1,3-DMAA

1,3-Dimethylamylamine (1,3-DMAA)

Identity and Chemical Characterization

1,3-Dimethylamylamine (1,3-DMAA), also known as 1,3-dimethylpentylamine and methylhexaneamine (MHA), is an aliphatic amine with stimulant properties. It is also known by the synonyms 4-methyl-2-hexaneamine, 1,3-dimethylpentylamine, and 2-amino-4-methylhexane, and it can be labeled as geranium extract in dietary supplements. Its trade names include Forthane (pharmaceutical) and Geranamine (supplement industry marketing). The CAS registry number is 105-41-9.

Methylhexanamine, also known as 1,3-dimethylamylamine (1,3-DMAA), is an alkylamine. It is closely structurally related to other alkylamines, including 1,3-dimethylbutylamine (1,3-DMBA), 1,4-dimethylamylamine (1,4-DMAA), heptaminol, iproheptine, isometheptene, octodrine, and tuaminoheptane. Methylhexanamine and other related alkylamines are similar in chemical structure to phenethylamines and amphetamines, but lack a closed ring.

1,3-Dimethylamylamine (DMAA) is not a single compound but rather a mixture of four stereoisomers. When produced synthetically, DMAA is a mixture of two racemates and has a distinct diastereomeric ratio. In studies examining the enantiomeric and diastereomeric ratios of synthetic DMAA and commercial supplements, the stereoisomeric ratios of DMAA in all commercial supplements tested were indistinguishable from those of the synthetic standards.

Physical Form and Common Preparations

1,3-DMAA may exist as a clear liquid or crystalline solid, depending on form. In the supplement marketplace, it has been formulated primarily as an oral powder (often in proprietary pre-workout blends), capsules, and tablet-based products. It has been known by the names 2-amino-4-methylhexane, 1,3-dimethylamylamine, 1,3-dimethylpentylamine, methylhexanamine, 4-methyl-2-hexylamine, and "Geranamine™," among others.

Claimed Natural Source and the Geranium Controversy

1,3-Dimethylamylamine (1,3-DMAA) is an aliphatic amine with stimulant properties that are reportedly found naturally only in geranium plants (Pelargonium graveolens). Significant controversy exists regarding the "natural" origin of DMAA, as claimed by manufacturers of supplements. Manufacturers often refer to its presence by the name Geranamine®, implying that DMAA is found in the plant species Geranium and Pelargonium, known collectively as Geraniaceae.

The presence of 1,3-DMAA in geranium plants was first reported in a paper published in 1996, but some have questioned the identification of 1,3-DMAA in that study. Since then, a number of additional studies have been published, largely reporting the absence of 1,3-DMAA in geranium plants and commercial geranium oils. However, in two more recent studies, 1,3-DMAA was detected in geranium plant tissues and a geranium oil sample using a simplified extraction approach on tissues and oil sourced from China.

The amount of DMAA found in dietary supplements was shown to be too high to be solely derived from natural geranium extracts, according to multiple independent investigations. Whether or not 1,3-DMAA is found naturally in plants has significant implications as to how commercial products containing 1,3-DMAA are regulated by the U.S. Food and Drug Administration. According to the FDA, some products list Pelargonium graveolens extract or geranium extract on the label, which may indicate that the product contains DMAA; without laboratory testing there is no way to know whether the "geranium extract" listed on the label is a different—possibly natural—ingredient or some form of synthetic DMAA.

Historical and Pharmaceutical Background

Dimethylamylamine (DMAA) is an aliphatic amine with sympathomimetic properties that has been referred to by numerous names, including methylhexaneamine, 2-amino-4-methylhexane, Forthane, and Geranamine, since its inception in 1944. It was initially developed in 1944 by Eli Lilly as a nasal decongestant. The pharmaceutical amphetamine derivative 1,3-dimethylamylamine (DMAA) was introduced in 1948 as a nasal inhaler for rhinitis by Eli Lilly & Co. By the 1970s, it had been withdrawn as an approved pharmaceutical.

Original reports indicated that DMAA was a less potent and longer-lasting vasoconstrictor compared to epinephrine, with systemic toxicity greater than ephedrine but less than amphetamine. In the original patent application, it was described as having less CNS effects than amphetamine, and less systemic symptoms than ephedrine. In comparison with ephedrine, it was deemed more volatile and therefore preferable in applications requiring volatility, such as nasal sprays and inhalers.

DMAA, promoted for weight loss, bodybuilding, and performance enhancement, was first introduced as a drug for nasal decongestion in 1948 before being voluntarily removed from the market in 1983. In 2006, DMAA was re-released as a dietary supplement by Ergopharm (E-Pharm) in the product "AMP," marketed as an extract of geranium oil. Since 2006, methylhexanamine has been sold extensively under many names as a stimulant or energy-boosting dietary supplement under the claim that it is similar to certain compounds found in geraniums, but its safety has been questioned as a number of adverse events and at least five deaths have been associated with methylhexanamine-containing supplements.

Dietary supplements containing DMAA were once widely available, with an estimated 440,000,000 servings of such supplements sold in recent years. These doses were primarily consumed as a component of "pre-workout" supplements marketed at those who exercise.

Active Compound and Mechanisms of Action

Sympathomimetic Classification

Methylhexanamine is an indirect sympathomimetic drug. Whereas the sympathomimetic effects of DMAA have been characterized, its exact pharmacological mechanism has not been fully elucidated. Pharmacologically, DMAA is classified as an α-1-adrenergic agonist. A review identified several animal studies from the 1940s and 1950s indicating that DMAA has similar effects to ephedrine and amphetamine, including an increase in arterial blood pressure, vasoconstriction, tachycardia, and bronchodilation.

Norepinephrine Transporter (NET) Inhibition

DMAA inhibits the norepinephrine transporter (NET), a known amphetamine target, with an IC50 of 0.41 µM. As DMAA has a greater preference for NET:DAT (norepinephrine transporter vs. dopamine transporter) than d-amphetamine, it may carry greater risks from pressor actions but lower risks from positive reinforcement, potentially limiting abuse potential.

Dopamine Transporter (DAT) Modulation

The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential.

In transport assays in human embryonic kidney cells, DMAA inhibited dopamine uptake by the human dopamine transporter in a competitive manner. Docking analysis and molecular dynamics simulations supported these findings, revealing that DMAA binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A–sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that DMAA elicits neurologic effects by binding to and regulating function of the dopamine transporter.

Alpha-Methyl Substituent and Monoamine Oxidase Resistance

Similar to amphetamine, DMAA possesses a methyl substituent on the alpha-carbon, which prolongs the drug's half-life by sterically interfering with monoamine oxidase. This substituent also enhances its ability to act as a catecholamine reuptake inhibitor.

Cardiovascular Pharmacodynamics

Like other sympathomimetics, acute use of DMAA appears to promote vasoconstriction, which can lead to a dose-dependent elevation in blood pressure—a finding that has been documented in controlled laboratory studies. The FDA has stated that methylhexanamine "is known to narrow the blood vessels and arteries, which can elevate blood pressure and may lead to cardiovascular events ranging from shortness of breath and tightening in the chest to heart attack."

Early investigations (1948) in a single human subject receiving 2 mg/kg DMAA produced elevations in both systolic and diastolic blood pressure of 22 mmHg each, accompanied by a decrement in heart rate of 8 beats per minute. A 3 mg/kg dosage was reported to produce intolerable side effects as well as an irregular heart rate.

Scientific Evidence by Area of Use

1. Cardiovascular and Blood Pressure Effects

The most consistently documented human effect of DMAA is its impact on blood pressure. The use of supplements containing DMAA and caffeine has been shown to increase blood pressure in the short term, with a peak at 60–90 minutes post-ingestion, with minimal effects on heart rate, across multiple studies. However, the picture at lower, label-directed doses is less clear.

In one pharmacokinetic study, eight men received a single 25 mg oral dose of DMAA after an overnight fast. Blood samples were collected before and through 24 hours post-DMAA ingestion and analyzed using high-performance liquid chromatography–mass spectrometry, while resting heart rate, blood pressure, and body temperature were also measured. Analysis of the remaining seven participants showed DMAA had an oral clearance of 20.02 ± 5 L·hr⁻¹, an oral volume of distribution of 236 ± 38 L, and a terminal half-life of 8.45 ± 1.9 hours. Lag time averaged approximately 8 minutes. The peak DMAA concentration for all subjects was observed within 3–5 hours following ingestion, with a mean of approximately 70 ng·mL⁻¹. Heart rate, blood pressure, and body temperature were largely unaffected by DMAA treatment.

Findings indicated a consistent pattern of peak DMAA concentration, with values approximately 15–30 times lower than those reported in case studies linking DMAA intake with adverse events. Limitation: This study involved only seven participants, used a single 25 mg dose, and did not include higher doses or combined-ingredient formulations.

In healthy adults ingesting 30 to 60 mg DMAA per day, studies reported transient increases in blood pressure but no toxic effects. The daily ingestion of DMAA-containing supplements for periods between 14 days and 12 weeks had no pathological consequences in the studied populations across several investigations. These controlled trial data are limited by small sample sizes, the use of multi-ingredient supplements (preventing attribution of effects to DMAA alone), and relatively short follow-up durations.

2. Athletic Performance and Exercise

DMAA was widely marketed as a pre-workout performance enhancer. Evidence from controlled human studies is limited and methodologically constrained, chiefly because available studies used multi-ingredient products rather than isolated DMAA.

1,3-DMAA has been used nonmedically as an appetite suppressant and exercise performance enhancer, despite adverse cardiovascular effects that have limited its legal status. DMAA has been touted as "safe"; despite this, it has been banned in several countries as well as by the World Anti-Doping Agency (WADA) because of suggestions it could enhance performance as well as pose a health threat.

DMAA, under the name methylhexaneamine, was placed on WADA's list of prohibited substances from 2010, and has since caused controversy, with athletes from several countries testing positive for its presence. In 2010, nine Australian athletes tested positive, and at the time it was thought that this had occurred inadvertently due to the substance's inclusion in many sports supplements.

Despite the ban of the substance by WADA in 2010, the number of positive DMAA-related doping test results increased from 123 in 2010 to 320 adverse analytical findings in 2012, which were 45% of all positive test results in the group of prohibited stimulants.

Evidence strength: Human performance evidence is weak. No well-powered, isolated DMAA randomized controlled trials examining exercise outcomes have been published. Studies using DMAA-containing multi-ingredient supplements cannot isolate the contribution of DMAA versus caffeine, creatine, beta-alanine, or other co-ingredients.

3. Weight Loss and Appetite Suppression

The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. DMAA is often touted as a "natural" stimulant, with many claimed functional uses including a body-building aid, an athletic performance enhancer, and a weight-loss aid.

Evidence strength: No rigorous, isolated human clinical trials have demonstrated efficacy of DMAA alone for weight loss or appetite suppression. Claims rest on its stimulant and sympathomimetic properties (by extrapolation from ephedrine/amphetamine-class pharmacology), not on controlled weight-loss outcome data specifically for DMAA.

4. Central Nervous System Stimulation and Mood

An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. DMAA's demonstrated ability to interact with both the NET and DAT provides a plausible mechanistic basis for stimulant and mood-altering effects, but formal human studies on cognitive or mood endpoints using isolated DMAA are absent from the peer-reviewed literature.

Most studies have been done on pharmacological effects when the drug is inhaled; the understanding of what methylhexanamine does when taken orally is mostly based on extrapolating from the activities of similar compounds.

5. Nasal Decongestion (Historical Pharmaceutical Use)

DMAA was originally developed by Eli Lilly in 1948 and later trademarked as Forthane to be used as a nasal decongestant (Eli Lilly patented the molecule in the early 1940s, trademarked and marketed it as Forthane in 1971 for allergic rhinitis, and then voluntarily withdrew it in 1983). The mechanism of action was vasoconstriction—the blood vessels in the nose would constrict so that less blood flow would lead to less nasal discharge. Although DMAA at one time was approved as a drug for nasal decongestion, no medical use of DMAA is recognized today.

Pharmacokinetics

Analysis of participants in the key oral pharmacokinetic study showed DMAA had an oral clearance of 20.02 ± 5 L·hr⁻¹, an oral volume of distribution of 236 ± 38 L, and a terminal half-life of 8.45 ± 1.9 hours. Lag time, the delay in appearance of DMAA in the circulation following extravascular administration, varied among participants but averaged approximately 8 minutes. The peak DMAA concentration for all subjects was observed within 3–5 hours following ingestion, with a mean of approximately 70 ng·mL⁻¹.

Blood plasma concentrations of 1,3-dimethylamylamine after oral administration have been shown to reach up to 20 µM, which is a concentration above the IC50 shown to inhibit the NET in vitro (IC50 = 0.4 µM). Accordingly, these products are used at doses that are likely pharmacologically active.

Dosages Reported in Studies and Supplement Products

• Pharmacokinetic study (Schilling et al., 2013): Eight men received a single 25 mg oral dose of DMAA.
• Controlled laboratory studies: Studies of healthy adults ingesting 30 to 60 mg DMAA per day reported transient increases in blood pressure.
• Recreational "party pill" use: DMAA-containing dietary supplement products, by virtue of their formulations and label instructions, may result in an order of magnitude lower DMAA consumption than DMAA "party pills," which may contain 300 mg DMAA per pill.
• Adverse event cases: One case-report patient purportedly ingested two "tablets" containing DMAA (later confirmed by analysis to contain 278 mg of DMAA per capsule: total dosage of 556 mg), along with 150 mg of caffeine and one can of beer.

Body Systems and Health Areas Associated with DMAA

Cardiovascular System

DMAA is a stimulant and vasoconstrictor that narrows blood vessels and arteries and increases blood pressure. The FDA warns this could lead to problems such as heart attack, shortness of breath, and tightening of the chest.

Central Nervous System

DMAA elicits neurologic effects by binding to and regulating the function of the dopamine transporter. It also inhibits the norepinephrine transporter (NET) with an IC50 of 0.41 µM. These dual monoamine transporter interactions underlie its stimulant, alerting, and potential mood-altering properties.

Hepatic System

Products containing DMAA have been linked to several serious adverse events, including liver injury. Health authorities in Hawaii linked cases of liver failure and one death to OxyElite Pro, a weight-loss and bodybuilding dietary supplement.

Ocular System

There have also been reports of secondary open-angle glaucoma related to methylhexanamine supplementation.

Safety Considerations, Adverse Events, and Regulatory Status

Documented Adverse Events

Notable case reports have associated DMAA consumption with cerebral hemorrhaging, myocardial infarction (MI), liver injury, and death. In two publications, Gee et al. reviewed four separate cases in which individuals reported ingesting pure DMAA in conjunction with alcohol in recreational settings. Individuals experienced adverse outcomes including severe headaches, vomiting, and involuntary twitching. Hospitalization revealed cerebral hemorrhaging in all cases.

Numerous adverse events and at least five deaths have been reported in association with methylhexanamine-containing dietary supplements. In April 2013, the FDA warned consumers not to use products containing DMAA due to the risk of serious cardiovascular injuries and death. The FDA has received over 100 adverse event reports involving DMAA.

Reported adverse effects include a higher risk of increased blood pressure, tachycardia, hemorrhagic stroke, and cardiac arrest.

Dose-Dependence and Confounding Factors

Concluding on the safety profile of DMAA based solely on case reports is problematic, particularly when accepting testimony from patients in uncontrolled environments, potentially under the influence of alcohol and other drugs. This is especially true given that no prospective studies have shown these effects.

DMAA-containing dietary supplement products, by virtue of their formulations and label instructions, may result in an order of magnitude lower DMAA consumption than DMAA party pills. Authors of numerous clinical studies of DMAA in healthy adults ingesting 30 to 60 mg DMAA per day reported transient increases in blood pressure but no toxic effects.

The general practice by the supplement industry of producing products containing multiple substances makes it difficult to attribute specific effects caused by the supplement to one of them; the case reports referenced regarding supplements containing 1,3-DMAA only give an idea of the potential effects of 1,3-DMAA, with additional studies being necessary to confirm these effects.

Interaction with Caffeine

Given the pressor action and widespread use of caffeine, a synergistic effect between DMAA and caffeine may be responsible for some of the adverse effects reported. The mixed consumption of different stimulant-like substances, including caffeine in high dosages, can be highly problematic and can lead to severe adverse effects including cardiovascular risks.

Animal Toxicology

Animal studies have indicated that the LD50 of DMAA is 39 mg·kg⁻¹ for intravenous and 185 mg·kg⁻¹ for intraperitoneal administration.

Abuse Liability

As DMAA has a greater preference for the norepinephrine transporter over the dopamine transporter compared to d-amphetamine, it may carry greater risks from pressor actions but potentially lower risks from positive reinforcement, limiting abuse potential relative to classical amphetamines. However, formal human abuse-liability studies are limited.

Amphetamine Cross-Reactivity and Drug Testing

DMAA is known to cause positive immunoassay results for amphetamines in standard urine drug screens, a finding documented in the peer-reviewed literature. This has significant implications for both occupational and anti-doping testing contexts.

Regulatory and Banned Status

DMAA would be classified as a New Dietary Ingredient (NDI) by the FDA under the Dietary Supplement Health and Education Act of 1994 (DSHEA). In 2012, the FDA issued warning letters to manufacturers and distributors calling for cessation of DMAA sales and use within dietary supplement formulations, partly because required safety data supporting DMAA's use was lacking. Supplements containing DMAA were considered "adulterated."

In April 2013, the FDA declared DMAA illegal for use as a dietary supplement ingredient. DMAA presents a readiness risk to service members and is included on the DoD Prohibited Dietary Supplement Ingredients list.

In 2010, the World Anti-Doping Agency (WADA) added DMAA to the list of substances prohibited for use by athletes. DMAA is classified as a stimulant and is banned in competition by WADA under the category of "Non-Specified Stimulants."

Despite multiple warning letters from the FDA, as of 2019, the stimulant remained available in sports and weight-loss supplements in the United States. Many countries banned or restricted the sale of 1,3-DMAA, yet despite the efforts of regulating agencies, 1,3-DMAA has been reported to still appear in dietary supplements and has been identified in doping controls.

Summary of Evidence Quality

The overall body of evidence for 1,3-DMAA as a dietary supplement ingredient is characterized by significant limitations across all proposed applications:

• Pharmacokinetics: One small human study (n=7) exists characterizing oral pharmacokinetics at a single 25 mg dose. Evidence is preliminary.
• Blood pressure/cardiovascular effects: Multiple short-term human studies document acute pressor effects at 30–60 mg/day doses; effects at a single 25 mg dose appear minimal. Multi-ingredient formulations confound attribution.
• Athletic performance: No well-controlled, isolated DMAA human RCTs on performance outcomes; evidence comes from multi-ingredient supplement studies with methodological confounds.
• Weight loss/appetite suppression: No rigorous isolated human clinical trials exist; claims rest on sympathomimetic pharmacology by analogy.
• Mechanism of action: Characterized primarily in cell-based (in vitro) and molecular docking studies; limited translational data to intact human physiology.
• Safety: Dominated by case reports and adverse event databases rather than prospective trial data; causality is difficult to establish given polypharmacy confounds in most reported cases.

References

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