Chemistry:5-Hydroxytryptophan

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5-Hydroxytryptophan
Skeletal formula
Ball-and-stick model
Names
IUPAC name
2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
MeSH 5-Hydroxytryptophan
UNII
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)
Pharmacology
1=ATC code }} N06AX01 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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

Uses

5-HTP is sold over the counter in the United States , France , Canada , Singapore, the Netherlands, and the United Kingdom as a dietary supplement for use as an antidepressant, appetite suppressant, and sleep aid. It is also marketed in many European countries for the indication of major depression under the trade names Cincofarm, Levothym, Levotonine, Oxyfan, Telesol, Tript-OH, and Triptum.[1]

A 2002 review concluded that although the data evaluated suggests that 5-HTP is more effective than placebo in the treatment of depression, the evidence was insufficient to be conclusive due to a lack of clinical data meeting the rigorous standards of the day.[2] More and larger studies using current methodologies are needed to determine if 5-HTP is truly effective in treating depression.[3][4] In small, controlled trials 5-HTP has also been reported to augment the antidepressant efficacy of the antidepressant clomipramine.[5][6][7] A 2020 meta-analysis found oral 5-HTP supplementation had a large effect size on depression symptom severity. However, the included studies were considered relatively weak and the methods and treatment duration varied between the seven studies examined.[8]

5-HTP use after MDMA

MDMA is an empathogenic-entactogenic and serotonergic psychotropic drug used primarily for recreational, though sometimes also therapeutic, purposes. Among users of MDMA, the serotonergic effects of the drug are often of particular interest and concern: After consuming MDMA, serotonin concentrations are greatly reduced in the brain. 5-HTP is necessary for serotonin production and its concentrations in the brain also decrease after taking MDMA.

Other usage

At high doses, or in combination with carbidopa, 5-HTP has been used to treat obesity (by promoting weight loss).[9][10]

In clinical trials of various design, 5-HTP has also been reported to treat fibromyalgia,[11] myoclonus,[12] migraine,[13] and cerebellar ataxia.[14] However, these clinical findings, as for all therapeutic findings with 5-HTP, are preliminary and need confirmation in larger trials.

Drawbacks

5-HTP's short half-life (<2h)[15] may inherently limit its therapeutic potential,[16] as systemic 5-HTP exposure levels will fluctuate substantially even with relatively frequent dosing. Such exposure fluctuations are usually associated with increased adverse event burdens resulting from Cmax (time to maximal systemic concentration) drug spikes, and decreased clinical efficacy resulting from sub-therapeutic exposure for large parts of the day, when taken as a single dose unit or at intervals significantly larger than Cmax. It has been proposed that 5-HTP dosage forms achieving prolonged delivery would be more effective,[16] as has been demonstrated many times with other pharmaceuticals with short durations of action.[17] For example, controlled release oxycodone (OxyContin) or morphine (MS-Contin) are intended to, via novel delivery mechanisms, permit pain relief for up to twelve hours with an active ingredient which only provides relief for 3–6 hours. However, the inherent variability amongst different people with respect to drug metabolism makes this task challenging.

Side effects

Potential side effects of 5-HTP include heartburn, stomach pain, nausea, vomiting, diarrhea, drowsiness, sexual problems, vivid dreams or nightmares, and muscle problems.[18] Because 5-HTP has not been thoroughly studied in a clinical setting, possible side effects and interactions with other drugs are not well known. According to the US National Library of Medicine, 5-HTP has not been associated with serotonin syndrome or any serious adverse events in humans.[19] Across multiple studies, 5-HTP has also been reported to not cause any noticeable hematological or cardiovascular changes.[20] 5-HTP had also been associated with eosinophilia, but later studies have not found any causal connection.[21]

Interactions

When combined with antidepressants of the MAOI or SSRI class, very high parenteral doses of 5-HTP can cause acute serotonin syndrome in rats.[22][23] It is unclear if such findings have clinical relevance, as most drugs will cause serious adverse events or death in rodents at very high doses. In humans 5-HTP has never been clinically associated with serotonin syndrome, although a case report suggests 5-HTP can precipitate mania when added to an MAOI.[24]

When combined with carbidopa (as a treatment for symptoms of Parkinson's disease), 5-HTP causes nausea and vomiting; however this can be alleviated via administration of granisetron.[25] As mentioned below under pharmacology, cases of scleroderma-like illness have been reported in patients using carbidopa and 5-HTP.[26]

Oral 5-HTP results in an increase in urinary 5-HIAA, a serotonin metabolite, indicating that 5-HTP is peripherally metabolized to serotonin, which is then metabolized. This might cause false positive results in tests looking for carcinoid syndrome.[27][28] Due to the conversion of 5-HTP into serotonin by the liver, there could be a risk of heart valve disease from serotonin's effect on the heart, as based on preclinical findings.[29][30] However, 5-HTP has not been associated with cardiac toxicity in humans.[21][20][19][31]

It has been suggested that 5-HTP may cause eosinophilia-myalgia syndrome (EMS), a serious condition which results in extreme muscle tenderness, myalgia, and blood abnormalities. However, there is evidence to show that EMS was likely caused by a contaminant in certain 5-HTP supplements.[32]

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.[33]

Absorption

After oral administration, 5-HTP is absorbed by the upper intestine.[15] The mode of absorption is not known, but presumably involves active transport via amino acid transporters. 5-HTP is adequately absorbed via oral cavity.[34] With a decarboxylase inhibitor, the bioavailability of 5-HTP can be higher than 50%.[35]

Pharmacokinetics

5-HTP is rapidly absorbed with a tmax of ≈1.5 h, and rapidly eliminated with a half-life of ≈1.5 – 2 h. Co-administration of a decarboxylase inhibitor (e.g. carbidopa, benserazide) doubles the half-life of 5-HTP to ≈ 3 – 4 h,[36][15] and enhances exposure several-fold, depending on the dosing regimen.[15][37]

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.[38] This reaction occurs both in nervous tissue and in the liver.[39] 5-HTP crosses the blood–brain barrier,[40] while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B6, is thought to be metabolized and excreted.[41][42]

5-HTP AAAD Serotonin
5-Hydroxy-L-Tryptophan (5-HTP).svg   Serotonin (5-HT).svg
PLP
Biochem reaction arrow forward YNNN horiz med.svg
 
 


Pharmacology

The psychoactive action of 5-HTP is derived from its increase in production of serotonin in central nervous system tissue.[43]

Metabolic pathway from tryptophan to serotonin.

Research shows that co-administration with carbidopa greatly increases plasma 5-HTP levels.[44] Other studies have indicated the risk of a scleroderma-like condition resulting from the combination of 5-HTP and carbidopa.[45]

Regulatory status

There are currently no approved drug products containing 5-HTP approved by the FDA.[46] All available 5-HTP products are nutraceuticals and are as such not regulated or verified for purity, integrity, or clinical efficacy or safety, mandating caution regarding human consumption.[47]

As of 25 August 2020, Hungary added 5-HTP to the controlled psychoactive substances list, prohibiting production, sale, import, storage and use, becoming the first country to do so.[48]

5-HTP slow-release

5-HTP's short half-life is impractical for chronic drug therapy. Research conducted at Duke University in mice have demonstrated that 5-HTP when administered as slow-release appears to gain drug properties.[49] Slow-release delivery attenuates or abolishes the peaks and valleys in 5-HTP exposure during treatment.[50] Slow-release delivery of 5-HTP markedly improved the safety profile of 5-HTP and conferred stable plasma exposure of 5-HTP and strong and sustained enhancement of brain serotonin function.[49] This discovery indicates that 5-HTP slow-release medications represent a new avenue for treatment of brain disorders responsive to serotonergic enhancement.

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.[51]

The seeds of the Griffonia simplicifolia, a climbing shrub native to West Africa and Central Africa, are used as an herbal supplement for their 5-HTP content.[52][53][54] In one 2010 trial, Griffonia simplicifolia extract appeared to increase satiety in overweight women.[55]

See also

References

  1. ↑ Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA773. 
  2. ↑ Shaw, Kelly A, ed (2002). "Tryptophan and 5-hydroxytryptophan for depression". The Cochrane Database of Systematic Reviews 2010 (1): CD003198. doi:10.1002/14651858.CD003198. PMID 11869656. https://espace.library.uq.edu.au/view/UQ:209937/UQ209937_OA.pdf. 
  3. ↑ "5-Hydroxytryptophan (5-HTP)". University of Maryland Medical Center. http://www.umm.edu/altmed/articles/5-hydroxytryptophan-000283.htm. 
  4. ↑ "Second-tier natural antidepressants: review and critique". Journal of Affective Disorders 130 (3): 343–357. May 2011. doi:10.1016/j.jad.2010.06.010. PMID 20579741. 
  5. ↑ "Serotonin precursors in the treatment of depression". Advances in Biochemical Psychopharmacology 34: 259–286. 1982. PMID 6753514. 
  6. ↑ "5-hydroxytryptophan in combination with clomipramine in "therapy-resistant" depressions". Psychopharmacologia 38 (3): 267–269. 1974. doi:10.1007/BF00421379. PMID 4547418. 
  7. ↑ "Treatment of depression with L-5-hydroxytryptophan combined with chlorimipramine, a double-blind study". International Journal of Clinical Pharmacology Research 3 (4): 239–250. 1983. PMID 6381336. 
  8. ↑ Javelle, Florian; Lampit, Amit; Bloch, Wilhelm; Häussermann, Peter; Johnson, Sheri; Zimmer, Philipp (2020). "Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis". Nutrition Reviews 78 (1): 77–88. doi:10.1093/nutrit/nuz039. PMID 31504850. https://academic.oup.com/nutritionreviews/article-abstract/78/1/77/5555860. 
  9. ↑ "Combinations of drugs in the Treatment of Obesity". Pharmaceuticals 3 (8): 2398–2415. July 2010. doi:10.3390/ph3082398. PMID 27713360. 
  10. ↑ "Off-label drugs for weight management". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 10: 223–234. 2017. doi:10.2147/DMSO.S95299. PMID 28652791. 
  11. ↑ "Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome". J Int Med Res. 18 (3): 201–209. 1990. doi:10.1177/030006059001800304. PMID 2193835. 
  12. ↑ "Treatment of myoclonus with L-5-hydroxytryptophan and carbidopa: clinical, electrophysiological, and biochemical observations". Ann Neurol 7 (6): 570–576. 1980. doi:10.1002/ana.410070611. PMID 6969054. 
  13. ↑ "5-OH-Tryptophane in migraine: clinical and neurophysiological considerations". J Neurol 225 (1): 41–46. 1981. doi:10.1007/bf00313460. PMID 6164755. 
  14. ↑ "Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan. A double-blind study with quantified data processing". Arch Neurol 45 (11): 1217–1222. Nov 1988. doi:10.1001/archneur.1988.00520350055016. PMID 3190503. 
  15. ↑ 15.0 15.1 15.2 15.3 "Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers". Journal of Clinical Psychopharmacology 22 (2): 183–189. April 2002. doi:10.1097/00004714-200204000-00012. PMID 11910264. 
  16. ↑ 16.0 16.1 "Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale". Trends in Pharmacological Sciences 37 (11): 933–944. November 2016. doi:10.1016/j.tips.2016.09.001. PMID 27692695. 
  17. ↑ "Assessment of the feasibility of oral controlled release in an exploratory development setting". Drug Discovery Today 10 (17): 1159–1166. September 2005. doi:10.1016/S1359-6446(05)03551-8. PMID 16182208. 
  18. ↑ "5-HTP". U.S. National Library of Medicine. https://www.nlm.nih.gov/medlineplus/druginfo/natural/794.html. 
  19. ↑ 19.0 19.1 "5-Hydroxytryptophan, C11H12N2O3, CID 144 - PubChem". https://pubchem.ncbi.nlm.nih.gov/compound/5-Hydroxytryptophan#section=Toxicity. 
  20. ↑ 20.0 20.1 "5-Hydroxytryptophan: a review of its antidepressant efficacy and adverse effects". J Clin Psychopharmacol 7 (3): 127–37. Jun 1987. doi:10.1097/00004714-198706000-00002. PMID 3298325. 
  21. ↑ 21.0 21.1 "Safety of 5-hydroxy-L-tryptophan". Toxicol. Lett. 150 (1): 111–22. 2004. doi:10.1016/j.toxlet.2003.12.070. PMID 15068828. 
  22. ↑ "Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats". European Journal of Pharmacology 588 (2–3): 198–206. July 2008. doi:10.1016/j.ejphar.2008.04.004. PMID 18499101. 
  23. ↑ "Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats". European Journal of Pharmacology 532 (3): 258–64. February 2006. doi:10.1016/j.ejphar.2005.12.075. PMID 16488409. 
  24. ↑ "Mania following addition of hydroxytryptophan to monoamine oxidase inhibitor". General Hospital Psychiatry 34 (1): 102.e13–4. 2012. doi:10.1016/j.genhosppsych.2011.08.014. PMID 21963353. 
  25. ↑ "Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron". Journal of Psychopharmacology 24 (1): 65–72. January 2010. doi:10.1177/0269881108094299. PMID 18719048. 
  26. ↑ "Carbidopa/Levodopa". Truestarhealth.com. http://www.truestarhealth.com/Notes/1339004.html. 
  27. ↑ "Increase of urinary 5-hydroxyindoleacetic acid excretion but not serum chromogranin A following over-the-counter 5-hydroxytryptophan intake". Canadian Journal of Gastroenterology 22 (1): 49–53. January 2008. doi:10.1155/2008/472159. PMID 18209781. 
  28. ↑ "'Sweet Dreams', 'Happy Days' and elevated 24-h urine 5-hydroxyindoleacetic acid excretion". Annals of Clinical Biochemistry 50 (Pt 1): 80–2. January 2013. doi:10.1258/acb.2012.012041. PMID 23086978. 
  29. ↑ "Long-term serotonin administration induces heart valve disease in rats". Circulation 111 (12): 1517–22. March 2005. doi:10.1161/01.CIR.0000159356.42064.48. PMID 15781732. 
  30. ↑ "Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells". The American Journal of Pathology 161 (6): 2209–18. December 2002. doi:10.1016/S0002-9440(10)64497-5. PMID 12466135. 
  31. ↑ "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacol. Ther. 109 (3): 325–38. Mar 2006. doi:10.1016/j.pharmthera.2005.06.004. PMID 16023217. http://www.escholarship.org/uc/item/58h866d5. 
  32. ↑ "An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan". The Journal of Rheumatology 21 (12): 2261–5. December 1994. PMID 7699627. 
  33. ↑ "Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan". Pharmacology & Therapeutics 109 (3): 325–38. March 2006. doi:10.1016/j.pharmthera.2005.06.004. PMID 16023217. https://escholarship.org/uc/item/58h866d5. 
  34. ↑ "Relationship between the absorption of 5-hydroxytryptophan from an integrated diet, by means of Griffonia simplicifolia extract, and the effect on satiety in overweight females after oral spray administration". Eat Weight Disord. 17 (1): e22-8. March 2012. doi:10.3275/8165. PMID 22142813. 
  35. ↑ "Bioavailability and related pharmacokinetics in man of orally administered L-5-hydroxytryptophan in steady state". Acta Pharmacologica et Toxicologica 46 (4): 257–62. April 1980. doi:10.1111/j.1600-0773.1980.tb02451.x. PMID 6966118. 
  36. ↑ "The effects of aromatic amino acid decarboxylase inhibitors on plasma concentrations of 5-hydroxytryptophan in man". Acta Pharmacologica et Toxicologica 43 (1): 36–42. July 1978. doi:10.1111/j.1600-0773.1978.tb02229.x. PMID 309271. 
  37. ↑ "Kinetics of l-5-hydroxytryptophan in healthy subjects". Psychiatry Research 7 (3): 373–85. December 1982. doi:10.1016/0165-1781(82)90074-9. PMID 6187038. 
  38. ↑ "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. October 1982. doi:10.1254/jjp.32.803. PMID 6983619. 
  39. ↑ "Characteristics of dihydroxyphenylalanine/5-hydroxytryptophan decarboxylase activity in brain and liver of cat". Journal of Neurochemistry 37 (3): 781–7. September 1981. doi:10.1111/j.1471-4159.1982.tb12555.x. PMID 6974228. 
  40. ↑ "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. May 2008. doi:10.1111/j.1460-9568.2008.06201.x. PMID 18445233. 
  41. ↑ "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. July 1979. doi:10.1139/o79-126. PMID 39668. 
  42. ↑ "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. September 1976. PMID 1088369. 
  43. ↑ "5-HTP: Uses, Side Effects, Interactions and Warnings - WebMD". http://www.webmd.com/vitamins-supplements/ingredientmono-794-5-HTP.aspx?activeIngredientId=794&activeIngredientName=5-HTP. 
  44. ↑ "Plasma accumulation of metabolism of orally administered single dose L-5-hydroxytryptophan in man". Acta Pharmacologica et Toxicologica 49 (3): 184–9. September 1981. doi:10.1111/j.1600-0773.1981.tb00890.x. PMID 6175178. 
  45. ↑ "Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa". The New England Journal of Medicine 303 (14): 782–7. October 1980. doi:10.1056/NEJM198010023031403. PMID 6997735. 
  46. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". https://www.accessdata.fda.gov/Scripts/cder/ob/index.cfm. 
  47. ↑ "5-HTP: MedlinePlus Supplements". https://medlineplus.gov/druginfo/natural/794.html. 
  48. ↑ MAGYARORSZÁG HIVATALOS LAPJA. Retrieved 2021-04-28.
  49. ↑ 49.0 49.1 "SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept". Neuropsychopharmacology 41 (9): 2324–34. Aug 2016. doi:10.1038/npp.2016.35. PMID 26932820. 
  50. ↑ "Assessment of the feasibility of oral controlled release in an exploratory development setting". Drug Discov Today 10 (17): 1159–66. 2005. doi:10.1016/S1359-6446(05)03551-8. PMID 16182208. 
  51. ↑ "5-Hydroxytryptophan". University of Maryland Medical Center. http://www.umm.edu/altmed/articles/5-hydroxytryptophan-000283.htm. 
  52. ↑ "5-Hydroxytryptophan (5-HTP)". A.D.A.M., Inc.. University of Maryland Medical Center. http://www.umm.edu/altmed/articles/5-hydroxytryptophan-000283.htm.  Animated Dissection of Anatomy for Medicine, Inc. (A.D.A.M., Inc.) provided health and benefits information and technology to healthcare organizations, employers, consumers, and educational institutions
  53. ↑ "An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress". Neuro Endocrinology Letters 31 (5): 663–6. 2010. PMID 21178946. 
  54. ↑ "5-hydroxy-L-tryptophan", National Center for Biotechnology Information, PubChem Compound Database, September 2004, https://pubchem.ncbi.nlm.nih.gov/compound/439280 CID=439280
  55. ↑ "Relationship between the absorption of 5-hydroxytryptophan from an integrated diet, by means of Griffonia simplicifolia extract, and the effect on satiety in overweight females after oral spray administration". Eating and Weight Disorders 17 (1): e22–8. March 2012. doi:10.3275/8165. PMID 22142813. 

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(tyrosine→epinephrine)
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