Tryptamine

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.

Mammalian gut microbiome

Tryptamine is relatively abundant in the gut and feces of humans and rodents. Commensal bacteria, including Ruminococcus gnavus and Clostridium sporogenes in the gastrointestinal tract, possess the enzyme tryptophan decarboxylase, which aids in the conversion of dietary tryptophan to tryptamine. Tryptamine is a ligand 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 tryptophan. Synthetic modifications to tryptamine can produce serotonin 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, however it is unclear which isoform is specific to tryptamine degradation.

Figure

Biological activity

Serotonin receptor agonist

Tryptamine is known to act as a serotonin receptor agonist, although its potency is limited by rapid inactivation by monoamine oxidases. It has specifically been found to act as a full agonist of the serotonin 5-HT2A receptor ( = 7.36 ± 0.56nM; Emax = 104 ± 4%). Tryptamine was of much lower potency in stimulating the 5-HT2A receptor β-arrestin pathway (EC50 = 3,485 ± 234nM; Emax = 108 ± 16%). In contrast to the 5-HT2A receptor, tryptamine was found to be inactive at the serotonin 5-HT1A 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 Gs alpha subunit to exchange GDP for GTP, and its liberation from the 5-HT4 receptor and βγ subunit. GTP-bound Gs activates adenylyl cyclase, 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.

Monoamine releasing agent

Tryptamine has been found to act as a monoamine releasing agent (MRA). It is a releaser of serotonin, dopamine, and norepinephrine, in that order of potency (EC50 = 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 serotonin, norepinephrine, and dopamine in addition to its serotonin receptor agonism. That is, it enhances the action potential-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 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 (GPCR) that is weakly expressed in the intracellular 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 ions.

TAAR1 agonists are under investigation as a novel treatment for neuropsychiatric conditions like schizophrenia, drug addiction, and depression. The TAAR1 is expressed in brain structures associated with dopamine systems, such as the ventral tegmental area (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 disorders and schizophrenia. Activation of TAAR1 suggests a potential novel treatment for neuropsychiatric disorders, as TAAR1 agonists produce antipsychotic-like, anti-addictive, and antidepressant-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 hallucinogenic effects or perceptual disturbances similar to those of small doses of lysergic acid diethylamide (LSD). It also produced other LSD-like effects, including pupil dilation, increased blood pressure, and increased force of the patellar reflex. Tryptamine produced side effects including nausea, vomiting, dizziness, tingling sensations, sweating, and bodily heaviness among others as well. Conversely, there were no changes in heart rate 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 of tryptamine by monoamine oxidase (MAO) and its very short elimination half-life.

In animals, tryptamine, alone and/or in combination with a monoamine oxidase inhibitor (MAOI), produces behavioral changes such as hyperlocomotion and reversal of reserpine-induced behavioral depression. In addition, it produces effects like hyperthermia, tachycardia, myoclonus, and seizures or convulsions, 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 and cortisol 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 endogenously or administered peripherally is readily able to cross the blood–brain barrier and enter the central nervous system. This is in contrast to serotonin, which is peripherally selective.

Tryptamine is metabolized by monoamine oxidase (MAO) to form indole-3-acetic acid (IAA). Its metabolism is described as extremely rapid and its elimination half-life and duration as very short. In addition, its duration is described as shorter than that of dimethyltryptamine (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 and its rate of urinary excretion has been reported to be pH-dependent.

Chemistry

Tryptamine is a substituted tryptamine derivative and trace amine and is structurally related to the amino acid tryptophan.

Properties

The experimental log P of tryptamine is 1.55.

Synthesis

The chemical synthesis of tryptamine has been described.

Derivatives

Main article: Substituted tryptamine

The endogenous monoamine neurotransmitters serotonin (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 derivatives of tryptamine.

A variety of drugs, including both naturally occurring and pharmaceutical substances, are derivatives of tryptamine. These include the tryptamine psychedelics like psilocybin, psilocin, DMT, and 5-MeO-DMT; tryptamine stimulants, entactogens, psychedelics, and/or antidepressants like α-methyltryptamine (αMT) and α-ethyltryptamine (αET); triptan antimigraine agents like sumatriptan; certain antipsychotics like oxypertine; and the sleep aid melatonin.

Various other drugs, including ergolines and lysergamides like the psychedelic lysergic acid diethylamide (LSD), the antimigraine agents ergotamine, dihydroergotamine, and methysergide, and the antiparkinsonian agents bromocriptine, cabergoline, lisuride, and pergolide; β-carbolines like harmine (some of which are monoamine oxidase inhibitors (MAOIs)); Iboga alkaloids like the hallucinogen 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.

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