IngredientesN-Methyltyramine (NMT), also known as 4-hydroxy-N-methylphenethylamine, is a human trace amine and natural phenethylamine alkaloid found in a variety of plants. As the name implies, it is the N-methyl analog of tyramine, which is a well-known biogenic trace amine with which NMT shares many pharmacological properties. The compound is also classified specifically as a protoalkaloid — an alkaloid in which the nitrogen atom is not incorporated into a ring structure but instead exists as a side-chain amine.
N-Methyltyramine HCl is chemically known as 4-[2-(Methylamino)ethyl]phenol hydrochloride. Its molecular formula is C₉H₁₃NO·HCl, and its CAS number is 13062-76-5. The free-base form (CAS 370-98-9) has the molecular formula C₉H₁₃NO and a molecular weight of 151.21 g/mol.
Chemically, hordenine is the N-methyl derivative of N-methyltyramine, and the N,N-dimethyl derivative of the well-known biogenic amine tyramine, from which it is biosynthetically derived. This places NMT as a key intermediate in a methylation cascade running from tyramine → N-methyltyramine → hordenine (N,N-dimethyltyramine) → candicine (N,N,N-trimethyltyramine).
NMT is encountered in commerce in two principal chemical forms: (1) as the free base (a waxy solid), and (2) as the hydrochloride salt (NMT HCl). In supplement and pharmaceutical contexts, it is commonly stabilized as a hydrochloride salt (HCl) to enhance solubility and shelf life. In botanical preparations, NMT is present within plant matrices (fresh fruit, dried peel, malt, and standardized extracts) alongside structurally related alkaloids such as synephrine, octopamine, and hordenine.
N-methyltyramine seems to be quite widely distributed in plants. NMT was isolated as a natural product for the first time, from germinating barley roots, by Kirkwood and Marion in 1950. These chemists found that 600 g of barley, after germination and 10-day growth, yielded 168 mg of N-methyltyramine.
Since barley, via its conversion to malt, is used extensively in the production of beer, beer and malt have been examined by several groups of investigators for the presence of NMT. Citing a 1965 study by McFarlane, Poocharoen reported that beer contained approximately 5–8 mg/L of NMT.
This compound is found naturally in various plants, including barley, where it plays a role in germination processes, and in citrus fruits, notably bitter orange (Citrus aurantium). The basic nitrogenous compounds found in citrus are alkaloids and protoalkaloids. Sweet and bitter orange fruits both contain phenethylamine alkaloids such as synephrine, tyramine, N-methyltyramine, octopamine and hordenine.
Additional sources include:
NMT is a biogenic amine found in a variety of plant species, where it serves as a crucial intermediate in the biosynthesis of numerous pharmacologically significant alkaloids, including hordenine and synephrine. The production of NMT is a targeted, two-step enzymatic pathway originating from the amino acid L-tyrosine. Specifically, biosynthetically, NMT is produced by the N-methylation of tyramine via the action of the enzyme phenylethanolamine N-methyltransferase in humans and tyramine N-methyltransferase in plants. NMT is itself a biosynthetic precursor of synephrine in citrus: synephrine is created in the fruit's growth in a chemical pathway involving tyramine and N-methyltyramine.
NMT is not employed as an isolated compound in traditional medicine; rather, it occurs as a constituent of botanicals that have long-standing use in ethnomedicinal traditions. Citrus aurantium (bitter orange) and its preparations are among the most important of these. Aurantii Fructus (called Zhiqiao, ZQ in Chinese), the dried unripe fruit of Citrus aurantium L. or its cultivated variety, is a common traditional edible-medicinal herb in regulating visceral functions for thousands of years. As a widely used ethnomedicine in Asia including China, Japan and Korea, ZQ possesses therapeutic effect on digestive system diseases, and is also used as a condiment in food for regular consumption to benefit health.
The juice, peel, and essential oil of Citrus aurantium have been utilized in traditional medicine systems like Chinese and Ayurvedic practices, where it was traditionally used to address digestive issues, fatigue, insomnia, and infections. N-methyltyramine, along with synephrine and related alkaloids, is a constituent underlying at least part of the pharmacological activity attributed to these preparations.
The TCM preparation Chenpi (dried tangerine peel, from Citrus reticulata) is another traditional source of NMT. Synephrine has also been reportedly found in the fruit and peel of some varieties of tangerine (e.g., C. reticulata, aka chenpi in TCM; unripe fruit peel = qingpi). Chinese HPLC studies have specifically determined the content of both synephrine and N-methyltyramine in Pericarpium Citri Reticulatae viride.
Barley (Hordeum vulgare) has been cultivated for millennia and used in brewing traditions across many cultures. Alcoholic beverages stimulate gastric acid secretion and increase the appetite. Although ingested ethanol stimulates pancreatic secretion, alcoholic beverages contain several congeners. N-methyltyramine was isolated from beer as a factor in stimulating gastric acid secretion. These findings suggest that the role of barley-derived NMT in stimulating digestion through beer consumption may have contributed to beer's long-standing association with appetite and digestive promotion in various cultures, though this relationship was not understood at a molecular level until modern phytochemical research.
NMT does not act in isolation in botanical sources; it is invariably found alongside related phenethylamine alkaloids. In Citrus aurantium extract, for example, several countries have established limits for the content of active amines: octopamine, synephrine, tyramine, N-methyltyramine, and hordenine.
The methylation series — tyramine → NMT → hordenine → candicine — represents a stepwise addition of methyl groups to the terminal amine nitrogen of tyramine. NMT occupies the second position in this chain. Structurally, the presence of a single N-methyl group (compared to tyramine's unsubstituted amine or hordenine's dimethyl amine) produces measurable differences in receptor selectivity, metabolic handling, and pharmacological activity as described in the sections below.
The predominant mechanistic finding in peer-reviewed literature challenges a widespread market assumption. N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis).
More specifically regarding α₂ receptors: in order to test the indications from earlier studies that, like tyramine itself, NMT produced most of its pharmacological effects by stimulating norepinephrine (NE) release, Koda and co-workers investigated the action of NMT on α₂ adrenoceptors, which are involved in the regulation of NE. These researchers found that NMT competed with the binding of [³H]-p-aminoclonidine to α₂ receptors from rat brain with an IC₅₀ of approximately 5.5 × 10⁻⁶M.
In common with other α₂ antagonists, NMT, at i.p. doses of 20 or 100 mg/kg, was also found to inhibit the hypermotility induced in mice by (−)-scopolamine in a dose-dependent manner. The same doses of NMT in the absence of scopolamine had no significant effects on locomotor activity in mice.
Regarding its activity on human adipocyte adrenergic receptors compared to rodent models: an extension of previous studies affirmed that the adrenergic receptor binding of p-synephrine and p-octopamine in rodents was at least 10-fold greater than in humans while tyramine and N-methyltyramine exhibited no binding activity.
NMT has been shown to be an agonist of the TAAR1, similarly to its parent compound tyramine. The EC₅₀ of NMT on the human TAAR1 receptor was approximately 2 μM, compared to approximately 1 μM for tyramine. TAAR1 is an intracellular G protein-coupled receptor expressed throughout the central nervous system and periphery. Dietary amines have been the subject of a novel interest in nutrition since the discovery of trace amine-associated receptors (TAARs), especially TAAR-1, which recognizes tyramine, phenethylamine, tryptamine, octopamine, N-methyltyramine (NMT), synephrine, amphetamine and related derivatives.
The phenethylamine alkaloid hordenine, present in germinated barley, was identified recently as a functionally selective dopamine D2 receptor agonist contributing potentially to the rewarding effects of drinking beer. Here, it was shown that the hordenine precursor N-methyltyramine binds with a similar affinity to the dopamine D2 receptor as hordenine (Ki 31.3 μM), showing also selectivity towards the G protein-mediated pathway over the β-arrestin pathway. This finding emerged from a 2019 study by Sommer et al. published in Food Chemistry that monitored the D2 receptor agonists hordenine and NMT during the brewing process and in commercial beer samples.
NMT is a competitive substrate for monoamine oxidase (MAO). This means NMT is metabolically degraded by MAO enzymes, and its pharmacological effects can be amplified substantially when MAO is inhibited, a key safety consideration discussed further below.
The secretagogue gastrin is one of a number of factors that increase gastric acid and pancreatic secretion. Yakoo et al. (1999) demonstrated that NMT was the gastrin-releasing factor in beer and that it had a specific gastrin-releasing activity approximately 10,000 times higher than the beer itself. In rats, the dose of NMT that exerted maximum release of gastrin was 25 μg/kg, and the 50% effective dose was approximately 10 μg/ml.
Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown of fats to energy.
A distinct proposed mechanism involves the biotransformation of NMT within intestinal nerve tissue. It was found that N-methyltyramine could relax mouse small intestinal smooth muscle and inhibit small intestinal propulsion. The effect of N-methyltyramine on relaxing small intestinal smooth muscle could be inhibited by α-methyl-L-tyrosine. The enzymes related to epinephrine synthesis and AR function were found in the mouse small intestine. The biotransformation process that converts N-methyltyramine to epinephrine was determined. The treatment of gastrointestinal disorders is associated with the alkaloid component N-methyltyramine via the regulation of adrenergic receptors (ARs), and the mechanism is considered to be the biotransformation of N-methyltyramine to epinephrine by serial synthase, which takes place at the nerve cells in small intestine.
Gastrin and Gastric Acid Secretion: The strongest and most replicated biological evidence for NMT involves gastrointestinal secretion. NMT was isolated from beer as a factor in stimulating gastric acid secretion. Tsutsumi et al. (2009/2010) examined NMT to determine whether the congener stimulated pancreatic secretion in conscious rats. Cannulae were inserted into male Wistar rats to separately drain bile and pancreatic secretions. After a 4-day recovery period, experiments were conducted on unanesthetized rats. Different concentrations of NMT (5, 25, and 50 μg/kg) solutions were infused into the stomach. Conclusions from this animal study: N-methyltyramine stimulates pancreatic secretion via the cholinergic gastro-pancreatic reflex. The NMT content in beer was 2 mg/l, so that if a person weighing 60 kg consumes 750 ml of beer, 25 μg/kg NMT will be ingested.
Evidence strength: The gastrointestinal evidence is derived entirely from animal models (conscious rats) and in vitro preparations. No controlled human clinical trials specifically targeting NMT's gastrointestinal effects have been published in the indexed literature.
In Vitro Human Adipocyte Studies: A 2022 study published in Nutrients (Carpéné et al., PMC9370673) directly investigated NMT in human adipocytes. The following results showed similarities between the in vitro actions of tyramine and NMT, regarding their partial activation of glucose transport, weak activation of lipolysis, impairment of β-adrenergic activation of triacylglycerol breakdown, and interplay with amine oxidases in adipocytes. These similarities do not justify why tyramine is almost banned in the diet of patients treated with MAO irreversible inhibitors or suffering from migraine crises, while NMT is advertised to promote body weight loss and lipid mobilization. The adipose samples were obtained from a total of 76 women undergoing abdominal surgery.
NMT activated 2-deoxyglucose uptake when incubated with freshly isolated adipocytes at 0.01–1 mM, reaching one-third of the maximal stimulation by insulin. However, when combined with insulin, NMT limited by half the action of the lipogenic hormone.
In rat adipocyte experiments conducted by Mercader and co-workers: in rat fat cells, at a concentration of 10 μg/ml, both p-synephrine and p-octopamine exhibited approximately 60% of the lipolytic activity of 1 nM/ml of isoprenaline, while tyramine and N-methyltyramine exhibited no effect or were weakly antagonistic. In human adipocytes, 10 μg/ml of both p-synephrine and p-octopamine exhibited approximately 10% of the lipolytic activity of 1 μM/ml of isoprenaline.
The earlier research by Mercader and co-workers on Citrus aurantium amines also showed: since NMT is one of the constituents of bitter orange, Citrus aurantium, Mercader and co-workers studied its effects on lipolysis, finding that it inhibited lipolysis in rats.
Evidence strength: In vitro (human and rat adipocyte cell preparations), no human clinical trials. The preponderance of evidence contradicts the commonly marketed claim that NMT is a lipolytic (fat-burning) agent. Carpene et al. (2014) showed that, in human and rat adipocytes, tyramine and N-methyltyramine, minor components found in bitter orange extract, inhibited lipolysis in contrast to p-synephrine. A review of the adrenergic receptor binding and effects of N-methyltyramine indicates that it acts as an α-adrenergic receptor antagonist while promoting appetite and inhibiting lipolysis, effects counter to commonly perceived ideas regarding its use in dietary supplements.
TAAR1 and Blood-Brain Barrier Penetration: The linkage between the central nervous system availability and neuropharmacological activity of the constituents of Ginkgo biloba extracts (GBE) remains incompletely characterized. In a study investigating the in vitro blood-brain barrier (BBB) permeability profile of standardized GBE using the parallel artificial membrane permeability assay (PAMPA), biomarkers such as terpene trilactones, flavonoid aglycones and ginkgotoxin exerted moderate or good BBB-permeability potential (BBB+), while glycosides and biflavones were predicted as unable to pass the BBB. N-methyltyramine (NMT) and N,N-dimethyltyramine or hordenine (Hor) were identified among BBB+ compounds.
Alongside the psychostimulant properties of TAAR-1 ligands, it is their ephedrine-like action on weight loss that drives their current consumption via dietary supplements advertised for 'fat-burning' properties. However, specific human clinical evidence for central nervous system effects of isolated NMT supplementation is absent in the indexed literature.
Dopamine D2 Receptor: NMT is a hordenine precursor in barley malt with high structural similarity. Therefore, the goal of Sommer et al. (2019) was to investigate the D2-related effects of NMT. The binding affinity of NMT at the D2 receptor was determined using radioligand binding assays. In summary, it was shown that the activity of NMT towards the D2 receptor is similar to hordenine.
Evidence strength: In vitro receptor binding and PAMPA permeability assay data only. No human clinical trials on NMT's CNS effects have been published. The in vitro BBB permeability data suggests that NMT, if absorbed into systemic circulation, could theoretically cross into the CNS, but the clinical relevance of this finding has not been demonstrated in humans.
NMT is frequently marketed in the dietary supplement industry as a weight-loss or "fat-burning" ingredient. The peer-reviewed literature does not support this characterization. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown of fats to energy.
Evidence strength: The conclusion that NMT does not promote fat loss and may in fact counteract it is based on multiple convergent lines of mechanistic in vitro and animal research. Zero human randomized controlled trials on isolated NMT for weight management have been published.
Animal pharmacokinetic studies have demonstrated that NMT is rapidly distributed from blood to tissues following intravenous administration. The pharmacokinetics of NMT have been studied in rabbits and mice using drug that had been radiolabeled with tritium at C-3 and C-5 on the benzene ring. Plasma concentrations were measured in the rabbits, whereas distribution, metabolism and excretion were determined in the mice. After i.v. administration to rabbits, the α-phase T₁/₂ was found to be 0.3 minutes, and the β-phase T₁/₂ was 5.6 minutes. These figures were indicative of a rapid distribution from blood to tissue and a very short plasma half-life. Within 2 minutes of injection, significant levels of radioactivity were detected in all tissues examined, with the highest amounts being in kidney and liver.
The immature citrus fruit contains synephrine and N-methyltyramine, which are sympathomimetic alkaloids that can raise blood pressure and increase heart rate, particularly at high doses or via injection. Animal studies show that very large doses can cause cardiac arrhythmias (ventricular tachycardia or atrioventricular block), though these effects were not severe in experimental settings.
The prediction method for the plasma concentration-time profile of NMT after oral ingestion in rats was examined using a Gastrointestinal (GI)-Transit-Absorption Model with the addition of a process of hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for estimation of the GI transit rate constant. The results of in situ absorption experiments showed that NMT is well absorbed in the small intestine, especially in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was demonstrated that more than 90% of orally ingested NMT is absorbed in the small intestine, and that the substantial absorption site for NMT in vivo is the lower jejunum and the ileum.
However, the observed bioavailability was only 39.0%. The in vitro metabolism study clarified that NMT is metabolized in the liver, but not in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0 liters/h) calculated from the rate of metabolism in vitro, the hepatic availability was estimated to be 0.510 on the basis of a well-stirred model. The plasma concentration-time curve and bioavailability of NMT after oral ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic first-pass metabolism process.
These pharmacokinetic studies were conducted in rats; human pharmacokinetic data for isolated NMT supplementation have not been published in the indexed literature.
The following dosages are reported only as stated in the primary sources cited; they do not constitute dosing guidance.
NMT is a competitive substrate for MAO. Like its parent compound tyramine, NMT can in principle accumulate to pharmacologically relevant levels when MAO is inhibited. Several non-subtype-selective irreversible MAO inhibitors, including the hydrazines phenelzine and isocarboxazid, the propargylamine pargyline, and the cyclopropylamine tranylcypromine, can all lead to potentiation of the cardiovascular effects of the dietary amine tyramine (the "cheese effect"). Although the specific interaction between NMT and pharmaceutical MAO inhibitors has not been characterized in human studies to the same degree as tyramine, the structural similarity and identical MAO substrate status of NMT imply an analogous potential for pressor interactions under MAO inhibition.
The similarities between the in vitro actions of tyramine and NMT regarding partial activation of glucose transport, weak activation of lipolysis, impairment of β-adrenergic activation of triacylglycerol breakdown, and interplay with amine oxidases in adipocytes do not justify why tyramine is almost banned in the diet of patients treated with MAO irreversible inhibitors or suffering from migraine crises, while NMT is advertised to promote body weight loss and lipid mobilization. The authors (Carpéné et al., 2022) explicitly raise this concern as a pharmacovigilance issue.
The immature citrus fruit (Zhi Shi) contains synephrine and N-methyltyramine, which are sympathomimetic alkaloids that can raise blood pressure and increase heart rate, particularly at high doses or via injection. Animal studies show that very large doses can cause cardiac arrhythmias (ventricular tachycardia or atrioventricular block), though these effects were not severe in experimental settings.
Alpha-adrenergic blockers may antagonize the blood pressure-raising effects of active compounds including synephrine and N-methyltyramine, potentially causing unpredictable hemodynamic effects.
A specific safety-relevant finding from Stohs and Hartman (2015) in Phytotherapy Research concerns the mislabeling of NMT's function in supplements: the receptor-binding studies, the gastric-infusion study concerning pancreatic secretion, and the identification and verification that NMT is the predominant factor responsible for the release of gastrin indicate that if given orally and present in appropriate amounts, NMT will have an effect opposite to that which is widely and erroneously believed to occur with respect to metabolism. This represents a fundamental accuracy concern for products claiming NMT promotes fat loss.
C. aurantium extract is permitted in food supplements, but several countries have established limits for the content of active amines (octopamine, synephrine, tyramine, N-methyltyramine, and hordenine). A problem associated with C. aurantium is that it can act as an alternative to Ephedra, with possible risks for consumers.
The secondary amine barley malt alkaloids N-methyltyramine and N-methyl-3-aminomethylindole were synthesized, nitrosated in dilute acetic acid and the products characterized by mass spectrometry and NMR spectroscopy. The nitrosation products of N-methyltyramine were p-hydroxy-m-nitro-N-nitroso-N-methyl-2-phenylethylamine and p-hydroxy-N-nitroso-N-methyl-2-phenylethylamine. The relevance of these nitrosation products to dietary exposure from malt-containing foods and beverages has been examined in the food safety literature, though specific risk quantification remains an area of ongoing research.
NMT is sold commercially as a dietary supplement ingredient, most often in hydrochloride salt form as a powder or encapsulated product, typically as part of multi-ingredient "thermogenic" or "pre-workout" formulations that often also contain synephrine, caffeine, and other stimulants. Numerous studies have been conducted with respect to p-synephrine and bitter orange extract because ephedra and ephedrine were banned from use in dietary supplements in 2004. NMT emerged alongside other Citrus-derived amines as ingredients in the reformulated supplement market following that ban.
The principal regulatory concern flagged by researchers is that the pharmacological evidence does not support the lipolytic and thermogenic claims associated with NMT in supplements, and that the compound's role as an MAO substrate and α-adrenergic antagonist has received inadequate attention in supplement labeling and safety disclosures.
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