5-Hydroxytryptophan

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 Template:Abbrlink 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.<ref name="TurnerLoftisBlackwell2006">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> This reaction occurs both in nervous tissue and in the liver.<ref>Template:Cite journal</ref> 5-HTP crosses the blood–brain barrier,<ref>Template:Cite journal</ref> while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B₆, is thought to be metabolized and excreted.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Metabolic pathway from tryptophan to serotonin.

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Use as a medication and supplement

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5-HTP is used medically and as a supplement under the name oxitriptan in the treatment of depression and for certain other indications.

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.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2018" /><ref name="JasterdelaFuenteRevengaGonzález-Maeso2022">Template:Cite journal</ref><ref name="SchmidBohn2010">Template:Cite journal</ref><ref name="ShaharBotvinnikEsh-Zuntz2022">Template:Cite journal</ref> It dose-dependently induces the HTR in mice across a dose range of 50 to 250Template:Nbspmg/kg via intraperitoneal administration, with an inverted U-shaped dose–response curve and maximal induction of the HTR at a dose of 200Template:Nbspmg/kg.<ref name="ShaharBotvinnikEsh-Zuntz2022" /><ref name="TurnerLoftisBlackwell2006" /> Similarly to the case of 5-HTP, intracerebroventricular injection of serotonin, but not peripheral administration of serotonin, produces the HTR.<ref name="SchmidBohn2018" /><ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2010" /> The HTR is induced by serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin and is a behavioral proxy of psychedelic effects.<ref name="CanalMorgan2012">Template:Cite journal</ref><ref name="KozlenkovGonzález-Maeso2013" />

The HTR of 5-HTP is blocked by serotonin 5-HT_2A 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.<ref name="SchmidBohn2018">Template:Cite book</ref><ref name="KozlenkovGonzález-Maeso2013" /><ref name="JasterdelaFuenteRevengaGonzález-Maeso2022" /><ref name="SchmidBohn2010" /><ref name="ShaharBotvinnikEsh-Zuntz2022" /> It is also suppressed by the serotonin 5-HT_1A receptor full agonist 8-OH-DPAT, is greatly augmented by the serotonin 5-HT_2C receptor antagonist RS-102221, and is reduced by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB.<ref name="ShaharBotvinnikEsh-Zuntz2022" /> 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).<ref name="KozlenkovGonzález-Maeso2013">Template:Cite book</ref><ref name="HalberstadtGeyer2018">Template:Cite book</ref><ref name="SchmidBohn2010" /> These N-methylated tryptamines are well-known for their psychedelic effects, whereas serotonin itself, without biotransformation, does not seem to produce psychedelic effects.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2010" /> 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.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="JasterdelaFuenteRevengaGonzález-Maeso2022" /> 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.<ref name="JasterdelaFuenteRevengaGonzález-Maeso2022" /><ref name="ShaharBotvinnikEsh-Zuntz2022" /> It remains unknown whether 5-HTP can produce psychedelic effects in humans.<ref name="HanksGonzález-Maeso2013">Template:Cite journal</ref><ref name="ShaharBotvinnikEsh-Zuntz2022" /> The highest dosage of 5-HTP that is known to have been evaluated in humans is about 3,000Template:Nbspmg per day.<ref name="ShaharBotvinnikEsh-Zuntz2022" /><ref name="TurnerLoftisBlackwell2006" /> Serotonin syndrome and associated hallucinations have been reported with overdose of serotonin-elevating drugs, but psychedelic-like effects have not been reported.<ref name="ShaharBotvinnikEsh-Zuntz2022" />

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-HT_2A receptors expressed in cortical neurons in the medial prefrontal cortex (mPFC) that lack the serotonin transporter (SERT) and are inaccessible to serotonin.<ref name="Sapienza2023">Template:Cite journal</ref><ref name="VargasDunlapDong2023">Template:Cite journal</ref> 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.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> These findings may also explain why selective serotonin reuptake inhibitors (SSRIs) and related serotonergic agents do not produce psychedelic effects.<ref name="Sapienza2023" />

The properties of 5-HTP in animal drug discrimination tests have been studied.<ref name="Glennon1988">Template:Cite journal</ref><ref name="BarrettBlackshearSanders-Bush1982">Template:Cite journal</ref><ref name="CunninghamCallahanAppel1985">Template:Cite journal</ref><ref name="FriedmanBarrettSanders-Bush1983">Template:Cite journal</ref><ref name="WitkinBradyBarrett1988">Template:Cite journal</ref><ref name="WinterRabin1988">Template:Cite journal</ref> 5-HTP generalizes with the serotonin releasing agent fenfluramine and its cue is markedly potentiated by the selective serotonin reuptake inhibitor (SSRI) fluoxetine.<ref name="Glennon1988" /><ref name="BarrettBlackshearSanders-Bush1982" /> 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.<ref name="Glennon1988" /><ref name="BarrettBlackshearSanders-Bush1982" /><ref name="CunninghamCallahanAppel1985" /><ref name="FriedmanBarrettSanders-Bush1983" /> Conflictingly however, in a subsequent study, pizotifen was able to fully block the discriminative stimulus properties of 5-HTP.<ref name="Glennon1988" /><ref name="FriedmanBarrettSanders-Bush1983" /> The inability of serotonin 5-HT_2A 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.<ref name="Glennon1992">Template:Cite book</ref> 5-HTP only partially substitutes for LSD in drug discrimination tests, whereas LSD and quipazine fully substitute for 5-HTP.<ref name="CunninghamCallahanAppel1985" /> The full substitution of LSD and quipazine for 5-HTP can be blocked by the serotonin 5-HT_2A receptor antagonist ketanserin.<ref name="CunninghamCallahanAppel1985" /> 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.<ref name="Glennon1988" /><ref name="CunninghamCallahanAppel1985" /><ref name="WinterRabin1988" /> Instead, a combination of actions at these and/or other receptors may be involved in its stimulus effects.<ref name="Glennon1988" /><ref name="CunninghamCallahanAppel1985" /><ref name="WinterRabin1988" />

See also

• α-Methyl-5-hydroxytryptophan

References

Template:Neurotransmitter metabolism intermediates Template:Serotonin receptor modulators {{#invoke:Navbox|navbox}}