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Methylhexanamine

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Methylhexanamine
IUPAC name

4-Methylhexan-2-amine[1]
Other names

  • 2-Amino-4-methylhexane
  • Dimethylamylamine
  • 1,3-Dimethylamylamine
  • 1,3-Dimethylpentylamine
  • 4-Methyl-2-hexanamine
  • 4-Methyl-2-hexylamine
Identifiers
Abbreviations DMAA[citation needed]
CAS number 105-41-9 YesY
PubChem 7753, 55289161 (4S)-4-methyl, 642321 (2R,4R)-4-methyl, -2-amine, 36688719 (2R,4S)-4-methyl, -2-amine, 36688723 (2S,4S)-4-methyl, -2-amine, 36688721 (2S,4R)-4-methyl, -2-amine
ChemSpider 7464 YesY, 557529 (2R,4R)-4-methyl, -2-amine YesY
EC number 203-296-1
Jmol-3D images Image 1
Properties
Molecular formula C7H17N
Molar mass 115.22 g mol−1
Appearance white crystal powder
Density 0.775 g/mL
Boiling point

134 °C, 407 K, 273 °F
Solubility in water soluble in water
Pharmacology
Routes of
administration
  • Inhalation
  • Oral
Related compounds
Related alkanamines
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Methylhexanamine, commonly known as 1,3-dimethylamylamine or DMAA, is an organic compound with the formula CH3CH2CH(CH3)CH2CH(CH3)NH2. DMAA is a simple aliphatic amine initially patented as a nasal decongestant and as a topical treatment for hypertrophied or hyperplastic oral tissues.[2] DMAA is a vasoconstrictor, and can be administered by inhalation to the nasal mucosa to exert its effect.

DMAA has also been marketed extensively under many names as a dietary supplement,[3][4][5] but its safety has been questioned as a number of adverse events and at least 5 deaths have been associated with DMAA-containing supplements.[6] In April 2013, the U.S. Food and Drug Administration warned supplement makers that it was illegal to market DMAA as a dietary supplement, and warned consumers of potentially serious health risks associated with DMAA-containing products.[6][7]

Contents

[edit] History

In April 1944, Eli Lilly and Company trademarked methylhexanamine, as Forthane, for potential use as a nasal decongestant. Forthane was also patented as a nasal decongestant and a treatment for hypertrophied or hyperplasic oral tissues[2] Aside from patent applications, methylhexanamine use is not mentioned in historical medical literature, and no medical use of methylhexanamine is recognized today. The trademark for Forthane has since expired. Methylhexanamine should not be confused with isoflurane, a general inhalation anaesthetic,[8] which has the proprietary name in Australia of Forthane.

Patrick Arnold reintroduced methylhexanamine in 2006 as a dietary supplement,[9][10] after the final ban of ephedrine as a dietary supplement 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 now use the ingredient in concert with other substances such as caffeine, a combination similar to the combination of ephedrine and caffeine; the former ingredient is now banned in a number of countries.

A 2012 Dutch literature study on the regulatory status of methylhexanamine concluded that food supplements with > 4 mg methylhexanamine are pharmacologically effective and therefore require licensing as a medicine. The authors deduce that oral methylhexanamine acts as a bronchodilator (above 4 mg), increases heart rate (above 50–75 mg), and increases blood pressure (above 100 mg). Serious adverse effects are expected for oral dosages above 200 mg.[11]

[edit] Chemistry

The structure of methylhexanamine has been described as similar to that of amphetamine.[12]

Methylhexanamine is synthesized by converting 4-methylhexan-2-one into the oxime, followed by reduction via sodium in ethanol, conditions similar to the Bouveault–Blanc reduction. Methylhexanamine is a releasing agent of the catecholamine neurotransmitter norepinephrine (noradrenaline) similar to related substances such as cyclopentamine and tuaminoheptane.[13]

[edit] Uses

Although intended by Eli Lilly to be used as a nasal decongestant, methylhexaneamine has been marketed as a dietary supplement in combination with caffeine and other ingredients, under trade names such as Geranamine, Floradrene, OxyElite, and Jack3d, to be used as an over-the-counter thermogenic or general-purpose stimulant. It "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."[14] Numerous adverse events and at least 5 deaths have been reported in association with DMAA-containing dietary supplements.[6] Methylhexaneamine has not been studied intensively and its pharmacological profile has not been evaluated since Eli Lilly filed its patent in 1944, stating that the stimulant effects on the CNS are less than that of the related compounds amphetamine and ephedrine.[15]

In New Zealand, methylhexanamine (under the name 1,3-dimethylamylamine or DMAA) is an emerging active ingredient of party pills.[16] In November 2009, the New Zealand government indicated methylhexanamine would be scheduled as a restricted substance.[17] The New Zealand government has not banned methylhexanamine, but its Ministry of Health has banned bulk powder purchases,[citation needed] and its sale in the form of capsules and tablets is permitted. The NZ Ministry of Health has now published a Temporary Class Drug Notice. The effect of this notice is to make illegal the sale of DMAA products after 7 April 2012.

[edit] Safety

The LD50 for methylhexanamine is 39 mg/kg for intravenous and 185 mg/kg for intraperitoneal administration (mouse).[18][19]

Anecdotal reports indicate extremely high doses of methylhexanamine combined with caffeine and alcohol may be harmful. A 21-year-old male in New Zealand presented with a cerebral hemorrhage after ingesting 556 mg of methylhexanamine, caffeine, and alcohol.[20]

DMAA-containing supplements sometimes list "geranium oil" or "geranium extract" as a source of DMAA. However, geranium oils do not contain DMAA, and the DMAA in these supplements is added in the form of synthetic material.[21]

A September 2011 study reported acute ingestion of 1,3-dimethylamylamine (75 mg) alone and in combination with caffeine results in increased blood pressure without an increase in heart rate.[22]

A manufacturer-sponsored study of 25 healthy men taking a methylhexanamine-containing preworkout sports supplement found methylhexanamine does not change resting heart rate, blood pressure, or affect liver and kidney function when used at recommended dosage levels.[23] According to an additional four studies, DMAA did not seem to cause any negative effects to the blood, blood pressure or heart rate when taken by test subjects for a short period.[24]

The US military issued a massive recall of all methylhexanamine-containing products from all military exchange stores worldwide, after two soldiers suffered fatal heart attacks during training in 2010. Methylhexanamine was found in their blood.[25] "These products are legal substances and, as yet, no link between DMAA and the medical conditions reported by military medical providers has been validated scientifically by us," said DoD spokesman Peter Graves. "DoD has asked that the products be pulled from the shelves as a precautionary measure."[26]

The death of Claire Squires, a runner who collapsed near the finish line of the April 2012 London Marathon, has been linked to DMAA. The Coroner stated that DMAA was "probably an important factor" during the inquest. It is believed that she consumed the substance through drinking an energy drink, which was subsequently adjusted to exclude DMAA.[27]

[edit] Controversy

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.[28][29][30][31][32][33]

In February 2012, the deaths of two US soldiers who collapsed during physical training in preceding months prompted a military investigation of the popular bodybuilding supplement that was found in their systems.[34] This prompted the Department of Defense to pull products containing methylhexaneamine from on-base store shelves pending an investigation.[35] A Pentagon spokesman, however, stressed, “These products are legal substances and, as yet, no link between DMAA and the medical conditions reported by military medical providers has been validated scientifically by us. DoD has asked that the products be pulled from the shelves as a precautionary measure.”[35]

On 19 June 2012, the South African Institute for Drug-Free Sport (SAIDS) confirmed the 2012 Comrades Marathon winner, Ludwick Mamabolo, tested positive for the banned stimulant. Mamabolo could face a two-year ban and be stripped of his title if found guilty by an independent tribunal.

[edit] Regulations

A number of countries have banned or heavily restricted the use of DMAA as a dietary supplement, due to serious concerns about its safety. These countries include the U.S., Canada, New Zealand, Sweden, Australia, the United Kingdom, and Brazil.

In July 2011, Health Canada decided DMAA was not a dietary substance, but was a drug requiring further approval. Consequently, Health Canada banned all sales of DMAA.[36] In April 2012, New Zealand formally banned DMAA, citing its use in "party pills".[37] In June 2012, the National Food Agency of Sweden issued a general warning regarding use of DMAA products, resulting in a sales ban in parts of the country.[38]

In July 2012, the National Health Surveillance Agency (ANVISA) of Brazil issued a warning to the general public on the hazards of products that contain DMAA.[39] It also updated the list of prohibited substances to insert DMAA, which translates into the banishment of products containing such ingredient from the Brazilian market.[40]

On 1 August 2012, Australia banned DMAA. In New South Wales, DMAA was classed as a "highly dangerous substance" on the poisons list.[41] In August 2012, the U.K. 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 DMAA containing products need to be removed from the UK market amid concerns of potential risks to public safety.[42] In April 2013, the U.S. Food and Drug Administration (FDA) determined that DMAA was potentially dangerous and did not qualify as a legal dietary supplement, making it illegal to market DMAA-containing supplements.[6][7]

[edit] See also

[edit] References

  1. ^ "1,3-Dimethylpentylamine - Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 26 march 2005. Identification and Related Records. Retrieved 27 May 2012. 
  2. ^ a b US 3574859, Kosti, "PROCESS FOR THE TREATMENT OF HYPERTROPHIED GUMS", issued Apr 1971 
  3. ^ SEC. 201. [21 U.S.C. 321]. Fda.gov. Retrieved on 2012-04-12.
  4. ^ Dietary Supplement Health and Education Act of 1994. Ods.od.nih.gov. Retrieved on 2012-04-12.
  5. ^ Chapter I – Dietary Supplement Health And Education Act of 1994. Health.gov. Retrieved on 2012-04-12.
  6. ^ a b c d Singer, Natasha; Peter Lattman (April 16, 2013). "F.D.A. Issues Warning on Workout Supplement". New York Times. Retrieved April 16, 2013. 
  7. ^ a b "Stimulant Potentially Dangerous to Health, FDA Warns". U.S. Food and Drug Administration. April 11, 2013. Retrieved April 16, 2013. 
  8. ^ Data Sheet. medsafe.govt.nz
  9. ^ Shipley, Amy (May 8, 2006). "Chemist's New Product Contains Hidden Substance". The Washington Post. 
  10. ^ Carroll, Will. (2010-08-16) Under The Knife: 997. Baseball Prospectus. Retrieved on 2012-04-12.
  11. ^ Venhuis, Bastiaan J.; De Kaste, Dries (November 2012). "Scientific opinion on the regulatory status of 1,3-Dimethylamylamine (DMAA)". European Journal for Food Research and Review 2 (4): 93–100. 
  12. ^ RMTC – Headlines. Rmtcnet.com. Retrieved on 2012-04-12.
  13. ^ [1]. High Tower Pharmacology. Retrieved on 2012-05-5.
  14. ^ "FDA challenges marketing of DMAA products for lack of safety evidence: Agency cites ten companies in warning letters". United States Food and Drug Administration. April 27, 2012. Retrieved March 17, 2013. "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." 
  15. ^ US 2350318, Rohrmann, Ewald, "AMINOALKANES", issued May 30, 1944 
  16. ^ "New pill ingredient worries ministry". Television New Zealand. October 4, 2008. Retrieved October 23, 2011. 
  17. ^ Steward, Ian (November 9, 2009). "Party pill inventor backs restriction". The Press. Retrieved October 23, 2011. 
  18. ^ JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 42,107,1953
  19. ^ 85KYAH "Merck Index; an Encyclopedia of Chemicals, Drugs, and Biologicals", 11th ed., Rahway, NJ 07065, Merck & Co., Inc. 1989 Volume(issue)/page/year: 11,957,1989
  20. ^ Bloomer, RJ; Paul Gee, Suzanne Jackson, Josie Easton (6). "Another bitter pill: a case of toxicity from DMAA party pills". Journal of the New Zealand Medical Association 39 (3): 111–20. doi:10.4137/NMI.S8566. PMID 22030947. 
  21. ^ Lisi A, Hasick N, Kazlauskas R, Goebel C (2011). "Studies of methylhexaneamine in supplements and geranium oil". Drug Test Anal 3 (11-12): 873–6. doi:10.1002/dta.392. PMID 22147493. 
  22. ^ McCarthy, Cameron G.; Robert E. Canale, Rick J. Alleman Jr., Jacob P. Reed and Richard J. Bloomer (6). "Biochemical and Effects of 1,3-dimethylamylamine and caffeine alone or in combination on heart rate and blood pressure in healthy men and women". Phys Sportsmed 39 (3): 111–20. doi:10.4137/NMI.S8566. PMID 22030947. 
  23. ^ Starling, Shane (February 27, 2012). "Jack3d is Safe: Study". Nutra Ingredients. 
  24. ^ Tritten, Travis (March 1, 2012). "Soldiers to be subjects as Army studies whether DMAA is dangerous". Stars & Stripes. 
  25. ^ http://newhope360.com/sports-amp-fitness-performance/dmaa-scandal-timeline#slide-7-field_images-226411
  26. ^ "DMAA products pulled from base shelves". Retrieved 24 January 2013. 
  27. ^ http://www.bbc.co.uk/news/uk-england-london-21262717. Retrieved 30 January 2013.  Missing or empty |title= (help)
  28. ^ WADA 2010 Prohibited List (pdf), World Anti-Doping Agency, Monday, 19 September 2009
  29. ^ "IAAF wait for Jamaica drug ruling". BBC Sport (BBC). August 11, 2009. 
  30. ^ "Rui Costa and his brother test positive". CyclingNews. CyclingNews. October 18, 2010. 
  31. ^ "Belgian amateur champion receives one-year ban". News. CyclingNews. December 9, 2010. 
  32. ^ "Minor Leaguer suspended 50 games". MLB.com (MLB.com). 2011-11-01. Retrieved 2011-11-01. 
  33. ^ "Doping: Sperren für Schweizer Aquathlet und Duathleten aus Portugal". DNF-is-no-option.com (DNF-is-no-option.com). 2012-02-16. Retrieved 2012-01-12. 
  34. ^ Chiaramonte, Perry (2 February 2012). "Soldier Deaths During Training Prompt Military Probe Into Supplement Use". FOX NEWS. Retrieved 2 February 2012. 
  35. ^ a b DMAA products pulled from base shelves – Military Off Duty, Army Health, military fitness, army physical fitness. Army Times. Retrieved on 2012-04-12.
  36. ^ Rovell, Darren (2 May 2012). "DMAA Brands Start To Reformulate Products Without the Ingredient". CNBC. Retrieved 1 August 2012. 
  37. ^ "DMAA Banned from 9 April 2012". New Zealand: Ministry of Health. Retrieved 1 August 2012. 
  38. ^ "Varning för kosttillskott som innehåller DMAA". 
  39. ^ "Anvisa alerta para risco de consumo de suplemento alimentar, July 2012". Brazilian Government: National Health Surveillance Agency (ANVISA). Retrieved 22 January 2013. 
  40. ^ "Resolução de Diretoria Colegiada (RDC) no. 37, July 2012". Brazilian Government: National Health Surveillance Agency (ANVISA). Retrieved 22 January 2013. 
  41. ^ McNeilage, Amy (1 August 2012). "Drug in workout drinks to be illegal". The Sydney Morning Herald. Retrieved 1 August 2012. 
  42. ^ "Press release: MHRA to remove popular sports supplement used by international athletes from the market". 
Decongestants and other nasal preparations (R01)
Topical
Antiallergic agents,
excluding corticosteroids
Other nasal preparations
Systemic use:
Sympathomimetics

M: RES

anat (n, x, l, c)/phys/devp

proc, drug (R1/2/3/5/6/7)

[edit] External links

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