Tryptamine
Template:Short description Template:About Template:Chembox
Tryptamine is an indolamine metabolite of the essential amino acid tryptophan.<ref name=NML>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":32">Template:Cite journal</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 neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.<ref name=":6">Template:Cite journal</ref><ref name=":03">Template:Cite journal</ref><ref name=":5">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Tryptamine has been shown to activate serotonin receptors<ref name="BloughLandavazoDecker2014" /><ref name="Mousseau1993" /> and trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems.<ref name="KhanNawaz2016">Template:Cite journal</ref><ref name="BerryGainetdinovHoener2017">Template:Cite journal</ref> In the human gut, bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility.<ref name=":32"/><ref name=":103">Template:Cite journal</ref><ref name=":152">Template:Cite journal</ref>
Multiple tryptamine-derived drugs have been developed to treat migraines, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders.<ref name=":16">Template:Citation</ref><ref name=":7">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":8">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Natural occurrencesEdit
For a list of plants, fungi and animals containing tryptamines, see List of psychoactive plants and List of naturally occurring tryptamines.
Mammalian brainEdit
Endogenous levels of tryptamine in the mammalian brain are less than 100 ng per gram of tissue.<ref name=":03"/><ref name="BerryGainetdinovHoener2017" /> However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia.<ref name="Miller2011">Template:Cite journal</ref>
Mammalian gut microbiomeEdit
Tryptamine is relatively abundant in the gut and feces of humans and rodents.<ref name=":32"/><ref name=":103"/> Commensal bacteria, including Ruminococcus gnavus and Clostridium sporogenes in the gastrointestinal tract, possess the enzyme tryptophan decarboxylase, which aids in the conversion of dietary tryptophan to tryptamine.<ref name=":32" /> Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.<ref name=":103"/>
MetabolismEdit
BiosynthesisEdit
To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan.<ref name=":03"/> 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
CatabolismEdit
Monoamine oxidases 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
FigureEdit
Biological activityEdit
| Target | Affinity (Ki, nM) | Species | ||
|---|---|---|---|---|
| 5-HT1A | 32–105 (Ki) 899–>10,000 (Template:Abbrlink) Template:Abbr (Template:Abbrlink) |
Human Human Human | ||
| 5-HT1B | 36–525 | Human | ||
| 5-HT1D | 23–521 | Human | ||
| 5-HT1E | 2,559 | Human | ||
| 5-HT1F | 2,409 | Human | ||
| 5-HT2A | 37–4,070 (Ki) 7.4–257 (Template:Abbr) 71–104% (Template:Abbr) |
Human Human Human | ||
| 5-HT2B | 25–113 (Ki) 29.5 (Template:Abbr) 92% (Template:Abbr) |
Human Human Human | ||
| 5-HT2C | 17–3,000 (Ki) 1.17–45.7 (Template:Abbr) 85–108% (Template:Abbr) |
Human Human Human | ||
| 5-HT3 | Template:Abbr | Template:Abbr | ||
| 5-HT4 | >10,000 13,500 (Template:Abbr) 96% (Template:Abbr) |
Mouse Pig Pig | ||
| 5-HT5A | Template:Abbr | Template:Abbr | ||
| 5-HT6 | 70–438 | Human | ||
| 5-HT7 | 148–158 | Human | ||
| α2A | 19,000 | Rat | ||
| Template:Abbrlink | 1,400 (Ki) 2,700 (Template:Abbr) 117% (Template:Abbr) 130 (Ki) 410 (Template:Abbr) 91% (Template:Abbr) 1,084 (Ki) 2,210–21,000 (Template:Abbr) 73% (Template:Abbr) |
Mouse Mouse Mouse Rat Rat Rat Human Human Human | ||
| Template:Abbrlink | 32.6 (Template:Abbr) a | Rat | ||
| Template:Abbrlink | 716 (Template:Abbr) a | Rat | ||
| Template:Abbrlink | 164 (Template:Abbr) a | Rat | ||
| Note: The smaller the value, the more avidly the compound binds to or activates the site. Footnotes: a = Neurotransmitter release. Refs: Main: <ref name="PDSPKiDatabase">{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref><ref name="BindingDB">{{#invoke:citation/CS1|citation |
CitationClass=web
}}</ref> Additional: <ref name="Toro-SazoBreaLoza2019">Template:Cite journal</ref><ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016">Template:Cite journal</ref><ref name="BloughLandavazoDecker2014" /><ref name="BloughLandavazoPartilla2014" /><ref name="PorterBenwellLamb1999">Template:Cite journal</ref><ref name="vanWijngaardenSoudijn1997">Template:Cite book</ref><ref name="ChenLiYu2023a">Template:Cite journal</ref><ref name="ChenLiYu2023b">Template:Citation</ref><ref name="EganGrindeDupre2000">Template:Cite journal</ref><ref name="MedhurstKaumann1993">Template:Cite journal</ref> | ||
Serotonin receptor agonistEdit
Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases.<ref name="Jones1982" /><ref name="BloughLandavazoDecker2014" /><ref name="Mousseau1993">Template:Cite journal</ref><ref name="AnwarFordBroadley2012">Template:Cite journal</ref><ref name="BradleyHumphreyWilliams1985">Template:Cite journal</ref> It has specifically been found to act as a full agonist of the serotonin 5-HT2A receptor (Template:Abbrlink = 7.36 ± 0.56Template:NbspnM; Emax = 104 ± 4%).<ref name="BloughLandavazoDecker2014" /> Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (Template:Abbr = 3,485 ± 234Template:NbspnM; Emax = 108 ± 16%).<ref name="BloughLandavazoDecker2014" /> In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A receptor.<ref name="BloughLandavazoDecker2014" />
Gastrointestinal motilityEdit
Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.<ref name=":103"/> Upon tryptamine binding, the activated 5-HT4 receptor undergoes a conformational change which allows its Gs alpha subunit to exchange GDP for GTP, and its liberation from the 5-HT4 receptor and βγ subunit.<ref name=":103" /> GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP).<ref name=":103" /> cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.<ref name=":152"/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Monoamine releasing agentEdit
Tryptamine has been found to act as a monoamine releasing agent (MRA).<ref name="Jones1982">Template:Cite journal</ref><ref name="BloughLandavazoDecker2014" /><ref name="BloughLandavazoPartilla2014">Template:Cite journal</ref> It is a releaser of serotonin, dopamine, and norepinephrine, in that order of potency (Template:Abbr = 32.6Template:NbspnM, 164Template:NbspnM, and 716Template:NbspnM, respectively).<ref name="Jones1982" /><ref name="BloughLandavazoDecker2014" /><ref name="BloughLandavazoPartilla2014" /> That is, it acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).<ref name="BloughLandavazoDecker2014" /><ref name="BloughLandavazoPartilla2014" />
| Compound | Template:Abbrlink | Template:Abbrlink | Template:Abbrlink | Ref | ||
|---|---|---|---|---|---|---|
| Tryptamine | 32.6 | 716 | 164 | <ref name="BloughLandavazoDecker2014" /><ref name="BloughLandavazoPartilla2014" /> | ||
| Serotonin | 44.4 | >10,000 | ≥1,960 | <ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> | ||
| Phenethylamine | >10,000 | 10.9 | 39.5 | <ref name="ReithBLoughHong2015">Template:Cite journal</ref><ref name="Forsyth2012">{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref><ref name="Blough2008">Template:Cite book</ref> | |
| Tyramine | 2,775 | 40.6 | 119 | <ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /> | ||
| 5-Methoxytryptamine | 2,169 | >10,000 | >10,000 | <ref name="BloughLandavazoPartilla2014" /> | ||
| N-Methyltryptamine | 22.4 | 733 | 321 | <ref name="BloughLandavazoDecker2014" /> | ||
| Dimethyltryptamine | 114 | 4,166 | >10,000 | <ref name="BloughLandavazoDecker2014" /> | ||
| Psilocin | 561 | >10,000 | >10,000 | <ref name="RothmanPartillaBaumann2012">Template:Cite journal</ref><ref name="BloughLandavazoDecker2014" /> | ||
| Bufotenin | 30.5 | >10,000 | >10,000 | <ref name="BloughLandavazoDecker2014" /> | ||
| 5-MeO-DMT | >10,000 | >10,000 | >10,000 | <ref name="NagaiNonakaKamimura2007" /> | ||
| α-Methyltryptamine | 21.7–68 | 79–112 | 78.6–180 | <ref name="NagaiNonakaKamimura2007">Template:Cite journal</ref> | ||
| α-Ethyltryptamine | 23.2 | 640 | 232 | <ref name="BloughLandavazoPartilla2014" /> | ||
| [[Dextroamphetamine|Template:Small-Amphetamine]] | 698–1,765 | 6.6–7.2 | 5.8–24.8 | <ref name="RothmanBaumannDersch2001">Template:Cite journal</ref><ref name="BaumannPartillaLehner2013">Template:Cite journal</ref> | ||
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:<ref name="RothmanBaumann2003">Template:Cite journal</ref><ref name="RothmanBaumann2006">Template:Cite journal</ref> | ||||||
Monoaminergic activity enhancerEdit
Tryptamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism.<ref name="ShimazuMiklya2004">Template:Cite journal</ref><ref name="Knoll2003">Template:Cite journal</ref> That is, it enhances the action potential-mediated release of these monoamine neurotransmitters.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /> The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism.<ref name="HarsingKnollMiklya2022">Template:Cite journal</ref><ref name="HarsingTimarMiklya2023">Template:Cite journal</ref> Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.<ref name="ShimazuMiklya2004" /><ref name="Knoll2003" /><ref name="Knoll2001">Template:Cite journal</ref><ref name="YonedaMotoSakae2001">Template:Cite journal</ref><ref name="KnollYonedaKnoll1999">Template:Cite journal</ref>
TAAR1 agonistEdit
Tryptamine is an agonist of the trace amine-associated receptor 1 (TAAR1).<ref name="GainetdinovHoenerBerry2018">Template:Cite journal</ref> It is a potent TAAR1 full agonist in rats, a weak TAAR1 full agonist in mice, and a very weak TAAR1 partial agonist in humans.<ref name="GainetdinovHoenerBerry2018" /> Tryptamine may act as a trace neuromodulator in some species via activation of TAAR1 signaling.<ref name="GainetdinovHoenerBerry2018" /><ref name="ZucchiChielliniScanlan2006">Template:Cite journal</ref>
The TAAR1 is a stimulatory G protein-coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons.<ref name="BerryGainetdinovHoener2017" /> TAAR1 agonists have been implicated in regulating monoaminergic neurotransmission, for instance by activating G protein-coupled inwardly-rectifying potassium channels (GIRKs) and reducing neuronal firing via facilitation of membrane hyperpolarization through the efflux of potassium ions.<ref name="GainetdinovHoenerBerry2018" /><ref name="GrandyMillerLi2016">Template:Cite journal</ref>
TAAR1 agonists are under investigation as a novel treatment for neuropsychiatric conditions like schizophrenia, drug addiction, and depression.<ref name="BerryGainetdinovHoener2017" /> 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 nuclei (DRN).<ref name="BerryGainetdinovHoener2017" /> Additionally, the human TAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia.<ref name="GainetdinovHoenerBerry2018" /> Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce antipsychotic-like, anti-addictive, and antidepressant-like effects in animals.<ref name="GrandyMillerLi2016" /><ref name="GainetdinovHoenerBerry2018" />
| Compound | Human TAAR1 | Mouse TAAR1 | Rat TAAR1 | |||
|---|---|---|---|---|---|---|
| EC50 (nM) | Ki (nM) | EC50 (nM) | Ki (nM) | EC50 (nM) | Ki (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 |
| Notes: (1) EC50 and Ki values are in nanomolar (nM). (2) EC50 reflects the concentration required to elicit 50% of the maximum TAAR1 response. (3) The smaller the Ki value, the stronger the compound binds to the receptor. | ||||||
Effects in animals and humansEdit
In a published clinical study, tryptamine, at a total dose of 23 to 277Template:Nbspmg by intravenous infusion, produced hallucinogenic effects or perceptual disturbances similar to those of small doses of lysergic acid diethylamide (LSD).<ref name="MartinSloan1977">Template:Cite book</ref><ref name="ShulginShulgin1997">Template:Cite book</ref><ref name="BloughLandavazoDecker2014">Template:Cite journal</ref><ref name="MartinSloan1970">Template:Cite journal</ref> It also produced other LSD-like effects, including pupil dilation, increased blood pressure, and increased force of the patellar reflex.<ref name="MartinSloan1977" /><ref name="BloughLandavazoDecker2014" /><ref name="ShulginShulgin1997" /><ref name="MartinSloan1970" /> Tryptamine produced side effects including nausea, vomiting, dizziness, tingling sensations, sweating, and bodily heaviness among others as well.<ref name="MartinSloan1977" /><ref name="MartinSloan1970" /> Conversely, there were no changes in heart rate or respiratory rate.<ref name="MartinSloan1970" /> The onset of the effects was rapid and the duration was very short.<ref name="Jones1982" /><ref name="BloughLandavazoDecker2014" /><ref name="ShulginShulgin1997" /><ref name="MartinSloan1970" /> This can be attributed to the very rapid metabolism of tryptamine by monoamine oxidase (MAO) and its very short elimination half-life.<ref name="Jones1982" /><ref name="BloughLandavazoDecker2014" /><ref name="ShulginShulgin1997" /><ref name="MartinSloan1970" />
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 behavioral depression.<ref name="MartinSloan1977" /><ref name="Jones1982" /><ref name="KellarCascio1986" /><ref name="MurphyTamarkinGarrick1985" /> In addition, it produces effects like hyperthermia, tachycardia, myoclonus, and seizures or convulsions, among others.<ref name="MartinSloan1977" /><ref name="Jones1982" /><ref name="KellarCascio1986" /><ref name="MurphyTamarkinGarrick1985" /> Findings on tryptamine and the head-twitch response in rodents have been mixed, with some studies reporting no effect,<ref name="Jones1981" /><ref name="YamadaSugimotoHorisaka1987">Template:Cite journal</ref> some studies reporting induction of head twitches by tryptamine,<ref name="HaberzettlBertFink2013">Template:Cite journal</ref><ref name="SugimotoYamadaHorisaka1986">Template:Cite journal</ref><ref name="OrikasaSloley1988">Template:Cite journal</ref> and others reporting that tryptamine actually antagonized 5-hydroxytryptophan (5-HTP)-induced head twitches.<ref name="KellarCascio1986" /><ref name="Jones1981">Template:Cite journal</ref> Another study found that combination of tryptamine with an MAOI dose-dependently produced head twitches.<ref name="IronsRobinsonMarsden1984">Template:Cite book</ref> Head twitches in rodents are a behavioral proxy of psychedelic-like effects.<ref name="CanalMorgan2012">Template:Cite journal</ref><ref name="KozlenkovGonzález-Maeso2013">Template:Cite book</ref> Many of the effects of tryptamine can be reversed by serotonin receptor antagonists like metergoline, metitepine (methiothepin), and cyproheptadine.<ref name="Jones1982" /><ref name="KellarCascio1986" /><ref name="MurphyTamarkinGarrick1985" /><ref name="MartinSloan1977" /> Conversely, the effects of tryptamine in animals are profoundly augmented by MAOIs due to inhibition of its metabolism.<ref name="Jones1982" /><ref name="MurphyTamarkinGarrick1985" /><ref name="MartinSloan1977" />
Tryptamine seems to also elevate prolactin and cortisol levels in animals and/or humans.<ref name="MurphyTamarkinGarrick1985" />
The Template:Abbrlink values of tryptamine in animals include 100Template:Nbspmg/kg i.p. in mice, 500Template:Nbspmg/kg s.c. in mice, and 223Template:Nbspmg/kg i.p. in rats.<ref name="PubChem" />
PharmacokineticsEdit
Tryptamine produced endogenously or administered peripherally is readily able to cross the blood–brain barrier and enter the central nervous system.<ref name="MurphyTamarkinGarrick1985">Template:Cite book</ref><ref name="KellarCascio1986">Template:Cite book</ref> This is in contrast to serotonin, which is peripherally selective.<ref name="MurphyTamarkinGarrick1985" />
Tryptamine is metabolized by monoamine oxidase (MAO) to form indole-3-acetic acid (IAA).<ref name="MurphyTamarkinGarrick1985" /><ref name="Jones1982" /><ref name="KellarCascio1986" /> Its metabolism is described as extremely rapid and its elimination half-life and duration as very short.<ref name="Jones1982" /><ref name="BloughLandavazoDecker2014" /><ref name="ShulginShulgin1997" /><ref name="MartinSloan1970" /> In addition, its duration is described as shorter than that of dimethyltryptamine (DMT).<ref name="MartinSloan1977" /> Brain tryptamine levels are increased up to 300-fold by MAOIs in animals.<ref name="KellarCascio1986" /> In addition, the effects of exogenous tryptamine are strongly augmented by monoamine oxidase inhibitors (MAOIs).<ref name="Jones1982" /><ref name="KellarCascio1986" />
Tryptamine is excreted in urine and its rate of urinary excretion has been reported to be pH-dependent.<ref name="MartinSloan1970" /><ref name="FranzenGross1965">Template:Cite journal</ref><ref name="Price1975">Template:Cite journal</ref>
ChemistryEdit
Tryptamine is a substituted tryptamine derivative and trace amine and is structurally related to the amino acid tryptophan.
The experimental log P of tryptamine is 1.55.<ref name="PubChem">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
DerivativesEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}
The endogenous monoamine neurotransmitters serotonin (5-hydroxytryptamine or 5-HT) and melatonin (5-methoxy-N-acetyltryptamine), as well as trace amines like N-methyltryptamine (NMT), N,N-dimethyltryptamine (DMT), and bufotenin (N,N-dimethylserotonin), are derivatives of tryptamine.
A variety of drugs, including both naturally occurring and pharmaceutical substances, are derivatives of tryptamine. These include the tryptamine psychedelics like psilocybin, psilocin, DMT, and 5-MeO-DMT; tryptamine stimulants, entactogens, psychedelics, and/or antidepressants like α-methyltryptamine (αMT) and α-ethyltryptamine (αET); triptan antimigraine agents like sumatriptan; certain antipsychotics like oxypertine; and the sleep aid melatonin.
Various other drugs, including ergolines and lysergamides like the psychedelic lysergic acid diethylamide (LSD), the antimigraine agents ergotamine, dihydroergotamine, and methysergide, and the antiparkinsonian agents bromocriptine, cabergoline, lisuride, and pergolide; β-carbolines like harmine (some of which are monoamine oxidase inhibitors (MAOIs)); Iboga alkaloids like the hallucinogen ibogaine; yohimbans like the α2 blocker yohimbine; antipsychotics like ciclindole and flucindole; and the MAOI antidepressant metralindole, can all be thought of as cyclized tryptamine derivatives.
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.
ReferencesEdit
External linksEdit
- Tryptamine FAQ
- Tryptamine Hallucinogens and Consciousness
- Tryptamind Psychoactives, reference site on tryptamine and other psychoactives.
- Tryptamine (T) entry in TiHKAL • info
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