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Methylhexanamine
Methylhexanamine
Methylhexanamine
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Methylhexanamine
Clinical data
Other namesMethylhexaneamine, methylhexamine, geranamine, geranium extract, geranium oil, 2-amino-4-methylhexane, dimethylamylamine, DMAA, 1,3-dimethylamylamine, 1,3-DMAA, 1,3-dimethylpentylamine, 4-methyl-2-hexanamine, 4-methyl-2-hexylamine
Routes of
administration		Nasal spray, oral
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life~8.5 hours
Identifiers
  • 4-Methylhexan-2-amine[7]
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.002.997 Edit this at Wikidata
Chemical and physical data
FormulaC7H17N
Molar mass115.220 g·mol−1
3D model (JSmol)
  • CCC(C)CC(C)N
  • InChI=1S/C7H17N/c1-4-6(2)5-7(3)8/h6-7H,4-5,8H2,1-3H3 ☒N
  • Key:YAHRDLICUYEDAU-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)

Methylhexanamine (also known as methylhexamine, 1,3-dimethylamylamine, 1,3-DMAA, dimethylamylamine, and DMAA; trade names Forthane and Geranamine) is an indirect sympathomimetic drug invented and developed by Eli Lilly and Company and marketed as an inhaled nasal decongestant from 1948 until it was voluntarily withdrawn from the market in the 1980s.[8][9]

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.[10] It is banned by many sports authorities and governmental agencies. Despite multiple warning letters from the FDA,[11] as of 2019, the stimulant remains available in sports and weight loss supplements in the US.[12]

History

[edit]

In April 1944, Eli Lilly and Company introduced methylhexanamine under the brand name Forthane as an inhaled nasal decongestant; Lilly voluntarily withdrew methylhexanamine from the market in 1983.[13]: 12  The compound is an aliphatic amine; the pharmaceutical industry had a strong interest in compounds in this class as nasal decongestants in the early 20th century, which led to methylhexanamine and four other similar compounds being brought to market for that use: tuaminoheptane, octin (isometheptene), oenethyl (2-methylaminoheptane), and propylhexedrine; octin and oenethyl were eventually approved for use in keeping blood pressure sufficiently high for patients under anesthesia.[citation needed]: 95–96 

Marketing as dietary supplement

[edit]

Patrick Arnold reintroduced methylhexanamine in 2006 as a dietary supplement,[14][15] after the final ban of ephedrine in the United States in 2005. Arnold introduced it under the trademarked name Geranamine, a name held by his company, Proviant Technologies. A large number of supplements focusing on fat loss and workout energy (thermogenic or general-purpose stimulants) used the ingredient in concert with other substances such as caffeine, a combination similar to the combination of ephedrine and caffeine.

Methylhexanamine-containing supplements sometimes list "geranium oil" or "geranium extract" as a source of methylhexanamine. However, geranium oils do not contain methylhexanamine, and the methylhexanamine in these supplements is added in the form of synthetic material.[16] A variety of studies have explored the possibility that DMAA is found in some types of geraniums, but at present, high quality evidence of DMAA's presence in plants is lacking.[17][18]

Methylhexanamine is synthesized by reacting 4-methylhexan-2-one with hydroxylamine, which converts the 4-methylhexan-2-one to 4-methylhexan-2-one oxime, which is reduced via catalytic hydrogenation; the resulting methylhexanamine can be purified by distillation.[19]: 995–996 

Pharmacology

[edit]

Methylhexanamine is an indirect sympathomimetic drug that constricts blood vessels and thus has effects on the heart, lungs, and reproductive organs. It also causes bronchodilation, inhibits peristalsis in the intestines, and has diuretic effects.

Most studies have been done on pharmacological effects when the drug is inhaled; the understanding of what methylhexanamine does when taken orally are mostly based on extrapolating from the activities of similar compounds.: 97  A 2013 review concluded that: "Pharmacological effects after oral intake can be expected on the lungs (bronchodilation) and the nasal mucosa following a single oral dose of about 4–15 mg. Pharmacological effects on the heart can be expected following a single oral dose of about 50–75 mg. Pharmacological effects on the blood pressure can be expected after a single oral dose of about 100 mg. Because of the long half-life, there is a risk that repeated doses within 24–36 hours could lead to steadily stronger pharmacological effects (build-up).": 98 

In 2019 and 2023, methylhexanamine was found to show activity consistent with being a norepinephrine and dopamine releasing agent (NDRA).[20][21][22]

Detection in body fluids

[edit]

Methylhexanamine may be quantified in blood, plasma, or urine by gas or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalized patients or to provide evidence in a medicolegal death investigation. Blood or plasma methylhexanamine concentrations are expected to be in a range of 10–100 μg/L in persons using the drug recreationally, >100 μg/L in intoxicated patients, and >300 μg/L in victims of acute overdosage.[23][24]

Safety

[edit]

The LD50 for methylhexanamine is 39 mg/kg in mice and 72.5 mg/kg in rats, when administered intravenously.: 95 [25]: 110 

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".[26] Numerous adverse events and at least five deaths have been reported in association with methylhexanamine-containing dietary supplements.[10] There have also been reports of secondary open-angle glaucoma related to methylhexanamine supplementation.[27]

A 2012 review by a panel convened by the U.S. Department of Defense to study whether the military should ban methylhexanamine supplements from stores on its bases concluded that: "The existing evidence does not conclusively establish that DMAA-containing substances are causally-associated with adverse medical events. However, a consistent theme among the studies is that DMAA use potentially affects cardiovascular function, just as other sympathomimetic stimulants. Without further rigorous study designs developed to evaluate the safety of DMAA, especially in patients with concomitant use of other substances, co-morbid conditions and high frequency use, the magnitude of the association of DMAA with adverse medical events is uncertain. Widespread use of DMAA-containing products by tens of thousands of Service members – often in combination with other substances – increases the likelihood of observing serious adverse events, even if the overall risk of a DMAA-related event is low, resulting in consequential impact to some Service members and other beneficiaries. DMAA should be further studied to evaluate its safety. Data from the case control study suggest that the frequency and amount of DMAA use and risk of specific [acquired medical events], particularly heat injuries and rhabdomyolysis, need to be examined in greater detail. ... The Safety Review Panel recommended ... to continue the prohibition of sales of DMAA-containing products in Exchanges and concessions. The Panel judged that the evidence supports sufficient risk, even if very low, of another death or catastrophic illness of a Service member who has used DMAA-containing products, without any offsetting benefit of these products."[13]: 10 

Deaths and injuries

[edit]

In 2010, a 21-year-old man in New Zealand presented with a cerebral hemorrhage after ingesting 556 mg of methylhexanamine, caffeine, and alcohol.[28] Health authorities in Hawaii linked cases of liver failure and one death to OxyElite Pro, a weight loss and bodybuilding dietary supplement.[29]

The death of Claire Squires, a runner who collapsed near the finish-line of the April 2012 London Marathon, has been linked to methylhexanamine. The coroner stated that methylhexanamine was "probably an important factor" during the inquest. Despite, according to a friend, having been diagnosed with an irregular heartbeat[30] and advised not to consume methylhexanamine, it is believed that she consumed the substance through drinking an energy drink, which was subsequently reformulated to exclude methylhexanamine.[31]

Chemistry

[edit]
Chemical structures of amphetamine and methylhexanamine compared.

Methylhexanamine, also known as 1,3-dimethylamylamine (1,3-DMAA), is an alkylamine.[32][33]

It is closely structurally related to other alkylamines, including 1,3-dimethylbutylamine (1,3-DMBA), 1,4-dimethylamylamine (1,4-DMAA), heptaminol (2-methyl-6-amino-2-heptanol), iproheptine (N-isopropyl-1,5-dimethylhexylamine), isometheptene (2-methyl-6-methylamino-2-heptene), octodrine (2-amino-6-methylheptane or 1,5-dimethylhexylamine), and tuaminoheptane (tuamine; 2-aminoheptane or 1-methylhexylamine).[32][33]

Methylhexanamine and other related alkylamines are similar in chemical structure to phenethylamines and amphetamines, but lack a closed ring.[32][33]

The predicted log P (XLogP3) of methylhexanamine is 1.9.[32]

Regulation

[edit]

A number of sporting authorities and countries have banned or heavily restricted the use of methylhexanamine as a dietary supplement, due to serious concerns about its safety. These countries include Australia, Brazil, Canada, Finland, New Zealand, Sweden, Switzerland, the United Kingdom, and the United States.

Sports authorities

[edit]

Many professional and amateur sports bodies, such as the World Anti Doping Agency, have banned methylhexanamine as a performance-enhancing substance and suspended athletes that have used it.[34][35][36][37][38][39]

  • March, 2012, a minor league baseball player, Cody Stanley, was suspended 50 games for testing positive after using a dietary supplement.[40]
  • In July 2012, Welsh boxer Enzo Maccarinelli was banned for six months after testing positive for methylhexanamine.[41]
  • VFL player Matthew Clark was suspended for two years after the banned substance was detected in his system after a game in 2011.[42]
  • August, 2012, then minor league baseball player Marcus Stroman was suspended 50 games for testing positive for methylhexanamine.[43]
  • On 8 August 2013, US Weightlifter Brian Wilhelm accepted a nine-month suspension after testing positive for the drug in a urine sample from December 2012 at the American Open.[44]
  • MotoGP rider Anthony West was suspended for one month by the FIM International Disciplinary Court (CDI) on 29 October 2012 after testing positive for the drug on 20 May 2012 at the French Grand Prix. This was increased retroactively to an 18-month suspension, starting from 20 May 2012, on 28 November 2013 after an appeal by the World Anti-Doping Agency (WADA).[45]
  • In December 2013, boxer Brandon Rios, after losing a unanimous decision to Manny Pacquiao, was suspended by the China Professional Boxing Association after testing positive for the drug.[46]
  • During the 2014 Winter Olympics in Sochi, three athletes tested positive for the drug: Italian bobsleigh brakeman and former decathlete William Frullani, German biathlete Evi Sachenbacher-Stehle and Latvian ice hockey forward Vitalijs Pavlovs.[47][48]
  • During the 2015 Asian Cup, Iraqi player Alaa Abdul-Zahra was subject to an investigation relating to illegal usage of the drug.[49]
  • In January 2016, Algerian footballer Kheiredine Merzougi was banned for two years by the Confederation of African Football after testing positive for the drug.[50] However, in March 2016, the international body FIFA confirmed they were giving an extended four-year ban to apply worldwide through January 2020.[51]
  • In November 2016, heavyweight boxer Bermane Stiverne was fined US$75,000 after testing positive for methylhexanamine by the World Boxing Council.[52] The WBC, however, still allowed this fight to happen.
  • In 2017, the International Olympic Committee disqualified Jamaica's 2008 gold-winning 4x100 men's relay in Beijing due to Nesta Carter's positive testing for methylhexanamine. This cost Usain Bolt a medal.[53]
  • AMA Supercross Championship rider Broc Tickle was provisionally suspended by the FIM International Disciplinary Court (CDI) on 13 April 2018 after testing positive for the drug following a drug test after the supercross round held in San Diego on 10 February 2018.[54]
  • On May 22, 2018, Filipino basketball player Kiefer Ravena was handed 18 months suspension by FIBA to compete in international competition. He was found testing positive for methylhexanamine and 1,3-dimethlybutylamine by WADA. Urine samples were taken after the Philippines vs Japan game at Manila during the 2019 FIBA Basketball World Cup Qualification. Ravena explained that he consumes a pre-workout drink called C4, which can be bought from retailers around Metro Manila. He ran out of supplies shortly before a training camp in Australia and took Blackstone Labs DUST, a supplement which is mixed with water and is supposedly similar to C4.[55]
  • On August 26, 2019, NASCAR crew chief Matt Borland was indefinitely suspended under the sanctioning body's substance abuse policy after testing positive for DMAA. In a statement, Borland said that the positive test was most likely caused by a diet coffee he had felt comfortable drinking "after doing my due diligence." Team owner Bob Germain Jr. also said that he did not believe Borland “had reason to know that the coffee contained a banned substance. However, we also understand and respect NASCAR’s decisions to strictly uphold their policies for each and every owner, driver and crew member in the garage."[56] The suspension was lifted on September 24 after completing NASCAR's mandatory "Road to Recovery Program".[57]

Governmental agencies

[edit]

In 2010, the US military issued a recall of all methylhexanamine-containing products from all military exchange stores worldwide.[58][59]

In July 2011, Health Canada decided methylhexanamine was not a dietary substance, but was a drug requiring further approval. Consequently, Health Canada banned all sales of methylhexanamine.[60]

In June 2012, the National Food Agency of Sweden issued a general warning regarding use of methylhexanamine products, resulting in a sales ban in parts of the country.[61]

In July 2012, the National Health Surveillance Agency of Brazil issued a warning to the general public on the hazards of products that contain methylhexanamine.[62] It also updated the list of prohibited substances to insert methylhexanamine, which translates into the banishment of products containing such ingredient from the Brazilian market.[63]

In 2012, Australia banned methylhexanamine. In New South Wales, methylhexanamine was classed as a "highly dangerous substance" on the poisons list.[64]

In August 2012, the UK Medicines and Healthcare products Regulatory Agency (MHRA) has ruled that the popular DMAA containing sports supplement Jack3D is an unlicensed medicinal product and that it and all other methylhexanamine containing products need to be removed from the UK market amid concerns of potential risks to public safety.[65]

In 2012 the New Zealand Ministry of Health banned the sale of methylhexanamine products,[66] due in part to its growing recreational use as party pills.[67][68]

In April 2013, the US Food and Drug Administration determined that methylhexanamine was potentially dangerous and did not qualify as a legal dietary supplement; it warned supplement makers that it was illegal to market methylhexanamine and warned consumers of potentially serious health risks associated with methylhexanamine-containing products.[10][69] The FDA has issued warning letters to manufacturers and distributors who continued to market products containing methylhexanamine.[70]

See also

[edit]

Notes

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Methylhexanamine

View on Grokipedia
from Grokipedia
Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA) or 4-methyl-2-hexanamine, is a synthetic aliphatic compound with the molecular formula C₇H₁₇N that functions as a exhibiting sympathomimetic and effects. Developed in the and patented as a nasal , it was marketed by under the trade name Forthane as an inhaled sympathomimetic agent until its withdrawal from pharmaceutical use in due to limited efficacy and safety concerns. In the mid-2000s, DMAA reemerged as an ingredient in dietary supplements promoted for , energy enhancement, and athletic performance, often misleadingly labeled as a natural extract from () oil despite lacking verifiable pre-1994 dietary use history under U.S. regulations and evidence of synthetic origin. Its pharmacological actions, including elevation of , modulation in combination with , and substrate inhibition at the , have linked it to adverse events such as cardiovascular incidents and neurological disturbances in users. Regulatory scrutiny intensified following reports of toxicity exceeding that of related like , leading to bans by the U.S. on its inclusion in supplements, prohibition by the in competitive sports, and restrictions in multiple countries amid ongoing detections in adulterated products.

Chemical Properties

Structure and Synthesis

Methylhexanamine, systematically named 4-methylhexan-2- or 1,3-dimethylamylamine, possesses the molecular C₇H₁₇N. Its structure comprises a branched six-carbon chain with a primary group at the 2-position and a methyl at the 4-position, resulting in the configuration CH₃CH(NH₂)CH₂CH(CH₃)CH₂CH₃. The compound is entirely synthetic, with no verified natural occurrence in sources like oil, contrary to prior assertions lacking empirical support. Initial synthesis routes were patented in 1944 by under U.S. Patent 2,350,318 for aminoalkane production, targeting nasal decongestants. The process employs via oxime formation: 4-methylhexan-2-one reacts with hydroxylamine hydrochloride to yield the intermediate, followed by catalytic to reduce the C=N bond to the primary . This method exemplifies classical for aliphatic amines from ketones, ensuring high yield and purity suitable for pharmaceutical applications.

Physical and Chemical Characteristics


Methylhexanamine appears as a liquid with an odor. It has a density of 0.762–0.766 g/mL at 20 °C and a of 1.417–1.419 at 20 °C. The boiling point is reported as 130–135 °C at 760 mmHg, with an estimated melting point of -19 °C. The compound exhibits limited solubility in but is highly soluble in organic solvents such as , , and . As a primary aliphatic , methylhexanamine displays basic character, with the pKa of its conjugate acid approximately 10.54 in at 24 °C. This basicity influences its behavior in aqueous environments. Methylhexanamine remains stable under standard storage conditions but may undergo gradual degradation in oxidative settings, as observed in analytical samples over time.

Pharmacology

Mechanism of Action

Methylhexanamine (1,3-dimethylamylamine; DMAA) primarily exerts its stimulant effects as an indirect sympathomimetic agent by acting as a substrate at the (NET), with an IC50 of 0.41 µM for inhibition. This interaction promotes reverse transport of norepinephrine, elevating extracellular concentrations in synaptic clefts and mimicking the physiological actions of endogenous catecholamines such as norepinephrine and epinephrine. The resulting noradrenergic surge stimulates postsynaptic alpha- and beta-adrenergic receptors, inducing via alpha-1 receptor activation, increased and through beta-1 agonism, and heightened arousal via beta-2 and alpha-2 influences on noradrenergic pathways. DMAA also demonstrates weaker substrate-like activity at the dopamine transporter (DAT), inhibiting dopamine uptake with an IC50 of 29.4 µM—approximately 60-fold less potent than d-amphetamine—and inducing DAT endocytosis, which may contribute to dopaminergic components of its psychostimulant profile. However, its preferential affinity for NET over DAT underscores norepinephrine-mediated sympathomimetic dominance, aligning with early physiological observations of pressor and tachycardic responses in animal models. Direct binding affinity data for adrenergic receptors remain sparse, with effects inferred to arise mainly from displacement and release rather than potent receptor , distinguishing DMAA from direct-acting sympathomimetics like . This indirect mechanism, structurally analogous to amphetamines, accounts for its vasoconstrictive and alerting properties without robust evidence of primary direct receptor interaction.

Pharmacokinetics and Metabolism

Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA), exhibits rapid initial absorption after , with a mean lag time of 0.14 ± 0.13 hours observed in healthy adult males following a 25 mg dose. Peak plasma concentrations (C_max ≈ 70 ng/mL) are attained at a mean t_max of 3.57 ± 1.48 hours, ranging from 3 to 5 hours across individuals. These parameters derive from a controlled pharmacokinetic study using noncompartmental of plasma samples collected over 24 hours via HPLC-MS. The compound demonstrates extensive tissue distribution, evidenced by a large apparent (V_z/F) of 236 ± 38 L, suggesting broad penetration beyond the plasma compartment. Elimination occurs primarily via renal , with an oral clearance (CL/F) of 20.02 ± 5 L/h and a terminal elimination (t_{1/2}) of 8.45 ± 1.9 hours. data remain limited to small-scale studies, precluding precise quantification of absolute , though the appear consistent with low first-pass effects given the clearance values relative to hepatic blood flow. Metabolism of methylhexanamine is minimal, with the parent compound predominating in pathways and little evidence of significant . No major metabolites have been consistently identified in pharmacokinetic evaluations, and recovery studies indicate most DMAA is eliminated unchanged, potentially via glomerular filtration and tubular secretion. While co-administration with other stimulants like in dietary supplements may alter absorption kinetics through pharmacodynamic interactions, dedicated interaction studies are scarce. Overall, the compound's profile supports prolonged systemic exposure, consistent with its observed .

Detection in Biological Fluids

Methylhexanamine, primarily excreted unchanged in due to minimal , is detected using sensitive chromatographic techniques in biological fluids such as and plasma for anti-doping and forensic purposes. Gas chromatography-mass spectrometry (GC-MS) serves as a standard method, often requiring derivatization to improve the compound's chromatographic behavior and sensitivity, achieving limits of detection in the low ng/mL range. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides an alternative without derivatization, employing and (e.g., m/z 116.2 → 57.3 transition) for specificity, with validated linear ranges from 50–700 ng/mL in . The (WADA) classifies methylhexanamine as a non-threshold , requiring reporting of adverse findings above the minimum required performance limit (MRPL), typically 10–50 ng/mL for similar s, though laboratories must achieve reliable detection at these levels using confirmatory tandem MS to distinguish the parent from potential interferences or isomers. Challenges include the 's two chiral centers, potentially yielding multiple peaks in racemic samples, and the need for high-resolution MS in complex matrices to confirm identity amid endogenous amines. analysis in real-time (DART-MS) has also been applied for rapid screening in urine and supplements. Detection windows in vary by dose and individual factors like renal clearance and hydration; following a 25–40 mg oral dose, peak urinary concentrations reach 18 µg/mL within 2–4 hours, remaining detectable at 500–2000 ng/mL up to 50 hours and beyond, with reports of persistence up to 105 hours (approximately 4 days) based on terminal of about 8.5 hours. Plasma levels peak at ~70 ng/mL 3–5 hours post-ingestion, but urine analysis predominates due to higher concentrations and non-invasive collection.

History

Early Development and Pharmaceutical Use

Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA), was patented in 1944 by as part of a class of aliphatic amines intended for use as vasoconstrictors in nasal applications. The compound was specifically described in U.S. Patent 2,350,318 for its potential to alleviate through localized , reflecting early pharmaceutical interest in sympathomimetic agents for short-term symptomatic relief of . Eli Lilly synthesized it via methods outlined in the patent, emphasizing its aliphatic amine structure as suitable for inhalation delivery without the stimulation seen in related amphetamines. Commercial introduction occurred in 1948 under the Forthane, marketed as an over-the-counter inhaled nasal for treating acute and associated congestion. Clinical use focused on its properties, which induced rapid mucosal to reduce swelling and improve airflow, with studies from the era reporting efficacy comparable to or exceeding in potency for this purpose—approximately 19 times stronger in effect based on comparative vasoconstrictive assays. Through the 1950s to 1970s, Forthane remained available for episodic use, with limited reports of misuse or dependency during this period, as its formulation and delivery limited systemic absorption and abuse potential compared to oral sympathomimetics. Production and distribution continued until 1983, when voluntarily withdrew the (NDA) for methylhexanamine, leading to its discontinuation as a pharmaceutical product. This decision aligned with the emergence of alternative decongestants, such as and , which offered similar or improved profiles for over-the-counter use without necessitating the withdrawal due to emergent safety concerns; contemporaneous data showed no pattern of acute adverse events or widespread abuse prompting regulatory action at the time. The compound's early pharmaceutical tenure thus established its role as a targeted vasoconstrictor, distinct from broader applications that arose later.

Discontinuation and Reemergence in Supplements

Following the withdrawal of methylhexanamine from pharmaceutical use as a nasal in 1983, the compound saw no significant commercial application for over two decades. Its dormancy ended with reintroduction into the market in 2006, primarily as a alternative after the U.S. ban on alkaloids in supplements under the Combat Methamphetamine Epidemic Act of 2005. This revival positioned it in products aimed at enhancing exercise performance and promoting fat loss, capitalizing on demand for legal stimulants in the post- era. The reemergence was enabled by the regulatory framework established by the Health and Education Act (DSHEA) of , which classified dietary supplements separately from drugs and did not require FDA pre-market approval for safety or efficacy. Under DSHEA, manufacturers faced no obligation to notify the FDA of ingredients unless classified as new dietary ingredients (NDIs), a threshold often circumvented by claiming methylhexanamine occurred naturally in oil extracts. This labeling strategy allowed rapid market entry without prior safety demonstrations, fostering proliferation in and weight-loss formulations. Companies like USP Labs exemplified this trend by incorporating the substance into flagship products such as Jack3d, launched in the late as a high-potency aid. Marketed for its purported energy-boosting effects amid minimal oversight, these supplements achieved widespread adoption in fitness communities, with annual U.S. sales of DMAA-containing products exceeding $100 million by the early before heightened FDA examinations. The absence of proactive regulatory hurdles under DSHEA thus drove a surge in availability, shifting methylhexanamine from obscurity to a staple in non-pharmaceutical performance enhancers.

Uses and Marketing

Original Medical Applications

Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA), was patented in 1944 by and marketed starting in 1948 under the brand name Forthane as an inhaled specifically for relieving . The product was formulated as a at a concentration of 0.6 mg/mL, delivering low inhaled doses typically around 0.6 mg per use to provide targeted relief from nasal swelling and stuffiness. This application leveraged its vasoconstrictive properties for short-term symptomatic treatment, with efficacy observations from mid-20th-century use indicating rapid onset of decongestion comparable to or exceeding alternatives like , where its intrinsic effect on nasal passages was estimated at 19 times stronger. Prescribed in this form, methylhexanamine was administered via to minimize systemic exposure, distinguishing it from later oral high-dose formulations and resulting in low reported abuse potential during its pharmaceutical era. voluntarily discontinued marketing Forthane by the late to early , after which no recognized medical uses persisted. While short-term clinical benefits were noted in observational data, formal long-term studies on safety and efficacy were limited, reflecting the era's standards for .

Promotion in Dietary Supplements and Performance Enhancers

Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA), has been marketed in dietary supplements primarily as a aid and fat burner, appearing in products such as OxyElite Pro and Jack3d from manufacturers like USPlabs. These supplements typically contained DMAA at doses ranging from 25 to 75 mg per serving, substantially higher than the low milligram quantities used in its original pharmaceutical applications as a nasal . Promoters positioned DMAA as a potent ingredient synergizing with and other compounds to deliver rapid effects, targeting bodybuilders and athletes seeking competitive edges. Marketing claims emphasized DMAA's role in boosting energy levels, enhancing mental focus, and accelerating fat metabolism through , with assertions of improved and strength during workouts. Supplements were advertised for support, purportedly aiding calorie expenditure and appetite suppression when combined with exercise regimens. User testimonials, often featured in promotional materials and online forums, described sensations of and heightened alertness, reinforcing perceptions of DMAA as a superior alternative to ephedrine-based formulas banned earlier. These narratives contrasted sharply with regulatory assessments viewing such products as adulterated due to unapproved synthetic stimulants. A key tactic involved labeling DMAA as a "natural" extract from (), ostensibly qualifying it as a dietary exempt from pre-market approval under U.S. . Manufacturers cited selective studies claiming trace occurrences in geranium oils to substantiate this positioning, aiming to evade scrutiny as a new drug. However, independent chemical analyses, including those using gas chromatography-mass spectrometry on multiple geranium species and commercial oils, consistently failed to detect DMAA, indicating its synthetic origin rather than botanical derivation. This discrepancy highlighted a reliance on contested to sustain market viability amid growing regulatory challenges.

Safety Profile

Purported Physiological Benefits and Supporting Evidence

Methylhexanamine, also known as 1,3-dimethylamylamine (DMAA), was originally developed and marketed by as an inhaled nasal under the Forthane starting in 1948, leveraging its sympathomimetic properties to induce in , thereby reducing congestion. In vitro and animal studies have demonstrated its potent activity, with effects on nasal decongestion reported to be approximately 19 times stronger than those of when administered orally in comparative assays. At low therapeutic doses (typically 0.125% in nasal solutions), it provided short-term symptomatic relief with minimal reported side effects in clinical use, supporting its efficacy as a prior to discontinuation in favor of more selective agents. In dietary supplements, methylhexanamine has been promoted for acute physiological enhancements including heightened , improved focus, and increased , attributed to its indirect sympathomimetic action via catecholamine release and inhibition of the , mimicking mild amphetamine-like stimulation. Anecdotal reports from users in non-controlled settings describe ergogenic effects such as enhanced energy during exercise and suppressed appetite, potentially linked to elevated systolic (up to 8-12 mm Hg at doses of 50-75 mg) and activation. However, controlled human studies, including pharmacokinetic evaluations of single 25 mg oral doses, show no meaningful changes in resting , , or body temperature, indicating limited acute physiological impact at lower supplement-relevant levels. Empirical support for performance-enhancing claims remains scant, with no robust randomized controlled trials (RCTs) demonstrating improvements in exercise outcomes such as run time or power output when methylhexanamine is ingested alone or combined with . One double-blind, placebo-controlled study of a multi-ingredient supplement containing DMAA reported no ergogenic benefits on anaerobic capacity or perceived , despite minor hemodynamic shifts. Animal models suggest vasoconstrictive and pressor effects that could theoretically aid short-term endurance by enhancing oxygen delivery, but human translation lacks validation through long-term RCTs, particularly for purported via metabolic boosting, where lipolysis markers show inconsistent elevation without sustained fat reduction data. Overall, while original decongestant utility aligns with verifiable sympathomimetic , supplement-related benefits rely predominantly on user reports rather than high-quality clinical evidence.

Documented Adverse Effects and Empirical Risks

Methylhexanamine (DMAA), a sympathomimetic , exerts physiological stress primarily through alpha- and beta-adrenergic receptor agonism, leading to documented cardiovascular effects such as and . In rat models, intravenous administration of DMAA at doses of 1-10 mg/kg produced dose-dependent increases in and , alongside vasopressor responses indicative of . Human observational data from regulatory surveillance corroborate these findings, with reports of transient systolic elevations following oral doses exceeding 25 mg, potentially escalating to arrhythmias in susceptible individuals due to sustained catecholamine-like overload. The U.S. (FDA) documented over 80 adverse event reports by early 2013, including instances of and irregular heart rhythms linked to DMAA-containing supplements, though causality was complicated by in many cases. Neurological risks stem from DMAA's central properties, manifesting as headaches, jitteriness, and acute anxiety, particularly at doses above therapeutic precedents (e.g., 25-75 mg). Preclinical assessments reveal potential for reinforcing effects akin to amphetamines, with self-administration studies in suggesting abuse liability through and norepinephrine release in reward pathways. By , FDA monitoring captured at least 86 illnesses attributable to DMAA exposure, encompassing neurological symptoms like severe headaches and presumed dependence signals in chronic users, though empirical thresholds for remain understudied due to ethical constraints on controlled trials. These effects align mechanistically with sympathomimetic excess, where unchecked noradrenergic surge disrupts autonomic balance without dose-response data establishing safe margins in humans. Hepatotoxicity signals appear in isolated reports, with elevated liver enzymes (e.g., ALT peaks exceeding 1,700 U/L) observed post-exposure to DMAA-adulterated supplements, yet confounded by concurrent hepatotoxins like or . cytotoxicity assays indicate membrane disruption at supratherapeutic concentrations, implying a plausible first-principles from metabolic overload during escalated dosing beyond original nasal levels (e.g., 0.125% solutions). Clinical is tentative, as multi-ingredient formulations preclude isolation, but regulatory bodies such as the FDA classify DMAA as a contributor to idiosyncratic based on temporal associations in post-marketing data. Overall, empirical risks amplify with dose and duration, underscoring sympathomimetic-mediated end-organ strain absent from low-dose pharmaceutical contexts.

Case Reports of Injuries and Fatalities

In 2010, two active-duty U.S. Army soldiers collapsed and died during routine physical training after consuming dietary supplements containing 1,3-dimethylamylamine (DMAA). findings for both cases revealed elevated levels indicative of myocardial injury, along with the presence of DMAA in their systems; the deaths were attributed to cardiac arrhythmias precipitated by the supplement in combination with physical exertion. Civilian case reports have linked DMAA ingestion to severe cardiovascular incidents, including and cerebral hemorrhage. For instance, in 2011, a 22-year-old male experienced shortly after consuming a DMAA-containing supplement, with confirming DMAA exposure and no other explanatory factors identified in clinical evaluation. The U.S. (FDA) documented 86 adverse event reports associated with DMAA products as of April 2013, encompassing fatalities, heart attacks, strokes, and , though many involved multi-ingredient formulations complicating direct attribution. A 2013 case involved a marathon runner who suffered fatal collapse during the event, with postmortem analysis detecting DMAA in whole blood at levels consistent with recent ingestion, alongside evidence of and multi-organ failure. Elevated risks in databases, such as the FDA's, show disproportionate reporting of hemorrhagic and cardiac events relative to other supplements, despite confounding factors like and underlying health conditions. These incidents underscore DMAA's role in acute toxicities, though definitive often requires exclusion of co-factors via detailed forensic review.

Regulatory Status

Actions by Sports Governing Bodies

The (WADA) added methylhexanamine to its Prohibited List effective January 1, 2010, categorizing it as a non-specified under section S6, banned in-competition with no threshold for detection. This status requires , where any urinary concentration above trace contamination levels triggers an anti-doping rule violation (ADRV), reflecting WADA's rationale of preventing potential ergogenic benefits—such as increased and —from conferring unfair advantages, alongside concerns over cardiovascular risks in athletes. Detections surged post-prohibition, with 12 ADRVs reported globally in 2009 (pre-full enforcement), rising to 33 in 2010 and 114 in 2011, often linked to contaminated supplements. The (IOC) aligns with WADA protocols, enforcing sanctions via sample re-analysis and immediate disqualifications; for instance, during the 2012 London Olympics, at least three athletes—including Italian bobsledder William Frullani and a German biathlete—tested positive, resulting in event exclusions and medal reviews. Similarly, at the 2014 Winter Olympics, Latvian ice hockey player Vitalijs Pavlovs was expelled after a positive test, underscoring zero-tolerance application to maintain competitive integrity. National anti-doping organizations like the U.S. Anti-Doping Agency (USADA) have issued hundreds of sanctions, such as 12-month suspensions for cyclists testing positive in events like the 2022 Joe Martin Stage Race, citing both performance enhancement risks and health hazards like elevated during exertion. Some retrospective analyses have critiqued the non-specified status, arguing that methylhexanamine's ergogenic effects may be modest and comparable to permitted caffeine levels, where thresholds allow low-dose use without sanction; proponents of threshold-based policies for select stimulants suggest blanket prohibitions overlook dose-dependent risks and contaminate inadvertent positives from trace supplement impurities, potentially eroding trust in anti-doping without proportional evidence of widespread abuse or severe outcomes. However, WADA and bodies like the IOC maintain zero-tolerance to deter intentional use and align with precautionary principles, given empirical links to over 100 annual ADRVs and isolated severe incidents, such as the 2009 Jamaican Championships positives involving sprinter Yohan Blake, who received a warning rather than a ban due to contamination claims.

Governmental Bans and Enforcement

In April 2013, the U.S. Food and Drug Administration (FDA) issued warning letters to companies marketing products containing 1,3-dimethylamylamine (DMAA, synonymous with methylhexanamine), stating that DMAA does not qualify as a dietary ingredient under the Federal Food, Drug, and Cosmetic Act and is not generally recognized as safe (GRAS) for use in foods or supplements, based on insufficient historical evidence of safe consumption prior to 1958 and lack of expert consensus on its safety. This determination prompted import alerts for DMAA-containing goods and led to federal seizures, such as the July 2013 action by U.S. Marshals in three states confiscating over $2,000 worth of tainted supplements from a distributor, citing violations of federal law prohibiting interstate sale of unsafe additives. The FDA's position was upheld in subsequent court rulings, including a 2020 federal appeals court affirmation that DMAA is neither an herb nor GRAS, reinforcing enforcement through ongoing warning letters to manufacturers, as seen in cases against Total Body Nutrition in 2017 and Lose Fat Gain Life in 2020 for adulterated products. FDA post-market reviews have reaffirmed these findings into the , with a 2021 memorandum reiterating the absence of GRAS status due to inadequate data and a May 2025 update to the agency's public inventory of non-GRAS substances listing DMAA explicitly. Enforcement has reduced overt market availability, though challenges persist with clandestine sales and structural analogs like 1,3-dimethylhexylamine (DMHA), prompting continued monitoring and seizures of misbranded imports under broader adulteration authorities. Internationally, classified DMAA as a prescription in 2012 via Medsafe, effectively banning its over-the-counter sale in supplements due to cardiovascular risks evidenced by reports, with compliance enforced through product recalls and import restrictions. Australia's listed DMAA in Schedule 10 (prohibited substances) in 2012, following Food Standards Australia New Zealand warnings about health hazards, leading to market withdrawals and border detentions. In the , the Medicines and Healthcare products Regulatory Agency (MHRA) ruled in August 2012 that DMAA products like Jack3d constituted unlicensed medicines, resulting in bans, seizures, and appeals upholding the decision based on pharmacological similarity to amphetamines and reported toxicities. Within the , DMAA falls under regulations requiring pre-market authorization, which it lacks due to no proven history of significant consumption before 1997, leading to prohibitions in member states like and , with the Dutch National Institute for enforcing via supplement alerts and analog restrictions. These actions, grounded in data linking DMAA to and arrhythmias, have similarly curbed legitimate distribution while spurring underground persistence.

Controversies and Debates

Claims of Natural Origin Versus Synthetic Production

Supplement manufacturers, such as those producing products like Jack3d, marketed methylhexanamine (DMAA) as a natural extract from derived from , implying botanical safety and compliance with regulations. However, multiple gas chromatography-mass spectrometry (GC-MS) analyses of oils and plant materials have consistently failed to detect DMAA at levels sufficient for commercial extraction, with detection limits often below 0.1 ppm yielding negative results across samples from various sources. A 2012 study examining multiple variants concluded that DMAA presence is unlikely from natural sources, as chromatographic profiles did not match expected botanical contaminants. Further evidence from isotopic and stereochemical analyses reinforces synthetic origins, revealing that DMAA in supplements exhibits enantiomeric and diastereomeric ratios characteristic of laboratory synthesis rather than plant-derived variability. For instance, synthetic DMAA standards from commercial suppliers display distinct isomeric profiles inconsistent with hypothetical natural biosynthesis in Geraniaceae species. These findings undermine assumptions of inherent safety tied to "natural" labeling, as synthetic production—often sourced from Chinese chemical suppliers—lacks the regulatory scrutiny applied to verified botanicals. Legal consequences have validated this synthetic status, with U.S. federal indictments against USP Labs in 2015 charging the company with for importing synthetic DMAA while falsely certifying it as extract via fabricated documentation. The case resulted in convictions and forfeiture exceeding $4.7 million, highlighting deceptive labeling practices that misled consumers and retailers under the Federal Food, Drug, and Cosmetic Act. Such rulings emphasize empirical chemical verification over unsubstantiated marketing claims, exposing risks of adulteration in performance-enhancing supplements.

Balancing Efficacy Claims Against Risk Data

Proponents of methylhexanamine use contend that controlled low doses, such as 25 mg, offer benefits for acute exercise and in healthy adults with minimal risk, drawing on limited experimental evidence of sympathomimetic stimulation akin to . In a randomized pharmacokinetic study involving healthy men, a single 25 mg oral dose elicited no significant alterations in resting (mean 64 bpm), systolic (mean 118 mm Hg), or body temperature, with peak plasma levels approximately 15–30 times lower than those in case reports of adverse events. Complementary laboratory data indicate that such doses can enhance and metabolic rate, potentially supporting short-term energy and focus without hemodynamic disruption in tolerant individuals. This perspective incorporates recognition of inter-individual variability in stimulant tolerance, where healthy adults may exhibit differential responses based on factors like baseline , though quantitative data specific to methylhexanamine remain sparse. Historical development as a vasoconstrictor by , patented in 1944 for nasal applications, implies prior assessments of tolerability at therapeutic exposures, contrasting with modern supplement contexts involving higher or unmonitored intakes. Advocates thus prioritize self-regulated dosing and , arguing that absolute prohibitions overlook capacity for personal risk calibration absent contraindications. Regulatory restrictions face scrutiny for relying on precautionary interpretations of risks, given the dearth of randomized trials establishing causal links to mortality or widespread harm; documented severe events derive chiefly from retrospective case reports, often involving doses exceeding 375 mg or concurrent substances, with symptoms frequently resolving post-cessation. A review of 16 pertinent studies—eight experimental and eight clinical—found insufficient evidence of acute or at typical levels to warrant global bans, as experimental designs were underpowered and unproven. Such critiques posit that alarmist policies amplify confounded reports while sidelining probabilistic assessments of rarity versus utility. Persistent evidentiary voids, notably the absence of rigorous dose-response investigations, impede precise weighing of transient ergogenic effects against infrequent but grave outcomes like exertional or hemorrhage. Experimental constraints imposed by prohibitions further stall elucidation of safe thresholds, tilting toward empirical voids over causal clarity and favoring, in principle, targeted to inform stratified access—such as for low-risk cohorts—rather than uniform .

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