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 aromat ...

. The chemical structure is defined by an

indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

—a fused

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen). The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin,

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, ...

, bufotenin and psychedelic derivatives such as

dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...

(DMT),

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 ...

, psilocin and others. Tryptamine has been shown to activate serotonin receptors and

trace amine-associated receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...

s expressed in the mammalian brain, and regulates the activity of

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

, serotonergic and glutamatergic systems. In the human gut, 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.

Natural occurrences

''For a list of plants, fungi and animals containing tryptamines, see List of psychoactive plants and List of naturally occurring tryptamines.''

Mammalian brain

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

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

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 f ...

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 Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

, possess 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 ...

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

ligand In coordination chemistry, a ligand is an ion or molecule with a 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 el ...

for gut epithelial serotonin type 4 (5-HT₄) receptors and regulates gastrointestinal

electrolyte An electrolyte is a substance that conducts electricity through the movement of ions, but not through the movement of electrons. This includes most soluble Salt (chemistry), salts, acids, and Base (chemistry), bases, dissolved in a polar solven ...

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

and melatonin; however, these pathways do not occur naturally as the main pathway for endogenous neurotransmitter synthesis.

Catabolism

Monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

s 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.

Figure

Biosynthesis and degradation of tryptamine

Biological activity

Serotonin receptor agonist

Tryptamine is known to act as a serotonin receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

, although its potency is limited by rapid inactivation by

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

s. It has specifically been found to act as a full agonist of the

5-HT_2A receptor ( = 7.36 ± 0.56nM; E_max = 104 ± 4%). Tryptamine was of much lower potency in stimulating the 5-HT_2A receptor β-arrestin pathway ( = 3,485 ± 234nM; E_max = 108 ± 16%). In contrast to the 5-HT_2A receptor, tryptamine was found to be inactive at the serotonin 5-HT_1A receptor.

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 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 into cyclic adenosine monophosphate (cAMP). cAMP opens chloride and potassium ion channels to drive colonic electrolyte secretion and promote intestinal motility. Tryptamine_mechanism_of_action_in_the_human_gut

Tryptamine_mechanism_of_action_in_the_human_gut

Monoamine releasing agent

Tryptamine has been found to act as a monoamine releasing agent (MRA). It is a releaser of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, in that order of potency ( = 32.6nM, 164nM, and 716nM, respectively). That is, it acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).

Monoaminergic activity enhancer

Tryptamine is a monoaminergic activity enhancer (MAE) of

, and

in addition to its serotonin receptor

agonism Agonism (from Greek 'struggle') is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks to show how indivi ...

. That is, it enhances the

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

-mediated release of these monoamine neurotransmitters. The MAE actions of tryptamine and other MAEs may be mediated by TAAR1 agonism. Synthetic and more potent MAEs like benzofuranylpropylaminopentane (BPAP) and indolylpropylaminopentane (IPAP) have been derived from tryptamine.

TAAR1 agonist

Tryptamine is an agonist of the trace amine-associated receptor 1 (TAAR1). It is a potent TAAR1 full agonist in rats, a weak TAAR1 full agonist in mice, and a very weak TAAR1

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

in humans. Tryptamine may act as a trace neuromodulator in some species via activation of TAAR1 signaling. The TAAR1 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 ...

(GPCR) that is weakly expressed in the

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 ...

compartment of both pre- and postsynaptic neurons. TAAR1 agonists have been implicated in regulating monoaminergic neurotransmission, for instance by activating G protein-coupled inwardly-rectifying potassium channels (GIRKs) and reducing neuronal firing via facilitation of membrane hyperpolarization through the efflux of

potassium ion Potassium is a chemical element; it has symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to form flaky white pot ...

s. TAAR1 agonists are under investigation as a novel treatment for neuropsychiatric conditions like

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, and depression. The TAAR1 is 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 human TAAR1 gene is localized at 6q23.2 on the human chromosome, which is a susceptibility locus for

mood disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the ''Diagnostic ...

s and schizophrenia. Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

-like, anti-addictive, and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like effects in animals.

Effects in animals and humans

In a published clinical study, tryptamine, at a total dose of 23 to 277mg by intravenous infusion, produced

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 or perceptual disturbances similar to those of small doses of

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). It also produced other LSD-like effects, including pupil dilation, increased

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

, and increased force of the

patellar reflex The patellar reflex, also called the knee reflex or knee-jerk, is a stretch reflex which tests the L2, L3, and L4 segments of the spinal cord. Many animals, most significantly humans, have been seen to have the patellar reflex, including dogs, cat ...

. Tryptamine produced

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s including

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, tingling sensations, sweating, and bodily heaviness among others as well. Conversely, there were no changes in

heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

or respiratory rate. The onset of the effects was rapid and the duration was very short. This can be attributed to the very rapid

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of tryptamine by

(MAO) and its very short

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

. In animals, tryptamine, alone and/or in combination with a monoamine oxidase inhibitor (MAOI), produces behavioral changes such as hyperlocomotion and reversal of

reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...

-induced behavioral depression. In addition, it produces effects like

hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

, myoclonus, and

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s or

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

s, among others. Findings on tryptamine and the head-twitch response in rodents have been mixed, with some studies reporting no effect, some studies reporting induction of head twitches by tryptamine, and others reporting that tryptamine actually antagonized 5-hydroxytryptophan (5-HTP)-induced head twitches. Another study found that combination of tryptamine with an MAOI dose-dependently produced head twitches. Head twitches in rodents are a behavioral proxy of psychedelic-like effects. Many of the effects of tryptamine can be reversed by serotonin receptor antagonists like metergoline, metitepine (methiothepin), and cyproheptadine. Conversely, the effects of tryptamine in animals are profoundly augmented by MAOIs due to inhibition of its metabolism. Tryptamine seems to also elevate

prolactin Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...

and

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

levels in animals and/or humans. The values of tryptamine in animals include 100mg/kg i.p. in mice, 500mg/kg s.c. in mice, and 223mg/kg i.p. in rats.

Pharmacokinetics

Tryptamine produced

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 ...

ly or administered peripherally is readily able to cross 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 ...

and enter the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. This is in contrast to

, which is peripherally selective. Tryptamine is metabolized by

(MAO) to form indole-3-acetic acid (IAA). Its metabolism is described as extremely rapid and its

and duration as very short. In addition, its duration is described as shorter than that of

(DMT). Brain tryptamine levels are increased up to 300-fold by MAOIs in animals. In addition, the effects of exogenous tryptamine are strongly augmented by monoamine oxidase inhibitors (MAOIs). Tryptamine is excreted in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and its rate of urinary excretion has been reported to be pH-dependent.

Chemistry

Tryptamine is a substituted tryptamine

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and

trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to ...

and is structurally related to the

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 ...

. The experimental log P of tryptamine is 1.55.

Derivatives

The

monoamine neurotransmitters

(5-hydroxytryptamine or 5-HT) and melatonin (5-methoxy-''N''-acetyltryptamine), as well as trace amines like ''N''-methyltryptamine (NMT), ''N'',''N''-dimethyltryptamine (DMT), and bufotenin (''N'',''N''-dimethylserotonin), are

s of tryptamine. Tryptamine Alkaloids 2

A variety of drugs, including both

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 ...

and

pharmaceutical Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

substances, are derivatives of tryptamine. These include the tryptamine psychedelics like

, psilocin, DMT, and 5-MeO-DMT; tryptamine

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s, entactogens, psychedelics, and/or

s like α-methyltryptamine (αMT) and α-ethyltryptamine (αET);

triptan Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...

antimigraine agents like sumatriptan; certain

s like oxypertine; and the sleep aid melatonin. Various other drugs, including ergolines and lysergamides like the psychedelic

(LSD), the antimigraine agents ergotamine, dihydroergotamine, and methysergide, and the

antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutr ...

s bromocriptine, cabergoline, lisuride, and pergolide; β-carbolines like harmine (some of which are monoamine oxidase inhibitors (MAOIs)); ''Iboga'' alkaloids like the

ibogaine; yohimbans like the α₂ blocker yohimbine; antipsychotics like ciclindole and flucindole; and the MAOI antidepressant metralindole, can all be thought of as cyclized tryptamine derivatives. Drugs very closely related to tryptamines, but technically not tryptamines themselves, include certain triptans like avitriptan and naratriptan; the antipsychotics sertindole and tepirindole; and the MAOI antidepressants pirlindole and tetrindole.

References

External links

Tryptamine FAQ

Tryptamind Psychoactives
reference site on tryptamine and other psychoactives.
Tryptamine (T) entry in TiHKAL • info
{{Chocolate 5-HT1A agonists 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists Biogenic amines Monoaminergic activity enhancers Psychedelic tryptamines Serotonin receptor agonists Serotonin-norepinephrine-dopamine releasing agents TAAR1 agonists Trace amines Aminoethyl compounds