5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

and

chemical A chemical substance is a unique form of matter with constant chemical composition and characteristic properties. Chemical substances may take the form of a single element or chemical compounds. If two or more chemical substances can be combin ...

precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), hypothesized genus of fossil birds that was composed of fossilized parts of unre ...

as well as a

metabolic intermediate Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells. Although these intermediates are of relatively minor direct importance to cell ...

in the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

. 5-HTP can be manufactured and used as a

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

and supplement with the ''

oxitriptan Oxitriptan, also known as L-5-hydroxytryptophan (5-HTP) and sold under various brand names, is a medication and over-the-counter drug, over-the-counter dietary supplement used in the treatment of depression (mood), depression and for other indi ...

''. 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 Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

through the action of the enzyme

tryptophan hydroxylase Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-depen ...

. 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.

Metabolism

5-HTP is

decarboxylated Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

(5-hydroxytryptamine or 5-HT) by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

aromatic-L-amino-acid decarboxylase Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (), located in region 7p12.2-p12.1. Mechanism The enzyme uses pyri ...

with the help of vitamin B₆. This reaction occurs both in nervous tissue and in the liver. 5-HTP crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B₆, is thought to be metabolized and excreted.

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.

Use as a medication and supplement

5-HTP is used medically and as a supplement under the name ''

'' in the treatment of depression and for certain other indications. It can be potentiated in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

with a peripherally selective aromatic L-amino acid decarboxylase (AAAD)

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

such as

carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...

benserazide Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is on the World Health Organization's List of Essential Medicines. Medical use ...

. These agents increase the strength and duration of oxitriptan. An investigational combination formulation is

oxitriptan/carbidopa Carbidopa/oxitriptan (developmental code name EVX-101), or carbidopa/5-hydroxytryptophan (carbidopa/5-HTP), is a combination of 5-hydroxytryptophan (oxitriptan), a serotonin precursor, and carbidopa, a peripherally selective aromatic L-amino ...

Research

Psychedelic effects

5-HTP robustly produces the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

(HTR) in rodents when administered at relatively high doses. It dose-dependently induces the HTR in mice across a dose range of 50 to 250mg/kg via intraperitoneal administration, with an

inverted U-shaped In mathematics, a parabola is a plane curve which is Reflection symmetry, mirror-symmetrical and is approximately U-shaped. It fits several superficially different Mathematics, mathematical descriptions, which can all be proved to define exactl ...

dose–response curve and maximal induction of the HTR at a dose of 200mg/kg. Similarly to the case of 5-HTP,

intracerebroventricular injection Intracerebroventricular injection (often abbreviated as ICV injection) is a route of administration for drugs via injection into the cerebral ventricles so that it reaches the cerebrospinal fluid (CSF). This route of administration is often used ...

of serotonin, but not peripheral administration of serotonin, produces the HTR. The HTR is induced by

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s like

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD) and

psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

and is a behavioral proxy of psychedelic effects. The HTR of 5-HTP is blocked by serotonin 5-HT_2A receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic effects of serotonergic psychedelics in humans, is prevented by aromatic L-amino acid decarboxylase (AAAD)

s, which block conversion of 5-HTP into serotonin, and is potentiated by

monoamine oxidase A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative dea ...

(MAO-A)

s, which prevent the degradation of serotonin and other

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. 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 firs ...

s. It is also suppressed by the serotonin 5-HT_1A receptor

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

8-OH-DPAT 8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor, 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonis ...

, is greatly augmented by the serotonin 5-HT_2C receptor antagonist

RS-102221 RS-102221 is a drug developed by Hoffmann–La Roche, which was one of the first compounds discovered that acts as a potent and selective antagonist at the serotonin 5-HT2C receptor, with around 100× selectivity over the closely related 5-HT2A ...

, and is reduced by the

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1) antagonist EPPTB. In addition, the HTR of 5-HTP is abolished by indolethylamine ''N''-methyltransferase (INMT)

s, which block conversion of serotonin and other endogenous tryptamines into ''N''-

methylated Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...

tryptamines, such as ''N''-methylserotonin (NMS; norbufotenin),

bufotenin Bufotenin, also known as dimethylserotonin or as 5-hydroxy-''N'',''N''-dimethyltryptamine (5-HO-DMT), is a serotonergic psychedelic of the tryptamine family. It is a derivative of the psychedelic dimethyltryptamine (DMT) and of the neurotransmi ...

(5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT), and ''N'',''N''-dimethyltryptamine (DMT). These ''N''-methylated tryptamines are well-known for their psychedelic effects, whereas serotonin itself, without

biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected ...

, does not seem to produce psychedelic effects. 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. 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. It remains unknown whether 5-HTP can produce psychedelic effects in humans. The highest dosage of 5-HTP that is known to have been evaluated in humans is about 3,000mg per day.

Serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

and associated

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s have been reported with

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

of serotonin-elevating drugs, but psychedelic-like effects have not been reported. 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 This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

5-HT_2A receptors expressed in cortical

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s in the

medial prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA ...

(mPFC) that lack the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT) and are inaccessible to serotonin. Serotonin itself is too

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

to enter serotonergic neurons without the SERT, whereas serotonergic psychedelics and serotonin's ''N''-methylated

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s and analogues are

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

and readily enter these neurons. These findings may also explain why

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs) and related serotonergic agents do not produce psychedelic effects. The properties of 5-HTP in animal

drug discrimination Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties or interoceptive cues of psychoactive drugs. In drug discrimination, a subject is trained on a training drug, and then i ...

tests have been studied. 5-HTP generalizes with the

serotonin releasing agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...

fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

and its cue is markedly potentiated by the

(SSRI)

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

. However, numerous

serotonin receptor antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin receptor, serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A, 5-HT2A re ...

s, including

methysergide Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from th ...

cyproheptadine Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine, first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. It was patented in 1959 a ...

metergoline Metergoline (, ), also known as methergoline and sold under the brand names Contralac (veterinary) and Liserdol (clinical), is a monoaminergic medication of the ergoline group which is used as a prolactin inhibitor in the treatment of hyperprola ...

methiothepin Metitepine (; developmental code names Ro 8-6837 (maleate), VUFB-6276 (mesylate)), also known as methiothepin, is a drug described as a " psychotropic agent" of the tricyclic or tetracyclic group which was never marketed. It acts as a non-sele ...

(metitepine),

ketanserin Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...

, pirenperone,

pizotifen Pizotifen, also known as pizotyline and sold under the brand names Sandomigran and Mosegor among others, is an antimigraine agent of the tricyclic group which is used primarily as a preventative to reduce the frequency of recurrent migraine h ...

, and

mianserin Mianserin, sold under the brand name Tolvon among others, is an atypical antidepressant that is used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is closel ...

, all failed to block the discriminative stimulus properties of 5-HTP. Conflictingly however, in a subsequent study, pizotifen was able to fully block the discriminative stimulus properties of 5-HTP. 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. 5-HTP only partially substitutes for LSD in drug discrimination tests, whereas LSD and

quipazine Quipazine, also known as 1-(2-quinolinyl)piperazine (2-QP), is a serotonin, serotonergic drug of the arylpiperazine family and an structural analog, analogue of 1-(2-pyridinyl)piperazine which is used in scientific research. It was first describ ...

fully substitute for 5-HTP. The full substitution of LSD and quipazine for 5-HTP can be blocked by the serotonin 5-HT_2A receptor antagonist ketanserin. 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. Instead, a combination of actions at these and/or other receptors may be involved in its stimulus effects.

References

{{DEFAULTSORT:Hydroxytryptophan, 5- Alpha-Amino acids 5-Hydroxytryptamines Monoamine precursors Serotonin