Tryptamine Explained

Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan.[1] [2] 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).[1] 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.[3] [4] [5]

Tryptamine has been shown to activate serotonin receptors and trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems.[6] [7] In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility.[8] [9]

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.[10] [11]

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 ng per gram of tissue.[12] [13] However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders taking medications, such as bipolar depression and schizophrenia.[14]

Mammalian gut microbiome

Tryptamine is relatively abundant in the gut and feces of humans and rodents.[15] [16] 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. Tryptamine is a ligand for gut epithelial serotonin type 4 (5-HT4) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.

Metabolism

Biosynthesis

To yield tryptamine in vivo, tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of tryptophan.[17] Synthetic modifications to tryptamine can produce serotonin and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.[18]

Catabolism

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.[19]

Mechanisms of action and biological effects

Neuromodulation

Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases.[20] [21] [22] [23] It has specifically been found to act as a full agonist of the serotonin 5-HT2A receptor (= 7.36 ± 0.56nM; Emax = 104 ± 4%). Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (= 3,485 ± 234nM; Emax = 108 ± 16%). In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A receptor. Alexander Shulgin tested tryptamine at high doses intravenously and found that it produced weak serotonergic psychedelic-like effects as well as peripheral nervous system changes.[24]

It can also weakly activate the trace amine-associated receptor, TAAR1 (hTAAR1 in humans).[25] [26] [27] Limited studies have considered tryptamine to be a trace neuromodulator capable of regulating the activity of neuronal cell responses without binding to the associated postsynaptic receptors.[28]

Tryptamine has been found to act as a monoamine releasing agent.[29] It is a releaser of serotonin, dopamine, and norepinephrine, in that order of potency (= 32.6 ± 2.6nM, 164 ± 16nM, and 716 ± 46nM, respectively). It is also a monoaminergic activity enhancer of these neurotransmitters.

hTAAR1

hTAAR1 is a stimulatory G-protein coupled receptor (GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons.[30] Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent phosphorylation of the monoamine reuptake transporter.[31] This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation. Conversely, when hTAAR1 are colocalized with G protein-coupled inwardly-rectifying potassium channels (GIRKs), receptor activation reduces neuronal firing by facilitating membrane hyperpolarization through the efflux of potassium ions. The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity.[32]

Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction, and schizophrenia.[33] hTAAR1 is primarily expressed in brain structures associated with dopamine systems, such as the ventral tegmental area (VTA) and serotonin systems in the dorsal raphe nuclei (DRN). Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for mood disorders and schizophrenia.[34] Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce anti-depressive activity, increased cognition, reduced stress and anti-addiction effects.

Monoaminergic activity enhancer

Tryptamine is a monoaminergic activity enhancer (MAE) of serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism.[35] [36] That is, it enhances the action potential-mediated release of these monoamine neurotransmitters. The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism.[37] [38] Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.[39] [40] [41]

Gastrointestinal motility

Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium.[42] 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. GTP-bound Gs activates adenylyl cyclase, which catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.[43] [44]

Pharmacodynamics

TAAR1 Activation (EC50) and Binding Affinity (Ki) of Tryptamines[45]
TryptamineHuman TAAR1Mouse TAAR1Rat TAAR
EC50KiEC50KiEC50Ki
Tryptamine21N/A2.71.40.410.13
Serotonin>50N/A>50N/A5.2N/A
Psilocin>30N/A2.7170.921.4
DMT>10N/A1.23.31.522
EC50 and Ki values are in micromolar (μM). EC50 reflects the amountof tryptamine required to elicit 50% of the maximum TAAR1 response.

The smaller the Ki value, the stronger the tryptamine binds to the receptor.

Tryptamine-based therapeutics

DrugMechanismTreatmentEffectStructure
Sumatriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Rizatriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Zolmitriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Almotriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Eletriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Frovatriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels
Naratriptan5-HT1B and 5-HT1D agonistMigraine HeadachesVasoconstriction of brain blood vessels

See also

External links

Notes and References

  1. Web site: Tryptamine. 2020-12-01. pubchem.ncbi.nlm.nih.gov.
  2. Jenkins. Trisha A.. Nguyen. Jason C. D.. Polglaze. Kate E.. Bertrand. Paul P.. 2016-01-20. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 8. 1. 56. 10.3390/nu8010056. 2072-6643. 4728667. 26805875. free.
  3. Tylš. Filip. Páleníček. Tomáš. Horáček. Jiří. 2014-03-01. Psilocybin – Summary of knowledge and new perspectives. European Neuropsychopharmacology. en. 24. 3. 342–356. 10.1016/j.euroneuro.2013.12.006. 24444771. 10758314. 0924-977X.
  4. Tittarelli. Roberta. Mannocchi. Giulio. Pantano. Flaminia. Romolo. Francesco Saverio. 2015. Recreational Use, Analysis and Toxicity of Tryptamines. Current Neuropharmacology. 13. 1. 26–46. 10.2174/1570159X13666141210222409. 1570-159X. 4462041. 26074742.
  5. Web site: The Ayahuasca Phenomenon. 2020-10-03. MAPS. 21 November 2014 . en-gb.
  6. Khan. Muhammad Zahid. Nawaz. Waqas. 2016-10-01. The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system. Biomedicine & Pharmacotherapy. en. 83. 439–449. 10.1016/j.biopha.2016.07.002. 27424325. 0753-3322.
  7. 2017-12-01. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacology & Therapeutics. en. 180. 161–180. 10.1016/j.pharmthera.2017.07.002. 0163-7258. Berry. Mark D.. Gainetdinov. Raul R.. Hoener. Marius C.. Shahid. Mohammed. 28723415. 207366162. free.
  8. Bhattarai. Yogesh. Williams. Brianna B.. Battaglioli. Eric J.. Whitaker. Weston R.. Till. Lisa. Grover. Madhusudan. Linden. David R.. Akiba. Yasutada. Kandimalla. Karunya K.. Zachos. Nicholas C.. Kaunitz. Jonathan D.. 2018-06-13. Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host & Microbe. en. 23. 6. 775–785.e5. 10.1016/j.chom.2018.05.004. 1931-3128. 29902441. 6055526.
  9. Field. Michael. 2003. Intestinal ion transport and the pathophysiology of diarrhea. Journal of Clinical Investigation. 111. 7. 931–943. 10.1172/JCI200318326. 0021-9738. 12671039. 152597.
  10. Web site: 2020-12-09. New Compound Related to Psychedelic Ibogaine Could Treat Addiction, Depression. 2020-12-11. UC Davis. EN.
  11. Web site: ServiceDec. 9. Robert F.. Chemists re-engineer a psychedelic to treat depression and addiction in rodents. 2020-12-11. Science AAAS. en.
  12. Tittarelli. Roberta. Mannocchi. Giulio. Pantano. Flaminia. Romolo. Francesco Saverio. 2015. Recreational Use, Analysis and Toxicity of Tryptamines. Current Neuropharmacology. 13. 1. 26–46. 10.2174/1570159X13666141210222409. 1570-159X. 4462041. 26074742.
  13. 2017-12-01. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacology & Therapeutics. en. 180. 161–180. 10.1016/j.pharmthera.2017.07.002. 0163-7258. Berry. Mark D.. Gainetdinov. Raul R.. Hoener. Marius C.. Shahid. Mohammed. 28723415. 207366162. free.
  14. Miller. Gregory M.. 2011. The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity. Journal of Neurochemistry. 116. 2. 164–176. 10.1111/j.1471-4159.2010.07109.x. 0022-3042. 3005101. 21073468.
  15. Jenkins. Trisha A.. Nguyen. Jason C. D.. Polglaze. Kate E.. Bertrand. Paul P.. 2016-01-20. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 8. 1. 56. 10.3390/nu8010056. 2072-6643. 4728667. 26805875. free.
  16. Bhattarai. Yogesh. Williams. Brianna B.. Battaglioli. Eric J.. Whitaker. Weston R.. Till. Lisa. Grover. Madhusudan. Linden. David R.. Akiba. Yasutada. Kandimalla. Karunya K.. Zachos. Nicholas C.. Kaunitz. Jonathan D.. 2018-06-13. Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host & Microbe. en. 23. 6. 775–785.e5. 10.1016/j.chom.2018.05.004. 1931-3128. 29902441. 6055526.
  17. Tittarelli. Roberta. Mannocchi. Giulio. Pantano. Flaminia. Romolo. Francesco Saverio. 2015. Recreational Use, Analysis and Toxicity of Tryptamines. Current Neuropharmacology. 13. 1. 26–46. 10.2174/1570159X13666141210222409. 1570-159X. 4462041. 26074742.
  18. Web site: 2020. Serotonin Synthesis and Metabolism. Sigma Aldrich.
  19. Web site: MetaCyc L-tryptophan degradation VI (via tryptamine). 2020-12-11. biocyc.org.
  20. Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB . Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes . Psychopharmacology (Berl) . 231 . 21 . 4135–4144 . October 2014 . 24800892 . 4194234 . 10.1007/s00213-014-3557-7 .
  21. Mousseau DD . Tryptamine: a metabolite of tryptophan implicated in various neuropsychiatric disorders . Metab Brain Dis . 8 . 1 . 1–44 . March 1993 . 8098507 . 10.1007/BF01000528 .
  22. Anwar MA, Ford WR, Broadley KJ, Herbert AA . Vasoconstrictor and vasodilator responses to tryptamine of rat-isolated perfused mesentery: comparison with tyramine and β-phenylethylamine . Br J Pharmacol . 165 . 7 . 2191–2202 . April 2012 . 21958009 . 3413856 . 10.1111/j.1476-5381.2011.01706.x .
  23. Bradley PB, Humphrey PP, Williams RH . Tryptamine-induced vasoconstrictor responses in rat caudal arteries are mediated predominantly via 5-hydroxytryptamine receptors . Br J Pharmacol . 84 . 4 . 919–925 . April 1985 . 3159458 . 1987057 . 10.1111/j.1476-5381.1985.tb17386.x .
  24. Book: Shulgin, A. . Shulgin . A. . Tihkal: The Continuation . Transform Press . 1997 . 978-0-9630096-9-2 . 17 August 2024 .
    1. 53. T
     . (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.".
  25. Yu. Ai-Ming. Granvil. Camille P.. Haining. Robert L.. Krausz. Kristopher W.. Corchero. Javier. Küpfer. Adrian. Idle. Jeffrey R.. Gonzalez. Frank J.. 2003-02-01. The Relative Contribution of Monoamine Oxidase and Cytochrome P450 Isozymes to the Metabolic Deamination of the Trace Amine Tryptamine. Journal of Pharmacology and Experimental Therapeutics. en. 304. 2. 539–546. 10.1124/jpet.102.043786. 0022-3565. 12538805. 18279145.
  26. Khan. Muhammad Zahid. Nawaz. Waqas. 2016-10-01. The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system. Biomedicine & Pharmacotherapy. en. 83. 439–449. 10.1016/j.biopha.2016.07.002. 27424325. 0753-3322.
  27. Zucchi. R. Chiellini. G. Scanlan. T S. Grandy. D K. 2006. Trace amine-associated receptors and their ligands. British Journal of Pharmacology. 149. 8. 967–978. 10.1038/sj.bjp.0706948. 0007-1188. 2014643. 17088868.
  28. Miller. Gregory M.. 2011. The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity. Journal of Neurochemistry. 116. 2. 164–176. 10.1111/j.1471-4159.2010.07109.x. 0022-3042. 3005101. 21073468.
  29. Blough BE, Landavazo A, Partilla JS, Decker AM, Page KM, Baumann MH, Rothman RB . Alpha-ethyltryptamines as dual dopamine-serotonin releasers . Bioorg Med Chem Lett . 24 . 19 . 4754–4758 . October 2014 . 25193229 . 4211607 . 10.1016/j.bmcl.2014.07.062 .
  30. 2017-12-01. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacology & Therapeutics. en. 180. 161–180. 10.1016/j.pharmthera.2017.07.002. 0163-7258. Berry. Mark D.. Gainetdinov. Raul R.. Hoener. Marius C.. Shahid. Mohammed. 28723415. 207366162. free.
  31. Jing. Li. Li. Jun-Xu. 2015-08-15. Trace amine-associated receptor 1: a promising target for the treatment of psychostimulant addiction. European Journal of Pharmacology. 761. 345–352. 10.1016/j.ejphar.2015.06.019. 0014-2999. 4532615. 26092759.
  32. Grandy. David K.. Miller. Gregory M.. Li. Jun-Xu. 2016-02-01. "TAARgeting Addiction" The Alamo Bears Witness to Another Revolution. Drug and Alcohol Dependence. 159. 9–16. 10.1016/j.drugalcdep.2015.11.014. 0376-8716. 4724540. 26644139.
  33. 2017-12-01. Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. Pharmacology & Therapeutics. en. 180. 161–180. 10.1016/j.pharmthera.2017.07.002. 0163-7258. Berry. Mark D.. Gainetdinov. Raul R.. Hoener. Marius C.. Shahid. Mohammed. 28723415. 207366162. free.
  34. Gainetdinov. Raul R.. Hoener. Marius C.. Berry. Mark D.. 2018-07-01. Trace Amines and Their Receptors. Pharmacological Reviews. en. 70. 3. 549–620. 10.1124/pr.117.015305. 0031-6997. 29941461. 49411553. free.
  35. Shimazu S, Miklya I . Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 28 . 3 . 421–427 . May 2004 . 15093948 . 10.1016/j.pnpbp.2003.11.016 . 37564231 .
  36. Knoll J . Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives . Neurochem Res . 28 . 8 . 1275–1297 . August 2003 . 12834268 . 10.1023/a:1024224311289 .
  37. Harsing LG, Knoll J, Miklya I . Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum . Int J Mol Sci . 23 . 15 . August 2022 . 8543 . 35955676 . 9369307 . 10.3390/ijms23158543 . free .
  38. Harsing LG, Timar J, Miklya I . Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline . Int J Mol Sci . 24 . 17 . August 2023 . 13334 . 37686140 . 10487936 . 10.3390/ijms241713334 . free .
  39. Knoll J . 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 . CNS Drug Rev . 7 . 3 . 317–45 . 2001 . 11607046 . 6494119 . 10.1111/j.1527-3458.2001.tb00202.x .
  40. Yoneda F, Moto T, Sakae M, Ohde H, Knoll B, Miklya I, Knoll J . 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 . Bioorg Med Chem . 9 . 5 . 1197–1212 . May 2001 . 11377178 . 10.1016/s0968-0896(01)00002-5 .
  41. Knoll J, Yoneda F, Knoll B, Ohde H, Miklya I . (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain . British Journal of Pharmacology . 128 . 8 . 1723–1732 . December 1999 . 10588928 . 1571822 . 10.1038/sj.bjp.0702995 .
  42. Bhattarai. Yogesh. Williams. Brianna B.. Battaglioli. Eric J.. Whitaker. Weston R.. Till. Lisa. Grover. Madhusudan. Linden. David R.. Akiba. Yasutada. Kandimalla. Karunya K.. Zachos. Nicholas C.. Kaunitz. Jonathan D.. 2018-06-13. Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion. Cell Host & Microbe. en. 23. 6. 775–785.e5. 10.1016/j.chom.2018.05.004. 1931-3128. 29902441. 6055526.
  43. Field. Michael. 2003. Intestinal ion transport and the pathophysiology of diarrhea. Journal of Clinical Investigation. 111. 7. 931–943. 10.1172/JCI200318326. 0021-9738. 12671039. 152597.
  44. Web site: 2018-06-15. Microbiome-Lax May Relieve Constipation. 2020-12-11. GEN - Genetic Engineering and Biotechnology News. en-US.
  45. Gainetdinov. Raul R.. Hoener. Marius C.. Berry. Mark D.. 2018-07-01. Trace Amines and Their Receptors. Pharmacological Reviews. en. 70. 3. 549–620. 10.1124/pr.117.015305. 0031-6997. 29941461. 49411553. free.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Tryptamine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.