Hordenine: A Comprehensive Reference
1. Identity: Chemical and Botanical Profile
1.1 Chemical Names and Synonyms
Hordenine, also known as N,N-dimethyltyramine or as 4-hydroxy-N,N-dimethylphenethylamine, is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley (Hordeum species). Additional synonyms include 4-(2-(dimethylamino)ethyl)phenol, 4-[2-(dimethylamino)ethyl]phenol, and anhaline. The molecular formula is C10H15NO.
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 and with which it shares some pharmacological properties.
1.2 Natural Sources
Hordenine is present in a fairly wide range of plants, notably among the cacti, but has also been detected in some algae and fungi. It occurs in grasses, and is found at significantly high concentrations in the seedlings of cereals such as barley (Hordeum vulgare) (about 0.2%, or 2000 μg/g), proso millet (Panicum miliaceum) (about 0.2%), and sorghum (Sorghum vulgare) (about 0.1%).
Reti, in his 1953 review of naturally occurring phenethylamines, noted that the richest source of hordenine is the cactus Trichocereus candicans (now reclassified as Echinopsis candicans), which was found to contain 0.5–5% of the alkaloid. Hordenine is also a naturally occurring substance found in Aconitum tanguticum (Maxim.) Stapf, Senecio scandens, Coryphantha ramillosa, and Citrus aurantium (bitter orange).
Hordenine has also been quantified in six commercially available products derived from the foliage and stems of Sceletium tortuosum (kanna), with concentrations ranging from 0.02738 to 1.071 mg of hordenine per gram of plant material.
1.3 Biosynthesis
Hordenine is biosynthesized by the step-wise N-methylation of tyramine, which is first converted to N-methyltyramine, which in turn is methylated to hordenine. The alkaloid is one of the major allelochemicals involved in the allelopathic ability of barley (Hordeum vulgare L.), with biosynthesis and accumulation preferentially located in roots. Hordenine appears to have been unintentionally favored during domestication in modern and cultivated barley cultivars at the expense of another alkaloid, gramine.
In plants, hordenine acts as an allelopathic compound and inhibits root growth of other plants. Hordenine has also been demonstrated to trigger the plant defence response through the jasmonate-dependent defence pathway.
1.4 Common Preparations and Supplement Forms
Hordenine can also be made in a laboratory as a synthetic chemical. As of September 2012, hordenine is widely sold as an ingredient of nutritional supplements, with sellers claiming that it stimulates the central nervous system and promotes weight loss by enhancing metabolism. It is marketed most frequently as a free base or hydrochloride salt in capsule, tablet, and loose powder form, often in combination with other stimulant or "pre-workout" ingredients.
2. Historical Discovery and Early Research
The first report of the isolation from a natural source of the compound now known as hordenine was made by Arthur Heffter in 1894, who extracted this alkaloid from the cactus Anhalonium fissuratus (now reclassified as Ariocarpus fissuratus), naming it "anhalin." Twelve years later, E. Léger independently isolated an alkaloid, which he named hordenine, from germinated barley (Hordeum vulgare) seeds. Ernst Späth subsequently showed that these alkaloids were identical and proposed the correct molecular structure for the substance, for which the name "hordenine" was ultimately retained.
The first pharmacological study of hordenine to be recorded is that of Heffter, who was also the first to isolate it. Using the sulfate salt, Heffter gave a subcutaneous dose of 0.3 g to a 2.8-kg cat (about 107 mg/kg), and observed no effects besides violent vomiting; the cat behaved normally within 45 minutes. He also took a dose of 100 mg orally himself, without experiencing any observable effect.
The cardiovascular and other effects of hordenine were reviewed in detail by Reitschel, writing in 1937. More modern, systematic pharmacological characterization commenced with mid-20th century animal studies and accelerated substantially in the 2010s with the discovery of hordenine's activity at the dopamine D2 receptor.
3. Traditional and Historical Use
There is no well-documented tradition of the deliberate use of isolated hordenine as a medicine or stimulant in any classical pharmacopeia. Its historical relevance is inseparable from the plants that contain it. Barley (Hordeum vulgare) has been cultivated for at least ten thousand years in the Fertile Crescent and has featured in the traditional medicine, food, and fermentation practices of cultures from ancient Mesopotamia to East Asia, but no historical sources specifically identify hordenine as a discrete active constituent. Similarly, peyote cactus (Lophophora williamsii) and related cactus species, which also contain hordenine alongside psychoactive mescaline, were used ceremonially by Indigenous peoples of North America, but the pharmacological role of hordenine within those preparations was not recognized by those traditions.
Hordenine is structurally similar to other natural phenethylamines such as N-methyltyramine and synephrine. When ephedra-containing products were removed from the dietary supplement market due to safety concerns, other stimulant substances including hordenine began to emerge as ingredients in dietary supplement products. Its contemporary use as a supplement ingredient therefore lacks a true "traditional" precedent and is better understood as a product of modern botanical extraction and pharmacological re-purposing beginning in the early 2000s.
Hordenine is an ingredient of some plants used as feed for animals, notably sprouting barley. After ingestion of such feed, hordenine may be detected in blood or urine of horses, which in the case of racing horses may imply the use of prohibited compounds. This veterinary context represents the most historically documented non-dietary encounter with hordenine.
Hordenine is naturally found in malted barley, which is one of the most important cereals for beer production, and is transferred into beer during the brewing process. Drinking beer can quickly raise blood hordenine levels.
4. Chemistry: Key Constituents and Structural Context
Hordenine is a notable phenethylamine derivative with an ethylamine chain linked to a benzene ring and N-methyl group bonded to the side chain's nitrogen atom. This structural characteristic contributes to its distinct biological action and differentiates it from its parent compound, phenethylamine.
The hordenine precursor N-methyltyramine binds with a similar affinity to the dopamine D2 receptor as hordenine (Ki 31.3 μM), also showing selectivity towards the G protein-mediated pathway over the β-arrestin pathway.
When found in beer, hordenine and N-methyltyramine are released continuously from barley malt during mashing and are stable during fermentation and conditioning.
5. Established Mechanisms of Action
5.1 Indirect Adrenergic Activity and Norepinephrine Release
Pharmacological model studies show that hordenine is an indirectly acting adrenergic drug. It liberates norepinephrine from stores. In isolated organs and structures with reduced epinephrine contents, the hordenine effect is only very poor.
Experiments in intact animals (rats, dogs) show that hordenine has a positive inotropic effect upon the heart, increases systolic and diastolic blood pressure, peripheral blood flow volume, and inhibits gut movements, but has no effect upon the psychomotor behaviour of mice. All effects are short and only possible after high doses not expected after ingestion of hordenine-containing feed.
5.2 Dopamine D2 Receptor Agonism
D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM.
Hordenine shows agonist properties in the inhibition of forskolin-stimulated cAMP accumulation, while no β-arrestin-2 recruitment was determined for hordenine, and the test substance completely antagonised quinpirole-stimulated recruitment. This profile — G-protein activation without β-arrestin recruitment — identifies hordenine as a biased agonist at the D2 receptor, a property with potential implications for tolerability and side-effect profile compared to non-selective D2 agonists.
One study specifically aimed to identify hordenine as a dopamine D2 receptor (DRD2) agonist in living cells. Results confirmed that hordenine is an agonist of DRD2, but not DRD1, in living cells.
Hordenine has been identified as a dopamine D2 receptor (D2R) agonist, is a highly selective substrate for monoamine oxidase B (MAO-B) in the liver, and may inhibit norepinephrine (NE) uptake. Furthermore, it has also been suggested to act as a trace amine-associated receptor 1 (TAAR1) agonist.
5.3 MAO-B Substrate and Inhibition
Hordenine is a highly selective substrate of MAO-B and acts as a temporary reversible MAO-B inhibitor. Because hordenine crosses the blood-brain barrier, it is able to inhibit MAO-B enzymes in both the body and brain. By inhibiting MAO-B, hordenine reduces the degradation of neurotransmitters such as dopamine and norepinephrine in the brain, thereby increasing their levels and prolonging their effects.
5.4 Anti-inflammatory Signalling
Hordenine inhibits increases in the levels of inflammatory factors both in vivo and in vitro, and its anti-inflammatory effect inhibits activation of protein kinase B (AKT), nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signalling.
5.5 Melanogenesis Inhibition
Hordenine inhibits melanogenesis by suppressing cAMP production, which is involved in the expression of melanogenesis-related proteins. Hordenine may be an effective inhibitor of hyperpigmentation. In humans, hordenine inhibits melanogenesis partly due to inhibition of tyrosinase activity and the signalling pathways involved in melanin pigmentation.
6. Pharmacokinetics
6.1 Absorption, Distribution, and Metabolism
The pharmacokinetic profile of hordenine has been described to a limited extent. One study focused on the transfer and transport of hordenine across the intestinal epithelium and the blood-brain barrier (BBB) in vitro. Hordenine was quickly transferred through the Caco-2 monolayer in only a few hours, indicating rapid oral uptake. However, the high bioavailability may be reduced by the observed efflux transport of hordenine from the bloodstream back into the intestinal lumen and by first-pass metabolism in intestinal epithelial cells.
Transfer studies using primary porcine brain capillary endothelial cells (PBCEC) showed that hordenine is able to rapidly penetrate the blood-brain barrier.
Hordenine, a natural constituent of germinated barley, is a biased agonist of the dopamine D2 receptor. A pilot study investigating biokinetics in four volunteers consuming beer equal to 0.075 mg hordenine/kg body weight determined maximum plasma concentrations of 12.0–17.3 nM free hordenine after 0–60 minutes.
Hordenine phase-II metabolism was first dominated by sulfation, but later by glucuronidation. Elimination half-lives in plasma were 52.7–66.4 minutes for free hordenine and about 60–80 minutes longer for hordenine sulfate and hordenine glucuronide. Urinary excretion peaked 2–3.5 hours after consumption and accumulated to 3.78 μmol within 24 hours, corresponding to 9.9% of the ingested dose.
6.2 Pharmacokinetics in Horses
The pharmacokinetics of hordenine have been studied in horses. After IV administration, the α-phase T1/2 was found to be about 3 minutes, and the β-phase T1/2 was about 35 minutes. Because of the low plasma levels, it would appear to be particularly difficult to obtain a pharmacological effect of hordenine after oral administration.
7. Scientific Evidence by Area of Use
7.1 Athletic Performance Enhancement
Hordenine is included in many dietary supplements used for athletic performance and weight loss. People take hordenine by mouth for obesity and improving athletic performance, but there is no good scientific evidence to support these uses.
Some research shows that hordenine might stimulate the central nervous system and increase heart rate, blood pressure, and breathing rate. These effects seem to be short-lived and require high doses. The evidence for these effects derives from animal studies and has not been confirmed in randomized controlled trials in humans. There are no robust randomized controlled trials of isolated hordenine in healthy humans addressing performance outcomes. Long-term safety data in humans are lacking, and most information comes from short exposures, animal studies, or indirect inference from related compounds.
Evidence strength: Insufficient (no qualifying human clinical trials).
7.2 Weight Loss and Metabolic Effects
Hordenine's inclusion in weight-loss supplements is premised on its indirect sympathomimetic mechanism — specifically, the release of norepinephrine, which in animal models increases heart rate and blood pressure. While some anecdotal reports and preliminary research suggest potential benefits, there is a lack of large-scale, well-controlled clinical trials that confirm its effectiveness for weight loss, performance enhancement, or cognitive function. Its use for these purposes remains controversial and not widely endorsed by the medical community.
Evidence strength: Insufficient (mechanistic hypotheses only; no human trials).
7.3 Neurological Effects: Parkinson's Disease Models
Parkinson's disease (PD) is characterised by selective loss of dopaminergic neurons, leading to dopamine deficiency and motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer.
In a published study aimed at identifying hordenine as a DRD2 agonist in living cells, results showed that hordenine is an agonist of DRD2, but not DRD1, in living cells. Moreover, hordenine could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway. These findings are preclinical only; no human trials in Parkinson's disease patients have been reported.
Evidence strength: Preliminary — animal and in vitro data only.
7.4 Alcohol Use Disorder
A 2023 study investigated the effects of hordenine, a barley-derived beer compound, on alcohol use-related behaviours. The study found that the dopamine D2 receptor agonist hordenine (50 mg/kg) limited ongoing alcohol consumption and prophylactically diminished relapse drinking after withdrawal in mice. The study concluded that the beer compound hordenine inhibits alcohol drinking when consumption is established and before relapse. These results are based on mouse models and have not been replicated in human populations.
Evidence strength: Preliminary — animal (mouse) models only.
7.5 Acute Lung Injury (ALI) and Anti-inflammatory Effects
Hordenine, a barley-derived natural product, has various biological activities including anti-inflammatory and anti-oxidation activities. One study investigated the effect of hordenine on lipopolysaccharide-induced ALI and its potential mechanism. Hordenine inhibited increases in the levels of inflammatory factors both in vivo and in vitro, and its anti-inflammatory effect inhibited activation of AKT, NF-κB, and MAPK signalling. Hordenine alleviated lipopolysaccharide-induced ALI by inhibiting inflammatory cytokine increases and shows potential for preventing inflammatory disease. All findings are from rodent and cell-culture models.
Evidence strength: Preliminary — in vivo (rodent) and in vitro data only.
7.6 Gastrointestinal / Ulcerative Colitis
Hordenine, a phenethylamine alkaloid found in a variety of plants, exhibits a broad array of biological activities including anti-inflammatory and anti-fibrotic effects. However, the efficacy and underlying mechanisms of hordenine in treating ulcerative colitis (UC) remain unclear. To address this, a 2023 study examined the therapeutic effects of hordenine on dextran sodium sulphate (DSS)-induced UC in mice.
The study found that hordenine significantly reduced disease activity index (DAI) and levels of pro-inflammatory factors including IL-6, IL-1β, and TNF-α, and alleviated colon tissue oedema, colonic lesions, and inflammatory cell infiltration. In vitro experiments showed that hordenine protected intestinal epithelial barrier function by increasing the expression of tight junction proteins including ZO-1 and occludin, while also promoting the healing of intestinal mucosa.
Hordenine reduced expression of SPHK1, S1PR1, and Rac1 and inhibited phosphorylated STAT3 (p-STAT3) in colon tissues. Hordenine appears effective in UC treatment owing to pharmacological mechanisms that favor mucosal healing and the inhibition of SPHK-1/S1PR1/STAT3 signalling.
Evidence strength: Preliminary — mouse and cell-culture models; no human data.
7.7 Melanogenesis / Skin Hyperpigmentation
Research has demonstrated that hordenine inhibits melanogenesis by suppressing cAMP production, which is involved in the expression of melanogenesis-related proteins, and may be an effective inhibitor of hyperpigmentation. In humans, hordenine inhibits melanogenesis partly due to inhibition of tyrosinase activity and the signalling pathways involved in melanin pigmentation. The 2013 Kim et al. study, performed on human melanocytes, represents one of the very few instances of human cell-level data, though it does not constitute a clinical trial.
Evidence strength: Preliminary — cell-culture data (human melanocytes); no in vivo clinical trials.
7.8 Skeletal Muscle Effects
Intramuscular injection of gramine or hordenine in mice facilitated gene expression of several cAMP response element binding protein targets, which is thought to result in increased skeletal muscle protein synthesis. This study provides evidence that several food factors might exert potential health effects on skeletal muscle by enhancing cAMP signalling through the activation of β2-adrenergic receptors.
Evidence strength: Preliminary — animal (mouse) data; injection route only, not oral.
7.9 Cognitive Enhancement / Nootropic Claims
No published human clinical trials testing hordenine for cognitive or nootropic outcomes exist in the peer-reviewed literature. A D2R interaction of hordenine and activation of dopaminergic signalling is conceivable, assuming that the intestinal barrier can be circumvented by a route of administration alternative to oral uptake. This important caveat is confirmed by the human biokinetics study finding that oral beer consumption produced maximum free plasma hordenine concentrations of only 12.0–17.3 nM — well below the Ki of 13 μM required for meaningful D2R engagement.
Evidence strength: Insufficient — no human trials; significant bioavailability obstacles after oral dosing.
8. Body Systems Associated with Hordenine
- Cardiovascular system: Experiments in intact animals (rats, dogs) show that hordenine has a positive inotropic effect upon the heart, increases systolic and diastolic blood pressure, and peripheral blood flow volume.
- Central nervous system: Hordenine crosses the blood-brain barrier and acts as an indirect sympathomimetic, a MAO-B inhibitor, and a biased D2 receptor agonist; however, functional CNS effects at oral doses in humans remain unestablished.
- Respiratory system: In horses administered 2.0 mg/kg IV, respiratory rates increased about 250 percent and heart rates were approximately double resting values.
- Gastrointestinal system: Hordenine inhibits gut motility in animal models and has demonstrated anti-inflammatory effects in rodent colitis models.
- Integumentary system: Hordenine inhibits melanogenesis in human melanocytes via suppression of tyrosinase activity and cAMP signalling.
- Musculoskeletal system: Animal data (injection route) suggest a potential role in cAMP-mediated skeletal muscle protein synthesis.
9. Dosage Forms and Reported Dosages
There is no established therapeutic dose of hordenine in humans. The following figures appear in the scientific literature:
- A human biokinetics pilot study administered hordenine via beer consumption equivalent to 0.075 mg hordenine/kg body weight in four volunteers.
- In the equine pharmacology study, hordenine was administered at 2.0 mg/kg body weight by rapid intravenous injection to 10 horses.
- In the mouse alcohol use disorder model, hordenine was administered at 50 mg/kg.
- In the earliest recorded human self-experiment, Heffter took a dose of 100 mg orally and experienced no observable effect.
There is no standardized therapeutic dose for hordenine, and safety in long-term, everyday use has not been established. Supplement products on the market have listed varying amounts, and the latest studies analyzing products that list hordenine as an ingredient show that such products sometimes contain more hordenine than reported on product labels, while others can contain additional substances either listed or not shown on labels not approved for use in dietary supplements.
10. Regulatory Status
The U.S. Food and Drug Administration (FDA) has determined hordenine to be a "new dietary ingredient (NDI) for which an NDI notification is required and has not yet been submitted" and not an approved dietary ingredient under the Dietary Supplement Health and Education Act of 1994 (DSHEA). Therefore, any product containing hordenine is considered "adulterated."
Hordenine is on the Department of Defense (DoD) Prohibited Dietary Supplement Ingredients list and the National Collegiate Athletic Association's (NCAA) list of banned substances.
Hordenine might register on an initial urine screening test for amphetamines or opioids, but it will not cause a positive result on a confirmation drug test.
Hordenine has also been the subject of FDA enforcement actions and warning letters.
11. Safety Considerations and Interactions
11.1 General Safety Profile
Hordenine is possibly unsafe when taken by mouth and might cause stimulant side effects such as rapid heart rate and high blood pressure. Most studies showing these effects were done with animals, and limited human studies are available to date.
In experiments in which animals are given sufficiently large doses parenterally, hordenine produces an increase in blood pressure as well as other disturbances of the cardiovascular, respiratory, and nervous systems. These effects are generally not reproduced by oral administration. The human biokinetics data support this, showing plasma concentrations after typical oral exposure far below pharmacologically active thresholds.
11.2 Cardiovascular Risk
Hordenine is similar to stimulants found in bitter orange. In theory, taking hordenine might make high blood pressure worse. Rapid heart rates and high blood pressure are side effects of hordenine that are more likely to occur in sensitive subpopulations such as pregnant women and consumers with cardiovascular disease.
11.3 Surgical Risk
Hordenine might interfere with surgery by increasing blood pressure and heart rate. Stopping hordenine at least 2 weeks before surgery is advised.
11.4 Kidney Stones
Taking hordenine might increase the risk for kidney stones. The mechanistic basis for this concern is not fully elucidated in the available literature, and direct clinical evidence is lacking.
11.5 Drug Interactions
Hordenine might stimulate the body. Some medications used for depression can increase chemicals that also have stimulant effects. Taking hordenine with these medications used for depression might cause serious side effects. This concern is particularly relevant for monoamine oxidase inhibitor (MAOI) antidepressants, given that hordenine itself affects MAO-B activity.
Because hordenine releases norepinephrine and acts on adrenergic receptors, co-administration with other sympathomimetics (e.g., ephedrine, pseudoephedrine, stimulant medications) carries an additive risk of cardiovascular adverse effects.
11.6 Pregnancy and Lactation
There isn't enough reliable information to know if hordenine is safe to use when pregnant or breast-feeding.
11.7 Product Quality and Adulteration Concerns
Studies analyzing products that list hordenine as an ingredient show that such products sometimes contain more hordenine than reported on product labels, while others can contain additional substances not approved for use in dietary supplements. Both natural and synthetic hordenine might promote stimulant effects, and products containing hordenine are considered "adulterated."
References
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