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 aromatic ...
.
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 environmen ...
─ 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
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
including
melatonin,
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
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.
...
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 a ...
(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.&nbs ...
,
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 counte ...
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 d ...
,
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
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 receptor agonist ...
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, 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.''
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 ...
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 (NH2) group via an ethy ...
.''
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 withdra ...
.
Mammalian gut microbiome
Tryptamine is relatively abundant in the
gut 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 fro ...
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 organ (biology), organs of the digestive syste ...
, possess the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 a ...
, 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 electr ...
for gut epithelial serotonin type 4 (5-HT
4) receptors and regulates gastrointestinal
electrolyte
An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
balance through colonic secretions.
Metabolism
Biosynthesis
To yield tryptamine ''in vivo'', tryptophan decarboxylase removes the carboxylic acid group on the α-carbon of
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 aromatic ...
.
Synthetic modifications to tryptamine can produce
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
and
melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.
Catabolism
Monoamine oxidases A and B are the primary enzymes involved in tryptamine metabolism to produce
indole-3-acetaldehyde
Indole-3-acetaldehyde belongs to the class of organic compounds known as indoles. These are compounds containing an indole moiety, which consists of pyrrole ring fused to benzene to form 2,3-benzopyrrole.
Indole-3-acetaldehyde is a substrate fo ...
, 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](https://upload.wikimedia.org/wikipedia/commons/0/09/Tryptamine_mechanism_of_action_in_the_human_gut.png)
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 protein family, evolution ...
(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
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
-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, wh ...
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 the ...
(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, thought, ...
, 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-HT
4 receptor undergoes a conformational change which allows its
Gs 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 ofte ...
for
GTP, and its liberation from the 5-HT
4 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 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
See also
*
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 aromatic ...
*
Substituted 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 (NH2) group via an ethy ...
*
Trace amines
Trace amines are an endogenous group of TAAR1 agonist, trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Co ...
*
Serotonin receptor agonist
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the ...
*
Human trace amine associated receptor 1
*
Neuromodulation
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second ...
References
External links
Tryptamine FAQTryptamind 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