Methylhexanamine

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Methylhexanamine


IUPAC name[hide]4-Methylhexan-2-amine[1]

Other names[hide]
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 Y
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 Y, 557529 (2R,4R)-4-methyl, -2-amine Y
EC number 203-296-1
Jmol-3D images Image 1
SMILES
[show]
CCC(C)CC(C)N




InChI
[show]
InChI=1S/C7H17N/c1-4-6(2)5-7(3)8/h6-7H,4-5,8H2,1-3H3 Y
Key: YAHRDLICUYEDAU-UHFFFAOYSA-N Y

Properties
Molecular formula C7H17N
Molar mass 115.22 g mol−1
Pharmacology
Routes of
administration Inhalation
Oral

Related compounds
Related alkanamines Pentylamine
Cadaverine
Hexamethylenediamine
Tuaminoheptane

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. It is marketed under many names as a dietary supplement,[2][3][4] but its safety has been questioned. It is also a simple aliphatic amine used as a nasal decongestant, as well as treatment for hypertrophied or hyperplasic oral tissues.[5] It is a vasoconstrictor, and can be administered by inhalation to the nasal mucosa to exert its effect.

Contents [hide]
1 History
2 Chemistry
3 Uses
4 Safety
5 Controversy
6 Regulations
7 See also
8 References

[edit] HistoryIn 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[5] 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,[6] which has the proprietary name in Australia of Forthane.

Patrick Arnold reintroduced methylhexanamine in 2006 as a dietary supplement,[7][8] 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 methylhexamine concluded that food supplements with > 4 mg methylhexamine are pharmacologically effective and therefore require licensing as a medicine. The authors deduce that oral methylhexamine 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. [9]

[edit] Chemistry
The structure of methylhexanamine has been described as similar to that of amphetamine.[10]Methylhexaneamine 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. Methylhexaneamine is a releasing agent of the catecholamine neurotransmitter norepinephrine (noradrenaline) similar to related substances such as cyclopentamine and tuaminoheptane[11].

[edit] UsesAlthough 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 and Floradrene, to be used as an over-the-counter thermogenic or general-purpose stimulant. 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.[12]

In New Zealand, methylhexanamine (under the name 1,3-dimethylamylamine or DMAA) is an emerging active ingredient of party pills.[13] In November 2009, the New Zealand government indicated methylhexanamine would be scheduled as a restricted substance.[14] 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] SafetyThe LD50 for methylhexanamine is 39 mg/kg for intravenous and 185 mg/kg for intraperitoneal administration (mouse).[15][16]

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.[17] The man's hydration status, food intake, illicit drug use, and body weight were not reported. A spokesman for the manufacturer said, "DMAA is, in fact, a constituent of geranium (Pelargonium graveolens) and its derived oil and has been consumed as part of the human diet for more than 100 years."[18]

However, a study published in December 2011 by A. Lisi, N. Hasick, R. Kazlauskas, and C. Goebel contradicts the claim by methylhexaneamine manufacturers and reports, "geranium oils do not contain methylhexaneamine" and "products labelled as containing geranium oil but which contain methylhexaneamine can only arise from the addition of synthetic material."[19]

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.[20]

A 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.[21] 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.[22]

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.[23]

[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.[24][25][26][27][28][29]

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.[30] This prompted the Department of Defense to pull products containing methylhexaneamine from on-base store shelves pending an investigation.[31] 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.”[31] DoD findings on the matter were expected in late March 2012. The Surgeon General of the US Army said, “I want to emphasize that no link between DMAA and the medical conditions reported by military medical providers has been validated scientifically by us. While the DOD leadership and the USAPHC take these reports very seriously, all of these medical conditions have multiple causes. It is too soon to tell if there is a relationship with DMAA.”[18]

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] RegulationsIn 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.[32]

In March 2012, New Zealand issued a notice to declare DMAA a temporary class drug.[33] In April 2012, New Zealand formally banned DMAA, citing its use in "party pills".[34]

In April 2012, the United States' FDA issued warning letters to manufacturers of DMAA products. The FDA has challenged the manufacturers' marketing of DMAA products for lack of safety evidence.[35]

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.[36]

In July 2012, Australia issued a notice on DMAA.[37] On 01 August 2012, Australia decided to ban DMAA. In New South Wales, DMAA was classed as a "highly dangerous substance" on the poisons list.[38]




[edit] See alsoHeptaminol
Isometheptene
Pelargonium
Tuaminoheptane
[edit] References^ "1,3-Dimethylpentylamine - Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 26 march 2005. Identification and Related Records. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7753&loc=ec_rcs. Retrieved 27 May 2012.
^ SEC. 201. [21 U.S.C. 321]. Fda.gov. Retrieved on 2012-04-12.
^ Dietary Supplement Health and Education Act of 1994. Ods.od.nih.gov. Retrieved on 2012-04-12.
^ Chapter I – Dietary Supplement Health And Education Act of 1994. Health.gov. Retrieved on 2012-04-12.
^ a b US 3574859, Kosti, "PROCESS FOR THE TREATMENT OF HYPERTROPHIED GUMS", issued Apr 1971
^ Data Sheet. medsafe.govt.nz
^ Shipley, Amy (May 8, 2006). "Chemist's New Product Contains Hidden Substance". The Washington Post. http://www.washingtonpost.com/wp-dyn/content/article/2006/05/07/AR2006050700913.html.
^ Carroll, Will. (2010-08-16) Under The Knife: 997. Baseball Prospectus. Retrieved on 2012-04-12.
^ Venhuis, Bastiaan J.; De Kaste, Dries (in press). "Scientific opinion on the regulatory status of 1,3-Dimethylamylamine (DMAA).". European Journal for Food Research and Review.
^ RMTC – Headlines. Rmtcnet.com. Retrieved on 2012-04-12.
^ [1]. High Tower Pharmacology. Retrieved on 2012-05-5.
^ US 2350318, Rohrmann, Ewald, "AMINOALKANES", issued May 30, 1944
^ "New pill ingredient worries ministry". Television New Zealand. October 4, 2008. http://tvnz.co.nz/view/page/1316907/2174371. Retrieved October 23, 2011.
^ Steward, Ian (November 9, 2009). "Party pill inventor backs restriction". The Press. http://www.stuff.co.nz/the-press/news/3043395/Party-pill-inventor-backs-restriction. Retrieved October 23, 2011.
^ 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
^ 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
^ "Another bitter pill: a case of toxicity from DMAA party pills". Journal of the New Zealand Medical Association 39 (3): 111–20. 6. doi:10.4137/NMI.S8566. PMID 22030947. http://journal.nzma.org.nz/journal/123-1327/4480/.
^ a b USPLabs: DMAA is from geranium oil – and critics are ‘uninformed’. Nutraingredients-usa.com. Retrieved on 2012-04-12.
^ Studies of methylhexaneamine in supplements and geranium oil
^ 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.
^ Starling, Shane (February 27, 2012). "Jack3d is Safe: Study". Nutra Ingredients. http://www.nutraingredients.com/Research/Jack3D-is-safe-Study.
^ Tritten, Travis (March 1, 2012). "Soldiers to be subjects as Army studies whether DMAA is dangerous". Stars & Stripes. http://www.stripes.com/news/soldiers-to-be-subjects-as-army-studies-whether-dmaa-is-dangerous-1.170432.
^ http://newhope360.com/sports-amp-fitness-performance/dmaa-scandal-timeline#slide-7-field_images-226411
^ WADA 2010 Prohibited List (pdf), World Anti-Doping Agency, Monday, 19 September 2009
^ "IAAF wait for Jamaica drug ruling". BBC Sport (BBC). August 11, 2009. http://news.bbc.co.uk/sport1/hi/athletics/8194466.stm.
^ "Rui Costa and his brother test positive". CyclingNews. CyclingNews. October 18, 2010. http://www.cyclingnews.com/news/rui-costa-and-his-brother-test-positive.
^ "Belgian amateur champion receives one-year ban". News. CyclingNews. December 9, 2010. http://www.cyclingnews.com/news/belgian-amateur-champion-receives-one-year-ban.
^ "Minor Leaguer suspended 50 games". MLB.com. 2011-11-01. http://stlouis.cardinals.mlb.com/news/article.jsp?ymd=20111101&content_id=25861792¬ebook_id=25864342&vkey=notebook_stl&c_id=stl#25864344. Retrieved 2011-11-01.
^ "Doping: Sperren für Schweizer Aquathlet und Duathleten aus Portugal". DNF-is-no-option.com. 2012-02-16. http://www.dnf-is-no-option.com/2012/02/doping-sperren-fur-schweizer-aquathlet.html. Retrieved 2012-01-12.
^ Chiaramonte, Perry (2 February 2012). "Soldier Deaths During Training Prompt Military Probe Into Supplement Use". FOX NEWS. http://www.foxnews.com/us/2012/02/02/soldier-deaths-during-training-sparks-military-probe-into-supplement-use/. Retrieved 2 February 2012.
^ 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.
^ Rovell, Darren (2 May 2012). "DMAA Brands Start To Reformulate Products Without the Ingredient". CNBC. http://www.cnbc.com/id/47266147/DMAA_Brands_Start_To_Reformulate_Products_Without_the_Ingredient. Retrieved 1 August 2012.
^ "Notice 1446: Temporary Class Drug Notice". New Zealand; Department of Internal Affairs. http://www.dia.govt.nz/MSOS118/On-Line/NZGazette.nsf/6cee7698a9bbc7cfcc256d510059ed0b/09f30e09935d03cecc2579bb00559838!OpenDocument. Retrieved 1 August 2012.
^ "DMAA Banned from 9 April 2012". New Zealand: Ministry of Health. http://www.health.govt.nz/news-media/news-items/dmaa-banned-9-april-2012. Retrieved 1 August 2012.
^ "FDA challenges marketing of DMAA products for lack of safety evidence". U.S. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302133.htm. Retrieved 1 August 2012.
^ "Varning för kosttillskott som innehåller DMAA". http://www.slv.se/sv/grupp3/Pressrum/Nyheter/Pressmeddelanden/Varning-for-kosttillskott-som-innehaller-DMAA/.
^ "Reasons for scheduling delegates' interim decisions & invitation for further comment, July 2012". Australian Government: Department of Health and Ageing: Therapeutic Goods Administration. http://www.tga.gov.au/industry/scheduling-decisions-1207-interim.htm. Retrieved 1 August 2012.