Lepouriel H, Penzenstadler L, Böge K, Kirchner M, Zullino D, Højlund M, Sapienza J, Bosia M, Catalan A, Vieta E, Solmi M, Sabé M | title = Psychedelic-induced hypomania and mania: a systematic review and meta-analysis | journal = Mol Psychiatry | volume = | issue = | pages = | date = May 2026 | pmid = 42215638 | doi = 10.1038/s41380-026-03657-6 | url = }}</ref> This is of low but clinically meaningful incidence (5.8% in clinical trials, 30% in naturalistic settings) and is typically acute and self-limited.<ref name="EskinaziNasserdineCusin2026" />

Some people with aphantasia have been reported to have acquired visual mental imagery after using psychedelics.<ref name="Koenig-RobertKeoghPearson2025">{{cite journal | vauthors = Koenig-Robert R, Keogh R, Pearson J | title = The potential risks of opening the mind's eye with psychedelic therapies | journal = Cortex | volume = 191 | issue = | pages = 167–171 | date = October 2025 | pmid = 40850037 | doi = 10.1016/j.cortex.2025.08.002 | url = }}</ref> While enhanced mental imagery may seem appealing, it may also pose risks such as increased risk of psychiatric disorders.<ref name="Koenig-RobertKeoghPearson2025" />

===Tolerance=== A very rapid and strong tolerance, known as tachyphylaxis, develops to the effects of psychedelics with repeated administration.<ref name="Nichols2004" /><ref name="Halberstadt2015" /><ref name="BuchbornGreckschDieterich2016">{{cite book | last1=Buchborn | first1=T. | last2=Grecksch | first2=G. | last3=Dieterich | first3=D.C. | last4=Höllt | first4=V. | title=Neuropathology of Drug Addictions and Substance Misuse | chapter=Tolerance to Lysergic Acid Diethylamide: Overview, Correlates, and Clinical Implications | publisher=Elsevier | date=2016 | isbn=978-0-12-800212-4 | doi=10.1016/b978-0-12-800212-4.00079-0 | url=https://linkinghub.elsevier.com/retrieve/pii/B9780128002124000790 | access-date=27 November 2025 | pages=846–858}}</ref><ref name="PassieHalpernStichtenothEmrich2008">{{cite journal | vauthors = Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A | title = The pharmacology of lysergic acid diethylamide: a review | journal = CNS Neurosci Ther | volume = 14 | issue = 4 | pages = 295–314 | date = 2008 | pmid = 19040555 | pmc = 6494066 | doi = 10.1111/j.1755-5949.2008.00059.x | url = }}</ref><ref name="GeigerWurstDaniels2018">{{cite journal | vauthors = Geiger HA, Wurst MG, Daniels RN | title = DARK Classics in Chemical Neuroscience: Psilocybin | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2438–2447 | date = October 2018 | pmid = 29956917 | doi = 10.1021/acschemneuro.8b00186 | url = | quote = Tachyphylaxis, the rapid desensitization to a drug or toxin resulting in diminished physiologic effect, is a phenomenon seen with most hallucinogens. Tolerance begins to develop after the administration of a single dose. The mechanism behind this rapid desensitization is the physiologic response to 5-HT2A receptor overstimulation by quickly downregulating receptor sites.41,42 In general, it is thought that these receptor sites return to 50 percent of their baseline within 3−7 days of the initial dose and return to baseline within 1−4 weeks, depending on dose and duration of repeated use. Additionally, cross-tolerance is evident between indolealkylamine and phenylalkylamine classes of hallucinogens.22}}</ref><ref name="HalberstadtGeyer2011">{{cite journal | vauthors = Halberstadt AL, Geyer MA | title = Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens | journal = Neuropharmacology | volume = 61 | issue = 3 | pages = 364–381 | date = September 2011 | pmid = 21256140 | pmc = 3110631 | doi = 10.1016/j.neuropharm.2011.01.017 | url = }}</ref> It develops with a single dose and is present within hours to days.<ref name="Halberstadt2015" /><ref name="BuchbornGreckschDieterich2016" /><ref name="GeigerWurstDaniels2018" /> Already by the second day, with LSD, there was a 50% decrease in psychoactive effects in one study.<ref name="BuchbornGreckschDieterich2016" /> Following a few days of repeated administration, or 3 to 4{{nbsp}}days in the case of LSD, there is an almost complete absence of effects.<ref name="Nichols2004" /><ref name="Halberstadt2015" /><ref name="BuchbornGreckschDieterich2016" /><ref name="Dinis-OliveiraPereiradaSilva2019" /> The tolerance remains stable thereafter.<ref name="BuchbornGreckschDieterich2016" /> In one study that gave LSD continuously for up to 84{{nbsp}}days, doubling, tripling, and quadrupling the dose was unable to fully overcome the tolerance and restore effects.<ref name="BuchbornGreckschDieterich2016" /> An abstinence period of 3 to 6{{nbsp}}days is required for sensitivity to return and tolerance to fully reset.<ref name="BuchbornGreckschDieterich2016" /><ref name="PassieHalpernStichtenothEmrich2008" /><ref name="VamvakopoulouNarineCampbell2023" /><ref name="Dinis-OliveiraPereiradaSilva2019" /> LSD, psilocybin, and mescaline all show cross-tolerance with each other.<ref name="Nichols2004" /><ref name="BuchbornGreckschDieterich2016" /><ref name="PassieHalpernStichtenothEmrich2008" /><ref name="VamvakopoulouNarineCampbell2023">{{cite journal | vauthors = Vamvakopoulou IA, Narine KA, Campbell I, Dyck JR, Nutt DJ | title = Mescaline: The forgotten psychedelic | journal = Neuropharmacology | volume = 222 | article-number = 109294 | date = January 2023 | pmid = 36252614 | doi = 10.1016/j.neuropharm.2022.109294 | doi-access = free | quote = A cross-tolerance study of mescaline with other serotonergic psychedelics, like LSD and psilocybin, shows evidence of tolerance developing a few days after mescaline consumption. These effects were restored following 3–4 days of abstinence (Wolbach et al., 1962a, 1962b).}}</ref><ref name="HalberstadtGeyer2011" /><ref name="Dinis-OliveiraPereiradaSilva2019">{{cite journal | vauthors = Dinis-Oliveira RJ, Pereira CL, da Silva DD | title = Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions | journal = Curr Mol Pharmacol | volume = 12 | issue = 3 | pages = 184–194 | date = 2019 | pmid = 30318013 | pmc = 6864602 | doi = 10.2174/1874467211666181010154139 | url = | quote = Cross tolerance of mescaline with other serotonergic drugs such as LSD and psilocybin has been described in humans and other animals [61]; mescaline tolerance develops after a few days of consumption but sensitivity is restored after 3-4 days of drug abstinence [43, 61].}}</ref> Tolerance has been shown to develop to numerous psychedelics in animals and/or humans.<ref name="Nichols2004" /><ref name="Halberstadt2015" /><ref name="SmithBaileyWilliams2014">{{cite journal | vauthors = Smith DA, Bailey JM, Williams D, Fantegrossi WE | title = Tolerance and cross-tolerance to head twitch behavior elicited by phenethylamine- and tryptamine-derived hallucinogens in mice | journal = J Pharmacol Exp Ther | volume = 351 | issue = 3 | pages = 485–491 | date = December 2014 | pmid = 25271256 | pmc = 4309922 | doi = 10.1124/jpet.114.219337 | url = }}</ref><ref name="BuchbornGreckschDieterich2016" /> Tolerance with psychedelics develops to both their psychoactive effects and their physical effects, such as pupil dilation and tachycardia.<ref name="BuchbornGreckschDieterich2016" /> As a result of the tolerance, recreational psychedelic users do not use the drugs daily but often show a once-per-week use pattern.<ref name="BuchbornGreckschDieterich2016" />

Some possible exceptions among psychedelics which may not build tolerance or may develop it much less rapidly include dimethyltryptamine (DMT),<ref name="Nichols2004" /><ref name="CarbonaroGatch2016">{{cite journal | vauthors = Carbonaro TM, Gatch MB | title = Neuropharmacology of N,N-dimethyltryptamine | journal = Brain Res Bull | volume = 126 | issue = Pt 1 | pages = 74–88 | date = September 2016 | pmid = 27126737 | pmc = 5048497 | doi = 10.1016/j.brainresbull.2016.04.016 | url = }}</ref><ref name="Halberstadt2015" /><ref name="StrassmanQuallsBerg1996">{{cite journal | vauthors = Strassman RJ, Qualls CR, Berg LM | title = Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans | journal = Biol Psychiatry | volume = 39 | issue = 9 | pages = 784–795 | date = May 1996 | pmid = 8731519 | doi = 10.1016/0006-3223(95)00200-6 | url = }}</ref> ayahuasca (which contains DMT),<ref name="DosSantosHallak2024">{{cite journal | vauthors = Dos Santos RG, Hallak JE | title = Ayahuasca: pharmacology, safety, and therapeutic effects | journal = CNS Spectr | volume = 30| issue = 1| article-number = e2 | date = November 2024 | pmid = 39564645 | doi = 10.1017/S109285292400213X | url = | doi-access = free }}</ref><ref name="DosSantosGrasaValle2012">{{cite journal | vauthors = Dos Santos RG, Grasa E, Valle M, Ballester MR, Bouso JC, Nomdedéu JF, Homs R, Barbanoj MJ, Riba J | title = Pharmacology of ayahuasca administered in two repeated doses | journal = Psychopharmacology (Berl) | volume = 219 | issue = 4 | pages = 1039–1053 | date = February 2012 | pmid = 21842159 | doi = 10.1007/s00213-011-2434-x | url = }}</ref> and 5-MeO-DMT.<ref name="ErmakovaDunbarRucker2022" /><ref name="BloughLandavazoDecker2014">{{cite journal | vauthors = Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB | title = Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes | journal = Psychopharmacology (Berl) | volume = 231 | issue = 21 | pages = 4135–4144 | date = October 2014 | pmid = 24800892 | pmc = 4194234 | doi = 10.1007/s00213-014-3557-7 | url = }}</ref><ref name="ReckwegUthaugSzabo2022" /><ref name="DourronNicholsSimonsson2023">{{cite journal | vauthors = Dourron HM, Nichols CD, Simonsson O, Bradley M, Carhart-Harris R, Hendricks PS | title = 5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk? | journal = Psychopharmacology (Berl) | volume = 242| issue = 7| pages = 1457–1479| date = December 2023 | pmid = 38072874 | doi = 10.1007/s00213-023-06517-1 | url = }}</ref> Similarly, the structurally related dipropyltryptamine (DPT) and diisopropyltryptamine (DiPT) did not show behavioral tolerance in rodents, in contrast to DOI and 2C-T-7.<ref name="SmithBaileyWilliams2014">{{cite journal | vauthors = Smith DA, Bailey JM, Williams D, Fantegrossi WE | title = Tolerance and cross-tolerance to head twitch behavior elicited by phenethylamine- and tryptamine-derived hallucinogens in mice | journal = J Pharmacol Exp Ther | volume = 351 | issue = 3 | pages = 485–491 | date = December 2014 | pmid = 25271256 | pmc = 4309922 | doi = 10.1124/jpet.114.219337 | url = }}</ref> The reasons for the apparently reduced tolerance development with the preceding psychedelics is unclear.<ref name="Nichols2004" /><ref name="SmithBaileyWilliams2014" /> It has been suggested that the lack of tolerance with shorter-acting psychedelics like DMT and DPT might simply be due to their short durations.<ref name="SmithBaileyWilliams2014" /><ref name="MartinSloan1977">{{cite book | last1=Martin | first1=W. R. | last2=Sloan | first2=J. W. | title=Drug Addiction II: Amphetamine, Psychotogen, and Marihuana Dependence | chapter=Pharmacology and Classification of LSD-like Hallucinogens | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=1977 | isbn=978-3-642-66711-4 | doi=10.1007/978-3-642-66709-1_3 | chapter-url=https://books.google.com/books?id=gb_uCAAAQBAJ&pg=PA305 | pages=305–368 | quote=The observation that tolerance to LSD does not confer cross tolerance to several of DMT's autonomic effects suggests that these N-disubstituted compounds may differ in some respects from LSD. The duration of action of DMT is less than that of LSD. Further, we have not been able to demonstrate tachyphylaxis to the actions of tryptamine in the dog (MARTIN and EADES, 1972). Tryptamine's duration of action is less than that of DMT. It is possible that a long duration of action is a necessary attribute of LSD-like hallucinogens for them to effectively induce tolerance (see Subsect. E.III).}}</ref> Contrary to earlier findings, subsequent clinical studies employing DMT by continuous intravenous infusion (also known as DMTx) have found rapid and moderate acute tolerance development.<ref name="VogtLeyErne2023">{{cite journal | vauthors = Vogt SB, Ley L, Erne L, Straumann I, Becker AM, Klaiber A, Holze F, Vandersmissen A, Mueller L, Duthaler U, Rudin D, Luethi D, Varghese N, Eckert A, Liechti ME | title = Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants | journal = Transl Psychiatry | volume = 13 | issue = 1 | article-number = 172 | date = May 2023 | pmid = 37221177 | pmc = 10206108 | doi = 10.1038/s41398-023-02477-4 | url = }}</ref><ref name="LuanEckernäsAshton2024">{{cite journal | vauthors = Luan LX, Eckernäs E, Ashton M, Rosas FE, Uthaug MV, Bartha A, Jagger S, Gascon-Perai K, Gomes L, Nutt DJ, Erritzøe D, Carhart-Harris RL, Timmermann C | title = Psychological and physiological effects of extended DMT | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 56–67 | date = January 2024 | pmid = 37897244 | pmc = 10851633 | doi = 10.1177/02698811231196877 | url = }}</ref><ref name="ErneVogtMüller2025">{{cite journal | vauthors = Erne L, Vogt SB, Müller L, Nuraj A, Becker A, Klaiber A, Zuparic M, Varghese N, Eckert A, Rudin D, Luethi D, Liechti ME | title = Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants | journal = Neuropsychopharmacology | volume = 50 | issue = 6 | pages = 1008–1016 | date = May 2025 | pmid = 39702577 | pmc = 12032411 | doi = 10.1038/s41386-024-02041-8 | url = }}</ref>

The mechanism of the tolerance with psychedelics is thought to be rapid serotonin 5-HT2A receptor downregulation with very slow recovery.<ref name="Nichols2004" /><ref name="GeigerWurstDaniels2018" /><ref name="SmithCantonBarrett1998">{{cite journal | vauthors = Smith RL, Canton H, Barrett RJ, Sanders-Bush E | title = Agonist properties of N,N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors | journal = Pharmacol Biochem Behav | volume = 61 | issue = 3 | pages = 323–330 | date = November 1998 | pmid = 9768567 | doi = 10.1016/s0091-3057(98)00110-5 | url = }}</ref><ref name="BuchbornGreckschDieterich2016" /> Downstream targets of the serotonin 5-HT2A receptor such as metabotropic glutamate mGlu2 and mGlu3 receptors may also downregulate.<ref name="BuchbornGreckschDieterich2016" /> It is thought that serotonin 5-HT2A receptors recover to 50% of baseline within 3 to 7{{nbsp}}days of the initial psychedelic dose and fully return to baseline within 1 to 4{{nbsp}}weeks, with the recovery dependent on the doses and the length of repeated use.<ref name="GeigerWurstDaniels2018" />

Tolerance may limit the effects and potential benefits of psychedelic microdosing, with this having been observed clinically.<ref name="KuypersNgErritzoe2019">{{cite journal | vauthors = Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, Pani L, Soula A, Nutt D | title = Microdosing psychedelics: More questions than answers? An overview and suggestions for future research | journal = J Psychopharmacol | volume = 33 | issue = 9 | pages = 1039–1057 | date = September 2019 | pmid = 31303095 | pmc = 6732823 | doi = 10.1177/0269881119857204 | url = }}</ref><ref name="Kuypers2020">{{cite journal | vauthors = Kuypers KP | title = The therapeutic potential of microdosing psychedelics in depression | journal = Ther Adv Psychopharmacol | volume = 10 | issue = | article-number = 2045125320950567 | date = 2020 | pmid = 32922736 | pmc = 7457631 | doi = 10.1177/2045125320950567 | url = }}</ref>

===Cardiovascular toxicity=== {{See also|Psychedelic microdosing#Cardiovascular toxicity}}

Serotonergic psychedelics are agonists not only of the serotonin 5-HT2A receptor but also of the serotonin 5-HT2B receptor and other serotonin receptors.<ref name="TagenMantuanivanHeerden2023">{{cite journal | vauthors = Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R | title = The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | journal = J Psychopharmacol | volume = 37 | issue = 9 | pages = 876–890 | date = September 2023 | pmid = 37572027 | doi = 10.1177/02698811231190865 | url = }}</ref><ref name="RouaudCalderHasler2024">{{cite journal | vauthors = Rouaud A, Calder AE, Hasler G | title = Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins | journal = J Psychopharmacol | volume = 38 | issue = 3 | pages = 217–224 | date = March 2024 | pmid = 38214279 | pmc = 10944580 | doi = 10.1177/02698811231225609 | url = }}</ref> A potential risk of frequent repeated use of serotonergic psychedelics is cardiac fibrosis and valvulopathy caused by serotonin 5-HT2B receptor activation.<ref name="TagenMantuanivanHeerden2023" /><ref name="RouaudCalderHasler2024" /> However, single high doses or widely spaced doses (e.g., months) are widely thought to be safe and concerns about cardiac toxicity apply more to chronic psychedelic microdosing or very frequent use (e.g., weekly).<ref name="TagenMantuanivanHeerden2023" /><ref name="RouaudCalderHasler2024" /> Selective serotonin 5-HT2A receptor agonists that do not activate the serotonin 5-HT2B receptor or other serotonin receptors, such as 25CN-NBOH, DMBMPP, and LPH-5, have been developed and are being studied.<ref name="MärcherRørstedJensenKristensen2021">{{cite journal | vauthors = Märcher Rørsted E, Jensen AA, Kristensen JL | title = 25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor | journal = ChemMedChem | volume = 16 | issue = 21 | pages = 3263–3270 | date = November 2021 | pmid = 34288515 | doi = 10.1002/cmdc.202100395 | url = }}</ref><ref name="DuanCaoWang2024"/><ref name="Peplow2024">{{cite journal | last=Peplow | first=Mark | title=Next-generation psychedelics: should new agents skip the trip? | journal=Nature Biotechnology | volume=42 | issue=6 | date=2024 | issn=1087-0156 | doi=10.1038/s41587-024-02285-1 | pages=827–830 | pmid=38831049 | quote=Another problem is that some classical psychedelics are also agonists of the 5-HT2B receptor, which is expressed in heart tissue and can cause long-term cardiac problems. Kristensen's company Lophora aims to solve that with its lead compound LPH-5, a phenylethylamine derivative with an extra molecular ring that makes it less flexible. LPH-5 has a 60-fold higher selectivity for 5-HT2A over 5-HT2B.}}</ref> Selective serotonin 5-HT2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT2B receptor activation.<ref name="Peplow2024" />

==Overdose== There have been a handful of cases of fatal overdose with LSD, psilocybin, and mescaline.<ref name="Thomas2024">{{cite book | last=Thomas | first=Kelan | title=Toxicology and Pharmacological Interactions of Classic Psychedelics | series=Current Topics in Behavioral Neurosciences | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=2024 | doi=10.1007/7854_2024_508 | url=https://link.springer.com/10.1007/7854_2024_508 | access-date=14 May 2025 | page=| pmid=39042251 }}</ref><ref name="Henríquez-HernándezRojas-HernándezQuintana-Hernández2023">{{cite journal | vauthors = Henríquez-Hernández LA, Rojas-Hernández J, Quintana-Hernández DJ, Borkel LF | title = Hofmann vs. Paracelsus: Do Psychedelics Defy the Basics of Toxicology?-A Systematic Review of the Main Ergolamines, Simple Tryptamines, and Phenylethylamines | journal = Toxics | volume = 11 | issue = 2 | date = February 2023 | page = 148 | pmid = 36851023 | pmc = 9963058 | doi = 10.3390/toxics11020148 | doi-access = free | bibcode = 2023Toxic..11..148H | url = }}</ref> There have also been cases of death with dimethyltryptamine (DMT), 5-MeO-DMT, 2C-B, Bromo-DragonFLY, NBOMes like 25I-NBOMe, and other psychedelics.<ref name="Thomas2024" /><ref name="HillThomas2011">{{cite journal | vauthors = Hill SL, Thomas SH | title = Clinical toxicology of newer recreational drugs | journal = Clin Toxicol (Phila) | volume = 49 | issue = 8 | pages = 705–719 | date = October 2011 | pmid = 21970769 | doi = 10.3109/15563650.2011.615318 | url = }}</ref> LSD and psilocybin appear to have very wide margins of safety with overdose, whereas mescaline and 2C-B have much narrower margins, and NBOMes appear to be especially toxic and uniquely linked to serotonin syndrome-type symptoms.<ref name="Thomas2024" /> Major psychedelics like LSD and psilocybin do not cause serotonin syndrome, which is thought to be due to the fact that they act as partial agonists of the serotonin 5-HT2A receptor.<ref name="MalcolmThomas2022">{{cite journal | vauthors = Malcolm B, Thomas K | title = Serotonin toxicity of serotonergic psychedelics | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1881–1891 | date = June 2022 | pmid = 34251464 | doi = 10.1007/s00213-021-05876-x | url = }}</ref><ref name="Thomas2024" /><ref name="TapThomasPáleníček2025">{{cite journal | vauthors = Tap SC, Thomas K, Páleníček T, Stenbæk DS, Oliveira-Maia AJ, van Dalfsen J, Schoevers R | title = Concomitant use of antidepressants and classic psychedelics: A scoping review | journal = J Psychopharmacol | volume = 39| issue = 10 | date = September 2025 |pages=1072–1088 | pmid = 40937732 | doi = 10.1177/02698811251368360 | pmc = 12572353 | url = | quote = Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).}}</ref> Conversely, psychedelics like NBOMes have higher activational efficacy at this receptor.<ref name="MalcolmThomas2022" /><ref name="TapThomasPáleníček2025" /> In terms of extrapolated human lethal doses based on animal studies and human case reports, lethal doses of psychedelics relative to typical recreational doses are estimated to be 1,000-fold for LSD, 200-fold for psilocybin, 50-fold for oral DMT (as ayahuasca), and 24-fold for mescaline.<ref name="Thomas2024" /> Estimates for other psychedelics, like 5-MeO-DMT and 2C-B, could not be made.<ref name="Thomas2024" />

==Interactions== {{See also|Trip killer#Serotonergic psychedelic antidotes|Head-twitch response#Modulators of the head-twitch response}}

Serotonin 5-HT2A receptor antagonists can block the subjective psychedelic effects of serotonergic psychedelics in humans.<ref name="Vollenweider1998">{{cite journal | last1 = Vollenweider | first1 = F. X. | last2 = Vollenweider-Scherpenhuyzen | first2 = M. F. | last3 = Babler | first3 = A. | last4 = Vogel | first4 = H. | last5 = Hell | first5 = D. | year = 1998 | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | pages = 3897–3902 | doi = 10.1097/00001756-199812010-00024

}}</ref><ref name="Kometer2013">{{cite journal | last1 = Kometer | first1 = M. | last2 = Schmidt | first2 = A. | last3 = Jancke | first3 = L. | last4 = Vollenweider | first4 = F. X. | year = 2013 | title = Activation of serotonin 2A receptors underlies the psilocybin-induced effects on alpha oscillations, N170 visual-evoked potentials, and visual hallucinations | journal = Journal of Neuroscience | volume = 33 | pages = 10544–10551 | doi = 10.1523/JNEUROSCI.3007-12.2013 }}</ref><ref name="Preller2017">{{cite journal | last1 = Preller | first1 = K. H. | last2 = Herdener | first2 = M. | last3 = Pokorny | first3 = T. | last4 = Planzer | first4 = A. | last5 = Kraehenmann | first5 = R. | last6 = Stampfli | first6 = P. | last7 = Liechti | first7 = M. E. | last8 = Seifritz | first8 = E. | last9 = Vollenweider | first9 = F. X. | year = 2017 | title = The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation | journal = Current Biology | volume = 27 | pages = 451–457 | doi = 10.1016/j.cub.2016.12.030 }}</ref><ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref> Numerous drugs act as serotonin 5-HT2A receptor antagonists, for instance antidepressants like trazodone and mirtazapine, antipsychotics like quetiapine, olanzapine, and risperidone, and other agents like ketanserin, pimavanserin, cyproheptadine, and pizotifen.<ref name="Vollenweider1998" /><ref name="Preller2017" /><ref name="HalmanKongSarris2024" /><ref name="YatesMelon2024">{{Cite journal |vauthors=Yates G, Melon E |date=January 2024 |title=Trip-killers: a concerning practice associated with psychedelic drug use |journal=Emerg Med J |volume=41 |issue=2 |pages=112–113 |doi=10.1136/emermed-2023-213377 |pmid=38123961 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|archive-date=2025-05-11 }}</ref> Such drugs are sometimes referred to as "trip killers" due to their ability to prevent or abort the hallucinogenic effects of psychedelics.<ref name="Jayasinha2024">{{Cite thesis |last=Bellanavidanalage Gothami Ayanthie Vis Jayasinha |title=Towards Safer Trips: Exploring Harm Reduction Strategies for Recreational Psychedelic Use in Aotearoa New Zealand |date=8 February 2024 |access-date=3 October 2024 |publisher=University of Otago |url=https://ourarchive.otago.ac.nz/esploro/outputs/graduate/Towards-Safer-Trips-Exploring-Harm-Reduction/9926550679501891 }}</ref><ref name="YatesMelon2024" /><ref name="Suran2024">{{Cite journal |vauthors=Suran M |date=February 2024 |title=Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs |journal=JAMA |volume=331 |issue=8 |pages=632–634 |doi=10.1001/jama.2023.28257 |pmid=38294772}}</ref> Besides serotonin 5-HT2A receptor antagonists, non-hallucinogenic serotonin 5-HT2A receptor partial agonists, such as lisuride, may also block the hallucinogenic effects of serotonergic psychedelics.<ref name="LewisBonniwellLanham2023" /><ref name="GlatfelterPottiePartilla2024">{{cite journal | vauthors = Glatfelter GC, Pottie E, Partilla JS, Stove CP, Baumann MH | title = Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited | journal = ACS Pharmacol Transl Sci | volume = 7 | issue = 3 | pages = 641–653 | date = March 2024 | pmid = 38481684 | doi = 10.1021/acsptsci.3c00192 | pmc = 10928901 | url = }}</ref>

The serotonin 5-HT1A receptor partial agonist buspirone has been found to markedly reduce the hallucinogenic effects of psilocybin in humans.<ref name="HalmanKongSarris2024" /><ref name="BrandtKavanaghTwamley2018">{{cite journal | vauthors = Brandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, Stratford A, Klein LM, McCorvy JD, Nichols DE, Halberstadt AL | title = Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775) | journal = Drug Test Anal | volume = 10 | issue = 2 | pages = 310–322 | date = February 2018 | pmid = 28585392 | pmc = 6230476 | doi = 10.1002/dta.2222 | url = | quote = Additionally, pretreatment with the 5‐HT1A agonist buspirone (20 mg p.o.) markedly attenuates the visual effects of psilocybin in human volunteers.59 Although buspirone failed to completely block the hallucinogenic effects of psilocybin, the limited inhibition is not necessarily surprising because buspirone is a low efficacy 5‐HT1A partial agonist.60 The level of 5‐HT1A activation produced by buspirone may not be sufficient to completely counteract the stimulation of 5‐HT2A receptors by psilocin (the active metabolite of psilocybin). Another consideration is that psilocin acts as a 5‐HT1A agonist.30 If 5‐HT1A activation by psilocin buffers its hallucinogenic effects similar to DMT58 then competition between psilocin and a weaker partial agonist such as buspirone would limit attenuation of the hallucinogenic response.}}</ref><ref name="PokornyPrellerKraehenmann2016">{{cite journal | vauthors = Pokorny T, Preller KH, Kraehenmann R, Vollenweider FX | title = Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 4 | pages = 756–766 | date = April 2016 | pmid = 26875114 | doi = 10.1016/j.euroneuro.2016.01.005 | url = }}</ref> Conversely, the serotonin 5-HT1A receptor antagonist pindolol has been found to potentiate the hallucinogenic effects of DMT by 2- to 3-fold in humans.<ref name="PokornyPrellerKraehenmann2016" /><ref name="Strassman1996">{{cite journal | vauthors = Strassman RJ | title = Human psychopharmacology of N,N-dimethyltryptamine | journal = Behav Brain Res | volume = 73 | issue = 1–2 | pages = 121–124 | date = 1996 | pmid = 8788488 | doi = 10.1016/0166-4328(96)00081-2 | url = }}</ref> Serotonin 5-HT1A receptor agonism may modify and self-inhibit the effects of psychedelics that possess this property.<ref name="DourronNicholsSimonsson2023"/><ref name="HalberstadtNichols2020" /><ref name="BrandtKavanaghTwamley2018" /><ref name="ShaharBotvinnikEsh-Zuntz2022">{{cite journal | vauthors = Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T | title = Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications | journal = Int J Mol Sci | volume = 23 | issue = 22 | date = November 2022 |article-number=14148 | pmid = 36430623 | pmc = 9698447 | doi = 10.3390/ijms232214148 | doi-access = free | url = }}</ref><ref name="ZhuWangWang2024">{{cite journal | vauthors = Zhu H, Wang L, Wang X, Yao Y, Zhou P, Su R | title = 5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice | journal = Psychopharmacology (Berl) | volume = 241 | issue = 11 | pages = 2315–2330 | date = November 2024 | pmid = 38916640 | doi = 10.1007/s00213-024-06635-4 | url = }}</ref><ref name="GlatfelterClarkCavalco2024">{{cite journal | vauthors = Glatfelter GC, Clark AA, Cavalco NG, Landavazo A, Partilla JS, Naeem M, Golen JA, Chadeayne AR, Manke DR, Blough BE, McCorvy JD, Baumann MH | title = Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice | journal = ACS Chem Neurosci | volume = 15 | issue = 24 | pages = 4458–4477 | date = December 2024 | pmid = 39636099 | doi = 10.1021/acschemneuro.4c00513 | pmc = 12745965 | url = }}</ref> A particularly notable example is 5-methoxytryptamine derivatives such as 5-MeO-DMT, which are more potent serotonin 5-HT1A receptor agonists than other psychedelics and have qualitatively unique and differing hallucinogenic effects.<ref name="DourronNicholsSimonsson2023" /><ref name="GlatfelterClarkCavalco2024" /><ref name="PuigsesllosesNadal-GratacósKetsela2024">{{cite journal | vauthors = Puigseslloses P, Nadal-Gratacós N, Ketsela G, Weiss N, Berzosa X, Estrada-Tejedor R, Islam MN, Holy M, Niello M, Pubill D, Camarasa J, Escubedo E, Sitte HH, López-Arnau R | title = Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties | journal = Mol Psychiatry | volume = 29 | issue = 8 | pages = 2346–2358 | date = August 2024 | pmid = 38486047 | pmc = 11412900 | doi = 10.1038/s41380-024-02506-8 | url = }}</ref>

Benzodiazepines, for example diazepam, alprazolam, clonazepam, and lorazepam, as well as alcohol, which act as GABAA receptor positive allosteric modulators, have been limitedly studied in combination with psychedelics and are not currently known to directly interact with them.<ref name="SarparastThomasMalcolm2022">{{cite journal | vauthors = Sarparast A, Thomas K, Malcolm B, Stauffer CS | title = Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1945–1976 | date = June 2022 | pmid = 35253070 | pmc = 9177763 | doi = 10.1007/s00213-022-06083-y | url = }}</ref><ref name="HalmanKongSarris2024" /> However, these GABAergic drugs produce effects such as anxiolysis, sedation, and amnesia, and in relation to this, may diminish or otherwise oppose the effects of psychedelics.<ref name="HalmanKongSarris2024" /><ref name="Jayasinha2024" /><ref name="YatesMelon2024" /><ref name="Suran2024" /><ref name="Olsen2018">{{Cite journal |vauthors=Olsen RW |date=July 2018 |title=GABAA receptor: Positive and negative allosteric modulators |journal=Neuropharmacology |volume=136 |issue=Pt A |pages=10–22 |doi=10.1016/j.neuropharm.2018.01.036 |pmc=6027637 |pmid=29407219}}</ref> As a result of this, benzodiazepines and alcohol are often used by recreational users as "trip killers" to manage difficult hallucinogenic experiences with psychedelics, for instance experiences with prominent anxiety.<ref name="Jayasinha2024" /><ref name="YatesMelon2024" /><ref name="Suran2024" /> The safety of this strategy is not entirely clear and might have risks.<ref name="Jayasinha2024" /><ref name="SarparastThomasMalcolm2022" /><ref name="YatesMelon2024" /><ref name="Suran2024" /> However, benzodiazepines have been used clinically to manage the adverse psychological effects of psychedelics, for instance in clinical studies and in the emergency department.<ref name="SarparastThomasMalcolm2022" /><ref name="KaminskiReinert2024">{{cite journal | vauthors = Kaminski D, Reinert JP | title = The Tolerability and Safety of Psilocybin in Psychiatric and Substance-Dependence Conditions: A Systematic Review | journal = Ann Pharmacother | volume = 58 | issue = 8 | pages = 811–826 | date = August 2024 | pmid = 37902038 | doi = 10.1177/10600280231205645 | url = }}</ref><ref name="LeikinKrantzZell-Kanter1989">{{Cite journal |last1=Leikin |first1=Jerrold B. |last2=Krantz |first2=Anne J. |last3=Zell-Kanter |first3=Michele |last4=Barkin |first4=Robert L. |last5=Hryhorczuk |first5=Daniel O. |year=1989 |title=Clinical Features and Management of Intoxication Due to Hallucinogenic Drugs |journal=Medical Toxicology and Adverse Drug Experience |publisher=Springer Science and Business Media LLC |volume=4 |issue=5 |pages=324–350 |doi=10.1007/bf03259916 |issn=0113-5244 |pmid=2682130}}</ref><ref name="HalpernSuzukiHuertas2010">{{Cite book |last1=Halpern |first1=John H. |title=Addiction Medicine |last2=Suzuki |first2=Joji |last3=Huertas |first3=Pedro E. |last4=Passie |first4=Torsten |publisher=Springer New York |year=2010 |isbn=978-1-4419-0337-2 |publication-place=New York, NY |pages=1083–1098 |chapter=Hallucinogens |doi=10.1007/978-1-4419-0338-9_54}}</ref><ref name="GartnerWanSimmons2024">{{cite journal | vauthors = Gartner HT, Wan HZ, Simmons RE, Sollee DR, Sheikh S | title = Psychedelic mushroom-containing chocolate exposures: Case series | journal = Am J Emerg Med | volume = 85 | issue = | pages = 208–213 | date = November 2024 | pmid = 39288500 | doi = 10.1016/j.ajem.2024.09.038 | url = }}</ref> A clinical trial of psilocybin and midazolam coadministration found that midazolam clouded the effects of psilocybin and impaired memory of the experience.<ref name="LimaSoaresTeixeira2024">{{cite journal | vauthors = Lima G, Soares C, Teixeira M, Castelo-Branco M | title = Psychedelic research, assisted therapy and the role of the anaesthetist: A review and insights for experimental and clinical practices | journal = Br J Clin Pharmacol | volume = 90 | issue = 12 | pages = 3119–3134 | date = December 2024 | pmid = 39380091 | doi = 10.1111/bcp.16264 | url = }}</ref><ref name="NicholasBanksLennertz2024">{{cite journal | vauthors = Nicholas CR, Banks MI, Lennertz RC, Wenthur CJ, Krause BM, Riedner BA, Smith RF, Hutson PR, Sauder CJ, Dunne JD, Roseman L, Raison CL | title = Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience | journal = Transl Psychiatry | volume = 14 | issue = 1 | article-number = 372 | date = September 2024 | pmid = 39266503 | pmc = 11393325 | doi = 10.1038/s41398-024-03059-8 | url = }}</ref> Benzodiazepines might interfere with the therapeutic effects of psychedelics, such as sustained antidepressant effects.<ref name="BarnettVestDelatte2025">{{cite journal | vauthors = Barnett BS, Vest MF, Delatte MS, King Iv F, Mauney EE, Coulson AJ, Nayak SM, Hendricks PS, Greer GR, Murnane KS | title = Practical considerations in the establishment of psychedelic research programs | journal = Psychopharmacology (Berl) | volume = 242 | issue = 1 | pages = 27–43 | date = January 2025 | pmid = 39627438 | pmc = 11742797 | doi = 10.1007/s00213-024-06722-6 | url = | quote = Furthermore, benzodiazepines might attenuate the antidepressant effects of psychedelics (Hibicke et al. 2024).}}</ref><ref name="HibickeBillacNichols2024">{{cite journal | vauthors = Hibicke M, Billac G, Nichols CD | title = Preadministration of Lorazepam Reduces Efficacy and Longevity of Antidepressant-Like Effect from a Psychedelic | journal = Psychedelic Med (New Rochelle) | volume = 2 | issue = 1 | pages = 10–14 | date = March 2024 | pmid = 40051761 | doi = 10.1089/psymed.2023.0037 | url = | pmc = 11658646 }}</ref>

Some serotonergic psychedelics, for instance dimethyltryptamine (DMT) and 5-MeO-DMT, are highly susceptible substrates for monoamine oxidase (MAO), specifically MAO-A, and hence can be greatly potentiated by monoamine oxidase inhibitors (MAOIs).<ref name="HalmanKongSarris2024" /><ref name="EggerAicherCumming2024">{{cite journal | last1=Egger | first1=Klemens | last2=Aicher | first2=Helena D. | last3=Cumming | first3=Paul | last4=Scheidegger | first4=Milan | title=Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors | journal=Cellular and Molecular Life Sciences | publisher=Springer Science and Business Media LLC | volume=81 | issue=1 | date=10 September 2024 | issn=1420-682X | doi=10.1007/s00018-024-05353-6 | doi-access=free | page=395| pmid=39254764 | pmc=11387584 }}</ref><ref name="ShenJiangWinter2010" /> An example of this is ayahuasca, in which plants containing both DMT and harmala alkaloids acting as MAOIs such as harmine and harmaline are combined.<ref name="EggerAicherCumming2024" /> This allows DMT to become orally active and to have a much longer duration of action than usual.<ref name="EggerAicherCumming2024" /> The 2C psychedelics, such as 2C-B, 2C-I, and 2C-E, are also substrates of both MAO-A and MAO-B, and may likewise be greatly potentiated by MAOIs.<ref name="DeanStellpflugBurnett2013">{{cite journal | vauthors = Dean BV, Stellpflug SJ, Burnett AM, Engebretsen KM | title = 2C or not 2C: phenethylamine designer drug review | journal = J Med Toxicol | volume = 9 | issue = 2 | pages = 172–178 | date = June 2013 | pmid = 23494844 | pmc = 3657019 | doi = 10.1007/s13181-013-0295-x | url = }}</ref><ref name="TheobaldMaurer2007">{{cite journal | vauthors = Theobald DS, Maurer HH | title = Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series) | journal = Biochem Pharmacol | volume = 73 | issue = 2 | pages = 287–297 | date = January 2007 | pmid = 17067556 | doi = 10.1016/j.bcp.2006.09.022 | url = }}</ref> Examples of MAOIs that may potentiate psychedelics behaving as MAO-A and/or MAO-B substrates include phenelzine, tranylcypromine, isocarboxazid, moclobemide, and selegiline.<ref name="HalmanKongSarris2024" /> Combination of MAO-substrate psychedelics with MAOIs can result in overdose and serious toxicity, including death.<ref name="HalmanKongSarris2024" /><ref name="DeanStellpflugBurnett2013" /> Other psychedelics, such as LSD, are not substrates of MAO and are not potentiated by MAOIs.<ref name="HalmanKongSarris2024" /> The extent to which psilocin (and by extension psilocybin) is metabolized by MAO, specifically MAO-A, is not fully clear, but has ranged from 4% to 33% in different studies based on metabolite excretion.<ref name="ThomannKolaczynskaStoeckmann2024">{{cite journal | vauthors = Thomann J, Kolaczynska KE, Stoeckmann OV, Rudin D, Vizeli P, Hoener MC, Pryce CR, Vollenweider FX, Liechti ME, Duthaler U | title = In vitro and in vivo metabolism of psilocybin's active metabolite psilocin | journal = Front Pharmacol | volume = 15 | issue = | article-number = 1391689 | date = 2024 | pmid = 38741590 | pmc = 11089204 | doi = 10.3389/fphar.2024.1391689 | doi-access = free | url = }}</ref><ref name="HolzeBeckerKolaczynska2023">{{cite journal | vauthors = Holze F, Becker AM, Kolaczynska KE, Duthaler U, Liechti ME | title = Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants | journal = Clin Pharmacol Ther | volume = 113 | issue = 4 | pages = 822–831 | date = April 2023 | pmid = 36507738 | doi = 10.1002/cpt.2821 | url = https://www.researchgate.net/publication/366214647| doi-access = free }}</ref><ref name="TylšPáleníčekHoráček2014">{{cite journal | vauthors = Tylš F, Páleníček T, Horáček J | title = Psilocybin - summary of knowledge and new perspectives | journal = Eur Neuropsychopharmacol | volume = 24 | issue = 3 | pages = 342–356 | date = March 2014 | pmid = 24444771 | doi = 10.1016/j.euroneuro.2013.12.006 | url = https://www.researchgate.net/publication/259517753}}</ref> However, circulating levels of the deaminated metabolite of psilocin are far higher than those of free unmetabolized psilocin with psilocybin administration.<ref name="DoddNormanEyre2023">{{cite journal | vauthors = Dodd S, Norman TR, Eyre HA, Stahl SM, Phillips A, Carvalho AF, Berk M | title = Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy | journal = CNS Spectr | volume = 28 | issue = 4 | pages = 416–426 | date = August 2023 | pmid = 35811423 | doi = 10.1017/S1092852922000888 | url = https://www.cambridge.org/core/services/aop-cambridge-core/content/view/AA1FB4F49C14BA3F398238D6E5A3947A/S1092852922000888a.pdf/div-class-title-psilocybin-in-neuropsychiatry-a-review-of-its-pharmacology-safety-and-efficacy-div.pdf}}</ref><ref name="HaslerBourquinBrenneisen1997">{{cite journal | vauthors = Hasler F, Bourquin D, Brenneisen R, Bär T, Vollenweider FX | title = Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man | journal = Pharm Acta Helv | volume = 72 | issue = 3 | pages = 175–184 | date = June 1997 | pmid = 9204776 | doi = 10.1016/s0031-6865(97)00014-9 | url = }}</ref> An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated the peripheral effects of psilocybin, including pressor effects and mydriasis, but overall did not significantly modify the psychoactive and hallucinogenic effects of the psilocybin, although some of its emotional effects were said to be reduced and some of its perceptual effects were said to be amplified.<ref name="FradetKellyDonnelly2024">{{cite journal | vauthors = Fradet M, Kelly CM, Donnelly AJ, Suppes T | title = Psilocybin and hallucinogenic mushrooms | journal = CNS Spectr | volume = 29 | issue = 6 | pages = 611–632 | date = December 2024 | pmid = 39789676 | doi = 10.1017/S1092852924002487 | url = }}</ref><ref name="BarnettKoonsVandenEynde2024">{{cite journal | vauthors = Barnett BS, Koons CJ, Van den Eynde V, Gillman PK, Bodkin JA | title = Hypertensive Emergency Secondary to Combining Psilocybin Mushrooms, Extended Release Dextroamphetamine-Amphetamine, and Tranylcypromine | journal = J Psychoactive Drugs | volume = 57| issue = 3| pages = 297–303 | date = June 2024 | pmid = 38903003 | doi = 10.1080/02791072.2024.2368617 | url = | doi-access = free }}</ref><ref name="VojtĕchovskýHortSafratová1968">{{cite journal | vauthors = Vojtĕchovský M, Hort V, Safratová V | title = Ovlvinĕní experimntálních psychóz po psilocybinu inhibitory MAO | trans-title = Influence of MAO inhibitors on psilocybine induced psychosis | language = Czech | journal = Act Nerv Super (Praha) | volume = 10 | issue = 3 | pages = 278–279 | date = October 1968 | pmid = 5702524 | doi = | url = }}</ref>

Some psychedelics are substrates of cytochrome P450 (CYP450) enzymes, for instance LSD being a substrate of CYP2D6 as well as of several other CYP450 enzymes.<ref name="HalmanKongSarris2024" /><ref name="BeckerHumbert-DrozMueller2025">{{cite journal | vauthors = Becker AM, Humbert-Droz M, Mueller L, Jelušić A, Tolev A, Straumann I, Avedisian I, Erne L, Thomann J, Luethi D, Grünblatt E, Meyer Zu Schwabedissen H, Liechti ME | title = Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial | journal = Clin Pharmacol Ther | volume = 117| issue = 6| pages = 1784–1792| date = February 2025 | pmid = 40022427 | doi = 10.1002/cpt.3618 | url = | doi-access = free | pmc = 12087691 }}</ref> As such, CYP450 inhibitors may increase exposure to CYP450-substrate psychedelics such as LSD and thereby potentiate their effects as well as risks.<ref name="HalmanKongSarris2024" /><ref name="BeckerHumbert-DrozMueller2025" /> A clinical study found that administration of LSD to people taking paroxetine, a selective serotonin reuptake inhibitor (SSRI) and strong CYP2D6 inhibitor, increased LSD exposure by about 1.5-fold.<ref name="BeckerHumbert-DrozMueller2025" /> The combination was well-tolerated and did not modify the pleasant subjective effects or physiological effects of LSD, whereas negative effects of LSD, including "bad drug effect", anxiety, and nausea, were reduced.<ref name="BeckerHumbert-DrozMueller2025" /> Similarly to the findings with a strong CYP2D6 inhibitor, a pharmacogenomic clinical study with LSD found that LSD levels were 75% higher in people with non-functional CYP2D6 (poor metabolizers) compared to those with functional CYP2D6.<ref name="HalmanKongSarris2024" /><ref name="VizeliStraumannHolze2021">{{cite journal | vauthors = Vizeli P, Straumann I, Holze F, Schmid Y, Dolder PC, Liechti ME | title = Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis | journal = Sci Rep | volume = 11 | issue = 1 | article-number = 10851 | date = May 2021 | pmid = 34035391 | pmc = 8149637 | doi = 10.1038/s41598-021-90343-y | bibcode = 2021NatSR..1110851V | url = }}</ref>

Serotonin syndrome can be caused by combining psychedelics with other serotonergic drugs, including certain antidepressants, opioids, psychostimulants (e.g. MDMA), serotonin 5-HT1 receptor agonists (e.g. triptans), herbs or supplements, and others.<ref>{{cite journal|author=Bijl D |title=The serotonin syndrome |journal=Neth J Med |volume=62 |issue=9 |pages=309–13 |date=October 2004 |pmid=15635814 |quote= Mechanisms of serotonergic drugs implicated in serotonin syndrome... Stimulation of serotonin receptors... LSD}}</ref><ref>{{Cite web |url= https://www.drugwise.org.uk/amt/ |title=AMT |date=2016-01-03 |website=DrugWise.org.uk |language=en-gb |access-date=2019-11-18}}</ref><ref>{{Cite report |title=Alpha-methyltryptamine (AMT) – Critical Review Report |date=20 June 2014 |publisher=World Health Organisation – Expert Committee on Drug Dependence |publication-date=2014-06-20 |url=https://legal-high-inhaltsstoffe.de/sites/default/files/uploads/amt.pdf |access-date=2019-11-18}}</ref><ref name=Boy2005>{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–20 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 | url = http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | archive-url = https://web.archive.org/web/20130618053344/http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | url-status = live | archive-date = 2013-06-18 | author-link2 = Michael Shannon (pediatrician) }}</ref>

A high rate of seizures has been reported when people on lithium have taken serotonergic psychedelics.<ref name="FradetKellyDonnelly2024" /><ref name="HolzeLiechtiMüller2024">{{cite journal | vauthors = Holze F, Liechti ME, Müller F | title = Pharmacological Properties of Psychedelics with a Special Focus on Potential Harms | journal = Current Topics in Behavioral Neurosciences | series = Curr Top Behav Neurosci | volume = | issue = | pages = | date = July 2024 | pmid = 39080236 | doi = 10.1007/7854_2024_510 | url = }}</ref><ref name="NayakGukasyanBarrett2021">{{cite journal | vauthors = Nayak SM, Gukasyan N, Barrett FS, Erowid E, Erowid F, Griffiths RR | title = Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports | journal = Pharmacopsychiatry | volume = 54 | issue = 5 | pages = 240–245 | date = September 2021 | pmid = 34348413 | doi = 10.1055/a-1524-2794 | url = https://www.thieme-connect.com/products/ejournals/pdf/10.1055/a-1524-2794.pdf}}</ref> In an analysis of online reports, 47% of 62{{nbsp}}accounts reported seizures when a psychedelic was taken while on lithium.<ref name="FradetKellyDonnelly2024" /><ref name="HolzeLiechtiMüller2024" /><ref name="NayakGukasyanBarrett2021" /> The mechanism of this interaction is unclear.<ref name="FradetKellyDonnelly2024" /><ref name="NayakGukasyanBarrett2021" />

==Pharmacology== ===Mechanism of action=== {{See also|Serotonin 5-HT2A receptor agonist|Serotonin#Psychedelics|Entactogen#Mechanism of action}}

Most serotonergic psychedelics act as non-selective agonists of serotonin receptors, including of the serotonin 5-HT2 receptors, but often also of other serotonin receptors, such as the serotonin 5-HT1 receptors.<ref name="HolzeSinghLiechti2024">{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = 38301886 | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }}</ref><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 |article-number=e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | doi-access = free | bibcode = 2010PLoSO...5.9019R | url = }}</ref> They are thought to mediate their hallucinogenic effects specifically by activation of serotonin 5-HT2A receptors.<ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /> Psychedelics (including tryptamines like psilocin, DMT, and 5-MeO-DMT; phenethylamines like mescaline, DOM, and 2C-B; and ergolines and lysergamides like LSD) all act as agonists of the serotonin 5-HT2A receptors.<ref name="HalberstadtNichols2020">{{Cite book |last1=Halberstadt |first1=Adam L. |title=Handbook of Behavioral Neuroscience |last2=Nichols |first2=David E. |publisher=Elsevier |year=2020 |isbn=978-0-444-64125-0 |volume=31 |pages=843–863 |chapter=Serotonin and serotonin receptors in hallucinogen action |doi=10.1016/b978-0-444-64125-0.00043-8 |issn=1569-7339}}</ref><ref name="Halberstadt2015" /><ref name="DuanCaoWang2024" /> Some psychedelics, such as phenethylamines like DOM and 2C-B, show high selectivity for the serotonin 5-HT2 receptors over other serotonin receptors.<ref name="Halberstadt2015" /><ref name="DuanCaoWang2024">{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chem Rev | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 | url = }}</ref> There is a very strong correlation between 5-HT2A receptor affinity and human hallucinogenic potency.<ref name="Halberstadt2015" /> In addition, the intensity of hallucinogenic effects in humans is directly correlated with the level of serotonin 5-HT2A receptor occupancy as measured with positron emission tomography (PET) imaging.<ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /> Serotonin 5-HT2A receptor blockade with drugs like the semi-selective ketanserin and the non-selective risperidone can abolish the hallucinogenic effects of psychedelics in humans.<ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /> However, studies with more selective serotonin 5-HT2A receptor antagonists, like pimavanserin, are still needed.<ref name="RothGumpper2023">{{cite journal | vauthors = Roth BL, Gumpper RH | title = Psychedelics as Transformative Therapeutics | journal = Am J Psychiatry | volume = 180 | issue = 5 | pages = 340–347 | date = May 2023 | pmid = 37122272 | doi = 10.1176/appi.ajp.20230172 | url = https://cdr.lib.unc.edu/downloads/37720q20d}}</ref>

[[File:5ht2a.jpg|thumb|The serotonin 5-HT2A receptor.]]

In animals, potency for stimulus generalization to the psychedelic DOM in drug discrimination tests is strongly correlated with serotonin 5-HT2A receptor affinity.<ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /> Non-selective serotonin 5-HT2A receptor antagonists, like ketanserin and pirenperone, and selective serotonin 5-HT2A receptor antagonists, like volinanserin (MDL-100907), abolish the stimulus generalization of psychedelics in drug discrimination tests.<ref name="Halberstadt2015" /> Conversely, serotonin 5-HT2B and 5-HT2C receptor antagonists are ineffective.<ref name="Halberstadt2015" /> The potencies of serotonin 5-HT2 receptor antagonists in blocking psychedelic substitution are strongly correlated with their serotonin 5-HT2A receptor affinities.<ref name="Halberstadt2015" /> Highly selective serotonin 5-HT2A receptor agonists have recently been developed and show stimulus generalization to psychedelics, whereas selective serotonin 5-HT2C receptor agonists do not do so.<ref name="Halberstadt2015" /> The head-twitch response (HTR) is induced by serotonergic psychedelics and is a behavioral proxy of psychedelic-like effects in animals.<ref name="Halberstadt2015">{{cite journal | vauthors = Halberstadt AL | title = Recent advances in the neuropsychopharmacology of serotonergic hallucinogens | journal = Behav Brain Res | volume = 277 | issue = | pages = 99–120 | date = January 2015 | pmid = 25036425 | doi = 10.1016/j.bbr.2014.07.016 | url = | pmc = 4642895 }}</ref><ref name="KozlenkovGonzález-Maeso2013">{{cite book | last1=Kozlenkov | first1=Alexey | last2=González-Maeso | first2=Javier | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | pages=253–277}}</ref> The HTR is invariably induced by serotonergic psychedelics, is blocked by selective serotonin 5-HT2A receptor antagonists, and is abolished in serotonin 5-HT2A receptor knockout mice.<ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /> In addition, there is a strong correlation between hallucinogenic potency in humans and potency in the HTR assay.<ref name="KwanOlsonPreller2022" /><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | article-number = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = }}</ref> Moreover, the HTR paradigm is one of the only animal tests that can distinguish between hallucinogenic serotonin 5-HT2A receptor agonists and non-hallucinogenic serotonin 5-HT2A receptor agonists, such as lisuride.<ref name="Halberstadt2015" /> In accordance with the preceding animal and human findings, it has been said that the evidence that the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics is overwhelming.<ref name="KwanOlsonPreller2022" />

The serotonin 5-HT2A receptor activates several downstream signaling pathways.<ref name="KwanOlsonPreller2022" /><ref name="GlennonDukat2024" /><ref name="BarksdaleDossFonzo2024" /> These include the Gq, β-arrestin2, and other pathways.<ref name="KwanOlsonPreller2022" /><ref name="BarksdaleDossFonzo2024" /> Activation of both the Gq and β-arrestin2 pathways have been implicated in mediating the hallucinogenic effects of serotonergic psychedelics.<ref name="KwanOlsonPreller2022" /><ref name="GlennonDukat2024" /><ref name="GumpperNichols2024" /> However, subsequently, activation of the Gq pathway and not β-arrestin2 has been implicated.<ref name="BarksdaleDossFonzo2024">{{cite journal | vauthors = Barksdale BR, Doss MK, Fonzo GA, Nemeroff CB | title = The mechanistic divide in psychedelic neuroscience: An unbridgeable gap? | journal = Neurotherapeutics | volume = 21 | issue = 2 | article-number = e00322 | date = March 2024 | pmid = 38278658 | doi = 10.1016/j.neurot.2024.e00322 | url = | pmc = 10963929 }}</ref><ref name="GlennonDukat2024">{{cite journal | vauthors = Glennon RA, Dukat M | title = 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 6 | pages = 1722–1745 | date = June 2024 | pmid = 38898956 | doi = 10.1021/acsptsci.4c00157 | quote = Although the specific signaling cascades mediating the HTR have not been conclusively identified, Gq and β-arrestin2 have been implicated. Recent studies with different existing and novel agents, including DOI, found that the HTR was correlated with Gq efficacy but not with β-arrestin2 recruitment.114 | doi-access = free | pmc = 11184610 }}</ref><ref name="GumpperNichols2024">{{cite journal | vauthors = Gumpper RH, Nichols DE | title = Chemistry/structural biology of psychedelic drugs and their receptor(s) | journal = Br J Pharmacol | volume = | issue = | date = October 2024 | article-number = bph.17361 | pmid = 39354889 | doi = 10.1111/bph.17361 | url = }}</ref><ref name="ChisamoreKaczmarekLe2024">{{cite journal | vauthors = Chisamore N, Kaczmarek E, Le GH, Wong S, Orsini DK, Mansur R, McIntyre RS, Rosenblat JD | title=Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review | journal=Current Treatment Options in Psychiatry | publisher=Springer Science and Business Media LLC | volume=11 | issue=2 | date=26 April 2024 | issn=2196-3061 | doi=10.1007/s40501-024-00319-8 | pages=90–105}}</ref><ref name="WallachCaoCalkins2023">{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential | journal = Nat Commun | volume = 14 | issue = 1 | article-number = 8221 | date = December 2023 | pmid = 38102107 | doi = 10.1038/s41467-023-44016-1 | url = | pmc = 10724237 | bibcode = 2023NatCo..14.8221W }}</ref> Interestingly, Gq signaling appeared to mediate hallucinogenic-like effects, whereas β-arrestin2 mediated receptor downregulation and tachyphylaxis.<ref name="BarksdaleDossFonzo2024" /><ref name="WallachCaoCalkins2023" /> The lack of psychedelic effects with non-hallucinogenic serotonin 5-HT2A receptor agonists may be due to partial agonism of the serotonin 5-HT2A receptor with efficacy insufficient to produce psychedelic effects or may be due to biased agonism of the serotonin 5-HT2A receptor.<ref name="Halberstadt2015" /> There appears to be a threshold level of Gq activation (in terms of intrinsic activity, with {{Abbrlink|Emax|maximal efficacy}} >70%) required for production of hallucinogenic effects.<ref name="DuanCaoWang2024" /><ref name="GumpperNichols2024" /><ref name="WallachCaoCalkins2023" /> Full agonists and partial agonists above this threshold are psychedelic 5-HT2A receptor agonists, whereas partial agonists below this threshold, such as lisuride, 2-bromo-LSD, 6-fluoro-DET, 6-MeO-DMT, and Ariadne, are non-hallucinogenic 5-HT2A receptor agonists.<ref name="DuanCaoWang2024" /><ref name="WallachCaoCalkins2023" /><ref name="GlatfelterPottiePartilla2024"/><ref name="LewisBonniwellLanham2023">{{cite journal | vauthors = Lewis V, Bonniwell EM, Lanham JK, Ghaffari A, Sheshbaradaran H, Cao AB, Calkins MM, Bautista-Carro MA, Arsenault E, Telfer A, Taghavi-Abkuh FF, Malcolm NJ, El Sayegh F, Abizaid A, Schmid Y, Morton K, Halberstadt AL, Aguilar-Valles A, McCorvy JD | title = A non-hallucinogenic LSD analog with therapeutic potential for mood disorders | journal = Cell Rep | volume = 42 | issue = 3 | article-number = 112203 | date = March 2023 | pmid = 36884348 | doi = 10.1016/j.celrep.2023.112203 | url = | pmc = 10112881 }}</ref><ref name="CunninghamBockSerrano2023" /> In addition, biased agonists that activate β-arrestin2 signaling but not Gq signaling, such as ITI-1549, IHCH-7086, and 25N-N1-Nap, are non-hallucinogenic serotonin 5-HT2A receptor agonists.<ref name="DuanCaoWang2024" /><ref name="WallachCaoCalkins2023" /><ref name="DavisDutheilZhang2023">{{cite journal | vauthors = Davis R, Dutheil SS, Zhang L, Lehmann E, Awadallah N, Yao W, Snyder G, Li P | title = ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P358. Discovery and Characterization of ITI-1549, a Novel Non-Hallucinogenic Psychedelic for the Treatment of Neuropsychiatric Disorders | journal = Neuropsychopharmacology | volume = 48 | issue = Suppl 1 | pages = 211–354 (272–273) | date = December 2023 | pmid = 38040810 | pmc = 10729596 | doi = 10.1038/s41386-023-01756-4 | url = }}</ref>

The hallucinogenic effects of serotonergic psychedelics may be critically mediated by serotonin 5-HT2A receptor activation in the medial prefrontal cortex (mPFC).<ref name="Halberstadt2015" /> Layer V pyramidal neurons in this area are especially discussed.<ref name="Halberstadt2015" /><ref name="Marek2018">{{cite book | vauthors = Marek GJ | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 107–135 | date = 2018 | pmid = 28831734 | doi = 10.1007/7854_2017_480 | isbn = 978-3-662-55878-2 | chapter-url = }}</ref> Activation of serotonin 5-HT2A receptors in the mPFC results in marked excitatory and inhibitory effects as well as increased release of glutamate and GABA.<ref name="Halberstadt2015" /> Direct injection of serotonin 5-HT2A receptor agonists into the mPFC produces the HTR.<ref name="Halberstadt2015" /> Drugs that suppress glutamatergic activity in the mPFC, including AMPA receptor antagonists, metabotropic glutamate mGlu2/3 receptor agonists, μ-opioid receptor agonists, and adenosine A1 receptor agonists, block or suppress many of the neurochemical and behavioral effects of serotonergic psychedelics, including the HTR.<ref name="Halberstadt2015" /><ref name="SalinskyMerrittZamora2023">{{cite journal | vauthors = Salinsky LM, Merritt CR, Zamora JC, Giacomini JL, Anastasio NC, Cunningham KA | title = μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges | journal = Front Pharmacol | volume = 14 | issue = | article-number = 1239159 | date = 2023 | pmid = 37886127 | pmc = 10598667 | doi = 10.3389/fphar.2023.1239159 | doi-access = free | url = }}</ref> Metabotropic glutamate mGlu2 receptors are primarily expressed as presynaptic autoreceptors and have inhibitory effects on glutamate release.<ref name="Halberstadt2015" /><ref name="HalberstadtGeyer2018" /> Serotonergic psychedelics have been found to produce frontal cortex hyperactivity in humans in PET and single-photon emission computed tomography (SPECT) imaging studies.<ref name="Halberstadt2015" /> The PFC projects to many other cortical and subcortical brain areas, such as the locus coeruleus, nucleus accumbens, and amygdala, among others, and activation of the PFC by serotonergic psychedelics may thereby indirectly modulate these areas.<ref name="Halberstadt2015" /> In addition to the PFC, there is moderate to high expression of serotonin 5-HT2A receptors in the primary visual cortex (V1), as well as expression of the serotonin 5-HT2A receptor in other visual areas, and activation of these receptors may contribute to or mediate the visual effects of serotonergic psychedelics.<ref name="SiegelListonNicol2026">{{cite journal | vauthors = Siegel JS, Liston C, Nicol GE, Carhart-Harris RL, Bogenschutz MP | title = The science of psychedelic medicine | journal = Nat Med | volume = 32 | issue = 2 | pages = 449–462 | date = February 2026 | pmid = 41652120 | doi = 10.1038/s41591-025-04194-5 | url = }}</ref><ref name="Halberstadt2015" /><ref name="KwanOlsonPreller2022" /><ref name="AqilRoseman2023">{{cite journal | vauthors = Aqil M, Roseman L | title = More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics | journal = Neuropharmacology | volume = 223 | issue = | article-number = 109300 | date = February 2023 | pmid = 36334767 | doi = 10.1016/j.neuropharm.2022.109300 | url = }}</ref><ref name="Császár-NagyKapócsBókkon2019">{{cite journal | vauthors = Császár-Nagy N, Kapócs G, Bókkon I | title = Classic psychedelics: the special role of the visual system | journal = Rev Neurosci | volume = 30 | issue = 6 | pages = 651–669 | date = July 2019 | pmid = 30939118 | doi = 10.1515/revneuro-2018-0092 | url = }}</ref><ref name="BressloffCowanGolubitsky2002">{{cite journal | vauthors = Bressloff PC, Cowan JD, Golubitsky M, Thomas PJ, Wiener MC | title = What geometric visual hallucinations tell us about the visual cortex | journal = Neural Comput | volume = 14 | issue = 3 | pages = 473–491 | date = March 2002 | pmid = 11860679 | doi = 10.1162/089976602317250861 | url = }}</ref> Serotonergic psychedelics also directly or indirectly modulate a variety of other brain areas, like the claustrum, and this may be involved in their effects as well.<ref name="KwanOlsonPreller2022" /><ref name="DossMaddenGaddis2022">{{cite journal | vauthors = Doss MK, Madden MB, Gaddis A, Nebel MB, Griffiths RR, Mathur BN, Barrett FS | title = Models of psychedelic drug action: modulation of cortical-subcortical circuits | journal = Brain | volume = 145 | issue = 2 | pages = 441–456 | date = April 2022 | pmid = 34897383 | pmc = 9014750 | doi = 10.1093/brain/awab406 | url = }}</ref><ref name="RieserSchmidtPreller2024">{{cite book | vauthors = Rieser NM, Schmidt TT, Preller KH | title = Neurobiological Correlates of Psychedelic Experiences and Psychedelic-Associated Adverse Effects | series = Current Topics in Behavioral Neurosciences | volume = | pages = | date = July 2024 | pmid = 39080245 | doi = 10.1007/7854_2024_507 | url = }}</ref> Psychedelics may work in part by disrupting the default mode network (DMN), a collection of interconnected brain areas which has high serotonin 5-HT2A receptor expression and is said to construct our sense of space, time, and self.<ref name="SiegelListonNicol2026" /> The ego dissolution and altered time perception caused by psychedelics correlates with DMN desynchronization, whereas psychedelic visual imagery correlates with disruption in the visual cortex.<ref name="SiegelListonNicol2026" />

Serotonin, as well as drugs that increase serotonin levels, like the serotonin precursor 5-hydroxytryptophan (5-HTP), serotonin reuptake inhibitors, and serotonin releasing agents, are non-hallucinogenic in humans despite increasing activation of serotonin 5-HT2A receptors.<ref name="HalberstadtGeyer2018" /><ref name="Sapienza2023">{{cite journal | vauthors = Sapienza J | title=The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? | journal=Psychoactives | volume=2 | issue=4 | date=13 October 2023 | issn=2813-1851 | doi=10.3390/psychoactives2040018 | doi-access=free | pages=287–293}}</ref><ref name="WojtasGołembiowska2023">{{cite journal | vauthors = Wojtas A, Gołembiowska K | title = Molecular and Medical Aspects of Psychedelics | journal = Int J Mol Sci | volume = 25 | issue = 1 | date = December 2023 | page = 241 | pmid = 38203411 | pmc = 10778977 | doi = 10.3390/ijms25010241 | doi-access = free | url = | quote = While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].}}</ref><ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = | quote = In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49). Thus, activation of intracellular cortical 5-HT2ARs may play a role in the subjective effects of psychedelics. This hypothesis is further supported by previous work demonstrating that a high dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces a HTR in WT mice, which can be blocked by an N-methyltransferase inhibitor that prevents the metabolism of 5-HTP to N-methyltryptamines (50). Inhibition of N-methyltransferase failed to block the HTR induced by 5-MeO-DMT (50). Taken together, this work emphasizes that accessing intracellular 5-HT2ARs is important for 5-HT2AR agonists to produce a HTR.}}</ref> Serotonin is a hydrophilic molecule which cannot easily cross biological membranes without active transport, and the serotonin 5-HT2A receptor is usually expressed as a cell surface receptor that is readily accessible to extracellular serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> The HTR, a behavioral proxy of psychedelic-like effects, appears to be mediated by activation of intracellularly expressed serotonin 5-HT2A receptors in a population of mPFC neurons that do not also express the serotonin transporter (SERT) and hence cannot be activated by serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In contrast to serotonin, serotonergic psychedelics are more lipophilic than serotonin and are able to readily enter these neurons and activate the serotonin 5-HT2A receptors within them.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Artificial expression of the SERT in this population of neurons in animals resulted in a serotonin releasing agent that doesn't normally produce the HTR being able to do so.<ref name="VargasDunlapDong2023" /> Although serotonin itself is non-hallucinogenic, at very high concentrations achieved pharmacologically (e.g., injected into the brain or with massive doses of 5-HTP) it can produce psychedelic-like effects in animals by being metabolized by indolethylamine ''N''-methyltransferase (INMT) into more lipophilic ''N''-methylated tryptamines like ''N''-methylserotonin and bufotenin (''N'',''N''-dimethylserotonin).<ref name="SchmidBohn2018">{{cite book | vauthors = Schmid CL, Bohn LM | title=5-HT2A Receptors in the Central Nervous System | chapter=βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events | publisher=Springer International Publishing | publication-place=Cham | date=2018 | isbn=978-3-319-70472-2 | doi=10.1007/978-3-319-70474-6_2 | pages=31–55}}</ref><ref name="KozlenkovGonzález-Maeso2013" /><ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = | quote = [...] the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.}}</ref><ref name="SchmidBohn2010">{{cite journal | vauthors = Schmid CL, Bohn LM | title = Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo | journal = J Neurosci | volume = 30 | issue = 40 | pages = 13513–24 | date = October 2010 | pmid = 20926677 | pmc = 3001293 | doi = 10.1523/JNEUROSCI.1665-10.2010 | url = }}</ref><ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" />

In addition to their hallucinogenic effects, serotonergic psychedelics may also produce a variety of other effects, including psychoplastogenic (i.e., neuroplasticity-enhancing),<ref name="Olson2018">{{cite journal | vauthors = Olson DE | title = Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics | journal = J Exp Neurosci | volume = 12 | issue = | article-number = 1179069518800508 | date = 2018 | pmid = 30262987 | pmc = 6149016 | doi = 10.1177/1179069518800508 | url = }}</ref><ref name="VargasMeyerAvanes2021">{{cite journal | vauthors = Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE | title = Psychedelics and Other Psychoplastogens for Treating Mental Illness | journal = Front Psychiatry | volume = 12 | issue = | article-number = 727117 | date = 2021 | pmid = 34671279 | pmc = 8520991 | doi = 10.3389/fpsyt.2021.727117 | doi-access = free | url = }}</ref><ref name="Olson2022">{{cite journal | vauthors = Olson DE | title = Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity | journal = Biochemistry | volume = 61 | issue = 3 | pages = 127–136 | date = February 2022 | pmid = 35060714 | pmc = 9004607 | doi = 10.1021/acs.biochem.1c00812 | url = }}</ref><ref name="HatzipantelisOlson2024">{{cite journal | vauthors = Hatzipantelis CJ, Olson DE | title = The Effects of Psychedelics on Neuronal Physiology | journal = Annu Rev Physiol | volume = 86 | issue = | pages = 27–47 | date = February 2024 | pmid = 37931171 | doi = 10.1146/annurev-physiol-042022-020923 | pmc = 10922499 | url = }}</ref> antidepressant,<ref name="DuanCaoWang2024" /><ref name="HusainLedwosFellows2022">{{cite journal | vauthors = Husain MI, Ledwos N, Fellows E, Baer J, Rosenblat JD, Blumberger DM, Mulsant BH, Castle DJ | title = Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? | journal = Front Psychiatry | volume = 13 | issue = | article-number = 1076459 | date = 2022 | pmid = 36844032 | pmc = 9950579 | doi = 10.3389/fpsyt.2022.1076459 | doi-access = free | url = }}</ref><ref name="ChisamoreKaczmarekLe2024" /> anxiolytic,<ref name="FeulnerSermchaiwongRodland2023">{{cite journal | vauthors = Feulner L, Sermchaiwong T, Rodland N, Galarneau D | title = Efficacy and Safety of Psychedelics in Treating Anxiety Disorders | journal = Ochsner J | volume = 23 | issue = 4 | pages = 315–328 | date = 2023 | pmid = 38143548 | pmc = 10741816 | doi = 10.31486/toj.23.0076 | url = }}</ref><ref name="WerleBertoglio2024">{{cite journal | vauthors = Werle I, Bertoglio LJ | title = Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents | journal = Neurosci Biobehav Rev | volume = 167 | issue = | article-number = 105899 | date = December 2024 | pmid = 39305969 | doi = 10.1016/j.neubiorev.2024.105899 | url = }}</ref> empathy-enhancing or prosocial effects,<ref name="MarkopoulosInserraDeGregorio2021">{{cite journal | vauthors = Markopoulos A, Inserra A, De Gregorio D, Gobbi G | title = Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder | journal = Front Pharmacol | volume = 12 | issue = | article-number = 749068 | date = 2021 | pmid = 35177979 | pmc = 8846292 | doi = 10.3389/fphar.2021.749068 | doi-access = free | url = }}</ref><ref name="BhattWeissman2024">{{cite journal | vauthors = Bhatt KV, Weissman CR | title = The effect of psilocybin on empathy and prosocial behavior: a proposed mechanism for enduring antidepressant effects | journal = npj Ment Health Res | volume = 3 | issue = 1 | article-number = 7 | date = February 2024 | pmid = 38609500 | pmc = 10955966 | doi = 10.1038/s44184-023-00053-8 | url = }}</ref><ref name="KupferbergHasler2024">{{cite journal | vauthors = Kupferberg A, Hasler G | title = From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression | journal = Front Psychiatry | volume = 15 | issue = | article-number = 1372650 | date = 2024 | pmid = 39469469 | pmc = 11513289 | doi = 10.3389/fpsyt.2024.1372650 | doi-access = free | url = }}</ref> anti-obsessional,<ref name="DelgadoMoreno1998">{{cite journal | vauthors = Delgado PL, Moreno FA | title = Hallucinogens, serotonin and obsessive-compulsive disorder | journal = J Psychoactive Drugs | volume = 30 | issue = 4 | pages = 359–366 | date = 1998 | pmid = 9924841 | doi = 10.1080/02791072.1998.10399711 | url = }}</ref><ref name="EhrmannAllenMoreno2022">{{cite book | vauthors = Ehrmann K, Allen JJ, Moreno FA | title = Disruptive Psychopharmacology | chapter = Psilocybin for the Treatment of Obsessive-Compulsive Disorders | series = Current Topics in Behavioral Neurosciences | volume = 56 | pages = 247–259 | date = 2022 | pmid = 34784024 | doi = 10.1007/7854_2021_279 | isbn = 978-3-031-12183-8 | chapter-url = }}</ref><ref name="Collins2024">{{cite journal | vauthors = Collins HM | title = Psychedelics for the Treatment of Obsessive Compulsive Disorder: Efficacy and Proposed Mechanisms | journal = Int J Neuropsychopharmacol | volume = 27| issue = 12| date = November 2024 | article-number = pyae057 | pmid = 39611453 | doi = 10.1093/ijnp/pyae057 | url = | doi-access = free | pmc = 11635828 }}</ref><ref name="SzafoniGręblowskiGrabowska2024">{{cite journal | vauthors = Szafoni S, Gręblowski P, Grabowska K, Więckiewicz G | title = Unlocking the healing power of psilocybin: an overview of the role of psilocybin therapy in major depressive disorder, obsessive-compulsive disorder and substance use disorder | journal = Front Psychiatry | volume = 15 | issue = | article-number = 1406888 | date = 2024 | pmid = 38919636 | pmc = 11196758 | doi = 10.3389/fpsyt.2024.1406888 | doi-access = free | url = }}</ref><ref name="Owe-LarssonKamińskaBuchalska2024">{{cite journal | vauthors = Owe-Larsson M, Kamińska K, Buchalska B, Mirowska-Guzel D, Cudnoch-Jędrzejewska A | title = Psilocybin in pharmacotherapy of obsessive-compulsive disorder | journal = Pharmacol Rep | volume = 76 | issue = 5 | pages = 911–925 | date = October 2024 | pmid = 39088105 | pmc = 11387457 | doi = 10.1007/s43440-024-00633-1 | url = }}</ref> anti-addictive,<ref name="UrbanStinglMeinhardt2023">{{cite journal | vauthors = Urban MM, Stingl MR, Meinhardt MW | title = Mini-review: The neurobiology of treating substance use disorders with classical psychedelics | journal = Front Neurosci | volume = 17 | issue = | article-number = 1156319 | date = 2023 | pmid = 37139521 | pmc = 10149865 | doi = 10.3389/fnins.2023.1156319 | doi-access = free | url = }}</ref><ref name="Vamvakopoulou2024">{{cite journal | vauthors = Vamvakopoulou IA, Nutt DJ | title = Psychedelics: From Cave Art to 21st-Century Medicine for Addiction | journal = Eur Addict Res | volume = 30 | issue = 5 | pages = 302–320 | date = 2024 | pmid = 39321788 | pmc = 11527458 | doi = 10.1159/000540062 | url = }}</ref><ref name="Gomez-EscolarFolch-SanchezStefaniuk2024">{{cite journal | vauthors = Gomez-Escolar A, Folch-Sanchez D, Stefaniuk J, Swithenbank Z, Nisa A, Braddick F, Idrees Chaudhary N, van der Meer PB, Batalla A | title = Current Perspectives on the Clinical Research and Medicalization of Psychedelic Drugs for Addiction Treatments: Safety, Efficacy, Limitations and Challenges | journal = CNS Drugs | volume = 38 | issue = 10 | pages = 771–789 | date = October 2024 | pmid = 39033264 | doi = 10.1007/s40263-024-01101-3 | url = https://orcid.org/0000-0001-6957-6196}}</ref><ref name="ValdezPatelSenesombath2024">{{cite journal | vauthors = Valdez T, Patel V, Senesombath N, Hatahet-Donovan Z, Hornick M | title = Therapeutic Potential of Psychedelic Compounds for Substance Use Disorders | journal = Pharmaceuticals | volume = 17 | issue = 11 | date = November 2024 | page = 1484 | pmid = 39598395 | pmc = 11597566 | doi = 10.3390/ph17111484 | doi-access = free | url = }}</ref> anti-inflammatory and immunomodulatory effects,<ref name="NicholsJohnsonNichols2017">{{cite journal | vauthors = Nichols DE, Johnson MW, Nichols CD | title = Psychedelics as Medicines: An Emerging New Paradigm | journal = Clin Pharmacol Ther | volume = 101 | issue = 2 | pages = 209–219 | date = February 2017 | pmid = 28019026 | doi = 10.1002/cpt.557 | url = }}</ref><ref name="FlanaganNichols2022">{{cite book | vauthors = Flanagan TW, Nichols CD | title = Disruptive Psychopharmacology | chapter = Psychedelics and Anti-inflammatory Activity in Animal Models | series = Current Topics in Behavioral Neurosciences | volume = 56 | pages = 229–245 | date = 2022 | pmid = 35546383 | doi = 10.1007/7854_2022_367 | isbn = 978-3-031-12183-8 | chapter-url = }}</ref><ref name="Nichols2022a">{{cite journal | vauthors = Nichols CD | title = Psychedelics as potent anti-inflammatory therapeutics | journal = Neuropharmacology | volume = 219 | issue = | article-number = 109232 | date = November 2022 | pmid = 36007854 | doi = 10.1016/j.neuropharm.2022.109232 | url = | doi-access = free }}</ref><ref name="ThompsonSzabo2020">{{cite journal | vauthors = Thompson C, Szabo A | title = Psychedelics as a novel approach to treating autoimmune conditions | journal = Immunol Lett | volume = 228 | issue = | pages = 45–54 | date = December 2020 | pmid = 33035575 | doi = 10.1016/j.imlet.2020.10.001 | url = | hdl = 10852/80687 | hdl-access = free }}</ref><ref name="LowNgLimGoh2024">{{cite journal | vauthors = Low ZX, Ng WS, Lim ES, Goh BH, Kumari Y | title = The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 136| issue = | article-number = 111139 | date = September 2024 | pmid = 39251080 | doi = 10.1016/j.pnpbp.2024.111139 | url = | doi-access = free }}</ref> analgesic effects,<ref name="CastellanosWoolleyBruno2020">{{cite journal | vauthors = Castellanos JP, Woolley C, Bruno KA, Zeidan F, Halberstadt A, Furnish T | title = Chronic pain and psychedelics: a review and proposed mechanism of action | journal = Reg Anesth Pain Med | volume = 45 | issue = 7 | pages = 486–494 | date = July 2020 | pmid = 32371500 | doi = 10.1136/rapm-2020-101273 | url = }}</ref><ref name="ZiaBaumannBelouin2023">{{cite journal | vauthors = Zia FZ, Baumann MH, Belouin SJ, Dworkin RH, Ghauri MH, Hendricks PS, Henningfield JE, Lanier RK, Ross S, Berger A | title = Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs | journal = Neuropharmacology | volume = 233 | issue = | article-number = 109528 | date = August 2023 | pmid = 37015315 | doi = 10.1016/j.neuropharm.2023.109528 | url = | doi-access = free }}</ref><ref name="GoelRaiSivadas2023">{{cite journal | vauthors = Goel A, Rai Y, Sivadas S, Diep C, Clarke H, Shanthanna H, Ladha KS | title = Use of Psychedelics for Pain: A Scoping Review | journal = Anesthesiology | volume = 139 | issue = 4 | pages = 523–536 | date = October 2023 | pmid = 37698433 | doi = 10.1097/ALN.0000000000004673 | url = }}</ref> and/or antimigraine effects.<ref name="Schindler2022">{{cite book | vauthors = Schindler EA | title = Disruptive Psychopharmacology | chapter = Psychedelics in the Treatment of Headache and Chronic Pain Disorders | series = Current Topics in Behavioral Neurosciences | volume = 56 | pages = 261–285 | date = 2022 | pmid = 35546382 | doi = 10.1007/7854_2022_365 | isbn = 978-3-031-12183-8 | chapter-url = }}</ref><ref name="SchindlerHendricks2023">{{cite journal | vauthors = Schindler EA, Hendricks PS | title = Adapting psychedelic medicine for headache and chronic pain disorders | journal = Expert Rev Neurother | volume = 23 | issue = 10 | pages = 867–882 | date = 2023 | pmid = 37652000 | doi = 10.1080/14737175.2023.2246655 | url = }}</ref><ref name="Schindler2023">{{cite journal | vauthors = Schindler EA | title = The Potential of Psychedelics for the Treatment of Episodic Migraine | journal = Curr Pain Headache Rep | volume = 27 | issue = 9 | pages = 489–495 | date = September 2023 | pmid = 37540398 | doi = 10.1007/s11916-023-01145-y | url = }}</ref> While psychedelics themselves are also being clinically evaluated for these potential therapeutic benefits, non-hallucinogenic serotonin 5-HT2A receptor agonists, which are often analogues of serotonergic psychedelics, have been developed and are being studied for potential use in medicine in an attempt to provide some such benefits without hallucinogenic effects.<ref name="DuanCaoWang2024" /><ref name="AtiqBakerVoort2024">{{cite journal | vauthors = Atiq MA, Baker MR, Voort JL, Vargas MV, Choi DS | title = Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties | journal = Psychopharmacology (Berl) | volume = 242| issue = 7| pages = 1481–1506| date = May 2024 | pmid = 38743110 | doi = 10.1007/s00213-024-06599-5 | pmc = 12226698 | url = | doi-access = free }}</ref><ref name="SchmitzRoth2023">{{cite journal | vauthors = Schmitz GP, Roth BL | title = G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics | journal = Am J Physiol Cell Physiol | volume = 325 | issue = 1 | pages = C17–C28 | date = July 2023 | pmid = 37067459 | pmc = 10281788 | doi = 10.1152/ajpcell.00397.2022 | url = }}</ref>

Although the hallucinogenic effects of serotonergic psychedelics are thought to be mediated by serotonin 5-HT2A receptor activation, interactions with other receptors, such as the serotonin 5-HT1A, 5-HT1B, 5-HT2B, and 5-HT2C receptors among many others, may additionally contribute to and modulate their effects.<ref name="Halberstadt2015" /><ref name="CameronBenetatosLewis2023">{{cite journal | vauthors = Cameron LP, Benetatos J, Lewis V, Bonniwell EM, Jaster AM, Moliner R, Castrén E, McCorvy JD, Palner M, Aguilar-Valles A | title = Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action | journal = J Neurosci | volume = 43 | issue = 45 | pages = 7472–7482 | date = November 2023 | pmid = 37940583 | doi = 10.1523/JNEUROSCI.1384-23.2023 | url = | pmc = 10634557 }}</ref> Many psychedelics show pronounced biased agonism at the serotonin 5-HT2C receptor.<ref name="BonniwellAlabadaliHennessey2025">{{cite journal | vauthors = Bonniwell EM, Alabdali R, Hennessey JJ, McKee JL, Cavalco NG, Lammers JC, Moore EJ, Franchini L, Orlandi C, McCorvy JD | title = Serotonin 5-HT2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism | journal = ACS Chem Neurosci | volume = 16 | issue = 19 | pages = 3899–3914 | date = October 2025 | pmid = 40944639 | doi = 10.1021/acschemneuro.5c00647 | pmc = 12629614 | url = }}</ref> Certain psychedelics, including LSD and psilocin, have been reported to act as highly potent positive allosteric modulators of the tropomyosin receptor kinase B (TrkB), one of the signaling receptors of brain-derived neurotrophic factor (BDNF).<ref name="HatzipantelisOlson2024" /><ref name="BrunelloCannarozzoCastrén2024">{{cite journal | vauthors = Brunello CA, Cannarozzo C, Castrén E | title = Rethinking the role of TRKB in the action of antidepressants and psychedelics | journal = Trends Neurosci | volume = 47 | issue = 11 | pages = 865–874 | date = November 2024 | pmid = 39304417 | doi = 10.1016/j.tins.2024.08.011 | url = | doi-access = free }}</ref><ref name="CameronBenetatosLewis2023" /><ref name="MolinerGirychBrunello2023">{{cite journal | vauthors = Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E | title = Psychedelics promote plasticity by directly binding to BDNF receptor TrkB | journal = Nat Neurosci | volume = 26 | issue = 6 | pages = 1032–1041 | date = June 2023 | pmid = 37280397 | pmc = 10244169 | doi = 10.1038/s41593-023-01316-5 | url = }}</ref> However, subsequent studies failed to reproduce these findings and instead found no interaction of LSD or psilocin with TrkB.<ref name="JainGumpperSlocum2025">{{cite journal | vauthors = Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL | title = The polypharmacology of psychedelics reveals multiple targets for potential therapeutics | journal = Neuron | volume = 113| issue = 19| pages = 3129–3142.e9| date = July 2025 | pmid = 40683247 | doi = 10.1016/j.neuron.2025.06.012 | url = https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf | quote = Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63}}</ref> Moreover, the psychoplastogenic effects of serotonergic psychedelics, including dendritogenesis, spinogenesis, and synaptogenesis, appear to be mediated by activation of multiple serotonin receptors as well as non‑serotonergic targets, whereas psychedelics do not generally stimulate neurogenesis.<ref name="HatzipantelisOlson2024" /><ref name="Olson2022" /><ref name="CameronBenetatosLewis2023" /><ref name="Sonda2025">{{cite journal | vauthors = Sonda S, Pendin D, Comai S, De Martin S, Manfredi P, Mattarei A | year = 2025 | title = Emerging mechanisms of psilocybin-induced neuroplasticity | journal = Trends in Pharmacological Sciences | volume = 46 | pages = 1130–1143 | doi = 10.1016/j.tips.2025.08.012 }}</ref>

The factors responsible for differences in psychoactive and hallucinogenic effects between different psychedelics are incompletely understood but may include (1) differences in selectivity for the serotonin 5-HT2A receptor or off-target activity; (2) differences in functional selectivity for different serotonin 5-HT2A receptor downstream signaling pathways; and (3) differences in patterns or balances of distribution to different brain areas.<ref name="Nichols2018" /><ref name="Nichols2004" /><ref name="DourronNicholsSimonsson2023" /><ref name="SiegelListonNicol2026" /><ref name="BrimblecombePinder1975" />

Various approaches are available for estimating equivalent doses of psychedelics between animals and humans.<ref name="KwanMantschMcCorvy2025">{{cite journal | vauthors = Kwan AC, Mantsch JR, McCorvy JD | title = The ABCs of psychedelics: a preclinical roadmap for drug discovery | journal = Trends Pharmacol Sci | volume = 46 | issue = 12 | pages = 1224–1240 | date = December 2025 | pmid = 40877079 | pmc = 12404667 | doi = 10.1016/j.tips.2025.07.017 | url = | quote = Dosing is an important consideration when performing translating across species. The approximate dose can be estimated using allometric scaling formulas that account for metabolic rate and surface area differences between animals [116]. For psilocybin, the standard dose of 25 mg in a 60 kg human translates to 5.1 mg/kg in mice. These numbers provide a rough guideline dosage but are not determined specifically with psychedelics in mind. Ideally, it should be empirically determined that the chosen dosages produce similar levels of receptor occupancy in animals and humans.}}</ref><ref name="MasthayKwanChang2026">{{cite journal | vauthors = Masthay JC, Kwan AC, Chang SW | title = Psychedelic studies in nonhuman primates: Past and future | journal = Mol Psychiatry | volume = 31 | issue = 1 | pages = 514–525 | date = January 2026 | pmid = 40940559 | pmc = 12709594 | doi = 10.1038/s41380-025-03240-5 | url = }}</ref> Examples include allometric scaling formulas and receptor occupancy studies.<ref name="KwanMantschMcCorvy2025" /><ref name="MasthayKwanChang2026" />

===Neurotoxicity=== {{See also|Psychedelic microdosing#Neurological toxicity}}

A variety of serotonergic psychedelics have been assessed and found to produce neurotoxicity at high concentrations ''in vitro'' and/or high doses ''in vivo'' in rodents.<ref name="RudinLiechtiLuethi2021">{{cite journal | vauthors = Rudin D, Liechti ME, Luethi D | title = Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics | journal = Exp Neurol | volume = 343 | issue = | article-number = 113778 | date = September 2021 | pmid = 34090893 | doi = 10.1016/j.expneurol.2021.113778 | url = }}</ref><ref name="CustodioOrtizLee2025">{{cite journal | vauthors = Custodio RJ, Ortiz DM, Lee HJ, Sayson LV, Kim M, Lee YS, Kim KM, Cheong JH, Kim HJ | title = Serotonin 2C receptors are also important in head-twitch responses in male mice | journal = Psychopharmacology (Berl) | volume = 242 | issue = 7 | pages = 1585–1605 | date = July 2025 | pmid = 37882810 | doi = 10.1007/s00213-023-06482-9 | url = }}</ref><ref name="CapelaRuscherLautenschlager2006">{{cite journal | vauthors = Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F | title = Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia | journal = Neuroscience | volume = 139 | issue = 3 | pages = 1069–1081 | date = 2006 | pmid = 16504407 | doi = 10.1016/j.neuroscience.2006.01.007 | url = }}</ref><ref name="CapelaCarmoRemião2009">{{cite journal | vauthors = Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F | title = Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview | journal = Mol Neurobiol | volume = 39 | issue = 3 | pages = 210–271 | date = June 2009 | pmid = 19373443 | doi = 10.1007/s12035-009-8064-1 | url = | quote = To further corroborate the fact that MDMA agonistic properties at the 5-HT2A receptor could produce neuronal death, DOI, a prototypical agonist of that receptor was added to cortical neurons [289]. DOI (10 to 100 μM for 24 or 48 h) also induced a dose- and time-dependent apoptotic cortical neuronal apoptosis, which was attenuated by ketanserin and R-96544 [289]. Ketanserin and R-96544 are competitive selective 5-HT2A receptor antagonists and only attenuated MDMA-induced cortical neurodegeneration. However, an antibody raised against the 5-HT2A-receptor, an "irreversible" non-competitive 5-HT2A receptor blocker, prevented almost completely MDMA- and DOI-induced cortical neurotoxicity [289, 290]. Neuronal apoptosis mediated by MDMA is accompanied by activation of caspase 3, which could be blocked by the antibody raised against the 5-HT2A receptor [290]. Therefore, it is likely that DOI- and MDMA-induced neuronal apoptosis arises from direct stimulation of the 5-HT2A receptor [289, 290].}}</ref> These psychedelics have included DOI, 2C-B, 25B-NBOMe, 25C-NBOMe, 5-MeO-DiPT, 5-MeO-MiPT, methallylescaline (MAL), and BOD, among others.<ref name="RudinLiechtiLuethi2021" /><ref name="CustodioOrtizLee2025" /><ref name="CapelaRuscherLautenschlager2006" /><ref name="CapelaCarmoRemião2009" /> The neurotoxicity induced by the preceding psychedelics has included MDMA-like serotonergic neurotoxicity, for instance with DOI, MAL, and 5-MeO-DiPT.<ref name="RudinLiechtiLuethi2021" /><ref name="CustodioOrtizLee2025" /><ref name="CapelaRuscherLautenschlager2006" /><ref name="CapelaCarmoRemião2009" /> The neurotoxicity of psychedelics has been found to be partially blocked by serotonin 5-HT2A receptor inhibition, which was also the case with the neurotoxicity of MDMA.<ref name="CapelaCarmoRemião2009" /><ref name="RudinLiechtiLuethi2021" /> Besides producing neurotoxicity on their own, psychedelics have been found to potentiate the serotonergic neurotoxicity of MDMA via serotonin 5-HT2 receptor activation in rodents.<ref name="GreenMechanElliott2003">{{cite journal | vauthors = Green AR, Mechan AO, Elliott JM, O'Shea E, Colado MI | title = The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") | journal = Pharmacol Rev | volume = 55 | issue = 3 | pages = 463–508 | date = September 2003 | pmid = 12869661 | doi = 10.1124/pr.55.3.3 | url = }}</ref><ref name="GudelskyYamamotoNash1994">{{cite journal | vauthors = Gudelsky GA, Yamamoto BK, Nash JF | title = Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists | journal = Eur J Pharmacol | volume = 264 | issue = 3 | pages = 325–330 | date = November 1994 | pmid = 7698172 | doi = 10.1016/0014-2999(94)90669-6 | url = }}</ref><ref name="SchmidtBlackAbbate1990">{{cite journal | vauthors = Schmidt CJ, Black CK, Abbate GM, Taylor VL | title = Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors | journal = Brain Res | volume = 529 | issue = 1–2 | pages = 85–90 | date = October 1990 | pmid = 1980848 | doi = 10.1016/0006-8993(90)90813-q | url = }}</ref><ref name="Armstrong_2004">{{cite journal | vauthors = Armstrong BD, Paik E, Chhith S, Lelievre V, Waschek JA, Howard SG | title = Potentiation of (DL)-3,4-methylenedioxymethamphetamine (MDMA)-induced toxicity by the serotonin 2A receptior partial agonist d-lysergic acid diethylamide (LSD), and the protection of same by the serotonin 2A/2C receptor antagonist MDL 11,939 | journal = Neuroscience Research Communications | volume = 35 | issue = 2 | pages = 83–95 | date = 2004 | doi = 10.1002/nrc.20023 }}</ref>

DOM is known to metabolize into 2,5-DDM-DOM (2-''O''-,5-''O''-didesmethyl-DOM; 2,5-dihydroxy-4-methylamphetamine), which bears a close resemblance to 6-hydroxydopamine (6-OHDA; 2,4,5-trihydroxyphenethylamine) and has been found to be a potent neurotoxin similarly.<ref name="Shulgin1980">{{cite book | vauthors = Shulgin AT | chapter = Hallucinogens | pages = 1109–1137 | chapter-url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6ac0c892ee380436f614d3aae0686ef617b2e0c5 | veditors = Burger A, Wolf ME | title = Burger's Medicinal Chemistry | edition = 4 | volume = 3 | date = 1980 | publisher = Wiley | location = New York | isbn = 978-0-471-01572-7 | oclc = 219960627 | url = https://books.google.com/books?id=2b3wAAAAMAAJ | quote = The third principal metabolic route common to the hallucinogenic drugs is oxidation. Benzylic oxidation had been reported with both DOM (60.22aa) and DOET (60.22bb) (61, 62). Of greater theoretical interest is oxidative cyclization to form an indole species, reminiscent of the conversion of epinephrine to adrenochrome. Many of the hallucinogens are in fact indoles, and since the phenethylamine chain has the exact atom composition of indole itself, there has been frequent speculation that there might be some metabolic conversion from one family to the other. It has been shown (63) that one of the metabolites of DOM (2,5-dihydroxy[-4-methyl]phenylisopropylamine, 60.17), which bears a close chemical and pharmacological resemblance to the potent neurodegenerative agent 6-hydroxydopamine (60.18) (64), can undergo a facile oxidative cyclization to form a 5-hydroxyindole. The intermediate iminoquinone is potentially very reactive with nucleophilic agents found in normal body chemistry, and may be important in any explanation of biological activity.}}</ref><ref name="Castagnoli1978">{{cite book | last=Castagnoli | first=Neal | title=Stimulants | chapter=Drug Metabolism: Review of Principles and the Fate of One-Ring Psychotomimetics | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_7 | url=http://link.springer.com/10.1007/978-1-4757-0510-2_7 | access-date=3 February 2026 | page=335–387 | quote=FIG. 9. Metabolic pathways for amine III (DOM). [...] The third general metabolic pathway for 111 is oxidative O-demethylation of the methyl phenyl ether groups. All three possible O-demethylated metabolites, compounds 118-120, have been characterized in rabbit liver homogenates (Zweig and Castagnoli, 1975, 1977). The p-hydroquinone 120 is an analog of the sympatholytic agent 6-hydroxydopamine (107) and has been shown to possess some of the neurodegenerative properties of 6-hydroxydopamine (Butcher, 1975). Similar to 6-hydroxydopamine (Blank et ai., 1972), hydroquinone 120 undergoes facile oxidation to form the quinone 129 (Fig. 10), which cyclizes to the iminoquinone 130 (Zweig and Castagnoli, 1974). In the absence of nucleophiles, 130 is relatively stable at pH 7.4. As the pH is raised, however, proton rearrangements take place, eventually leading to the indole 132 via the indolinine 131. In view of the ease with which the hydroquinone 120 undergoes oxidation at pH 7.4, it is somewhat surprising that this compound survives the one hour pH 7.4 incubation. This stabilization may be analogous to the inhibition by liver constituents of hydroxylamine auto-oxidation. It should prove of interest to determine the nature and significance of the protection of these substances from air oxidation. [...] FIG. 10. Oxidative cyclization of p-hydroquinone metabolite derived from DOM. [...]}}</ref><ref name="Glennon2017">{{cite journal | vauthors = Glennon RA | title = The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse | journal = J Med Chem | volume = 60 | issue = 7 | pages = 2605–2628 | date = April 2017 | pmid = 28244748 | doi = 10.1021/acs.jmedchem.7b00085 | url = | quote = However, there was some concern that 2-DM-DOM and 5-DM-DOM might undergo further O-demethylation in vivo to a hydroquinone. It had been shown years earlier that DOM can undergo metabolic bis-demethylation to a hydroquinone, and that the hydroquinone undergoes oxidation to a para-quinone (and/or a cyclic iminoquinone) that reacts irreversibly with various proteins.44 As a consequence, this approach was not pursued because of potential risks of neurotoxicity. [...] 44. Jacob P. 3rd; Kline, T., Castagnoli, N. Jr. Chemical and biological studies of 1-(2,5-dihydroxy-4- methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine. J Med Chem. 1979; 22:662– 671. [PubMed: 458821]}}</ref><ref name="JacobKlineCastagnoli1979">{{cite journal | vauthors = Jacob P, Kline T, Castagnoli N | title = Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine | journal = J Med Chem | volume = 22 | issue = 6 | pages = 662–671 | date = June 1979 | pmid = 458821 | doi = 10.1021/jm00192a011 | url = }}</ref><ref name="Butcher1975">{{cite journal | vauthors = Butcher LL | title = Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine | journal = J Neural Transm | volume = 37 | issue = 3 | pages = 189–203 | date = 1975 | pmid = 1185165 | doi = 10.1007/BF01670128 | url = | quote = Similarly, 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane was not a more potent cytotoxin than 6-OHDA even though this new neurotoxin has a propane side chain which renders it immune to monoamine oxidase. [...] The neurotoxin 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane-HC1 (DIMPAP) was synthesized by Dr. Nell Castagnoli, University of California Medical Center, San Francisco, CA, U.S.A. [...] Fig. 28. Chemical structure of 1-(2, 5-dihydroxy-4-methylphenyl)-2-aminopropaneHC1 (DIMPAP) [...] The extent of zone-3 damage: after intrastriatal infusion of various doses of DIMPAP is depicted in figures 29–33. No significant difference exists between the non-selective damage produced by DIMPAP and similar doses of 6-OHDA (e.g., compare Figs. 29–33 with Figs. 25–30 in Butcher et al., 1974). Furthermore, nialamide pre-treatment does not alter the destructive potency of either 6-OHDA or DIMPAP (compare Figs. 34–38 with Figs. 39–43 and Figs. 44–47).}}</ref> Other related phenethylamine psychedelics may also undergo similar metabolism and form analogous potentially neurotoxic metabolites.<ref name="BlankLewisLehr1998">{{cite book | last1=Blank | first1=C. LeRoy | last2=Lewis | first2=Russell J. | last3=Lehr | first3=Roland E. | title=Highly Selective Neurotoxins | chapter=6-Hydroxydopamine and Related Catecholaminergic Neurotoxins: Molecular Mechanisms | publisher=Humana Press | publication-place=Totowa, NJ | date=1998 | isbn=978-1-61737-047-2 | doi=10.1007/978-1-59259-477-1_1 | url=http://link.springer.com/10.1007/978-1-59259-477-1_1 | access-date=3 February 2026 | page=1–18 | quote=A number of agents structurally similar to the original 6-HDA have been demonstrated, or are strongly suspected, to possess neurodegenerative properties. These include: 1. The 16 trisubstituted phenethylamines or α-methylphenethylamines in which the trisubstitution pattern on the ring is of the 2,3,5- or 2,4,5- variety with respect to the side chain, and involves either trihydroxy or aminodihydroxy functional group entities (15-18); [...] For example, in regard to CNS noradrenergic effects, the seven other derivatives implicated in Fig. 2 have been shown equipotent or more potent than the standard 6-HDA while simultaneously being equally or more selective (13,15-17,19,24,25). [...]}}</ref><ref name="ChengCastagnoli1984">{{cite journal | vauthors = Cheng AC, Castagnoli N | title = Synthesis and physicochemical and neurotoxicity studies of 1-(4-substituted-2,5-dihydroxyphenyl)-2-aminoethane analogues of 6-hydroxydopamine | journal = J Med Chem | volume = 27 | issue = 4 | pages = 513–520 | date = April 1984 | pmid = 6423824 | doi = 10.1021/jm00370a014 | url = }}</ref><ref name="Shulgin1976">{{cite journal | last=Shulgin | first=Alexander T. | title=Profiles of Psychedelic Drugs: 1. DMT & 2. TMA-2 | journal=Journal of Psychedelic Drugs | volume=8 | issue=2 | date=1976 | issn=0022-393X | doi=10.1080/02791072.1976.10471846 | pages=167–169 | url=https://bitnest.netfirms.com/external/10.1080/02791072.1976.10471846 | quote = Theoretical interest in TMA-2 stems from the recognition of 6-hydroxy dopamine as an extremely potent disrupter of the adrenergic nervous system. TMA-2 is structurally related with an identical oxygenation pattern, and has been shown to be partially demethylated in vivo. The end product, 2,4,5-trihydroxyamphetamine, has been studied clinically as an antihypertensive, but has not been reported to produce sensory or perceptual changes in humans even at dosages of 200 mg. The metabolism and fate of TMA-2 in humans is unknown.}}</ref>

Chronic administration of LSD has been associated with long-lasting schizophrenia-like behavioral changes in rodents, which was not blocked by serotonin 5-HT2A receptor antagonism but may instead be related to LSD's dopamine D2-like receptor agonism.<ref name="Nichols2016" /><ref name="KuypersNgErritzoe2019" /><ref name="KyzarNicholsGainetdinov2017">{{cite journal | vauthors = Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff AV | title = Psychedelic Drugs in Biomedicine | journal = Trends Pharmacol Sci | volume = 38 | issue = 11 | pages = 992–1005 | date = November 2017 | pmid = 28947075 | doi = 10.1016/j.tips.2017.08.003 | url = }}</ref><ref name="Marona-LewickaNicholsNichols2011">{{cite journal | vauthors = Marona-Lewicka D, Nichols CD, Nichols DE | title = An animal model of schizophrenia based on chronic LSD administration: old idea, new results | journal = Neuropharmacology | volume = 61 | issue = 3 | pages = 503–512 | date = September 2011 | pmid = 21352832 | pmc = 3110609 | doi = 10.1016/j.neuropharm.2011.02.006 | url = }}</ref> Single macrodoses of LSD do not produce such changes in rodents, but the preceding findings may have implications for continuous psychedelic microdosing with LSD.<ref name="NicholsNichols2021">{{cite book | last1=Nichols | first1 = D.E. | last2=Nichols | first2=C. D. | chapter=The Pharmacology of Psychedelics | editor1-last=Grob | editor1-first=C.S. | editor2-last=Grigsby | editor2-first=J. | title=Handbook of Medical Hallucinogens | publisher=Guilford Publications | year=2021 | isbn=978-1-4625-4544-5 | chapter-url=https://books.google.com/books?id=ebb2DwAAQBAJ&pg=PA3 | access-date=17 January 2025 | pages=3–28}}</ref><ref name="KuypersNgErritzoe2019" />

==Chemistry== The three major chemical groups of serotonergic psychedelics include the tryptamines, phenethylamines, and lysergamides, which each have different profiles of pharmacological activity.<ref name="Nichols2018">{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = https://bitnest.netfirms.com/external/10.1007/7854_2017_475 | quote = Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.}}</ref><ref name="GumpperNichols2024" /> A number of other miscellaneous structural groups also exist.<ref name="Nichols2018" /><ref name="GumpperNichols2024" />

===Tryptamines=== {{Main|Substituted tryptamine}} [[File:DMT.svg|thumb|right|175px|class=skin-invert-image|Dimethyltryptamine (DMT).]]

Tryptamines are derivatives of tryptamine and are structurally related to the monoamine neurotransmitter serotonin (also known as 5-hydroxytryptamine or 5-HT). Many tryptamines act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor. Some tryptamines also act as monoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine. Examples of psychedelic tryptamines include psilocin and psilocybin, dimethyltryptamine (DMT), 5-MeO-DMT, bufotenin, α-methyltryptamine (αMT), 4-AcO-DMT (psilacetin), 4-HO-MET, 5-MeO-MiPT, and 5-MeO-DiPT, among others.<ref name="Nichols2018" /><ref name="AraújoCarvalhoBastos2015">{{cite journal | last1=Araújo | first1=Ana Margarida | last2=Carvalho | first2=Félix | last3=Bastos | first3=Maria de Lourdes | last4=Guedes de Pinho | first4=Paula | last5=Carvalho | first5=Márcia | title=The hallucinogenic world of tryptamines: an updated review | journal=Archives of Toxicology | volume=89 | issue=8 | date=2015 | issn=0340-5761 | doi=10.1007/s00204-015-1513-x | pages=1151–1173| pmid=25877327 | bibcode=2015ArTox..89.1151A }}</ref> Harmala alkaloids like harmaline and iboga-type alkaloids like ibogaine are cyclized tryptamines and may also be considered hallucinogenic tryptamines.<ref name="Shulgin2003">{{cite book | vauthors = Shulgin AT | chapter=Basic Pharmacology and Effects | pages=67–137 | veditors = Laing RR | title=Hallucinogens: A Forensic Drug Handbook | publisher=Elsevier Science | series=Forensic Drug Handbook Series | year=2003 | isbn=978-0-12-433951-4 | url=https://books.google.com/books?id=l1DrqgobbcwC | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 | access-date=1 February 2025}}</ref><ref name="JacobShulgin1994">{{cite journal | vauthors = Jacob P, Shulgin AT | title = Structure-activity relationships of the classic hallucinogens and their analogs | journal = NIDA Res Monogr | volume = 146 | issue = | pages = 74–91 | date = 1994 | pmid = 8742795 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | archive-url = https://web.archive.org/web/20230805004551/https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | archive-date = August 5, 2023 }}</ref>

===Phenethylamines=== {{Main|Substituted phenethylamine|Scaline|2C (psychedelics)|DOx|25-NB}} [[File:Mescaline Structural Formulae bondline.svg|thumb|right|225px|class=skin-invert-image|Mescaline.]]

Phenethylamines, as well as amphetamines (α-methylphenethylamines), are derivatives of β-phenethylamine and are structurally related to the monoamine neurotransmitters dopamine, norepinephrine, and epinephrine. Some phenethylamines and amphetamines, particularly those with methoxy and other substitions on the phenyl ring, are potent serotonin 5-HT2 receptor agonists, including of the serotonin 5-HT2A receptor, and can produce psychedelic effects. In contrast to phenethylamines and amphetamines generally, most psychedelic phenethylamines are not monoamine releasing agents.<ref name="NagaiNonakaSatohHishashiKamimura2007">{{cite journal | vauthors = Nagai F, Nonaka R, Satoh Hisashi Kamimura K | title = The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain | journal = Eur J Pharmacol | volume = 559 | issue = 2–3 | pages = 132–137 | date = March 2007 | pmid = 17223101 | doi = 10.1016/j.ejphar.2006.11.075 | url = }}</ref><ref name="EshlemanForsterWolfrum2014">{{cite journal | vauthors = Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB | title = Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function | journal = Psychopharmacology (Berl) | volume = 231 | issue = 5 | pages = 875–888 | date = March 2014 | pmid = 24142203 | pmc = 3945162 | doi = 10.1007/s00213-013-3303-6 | url = }}</ref> Examples of psychedelic phenethylamines and amphetamines include mescaline and other scalines like trimethoxyamphetamine (TMA) and escaline, the 2C drugs like 2C-B, 2C-E, and 2C-I, the DOx drugs like DOM, DOB, DOI, certain MDxx drugs like MDA and MDMA (weak psychedelics), FLY drugs like 2C-B-FLY and Bromo-DragonFLY, and the NBOMe (25x-NBx) drugs like 25I-NBOMe, among others.<ref name="Nichols2018" />

===Lysergamides=== {{Main|Substituted lysergamide}} [[File:LSD skeletal formula.svg|thumb|right|150px|class=skin-invert-image|LSD.]]

Lysergamides are ergoline derivatives related to the ergot alkaloids. They are notable in containing both tryptamine and phenethylamine within their chemical structures. As such, ergolines and lysergamides may be considered structurally related to the monoamine neurotransmitters. Many ergolines and lysergamides act as highly promiscuous ligands of monoamine receptors, including of serotonin, dopamine, and adrenergic receptors. Some lysergamides are efficacious serotonin 5-HT2A receptor agonists and thereby produce psychedelic effects. Examples of psychedelic lysergamides include lysergic acid diethylamide (LSD), ergine (lysergic acid amide; LSA), isoergine (isolysergic acid amide; iso-LSA), ETH-LAD, AL-LAD, 1P-LSD, 1S-LSD, ALD-52 (1A-LSD), LSZ, ergonovine (ergometrine; lysergic acid propanolamide), methylergometrine (methylergonovine), and methysergide (methylmethylergonovine), among others.<ref name="Nichols2018" /> Ergine, isoergine, and ergonovine occur naturally in morning glories and certain fungi like ergot and ''Periglandula'' species, while others like LSD are synthetic. LSD is among the most potent psychedelics, as well as psychoactive drugs in general, that are known.<ref name="Nichols2018" />

===Others=== {{Main|List of miscellaneous 5-HT2A receptor agonists|Substituted piperazine|Partial lysergamide}}

Other psychedelics not belonging to any of the above three structural families have been discovered, for instance certain arylpiperazine derivatives like quipazine,<ref>{{cite journal | vauthors = Glennon RA, Dukat M | title=Quipazine: Classical hallucinogen? Novel psychedelic? | journal=Australian Journal of Chemistry | volume=76 | issue=5 | date=2 May 2023 | issn=0004-9425 | doi=10.1071/CH22256 | pages=288–298}}</ref><ref name="deLaFuenteRevengaShahNassehi2021">{{cite journal | vauthors = de la Fuente Revenga M, Shah UH, Nassehi N, Jaster AM, Hemanth P, Sierra S, Dukat M, González-Maeso J | title = Psychedelic-like Properties of Quipazine and Its Structural Analogues in Mice | journal = ACS Chem Neurosci | volume = 12 | issue = 5 | pages = 831–844 | date = March 2021 | pmid = 33400504 | pmc = 7933111 | doi = 10.1021/acschemneuro.0c00291}}</ref> the antiretroviral drug efavirenz,<ref name="ZareifopoulosLagadinouKarela2020">{{cite journal | vauthors = Zareifopoulos N, Lagadinou M, Karela A, Pouliasi F, Economou I, Tsigkou A, Velissaris D | title = Efavirenz as a psychotropic drug | journal = Eur Rev Med Pharmacol Sci | volume = 24 | issue = 20 | pages = 10729–10735 | date = October 2020 | pmid = 33155233 | doi = 10.26355/eurrev_202010_23433 | url = }}</ref><ref name="ZareifopoulosLagadinouKarela2020b">{{cite journal | vauthors = Zareifopoulos N, Lagadinou M, Karela A, Kyriakopoulou O, Velissaris D | title = Neuropsychiatric Effects of Antiviral Drugs | journal = Cureus | volume = 12 | issue = 8 | article-number = e9536 | date = August 2020 | pmid = 32905132 | pmc = 7465925 | doi = 10.7759/cureus.9536 | doi-access = free}}</ref><ref name="DalwadiKimAmdani2016">{{cite journal | vauthors = Dalwadi DA, Kim S, Amdani SM, Chen Z, Huang RQ, Schetz JA | title = Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz | journal = Pharmacol Res | volume = 110 | issue = | pages = 10–24 | date = August 2016 | pmid = 27157251 | pmc = 4914440 | doi = 10.1016/j.phrs.2016.04.028}}</ref><ref name="GatchKozlenkovHuang2013">{{cite journal | vauthors = Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA | title = The HIV antiretroviral drug efavirenz has LSD-like properties | journal = Neuropsychopharmacology | volume = 38 | issue = 12 | pages = 2373–2384 | date = November 2013 | pmid = 23702798 | pmc = 3799056 | doi = 10.1038/npp.2013.135 | url = }}</ref><ref name="Morris2014">{{cite episode | credits = Hamilton Morris | date=31 March 2014 | title=Getting High on HIV Medication | series=Hamilton's Pharmacopeia [web series] | number = S0E10 | publisher = Vice Media | url = https://www.youtube.com/watch?v=wyuFBmlQS_s | transcript = [Web article] | transcript-url=https://www.vicetv.com/en_us/video/getting-high-on-hiv-medication/55ccf50623652a5532d4fba5}}</ref> and simplified or partial lysergamides (which are also conformationally constrained tryptamines and/or phenethylamines) like NDTDI (9-nor-LSD; 8,10-seco-LSD) and DEMPDHPCA (dides-''B'',''C''-LSD).<ref name="Mangner1978">{{cite thesis | vauthors = Mangner TJ | degree = Ph.D. | publisher = University of Michigan | title = Potential Psychotomimetic Antagonists. N,N-diethyl-1-methyl-3-aryl-1,2,5,6-tetrahydropyridine-5-carboxamides. | date = 1978 | doi = 10.7302/11268 | url = https://www.proquest.com/openview/f845a6810749d00f70305960adfde737/ | archive-url = https://web.archive.org/web/20250330031605/https://media.proquest.com/media/hms/ORIG/2/9yQxJ?cit%3Aauth=MANGNER%2C+THOMAS+JOSEPH&cit%3Atitle=POTENTIAL+PSYCHOTOMIMETIC+ANTAGONISTS.+N%2CN+...&cit%3Apub=ProQuest+Dissertations+and+Theses&cit%3Avol=&cit%3Aiss=&cit%3Apg=&cit%3Adate=1978&ic=true&cit%3Aprod=ProQuest+Dissertations+%26+Theses+Global&_a=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&_s=QP3F3liRMGFAbHtX3wDWE8eO1gs%3D | archive-date=30 March 2025}}</ref><ref name="Nichols1973">{{cite thesis | vauthors = Nichols DE | title = Potential Psychotomimetics: Bromomethoxyamphetamines and Structural Congeners of Lysergic Acid | date = May 1973 | publisher = University of Iowa | page = 23 | oclc = 1194694085 | url = https://bitnest.netfirms.com/external/Theses/Nichols1973}}</ref><ref name="Likumi2017">{{cite web | author=Autorizēties savā kontā | title=Par aizlieguma noteikšanu vielai NDTDI un tās saturošiem izstrādājumiem | trans-title=On the prohibition of the substance NDTDI and products containing it | website=LIKUMI.LV | date=March 2017 | url=https://likumi.lv/ta/id/289200 | language=lv | access-date=20 March 2025}}</ref>

==History== ===Early history=== {{See also|Entheogenic drugs and the archaeological record|Aztec use of entheogens|Entheogenics and the Maya}}

Psychedelics occurring in plants, fungi, and animals have been used by indigenous peoples throughout the world for thousands of years.<ref name="WalkerPullellaPiggott2023">{{cite journal | last1=Walker | first1=Scott R. | last2=Pullella | first2=Glenn A. | last3=Piggott | first3=Matthew J. | last4=Duggan | first4=Peter J. | title=Introduction to the chemistry and pharmacology of psychedelic drugs | journal=Australian Journal of Chemistry | volume=76 | issue=5 | date=5 July 2023 | issn=0004-9425 | doi=10.1071/CH23050 | doi-access=free | pages=236–257 | url=https://www.publish.csiro.au/ch/pdf/CH23050 | access-date=4 April 2025}}</ref><ref name="McKenna1999">{{cite book | last=McKenna | first=Terence | chapter=[Chapter 14:] A Brief History of Psychedelics | pages=223–245 | title=Food of the Gods: The Search for the Original Tree of Knowledge: a Radical History of Plants, Drugs and Human Evolution | publisher=Rider | date=1999 | isbn=978-0-7126-7038-8 | url=https://alquimiahealingarts.com/wp-content/uploads/2020/03/Food-Of-The-Gods-Terence-Mckenna.pdf#page=117}}</ref><ref name="Carod-Artal2015">{{cite journal | vauthors = Carod-Artal FJ | title = Hallucinogenic drugs in pre-Columbian Mesoamerican cultures | journal = Neurologia | volume = 30 | issue = 1 | pages = 42–49 | date = 2015 | pmid = 21893367 | doi = 10.1016/j.nrl.2011.07.003 | url = }}</ref><ref name="Simms2022" /> These psychedelics and their sources include psilocybin and psilocin in psilocybin-containing mushrooms (teonanacatl), dimethyltryptamine (DMT) in ayahuasca (a combination typically of ''Psychotria viridis'' and ''Banisteriopsis caapi''), bufotenin in ''Anadenanthera'' trees, 5-MeO-DMT in the Colorado River Toad, mescaline in peyote (peyotl) and San Pedro cacti, and ergine and isoergine in morning glories (ololiuqui, tlitliltzin) and ergot, among others.<ref name="WalkerPullellaPiggott2023" /><ref name="McKenna1999" /><ref name="Carod-Artal2015" /><ref name="Simms2022" /> The kykeon of the Eleusinian Mysteries in Ancient Greece might have been a psychedelic, for instance ergot or psilocybin-containing mushrooms.<ref name="Valencic1994">Valencic, I. (1994). Has the Mystery of the Eleusinian Mysteries been solved. Yearbook for Ethnomedicine and the Study of Consciousness, 3, 325–336. https://www.druglibrary.org/schaffer/lsd/valencic.htm</ref><ref name="WassonHofmann2008">{{cite book | last1=Wasson | first1=R. Gordon | last2=Hofmann | first2=Albert | last3=Ruck | first3=Carl A. P. | title=The Road to Eleusis: Unveiling the Secret of the Mysteries | publisher=North Atlantic Books | date=25 November 2008 | isbn=978-1-55643-752-6 | page=}}</ref><ref name="Simms2022" /> The earliest archeological evidence of the use of psychedelic plants and fungi by humans dates back roughly 10,000{{nbsp}}years.<ref name="WalkerPullellaPiggott2023" /><ref name="Simms2022">{{cite web | last=Simms | first=Dan | title=The History of Psychedelics: Our Connection to Consciousness & Mind-Altering Substances Throughout Time | website=Tripsitter | date=21 December 2022 | url=https://tripsitter.com/the-history-of-psychedelics/ | access-date=4 April 2025}}</ref>

===Western characterization=== {{See also|History of entheogenic drugs|History of LSD}}

{| class="wikitable floatright" style="font-size:small;" |+ {{Nowrap|History of selected major psychedelic drugs}} |- ! Drug !! Type !! Major historical events and people |- | Mescaline || Natural || Arthur Heffter (isol, effects, 1897), Ernst Späth (synth, 1919) |- | MDA || Synthetic || Carl Mannich/Willy Jacobsohn (synth, 1910), Gordon Alles (effects, 1930) |- | LSD || Synthetic || Albert Hofmann (synth, 1938; effects, 1943) |- | Ergine (LSA) || Natural || Sidney Smith/Geoffrey Timmis (isol, 1932), Albert Hofmann (effects, 1947) |- | Bufotenin || Natural || Césaire Phisalix/Gabriel Bertrand (isol, 1893), Toshio Hoshino (synth, 1935), Howard Fabing et al./Jonathan Ott/others (effects, 1955–2001) |- | DMT || Natural || Richard Manske (synth, 1931), Oswaldo Gonçalves de Lima (isol, 1946), M. S. Fish et al. (isol, 1955), Stephen Szára (effects, 1956) |- | Psilocybina || Natural || Albert Hofmann (isol, synth, effects, 1958) |- | DOM || Synthetic || Alexander Shulgin (synth, 1963; effects, 1964) |- | 5-MeO-DMT || Natural || Toshio Hoshino (synth, 1936), Irwin Pachter et al. (isol, 1959), Alexander Shulgin (effects, 1970) |- | 2C-B || Synthetic || Alexander Shulgin (synth, effects, 1974) |- | MDMA || Synthetic || Anton Köllisch (synth, 1912), Alexander Shulgin (effects, 1976) |- | 25I-NBOMe || Synthetic || Ralf Heim (synth, 2000), designer drug (effects, 2010) |- class="sortbottom" | colspan="3" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Note:''' The compounds are ordered by the discovery of their psychoactive effects. '''Abbreviations:''' isol = isolation, synth = synthesis. '''Footnotes:''' a = And active form psilocin. |}

Psychedelics were discovered by the Western world and the scientific community relatively late.<ref name="McKenna1999" /> The use of hallucinogenic snuffs by indigenous South American people was first observed by Western explorers like Christopher Columbus as early as 1496.<ref name="McKennaRiba2018">{{cite book | vauthors = McKenna D, Riba J | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca | series = Curr Top Behav Neurosci | volume = 36 | pages = 283–311 | date = 2018 | pmid = 28401525 | doi = 10.1007/7854_2016_472 | isbn = 978-3-662-55878-2 | s2cid = 4398627 }}</ref><ref name="BrimblecombePinder1975" /><ref name="FishHorning1956">{{cite journal | vauthors = Fish MS, Horning EC | title = Studies on hallucinogenic snuffs | journal = J Nerv Ment Dis | volume = 124 | issue = 1 | pages = 33–37 | date = July 1956 | pmid = 13416916 | doi = 10.1097/00005053-195607000-00004 | url = }}</ref> The first written description of an observed psychedelic experience, with cohoba, was published by Ramon Pane in 1511.<ref name="HolmstedtLindgren1967">{{cite book | vauthors=Holmstedt B, Lindgren JE | chapter = Chemical Constituents and Pharmacology of South American Snuffs | pages = 339–373 | veditors=Efron DH, Holmstedt B, Kline NS | title=Ethnopharmacologic Search for Psychoactive Drugs, Proceedings of a Symposium held in San Francisco, California, January 28-30, 1967 | publisher=Raven Press | date=1967 | isbn=978-0-89004-047-8 | oclc = 14498182 | url = https://books.google.com/books?id=UeZsAAAAMAAJ | chapter-url = https://archive.org/details/ethnopharmacolog00efro_0/page/339/mode/1up | quote = The first written account of the action of the American intoxicating snuffs is that by Friar Ramon Pane on cohoba, published first in 1511 and quoted in detail by Wassén (this volume). Ramon Pane's observation of symptoms is revealing: [...] This undoubtedly constitutes the first written account of the psychotomimetic effects of the tryptamines, [...]}}</ref> Spanish explorers observed the use of psilocybin-containing mushrooms (teonanacatl) in Mexico as early as 1519 with the arrival of Hernán Cortés.<ref name="Nichols2020" /><ref name="Garcia-RomeuKersgaardAddy2016" /> Spanish ethnographer Bernardino de Sahagún traveled to Mexico in 1529 and described the use of these mushrooms in his books.<ref name="Nichols2020" /> The botanists Richard Spruce and Alfred Russel Wallace observed and described the use of ayahuasca in the Amazon in the 1850s.<ref name="McKenna1999" /><ref name="Garcia-RomeuKersgaardAddy2016" />

====The phenethylamine psychedelic mescaline==== Mescaline is sometimes described as the "first psychedelic", as it was the first to be discovered and characterized by the Western world.<ref name="Jay2019" /> American physician John Raleigh Briggs, living in Texas, learned of peyote from Native Americans and Mexicans, who told him that it produced "beautiful visions" and made them journey into the "spirit world".<ref name="Dawson2018">{{cite book | last=Dawson | first=Alexander S. | title=The Peyote Effect: From the Inquisition to the War on Drugs | chapter=1887: Dr. John Briggs Eats Some Peyote | publisher=University of California Press | date=4 September 2018 | isbn=978-0-520-28542-2 | doi=10.1525/california/9780520285422.003.0002 | url=https://content.ucpress.edu/title/9780520285422/9780520285422_chapter1.pdf | pages=11–22}}</ref><ref name="Jay2019">{{cite book | last=Jay | first=Mike | title=Mescaline: A Global History of the First Psychedelic | publisher=Yale University Press | date=18 June 2019 | isbn=978-0-300-23107-6 | pages=62, 65, 67, 85, 91–92, 98–100, 131–132, 135, 138 | url=https://books.google.com/books?id=6IKVDwAAQBAJ}}</ref><ref name="Briggs1887">{{cite journal | vauthors = Briggs JR | title = "Muscale Buttons" – Physiological Effects - Personal Experience | journal = The Medical Register | date = 8 April 1887 | pages = 267–268 | url = https://bibliography.maps.org/resources/download/12878| archive-url = https://web.archive.org/web/20250405031456/https://bibliography.maps.org/resources/download/12878 | archive-date = 5 April 2025 }}</ref> He obtained mescal buttons from Mexico and published a journal article about trying a very low dose of them in May 1887.<ref name="Dawson2018" /><ref name="Jay2019" /><ref name="Briggs1887" /> This article is said to have brought peyote into North American pharmacology.<ref name="Dawson2018" /><ref name="Briggs1887" /> Briggs described the physiological effects of his experience, such as increased heart rate, and of experiencing "intoxication".<ref name="Dawson2018" /><ref name="Briggs1887" /> The article was read by George Davis, of Parke, Davis and Company, who then obtained the buttons from Briggs in June 1887.<ref name="Dawson2018" /><ref name="Jay2019" /> Parke-Davis attempted to market peyote as a cardiac stimulant and for other uses, but met with little success.<ref name="Dawson2018" /><ref name="Jay2019" /> The German pharmacologist Louis Lewin obtained mescal buttons from Parke-Davis during a trip to the United States in 1887 and began studying them and sharing his findings.<ref name="Jay2019" /><ref name="McKenna1999" />

The first known published description of a hallucinogenic peyote experience was by American neurologist Silas Weir Mitchell in December 1896.<ref name="McKenna1999" /><ref name="Mitchell1896">{{cite journal | vauthors = Mitchell SW | title = Remarks on the Effects of Anhelonium Lewinii (the Mescal Button) | journal = Br Med J | volume = 2 | issue = 1875 | pages = 1625–1629 | date = December 1896 | pmid = 20756623 | pmc = 2511273 | doi = 10.1136/bmj.2.1875.1625 }}</ref> After reading Mitchell's article, others, including psychologist and sexologist Havelock Ellis, American psychologist William James, and German pharmacologist, chemist, and Lewin rival Arthur Heffter, among others, tried peyote and described their experiences.<ref name="Jay2019" /><ref name="Dawson2024">{{cite book | last=Dawson | first=Alexander | title=Oxford Research Encyclopedia of Latin American History | chapter=Peyote | publisher=Oxford University Press | date=30 January 2024 | isbn=978-0-19-936643-9 | doi=10.1093/acrefore/9780199366439.013.1139 | page=}}</ref><ref name="McKenna1999" /><ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="Ellis1898">{{cite journal | author = Havelock Ellis | title = Mescal: A New Artificial Paradise | journal = The Contemporary Review | volume = 73 | date = January 1898 | pages = 130–141 | url = https://www.mescaline.com/artificialparadise/index.html}}</ref> Heffter isolated and ingested mescaline from peyote, experiencing psychedelic effects with the pure compound, in 1897, and published his findings in 1898.<ref name="Perrine2001">{{cite journal | author = Daniel M. Perrine | title = Visions of the Night Western Medicine Meets Peyote 1887-1899 | journal = The Heffter Review of Psychedelic Research | volume = 2 | date = 2001 | pages = 6–52 | url = https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=78c291287af64d13ef9fbc348b9353226f9b047a}}</ref><ref name="Dawson2018" /><ref name="McKenna1999" /><ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="Heffter1898">{{cite journal | last=Heffter | first=A. | title=Ueber Pellote: Beiträge zur chemischen und pharmakologischen Kenntniss der Cacteen Zweite Mittheilung | trans-title=About Pellote: Contributions to the chemical and pharmacological knowledge of cacti, second communication | journal=Archiv für Experimentelle Pathologie und Pharmakologie | volume=40 | issue=5–6 | date=1898 | issn=0028-1298 | doi=10.1007/BF01825267 | doi-access=free | pages=385–429 | url=https://zenodo.org/records/2003381/files/article.pdf | language=de | access-date=5 April 2025}}</ref>

Austrian chemist Ernst Späth synthesized mescaline for the first time in 1919.<ref name="Jay2019" /> The German pharmaceutical company Merck then began distributing pharmaceutical mescaline in 1920.<ref name="Jay2019" /> The German psychiatrist Kurt Beringer, a student of Lewin and an acquaintance of Hermann Hesse and Carl Jung, became the father of psychedelic psychiatry and conducted experiments with mescaline in more than 60{{nbsp}}people starting in 1921.<ref name="Jay2019" /><ref name="McKenna1999" /> He published his monograph on the subject, ''Der Meskalinrausch'' (''Mescaline Intoxication''), in 1927.<ref name="Jay2019" /><ref name="McKenna1999" /><ref name="Beringer1927">{{cite book | last=Beringer | first=Kurt | title=Der Meskalinrausch: seine Geschichte und Erscheinungsweise | trans-title=Mescaline Intoxication: Its History and Manifestation | date=1927 | language=de | url=https://books.google.com/books?id=bKIyn-JitfIC}}</ref> German–American psychologist Heinrich Klüver published his monograph, ''Mescal: The Divine Plant and Its Psychological Effects'', in English in 1928.<ref name="Jay2019" /><ref name="McKenna1999" /><ref name="Klüver1928">{{cite book | last=Klüver | first=Heinrich | title=Mescal: The ʻdivine' Plant and Its Psychological Effects | publisher=K. Paul, Trench, Trubner & Company Limited | date=1928 | url=https://books.google.com/books?id=oZYaAAAAIAAJ}}</ref> He is said to have been the first to attempt to provide a phenomenological description of the psychedelic experience.<ref name="McKenna1999" />

====Tryptamine and lysergamide psychedelics==== Austrian anthropologist and ethnobotanist Blas Pablo Reko, traveling through Central and South America, wrote of the use of teonanacatl by native Mexican people in Oaxaca in 1919.<ref name="McKenna1999" /> Reko subsequently sent samples of teonanacatl (''Psilocybe mexicana'') as well as ''Ipomoea violacea'' (morning glory) seeds to Swedish anthropologist Henry Wassén in 1937.<ref name="McKenna1999" /> Reko had obtained the mushroom sample from Austrian engineer Robert Weitlaner who was working in Mexico.<ref name="McKenna1999" /> Eventually, Wassén forwarded Reko and Weitlaner's mushroom sample to Harvard University, where the mushrooms came to the attention of American ethnobotanist Richard Evans Schultes.<ref name="McKenna1999" /><ref name="Nichols2020" /> However, they had decomposed so badly that they could not be identified.<ref name="McKenna1999" /><ref name="Nichols2020" /> Prior to Wassén obtaining specimens around 1936, the existence of teonanacatl was very controversial and was debated and even denied by some.<ref name="Nichols2020" /> In 1938, a small group of Westerners, which included Weitlaner's daughter and American anthropologist Jean Basset Johnson, attended a mushroom ceremony.<ref name="McKenna1999" /><ref name="Nichols2020" /> They were the first Westerners known to do so and described the event.<ref name="McKenna1999" /><ref name="Nichols2020" /> Schultes published reviews of teonanacatl being a hallucinogenic mushroom in the late 1930s.<ref name="McKenna1999" /><ref name="Schultes1939">Schultes, R. E. (1939). The identifications of teonanácatl, a narcotic basidiomycete of the Aztecs. ''Botanical Museum Leaflets'', Harvard University, 7, 37–55.</ref> Schultes obtained specimens of three of the hallucinogenic mushrooms used in ceremonies, including ''Psilocybe caerulescens'', ''Panaeolus campanulatus'', and ''Stropharia cubensis'', but further investigations of the mushrooms were interrupted by World War II.<ref name="Nichols2020" />

Ergine (lysergic acid amide; LSA) and isoergine (isolysergic acid amide; iso-LSA) were first identified from hydrolysis of ergot alkaloids in 1932 and 1936, respectively.<ref name="BrimblecombePinder1975">{{cite book | vauthors = Brimblecombe RW, Pinder RM | chapter = Indolealkylamines and Related Compounds | pages = 98–144 | title = Hallucinogenic Agents | date = 1975 | publisher = Wright-Scientechnica | location = Bristol | isbn = 978-0-85608-011-1 | oclc = 2176880 | ol = OL4850660M | url = https://bitnest.netfirms.com/external/Books/978-0-85608-011-1}}</ref><ref name="SmithTimmis1932">{{cite journal | vauthors = Smith S, Timmis GM |date=1932 |title=98. The alkaloids of ergot. Part III. Ergine, a new base obtained by the degradation of ergotoxine and ergotinine |url=https://xlink.rsc.org/?DOI=jr9320000763 |journal=Journal of the Chemical Society (Resumed) |language=en |pages=763–766 |doi=10.1039/jr9320000763 |issn=0368-1769}}</ref><ref name="SmithTimmis1936">{{cite journal | vauthors = Smith S, Timmis GM | title=311. The alkaloids of ergot. Part VII. isoErgine and isolysergic acids | journal=Journal of the Chemical Society (Resumed) | date=1936 | issn=0368-1769 | doi=10.1039/jr9360001440 | page=1440}}</ref> In 1938, Swiss chemist Albert Hofmann, working at Sandoz Laboratories, synthesized lysergic acid diethylamide (LSD), a synthetic derivative of ergine, while developing new oxytocic drugs derived from ergot.<ref name="McKenna1999" /> LSD was not further investigated and was placed in storage for 5{{nbsp}}years.<ref name="McKenna1999" /> In 1943 however, Hofmann worked with LSD again and accidentally discovered its hallucinogenic effects when minute amounts of the potent psychedelic absorbed through his skin.<ref name="McKenna1999" /><ref name="WalkerPullellaPiggott2023" /> His subsequent self-experiment with LSD three days later on April 19 is the psychedelic holiday Bicycle Day.<ref name="BelouinHenningfield2018">{{cite journal | vauthors = Belouin SJ, Henningfield JE | title = Psychedelics: Where we are now, why we got here, what we must do | journal = Neuropharmacology | volume = 142 | issue = | pages = 7–19 | date = November 2018 | pmid = 29476779 | doi = 10.1016/j.neuropharm.2018.02.018 | url = | doi-access = free }}</ref> Hofmann and his colleague, psychiatrist Werner Stoll, first described LSD in 1943 and first described its psychedelic effects in 1947.<ref name="McKenna1999" /><ref name="Gach2008">{{cite book | vauthors = Gach J | title=History of Psychiatry and Medical Psychology | chapter=Biological Psychiatry in the Nineteenth and Twentieth Centuries | publisher=Springer US | publication-place=Boston, MA | date=2008 | isbn=978-0-387-34707-3 | doi=10.1007/978-0-387-34708-0_12 | pages=381–418 | url=https://www.timothydavidson.com/Library/Books/Wallace-2008-History%20of%20Psychiatry%20and%20Medical%20Psychology/Wallace%20and%20Gach-2008-History%20of%20Psychiatry%20and%20Medical%20Psychology.pdf#page=413 | archive-url=https://web.archive.org/web/20250319140308/https://www.timothydavidson.com/Library/Books/Wallace-2008-History%20of%20Psychiatry%20and%20Medical%20Psychology/Wallace%20and%20Gach-2008-History%20of%20Psychiatry%20and%20Medical%20Psychology.pdf#page=413 | archive-date=19 March 2025 | quote=In 1938 the Swiss chemist Albert Hofmann produced lysergic acid diethylamide (LSD)—the first, and most prominent, of these chemically synthesized agents—in the course of a systematic investigation of partially synthetic amides of lysergic acid in the Sandoz Pharmaceutical Laboratories in Basel (Hofmann 1970). [Taking] LSD by accident in 1943, Hofmann discovered its psychoactivity. He then experimented with it on himself and found that it produced a peculiar restlessness, extreme activity of the imagination, and an uninterrupted stream of images. Hofmann did not publish the results of his experiment, though he became quite famous later. Hofmann and Arthur Stoll, the head of the Sandoz pharmaceutical laboratory in Basle, published the first paper on the synthesis of LSD in 1943, while Stoll went on to publish the first paper on the effects of lysergic diethylamide acid in 1947. [...] Stoll, Arthur and Hofmann, Albert. 1943. Partialsynthese von Alkaloiden vom Typus des Ergobasins. Helv. Chim. Acta 26:944. Stoll, Arthur. 1947. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. Psychiat. 60:279. [The first paper on the hallucinogenic effect of LSD.]}}</ref><ref name="StollHofmann1943">{{cite journal | vauthors = Stoll A, Hofmann A | title=Partialsynthese von Alkaloiden vom Typus des Ergobasins. (6. Mitteilung über Mutterkornalkaloide) | trans-title=Partial synthesis of ergobasine-type alkaloids. (6th report on ergot alkaloids) | journal=Helvetica Chimica Acta | volume=26 | issue=3 | date=3 May 1943 | issn=0018-019X | doi=10.1002/hlca.19430260326 | pages=944–965 | bibcode=1943HChAc..26..944S }}</ref><ref name="Stoll1947">{{cite journal | vauthors = Stoll WA | title = 11. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe | trans-title = 11. Lysergic Acid Diethylamide, a Hallucinogen From the Ergot Group | journal = Schweizer Archiv für Neurologie und Psychiatrie | volume = 60 | issue = | date = 1947 | pages = 279–323 | issn = 0258-7661 | url = https://bibliography.maps.org/resources/download/16963| archive-url = https://web.archive.org/web/20250401005831/https://bibliography.maps.org/resources/download/16963 | archive-date = 1 April 2025 }}</ref><ref name="Stoll1949">{{cite journal | vauthors = Stoll W | title = Ein neues, in sehr kleinen Mengen wirksames Phantastikum | trans-title = A New Phantasticum, Effective in Very Tiny Amounts | journal = Schweizer Archiv für Neurologie und Psychiatrie | volume = 64 | issue = | pages = 483–484 | date = 1949 | issn = 0258-7661 | url = https://bibliography.maps.org/resources/download/16676| archive-url = https://web.archive.org/web/20250401012040/https://bibliography.maps.org/resources/download/16676 | archive-date = 1 April 2025 }}</ref> LSD began being distributed by Sandoz Laboratories for research purposes under the brand name Delysid in 1949.<ref name="Nichols2018b">{{cite journal | vauthors = Nichols DE | title = Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2331–2343 | date = October 2018 | pmid = 29461039 | doi = 10.1021/acschemneuro.8b00043 | url = }}</ref><ref name="Bonson2018">{{cite journal | vauthors = Bonson KR | title = Regulation of human research with LSD in the United States (1949-1987) | journal = Psychopharmacology (Berl) | volume = 235 | issue = 2 | pages = 591–604 | date = February 2018 | pmid = 29147729 | doi = 10.1007/s00213-017-4777-4 | url = }}</ref>

Schultes described the indigenous and shamanic use of dimethyltryptamine (DMT)-containing psychedelic plants in 1954 and also described the use of hallucinogenic morning glories in the 1950s.<ref name="McKenna1999" /> The psychedelic effects of synthesized DMT were described by Hungarian chemist and psychiatrist Stephen Szára in 1956.<ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="Szára2007">{{cite journal | vauthors = Szára S | title = DMT at fifty | journal = Neuropsychopharmacol Hung | volume = 9 | issue = 4 | pages = 201–205 | date = December 2007 | pmid = 18510265 | doi = | url = https://mppt.hu/magazin/pdf/ix-evfevfolyam-4-szam/dmt-az-oetvenes-evekben.pdf}}</ref><ref name="McKenna1999" /><ref name="Szara1956">{{cite journal | vauthors = Szara S | title = Dimethyltryptamin: its metabolism in man; the relation to its psychotic effect to the serotonin metabolism | journal = Experientia | volume = 12 | issue = 11 | pages = 441–442 | date = November 1956 | pmid = 13384414 | doi = 10.1007/BF02157378 | url = }}</ref><ref name="SzaraSai-HalaszBoszormenyi1958">{{cite journal | vauthors = Szara I, Sai-Halasz A, Boszormenyi Z | title = Dimethyltryptamine als neues Psychotikum | trans-title = Dimethyltryptamine as a new psychotic agent | language = German | journal = Acta Physiol Acad Sci Hung | volume = 11 | issue = Suppl | pages = 78–79 | date = 1958 | pmid = 13469470 | doi = | url = }}</ref> Osmond described the hallucinogenic and other effects of morning glory seeds in clinical studies in 1955.<ref name="BrimblecombePinder1975" /> Hofmann identified and described ergine and isoergine as the active constituents of morning glory seeds in 1960.<ref name="WalkerPullellaPiggott2023" /><ref name="HofferOsmond1967">{{cite book | author1=Abram Hoffer | author2=Humphrey Osmond | chapter=Chapter II A d-Lysergic Acid Diethylamide | pages=83–236 | chapter-url=https://bitnest.netfirms.com/external/Books/TheHallucinogens#page=91 | title=The Hallucinogens | publisher=Elsevier | date=1967 | isbn=978-1-4832-3296-6 | doi=10.1016/B978-1-4832-3296-6.50005-7 | lccn=66030086 | oclc=332437 | ol=OL35255701M | url=https://bitnest.netfirms.com/external/Books/TheHallucinogens}}</ref><ref name="Hofmann1963" /><ref name="HofmannTscherter1960">{{cite journal | vauthors = Hofmann A, Tscherter H | title=Isolierung von Lysergsäure-Alkaloiden aus der mexikanischen Zauberdroge Ololiuqui (Rivea corymbosa (L.) Hall. f.) | trans-title=Isolation of lysergic acid alkaloids from the Mexican magic drug Ololiuqui (Rivea corymbosa (L.) Hall. f.) | journal=Experientia | volume=16 | issue=9 | date=1960 | issn=0014-4754 | doi=10.1007/BF02178840 | doi-access=free | page=414 | pmid=13715089 | bibcode=1960Expea..16..414H | url=https://link.springer.com/content/pdf/10.1007/BF02178840.pdf | language=de | access-date=28 March 2025}}</ref> Their hallucinogenic effects were first described by Hofmann in 1963.<ref name="BrimblecombePinder1975" /><ref name="Hofmann1963">{{cite journal | vauthors = Hofmann A | title=The Active Principles of the Seeds of Rivea Corymbosa and Ipomoea Violacea | journal=Botanical Museum Leaflets, Harvard University | publisher=Harvard University Herbaria | volume=20 | issue=6 | year=1963 | issn=0006-8098 | jstor=41762231 | pages=194–212 | doi=10.5962/p.168542 }}</ref>

In 1952, couple and amateur ethnomycologists R. Gordon Wasson and Valentina Wasson learned of the ritual use of hallucinogenic mushrooms in the 16th century in Mexico from the published work of Schultes.<ref name="Nichols2020" /><ref name="Mangini2024">{{cite journal | last=Mangini | first=Mariavittoria | title=Unseen Women in Psychedelic History | journal=Journal of Humanistic Psychology | volume=64 | issue=4 | date=2024 | issn=0022-1678 | doi=10.1177/00221678211029186 | pages=635–652}}</ref> They made several trips to Mexico in search of the mushrooms.<ref name="Nichols2020" /><ref name="Mangini2024" /> In mid-1955, the Wassons participated in a mushroom ceremony with Mazatec curandera Maria Sabina in Huautla de Jiménez, Oaxaca, Mexico.<ref name="Nichols2020" /><ref name="Mangini2024" /> Gordon Wasson published his experience in an article for ''Life'' magazine titled "Seeking the Magic Mushroom" in 1957, while Valentina Wasson published her experience as "I Ate the Sacred Mushroom" in ''This Week'' magazine the same year.<ref name="Nichols2020" /><ref name="Mangini2024" /> Later in 1957, a second expedition was made by the Wassons to Mexico with French mycologist Roger Heim.<ref name="Nichols2020" /> Heim identified several of the mushrooms as belonging to the genus ''Psilocybe''.<ref name="Nichols2020" /> They collected samples of the mushrooms and Heim sent a sample to Hofmann.<ref name="Nichols2020" /> Hofmann identified psilocybin as the active constituent in 1958 and developed a chemical synthesis for it.<ref name="Nichols2020" /><ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="McKenna1999" /> Sandoz Pharmaceuticals began distributing tablets of psilocybin under the brand name Indocybin in 1960.<ref name="Nichols2020" />

French scientists Césaire Phisalix and Gabriel Bertrand isolated bufotenin from ''Bufo'' toads in 1893 and named it.<ref name="LyttleGoldsteinGartz1996">{{cite journal | vauthors = Lyttle T, Goldstein D, Gartz J | title = Bufo toads and bufotenine: fact and fiction surrounding an alleged psychedelic | journal = J Psychoactive Drugs | volume = 28 | issue = 3 | pages = 267–290 | date = 1996 | pmid = 8895112 | doi = 10.1080/02791072.1996.10472488 | url = }}</ref><ref name="BochnerGoyffon2007">Bochner, R., & Goyffon, M. (2007). L'œuvre scientifique de Césaire Phisalix (1852-1906), découvreur du sérum antivenimeux. Bull Soc Herp Fr, 123, 15-46. https://www.icict.fiocruz.br/sites/www.icict.fiocruz.br/files/L%20oeuvre%20scientifique%20de%20Cesaire%20Phisalix%20(1852--1906)%20decouvreur%20du%20serum%20antivenimeux.pdf</ref><ref name="PhisalixBertrand1893">Phisalix C, Bertrand G (1893) Toxicité comparée du sang et du venin de crapaud commun, considérée au point de vue de la sécrétion interne des glandes cutanées de cet animal. C R Soc Biol 45:477–479. https://scholar.google.com/scholar?cluster=14905926340091797397</ref> The compound was first isolated to purity by Austrian chemist Hans Handovsky in 1920.<ref name="LyttleGoldsteinGartz1996" /> Clinical studies assessed the effects of bufotenin and were published starting in 1956.<ref name="LyttleGoldsteinGartz1996" /><ref name="McBride2000" /><ref name="ShenJiangWinter2010" /> However, the findings of these studies were conflicting, and bufotenin developed a long-standing reputation of being inactive and toxic.<ref name="LyttleGoldsteinGartz1996" /><ref name="McBride2000">{{cite journal | vauthors = McBride MC | title = Bufotenine: toward an understanding of possible psychoactive mechanisms | journal = Journal of Psychoactive Drugs | volume = 32 | issue = 3 | pages = 321–331 | date = 2000 | pmid = 11061684 | doi = 10.1080/02791072.2000.10400456 }}</ref><ref name="ShenJiangWinter2010"/> American ethnobotanist Jonathan Ott and colleagues subsequently showed in 2001 that bufotenin is in fact a psychedelic and does not necessarily produce major adverse effects, although marked nausea and vomiting are prominent.<ref name="ShenJiangWinter2010" /><ref name="Ott2001b">{{cite book | vauthors = Ott J | chapter=Shamanic-Snuff Psychonautica: Pharmañopo: Bufotenine—Psychonautics | pages=99–116 (105–112, 114–115) | title=Shamanic Snuffs or Entheogenic Errhines | publisher=Entheobotanica | year=2001 | isbn=978-1-888755-02-2 | oclc=56061312 | url=https://books.google.com/books?id=AUP7NwAACAAJ | chapter-url=https://archive.org/details/vdocuments.mx_unknown-55b347d139b58/page/n51/mode/1up | access-date=24 January 2025 }}</ref><ref name="Ott2001a">{{cite journal | vauthors = Ott J | title = Pharmañopo-psychonautics: human intranasal, sublingual, intrarectal, pulmonary and oral pharmacology of bufotenine | journal = Journal of Psychoactive Drugs | volume = 33 | issue = 3 | pages = 273–281 | year = 2001 | pmid = 11718320 | doi = 10.1080/02791072.2001.10400574 | s2cid = 5877023 }}</ref> The related psychedelic 5-MeO-DMT was first synthesized by Japanese chemists Toshio Hoshino and Kenya Shimodaira in 1936.<ref name="Delgrasso2024" /><ref name="ErmakovaDunbarRucker2022" /> It was later isolated from ''Dictyoloma incanescens'' in 1959.<ref name="ErmakovaDunbarRucker2022" /> Subsequently, 5-MeO-DMT was isolated from numerous other plants and fungi.<ref name="ErmakovaDunbarRucker2022" /><ref name="Delgrasso2024" /> The compound was isolated from the skin of toads, specifically the Colorado River toad (''Incilius alvarius'', formerly ''Bufo alvarius''), by Italian chemist and pharmacologist Vittorio Erspamer in 1967.<ref name="Delgrasso2024">{{cite journal | last=Delgrasso | first=Azul | title=Defining 5-MeO-DMT in Historical and Cultural Contexts | journal=World Futures | volume=80 | issue=2 | date=17 February 2024 | issn=0260-4027 | doi=10.1080/02604027.2024.2330255 | pages=174–197}}</ref><ref name="ErmakovaDunbarRucker2022" /><ref name="ErspamerVitaliRoseghini1967">{{cite journal | vauthors = Erspamer V, Vitali T, Roseghini M, Cei JM | title = 5-Methoxy- and 5-hydroxyindoles in the skin of Bufo alvarius | journal = Biochem Pharmacol | volume = 16 | issue = 7 | pages = 1149–1164 | date = July 1967 | pmid = 6053590 | doi = 10.1016/0006-2952(67)90147-5 | url = https://sedici.unlp.edu.ar/handle/10915/88423}}</ref> A 1984 pamphlet by Albert Most (real name Ken Nelson), titled ''Bufo Alvarius: the Psychedelic Toad of the Sonoran Desert'', described how to obtain and use Colorado River toad secretions as a psychedelic drug, and this started its recreational use.<ref name="Siebert2021">{{cite web | last=Siebert | first=Amanda | title=Hamilton Morris On Mistakes, 5-MeO-DMT And Preserving Psychedelic Toads | website=Forbes | date=8 January 2021 | url=https://www.forbes.com/sites/amandasiebert/2021/01/08/hamilton-morris-on-mistakes-5-meo-dmt-and-preserving-psychedelic-toads/ | access-date=4 April 2025}}</ref><ref name="WeilDavis1994">{{cite journal | vauthors = Weil AT, Davis W | title = Bufo alvarius: a potent hallucinogen of animal origin | journal = J Ethnopharmacol | volume = 41 | issue = 1–2 | pages = 1–8 | date = January 1994 | pmid = 8170151 | doi = 10.1016/0378-8741(94)90051-5 | url = }}</ref><ref name="ErmakovaDunbarRucker2022" />

====Mid-20th-century research, popularization, and prohibition==== {{See also|Psychedelic era|Counterculture of the 1960s#Marijuana, LSD, and other recreational drugs}}

Extensive clinical research on almost exclusively LSD, mescaline, and psilocybin was conducted in the 1950s and 1960s.<ref name="Garcia-RomeuKersgaardAddy2016">{{cite journal | vauthors = Garcia-Romeu A, Kersgaard B, Addy PH | title = Clinical applications of hallucinogens: A review | journal = Exp Clin Psychopharmacol | volume = 24 | issue = 4 | pages = 229–268 | date = August 2016 | pmid = 27454674 | pmc = 5001686 | doi = 10.1037/pha0000084 | url = }}</ref> However, the amount of research done on psilocybin was nowhere near that of LSD.<ref name="Garcia-RomeuKersgaardAddy2016" /> Psychedelics like LSD started to become more visible in the mainstream sphere in the 1950s.<ref name="Garcia-RomeuKersgaardAddy2016" /> English writer Aldous Huxley tried mescaline, which he had obtained from English psychiatrist Humphry Osmond, in 1953, and described its effects in his 1954 book ''The Doors of Perception''.<ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="Webb2023">{{cite journal | last=Webb | first=Adrian | title=Nested hermeneutics: Mind at Large as a curated trope of psychedelic experience | journal=Interdisciplinary Science Reviews | volume=48 | issue=5 | date=2023 | issn=0308-0188 | doi=10.1080/03080188.2023.2249208 | doi-access=free | pages=768–787 | bibcode=2023ISRv...48..768W }}</ref><ref name="Swanson2018">{{cite journal | vauthors = Swanson LR | title = Unifying Theories of Psychedelic Drug Effects | journal = Front Pharmacol | volume = 9 | issue = | article-number = 172 | date = 2018 | pmid = 29568270 | pmc = 5853825 | doi = 10.3389/fphar.2018.00172 | doi-access = free | url = }}</ref> British politician Christopher Mayhew tried mescaline in 1955 and this was reported on in the media.<ref name="WalkerPullellaPiggott2023" /> Osmond, in correspondence with Huxley, coined the term "psychedelic", meaning "mind-manifesting", in 1956.<ref name="LukasiewiczBakerZuo2021">{{cite journal | vauthors = Lukasiewicz K, Baker JJ, Zuo Y, Lu J | title = Serotonergic Psychedelics in Neural Plasticity | journal = Front Mol Neurosci | volume = 14 | issue = | article-number = 748359 | date = 2021 | pmid = 34712118 | pmc = 8545892 | doi = 10.3389/fnmol.2021.748359 | doi-access = free | url = }}</ref><ref name="Swanson2018" />

Psychedelics became widely recreationally used by the public, for instance by the hippies, during the counterculture of the 1960s.<ref name="McKenna1999" /> Harvard psychologists Timothy Leary and Richard Alpert began studying LSD and psilocybin in the early 1960s and ended up being fired from the university in 1963.<ref name="Garcia-RomeuKersgaardAddy2016" /> Sandoz Laboratories ceased distribution of Delysid in 1965.<ref name="Garcia-RomeuKersgaardAddy2016" /> Psychedelics became controlled substances in the United States and internationally in the 1960s and 1970s.<ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="WalkerPullellaPiggott2023" /> By the end of the 1960s, psychedelic clinical research throughout the world had largely ceased.<ref name="McKenna1999" />

Besides public research, it was eventually learned that the United States government had also conducted research into psychedelics, as possible mind-control and truth-serum drugs, in the 1940s through the 1970s, for instance Project MKUltra by the Central Intelligence Agency (CIA) and the Edgewood Arsenal research by the U.S. Army.<ref name="PassieBenzenhöfer2018">{{cite journal | vauthors = Passie T, Benzenhöfer U | title = MDA, MDMA, and other "mescaline-like" substances in the US military's search for a truth drug (1940s to 1960s) | journal = Drug Test Anal | volume = 10 | issue = 1 | pages = 72–80 | date = January 2018 | pmid = 28851034 | doi = 10.1002/dta.2292 | url = https://psychedelic-science.org/fileadmin/user_upload/10_Passie_Benzenho__fer_MDMA_and_the_military_DTA_2017_Kopie.pdf}}</ref><ref name="SmithRaswyckDavidson2014">{{cite journal | vauthors = Smith DE, Raswyck GE, Davidson LD | title = From Hofmann to the Haight Ashbury, and into the future: the past and potential of lysergic acid diethlyamide | journal = J Psychoactive Drugs | volume = 46 | issue = 1 | pages = 3–10 | date = 2014 | pmid = 24830180 | doi = 10.1080/02791072.2014.873684 | url = }}</ref>

====Creation of other synthetic psychedelics==== The synthetic mescaline analogue 2,6-dibromomescaline was described by Arthur Heffter in 1901, although he is not known to have tested it and its psychedelic effects weren't reported until much later.<ref name="TrachselLehmannEnzensperger2013">{{cite book | vauthors = Trachsel D, Lehmann D, Enzensperger C | title = Phenethylamine: von der Struktur zur Funktion | location = Solothurn | year = 2013 | trans-title = Phenethylamines: From Structure to Function | edition = 1 | publisher = Nachtschatten-Verlag | series = Nachtschatten-Science | isbn = 978-3-03788-700-4 | oclc = 858805226 | url = https://books.google.com/books?id=-Us1kgEACAAJ | language = de | archive-url = https://archive.org/details/phenethylamine-von-der-struktur-zur-funktion-trachsel-lehmann-enzensperger-2013 | archive-date = 21 August 2025 }}</ref><ref name="Parker1998">{{cite thesis | vauthors = Parker M | title = Studies of perceptiotropic phenethylamines: Determinants of affinity for the 5-HT2A receptor | year = 1998 | type = PhD. Thesis | url = http://bitnest.ca/external.php?id=%251C%2B95%2522%250D%2519%2518%2505%250C%250Dtz%257D%2500%2501 | publisher = Purdue University | access-date = 2011-12-16 | archive-url = https://web.archive.org/web/20120425132418/http://bitnest.ca/external.php?id=%1C+95%22%0D%19%18%05%0C%0Dtz%7D%00%01 | archive-date = 2012-04-25 }}</ref><ref name="Aipsin-2,6-DBM">{{cite web | title = 2,6-BM (Dibromomescaline) | date = 1 May 1998 | website = АИПСИН | url = https://aipsin.com/newsubstance/112/ | language = ru | access-date = 25 November 2025 }}</ref><ref name="Heffter1901">{{cite journal | vauthors = Heffter A | date = 1901 | title = Ueber Cacteenalkaloide. (IV. Mittheilung). | trans-title = On cactus alkaloids. (IV. Communication) | journal = Berichte der Deutschen Chemischen Gesellschaft | trans-journal = Reports of the German Chemical Society | language = de | volume = 34 | pages = 3004–3015 | doi = 10.1002/cber.190103402266 | url = https://bibliography.maps.org/bibliography/default/resource/13624 }}</ref> The psychedelic effects of 3,4-methylenedioxyamphetamine (MDA), a synthetic analogue of mescaline that had been derived from amphetamine in 1910, were discovered by American chemist and pharmacologist Gordon Alles in 1930, but weren't subsequently published until 1959.<ref name="PsychedelicResearch2008">{{cite web|title=The First MDA trip and the measurement of 'mystical experience' after MDA, LSD, and Psilocybin|url=http://psychedelicresearch.org/?p=45|archive-url=https://web.archive.org/web/20110727191151/http://psychedelicresearch.org/?p=45|archive-date=2011-07-27 |date=18 July 2008|website=Psychedelic research}}</ref><ref name="BenzenhöferPassie2010" /><ref name="Alles1959a">{{cite book | author=Gordon A. Alles | chapter = Some Relations Between Chemical Structure and Physiological Action of Mescaline and Related Compounds / Structure and Action of Phenethylamines | veditors = Abramson HA | title = Neuropharmacology: Transactions of the Fourth Conference, September 25, 26, and 27, 1957, Princeton, N. J. | location = New York | publisher = Josiah Macy Foundation | date = 1959 | pages = 181–268 | oclc = 9802642 | url = https://books.google.com/books?id=sDQLAQAAMAAJ&q=%22Some+relations+between+chemical+structure+and+physiological+action+of+mescaline+and+related+compounds%22 | chapter-url = https://bitnest.netfirms.com/external/Books/NeuropharmacologyTrans.4.181#page=5 | archive-url = https://web.archive.org/web/20250321230359/https://bitnest.netfirms.com/external/Books/NeuropharmacologyTrans.4.181#page=5 | archive-date = 21 March 2025 }}</ref><ref name="Gordon A. Alles-1959">{{cite book | author = Gordon A. Alles | chapter = Subjective Reactions to Phenethylamine Hallucinogens | title = A Pharmacologic Approach to the Study of the Mind | date = 1959 | publisher = CC Thomas | location = Springfield | pages = 238–250 (241–246) | url = https://books.google.com/books?id=x45rAAAAMAAJ | chapter-url = https://archive.org/details/pharmacologicapp0000univ/page/238/mode/1up}}</ref> 3,4,5-Trimethoxyamphetamine (TMA), another synthetic mescaline analogue, was first described in 1947 and its psychedelic effects were described in 1955.<ref name="PeretzSmythiesGibson1955">{{cite journal | vauthors = Peretz DI, Smythies JR, Gibson WC | title = A new hallucinogen: 3,4,5-trimethoxyphenyl-beta-aminopropane with notes on the stroboscopic phenomenon | journal = J Ment Sci | volume = 101 | issue = 423 | pages = 317–329 | date = April 1955 | pmid = 13243046 | doi = 10.1192/bjp.101.423.317 | url = }}</ref><ref name="ShulginBunnell1961">{{cite journal | last1=Shulgin | first1=Alexander T. | last2=Bunnell | first2=Sterling | last3=Sargent | first3=Thornton | title=The Psychotomimetic Properties of 3,4,5-Trimethoxyamphetamine | journal=Nature | volume=189 | issue=4769 | date=1961 | issn=0028-0836 | doi=10.1038/1891011a0 | pages=1011–1012| bibcode=1961Natur.189.1011S }}</ref><ref name="Hey1947">{{cite journal | vauthors = Hey P | title = The synthesis of a new homologue of mescaline | journal = Q J Pharm Pharmacol | volume = 20 | issue = 2 | pages = 129–134 | date = 1947 | pmid = 20260568 | doi = | url = https://www.thevespiary.org/rhodium/Rhodium/chemistry/tma.hey.html | archive-url = https://web.archive.org/web/20190719130050/https://www.thevespiary.org/rhodium/Rhodium/chemistry/tma.hey.html | archive-date = 19 July 2019 }}</ref><ref name="Shulgin1978">{{cite book | veditors = Iversen LL, Iversen SD, Snyder SH | last=Shulgin | first=Alexander T. | title=Stimulants | chapter=Psychotomimetic Drugs: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_6 | pages=243–333 | chapter-url=https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6 | url=https://books.google.com/books?id=h0_uBwAAQBAJ&pg=PA261}}</ref> 2,4,5-Trimethoxyphenethylamine (2C-O), a synthetic positional isomer of mescaline, was synthesized and claimed to be psychedelic similarly to mescaline in 1931, but later trials found it to be inactive.<ref name="Shulgin1978" /><ref name="Jansen1931">{{cite journal |vauthors=Jansen, MPJM |date=1931 |title=β-2: 4: 5-Trimethoxyphenylethylamine, an isomer of mescaline |url=https://onlinelibrary.wiley.com/doi/10.1002/recl.19310500403 |journal=Recueil des Travaux Chimiques des Pays-Bas |volume=50 |issue=4 |pages=291–312 |doi=10.1002/recl.19310500403 |access-date=22 November 2022}}</ref> Various synthetic tryptamine psychedelics, such as diethyltryptamine (DET), 4-PO-DET (CEY-19), and 4-HO-DET (CZ-74), were developed in the late 1950s.<ref name="PassieGussKrähenmann2022">{{cite journal | vauthors = Passie T, Guss J, Krähenmann R | title = Lower-dose psycholytic therapy - A neglected approach | journal = Front Psychiatry | volume = 13 | issue = | article-number = 1020505 | date = 2022 | pmid = 36532196 | pmc = 9755513 | doi = 10.3389/fpsyt.2022.1020505 | doi-access = free | quote=Around 1960, Sandoz developed two short-acting derivatives of psilocybin, codenamed CZ-74 (4-HO-DET, 4-hydroxy-N,N-diethyltryptamine) and CEY-19 (ethocybin, 4-phosphoryloxy-N,N-diethyltryptamine) (37), which were used in psycholytic therapy [e.g. (34, 38, 39)].}}</ref><ref name="BoszormenyiDerNagy1959">{{cite journal | vauthors = Boszormenyi Z, Der P, Nagy T | title = Observations on the psychotogenic effect of N-N diethyltryptamine, a new tryptamine derivative | journal = J Ment Sci | volume = 105 | issue = 438 | pages = 171–181 | date = January 1959 | pmid = 13641966 | doi = 10.1192/bjp.105.438.171 | url = }}</ref><ref name="LeunerBaer1965">{{cite journal | vauthors = Leuner H, Baer G | title = Two new short-acting hallucinogens of the psilocybin group | date = 1965 | journal = Neuropsychopharmacology | volume = 4 | issue = | pages = 471–474 | url = https://bibliography.maps.org/resources/download/19910 | archive-url = https://web.archive.org/web/20250422014123/https://bibliography.maps.org/resources/download/19910 | archive-date = 2025-04-22 }}</ref> In addition, the synthetic α-alkyltryptamine analogues α-methyltryptamine (AMT; Indopan) and α-ethyltryptamine (AET; Monase), which are psychedelics and/or entactogens, were marketed and clinically used at non-hallucinogenic doses as antidepressants in the early 1960s, but were quickly withdrawn due to physical toxicity.<ref name="Barceloux2012">{{cite book | last=Barceloux | first=Donald G. | chapter=Tryptamine Designer Drugs | title=Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants | publisher=Wiley | date=9 March 2012 | isbn=978-0-471-72760-6 | doi=10.1002/9781118105955.ch11 | pages=193–199 | quote=During the early 1960s, α-ethyltryptamine [(AET)] (Monase®, Upjohn Company) was marketed in the United States as an antidepressant and stimulant, but the drug was removed shortly after introduction because of the occurrence of serious blood disorders. [...] [α-Methyltryptamine (AMT)] (Indopan) was marketed in the Soviet Union during the 1960s as an antidepressant. }}</ref><ref name="GlennonDukat2023">{{cite journal | vauthors = Glennon RA, Dukat MG | title = α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant | journal = ACS Pharmacology & Translational Science | volume = 6 | issue = 12 | pages = 1780–1789 | date = December 2023 | pmid = 38093842 | doi = 10.1021/acsptsci.3c00139 | pmc = 10714429 }}</ref><ref name="Oeri2021">{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = Journal of Psychopharmacology | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | quote = While an argument can be made that compounds like 4-bromo-2,5-dimethoxyphenethylamine (2CB) or N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT) are also entactogenic, and they have been described as such in the past (González et al., 2015; Palamar and Acosta, 2020; Schifano et al., 2019), they were also excluded due to their high affinity as agonists at post-synaptic 5-HT2 and 5-HT1A receptors (Fantegrossi et al., 2006; Nugteren-van Lonkhuyzen et al., 2015; Taylor et al., 1986; Villalobos et al., 2004), which would indicate that their effects also include a marked psychedelic component.}}</ref> Numerous synthetic psychedelic tryptamines were known by the mid-1970s.<ref name="BrimblecombePinder1975" />

Alexander Shulgin, an American chemist working at Dow Chemical Company, tried mescaline by 1960.<ref name="Baggott2023" /><ref name="Romero1995">{{cite news |first = Dennis |last = Romero |url = http://www.erowid.org/culture/characters/shulgin_alexander/shulgin_alexander_interview1.shtml |title = Sasha Shulgin, Psychedelic Chemist |newspaper = Los Angeles Times |date = September 5, 1995 |access-date = July 8, 2006 |archive-date = March 26, 2007 |archive-url = https://web.archive.org/web/20070326004128/http://www.erowid.org/culture/characters/shulgin_alexander/shulgin_alexander_interview1.shtml |url-status = live }}</ref> This experience has been described as "the most consequential mescaline trip of the sixties", as it caused Shulgin to redirect his focus and life's work to psychedelic chemistry.<ref name="Baggott2023" /><ref name="Romero1995" /> Starting in the 1960s, Shulgin synthesized and gradually described hundreds of novel synthetic psychedelics as well as entactogens in scientific publications and published books such as ''PiHKAL'' (1991) and ''TiHKAL'' (1997).<ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="WalkerPullellaPiggott2023" /><ref name="Baggott2023" /> Notable major examples of these drugs have included the DOx psychedelic DOM, the 2C psychedelic 2C-B, and the MDxx entactogen MDMA, among others.<ref name="WalkerPullellaPiggott2023" /><ref name="DunlapAndrewsOlson2018" /><ref name="BenzenhöferPassie2010">{{cite journal | vauthors = Benzenhöfer U, Passie T | title = Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin | journal = Addiction | volume = 105 | issue = 8 | pages = 1355–61 | date = August 2010 | pmid = 20653618 | doi = 10.1111/j.1360-0443.2010.02948.x | url = }}</ref> However, MDMA was not an original creation of Shulgin's but had previously been first synthesized in 1912 and had surfaced as a recreational drug related to MDA by the mid- to late-1960s.<ref name="Passie2023">{{cite book | last=Passie | first=Torsten | title=The History of MDMA | publisher=Oxford University Press | date=29 June 2023 | isbn=978-0-19-886736-4 | doi=10.1093/oso/9780198867364.001.0001 | url=https://books.google.com/books?id=KSvCEAAAQBAJ&pg=PA6 | pages=6–16, 18, 27, 29, 32, 40}}</ref><ref name="Bernschneider-ReifOxlerFreudenmann2006">{{cite journal | vauthors = Bernschneider-Reif S, Oxler F, Freudenmann RW | title = The origin of MDMA ("ecstasy")--separating the facts from the myth | journal = Pharmazie | volume = 61 | issue = 11 | pages = 966–972 | date = November 2006 | pmid = 17152992 | doi = | url = }}</ref><ref name="BenzenhöferPassie2010" /> Instead, Shulgin had merely served to help popularize and spread awareness about MDMA and its unique effects.<ref name="Passie2023" /><ref name="Bernschneider-ReifOxlerFreudenmann2006" /><ref name="BenzenhöferPassie2010" />

MDMA became outlawed in the mid-1980s.<ref name="WalkerPullellaPiggott2023" /><ref name="EmersonPontéJerome2014" /> In response to this, the Multidisciplinary Association for Psychedelic Studies (MAPS) was founded by Rick Doblin in 1986 and began efforts to develop MDMA and other psychedelics as medicines.<ref name="EmersonPontéJerome2014">{{cite journal | vauthors = Emerson A, Ponté L, Jerome L, Doblin R | title = History and future of the Multidisciplinary Association for Psychedelic Studies (MAPS) | journal = J Psychoactive Drugs | volume = 46 | issue = 1 | pages = 27–36 | date = 2014 | pmid = 24830183 | doi = 10.1080/02791072.2014.877321 | url = }}</ref> American chemist David E. Nichols has developed numerous novel psychedelics and entactogens from the 1970s to present.<ref name="Morris2021">{{cite episode | credits = Hamilton Morris | date = 8 February 2021 | title = Ultra LSD | series = Hamilton's Pharmacopeia | season = 3 | number = 6 | url = https://vimeo.com/489281122#t=19m41s | language = en | publisher = Vice Media | time = 19:41–22:17 | network = Viceland | transcript = | transcript-url = | quote = [Morris:] David Nichols has synthesized more psychedelic compounds than almost any other chemist in history. Maybe the most. He's made enormous contributions to the pharmacological understanding of how psychedelics act in the brain. And he's a real legend among anyone who cares about the science surrounding psychedelics.}}</ref><ref name="Nichols2022b">{{cite journal | vauthors = Nichols DE | title = Entactogens: How the Name for a Novel Class of Psychoactive Agents Originated | journal = Front Psychiatry | volume = 13 | issue = | article-number = 863088 | date = 2022 | pmid = 35401275 | pmc = 8990025 | doi = 10.3389/fpsyt.2022.863088 | doi-access = free | url = }}</ref><ref name="BaumeisterTojoTracy2015">{{cite journal | vauthors = Baumeister D, Tojo LM, Tracy DK | title = Legal highs: staying on top of the flood of novel psychoactive substances | journal = Ther Adv Psychopharmacol | volume = 5 | issue = 2 | pages = 97–132 | date = April 2015 | pmid = 26240749 | pmc = 4521440 | doi = 10.1177/2045125314559539 | url = }}</ref> Swiss chemist Daniel Trachsel, sometimes referred to as the "German Shulgin", has also developed and published numerous novel psychedelics as well as entactogens since the 1990s.<ref name="PassieBrandt2018">{{cite book | vauthors = Passie T, Brandt SD | title = New Psychoactive Substances | chapter = Self-Experiments with Psychoactive Substances: A Historical Perspective | volume = 252 | issue = | pages = 69–110 | date = 2018 | pmid = 30478735 | doi = 10.1007/164_2018_177 | isbn = 978-3-030-10560-0 | chapter-url = https://is-sp.org/fileadmin/user_upload/passie_brandt_self-experiments_w_psychoactive_substances_2018.pdf}}</ref><ref name="MorrisNichols2021">{{cite podcast | url=https://www.patreon.com/posts/podcast-34-four-59224393 | title=PODCAST 34: A Four Hour Interview with Dr. David E Nichols | website=The Hamilton Morris Podcast | publisher=Patreon | host=Hamilton Morris | date=27 November 2021 | time= | access-date=30 January 2025 }}</ref><ref name="TrachselLehmannEnzensperger2013" />

NBOMe psychedelics such as 25I-NBOMe, derived from structural modification of 2C psychedelics, were first described by Ralf Heim and colleagues by 2000.<ref name="HeimElz2000">{{cite journal | vauthors = Heim R, Elz S | title = 39. Novel Extremely Potent Partial 5-HT2A-Receptor Agonists: Successful Application of a New Structure-Activity Concept | date = March 2000 | journal = Arch. Pharm. Pharm. Med. Chem. | volume = 333 | issue = Suppl 1 | pages = 1–40 (18) | issn = 0365-6233 | url = https://scholar.google.com/scholar?cluster=5753981208249154444 | archive-url = https://web.archive.org/web/20250320195942/https://bitnest.netfirms.com/external/Arch.Pharm.Pharm.Med.Chem/333.S1.18 | archive-date = 20 March 2025 }}</ref><ref name="PertzHeimElz2000">{{cite journal | vauthors = Pertz HH, Heim R, Elz S | title = B 1.11. N-Benzylated phenylethanamines are highly potent partial agonists at 5-HT2A receptors | date = 2000 | journal = Arch. Pharm. Pharm. Med. Chem | volume = 333 | issue = Suppl 2 | pages = 1–84 (30) | url = https://scholar.google.com/scholar?cluster=18169232060279208950 | archive-url = https://web.archive.org/web/20250320194355/https://bitnest.netfirms.com/external/Arch.Pharm.Pharm.Med.Chem/333.S2.30 | archive-date = 20 March 2025}}</ref><ref name="Heim2003">{{cite web |vauthors=Heim R |title=Synthese und Pharmakologie potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur. Entwicklung eines neuen Struktur-Wirkungskonzepts. | trans-title=Synthesis and pharmacology of potent 5-HT2A receptor agonists with an N-2-methoxybenzyl partial structure. Development of a new structure-activity concept. | url=http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000001221 |publisher=diss.fu-berlin.de |date=25 March 2003 |language=German |access-date=2013-05-10 |archive-date=2012-04-16 |archive-url=https://web.archive.org/web/20120416040543/http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000001221 |url-status=live }}</ref> The NBOMe drugs were subsequently encountered as novel recreational drugs by 2010, and by 2012 had eclipsed other psychedelics like LSD and psilocybin-containing mushrooms in popularity, at least for a time.<ref name="WoodSedefovCunningham2015">{{cite journal | vauthors = Wood DM, Sedefov R, Cunningham A, Dargan PI | title = Prevalence of use and acute toxicity associated with the use of NBOMe drugs | journal = Clin Toxicol (Phila) | volume = 53 | issue = 2 | pages = 85–92 | date = February 2015 | pmid = 25658166 | doi = 10.3109/15563650.2015.1004179 | url = }}</ref><ref name="Morgans2017">{{cite web | last=Morgans | first=Julian | title=NBOMe in Australia: Everything We Know About the Drug and Why it's Killing People | website=VICE | date=8 February 2017 | url=https://www.vice.com/en/article/nbome-in-australia-everything-we-know-about-what-it-is-and-why-its-killing-people/ | access-date=4 April 2025}}</ref><ref name="LawnBarrattWilliams">{{cite journal | vauthors = Lawn W, Barratt M, Williams M, Horne A, Winstock A | title = The NBOMe hallucinogenic drug series: Patterns of use, characteristics of users and self-reported effects in a large international sample | journal = J Psychopharmacol | volume = 28 | issue = 8 | pages = 780–788 | date = August 2014 | pmid = 24569095 | doi = 10.1177/0269881114523866 | hdl = 1959.4/unsworks_73366 | hdl-access = free }}</ref>

====Psychedelics, serotonin, and their actions==== Serotonin, also known as 5-hydroxytryptamine (5-HT) and originally called enteramine, was discovered by Vittorio Erspamer in the 1930s<ref name="NicholsNichols2008" /> and its structural identity was fully characterized in the late 1940s and early 1950s.<ref name="NicholsNichols2008">{{cite journal | vauthors = Nichols DE, Nichols CD | title = Serotonin receptors | journal = Chem Rev | volume = 108 | issue = 5 | pages = 1614–1641 | date = May 2008 | pmid = 18476671 | doi = 10.1021/cr078224o | url = }}</ref><ref name="McCorvyRoth2015">{{cite journal | vauthors = McCorvy JD, Roth BL | title = Structure and function of serotonin G protein-coupled receptors | journal = Pharmacol Ther | volume = 150 | issue = | pages = 129–142 | date = June 2015 | pmid = 25601315 | pmc = 4414735 | doi = 10.1016/j.pharmthera.2015.01.009 | url = }}</ref><ref name="RapportGreenPage1948">{{cite journal | vauthors = Rapport MM, Green AA, Page IH | title = Serum vasoconstrictor, serotonin; isolation and characterization | journal = J Biol Chem | volume = 176 | issue = 3 | pages = 1243–1251 | date = December 1948 | pmid = 18100415 | doi = 10.1016/S0021-9258(18)57137-4| doi-access = free | url = }}</ref> Serotonin was discovered in the brain by Betty Twarog and Irvine Page in 1953.<ref name="NicholsNichols2008" /><ref name="McCorvyRoth2015" /><ref name="TwarogPage1953">{{cite journal | vauthors = Twarog BM, Page IH | title = Serotonin content of some mammalian tissues and urine and a method for its determination | journal = Am J Physiol | volume = 175 | issue = 1 | pages = 157–161 | date = October 1953 | pmid = 13114371 | doi = 10.1152/ajplegacy.1953.175.1.157 | url = }}</ref> It was quickly noticed that LSD contains the serotonin-like tryptamine scaffold within its chemical structure.<ref name="NicholsNichols2008" /><ref name="McCorvyRoth2015" /> Shortly thereafter, it was found that LSD showed serotonin-like effects and could antagonize serotonin in certain assays.<ref name="NicholsNichols2008" /><ref name="McCorvyRoth2015" /> Studies in the 1960s and 1970s showed that various serotonin antagonists could block the behavioral effects of psychedelics in animals.<ref name="Glennon1992">{{cite book | last=Glennon | first=Richard A. | title=Animal Models of Drug Addiction | chapter=Animal Models for Assessing Hallucinogenic Agents | publisher=Humana Press | publication-place=New Jersey | volume=24 | date=23 October 1992 | isbn=978-0-89603-217-0 | doi=10.1385/0-89603-217-5:345 | pages=345–382}}</ref><ref name="Nichols2004">{{cite journal | vauthors = Nichols DE | title = Hallucinogens | journal = Pharmacol Ther | volume = 101 | issue = 2 | pages = 131–181 | date = February 2004 | pmid = 14761703 | doi = 10.1016/j.pharmthera.2003.11.002 | url = https://bitnest.netfirms.com/external/10.1016/j.pharmthera.2003.11.002}}</ref><ref name="CornePickeringWarner1963">{{cite journal | vauthors = Corne SJ, Pickering RW, Warner BT | title = A method for assessing the effects of drugs on the central actions of 5-hydroxytryptamine | journal = Br J Pharmacol Chemother | volume = 20 | issue = 1 | pages = 106–120 | date = February 1963 | pmid = 14023050 | pmc = 1703746 | doi = 10.1111/j.1476-5381.1963.tb01302.x | url = }}</ref><ref name="BrowneHo1975">{{cite journal | vauthors = Browne RG, Ho BT | title = Role of serotonin in the discriminative stimulus properties of mescaline | journal = Pharmacol Biochem Behav | volume = 3 | issue = 3 | pages = 429–435 | date = 1975 | pmid = 125425 | doi = 10.1016/0091-3057(75)90052-0 | url = }}</ref><ref name="Winter1975">{{cite journal | vauthors = Winter JC | title = Blockade of the stimulus properties of mescaline by a serotonin antagonist | journal = Arch Int Pharmacodyn Ther | volume = 214 | issue = 2 | pages = 250–253 | date = April 1975 | pmid = 1156033 | doi = | url = }}</ref> It was first proposed that LSD may be acting as an agonist of serotonin receptors by N. E. Andén and colleagues in 1968.<ref name="NicholsNichols2021" /><ref name="AndénCorrodiFuxe1968">{{cite journal | vauthors = Andén NE, Corrodi H, Fuxe K, Hökfelt T | title = Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide | journal = Br J Pharmacol | volume = 34 | issue = 1 | pages = 1–7 | date = September 1968 | pmid = 5302837 | pmc = 1703426 | doi = 10.1111/j.1476-5381.1968.tb07943.x | url = }}</ref> The serotonin receptors, including the serotonin 5-HT2 receptors, were identified by the late 1970s.<ref name="NicholsNichols2008" /><ref name="McCorvyRoth2015" /><ref name="PeroutkaSnyder1979">{{cite journal | vauthors = Peroutka SJ, Snyder SH | title = Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol | journal = Mol Pharmacol | volume = 16 | issue = 3 | pages = 687–699 | date = November 1979 | pmid = 530254 | doi = 10.1016/S0026-895X(25)13812-1| url = }}</ref> Mediation of the hallucinogenic effects of psychedelics specifically by serotonin 5-HT2 receptor agonism was proposed by Richard Glennon and other researchers by the early 1980s.<ref name="Glennon1992" /><ref name="Halberstadt2015" /><ref name="Nichols2004" /><ref name="FordyceRoth2024">{{cite journal | vauthors = Fordyce BA, Roth BL | title = Making Sense of Psychedelics in the CNS | journal = Int J Neuropsychopharmacol | volume = 27 | issue = 2 | date = February 2024 | article-number = pyae007 | pmid = 38289825 | pmc = 10888522 | doi = 10.1093/ijnp/pyae007 | url = }}</ref><ref name="López-GiménezGonzález-Maeso2017">{{cite journal | last1=López-Giménez | first1=Juan F. | last2=González-Maeso | first2=Javier | title=Behavioral Neurobiology of Psychedelic Drugs: Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways | journal=Current Topics in Behavioral Neurosciences | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | volume=36 | date=2017 | isbn=978-3-662-55878-2 | pmid=28677096 | pmc=5756147 | doi=10.1007/7854_2017_478 | doi-access=free | pages=45–73}}</ref> The human serotonin 5-HT2A receptor was first cloned in 1990.<ref name="NicholsNichols2008" /><ref name="BranchekAdhamMacchi1990">{{cite journal | vauthors = Branchek T, Adham N, Macchi M, Kao HT, Hartig PR | title = [3H]-DOB(4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H] ketanserin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor | journal = Mol Pharmacol | volume = 38 | issue = 5 | pages = 604–609 | date = November 1990 | pmid = 2233697 | doi = 10.1016/S0026-895X(25)09519-7| url = }}</ref> The hallucinogenic effects of psilocybin in humans were shown to be blocked by the selective serotonin 5-HT2A receptor antagonist ketanserin by Franz Vollenweider and colleagues in 1998, solidifying theoretical notions that agonism of the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics.<ref name="NicholsNichols2008" /><ref name="VollenweiderVollenweider-ScherpenhuyzenBäbler1998">{{cite journal | vauthors = Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, Vogel H, Hell D | title = Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action | journal = NeuroReport | volume = 9 | issue = 17 | pages = 3897–3902 | date = December 1998 | pmid = 9875725 | doi = 10.1097/00001756-199812010-00024 | url = }}</ref>

===Psychedelic renaissance=== {{See also|List of investigational hallucinogens and entactogens}}

[[File:Search hits for serotonergic psychedelic terms on PubMed over time.png|thumb|right|250px|class=skin-invert-image|Number of publications with psychedelic-related terms on PubMed by publication date. The peak publications were 311 in the 1960s and 1970s and 1,460 in 2025.]]

Since the prohibition of the 1960s and 1970s, clinical research into psychedelics started to resume by the 1990s, for instance the studies of DMT by Rick Strassman, and they have once again started to be developed as pharmaceutical drugs for potential medical use.<ref name="Simms2022" /><ref name="Garcia-RomeuKersgaardAddy2016" /><ref name="Szára2007" /><ref name="Barker2018">{{cite journal | vauthors = Barker SA | title = N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function | journal = Front Neurosci | volume = 12 | issue = | article-number = 536 | date = 2018 | pmid = 30127713 | pmc = 6088236 | doi = 10.3389/fnins.2018.00536 | doi-access = free | url = }}</ref> A so-called "psychedelic renaissance", in which interest in psychedelics has resurged, began in the late 2010s and early 2020s.<ref name="Sessa2018">{{cite journal | vauthors = Sessa B | title = The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant | journal = Psychopharmacology (Berl) | volume = 235 | issue = 2 | pages = 551–560 | date = February 2018 | pmid = 28831571 | doi = 10.1007/s00213-017-4713-7 | url = }}</ref><ref name="RheeDavoudianSanacora2023">{{cite journal | vauthors = Rhee TG, Davoudian PA, Sanacora G, Wilkinson ST | title = Psychedelic renaissance: Revitalized potential therapies for psychiatric disorders | journal = Drug Discov Today | volume = 28 | issue = 12 | article-number = 103818 | date = December 2023 | pmid = 37925136 | doi = 10.1016/j.drudis.2023.103818 | url = }}</ref><ref name="Mikos2022">{{cite journal | last=Mikos | first=Robert A. | title=Observations on 25 Years of Cannabis Law Reforms and Their Implications for the Psychedelic Renaissance in the United States | journal=Annual Review of Law and Social Science | volume=18 | issue=1 | date=18 October 2022 | issn=1550-3585 | doi=10.1146/annurev-lawsocsci-120621-012645 | doi-access=free | pages=155–167 }}</ref> Michael Pollan's 2018 book ''How to Change Your Mind'', which was also adapted into a Netflix series in 2022, was especially impactful in terms of increasing mainstream awareness and interest in psychedelics.<ref name="NooraniBediMuthukumaraswamy2023">{{cite journal | vauthors = Noorani T, Bedi G, Muthukumaraswamy S | title = Dark loops: contagion effects, consistency and chemosocial matrices in psychedelic-assisted therapy trials | journal = Psychol Med | volume = 53 | issue = 13 | pages = 5892–5901 | date = October 2023 | pmid = 37466178 | pmc = 10520581 | doi = 10.1017/S0033291723001289 | url = | quote = }}</ref><ref name="BawksGomes2025">{{cite journal | vauthors = Bawks J, Gomes F | title = Bias and Balance in Psychedelic Academia- A Tricky Business | journal = Trends Psychiatry Psychother | volume = 47| issue = | pages = e20240990| date = February 2025 | pmid = 40009852 | doi = 10.47626/2237-6089-2024-0990 | url = | quote = The investigative journalist Michael Pollan brought the topic to public attention with his book How to Change Your Mind in 2018, which was then made into a Netflix documentary in 2022. By 2024, Yao and colleagues8 identified 126 trials spanning the 4 major serotonergic psychedelics; MDMA, LSD, psilocybin and ayahuasca.| doi-access = free }}</ref><ref name="Pollan2018">{{cite book | last=Pollan | first=Michael | title=How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence | publisher=Penguin | date=15 May 2018 | isbn=978-0-525-55894-1 | url=https://books.google.com/books?id=3vk5DwAAQBAJ&pg=PP1 | access-date=13 May 2025 | page=}}</ref> More than 100{{nbsp}}clinical trials of four major psychedelics, including psilocybin, LSD, ayahuasca, and MDMA, were identified as being underway in 2024.<ref name="BawksGomes2025" /><ref name="YaoGuoLu2024">{{cite journal | vauthors = Yao Y, Guo D, Lu TS, Liu FL, Huang SH, Diao MQ, Li SX, Zhang XJ, Kosten TR, Shi J, Bao YP, Lu L, Han Y | title = Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis | journal = Psychiatry Res | volume = 335 | issue = | article-number = 115886 | date = May 2024 | pmid = 38574699 | doi = 10.1016/j.psychres.2024.115886 | url = }}</ref>

==Society and culture== ===Etymology and nomenclature=== The term ''psychedelic'' was coined by the psychiatrist Humphrey Osmond during written correspondence with author Aldous Huxley (written in a rhyme: "To fathom Hell or soar angelic/Just take a pinch of psychedelic."<ref>{{Cite journal |last=Tanne |first=Janice Hopkins |date=2004-03-20 |title=Humphry Osmond |journal=BMJ: British Medical Journal |volume=328 |issue=7441 |page=713 |doi=10.1136/bmj.328.7441.713 |issn=0959-8138 |pmc=381240}}</ref>) and presented to the New York Academy of Sciences by Osmond in 1957.<ref name="tanne-osmond">{{cite journal |last1=Tanne |first1=Janice Hopkins |title=Humphrey Osmond |journal=BMJ |date=2004 |volume=328 |issue=7441 |page=713 |doi=10.1136/bmj.328.7441.713 |pmc=381240}}</ref> It is irregularly<ref>''Oxford English Dictionary'', 3rd edition, September 2007, ''[https://www.oed.com/view/Entry/153850 s.v.]'', Etymology</ref> derived from the Greek words ψυχή (''psychḗ'', meaning 'mind, soul') and δηλείν (''dēleín'', meaning 'to manifest'), with the intended meaning "mind manifesting" or alternatively "soul manifesting", and the implication that psychedelics can reveal unused potentials of the human mind.<ref>A. Weil, W. Rosen. (1993), ''From Chocolate To Morphine: Everything You Need To Know About Mind-Altering Drugs''. New York, Houghton Mifflin Company. p. 93</ref> The term was loathed by American ethnobotanist Richard Schultes but championed by American psychologist Timothy Leary.<ref>W. Davis (1996), "One River: Explorations and Discoveries in the Amazon Rain Forest". New York, Simon and Schuster, Inc. p. 120.</ref>

Aldous Huxley had suggested his own coinage ''phanerothyme'' (Greek ''phaneroein''- "to make manifest or visible" and Greek ''thymos'' "soul", thus "to reveal the soul") to Osmond in 1956.<ref>[https://archive.org/details/mokshawritingson00aldo iia700700.us.archive.org]</ref> Recently, the term entheogen (meaning "that which produces the divine within") has come into use to denote the use of psychedelic drugs, as well as various other types of psychoactive substances, in a religious, spiritual, and mystical context.<ref name="Nichols2004" />

In 2004, David E. Nichols wrote the following about the nomenclature used for psychedelic drugs:<ref name="Nichols2004" />

{{Blockquote|Many different names have been proposed over the years for this drug class. The famous German toxicologist Louis Lewin used the name phantastica earlier in this century, and as we shall see later, such a descriptor is not so farfetched. The most popular names—hallucinogen, psychotomimetic, and psychedelic ("mind manifesting")—have often been used interchangeably. ''Hallucinogen'' is now, however, the most common designation in the scientific literature, although it is an inaccurate descriptor of the actual effects of these drugs. In the lay press, the term ''psychedelic'' is still the most popular and has held sway for nearly four decades. Most recently, there has been a movement in nonscientific circles to recognize the ability of these substances to provoke mystical experiences and evoke feelings of spiritual significance. Thus, the term ''entheogen'', derived from the Greek word ''entheos'', which means "god within", was introduced by Ruck et al. and has seen increasing use. This term suggests that these substances reveal or allow a connection to the "divine within". Although it seems unlikely that this name will ever be accepted in formal scientific circles, its use has dramatically increased in the popular media and on internet sites. Indeed, in much of the counterculture that uses these substances, entheogen has replaced psychedelic as the name of choice and we may expect to see this trend continue.}}

Robin Carhart-Harris and Guy Goodwin write that the term ''psychedelic'' is preferable to ''hallucinogen'' for describing classical psychedelics because of the term ''hallucinogen''{{'}}s "arguably misleading emphasis on these compounds' hallucinogenic properties."<ref name="carhart-harris-goodwin">{{cite journal |last1=Carhart-Harris |first1=Robin |last2=Guy |first2=Goodwin |author-link2=Guy Goodwin |title=The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future |journal=Neuropsychopharmacology |date=2017 |volume=42 |issue=11 |pages=2105–2113 |doi=10.1038/npp.2017.84 |pmid=28443617 |pmc=5603818}}</ref>

While the term ''psychedelic'' is most commonly used to refer only to serotonergic hallucinogens,<ref name="Nichols2016"/><ref name="Nichols2018" /><ref name="divito-leger-2020">{{cite journal |last1=DiVito |first1=Alec J. |last2=Leger |first2=Robert F. |title=Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review |journal=Molecular Biology Reports |date=2020 |volume=47 |issue=12 |pages=9791–9799 |doi=10.1007/s11033-020-06009-x |pmid=33231817|s2cid=227157734 }}</ref><ref name="marks-and-cohen-2021">{{cite journal | vauthors = Marks M, Cohen IG | title = Psychedelic therapy: a roadmap for wider acceptance and utilization | journal = Nature Medicine | volume = 27 | issue = 10 | pages = 1669–1671 | date = October 2021 | pmid = 34608331 | doi = 10.1038/s41591-021-01530-3 | s2cid = 238355863 | doi-access = free }}</ref> it is sometimes used for a much broader range of drugs, including entactogens, dissociatives, and atypical hallucinogens/psychoactives such as ''Amanita muscaria'', ''Cannabis sativa'', ''Nymphaea nouchali'' and ''Salvia divinorum''.<ref name="reiff-et-al-2020"/><ref>{{cite journal |last1=Siegel |first1=Ashley N. |last2=Meshkat |first2=Shakila |last3=Benitah |first3=Katie |last4=Lipstiz |first4=Orly |last5=Gill |first5=Hartej |last6=Lui |first6=Leanna M. W. |last7=Teopiz |first7=Kayla M. |last8=McIntyre |first8=Roger S. |last9=Rosenblat |first9=Joshua D. |title=Registered clinical studies investigating psychedelic drugs for psychiatric disorders |journal=Journal of Psychiatric Research |date=2021 |volume=139 |pages=71–81 |doi=10.1016/j.jpsychires.2021.05.019 |pmid=34048997|s2cid=235242044 }}</ref> Thus, the term ''serotonergic psychedelic'' is sometimes used for the narrower class.<ref name="andersen-et-al-2020">{{cite journal |last1=Andersen |first1=Kristoffer A. A. |last2=Carhart-Harris |first2=Robin |last3=Nutt |first3=David J. |last4=Erritzoe |first4=David |title=Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies |journal=Acta Psychiatrica Scandinavica |date=2020 |volume=143 |issue=2 |pages=101–118 |doi=10.1111/acps.13249 |pmid=33125716|s2cid=226217912 }}</ref><ref name="malcolm-thomas-2022">{{cite journal |last1=Malcolm |first1=Benjamin |last2=Thomas |first2=Kelan |title=Serotonin toxicity of serotonergic psychedelics |journal=Psychopharmacology |date=2022 |volume=239 |issue=6 |pages=1881–1891 |doi=10.1007/s00213-021-05876-x |pmid=34251464|s2cid=235796130 }}</ref> It is important to check the definition of a given source.<ref name="Nichols2004" /> The present article uses the more common, narrower definition of ''psychedelic''. David E. Nichols and Charles D. Nichols have criticized the expansion of the definition of the term ''psychedelic'' and called for it to continue to refer only to serotonergic psychedelics.<ref name="NicholsHendricksNichols2023">{{cite journal | vauthors = Nichols DE, Hendricks PS, Nichols CD | title = If Everything Is Psychedelic, Then Nothing Is: A Response to O'Donnell et al. and Lepow et al | journal = Psychedelic Med (New Rochelle) | volume = 1 | issue = 4 | pages = 195–197 | date = December 2023 | pmid = 40046858 | pmc = 11665257 | doi = 10.1089/psymed.2023.29003.cdn | url = }}</ref>

===Surrounding culture=== [[File:Jefferson Airplane photo 1967.JPG|thumb|upright|Psychedelic rock band Jefferson Airplane in 1967]] {{Main|Psychedelia}}

Psychedelic culture includes manifestations such as psychedelic music,<ref name=Hicks2000>{{cite book |last1=Hicks |first1=Michael |title=Sixties Rock: Garage, Psychedelic, and Other Satisfactions |date=15 January 2000 |publisher=University of Illinois Press |location=Chicago, IL |isbn=0-252-06915-3 |pages=63–64}}</ref> psychedelic art,<ref name="krippner">{{cite journal |last1=Krippner |first1=Stanley |title=Ecstatic Landscapes: The Manifestation of Psychedelic Art |journal=Journal of Humanistic Psychology |date=2017 |volume=57 |issue=4 |pages=415–435 |doi=10.1177/0022167816671579|s2cid=151517152 }}</ref> psychedelic literature,<ref name="Dickins-2013">{{cite journal |last1=Dickins |first1=Robert |title=Preparing the Gaia connection: An ecological exposition of psychedelic literature 1954-1963 |journal=European Journal of Ecopsychology |date=2013 |volume=4 |pages=9–18 |citeseerx=10.1.1.854.6673 |url=http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.854.6673&rep=rep1&type=pdf |access-date=7 January 2021}}</ref> psychedelic film,<ref name="gallagher-2004">{{cite journal |last1=Gallagher |first1=Mark |title=Tripped Out: The Psychedelic Film and Masculinity |journal=Quarterly Review of Film and Video |date=2004 |volume=21 |issue=3 |pages=161–171 |doi=10.1080/10509200490437817|s2cid=191583864 }}</ref> and psychedelic festivals.<ref name=StJohn>St John, Graham. [https://dj.dancecult.net/index.php/dancecult/article/view/270 "Neotrance and the Psychedelic Festival."] ''Dancecult: Journal of Electronic Dance Music Culture,'' '''1'''(1) (2009).</ref> Examples of psychedelic music are found in the work of 1960s rock bands like the Grateful Dead, Jefferson Airplane, The 13th Floor Elevators, and Syd Barrett-era Pink Floyd. Many psychedelic bands and elements of the psychedelic subculture originated in San Francisco during the mid to late 1960s.<ref>{{Cite web |url=https://experiments.californiahistoricalsociety.org/what-was-the-trips-festival/|title=The Trips Festival explained|first=Adam |last=Hirschfelder|date=Jan 14, 2016|website=Experiments in Environment: The Halprin Workshops, 1966–1971}}</ref>

===Usage prevalence=== A September 2025 national survey of American adults conducted by the RAND Corporation found that the most commonly used psychedelics and related drugs (past-year use) were psilocybin (4.3%), MDMA or MDA (1.8%), ''Amanita muscaria'' (1.3%), ketamine (1.3%), LSD (1.1%), DMT (0.84%), mescaline (0.53%), 2C-B (0.46%), ''Salvia divinorum'' (0.43%), ibogaine or iboga (0.36%), and 5-MeO-DMT (0.30%).<ref name="PriestKilmerSenator2026">{{cite web | last1=Priest | first1=Michelle | last2=Kilmer | first2=Beau | last3=Senator | first3=Ben | last4=Setodji | first4=Claude Messan | title=U.S. Psychedelic Use and Microdosing in 2025: Insights from a Probability-Based and Nationally Representative Survey | website=RAND | date=21 January 2026 | url=https://www.rand.org/pubs/research_reports/RRA4334-1.html | access-date=26 April 2026 | quote=Figure 1. Past-Year Use of Psychedelic Substances by Adults in the United States [...] Table A.1. Past-Year Use of Psychedelic Substances by Adults in the United States [...]}}</ref> The survey also found that about 3.7% of adults had microdosed in the past year, with the most frequent drugs being psilocybin, MDMA, and LSD.<ref name="PriestKilmerSenator2026" />

===Legal status=== {{See also|Legal status of psilocybin mushrooms|Psilocybin decriminalization in the United States|Legal status of ayahuasca by country|Legal status of psychoactive cacti by country|Legal status of psychedelic drugs in the United States|Legal status of psychedelic drugs in the United Kingdom|Legal status of psychedelic drugs in Canada}}

Many psychedelics are classified under Schedule I of the United Nations Convention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses.<ref name="rucker-2015">{{cite journal |last1=Rucker |first1=James J. H. |title=Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential |journal=British Medical Journal |date=2015 |volume=350 |article-number=h2902 |doi=10.1136/bmj.h2902|pmid=26014506 |s2cid=46510541 }}</ref> In addition, many countries have analogue laws; for example, in the United States, the Federal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to prohibited substances if sold for human consumption.<ref>{{cite web |title=U.S.C. Title 21 – FOOD AND DRUGS |url=https://www.govinfo.gov/content/pkg/USCODE-2011-title21/html/USCODE-2011-title21-chap13.htm |website=www.govinfo.gov |access-date=28 February 2022}}</ref>

In July 2022, though, under the United States Food and Drug Administration, the drug psilocybin was on track to be approved of as a treatment for depression, and MDMA as a treatment for post-traumatic stress disorder.<ref>{{Cite journal |last=Harrington |first=Anne |date=2023-11-01 |title=Mental Health's Stalled (Biological) Revolution: Its Origins, Aftermath & Future Opportunities |url=https://direct.mit.edu/daed/article/152/4/166/118242/Mental-Health-s-Stalled-Biological-Revolution-Its |journal=Daedalus |language=en |volume=152 |issue=4 |pages=166–185 |doi=10.1162/daed_a_02037 |issn=0011-5266|doi-access=free }}</ref>

U.S. states such as Oregon and Colorado have also instituted decriminalization and legalization measures for accessing psychedelics<ref>{{cite web |title=Pot Prohibition Continues Collapsing, and Psychedelic Bans Could Be Next |url=https://reason.com/2022/11/09/pot-and-psychedelics-rack-up-wins-at-the-ballot-box/|date=November 9, 2022}}</ref> and states like New Hampshire are attempting to do the same.<ref>{{cite web |title=New Hampshire Lawmakers File Psilocybin And Broader Drug Decriminalization Bills For 2022 |url=https://www.marijuanamoment.net/new-hampshire-lawmakers-file-psilocybin-and-broader-drug-decriminalization-bills-for-2022/|date=December 29, 2021}}</ref> J.D. Tuccille argues that increasing rates of use of psychedelics in defiance of the law are likely to result in more widespread legalization and decriminalization of access to the substances in the United States (as has happened with alcohol and cannabis).<ref>{{cite web|last=Tuccille|first=J.D.|url=https://reason.com/2022/08/03/scofflaws-lead-the-way-to-legalizing-psychedelic-drugs/|title=Scofflaws Lead the Way To Legalizing Psychedelic Drugs|work=Reason|access-date=18 January 2023|date=3 August 2022}}</ref>

==Research== ===Therapeutic effects=== {{See also|Psychedelic therapy|Psilocybin#Depression|List of investigational hallucinogens and entactogens}} [[File:Johns Hopkins psilocybin session room-SessionRm 2176x.jpg|thumb|A psilocybin therapy session at Johns Hopkins.]]

Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline.<ref name="tupper-et-al">{{Cite journal|last1=Tupper|first1=Kenneth W.|last2=Wood|first2=Evan|last3=Yensen|first3=Richard|last4=Johnson|first4=Matthew W.|date=2015-10-06|title=Psychedelic medicine: a re-emerging therapeutic paradigm|journal=CMAJ: Canadian Medical Association Journal|volume=187|issue=14|pages=1054–1059|doi=10.1503/cmaj.141124|issn=0820-3946|pmc=4592297|pmid=26350908}}</ref> During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants.<ref name="tupper-et-al"/> Since then, research regarding the effectiveness of psychedelic therapy has been conducted under strict ethical guidelines, with fully informed consent and a pre-screening to avoid people with psychosis taking part.<ref name="tupper-et-al"/> Psychedelics, particularly psilocybin, show potential therapeutic benefits for depression, anxiety, and other mental disorders, with generally mild and transient adverse effects.<ref>{{Cite journal |last1=Yao |first1=Yuan |last2=Guo |first2=Dan |last3=Lu |first3=Tang-Sheng |last4=Liu |first4=Fang-Lin |last5=Huang |first5=Shi-Hao |last6=Diao |first6=Meng-Qi |last7=Li |first7=Su-Xia |last8=Zhang |first8=Xiu-Jun |last9=Kosten |first9=Thomas R |last10=Shi |first10=Jie |last11=Bao |first11=Yan-Ping |last12=Lu |first12=Lin |last13=Han |first13=Ying |date=2024-05-01 |title=Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis |url=https://www.sciencedirect.com/science/article/pii/S0165178124001719 |journal=Psychiatry Research |volume=335 |article-number=115886 |doi=10.1016/j.psychres.2024.115886 |pmid=38574699 |issn=0165-1781}}</ref>

It has long been known that psychedelics promote neurite growth and neuroplasticity and are potent psychoplastogens.<ref>{{cite journal|last1=Jones|first1=K.A.|last2=Srivastave|first2=D.P.|last3=Allen|first3=J.A.|last4=Roth|first4=B.L.|last5=Penzes|first5=P.|title=Psychedelics Promote Structural and Functional Neural Plasticity|journal=Proc Natl Acad Sci U S A|date= 2009|volume=106|issue=46|pages=19575–19580|doi=10.1073/pnas.0905884106|pmid=19889983|pmc=2780750|bibcode=2009PNAS..10619575J |doi-access=free}}</ref><ref>{{cite journal|last1=Yoshida|first1=H.|last2=Kanamaru|first2=C.|last3=Ohtani|first3=A.|last4=Senzaki|first4=K.|last5=Shiga|first5=T.|title=Subtype specific roles of serotonin receptors in the spine formation of cortical neurons in vitro|journal=Neurosci Res.|date=2011|volume=71|issue=3|pages=311–314|doi=10.1016/j.neures.2011.07.1824|pmid=21802453|hdl=2241/114624|s2cid=14178672|url=https://tsukuba.repo.nii.ac.jp/record/25719/files/NR_71-3.pdf |hdl-access=free}}</ref><ref>{{cite journal|last1=Ly|first1=Calvin|last2=Greb|first2=Alexandra C.|last3=Cameron|first3=Lindsay P.|last4=Wong|first4=Jonathan M.|last5=Barragan|first5=Eden V.|last6=Wilson|first6=Paige C.|last7=Burbach|first7=Kyle F.|last8=Soltanzadeh Zarandi|first8=Sina|last9=Sood|first9=Alexander|last10=Paddy|first10=Michael R.|last11=Duim|first11=Whitney C.|last12=Dennis|first12=Megan Y.|last13=McAllister |first13=A. Kimberley|last14=Ori-McKenney|first14=Kassandra M.|last15=Gray|first15=John A.|last16=Olson|first16=David E.|title=Psychedelics Promote Structural and Functional Neural Plasticity|journal=Cell Reports|date=June 2018|volume=23|issue=11|pages=3170–3182 |doi=10.1016/j.celrep.2018.05.022|pmid=29898390|pmc=6082376|doi-access=free}}</ref> There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits.<ref>{{Cite journal|last1=de Vos|first1=Cato M. H.|last2=Mason|first2=Natasha L.|last3=Kuypers|first3=Kim P. C.|date=2021|title=Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics|journal=Frontiers in Psychiatry|volume=12|page=1575|article-number=724606 |doi=10.3389/fpsyt.2021.724606|pmid=34566723|pmc=8461007|issn=1664-0640|doi-access=free}}</ref><ref>{{Cite journal |last1=Calder |first1=Abigail E. |last2=Hasler |first2=Gregor |date=2022-09-19 |title=Towards an understanding of psychedelic-induced neuroplasticity |journal=Neuropsychopharmacology |volume=48 |issue=1 |language=en |pages=104–112 |doi=10.1038/s41386-022-01389-z |pmid=36123427 |pmc=9700802 |s2cid=252381170 |issn=1740-634X|doi-access=free }}</ref>

The British critical psychiatrist Joanna Moncrieff has critiqued the use and study of psychedelic and related drugs like psilocybin, MDMA, and ketamine for treatment of psychiatric disorders.<ref name="Moncrieff2025" /> She has highlighted concerns including excessive hype around these drugs, questionable biologically-based theories of benefit, blurred lines between medical and recreational use, flawed clinical trial findings, financial conflicts of interest, strong expectancy effects and large placebo responses, small and short-term benefits over placebo, and their potential for difficult experiences and adverse effects.<ref name="Moncrieff2025">{{cite book | last=Moncrieff | first=Joanna | chapter=Alternative Approaches: The Good, the Bad and the Worrying: Psychedelics for Depression | title=Chemically Imbalanced: The Making and Unmaking of the Serotonin Myth | publisher=Flint | date=16 January 2025 | isbn=978-1-80399-680-6 | url=https://books.google.com/books?id=e0MkEQAAQBAJ | access-date=16 October 2025 | page=}}</ref>

==References== {{Reflist|30em}}

==Further reading== * {{cite book |last1=Dyck |first1=Erika |last2=Elcock |first2=Chris |title=Expanding Mindscapes: A Global History of Psychedelics |date=2023 |publisher=MIT Press |isbn=978-0-262-37689-1 |url=https://direct.mit.edu/books/oa-edited-volume/5697/Expanding-MindscapesA-Global-History-of}} * {{Cite book|title=Behavioral Neurobiology of Psychedelic Drugs|date=2018|publisher=Springer|isbn=978-3-662-55878-2|editor-first=Adam L.|editor-last=Halberstadt |editor2=Franz X. Vollenweider |editor3=David E. Nichols |volume=36|location=Berlin, Heidelberg}} * {{cite book |last1=Jay |first1=Mike |title=Mescaline: A Global History of the First Psychedelic |date=2019 |publisher=Yale University Press |location=New Haven, CT |doi=10.2307/j.ctvgc61q9 |isbn=978-0-300-25750-2|s2cid=241952235 }} * {{cite book |last1=Letheby |first1=Chris |title=Philosophy of Psychedelics |date=2021 |publisher=Oxford University Press |location=Oxford |isbn=978-0-19-884312-2|doi=10.1093/med/9780198843122.001.0001}} * {{cite book |last=Richards |first=William A. |title=Sacred Knowledge: Psychedelics and Religious Experiences |date=2016 |publisher=Columbia University Press |location=New York |isbn=978-0-231-54091-9}} * {{cite book |last=Siff |first=Stephen |title=Acid Hype: American News Media and the Psychedelic Experience |date=2015 |publisher=University of Illinois Press |location=Champaign, Illinois |isbn=978-0-252-09723-2}} * Winstock, Ar; Timmerman, C; Davies, E; Maier, Lj; Zhuparris, A; Ferris, Ja; Barratt, Mj; Kuypers, Kpc (2021). ''[https://www.globaldrugsurvey.com/wp-content/uploads/2021/03/GDS2020-Psychedelics-report.pdf Global Drug Survey (GDS) 2020 Psychedelics Key Findings Report]''.

==External links== {{Commons category|Psychedelics}} {{Wiktionary|psychedelic}} * [https://psychedelictimes.com/psychedelic-timeline/ Psychedelic Timeline - Tom Frame - Psychedelic Times] * [https://pageviews.wmcloud.org/massviews/?platform=all-access&agent=user&source=category&range=latest-365&subjectpage=0&subcategories=1&sort=views&direction=1&view=list&target=https://en.wikipedia.org/wiki/Category:Psychedelic_drugs Psychedelic Drugs - Wikipedia Massviews Analysis (Wikipedia Page Views of Individual Psychedelics)]

{{Psychedelics}} {{Major Drug Groups}} {{Drug use}} {{Serotonin receptor modulators}} {{Chemical classes of psychoactive drugs}}

Category:5-HT2A agonists Category:Hallucinations Category:Psychedelic drugs Category:Psychoplastogens