Methylhexanamine

Last updated
Methylhexanamine
Geranamine.svg
Geranamine-3D-balls.png
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 InfoCard 100.002.997 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H17N
Molar mass 115.220 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 X mark.svgN
  • Key:YAHRDLICUYEDAU-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (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and developed by Eli Lilly and Company and marketed as an inhaled nasal decongestant from 1948 until it was voluntarily withdrawn from the market in the 1980s.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]

Contents

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

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

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

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] It was also found to induce internalization of the dopamine transporter (DAT). [20] Methylhexanamine is not an agonist of the rodent or human trace amine-associated receptor 1 (TAAR1). [23] [24] [20] As such, TAAR1 agonism does not appear to be involved in monoamine release induction and DAT internalization by methylhexanamine. [20] [23] [24]

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. [25] [26]

Safety

The LD50 for methylhexanamine is 39 mg/kg in mice and 72.5 mg/kg in rats, when administered intravenously.: 95  [27] : 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". [28] 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. [29]

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

In 2010, a 21-year-old man in New Zealand presented with a cerebral hemorrhage after ingesting 556 mg of methylhexanamine, caffeine, and alcohol. [30] Health authorities in Hawaii linked cases of liver failure and one death to OxyElite Pro, a weight loss and bodybuilding dietary supplement. [31]

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 [32] 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. [33]

Chemistry

Chemical structures of amphetamine and methylhexanamine compared. Amphetamine vs methylhexaneamine.png
Chemical structures of amphetamine and methylhexanamine compared.

Methylhexanamine, also known as 1,3-dimethylamylamine (1,3-DMAA), is an alkylamine. [34] [35]

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). [34] [35]

Methylhexanamine and other related alkylamines are similar in chemical structure to phenethylamines and amphetamines, but lack a closed ring. [34] [35]

The predicted log P (XLogP3) of methylhexanamine is 1.9. [34]

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. [36] [37] [38] [39] [40] [41]

Governmental agencies

In 2010, the US military issued a recall of all methylhexanamine-containing products from all military exchange stores worldwide. [60] [61]

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. [62]

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. [63]

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. [64] 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. [65]

In 2012, Australia banned methylhexanamine. In New South Wales, methylhexanamine was classed as a "highly dangerous substance" on the poisons list. [66]

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. [67]

In 2012 the New Zealand Ministry of Health banned the sale of methylhexanamine products, [68] due in part to its growing recreational use as party pills. [69] [70]

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] [71] The FDA has issued warning letters to manufacturers and distributors who continued to market products containing methylhexanamine. [72]

See also

Notes

  1. ↑ The N.D.A (New Drug Application) for methylhexanamine was withdrawn in 1983. Consequently, any product containing methylhexanamine cannot be marketed in the United States until a new application is approved. [6]

Related Research Articles

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References

  1. ↑ Care, scheme=AGLSTERMS AglsAgent; corporateName=Health and Aged (2024-09-30), Therapeutic Goods (Poisons Standard—October 2024) Instrument 2024, scheme=AGLSTERMS.AglsAgent; corporateName=Office Parliamentary Counsel; address=Locked Bag 30 Kingston ACT 2604; contact=+61 2 6120 1400, retrieved 2024-10-31{{citation}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  3. ↑ "DMAA: A prohibited stimulant". United States Department of Defense: Operation Supplement Safety. U.S. Department of Defense. October 12, 2022. Retrieved August 28, 2023.
  4. ↑ "DMAA in Products Marketed as Dietary Supplements". United States Food and Drug Admistration . February 22, 2023. Retrieved 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. ↑ "United States v. Hi-Tech Pharmaceuticals, Inc., No. 17-13376 (11th Cir. 2019)". Justia Law. August 30, 2019. Retrieved 2023-08-29. 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. ↑ Meyer, Harry (November 9, 1983). "E. R. Squibb & Sons, inc. et al.; Withdrawal of Approval of New Drug Applications" (PDF). Federal Register . U.S. Food and Drug Administration through the United States Government Publishing Office.
  7. ↑ "1,3-Dimethylpentylamine - Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 26 March 2005. Identification and Related Records. Retrieved 27 May 2012.
  8. ↑ Cohen PA (July 2012). "DMAA as a dietary supplement ingredient". Archives of Internal Medicine. 172 (13): 1038–1039. doi: 10.1001/archinternmed.2012.1677 . PMID   22566490.
  9. ↑ Venhuis BJ, de Kaste D (2012). "Scientific Opinion on the Regulatory Status of 1,3-Dimethylamylamine (DMAA)" (PDF). European Journal of Food Research & Review. 2 (4): 93–100.
  10. 1 2 3 Singer N, Lattman P (April 16, 2013). "F.D.A. Issues Warning on Workout Supplement". New York Times . Retrieved April 16, 2013.
  11. ↑ "Products & Ingredients - DMAA in Products Marketed as Dietary Supplements". Center for Food Safety and Applied Nutrition (CFSAN). U.S Food and Drug Administratio. May 2019.
  12. ↑ Cohen PA, Wen A, Gerona R (December 2018). "Prohibited Stimulants in Dietary Supplements After Enforcement Action by the US Food and Drug Administration". JAMA Internal Medicine. 178 (12): 1721–1723. doi:10.1001/jamainternmed.2018.4846. PMC   6583602 . PMID   30422217.
  13. 1 2 Col John Lammie et al. Report of the Department Of Defense: 1,3 Dimethylamylamine (Dmaa) Safety Review Panel Archived 2014-01-19 at the Wayback Machine June 3, 2013
  14. ↑ Shipley A (May 8, 2006). "Chemist's New Product Contains Hidden Substance". The Washington Post.
  15. ↑ Carroll W (16 August 2010). "Under The Knife: 997". Baseball Prospectus. Retrieved 12 April 2012.
  16. ↑ Lisi A, Hasick N, Kazlauskas R, Goebel C (2011). "Studies of methylhexaneamine in supplements and geranium oil". Drug Testing and Analysis. 3 (11–12): 873–876. doi:10.1002/dta.392. PMID   22147493. S2CID   21294033.
  17. ↑ Fleming HL, Ranaivo PL, Simone PS (2012). "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. doi:10.4137/ACI.S10445. PMC   3512447 . PMID   23225994.
  18. ↑ Cohen PA (April 2013). "DMAA as a dietary ingredient-reply". JAMA Internal Medicine. 173 (7): 595. doi:10.1001/jamainternmed.2013.3776. PMID   23568632.
  19. ↑ "Methylhexaneamine Carbonate" entry in Marshall Sittig. Pharmaceutical Manufacturing Encyclopedia, Second Edition, Reprint Edition, Volume 1-2. 1988 Noyes Publications. Westwood, New Jersey.
  20. 1 2 3 4 Small C, Cheng MH, Belay SS, Bulloch SL, Zimmerman B, Sorkin A, Block ER (August 2023). "The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization". J Pharmacol Exp Ther. 386 (2): 266–273. doi:10.1124/jpet.122.001573. PMC   10353075 . PMID   37348963. [...] a proposed intracellular target for amphetamine is the [TAAR1], a [GPCR] that is expressed on intracellular membranes in DA neurons (Miller, 2011). Phenethylamine stimulants have been proposed to activate TAAR1, leading to increased cAMP generation and RhoA activation, with subsequent enhancement of DAT reverse transport and endocytosis (Xie and Miller, 2007, 2008, 2009; Underhill et al., 2021). Methamphetamine-induced DAT endocytosis was found to be dependent on TAAR1 expression and PKA activity as suggested by use of the kinase inhibitor H89 (Xie and Miller, 2009). However, evidence indicating that amphetamine-induced endocytosis is independent of TAAR1 includes 1) HEK-293 cells do not express TAAR1 (Reese et al., 2007; Xie and Miller, 2007) but do exhibit amphetamine-induced DAT endocytosis [present studies and (Saunders et al., 2014; Cheng et al., 2015; Wheeler et al., 2015)]; 2) cAMP and PKA activation, which are stimulated by TAAR1, antagonized amphetamine-induced DAT endocytosis in heterologous cells and DA neurons [present studies and (Wheeler et al., 2015)]; and 3) in cell lines and rodent striatal synaptosomes, PKA activation increased DAT Vmax, consistent with increased plasma membrane expression (Pristupa et al., 1998; Page et al., 2004; Batchelor and Schenk, 2018). Additionally, DMAA induced DAT endocytosis (Figs. 3 and 4) despite exhibiting no activity at human TAAR1 in receptor binding studies (Rickli et al., 2019). Therefore, although some evidence does support a role of TAAR1 in modulating amphetamine-induced DAT endocytosis, the present studies suggest that DMAA and amphetamine promote DAT endocytosis through a TAAR1-independent mechanism.
  21. ↑ Docherty JR, Alsufyani HA (August 2021). "Pharmacology of Drugs Used as Stimulants". J Clin Pharmacol. 61 Suppl 2: S53 –S69. doi: 10.1002/jcph.1918 . PMID   34396557.
  22. ↑ Alsufyani HA, Docherty JR (January 2019). "Methylhexaneamine causes tachycardia and pressor responses indirectly by releasing noradrenaline in the rat". Eur J Pharmacol. 843: 121–125. doi:10.1016/j.ejphar.2018.10.047. PMID   30395850.
  23. 1 2 Rickli A, Hoener MC, Liechti ME (September 2019). "Pharmacological profiles of compounds in preworkout supplements ("boosters")". Eur J Pharmacol. 859: 172515. doi:10.1016/j.ejphar.2019.172515. PMID   31265842. TAAR1 activation may reduce the rewarding properties of stimulant-type drugs of abuse (AsifMalik et al., 2017; Cotter et al., 2015; Di Cara et al., 2011; Pei et al., 2015; Simmler et al., 2016) and may theoretically counteract addictive properties of other stimulants that are contained in preworkout boosters or used concomitantly. In contrast to phenethylamines, TAAR1 was not activated by the alkylamines 1,3-dimethylamylamine and 1,3-dimethylbutylamine.
  24. 1 2 Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID   26791601.
  25. ↑ Gee P, Tallon C, Long N, Moore G, Boet R, Jackson S (October 2012). "Use of recreational drug 1,3 Dimethylamylamine (DMAA) [corrected] associated with cerebral hemorrhage". Annals of Emergency Medicine. 60 (4): 431–434. doi:10.1016/j.annemergmed.2012.04.008. PMID   22575212.
  26. ↑ Baselt RC (2014). Disposition of toxic drugs and chemicals in man, 10th edition. Seal Beach, Ca.: Biomedical Publications. p. 1329. ISBN   978-0-9626523-9-4.
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