Methylhexanamine Explained

Verifiedfields:changed
Watchedfields:changed
Iupac Name:4-Methylhexan-2-amine[1]
Legal Br:F2
Legal Br Comment:[2]
Legal Us:Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in dietary supplements, food, or medicine is unlawful; otherwise uncontrolled.[3] [4] [5]
Routes Of Administration:Nasal spray, oral
Elimination Half-Life:~8.5 hours
Cas Number:105-41-9
Unii:X49C572YQO
Atc Prefix:None
Pubchem:7753
Chemspiderid:7467
C:7
H:17
N:1
Smiles:CCC(C)CC(C)N
Stdinchi:1S/C7H17N/c1-4-6(2)5-7(3)8/h6-7H,4-5,8H2,1-3H3
Stdinchikey:YAHRDLICUYEDAU-UHFFFAOYSA-N
Synonyms:Methylhexaneamine, 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

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and developed by Eli Lilly and Company and marketed as an inhaled nasal decongestant from 1948 until it was voluntarily withdrawn from the market in the 1980s.[6]

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. It is banned by many sports authorities and governmental agencies. Despite multiple warning letters from the FDA,[7] as of 2019, the stimulant remains available in sports and weight loss supplements in the US.[8]

History

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.[9] 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.

Marketing as dietary supplement

Patrick Arnold reintroduced methylhexanamine in 2006 as a dietary supplement,[10] [11] 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.[12] 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.[13] [14]

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.[15]

Pharmacology

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. 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)."

Detection in body fluids

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.[16] [17]

Safety

The for methylhexanamine is 39 mg/kg in mice and 72.5 mg/kg in rats, when administered intravenously.[18]

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".[19] Numerous adverse events and at least five deaths have been reported in association with methylhexanamine-containing dietary supplements.[20] There have also been reports of secondary open-angle glaucoma related to methylhexanamine supplementation.[21]

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."

Deaths and injuries

In 2010, a 21-year-old man in New Zealand presented with a cerebral hemorrhage after ingesting 556 mg of methylhexanamine, caffeine, and alcohol.[22] Health authorities in Hawaii linked cases of liver failure and one death to OxyElite Pro, a weight loss and bodybuilding dietary supplement.[23]

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 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.[24]

Regulation

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

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.[25] [26] [27] [28] [29] [30]

Governmental agencies

In 2010, the US military issued a recall of all methylhexanamine-containing products from all military exchange stores worldwide.[49] [50]

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.[51]

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.[52]

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.[53] 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.[54]

In 2012, Australia banned methylhexanamine. In New South Wales, methylhexanamine was classed as a "highly dangerous substance" on the poisons list.[55]

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.[56]

In 2012 the New Zealand Ministry of Health banned the sale of methylhexanamine products,[57] due in part to its growing recreational use as party pills.[58] [59]

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.[20] [60] The FDA has issued warning letters to manufacturers and distributors who continued to market products containing methylhexanamine.[61]

See also

External links

Notes and References

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  2. Web site: Anvisa . Brazilian Health Regulatory Agency . 2023-07-24 . RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 . 2023-08-27 . 2023-08-27 . . pt-BR . 2023-07-25.
  3. Web site: October 12, 2022 . DMAA: A prohibited stimulant . August 28, 2023 . United States Department of Defense: Operation Supplement Safety . . en.
  4. Web site: February 22, 2023 . DMAA in Products Marketed as Dietary Supplements . August 28, 2023 . . [Methylhexanamine] is not a dietary ingredient, and [Methylhexanamine]-containing products marketed as dietary supplements are illegal and their marketing violates the law..
  5. Web site: August 30, 2019 . United States v. Hi-Tech Pharmaceuticals, Inc., No. 17-13376 (11th Cir. 2019) . 2023-08-29 . Justia Law . en . DMAA is not an 'herb or other botanical.' It is not a 'constituent' of an herb or other botanical. And it is not generally recognized by qualified experts, as adequately shown through scientific procedures, to be safe under the conditions of its intended use..
  6. Cohen PA . DMAA as a dietary supplement ingredient . Archives of Internal Medicine . 172 . 13 . 1038–1039 . July 2012 . 22566490 . 10.1001/archinternmed.2012.1677 . free .
  7. Web site: U.S Food and Drug Administratio . Center for Food Safety and Applied Nutrition (CFSAN) . Products & Ingredients - DMAA in Products Marketed as Dietary Supplements . en. May 2019 .
  8. Cohen PA, Wen A, Gerona R . Prohibited Stimulants in Dietary Supplements After Enforcement Action by the US Food and Drug Administration . JAMA Internal Medicine . 178 . 12 . 1721–1723 . December 2018 . 30422217 . 6583602 . 10.1001/jamainternmed.2018.4846 .
  9. Col John Lammie et al. Report of the Department Of Defense: 1,3 Dimethylamylamine (Dmaa) Safety Review Panel June 3, 2013
  10. News: Chemist's New Product Contains Hidden Substance . The Washington Post . Shipley A . May 8, 2006.
  11. Web site: Carroll W . 16 August 2010 . Under The Knife: 997 . Baseball Prospectus . 12 April 2012 .
  12. Lisi A, Hasick N, Kazlauskas R, Goebel C . Studies of methylhexaneamine in supplements and geranium oil . Drug Testing and Analysis . 3 . 11–12 . 873–876 . 2011 . 22147493 . 10.1002/dta.392 . 21294033 .
  13. Fleming HL, Ranaivo PL, Simone PS . Analysis and Confirmation of 1,3-DMAA and 1,4-DMAA in Geranium Plants Using High Performance Liquid Chromatography with Tandem Mass Spectrometry at ng/g Concentrations . Analytical Chemistry Insights . 7 . 7 . 59–78 . 2012 . 23225994 . 3512447 . 10.4137/ACI.S10445 .
  14. Cohen PA . DMAA as a dietary ingredient-reply . JAMA Internal Medicine . 173 . 7 . 595 . April 2013 . 23568632 . 10.1001/jamainternmed.2013.3776 .
  15. "Methylhexaneamine Carbonate" entry in Marshall Sittig. Pharmaceutical Manufacturing Encyclopedia, Second Edition, Reprint Edition, Volume 1-2. 1988 Noyes Publications. Westwood, New Jersey.
  16. Gee P, Tallon C, Long N, Moore G, Boet R, Jackson S . Use of recreational drug 1,3 Dimethylamylamine (DMAA) [corrected] associated with cerebral hemorrhage . Annals of Emergency Medicine . 60 . 4 . 431–434 . October 2012 . 22575212 . 10.1016/j.annemergmed.2012.04.008 .
  17. Book: Baselt RC . Disposition of toxic drugs and chemicals in man, 10th edition . 2014 . Biomedical Publications . Seal Beach, Ca. . 978-0-9626523-9-4 . 1329 .
  18. Miya TS, Edwards LD . A pharmacological study of certain alkoxyalkylamines . Journal of the American Pharmaceutical Association . 42 . 2 . 107–110 . February 1953 . 13034643 . 10.1002/jps.3030420216 .
  19. Web site: FDA challenges marketing of methylhexanamine products for lack of safety evidence: Agency cites ten companies in warning letters. United States Food and Drug Administration. March 17, 2013. April 27, 2012. 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..
  20. News: . April 16, 2013 . April 16, 2013 . F.D.A. Issues Warning on Workout Supplement . Singer N, Lattman P .
  21. Balas M, Mathew DJ . Secondary open-angle glaucoma in a young male related to dimethylamylamine supplementation . English . Canadian Journal of Ophthalmology. Journal Canadien d'Ophtalmologie . 58. 4. March 2023 . e171–e175 . 36965509 . 10.1016/j.jcjo.2023.02.011 . 257710303 . free .
  22. Gee P, Jackson S, Easton J . Another bitter pill: a case of toxicity from DMAA party pills . The New Zealand Medical Journal . 123 . 1327 . 124–127 . December 2010 . 21358791 . 2012-02-01 . 2012-01-20 . https://web.archive.org/web/20120120154827/http://journal.nzma.org.nz/journal/123-1327/4480/ . dead .
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  25. http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf WADA 2010 Prohibited List (pdf)
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  44. Web site: Usain Bolt: Sprinter loses one Olympic gold over teammate's failed dope test - CNN. 2017-01-25.
  45. Web site: Rider Broc Tickle provisionally suspended. www.fim-live.com.
  46. Web site: FIBA slaps 18-month ban on Ravena for doping violation. 2018-05-28. 2018-05-28. 2018-05-29. https://web.archive.org/web/20180529203014/http://www.foxsports.ph/basketball/gilas-pilipinas/862143/fiba-slaps-18-month-ban-ravena-doping-violation/. dead.
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  48. Web site: Crew chief Matt Borland reinstated after completing Road to Recovery Program . 2019-10-06 . 2019-10-06 . https://web.archive.org/web/20191006053511/https://sports.yahoo.com/crew-chief-matt-borland-reinstated-123010573.html . dead .
  49. Web site: DMAA products pulled from base shelves . 24 January 2013.
  50. http://www.armytimes.com/offduty/health/offduty-dmma-products-pulled-from-shelves-122911/ DMAA products pulled from base shelves – Military Off Duty, Army Health, military fitness, army physical fitness
  51. News: Rovell D. DMAA Brands Start To Reformulate Products Without the Ingredient. https://archive.today/20130119094919/http://www.cnbc.com/id/47266147/DMAA_Brands_Start_To_Reformulate_Products_Without_the_Ingredient. dead. January 19, 2013. 1 August 2012. CNBC. 2 May 2012.
  52. Web site: Varning för kosttillskott som innehåller DMAA. 2012-08-13. https://web.archive.org/web/20120804062245/http://www.slv.se/sv/grupp3/Pressrum/Nyheter/Pressmeddelanden/Varning-for-kosttillskott-som-innehaller-DMAA/. 2012-08-04. dead.
  53. Web site: Anvisa alerta para risco de consumo de suplemento alimentar, July 2012. Brazilian Government: National Health Surveillance Agency (ANVISA). 22 January 2013. https://web.archive.org/web/20130202110354/http://portal.anvisa.gov.br/wps/content/anvisa+portal/anvisa/sala+de+imprensa/assunto+de+interesse/noticias/anvisa+alerta+para+risco+de+consumo+de+suplemento+alimentar. 2 February 2013. dead.
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  57. New Zealand Ministry of Health. Dunne announces Temporary Class Drug Notice March 8, 2012
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  60. Web site: . Stimulant Potentially Dangerous to Health, FDA Warns . April 11, 2013 . April 16, 2013.
  61. FDA Press Release. OxyElite Pro Dietary Supplements by USP Labs: Recall - Products Linked to Liver Illnesses November 10, 2013

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