View source for Tryptamine

{{Short description|Metabolite of the amino acid tryptophan}}
{{About|the specific substance|the class of substances|substituted tryptamine}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| drug_name = 
| image = Tryptamine structure.svg
| image_class = skin-invert-image
| width = 225px
| image2 = Tryptamine molecule from xtal ball.png
| image_class2 = bg-transparent
| width2 = 175px

<!-- Clinical data -->
| pronounce = 
| tradename = 
| Drugs.com = 
| MedlinePlus = 
| licence_CA = 
| licence_EU = 
| DailyMedID = 
| licence_US = 
| pregnancy_AU = 
| pregnancy_category = 
| dependency_liability = 
| addiction_liability = 
| routes_of_administration = [[Intravenous injection]]<ref name="Martin_1977" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />
| class = [[Serotonin receptor agonist]]; [[Trace amine-associated receptor 1]] (TAAR1) [[agonist]]; [[Serotonin–norepinephrine–dopamine releasing agent]]; [[Serotonergic psychedelic]]; [[Hallucinogen]]
| ATC_prefix = None
| ATC_suffix = 

<!-- Legal status -->
| legal_status = Legal or unregulated

<!-- Pharmacokinetic data -->
| bioavailability = [[Oral administration|Oral]]: Very low
| protein_bound = 
| metabolism = Very rapid ([[oxidative deamination]] by {{Abbrlink|MAO|monoamine oxidase}})<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />
| metabolites = [[Indole-3-acetic acid]] (IAA)
| onset = {{Abbrlink|IV|Intravenous injection}}: Very rapid<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />
| elimination_half-life = Very short<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />
| duration_of_action = {{Abbrlink|IV|Intravenous injection}}: Very short<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />
| excretion = [[Urine]]<ref name="Martin_1970" /><ref name="Franzen_1965" /><ref name="Price_1975" />

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 61-54-1
| CAS_supplemental = 
| PubChem = 1150
| PubChemSubstance = 
| IUPHAR_ligand = 125
| DrugBank = DB08653
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1118
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 422ZU9N5TV
| KEGG = C00398
| ChEBI = 16765
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 6640
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = T; Triptamine; 3-(2-Aminoethyl)indole; 2-(3-Indolyl)ethylamine; Indolylethylamine; Indolethylamine; PAL-235; PAL235

<!-- Chemical data -->
| IUPAC_name = 2-(1''H''-indol-3-yl)ethan-1-amine
| C=10 | H=12 | N=2
| SMILES = c1ccc2c(c1)c(c[nH]2)CCN
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H12N2/c11-6-5-8-7-12-10-4-2-1-3-9(8)10/h1-4,7,12H,5-6,11H2
| StdInChIKey_Ref = {{stdinchicite|correc|chemspider}}
| StdInChIKey = APJYDQYYACXCRM-UHFFFAOYSA-N

<!-- Physical data -->
| melting_point = 118
| melting_notes = <ref name="CRC2005">{{cite book | veditors = Lide DR | title = CRC Handbook of Chemistry and Physics | pages = 3–564 | date = 2005 | edition = 85th | publisher = [[CRC Press]] | isbn = 978-0-8493-0484-2 }}</ref>
| boiling_point = 137
| boiling_notes = (0.15 mmHg)<ref name="CRC2005" />
| solubility = Negligible
}}

'''Tryptamine''', also known as '''2-(3-indolyl)ethylamine''', is an [[indolamines|indolamine]] [[metabolite]] of the [[essential amino acid]] [[tryptophan]].<ref name="NML">{{Cite web | title = Tryptamine | url = https://pubchem.ncbi.nlm.nih.gov/compound/1150 | access-date = 2020-12-01 | website = pubchem.ncbi.nlm.nih.gov }}</ref><ref name="Jenkins_2016">{{cite journal | vauthors = Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP | title = Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis | journal = Nutrients | volume = 8 | issue = 1 | pages = 56 | date = January 2016 | pmid = 26805875 | pmc = 4728667 | doi = 10.3390/nu8010056 | doi-access = free }}</ref> The chemical structure is defined by an [[indole]]—a fused [[benzene]] and [[pyrrole]] ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the [[heterocyclic]] nitrogen).<ref name="NML" /> The structure of tryptamine is a shared feature of certain aminergic [[Neuromodulation|neuromodulators]] including [[melatonin]], [[serotonin]], [[bufotenin]] and psychedelic derivatives such as [[N,N-Dimethyltryptamine|dimethyltryptamine]] (DMT), [[psilocybin]], [[psilocin]] and [[List of naturally occurring tryptamines|others]].<ref name="Tyls_2014">{{cite journal | vauthors = Tylš F, Páleníček T, Horáček J | title = Psilocybin--summary of knowledge and new perspectives | journal = European Neuropsychopharmacology | volume = 24 | issue = 3 | pages = 342–356 | date = March 2014 | pmid = 24444771 | doi = 10.1016/j.euroneuro.2013.12.006 | s2cid = 10758314 }}</ref><ref name="Tittarelli_2015">{{cite journal | vauthors = Tittarelli R, Mannocchi G, Pantano F, Romolo FS | title = Recreational use, analysis and toxicity of tryptamines | journal = Current Neuropharmacology | volume = 13 | issue = 1 | pages = 26–46 | date = January 2015 | pmid = 26074742 | pmc = 4462041 | doi = 10.2174/1570159X13666141210222409 }}</ref><ref name="cite2264771f">{{Cite web | title = The Ayahuasca Phenomenon | date = 21 November 2014 | url = https://maps.org/articles/5408-the-ayahuasca-phenomenon | access-date = 2020-10-03 | website = MAPS | language = en-gb }}</ref>

Tryptamine has been shown to activate [[serotonin receptor]]s<ref name="Blough_2014a" /><ref name="Mousseau_1993" /> and [[trace amine-associated receptor]]s expressed in the mammalian brain, and regulates the activity of [[Dopaminergic pathways|dopaminergic]], [[Serotonin pathway|serotonergic]] and [[Glutamic acid|glutamatergic]] systems.<ref name="Khan_2016">{{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal = Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie | volume = 83 | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 }}</ref><ref name="Berry_2017">{{cite journal | vauthors = Berry MD, Gainetdinov RR, Hoener MC, Shahid M | title = Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges | journal = Pharmacology & Therapeutics | volume = 180 | pages = 161–180 | date = December 2017 | pmid = 28723415 | doi = 10.1016/j.pharmthera.2017.07.002 | s2cid = 207366162 | doi-access = free }}</ref> In the human gut, bacteria convert dietary tryptophan to tryptamine, which activates [[5-HT4 receptor|5-HT<sub>4</sub>]] receptors and regulates gastrointestinal motility.<ref name="Jenkins_2016" /><ref name="Bhattarai_2018">{{cite journal | vauthors = Bhattarai Y, Williams BB, Battaglioli EJ, Whitaker WR, Till L, Grover M, Linden DR, Akiba Y, Kandimalla KK, Zachos NC, Kaunitz JD, Sonnenburg JL, Fischbach MA, Farrugia G, Kashyap PC | title = Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion | journal = Cell Host & Microbe | volume = 23 | issue = 6 | pages = 775–785.e5 | date = June 2018 | pmid = 29902441 | pmc = 6055526 | doi = 10.1016/j.chom.2018.05.004 }}</ref><ref name="Field_2003">{{cite journal | vauthors = Field M | title = Intestinal ion transport and the pathophysiology of diarrhea | journal = The Journal of Clinical Investigation | volume = 111 | issue = 7 | pages = 931–943 | date = April 2003 | pmid = 12671039 | pmc = 152597 | doi = 10.1172/JCI200318326 }}</ref>

Multiple tryptamine-derived drugs have been developed to treat [[migraine]]s, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders.<ref name="cite3c3145a8">{{cite book | chapter = Serotonin Receptor Agonists (Triptans) |date=2012 | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK548713/| title = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|place=Bethesda (MD)|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31644023|access-date=2020-10-15}}</ref><ref name="citecf2c9efd">{{Cite web | title = New Compound Related to Psychedelic Ibogaine Could Treat Addiction, Depression | date = 2020-12-09 | url = https://www.ucdavis.edu/news/new-compound-related-psychedelic-ibogaine-could-treat-addiction-depression | access-date = 2020-12-11 | website = UC Davis | language = EN }}</ref><ref name="cite10eeb722">{{Cite web | vauthors = Service RF | title = Chemists re-engineer a psychedelic to treat depression and addiction in rodents | url = https://www.science.org/content/article/chemists-re-engineer-psychedelic-treat-depression-and-addiction-rodents | access-date = 2020-12-11 | website = Science Magazine | publisher = AAAS |language=en}}</ref>

== Natural occurrences ==
''For a list of plants, fungi and animals containing tryptamines, see [[List of psychoactive plants]] and [[List of naturally occurring tryptamines]].''

=== Mammalian brain ===
Endogenous levels of tryptamine in the mammalian brain are less than 100&nbsp;ng per gram of tissue.<ref name="Tittarelli_2015" /><ref name="Berry_2017" /> However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as [[Bipolar disorder|bipolar depression]] and [[schizophrenia]].<ref name="Miller_2011">{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–176 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref>

=== Mammalian gut microbiome ===
Tryptamine is relatively abundant in the [[digestive system|gut]] and feces of humans and rodents.<ref name="Jenkins_2016" /><ref name="Bhattarai_2018" /> [[Commensalism|Commensal]] bacteria, including ''Ruminococcus gnavus'' and ''[[Clostridium sporogenes]]'' in the [[gastrointestinal tract]], possess the [[enzyme]] tryptophan [[Decarboxylation|decarboxylase]], which aids in the conversion of dietary tryptophan to tryptamine.<ref name="Jenkins_2016" /> Tryptamine is a [[ligand]] for gut epithelial serotonin type 4 (5-HT<sub>4</sub>) receptors and regulates gastrointestinal [[electrolyte]] balance through colonic secretions.<ref name="Bhattarai_2018" />

== Metabolism ==

=== Biosynthesis ===
To yield tryptamine ''in vivo'', tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of [[tryptophan]].<ref name="Tittarelli_2015" /> Synthetic modifications to tryptamine can produce [[serotonin]] and [[melatonin]]; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.<ref>{{Cite web | title = Serotonin Synthesis and Metabolism | date = 2020 | url = https://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/serotonin-synthesis-and-metabolism.html | website = Sigma Aldrich }}</ref>

=== Catabolism ===
[[Monoamine oxidase]]s A and B are the primary enzymes involved in tryptamine metabolism to produce [[indole-3-acetaldehyde]], however it is unclear which isoform is specific to tryptamine degradation.<ref>{{Cite web | title = MetaCyc L-tryptophan degradation VI (via tryptamine) | url = https://biocyc.org/META/new-image?object=PWY-3181 | access-date = 2020-12-11 | website = biocyc.org }}</ref>

=== Figure ===
[[File:Biosynthesis and degradation of tryptamine.png|class=skin-invert-image|thumb|none|600px|Conversion of tryptophan to tryptamine, followed by its degradation to indole-3-acetaldehyde.]]

== Biological activity ==
{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|Tryptamine target activities}}
|-
! [[Biological target|Target]] !! [[Affinity (pharmacology)|Affinity]] (K<sub>i</sub>, nM) !! Species
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 32–105 (K<sub>i</sub>)<br />899–>10,000 ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}})<br />{{Abbr|ND|No data}} ({{Abbrlink|E<sub>max</sub>|maximal efficacy}}) || Human<br />Human<br />Human
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 36–525 || Human
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 23–521 || Human
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 2,559 || Human
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || 2,409 || Human
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 37–4,070 (K<sub>i</sub>)<br />7.4–257 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />71–104% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) || Human<br />Human<br />Human
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 25–113 (K<sub>i</sub>)<br />29.5 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />92% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) || Human<br />Human<br />Human
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 17–3,000 (K<sub>i</sub>)<br />1.17–45.7 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />85–108% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) || Human<br />Human<br />Human
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || >10,000<br />13,500 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />96% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) || Mouse<br />Pig<br />Pig
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || {{Abbr|ND|No data}} || {{Abbr|ND|No data}}
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 70–438 || Human
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 148–158 || Human
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 19,000 || Rat
|-
| {{Abbrlink|TAAR1|Human trace amine-associated receptor 1}} || 1,400 (K<sub>i</sub>)<br />2,700 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />117% ({{Abbr|E<sub>max</sub>|maximal efficacy}})<br />130 (K<sub>i</sub>)<br />410 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />91% ({{Abbr|E<sub>max</sub>|maximal efficacy}})<br />1,084 (K<sub>i</sub>)<br />2,210–21,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />73% ({{Abbr|E<sub>max</sub>|maximal efficacy}}) || Mouse<br />Mouse<br />Mouse<br />Rat<br />Rat<br />Rat<br />Human<br />Human<br />Human
|-
| {{Abbrlink|SERT|Serotonin transporter}} || 32.6 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) <sup>a</sup> || Rat
|-
| {{Abbrlink|NET|Norepinephrine transporter}} || 716 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) <sup>a</sup> || Rat
|-
| {{Abbrlink|DAT|Dopamine transporter}} || 164 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) <sup>a</sup> || Rat
|-
| colspan="3" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Note:''' The smaller the value, the more avidly the compound binds to or activates the site. '''Footnotes:''' <sup>a</sup> = [[Monoamine releasing agent|Neurotransmitter release]]. '''Refs:''' ''Main:''<ref name="PDSPKiDatabase">{{cite web | title = PDSP Database | website = UNC | url = https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=Tryptamine&kiAllRadio=all&doQuery=Submit+Query | language = zu | access-date = 7 November 2024 }}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title = BindingDB BDBM50024210 1H-indole-3-ethanamine::2-(1H-indol-3-yl)ethanamine::2-(3-indolyl)ethylamine::CHEMBL6640::tryptamine | website = BindingDB | url = https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50024210 | access-date = 7 November 2024 }}</ref> ''Additional:''<ref name="ToroSazo_2019">{{cite journal | vauthors = Toro-Sazo M, Brea J, Loza MI, Cimadevila M, Cassels BK | title = 5-HT2 receptor binding, functional activity and selectivity in N-benzyltryptamines | journal = PLOS ONE | volume = 14 | issue = 1 | date = 2019 | pmid = 30629611 | pmc = 6328172 | doi = 10.1371/journal.pone.0209804 | bibcode = 2019PLoSO..1409804T | doi-access = free | article-number = e0209804 }}</ref><ref name="Gainetdinov_2018" /><ref name="Simmler_2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 9 May 2025 }}</ref><ref name="Blough_2014a" /><ref name="Blough_2014" /><ref name="Porter_1999">{{cite journal | vauthors = Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ | title = Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells | journal = British Journal of Pharmacology | volume = 128 | issue = 1 | pages = 13–20 | date = September 1999 | pmid = 10498829 | pmc = 1571597 | doi = 10.1038/sj.bjp.0702751 }}</ref><ref name="van_Wijngaarden_1997">{{cite book | vauthors = van Wijngaarden I, Soudijn W | chapter = 5-HT2A, 5-HT2B and 5-HT2C receptor ligands | title = Pharmacochemistry Library | volume = 27 | pages = 161–197 | date = 1997 | doi = 10.1016/s0165-7208(97)80013-x | publisher = Elsevier | isbn = 978-0-444-82041-9 }}</ref><ref name="Chen_2023">{{cite journal | vauthors = Chen X, Li J, Yu L, Maule F, Chang L, Gallant JA, Press DJ, Raithatha SA, Hagel JM, Facchini PJ | title = A cane toad (Rhinella marina) N-methyltransferase converts primary indolethylamines to tertiary psychedelic amines | journal = The Journal of Biological Chemistry | volume = 299 | issue = 10 | date = October 2023 | pmid = 37690691 | pmc = 10570959 | doi = 10.1016/j.jbc.2023.105231 | doi-access = free | article-number = 105231 }}</ref><ref name="Chen_2023a">{{cite journal | vauthors = Chen X, Li J, Yu L, Dhananjaya D, Maule F, Cook S, Chang L, Gallant J, Press D, Bains JS, Raithatha S | title=Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery| journal = Research Square | date=10 March 2023 | doi=10.21203/rs.3.rs-2667175/v1 | doi-access=free | url=https://www.researchsquare.com/article/rs-2667175/latest.pdf | access-date=18 March 2025 | page=}}</ref><ref name="Egan_2000">{{cite journal | vauthors = Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K | title = Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors | journal = Synapse | volume = 35 | issue = 2 | pages = 144–150 | date = February 2000 | pmid = 10611640 | doi = 10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K }}</ref><ref name="Medhurst_1993">{{cite journal | vauthors = Medhurst AD, Kaumann AJ | title = Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium | journal = British Journal of Pharmacology | volume = 110 | issue = 3 | pages = 1023–1030 | date = November 1993 | pmid = 8298790 | pmc = 2175817 | doi = 10.1111/j.1476-5381.1993.tb13916.x }}</ref>
|}

=== Serotonin receptor agonist ===
Tryptamine is known to act as a [[serotonin receptor]] [[agonist]], although its [[potency (pharmacology)|potency]] is limited by rapid [[catabolism|inactivation]] by [[monoamine oxidase]]s.<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Mousseau_1993">{{cite journal | vauthors = Mousseau DD | title = Tryptamine: a metabolite of tryptophan implicated in various neuropsychiatric disorders | journal = Metabolic Brain Disease | volume = 8 | issue = 1 | pages = 1–44 | date = March 1993 | pmid = 8098507 | doi = 10.1007/BF01000528 }}</ref><ref name="Anwar_2012">{{cite journal | vauthors = Anwar MA, Ford WR, Broadley KJ, Herbert AA | title = Vasoconstrictor and vasodilator responses to tryptamine of rat-isolated perfused mesentery: comparison with tyramine and β-phenylethylamine | journal = British Journal of Pharmacology | volume = 165 | issue = 7 | pages = 2191–2202 | date = April 2012 | pmid = 21958009 | pmc = 3413856 | doi = 10.1111/j.1476-5381.2011.01706.x }}</ref><ref name="Bradley_1985">{{cite journal | vauthors = Bradley PB, Humphrey PP, Williams RH | title = Tryptamine-induced vasoconstrictor responses in rat caudal arteries are mediated predominantly via 5-hydroxytryptamine receptors | journal = British Journal of Pharmacology | volume = 84 | issue = 4 | pages = 919–925 | date = April 1985 | pmid = 3159458 | pmc = 1987057 | doi = 10.1111/j.1476-5381.1985.tb17386.x }}</ref><ref name="Glennon_1987">{{cite journal | vauthors = Glennon RA | title = Central serotonin receptors as targets for drug research | journal = Journal of Medicinal Chemistry | volume = 30 | issue = 1 | pages = 1–12 | date = January 1987 | pmid = 3543362 | doi = 10.1021/jm00384a001 | quote = Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites }}</ref> It has specifically been found to act as a [[full agonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}} = 7.36 ± 0.56{{nbsp}}nM; [[intrinsic activity|E<sub>max</sub>]] = 104 ± 4%).<ref name="Blough_2014a" /> Tryptamine was of much lower potency in stimulating the 5-HT<sub>2A</sub> receptor [[β-arrestin]] pathway ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}} = 3,485 ± 234{{nbsp}}nM; E<sub>max</sub> = 108 ± 16%).<ref name="Blough_2014a" /> In contrast to the 5-HT<sub>2A</sub> receptor, tryptamine was found to be inactive at the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]].<ref name="Blough_2014a" />

==== Gastrointestinal motility ====
Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.<ref name="Bhattarai_2018" /> Upon tryptamine binding, the activated 5-HT<sub>4</sub> receptor undergoes a conformational change which allows its [[Gs alpha subunit|G<sub>s</sub> alpha subunit]] to exchange [[Guanosine diphosphate|GDP]] for [[Guanosine triphosphate|GTP]], and its liberation from the 5-HT<sub>4</sub> receptor and βγ subunit.<ref name="Bhattarai_2018" /> GTP-bound G<sub>s</sub> activates [[adenylyl cyclase]], which catalyzes the conversion of [[Adenosine triphosphate|ATP]] into [[cyclic adenosine monophosphate]] (cAMP).<ref name="Bhattarai_2018" /> cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.<ref name="Field_2003" /><ref>{{Cite web | title = Microbiome-Lax May Relieve Constipation | date = 2018-06-15 | url = https://www.genengnews.com/topics/omics/microbiome-lax-may-relieve-constipation/ | access-date = 2020-12-11 | website = GEN - Genetic Engineering and Biotechnology News | language = en-US }}</ref>

[[File:Tryptamine_mechanism_of_action_in_the_human_gut.png|thumb|none|550px|class=skin-invert-image|Tryptamine promotes intestinal motility by activating serotonin receptors in the gut to increase colonic secretions.]]

=== Monoamine releasing agent ===
Tryptamine has been found to act as a [[monoamine releasing agent]] (MRA).<ref name="Jones_1982">{{cite journal | vauthors = Jones RS | title = Tryptamine: a neuromodulator or neurotransmitter in mammalian brain? | journal = Progress in Neurobiology | volume = 19 | issue = 1–2 | pages = 117–139 | date = 1982 | pmid = 6131482 | doi = 10.1016/0301-0082(82)90023-5 }}</ref><ref name="Blough_2014a" /><ref name="Blough_2014">{{cite journal | vauthors = Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB | title = Alpha-ethyltryptamines as dual dopamine-serotonin releasers | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 19 | pages = 4754–4758 | date = October 2014 | pmid = 25193229 | pmc = 4211607 | doi = 10.1016/j.bmcl.2014.07.062 }}</ref> It is a releaser of [[serotonin]], [[dopamine]], and [[norepinephrine]], in that order of potency ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}} = 32.6{{nbsp}}nM, 164{{nbsp}}nM, and 716{{nbsp}}nM, respectively).<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Blough_2014" /> That is, it acts as a [[serotonin–norepinephrine–dopamine releasing agent]] (SNDRA).<ref name="Blough_2014a" /><ref name="Blough_2014" />

{| class="wikitable" style="font-size:small;"
|+ {{Nowrap|Monoamine release of tryptamine and related agents ({{Abbrlink|EC<sub>50</sub>|Half maximal effective concentration}}, nM)}}
|-
! Compound !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! Ref
|-
| Tryptamine || 32.6 || 716 || 164 || <ref name="Blough_2014a" /><ref name="Blough_2014" />
|-
| [[Serotonin]] || 44.4 || >10,000 || ≥1,960 || <ref name="Rothman_2001" /><ref name="Blough_2008" />
|-
| [[Phenethylamine]] || >10,000 || 10.9 || 39.5 || <ref name="Reith_2015">{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug and Alcohol Dependence | volume = 147 | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 }}</ref><ref name="Forsyth_2012">{{cite web | vauthors = Forsyth AN | title = Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | date = 22 May 2012 | website = ScholarWorks@UNO | url = https://scholarworks.uno.edu/td/1436/ | access-date = 4 November 2024 }}</ref><ref name="Blough_2008">{{cite book | vauthors = Blough B | veditors = Trudell ML, Izenwasser S | chapter = Dopamine-releasing agents | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | location = Hoboken [NJ] | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}</ref>
|-
| [[Tyramine]] || 2,775 || 40.6 || 119 || <ref name="Rothman_2001" /><ref name="Blough_2008" />
|-
| [[5-Methoxytryptamine]] || 2,169 || >10,000 || >10,000 || <ref name="Blough_2014" />
|-
| [[N-Methyltryptamine|''N''-Methyltryptamine]] || 22.4 || 733 || 321 || <ref name="Blough_2014a" />
|-
| [[Dimethyltryptamine]] || 114 || 4,166 || >10,000 || <ref name="Blough_2014a" />
|-
| [[Psilocin]] || 561 || >10,000 || >10,000 || <ref name="Rothman_2012">{{cite journal | vauthors = Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE | title = Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 341 | issue = 1 | pages = 251–262 | date = April 2012 | pmid = 22271821 | pmc = 3364510 | doi = 10.1124/jpet.111.188946 }}</ref><ref name="Blough_2014a" />
|-
| [[Bufotenin]] || 30.5 || >10,000 || >10,000 || <ref name="Blough_2014a" />
|-
| [[5-MeO-DMT]] || >10,000 || >10,000 || >10,000 || <ref name="Nagai_2007" />
|-
| [[α-Methyltryptamine]] || 21.7–68 || 79–112 || 78.6–180 || <ref name="Nagai_2007">{{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 = European Journal of Pharmacology | volume = 559 | issue = 2–3 | pages = 132–137 | date = March 2007 | pmid = 17223101 | doi = 10.1016/j.ejphar.2006.11.075 }}</ref>
|-
| [[α-Ethyltryptamine]] || 23.2 || 640 || 232 || <ref name="Blough_2014" />
|-
| [[Dextroamphetamine|{{Small|D}}-Amphetamine]] || 698–1,765 || 6.6–7.2 || 5.8–24.8 || <ref name="Rothman_2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 }}</ref><ref name="Baumann_2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | date = March 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref>
|-
| colspan="7" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the drug releases the neurotransmitter. The [[bioassay|assay]]s were done in rat brain [[synaptosome]]s and human [[potency (pharmacology)|potencies]] may be different. See also [[Monoamine releasing agent#Activity profiles|Monoamine releasing agent § Activity profiles]] for a larger table with more compounds. '''Refs:'''<ref name="Rothman_2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}</ref><ref name="Rothman_2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | year = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}</ref>
|}

=== Monoaminergic activity enhancer ===
Tryptamine is a [[monoaminergic activity enhancer]] (MAE) of [[serotonin]], [[norepinephrine]], and [[dopamine]] in addition to its [[serotonin receptor]] [[agonism]].<ref name="Shimazu_2004">{{cite journal | vauthors = Shimazu S, Miklya I | title = Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 28 | issue = 3 | pages = 421–427 | date = May 2004 | pmid = 15093948 | doi = 10.1016/j.pnpbp.2003.11.016 | s2cid = 37564231 }}</ref><ref name="Knoll_2003">{{cite journal | vauthors = Knoll J | title = Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives | journal = Neurochemical Research | volume = 28 | issue = 8 | pages = 1275–1297 | date = August 2003 | pmid = 12834268 | doi = 10.1023/a:1024224311289 }}</ref> That is, it enhances the [[action potential]]-mediated release of these [[monoamine neurotransmitter]]s.<ref name="Shimazu_2004" /><ref name="Knoll_2003" /> The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism.<ref name="Harsing_2022">{{cite journal | vauthors = Harsing LG, Knoll J, Miklya I | title = Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum | journal = International Journal of Molecular Sciences | volume = 23 | issue = 15 | pages = 8543 | date = August 2022 | pmid = 35955676 | pmc = 9369307 | doi = 10.3390/ijms23158543 | doi-access = free }}</ref><ref name="Harsing_2023">{{cite journal | vauthors = Harsing LG, Timar J, Miklya I | title = Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline | journal = International Journal of Molecular Sciences | volume = 24 | issue = 17 | date = August 2023 | pmid = 37686140 | pmc = 10487936 | doi = 10.3390/ijms241713334 | doi-access = free | article-number = 13334 }}</ref> [[Synthetic compound|Synthetic]] and more [[potency (pharmacology)|potent]] MAEs like [[benzofuranylpropylaminopentane]] (BPAP) and [[indolylpropylaminopentane]] (IPAP) have been [[chemical derivative|derived]] from tryptamine.<ref name="Shimazu_2004" /><ref name="Knoll_2003" /><ref name="Knoll_2001">{{cite journal | vauthors = Knoll J | title = Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain | journal = CNS Drug Reviews | volume = 7 | issue = 3 | pages = 317–345 | date = 2001 | pmid = 11607046 | pmc = 6494119 | doi = 10.1111/j.1527-3458.2001.tb00202.x }}</ref><ref name="Yoneda_2001">{{cite journal | vauthors = Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J | title = Structure-activity studies leading to (-)1-(benzofuran-2-yl)-2-propylaminopentane, ((-)BPAP), a highly potent, selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain | journal = Bioorganic & Medicinal Chemistry | volume = 9 | issue = 5 | pages = 1197–1212 | date = May 2001 | pmid = 11377178 | doi = 10.1016/s0968-0896(01)00002-5 }}</ref><ref name="Knoll_1999">{{cite journal | vauthors = Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I | title = (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain | journal = British Journal of Pharmacology | volume = 128 | issue = 8 | pages = 1723–1732 | date = December 1999 | pmid = 10588928 | pmc = 1571822 | doi = 10.1038/sj.bjp.0702995 }}</ref>

=== TAAR1 agonist ===
Tryptamine is an agonist of the [[trace amine-associated receptor 1]] (TAAR1).<ref name="Gainetdinov_2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacological Reviews | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | s2cid = 49411553 | doi-access = free }}</ref> It is a [[potency (pharmacology)|potent]] TAAR1 [[full agonist]] in rats, a weak TAAR1 full agonist in mice, and a very weak TAAR1 [[partial agonist]] in humans.<ref name="Gainetdinov_2018" /> Tryptamine may act as a trace [[neuromodulator]] in some species via activation of TAAR1 signaling.<ref name="Gainetdinov_2018" /><ref name="Zucchi_2006">{{cite journal | vauthors = Zucchi R, Chiellini G, Scanlan TS, Grandy DK | title = Trace amine-associated receptors and their ligands | journal = British Journal of Pharmacology | volume = 149 | issue = 8 | pages = 967–978 | date = December 2006 | pmid = 17088868 | pmc = 2014643 | doi = 10.1038/sj.bjp.0706948 }}</ref>

The TAAR1 is a stimulatory [[G protein-coupled receptor]] (GPCR) that is weakly [[gene expression|expressed]] in the [[intracellular]] compartment of both [[presynaptic|pre-]] and [[postsynaptic]] neurons.<ref name="Berry_2017" /> TAAR1 agonists have been implicated in regulating [[monoaminergic]] [[neurotransmission]], for instance by activating [[G protein-coupled inwardly-rectifying potassium channel]]s (GIRKs) and reducing [[action potential|neuronal firing]] via facilitation of [[hyperpolarization (biology)|membrane hyperpolarization]] through the [[efflux (microbiology)|efflux]] of [[potassium ion]]s.<ref name="Gainetdinov_2018" /><ref name="Grandy_2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug and Alcohol Dependence | volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | pmc = 4724540 | doi = 10.1016/j.drugalcdep.2015.11.014 }}</ref>

TAAR1 agonists are under investigation as a novel treatment for [[neuropsychiatric condition]]s like [[schizophrenia]], [[drug addiction]], and [[depression (mood)|depression]].<ref name="Berry_2017" /> The TAAR1 is expressed in brain structures associated with dopamine systems, such as the [[ventral tegmental area]] (VTA) and serotonin systems in the [[Dorsal raphe nucleus|dorsal raphe nuclei]] (DRN).<ref name="Berry_2017" /> Additionally, the human TAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility [[Locus (genetics)|locus]] for [[mood disorder]]s and schizophrenia.<ref name="Gainetdinov_2018" /> Activation of TAAR1 suggests a potential novel treatment for [[neuropsychiatric disorder]]s, as TAAR1 agonists produce [[antipsychotic]]-like, [[antiaddictive|anti-addictive]], and [[antidepressant]]-like effects in animals.<ref name="Grandy_2016" /><ref name="Gainetdinov_2018" />

{| class="wikitable" style="font-size:small;"
|+ {{Nowrap|TAAR1 affinities and activational potencies of tryptamines<ref name="Gainetdinov_2018" /><ref name="Simmler_2016" />}}
|-
! rowspan="2" | Compound
! colspan="2" | Human TAAR1
! colspan="2" | Mouse TAAR1
! colspan="2" | Rat TAAR1
|-
! EC<sub>50</sub> (nM)
! K<sub>i</sub> (nM)
! EC<sub>50</sub> (nM)
! K<sub>i</sub> (nM)
! EC<sub>50</sub> (nM)
! K<sub>i</sub> (nM)
|-
| Tryptamine
| 21,000
| N/A
| 2,700
| 1,400
| 410
| 130
|-
| [[Serotonin]]
| >50,000
| N/A
| >50,000
| N/A
| 5,200
| N/A
|-
| [[Psilocin]]
| >30,000
| N/A
| 2,700
| 17,000
| 920
| 1,400
|-
| [[Dimethyltryptamine]]
| >10,000
| N/A
| 1,200
| 3,300
| 1,500
| 22,000
|- class="sortbottom"
| colspan="7" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' (1) [[EC50|EC<sub>50</sub>]] and K<sub>i</sub> values are in nanomolar (nM). (2) [[EC50|EC<sub>50</sub>]] reflects the concentration required to elicit 50% of the maximum TAAR1 response. (3) The smaller the K<sub>i</sub> value, the stronger the compound binds to the receptor.
|}

===Effects in animals and humans===
In a published clinical study, tryptamine, at a total dose of 23 to 277{{nbsp}}mg by [[intravenous therapy|intravenous infusion]], produced [[hallucinogen]]ic effects or perceptual disturbances similar to those of small doses of [[lysergic acid diethylamide]] (LSD).<ref name="Martin_1977">{{cite book | vauthors = Martin WR, Sloan JW | chapter = Pharmacology and Classification of LSD-like Hallucinogens | title = Drug Addiction II | pages = 305–368 | year = 1977 | doi = 10.1007/978-3-642-66709-1_3 | publisher = Springer Berlin Heidelberg | publication-place = Berlin, Heidelberg | isbn = 978-3-642-66711-4 | quote = MARTIN and SLOAN (1970) found that intravenously infused tryptamine increased blood pressure, dilated pupils, enhanced the patellar reflex, and produced perceptual distortions. [...] Tryptamine, but not DMT, increases locomotor activity in the mouse, while both antagonize reserpine depression (V ANE et al., 1961). [...] In the rat, tryptamine causes backward locomotion, Straub tail, bradypnea and dyspnea, and clonic convulsions (TEDESCHI et al., 1959). [...] Tryptamine produces a variety of changes in the cat causing signs of sympathetic activation including mydriasis, retraction of nictitating membrane, piloerection, motor signs such as extension of limbs and convulsions and affective changes such as hissing and snarling (LAIDLAW, 1912). [...] }}</ref><ref name="Shulgin_1997">{{cite book | vauthors = Shulgin A | title = Tihkal: The Continuation | year = 1997 | publisher = Transform Press | isbn = 978-0-9630096-9-2 | url = https://books.google.com/books?id=jl_ik66IumUC | access-date = 17 August 2024 | at = [https://www.erowid.org/library/books_online/tihkal/tihkal53.shtml #53. T] | quote = (with 250 mg, intravenously) "Tryptamine was infused intravenously over a period of up to 7.5 minutes. Physical changes included an increases in blood pressure, in the amplitude of the patellar reflex, and in pupillary diameter. The subjective changes are not unlike those seen with small doses of LSD. A point-by-point comparison between the tryptamine and LSD syndromes reveals a close similarity which is consistent with the hypothesis that tryptamine and LSD have a common mode of action." }}</ref><ref name="Blough_2014a">{{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 | volume = 231 | issue = 21 | pages = 4135–4144 | date = October 2014 | pmid = 24800892 | pmc = 4194234 | doi = 10.1007/s00213-014-3557-7 | quote = [Tryptamine (T): [...] Psychoactive effects: Psychoactive, short acting due to metabolism, increased blood pressure, similar to LSD }}</ref><ref name="Martin_1970">{{cite journal | vauthors = Martin WR, Sloan JW | title = Effects of infused tryptamine in man | journal = Psychopharmacologia | volume = 18 | issue = 3 | pages = 231–237 | date = 1970 | pmid = 4922520 | doi = 10.1007/BF00412669 }}</ref> It also produced other LSD-like effects, including [[pupil dilation]], increased [[blood pressure]], and increased force of the [[patellar reflex]].<ref name="Martin_1977" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" /> Tryptamine produced [[side effect]]s including [[nausea]], [[vomiting]], [[dizziness]], [[tingling]] sensations, [[sweating]], and bodily heaviness among others as well.<ref name="Martin_1977" /><ref name="Martin_1970" /> Conversely, there were no changes in [[heart rate]] or [[respiratory rate]].<ref name="Martin_1970" /> The [[onset of action|onset]] of the effects was rapid and the [[duration of action|duration]] was very short.<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" /> This can be attributed to the very rapid [[drug metabolism|metabolism]] of tryptamine by [[monoamine oxidase]] (MAO) and its very short [[elimination half-life]].<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" />

In animals, tryptamine, alone and/or in combination with a [[monoamine oxidase inhibitor]] (MAOI), produces behavioral changes such as [[hyperlocomotion]] and reversal of [[reserpine]]-induced [[hypoactivity|behavioral depression]].<ref name="Martin_1977" /><ref name="Jones_1982" /><ref name="Kellar_1986" /><ref name="Murphy_1985" /> In addition, it produces effects like [[hyperthermia]], [[tachycardia]], [[myoclonus]], and [[seizure]]s or [[convulsion]]s, among others.<ref name="Martin_1977" /><ref name="Jones_1982" /><ref name="Kellar_1986" /><ref name="Murphy_1985" /> Findings on tryptamine and the [[head-twitch response]] in rodents have been mixed, with some studies reporting no effect,<ref name="Jones_1981" /><ref name="Yamada_1987">{{cite journal | vauthors = Yamada J, Sugimoto Y, Horisaka K | title = The behavioural effects of intravenously administered tryptamine in mice | journal = Neuropharmacology | volume = 26 | issue = 1 | pages = 49–53 | date = January 1987 | pmid = 3561719 | doi = 10.1016/0028-3908(87)90043-8 }}</ref> some studies reporting induction of head twitches by tryptamine,<ref name="Haberzettl_2013">{{cite journal | vauthors = Haberzettl R, Bert B, Fink H, Fox MA | title = Animal models of the serotonin syndrome: a systematic review | journal = Behavioural Brain Research | volume = 256 | pages = 328–345 | date = November 2013 | pmid = 24004848 | doi = 10.1016/j.bbr.2013.08.045 | doi-access = free }}</ref><ref name="Sugimoto_1986">{{cite journal | vauthors = Sugimoto Y, Yamada J, Horisaka K | title = Effect of tryptamine on the behavior of mice | journal = Journal of Pharmacobio-Dynamics | volume = 9 | issue = 1 | pages = 68–73 | date = January 1986 | pmid = 2940357 | doi = 10.1248/bpb1978.9.68 }}</ref><ref name="Orikasa_1988">{{cite journal | vauthors = Orikasa S, Sloley BD | title = Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin, p-chloroamphetamine, and tryptamine in mice | journal = Psychopharmacology | volume = 95 | issue = 1 | pages = 124–131 | date = 1988 | pmid = 3133691 | doi = 10.1007/BF00212780 }}</ref> and others reporting that tryptamine actually antagonized [[5-hydroxytryptophan]] (5-HTP)-induced head twitches.<ref name="Kellar_1986" /><ref name="Jones_1981">{{cite journal | vauthors = Jones RS | title = In vivo pharmacological studies on the interactions between tryptamine and 5-hydroxytryptamine | journal = British Journal of Pharmacology | volume = 73 | issue = 2 | pages = 485–493 | date = June 1981 | pmid = 6972243 | pmc = 2071674 | doi = 10.1111/j.1476-5381.1981.tb10447.x }}</ref> Another study found that combination of tryptamine with an MAOI dose-dependently produced head twitches.<ref name="Irons_1984">{{cite book | vauthors = Irons J, Robinson CM, Marsden CA | chapter = 5ht Involvement in Tryptamine Induced Behaviour in Mice | title = Neurobiology of the Trace Amines | pages = 423–427 | date = 1984 | doi = 10.1007/978-1-4612-5312-9_35 | publisher = Humana Press | publication-place = Totowa, NJ | isbn = 978-1-4612-9781-9 }}</ref> Head twitches in rodents are a behavioral proxy of psychedelic-like effects.<ref name="Canal_2012">{{cite journal | vauthors = Canal CE, Morgan D | title = Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model | journal = Drug Testing and Analysis | volume = 4 | issue = 7–8 | pages = 556–576 | date = 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}</ref><ref name="Kozlenkov_2013">{{cite book | vauthors = Kozlenkov A, González-Maeso J | chapter = Animal Models and Hallucinogenic Drugs | title = The Neuroscience of Hallucinations | pages = 253–277 | date = 2013 | doi = 10.1007/978-1-4614-4121-2_14 | publisher = Springer New York | publication-place = New York, NY | isbn = 978-1-4614-4120-5 }}</ref> Many of the effects of tryptamine can be reversed by [[serotonin receptor antagonist]]s like [[metergoline]], [[metitepine]] (methiothepin), and [[cyproheptadine]].<ref name="Jones_1982" /><ref name="Kellar_1986" /><ref name="Murphy_1985" /><ref name="Martin_1977" /> Conversely, the effects of tryptamine in animals are profoundly augmented by MAOIs due to inhibition of its metabolism.<ref name="Jones_1982" /><ref name="Murphy_1985" /><ref name="Martin_1977" />

Tryptamine seems to also elevate [[prolactin]] and [[cortisol]] levels in animals and/or humans.<ref name="Murphy_1985" />

The {{Abbrlink|LD<sub>50</sub>|median lethal dose}} values of tryptamine in animals include 100{{nbsp}}mg/kg i.p. in mice, 500{{nbsp}}mg/kg s.c. in mice, and 223{{nbsp}}mg/kg i.p. in rats.<ref name="PubChem" />

==Pharmacokinetics==
Tryptamine produced [[endogenous]]ly or [[peripheral administration|administered peripherally]] is readily able to cross the [[blood–brain barrier]] and enter the [[central nervous system]].<ref name="Murphy_1985">{{cite book | vauthors = Murphy DL, Tamarkin L, Garrick NA, Taylor PL, Markey SP | chapter = Trace Indoleamines in the Central Nervous System | title = Neuropsychopharmacology of the Trace Amines | pages = 343–360 | year = 1985 | doi = 10.1007/978-1-4612-5010-4_36 | publisher = Humana Press | publication-place = Totowa, NJ | isbn = 978-1-4612-9397-2 }}</ref><ref name="Kellar_1986">{{cite book | vauthors = Kellar KJ, Cascio CS | chapter = Tryptamine and Phenylethylamine Recognition Sites in Brain | title = Receptor Binding | volume = 4 | pages = 119–138 | date = 1986 | doi = 10.1385/0-89603-078-4:119 | publisher = Humana Press | publication-place = New Jersey | isbn = 978-0-89603-078-7 }}</ref> This is in contrast to [[serotonin]], which is [[peripherally selective drug|peripherally selective]].<ref name="Murphy_1985" />

Tryptamine is [[drug metabolism|metabolized]] by [[monoamine oxidase]] (MAO) to form [[indole-3-acetic acid]] (IAA).<ref name="Murphy_1985" /><ref name="Jones_1982" /><ref name="Kellar_1986" /> Its metabolism is described as extremely rapid and its [[elimination half-life]] and [[duration of action|duration]] as very short.<ref name="Jones_1982" /><ref name="Blough_2014a" /><ref name="Shulgin_1997" /><ref name="Martin_1970" /> In addition, its duration is described as shorter than that of [[dimethyltryptamine]] (DMT).<ref name="Martin_1977" /> Brain tryptamine levels are increased up to 300-fold by MAOIs in animals.<ref name="Kellar_1986" /> In addition, the effects of [[exogenous]] tryptamine are strongly augmented by [[monoamine oxidase inhibitor]]s (MAOIs).<ref name="Jones_1982" /><ref name="Kellar_1986" />

Tryptamine is [[excretion|excreted]] in [[urine]] and its rate of urinary excretion has been reported to be [[pH]]-dependent.<ref name="Martin_1970" /><ref name="Franzen_1965">{{cite journal | vauthors = Franzen F, Gross H | title = Tryptamine, N,N-dimethyltryptamine, N,N-dimethyl-5-hydroxytryptamine and 5-methoxytryptamine in human blood and urine | journal = Nature | volume = 206 | issue = 988 | pages = 1052 | date = June 1965 | pmid = 5839067 | doi = 10.1038/2061052a0 | bibcode = 1965Natur.206.1052F }}</ref><ref name="Price_1975">{{cite journal | vauthors = Price J | title = The dependence of tryptamine excretion on urinary pH | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 65 | issue = 3 | pages = 339–342 | date = December 1975 | pmid = 1161 | doi = 10.1016/0009-8981(75)90259-4 }}</ref>

==Chemistry==
Tryptamine is a [[substituted tryptamine]] [[chemical derivative|derivative]] and [[trace amine]] and is [[structural analog|structurally related]] to the [[amino acid]] [[tryptophan]].<ref name="Shulgin_1997" />

===Properties===
The experimental [[partition coefficient|log P]] of tryptamine is 1.55.<ref name="PubChem">{{cite web | title = Tryptamine | website = PubChem | url = https://pubchem.ncbi.nlm.nih.gov/compound/1150 | access-date = 7 November 2024 }}</ref>

===Synthesis===
The [[chemical synthesis]] of tryptamine has been described.<ref name="Shulgin_1997" />

===Derivatives===
{{Main|Substituted tryptamine}}

The [[endogenous]] [[monoamine neurotransmitter]]s [[serotonin]] (5-hydroxytryptamine or 5-HT) and [[melatonin]] (5-methoxy-''N''-acetyltryptamine), as well as trace amines like [[N-methyltryptamine|''N''-methyltryptamine]] (NMT), [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT), and [[bufotenin]] (''N'',''N''-dimethylserotonin), are [[chemical derivative|derivative]]s of tryptamine.<ref name="Shulgin_1997" />

[[File:Tryptamine Alkaloids 2.png|class=skin-invert-image|thumb|483x483px|All tryptamine derivatives possess a modified 2-aminoethyl group and/or the addition of a substituent on the indole.]]

A variety of drugs, including both [[natural product|naturally occurring]] and [[pharmaceutical drug|pharmaceutical]] substances, are derivatives of tryptamine.<ref name="Shulgin_1997" /> These include the tryptamine psychedelics like [[psilocybin]], [[psilocin]], DMT, and [[5-MeO-DMT]]; tryptamine [[stimulant]]s, [[entactogen]]s, psychedelics, and/or [[antidepressant]]s like [[α-methyltryptamine]] (αMT) and [[α-ethyltryptamine]] (αET); [[triptan]] [[antimigraine agent]]s like [[sumatriptan]]; certain [[antipsychotic]]s like [[oxypertine]]; and the [[sleep aid]] [[melatonin (medication)|melatonin]].<ref name="Shulgin_1997" />

Various other drugs, including [[ergoline]]s and [[lysergamide]]s like the psychedelic [[lysergic acid diethylamide]] (LSD), the antimigraine agents [[ergotamine]], [[dihydroergotamine]], and [[methysergide]], and the [[antiparkinsonian agent]]s [[bromocriptine]], [[cabergoline]], [[lisuride]], and [[pergolide]]; [[β-carboline]]s like [[harmine]] (some of which are [[monoamine oxidase inhibitor]]s (MAOIs)); [[Iboga-type alkaloid|''Iboga'' alkaloid]]s like the [[hallucinogen]] [[ibogaine]]; [[yohimban]]s like the [[alpha-2 blocker|α<sub>2</sub> blocker]] [[yohimbine]]; antipsychotics like [[ciclindole]] and [[flucindole]]; and the MAOI antidepressant [[metralindole]], can all be thought of as [[cyclic compound|cyclized]] tryptamine derivatives.<ref name="Shulgin_1997" />

Drugs very closely related to tryptamines, but technically not tryptamines themselves, include certain triptans like [[avitriptan]] and [[naratriptan]]; the antipsychotics [[sertindole]] and [[tepirindole]]; and the MAOI antidepressants [[pirlindole]] and [[tetrindole]].

== See also ==
* [[Substituted tryptamine]]
* [[Phenethylamine]]

== References ==
{{Reflist}}

== External links ==
* [https://www.erowid.org/psychoactives/faqs/faqs_tryptamine.shtml Tryptamine FAQ - Erowid]
* [https://isomerdesign.com/pihkal/explore/5053 Tryptamine - Isomer Design]
* [https://www.erowid.org/library/books_online/tihkal/tihkal53.shtml Tryptamine - TiHKAL - Erowid]
* [http://isomerdesign.com/PiHKAL/read.php?domain=tk&id=53 Tryptamine - TiHKAL - Isomer Design]

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