Editing 5-Hydroxytryptophan (section)

==Research==
===Psychedelic effects===
{{See also|Tryptophan#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">{{cite journal | vauthors = Jaster AM, de la Fuente Revenga M, González-Maeso J | title = Molecular targets of psychedelic-induced plasticity | journal = J Neurochem | volume = 162 | issue = 1 | pages = 80–88 | date = July 2022 | pmid = 34741320 | pmc = 9068831 | doi = 10.1111/jnc.15536 | url = }}</ref><ref name="SchmidBohn2010">{{cite journal | vauthors = Schmid CL, Bohn LM | title = Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo | journal = J Neurosci | volume = 30 | issue = 40 | pages = 13513–24 | date = October 2010 | pmid = 20926677 | pmc = 3001293 | doi = 10.1523/JNEUROSCI.1665-10.2010 | url = }}</ref><ref name="ShaharBotvinnikEsh-Zuntz2022">{{cite journal | vauthors = Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T | title = Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications | journal = Int J Mol Sci | volume = 23 | issue = 22 | date = November 2022 | page = 14148 | pmid = 36430623 | pmc = 9698447 | doi = 10.3390/ijms232214148 | doi-access = free | url = | quote = 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].}}</ref> It [[dose-dependently]] induces the HTR in mice across a dose range of 50 to 250{{nbsp}}mg/kg via [[intraperitoneal administration]], with an [[inverted U-shaped curve|inverted U-shaped]] [[dose–response curve]] and maximal induction of the HTR at a dose of 200{{nbsp}}mg/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 psychedelic]]s like [[lysergic acid diethylamide]] (LSD) and [[psilocybin]] and is a behavioral proxy of psychedelic effects.<ref name="CanalMorgan2012">{{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 Test Anal | volume = 4 | issue = 7–8 | pages = 556–576 | date = 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 | url = }}</ref><ref name="KozlenkovGonzález-Maeso2013" />

The HTR of 5-HTP is blocked by serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[receptor antagonist|antagonist]]s, which block the [[hallucinogen]]ic effects of serotonergic psychedelics in humans, is prevented by [[aromatic L-amino acid decarboxylase|aromatic <small>L</small>-amino acid decarboxylase]] (AAAD) [[aromatic L-amino acid decarboxylase inhibitor|inhibitor]]s, which block conversion of 5-HTP into serotonin, and is potentiated by [[monoamine oxidase A]] (MAO-A) [[monoamine oxidase inhibitor|inhibitor]]s, which prevent the [[catabolism|degradation]] of serotonin and other [[endogenous]] [[substituted tryptamine|tryptamine]]s.<ref name="SchmidBohn2018">{{cite book | last1=Schmid | first1=Cullen L. | last2=Bohn | first2=Laura M. | title=5-HT2A Receptors in the Central Nervous System | chapter=βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events | publisher=Springer International Publishing | publication-place=Cham | date=2018 | isbn=978-3-319-70472-2 | doi=10.1007/978-3-319-70474-6_2 | pages=31–55}}</ref><ref name="KozlenkovGonzález-Maeso2013" /><ref name="JasterdelaFuenteRevengaGonzález-Maeso2022" /><ref name="SchmidBohn2010" /><ref name="ShaharBotvinnikEsh-Zuntz2022" /> It is also suppressed by the serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] [[full agonist]] [[8-OH-DPAT]], is greatly augmented by the serotonin [[5-HT2C receptor|5-HT<sub>2C</sub> 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|indolethylamine ''N''-methyltransferase]] (INMT) [[enzyme inhibitor|inhibitor]]s, which block conversion of serotonin and other endogenous tryptamines into ''N''-[[methyl group|methylated]] tryptamines, such as [[N-Methylserotonin|''N''-methylserotonin]] (NMS; norbufotenin), [[bufotenin]] (5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT), and [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT).<ref name="KozlenkovGonzález-Maeso2013">{{cite book | last1=Kozlenkov | first1=Alexey | last2=González-Maeso | first2=Javier | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | pages=253–277}}</ref><ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = }}</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">{{cite journal | vauthors = Hanks JB, González-Maeso J | title = Animal models of serotonergic psychedelics | journal = ACS Chem Neurosci | volume = 4 | issue = 1 | pages = 33–42 | date = January 2013 | pmid = 23336043 | pmc = 3547517 | doi = 10.1021/cn300138m | url = | quote = 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}}</ref><ref name="ShaharBotvinnikEsh-Zuntz2022" /> The highest dosage of 5-HTP that is known to have been evaluated in humans is about 3,000{{nbsp}}mg per day.<ref name="ShaharBotvinnikEsh-Zuntz2022" /><ref name="TurnerLoftisBlackwell2006" /> [[Serotonin syndrome]] and associated [[hallucination]]s 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<sub>2A</sub> receptors expressed in [[Cerebral cortex|cortical]] [[neuron]]s in the [[medial prefrontal cortex]] (mPFC) that lack the [[serotonin transporter]] (SERT) and are inaccessible to serotonin.<ref name="Sapienza2023">{{cite journal | last=Sapienza | first=Jacopo | title=The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? | journal=Psychoactives | volume=2 | issue=4 | date=13 October 2023 | issn=2813-1851 | doi=10.3390/psychoactives2040018 | doi-access=free | pages=287–293}}</ref><ref name="VargasDunlapDong2023">{{cite journal | vauthors = 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 | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = }}</ref> Serotonin itself is too [[hydrophilic]] to enter serotonergic neurons without the SERT, whereas serotonergic psychedelics and serotonin's ''N''-methylated [[metabolite]]s and [[structural analogue|analogue]]s are [[lipophilic]] and readily enter these neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> These findings may also explain why [[selective serotonin reuptake inhibitor]]s (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">{{cite journal | vauthors = Glennon RA | title = Site-selective serotonin agonists as discriminative stimuli | journal = Psychopharmacol Ser | volume = 4 | issue = | pages = 15–31 | date = 1988 | pmid = 3293039 | doi = 10.1007/978-3-642-73223-2_2 | url = }}</ref><ref name="BarrettBlackshearSanders-Bush1982">{{cite journal | vauthors = Barrett RJ, Blackshear MA, Sanders-Bush E | title = Discriminative stimulus properties of L-5-hydroxytryptophan: behavioral evidence for multiple serotonin receptors | journal = Psychopharmacology (Berl) | volume = 76 | issue = 1 | pages = 29–35 | date = 1982 | pmid = 6805004 | doi = 10.1007/BF00430750 | url = }}</ref><ref name="CunninghamCallahanAppel1985">{{cite journal | vauthors = Cunningham KA, Callahan PM, Appel JB | title = Differentiation between the stimulus effects of l-5-hydroxytryptophan and LSD | journal = Eur J Pharmacol | volume = 108 | issue = 2 | pages = 179–186 | date = January 1985 | pmid = 3156756 | doi = 10.1016/0014-2999(85)90723-x | url = }}</ref><ref name="FriedmanBarrettSanders-Bush1983">{{cite journal | vauthors = Friedman R, Barrett RJ, Sanders-Bush E | title = Additional evidence that L-5-hydroxytryptophan discrimination models a unique serotonin receptor | journal = Psychopharmacology (Berl) | volume = 80 | issue = 3 | pages = 209–213 | date = 1983 | pmid = 6137018 | doi = 10.1007/BF00436154 | url = }}</ref><ref name="WitkinBradyBarrett1988">{{cite journal | vauthors = Witkin JM, Brady LS, Barrett JE | title = Antagonism by ketanserin of the behavioral effects of quipazine but not l-5-hydroxytryptophan in squirrel monkeys | journal = Psychopharmacology (Berl) | volume = 94 | issue = 3 | pages = 302–305 | date = 1988 | pmid = 3128804 | doi = 10.1007/BF00174679 | url = }}</ref><ref name="WinterRabin1988">{{cite journal | vauthors = Winter JC, Rabin RA | title = A comparison of the discriminative stimulus properties of l-5-hydroxytryptophan in the presence of either citalopram or Ro 4-4602 | journal = Pharmacol Biochem Behav | volume = 30 | issue = 3 | pages = 613–616 | date = July 1988 | pmid = 3264918 | doi = 10.1016/0091-3057(88)90073-1 | url = }}</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 antagonist]]s, 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<sub>2A</sub> 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">{{cite book | last=Glennon | first=Richard A. | title=Animal Models of Drug Addiction | chapter=Animal Models for Assessing Hallucinogenic Agents | publisher=Humana Press | publication-place=New Jersey | volume=24 | date=23 October 1992 | isbn=978-0-89603-217-0 | doi=10.1385/0-89603-217-5:345 | url=http://link.springer.com/10.1385/0-89603-217-5:345 | access-date=20 May 2025 | page=345–382}}</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<sub>2A</sub> 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 receptor|5-HT<sub>1</sub>]] or [[5-HT2 receptor|5-HT<sub>2</sub> receptor]]s 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" />