Geranamine
Encyclopedia
Methylhexanamine also spelled methylhexanenamine and known as dimethylamylamine (DMAA), is a dietary supplement
and simple aliphatic amine
used as a nasal decongestant, as well as treatment for hypertrophied
or hyperplasic
oral tissues. It is a vasoconstrictor, and can be administered by inhalation
to the nasal mucosa to exert its effect. Methylhexaneamine is also a constituent of flower oil, sold as an integral component of nutritional supplements.
trademarked methylhexanamine under Forthane for potential use as a nasal decongestant. Forthane was also used as a nasal decongestant and as treatment for hypertrophied
or hyperplasic
oral tissues The trademark for Forthane has since expired, and so methylhexanamine should not be confused with isoflurane
, a general inhalation anaesthetic, which has the proprietary name in Australia of Forthane.
Patrick Arnold
reintroduced methylhexanamine into the market in 2006 as a dietary supplement, 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.
by reacting
4-methylhexan-2-one with hydroxylammonium chloride
to give the oxime
, followed by reduction via sodium
in ethanol
.
and other ingredients, under trade names such as Geranamine and Floradrene, to be used as an OTC thermogenic or general purpose stimulant
. Methylhexaneamine itself 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
. Despite not being a catecholamine
, methylhexanamine exhibits structural similarity to other monoamines such as phenethylamine
and amphetamine, which may account for its similar mode of action to these compounds. The only structural difference between methylhexanamine and amphetamine is that methylhexanamine lacks the phenyl or benzene ring which is present in all phenethylamine derivatives, including all amphetamines, containing only 4 of the 6 carbons of the phenyl ring. The difference between geranamine and propylhexedrine
is that is lacks two carbons that create a cyclohexyl ring in propylhexedrine and a methyl group on the amine group. Despite these differences, it has a similar mode of action, being a stimulant and having norepinephrinergic effects.
In New Zealand, methylhexanamine (under the name 1,3-dimethylamylamine or DMAA) is an emerging active ingredient of party pills
. Side-effects including headache
, nausea
, and stroke
have been reported in recreational users of these products. In November 2009, the New Zealand government indicated that methylhexanamine would be scheduled as a restricted substance. The New Zealand
government has not banned methylhexanamine, however, its Ministry of Health has banned bulk powder purchases, but its sale in the form of capsules and tablets is permitted.
under the Dietary Health Supplement Education Act of 1994. It is a component of the oil from Pelargonium graveolens
, which is approved for use in food. Methylhexaneamine has been demonstrated to comprise 0.66 - 1% of geranium oil, a similar compound to plant ratio as many other commonly available herbs. Even pure synthetic methylhexaneamine is compliant under FDA law, and the Dietary Supplement Health and Education Act (DSHEA) in particular, as it allows for the synthesis of compounds which were originally found in commonly-known food sources. This law allows for compounds such as Vitamin C, originally stemming from citrus fruits, to be synthesized almost exclusively and still be compliant. (32)
. The LD50
for methylhexaneamine is 39 mg/kg for intravenous and 185 mg/kg for intraperitoneal administration (mouse), equivalent to 206 mg intravenously and 978 milligrams intraperitoneally injected for a 143 lb (65 kg) adult human by commonly used equivalency factors. It is important to note that these equivalency factors are never a perfect extrapolation of animal data and they should be taken as a suggestion of possible effects rather than an empirically demonstrated fact. There are many physiological and pharmacological differences between mice and humans that may elicit different effects and potency of a drug between the two animals (this is true of all organisms). A typical dose for supplementation with the pure extract is 25–50 mg, or about 0.5 mg/kg of body weight. Caffeine's LD50 in mice is 62 mg/kg, and for an adult human female is 57 mg/kg, or 3.705 grams intravenously injected. Oral toxicity is much lower for caffeine (400-1,000 mg/kg), and the oral toxicity of methylhexanamine would similarly be expected to be much lower than intravenous toxicity. Its oral LD50 is currently unknown.
added methylhexanamine to the 2010 prohibited list.
Methylhexanamine was implicated as a stimulant used by five Jamaican athletes in 2009. JADCO, the Jamaican anti-doping panel, was initially unable to determine whether it was prohibited by the rules, but subsequently decided to impose sanctions on some of the affected athletes on the grounds that the drug was similar in structure to the banned substance tuaminoheptane
.
During the 2010 Commonwealth Games, Nigerian athlete Damola Osayemi was stripped of her gold medal in the 100m after methylhexanamine was detected during drug testing. Subsequently, another Nigerian athlete, Samuel Okon, who finished sixth in the 110m hurdles, also tested positive for the drug.
In October 2010, two Portuguese cyclists—Rui Costa
and his brother Mario—tested positive for the substance. The samples were taken during the Portuguese National Championships at the end of June.
In October 2010, nine Australian athletes have been found by Australian Sports Anti-doping Authority to have tested positive for the substance. These players may include NRL and AFL players.
In November 2010 two South African rugby union players, Chiliboy Ralepelle
and Bjorn Basson
, were found to have tested positive for the substance on their annual tour of the Northern Hemisphere, and were immediately sent home from the tour by the South African Rugby Union, although it is possible that the players may have ingested the substance inadvertently in the form of medication for flu symptoms.
In 2010 Belgian National Amateur Masters Champion Rudy Taelman was suspended for one year for a positive test for methylhexanamine. He successfully defended himself from accusations of willful doping by proving that a supplement called "Crack" had caused the non-negative test. It should be noted that he was an active anti-doping advocate, and ironically the one to call for the doping controls to which he was submitted.
In January 2011, the Greek basketball team Iraklis
indefinitely suspended Matt Bouldin
after he tested positive for methylhexanamine.
American pro tennis player Robert Kendrick
was disqualified from the 2011 French Open, and banned from tennis for 12 months by the International Tennis Federation (ITF) after testing positive for Methylhexaneamine at the event. The ban is currently being appealed by Kendrick, as he claims he took a pill to cope with jetlag without knowing it contained the substance, and the ITF wrote in their summary that it did not believe that Kendrick took the substance as a performance enhancer. However, it is the long stated practice of the Tennis Anti-Doping Program that the players are responsible for ensuring that no prohibited substances enter their body, unless they hold a valid exemption for therapeutic use, which Kendrick did not.
In August 2011, American sprinter Mike Rodgers tested positive methylhexanamine, claiming he drank vodka
with an energy drink at a club two days before a meeting in Lignano, Italy
, which supposedly caused the positive test.
In October 2011, Canadian wakeboarder Aaron Rathy was stripped of his silver medal at the Pan American Games in Guadalajara, Mexico, for testing positive for methylhexaneamine. In a statement, he blamed the use of the supplement OxyElite Pro, which he did not know contained the banned substance, for testing positive.
Also in October 2011, Saint Louis Cardinals Minor League outfielder
Reggie Williams was suspended for 50 games for testing positive for methylhexaneamine.
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
and simple aliphatic amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
used as a nasal decongestant, as well as treatment for hypertrophied
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
or hyperplasic
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
oral tissues. It is a vasoconstrictor, and can be administered by inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....
to the nasal mucosa to exert its effect. Methylhexaneamine is also a constituent of flower oil, sold as an integral component of nutritional supplements.
History
In April 1971, Eli Lilly and CompanyEli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
trademarked methylhexanamine under Forthane for potential use as a nasal decongestant. Forthane was also used as a nasal decongestant and as treatment for hypertrophied
Hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
or hyperplasic
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
oral tissues The trademark for Forthane has since expired, and so methylhexanamine should not be confused with isoflurane
Isoflurane
Isoflurane is a halogenated ether used for inhalational anesthesia. Together with enflurane and halothane, it replaced the flammable ethers used in the pioneer days of surgery. Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula...
, a general inhalation anaesthetic, which has the proprietary name in Australia of Forthane.
Patrick Arnold
Patrick Arnold
Patrick Arnold is an American organic chemist responsible for creating the designer steroid tetrahydrogestrinone, also known as THG and "the clear". THG, along with two other anabolic steroids that Patrick Arnold manufactured , were drugs at the heart of the BALCO scandal...
reintroduced methylhexanamine into the market in 2006 as a dietary supplement, after the final ban of ephedrine
Ephedrine
Ephedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia....
as a dietary supplement
Dietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
in the United States in 2005. Arnold introduced it under the trademarked name Geranamine, a name held by his company, Proviant Technologies.
Chemistry
Methylhexaneamine may be synthesizedChemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
by reacting
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
4-methylhexan-2-one with hydroxylammonium chloride
Hydroxylammonium chloride
Hydroxylammonium chloride is the hydrochloric acid salt of hydroxylamine. Hydroxylamine is a biological intermediate in the nitrification and in the anammox which are important in the nitrogen cycle in soil and in wastewater...
to give the oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
, followed by reduction via sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
in ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
.
Uses
Although intended by Eli Lilly to be used as a nasal decongestant, methylhexaneamine has been marketed by certain companies as a dietary supplement in combination with caffeineCaffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
and other ingredients, under trade names such as Geranamine and Floradrene, to be used as an OTC thermogenic or general purpose stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
. Methylhexaneamine itself 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
are less than that of the related compounds amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and ephedrine
Ephedrine
Ephedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia....
. Despite not being a catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
, methylhexanamine exhibits structural similarity to other monoamines such as phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
and amphetamine, which may account for its similar mode of action to these compounds. The only structural difference between methylhexanamine and amphetamine is that methylhexanamine lacks the phenyl or benzene ring which is present in all phenethylamine derivatives, including all amphetamines, containing only 4 of the 6 carbons of the phenyl ring. The difference between geranamine and propylhexedrine
Propylhexedrine
Propylhexedrine is a stimulant drug related to methamphetamine. It is used mainly to provide temporary symptomatic relief of nasal congestion due to colds, allergies and allergic rhinitis...
is that is lacks two carbons that create a cyclohexyl ring in propylhexedrine and a methyl group on the amine group. Despite these differences, it has a similar mode of action, being a stimulant and having norepinephrinergic effects.
In New Zealand, methylhexanamine (under the name 1,3-dimethylamylamine or DMAA) is an emerging active ingredient of party pills
Party pills
Party pills, also known as "herbal highs", "pep pills" "dance pills" and "natural power", is a colloquialism for a type of recreational drug whose main ingredient was originally benzylpiperazine , but has now expanded to a wide range of compounds with a variety of effects...
. Side-effects including headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
have been reported in recreational users of these products. In November 2009, the New Zealand government indicated that methylhexanamine would be scheduled as a restricted substance. The New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
government has not banned methylhexanamine, however, its Ministry of Health has banned bulk powder purchases, but its sale in the form of capsules and tablets is permitted.
Classification as dietary supplement
In the U.S., Methylhexaneamine is classified as a dietary supplementDietary supplement
A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet...
under the Dietary Health Supplement Education Act of 1994. It is a component of the oil from Pelargonium graveolens
Pelargonium graveolens
Pelargonium graveolens is a species in the Pelargonium genus, which is indigenous to various parts of southern Africa, and in particular South Africa. It is often called geranium as it falls within the plant family Geraniaceae, although more correctly, it is referred to as Pelargonium. This...
, which is approved for use in food. Methylhexaneamine has been demonstrated to comprise 0.66 - 1% of geranium oil, a similar compound to plant ratio as many other commonly available herbs. Even pure synthetic methylhexaneamine is compliant under FDA law, and the Dietary Supplement Health and Education Act (DSHEA) in particular, as it allows for the synthesis of compounds which were originally found in commonly-known food sources. This law allows for compounds such as Vitamin C, originally stemming from citrus fruits, to be synthesized almost exclusively and still be compliant. (32)
Safety profile
Methylhexanamine's safety profile is similar to caffeineCaffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
. The LD50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...
for methylhexaneamine is 39 mg/kg for intravenous and 185 mg/kg for intraperitoneal administration (mouse), equivalent to 206 mg intravenously and 978 milligrams intraperitoneally injected for a 143 lb (65 kg) adult human by commonly used equivalency factors. It is important to note that these equivalency factors are never a perfect extrapolation of animal data and they should be taken as a suggestion of possible effects rather than an empirically demonstrated fact. There are many physiological and pharmacological differences between mice and humans that may elicit different effects and potency of a drug between the two animals (this is true of all organisms). A typical dose for supplementation with the pure extract is 25–50 mg, or about 0.5 mg/kg of body weight. Caffeine's LD50 in mice is 62 mg/kg, and for an adult human female is 57 mg/kg, or 3.705 grams intravenously injected. Oral toxicity is much lower for caffeine (400-1,000 mg/kg), and the oral toxicity of methylhexanamine would similarly be expected to be much lower than intravenous toxicity. Its oral LD50 is currently unknown.
Controversy
In 2009, the World Anti-Doping AgencyWorld Anti-Doping Agency
The World Anti-Doping Agency , , is an independent foundation created through a collective initiative led by the International Olympic Committee . It was set up on November 10, 1999 in Lausanne, Switzerland, as a result of what was called the "Declaration of Lausanne", to promote, coordinate and...
added methylhexanamine to the 2010 prohibited list.
Methylhexanamine was implicated as a stimulant used by five Jamaican athletes in 2009. JADCO, the Jamaican anti-doping panel, was initially unable to determine whether it was prohibited by the rules, but subsequently decided to impose sanctions on some of the affected athletes on the grounds that the drug was similar in structure to the banned substance tuaminoheptane
Tuaminoheptane
Tuaminoheptane is a nasal decongestant drug which is a sympathomimetic stimulant and vasoconstrictor. However, it can cause skin irritation, which limits its usefulness as a nasal decongestant...
.
During the 2010 Commonwealth Games, Nigerian athlete Damola Osayemi was stripped of her gold medal in the 100m after methylhexanamine was detected during drug testing. Subsequently, another Nigerian athlete, Samuel Okon, who finished sixth in the 110m hurdles, also tested positive for the drug.
In October 2010, two Portuguese cyclists—Rui Costa
Rui Costa (cyclist)
Rui Alberto Faria da Costa is a Portuguese professional road bicycle racer for UCI ProTeam ....
and his brother Mario—tested positive for the substance. The samples were taken during the Portuguese National Championships at the end of June.
In October 2010, nine Australian athletes have been found by Australian Sports Anti-doping Authority to have tested positive for the substance. These players may include NRL and AFL players.
In November 2010 two South African rugby union players, Chiliboy Ralepelle
Chiliboy Ralepelle
Mahlatse "Chiliboy" Ralepelle , generally referred to by his nickname, is a South African rugby union footballer. His usual position is at hooker...
and Bjorn Basson
Bjorn Basson
Bjorn Alberic Basson is a South African professional rugby union player who plays as wing - and sometimes as full-back - for the Bulls and the South Africa national rugby union team....
, were found to have tested positive for the substance on their annual tour of the Northern Hemisphere, and were immediately sent home from the tour by the South African Rugby Union, although it is possible that the players may have ingested the substance inadvertently in the form of medication for flu symptoms.
In 2010 Belgian National Amateur Masters Champion Rudy Taelman was suspended for one year for a positive test for methylhexanamine. He successfully defended himself from accusations of willful doping by proving that a supplement called "Crack" had caused the non-negative test. It should be noted that he was an active anti-doping advocate, and ironically the one to call for the doping controls to which he was submitted.
In January 2011, the Greek basketball team Iraklis
Iraklis
Iraklis , is a Greek football club, branch of Gymnastic Club Iraklis Thessaloniki, based in the city of Thessaloniki, Macedonia, Greece. The club used to play in the Greek Superleague and is one of the oldest clubs in Greek football and the oldest in Thessaloniki, hence the nickname Ghireos...
indefinitely suspended Matt Bouldin
Matt Bouldin
Matt Bouldin is an American professional basketball player who currently plays in Montenegro for the KK Budućnost Podgorica. He played his college basketball for the Gonzaga Bulldogs.-High school career:...
after he tested positive for methylhexanamine.
American pro tennis player Robert Kendrick
Robert Kendrick
Robert Bradley Kendrick is an American tennis player. He turned professional in 1999. His career high single ranking is world no. 69, achieved on July 20, 2009. He was suspended for a year after testing positive at the 2011 French Open for the drug methylhexanamine, which has been banned in sport...
was disqualified from the 2011 French Open, and banned from tennis for 12 months by the International Tennis Federation (ITF) after testing positive for Methylhexaneamine at the event. The ban is currently being appealed by Kendrick, as he claims he took a pill to cope with jetlag without knowing it contained the substance, and the ITF wrote in their summary that it did not believe that Kendrick took the substance as a performance enhancer. However, it is the long stated practice of the Tennis Anti-Doping Program that the players are responsible for ensuring that no prohibited substances enter their body, unless they hold a valid exemption for therapeutic use, which Kendrick did not.
In August 2011, American sprinter Mike Rodgers tested positive methylhexanamine, claiming he drank vodka
Vodka
Vodka , is a distilled beverage. It is composed primarily of water and ethanol with traces of impurities and flavorings. Vodka is made by the distillation of fermented substances such as grains, potatoes, or sometimes fruits....
with an energy drink at a club two days before a meeting in Lignano, Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
, which supposedly caused the positive test.
In October 2011, Canadian wakeboarder Aaron Rathy was stripped of his silver medal at the Pan American Games in Guadalajara, Mexico, for testing positive for methylhexaneamine. In a statement, he blamed the use of the supplement OxyElite Pro, which he did not know contained the banned substance, for testing positive.
Also in October 2011, Saint Louis Cardinals Minor League outfielder
Outfielder
Outfielder is a generic term applied to each of the people playing in the three defensive positions in baseball farthest from the batter. These defenders are the left fielder, the center fielder, and the right fielder...
Reggie Williams was suspended for 50 games for testing positive for methylhexaneamine.