5-Hydroxytryptophan

Last updated

Contents

5-Hydroxytryptophan
5-Hydroxy-L-Tryptophan (5-HTP).svg
5-Hydroxy-L-tryptophan-3D-balls.png
Names
IUPAC name
2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid
Other names
5-HTP; Oxitriptan; α-Carboxy-5-hydroxytryptamine; α-Carboxy-5-HT
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.022.193 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH 5-Hydroxytryptophan
PubChem CID
UNII
  • InChI=1S/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)/t9-/m0/s1 Yes check.svgY
    Key: LDCYZAJDBXYCGN-VIFPVBQESA-N Yes check.svgY
  • InChI=1/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)/t9-/m0/s1
    Key: LDCYZAJDBXYCGN-VIFPVBQEBZ
  • O=C(O)[C@@H](N)Cc2c1cc(O)ccc1[nH]c2
Properties
C11H12N2O3
Molar mass 220.228 g·mol−1
Density 1.484 g/mL
Melting point 298 to 300 °C (568 to 572 °F; 571 to 573 K)
Boiling point 520.6 °C (969.1 °F; 793.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

5-HTP can be manufactured and used as a drug and supplement with the INN Tooltip International Nonproprietary Name oxitriptan . Brand names include Cincofarm, Levothym, Levotonine, Oxyfan, Telesol, Tript-OH, and Triptum. As a drug, it is used in the treatment of depression and for certain other indications.

Production

5-HTP is produced from the amino acid tryptophan through the action of the enzyme tryptophan hydroxylase. Tryptophan hydroxylase is one of the biopterin-dependent aromatic amino acid hydroxylases. Production of 5-HTP is the rate-limiting step in 5-HT (serotonin) synthesis. 5-HTP is normally rapidly converted to 5-HT by amino acid decarboxylase. [1]

Metabolism

5-HTP is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6. [2] This reaction occurs both in nervous tissue and in the liver. [3] 5-HTP crosses the blood–brain barrier, [4] while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B6, is thought to be metabolized and excreted. [5] [6]

Metabolic pathway from tryptophan to serotonin. Trp-5ht-pathway.svg
Metabolic pathway from tryptophan to serotonin.
5-HTP AAAD Serotonin
5-Hydroxy-L-Tryptophan (5-HTP).svg   Serotonin (5-HT).svg
PLP
Biochem reaction arrow forward YNNN horiz med.svg

Dietary sources

Though 5-HTP is found in food only in insignificant quantities, it is a chemical involved intermediately in the metabolism of tryptophan, an amino acid found in all unfractionated foods, with lower total amino acid content correlating with increased tryptophan absorption. [7]

Use as a medication and supplement

5-HTP has been used medically and as a supplement under the name oxitriptan in the treatment of depression and for certain other indications. As of 2025, there are no current FDA approved medications containing 5-HTP.

It can be potentiated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor such as carbidopa or benserazide. These agents increase the strength and duration of oxitriptan. An investigational combination formulation is oxitriptan/carbidopa.

Research

Psychedelic effects

5-HTP robustly produces the head-twitch response (HTR) in rodents when administered at relatively high doses. [8] [9] [10] [11] [12] It dose-dependently induces the HTR in mice across a dose range of 50 to 250 mg/kg via intraperitoneal administration, with an inverted U-shaped dose–response curve and maximal induction of the HTR at a dose of 200 mg/kg. [12] [1] Similarly to the case of 5-HTP, intracerebroventricular injection of serotonin, but not peripheral administration of serotonin, produces the HTR. [9] [8] [11] The HTR is induced by serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin and is a behavioral proxy of psychedelic effects. [13] [8]

The HTR of 5-HTP is blocked by serotonin 5-HT2A receptor antagonists, which block the hallucinogenic effects of serotonergic psychedelics in humans, is prevented by aromatic L-amino acid decarboxylase (AAAD) inhibitors, which block conversion of 5-HTP into serotonin, and is potentiated by monoamine oxidase A (MAO-A) inhibitors, which prevent the degradation of serotonin and other endogenous tryptamines. [9] [8] [10] [11] [12] It is also suppressed by the serotonin 5-HT1A receptor full agonist 8-OH-DPAT, is greatly augmented by the serotonin 5-HT2C receptor antagonist RS-102221, and is reduced by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB. [12] In addition, the HTR of 5-HTP is abolished by indolethylamine N-methyltransferase (INMT) inhibitors, which block conversion of serotonin and other endogenous tryptamines into N-methylated tryptamines, such as N-methylserotonin (NMS; norbufotenin), bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT), and N,N-dimethyltryptamine (DMT). [8] [14] [11] These N-methylated tryptamines are well-known for their psychedelic effects, whereas serotonin itself, without biotransformation, does not seem to produce psychedelic effects. [8] [11] 5-HTP has not been found to produce psychedelic effects in humans, which has been attributed to the high doses required to produce such effects. [8] [10] The 5-HTP doses that produce the HTR in rodents are orders of magnitude higher than the doses of 5-HTP that have been used safely and therapeutically in humans. [10] [12] It remains unknown whether 5-HTP can produce psychedelic effects in humans. [15] [12] The highest dosage of 5-HTP that is known to have been evaluated in humans is about 3,000 mg per day. [12] [1] Serotonin syndrome and associated hallucinations have been reported with overdose of serotonin-elevating drugs, but psychedelic-like effects have not been reported. [12]

The lack of the HTR and psychedelic effects with serotonin itself has been attributed to the fact that these effects appear to be dependent on activation of a population of intracellular 5-HT2A receptors expressed in cortical neurons in the medial prefrontal cortex (mPFC) that lack the serotonin transporter (SERT) and are inaccessible to serotonin. [16] [17] Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, whereas serotonergic psychedelics and serotonin's N-methylated metabolites and analogues are lipophilic and readily enter these neurons. [16] [17] These findings may also explain why selective serotonin reuptake inhibitors (SSRIs) and related serotonergic agents do not produce psychedelic effects. [16]

The properties of 5-HTP in animal drug discrimination tests have been studied. [18] [19] [20] [21] [22] [23] 5-HTP generalizes with the serotonin releasing agent fenfluramine and its cue is markedly potentiated by the selective serotonin reuptake inhibitor (SSRI) fluoxetine. [18] [19] However, numerous serotonin receptor antagonists, including methysergide, cyproheptadine, metergoline, methiothepin (metitepine), ketanserin, pirenperone, pizotifen, and mianserin, all failed to block the discriminative stimulus properties of 5-HTP. [18] [19] [20] [21] Conflictingly however, in a subsequent study, pizotifen was able to fully block the discriminative stimulus properties of 5-HTP. [18] [21] The inability of serotonin 5-HT2A receptor antagonists to block the discriminative stimulus properties of 5-HTP is in notable contrast to their ability to block the 5-HTP-induced HTR. [24] 5-HTP only partially substitutes for LSD in drug discrimination tests, whereas LSD and quipazine fully substitute for 5-HTP. [20] The full substitution of LSD and quipazine for 5-HTP can be blocked by the serotonin 5-HT2A receptor antagonist ketanserin. [20] The findings of drug discrimination tests suggest that 5-HTP has a more complex or compound discriminative stimulus compared to other agents like LSD and that its stimulus properties may not be readily explained by either the serotonin 5-HT1 or 5-HT2 receptors alone. [18] [20] [23] Instead, a combination of actions at these and/or other receptors may be involved in its stimulus effects. [18] [20] [23]

See also

References

  1. 1 2 3 Turner EH, Loftis JM, Blackwell AD (March 2006). "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacology & Therapeutics. 109 (3): 325–338. doi:10.1016/j.pharmthera.2005.06.004. PMID   16023217. S2CID   2563606. 5-HTP is commonly given to rats or mice to test the SSRI potency of putative antidepressants (O'Neil & Moore, 2003). This simple in vivo test measures the potency of a compound in potentiating the serotonin syndrome induced by the administration of 5-HTP (Grahame-Smith, 1971). The behavioral and physiological features of this syndrome include hypolocomotion, head twitch, forepaw treading, tremors, hindlimb abduction, flat body posture or hunched back, cyanosis, and hyperthermia. In rodents, 5-HTP induces a serotonin syndrome at dosages of 100– 200 mg/ kg (Casal et al., 2000; Nisijima et al., 2000, 2001; see Section 4.4.3 for more on serotonin syndrome).
  2. ↑ Rahman MK, Nagatsu T, Sakurai T, Hori S, Abe M, Matsuda M (October 1982). "Effect of pyridoxal phosphate deficiency on aromatic L-amino acid decarboxylase activity with L-DOPA and L-5-hydroxytryptophan as substrates in rats". Japanese Journal of Pharmacology. 32 (5): 803–11. doi: 10.1254/jjp.32.803 . PMID   6983619.
  3. ↑ Bouchard S, Bousquet C, Roberge AG (September 1981). "Characteristics of dihydroxyphenylalanine/5-hydroxytryptophan decarboxylase activity in brain and liver of cat". Journal of Neurochemistry. 37 (3): 781–7. doi:10.1111/j.1471-4159.1982.tb12555.x. PMID   6974228. S2CID   43853143.
  4. ↑ Nakatani Y, Sato-Suzuki I, Tsujino N, Nakasato A, Seki Y, Fumoto M, Arita H (May 2008). "Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat". The European Journal of Neuroscience. 27 (9): 2466–72. doi:10.1111/j.1460-9568.2008.06201.x. PMID   18445233. S2CID   18940166.
  5. ↑ Bouchard S, Roberge AG (July 1979). "Biochemical properties and kinetic parameters of dihydroxyphenylalanine--5-hydroxytryptophan decarboxylase in brain, liver, and adrenals of cat". Canadian Journal of Biochemistry. 57 (7): 1014–8. doi:10.1139/o79-126. PMID   39668.
  6. ↑ Amamoto T, Sarai K (September 1976). "On the tryptophan-serotonin metabolism in manic-depressive disorders. Changes in plasma 5-HT and 5-HIAA levels and urinary 5-HIAA excretion following oral loading of L-5HTP in patients with depression". Hiroshima Journal of Medical Sciences. 25 (2–3): 135–40. PMID   1088369.
  7. ↑ "5-Hydroxytryptophan". University of Maryland Medical Center. Archived from the original on 6 January 2010. Retrieved 21 January 2010.
  8. 1 2 3 4 5 6 7 Kozlenkov, Alexey; González-Maeso, Javier (2013). "Animal Models and Hallucinogenic Drugs". The Neuroscience of Hallucinations. New York, NY: Springer New York. pp. 253–277. doi:10.1007/978-1-4614-4121-2_14. ISBN   978-1-4614-4120-5.
  9. 1 2 3 Schmid, Cullen L.; Bohn, Laura M. (2018). "βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events". 5-HT2A Receptors in the Central Nervous System. Cham: Springer International Publishing. pp. 31–55. doi:10.1007/978-3-319-70474-6_2. ISBN   978-3-319-70472-2.
  10. 1 2 3 4 Jaster AM, de la Fuente Revenga M, González-Maeso J (July 2022). "Molecular targets of psychedelic-induced plasticity". J Neurochem. 162 (1): 80–88. doi:10.1111/jnc.15536. PMC   9068831 . PMID   34741320.
  11. 1 2 3 4 5 Schmid CL, Bohn LM (October 2010). "Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo". J Neurosci. 30 (40): 13513–24. doi:10.1523/JNEUROSCI.1665-10.2010. PMC   3001293 . PMID   20926677.
  12. 1 2 3 4 5 6 7 8 Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T (November 2022). "Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications". Int J Mol Sci. 23 (22): 14148. doi: 10.3390/ijms232214148 . PMC   9698447 . PMID   36430623. HTR was first described in mice after administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP) [22], and has been further characterized by subsequent investigators [23–29]. Although extensive research has documented the effect of 5-HTP to induce HTR in rodents [30–33], psychedelic effects have not been reported at doses administered to humans [34]. [...] 5-HTP-induced HTR has previously described by multiple authors [30–33,48]. However, 5-HTP has not been reported to have psychedelic effects in humans [49]. Although, overdoses of compounds that increase serotonin release can result in serotonin syndrome, which may include hallucinations [50,51], classic psychedelic effects resembling those induced by tryptaminergic and other psychedelic drugs have not been reported. In our study, administration of 5-HTP at 150–250 mg/kg induced significant HTR. The implications of administering equivalent high doses of 5-HTP to humans are unknown. There are two instances of administering up to 3000 mg 5-HTP per os per day but not as a single dose. Such prolonged exposure that can result in tolerance effects [49].
  13. ↑ Canal CE, Morgan D (2012). "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". Drug Test Anal. 4 (7–8): 556–576. doi:10.1002/dta.1333. PMC   3722587 . PMID   22517680.
  14. ↑ Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 159–199. doi:10.1007/7854_2016_466. ISBN   978-3-662-55878-2. PMC   5787039 . PMID   28224459.
  15. ↑ Hanks JB, González-Maeso J (January 2013). "Animal models of serotonergic psychedelics". ACS Chem Neurosci. 4 (1): 33–42. doi:10.1021/cn300138m. PMC   3547517 . PMID   23336043. Following these initial studies, it was shown that a large dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces head-twitch behavior in mice.32 However, to our knowledge, equivalent doses of 5-HTP have not been tested in healthy volunteers, and therefore, it remains unknown whether 5-HTP is psychedelic in humans. Subsequently, numerous psychedelic compounds were shown to induce head-twitch behavior.27,33−36
  16. 1 2 3 Sapienza, Jacopo (13 October 2023). "The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research?". Psychoactives. 2 (4): 287–293. doi: 10.3390/psychoactives2040018 . ISSN   2813-1851.
  17. 1 2 Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE (February 2023). "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science. 379 (6633): 700–706. Bibcode:2023Sci...379..700V. doi:10.1126/science.adf0435. PMC   10108900 . PMID   36795823.
  18. 1 2 3 4 5 6 Glennon RA (1988). "Site-Selective Serotonin Agonists as Discriminative Stimuli". Transduction Mechanisms of Drug Stimuli. Psychopharmacology Series. Vol. 4. pp. 15–31. doi:10.1007/978-3-642-73223-2_2. ISBN   978-3-642-73225-6. PMID   3293039.
  19. 1 2 3 Barrett RJ, Blackshear MA, Sanders-Bush E (1982). "Discriminative stimulus properties of L-5-hydroxytryptophan: behavioral evidence for multiple serotonin receptors". Psychopharmacology (Berl). 76 (1): 29–35. doi:10.1007/BF00430750. PMID   6805004.
  20. 1 2 3 4 5 6 Cunningham KA, Callahan PM, Appel JB (January 1985). "Differentiation between the stimulus effects of l-5-hydroxytryptophan and LSD". Eur J Pharmacol. 108 (2): 179–186. doi:10.1016/0014-2999(85)90723-x. PMID   3156756.
  21. 1 2 3 Friedman R, Barrett RJ, Sanders-Bush E (1983). "Additional evidence that L-5-hydroxytryptophan discrimination models a unique serotonin receptor". Psychopharmacology (Berl). 80 (3): 209–213. doi:10.1007/BF00436154. PMID   6137018.
  22. ↑ Witkin JM, Brady LS, Barrett JE (1988). "Antagonism by ketanserin of the behavioral effects of quipazine but not l-5-hydroxytryptophan in squirrel monkeys". Psychopharmacology (Berl). 94 (3): 302–305. doi:10.1007/BF00174679. PMID   3128804.
  23. 1 2 3 Winter JC, Rabin RA (July 1988). "A comparison of the discriminative stimulus properties of l-5-hydroxytryptophan in the presence of either citalopram or Ro 4-4602". Pharmacol Biochem Behav. 30 (3): 613–616. doi:10.1016/0091-3057(88)90073-1. PMID   3264918.
  24. ↑ Glennon, Richard A. (23 October 1992). "Animal Models for Assessing Hallucinogenic Agents". Animal Models of Drug Addiction. Vol. 24. New Jersey: Humana Press. pp. 345–382. doi:10.1385/0-89603-217-5:345. ISBN   978-0-89603-217-0 . Retrieved 20 May 2025.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.