Tryptamine is an indolamine metabolite of the essential 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 aromati ...

. The chemical structure is defined by an

indole Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environme ...

─ a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

nitrogen). The structure of tryptamine is a shared feature of certain aminergic neuromodulators including

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrat ...

, serotonin,

bufotenin Bufotenin (5-HO-DMT, bufotenine) is a tryptamine derivative - more specifically, a DMT derivative - related to the neurotransmitter serotonin. It is an alkaloid found in some species of toads (especially the skin), mushrooms and plants. The na ...

and psychedelic derivatives such as

dimethyltryptamine ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as ...

(DMT),

psilocybin Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&n ...

psilocin Psilocin (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated cou ...

and others. Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...

serotonergic Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chem ...

and

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid agonist, excitato ...

systems. In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT₄ receptors and regulates gastrointestinal motility. Multiple tryptamine-derived drugs have been developed to treat

migraines Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders. ''For a list of tryptamine derivatives, see: List of substituted tryptamines.'' Tryptamine Alkaloids 2

Natural occurrences

''For a list of plants, fungi and animals containing tryptamines, see

List of psychoactive plants This is a list of plant species that, when consumed by humans, are known or suspected to produce psychoactive effects: changes in nervous system function that alter perception, mood, consciousness, cognition or behavior. Many of these plants a ...

and

List of naturally occurring tryptamines Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino group, amino (NH2) group ...

.''

Mammalian brain

Endogenous levels of tryptamine in the mammalian brain are less than 100ng per gram of tissue. However, elevated levels of trace amines have been observed in patients with certain neuropsychiatric disorders, such as

bipolar depression Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

and

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

Mammalian gut microbiome

Tryptamine is relatively abundant in the

gut Gut or guts may refer to: Anatomy * Abdomen or belly, the region of a vertebrate between the chest and pelvis * Abdominal obesity or "a gut", a large deposit of belly fat * Gastrointestinal tract or gut, the system of digestive organs * Ins ...

and feces of humans and rodents.

Commensal Commensalism is a long-term biological interaction ( symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fr ...

bacteria, including ''Ruminococcus gnavus'' and ''Clostridium sporogenes'' in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...

, possess the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

tryptophan

decarboxylase Carboxy-lyases, also known as decarboxylases, are carbon–carbon lyases that add or remove a carboxyl group from organic compounds. These enzymes catalyze the decarboxylation of amino acids, beta-keto acids and alpha-keto acids. Classification ...

, which aids in the conversion of dietary tryptophan to tryptamine. Tryptamine is a

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...

for gut epithelial serotonin type 4 (5-HT₄) receptors and regulates gastrointestinal electrolyte balance through colonic secretions.

Metabolism

Biosynthesis

To yield tryptamine ''in vivo'', tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of

. Synthetic modifications to tryptamine can produce serotonin and

; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis. Biosynthesis and degradation of tryptamine

Biosynthesis and degradation of tryptamine

Catabolism

Monoamine oxidases A and B are the primary enzymes involved in tryptamine metabolism to produce indole-3-acetaldehyde, however it is unclear which isoform is specific to tryptamine degradation.

Mechanisms of Action and Biological Effects

Neuromodulation

Tryptamine can weakly activate the trace amine-associated receptor,

TAAR1 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 an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...

(hTAAR1 in humans). Limited studies have considered tryptamine to be a trace neuromodulator capable of regulating the activity of neuronal cell responses without binding to the associated postsynaptic receptors.

hTAAR1

Tryptamine_mechanism_of_action_in_the_human_gut

hTAAR1 is a stimulatory

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

(GPCR) that is weakly expressed in the intracellular compartment of both pre- and postsynaptic neurons. Tryptamine and other hTAAR1 agonists can increase neuronal firing by inhibiting neurotransmitter recycling through cAMP-dependent

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

of the monoamine reuptake transporter. This mechanism increases the amount of neurotransmitter in the synaptic cleft, subsequently increasing postsynaptic receptor binding and neuronal activation. Conversely, when hTAAR1 are colocalized with G protein-coupled inwardly-rectifying potassium channels (GIRKs), receptor activation reduces neuronal firing by facilitating membrane hyperpolarization through the efflux of potassium ions. The balance between the inhibitory and excitatory activity of hTAAR1 activation highlights the role of tryptamine in the regulation of neural activity. Activation of hTAAR1 is under investigation as a novel treatment for depression, addiction, and schizophrenia. hTAAR1 is primarily expressed in brain structures associated with dopamine systems, such as the

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...

(VTA) and serotonin systems in the dorsal raphe nuclei (DRN). Additionally, the hTAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility

locus Locus (plural loci) is Latin for "place". It may refer to: Entertainment * Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front * ''Locus'' (magazine), science fiction and fantasy magazine ** ''Locus Award ...

for mood disorders and schizophrenia. Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce anti-depressive activity, increased

cognition Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thoug ...

, reduced stress and anti-addiction effects.

Gastrointestinal Motility

Tryptamine produced by mutualistic bacteria in the human gut activates serotonin GPCRs ubiquitously expressed along the colonic epithelium. Upon tryptamine binding, the activated 5-HT₄ receptor undergoes a conformational change which allows its G_s alpha subunit to exchange

GDP Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is of ...

for GTP, and its liberation from the 5-HT₄ receptor and βγ subunit. GTP-bound G_s activates

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, which catalyzes the conversion of

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

into

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP). cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility.

Pharmacodynamics

Tryptamine-Based Therapeutics

References

External links

Tryptamine FAQ

Tryptamind Psychoactives
reference site on tryptamine and other psychoactives.
Tryptamine (T) entry in TiHKAL • info
{{Tryptamines TAAR1 agonists Trace amines Serotonin receptor agonists Serotonin-norepinephrine-dopamine releasing agents