Methylhexanamine

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Methylhexanamine
Identifiers
AbbreviationsDMAA
CAS number105-41-9 YesY
PubChem7753, 55289161 (4S), 642321 (2R,4R), 36688719 (2R,4S), 36688723 (2S,4S), 36688721 (2S,4R)
ChemSpider7464 YesY, 557529 (2R,4R) YesY
EC number203-296-1
Jmol-3D imagesImage 1
Properties
Molecular formulaC7H17N
Molar mass115.22 g mol−1
Appearancewhite crystal powder
Density0.775 g/mL
Boiling point134 °C; 273 °F; 407 K
Solubility in watersoluble 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 (77 °F), 100 kPa)
Infobox references
 
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Methylhexanamine
Identifiers
AbbreviationsDMAA
CAS number105-41-9 YesY
PubChem7753, 55289161 (4S), 642321 (2R,4R), 36688719 (2R,4S), 36688723 (2S,4S), 36688721 (2S,4R)
ChemSpider7464 YesY, 557529 (2R,4R) YesY
EC number203-296-1
Jmol-3D imagesImage 1
Properties
Molecular formulaC7H17N
Molar mass115.22 g mol−1
Appearancewhite crystal powder
Density0.775 g/mL
Boiling point134 °C; 273 °F; 407 K
Solubility in watersoluble 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 (77 °F), 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. Methylhexanamine is a simple aliphatic amine initially patented as a nasal decongestant and as a topical treatment for hypertrophied or hyperplastic oral tissues.[2] Methylhexanamine is a vasoconstrictor, and can be administered by inhalation to the nasal mucosa to exert its effect.

Methylhexanamine 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 methylhexanamine-containing supplements.[6] In April 2013, the U.S. Food and Drug Administration warned supplement makers that it was illegal to market methylhexanamine as a dietary supplement, and warned consumers of potentially serious health risks associated with methylhexanamine-containing products.[6][7]

History[edit]

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.

According to literature methylhexanamine is a pharmacologically active compound of synthetic origin. The single known reason for using methylhexanamine in humans is pharmacological. The body absorbs methylhexanamine adequately, but relatively slowly, when taken orally. 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 halflife, there is a risk that repeated doses within 24–36 hours could lead to steadily stronger pharmacological effects (build up). Based on our findings we conclude that oral preparations with >4 mg methylhexanamine should be considered as effective as a bronchodilator. Therefore, food supplements containing >4 mg methylhexanamine should be treated as subject to the Medicines Act and require licensing as a medicine. Dosages higher than 100–200 mg are expected to cause serious adverse events.[11]

Chemistry[edit]

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]

Uses[edit]

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 methylhexanamine-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 methylhexanamine products after 7 April 2012.

Safety[edit]

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

There are published reports of recommended doses of methylhexanamine followed by stroke or death. A 21-year-old male in New Zealand presented with a cerebral hemorrhage after ingesting 556 mg of methylhexanamine, caffeine, and alcohol.[20] Health authorities in Hawaii linked cases of liver failure and one death to OxyElite Pro.[21] OxyElite Pro has been subject to an FDA recall as of November 10, 2013.[22] Methylhexanamine-containing supplements have similarly been linked to gynecomastia due to its mechanism of action and potentially harmful metabolites.[citation needed]

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.[23]

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.[24]

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.[25] According to an additional four studies, methylhexanamine 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.[26]

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,[27] but after an investigation the army later found that DMAA did not contribute to their death.[28] "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."[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 having according to a friend 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 adjusted to exclude methylhexanamine.[31]

Controversy[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.[32][33][34][35][36][37]

In February 2012, the deaths of two US soldiers who collapsed during physical training in preceding months prompted a military investigation of the methylhexanamine that was found in their systems.[38] This prompted the Department of Defense to pull products containing methylhexaneamine from on-base store shelves pending an investigation.[39]

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.

VFL player Matthew Clark was suspended for two years after the banned substance methylhexanamine was detected in his system after a game in 2011.[40]

On 8 August 2013, US Weightlifter Brian Wilhelm accepted a nine-month suspension after testing positive for methylhexaneamine in a urine sample from December 2012 at the American Open.[41]

MotoGP rider Anthony West was suspended for one month by the FIM International Disciplinary Court (CDI) on 29 October 2012 after testing positive for methylhexaneamine 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).[42]

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.[43]

Regulations[edit]

A number of countries have banned or heavily restricted the use of methylhexanamine 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 methylhexanamine was not a dietary substance, but was a drug requiring further approval. Consequently, Health Canada banned all sales of methylhexanamine.[44] In April 2012, New Zealand formally banned methylhexanamine, citing its use in "party pills".[45] 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.[46]

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 methylhexanamine.[47] 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.[48]

On 1 August 2012, Australia banned methylhexanamine. In New South Wales, methylhexanamine was classed as a "highly dangerous substance" on the poisons list.[49] 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 methylhexanamine containing products need to be removed from the UK market amid concerns of potential risks to public safety.[50] In April 2013, the U.S. Food and Drug Administration (FDA) determined that methylhexanamine was potentially dangerous and did not qualify as a legal dietary supplement, making it illegal to market methylhexanamine-containing supplements.[6][7]

See also[edit]

References[edit]

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  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 (2012). "Scientific opinion on the regulatory status of 1,3-Dimethylamylamine (DMAA)". European Journal of Food Research & 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 methylhexanamine 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 December 2010). "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. ^ Medical News & Perspectives: Dietary Supplement Linked to Cases of Acute Hepatitis, Bridget M. Kuehn, JAMA. 2013;310(17):1784. doi:10.1001/jama.2013.281868. November 6, 2013
  22. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm374398.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery
  23. ^ 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. 
  24. ^ McCarthy, Cameron G.; Robert E. Canale, Rick J. Alleman Jr., Jacob P. Reed and Richard J. Bloomer (6 September 2011). "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. 
  25. ^ Starling, Shane (February 27, 2012). "Jack3d is Safe: Study". Nutra Ingredients. 
  26. ^ Tritten, Travis (March 1, 2012). "Soldiers to be subjects as Army studies whether DMAA is dangerous". Stars & Stripes. 
  27. ^ [2][dead link]
  28. ^ http://www.naturalproductsinsider.com/news/2013/08/dmaa-cleared-in-army-deaths-still-poses-risks.aspx
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  30. ^ ["http://www.telegraph.co.uk/sport/othersports/athletics/london-marathon/9237808/Claire-Squires-runner-who-died-during-London-Marathon-suffered-from-heart-condition.html" Claire Squires: runner who died during London Marathon 'suffered from heart condition'] 
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  34. ^ "Rui Costa and his brother test positive". CyclingNews. CyclingNews. October 18, 2010. 
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  40. ^ St Kilda's Ahmed Saad faces two-year drugs ban
  41. ^ US Weightlifting Athlete, Wilhelm, Accepts Sanction For Anti-Doping Rule Violation http://www.usada.org/media/sanction-wilhelm8813 (2013-08-8)
  42. ^ Anthony West loses results after Anti-Doping appeal http://www.crash.net/motogp/news/198653/1/moto2_anthony_west_erased_from_results.html
  43. ^ Ronnie Nathanielsz (December 16, 2013). "Brandon Rios is Suspended By CPBO Until April 24th". BoxingScene.com. Retrieved 2013-12-16. 
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  46. ^ "Varning för kosttillskott som innehåller DMAA". 
  47. ^ "Anvisa alerta para risco de consumo de suplemento alimentar, July 2012". Brazilian Government: National Health Surveillance Agency (ANVISA). Retrieved 22 January 2013. 
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  50. ^ "Press release: MHRA to remove popular sports supplement used by international athletes from the market". 

External links[edit]