You are here

Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017

Scheduling medicines and poisons

17 May 2017

Book pagination

1.2. 1,3-Dimethylbutylamine (DMBA) and other aliphatic alkylamines including 1,5-dimethylhexylamine (DMHA)

1. Advisory Committee on Medicines Scheduling (ACMS #20)

1.2. 1,3-Dimethylbutylamine (DMBA) and other aliphatic alkylamines including 1,5-dimethylhexylamine (DMHA)

Referred scheduling proposal

An application was submitted to include entries for 1,3-dimethylbutylamine (DMBA) and other aliphatic alkylamines with stimulant properties including 1,5-dimethylhexylamine (DMHA) in Schedule 10.

Current scheduling status

DMBA and DMHA are currently not specifically scheduled. However, the related substances, 1,3-dimethylamylamine (DMAA), propylhexedrine and tuaminoheptane are in the Poisons Standard as follows:

Schedule 10

1,3-DIMETHYLAMYLAMINE (DMAA)

Schedule 4

PROPYLHEXEDRINE.

Schedule 2

TUAMINOHEPTANE.

Scheduling history

DMBA and DMHA have not been previously considered for scheduling; therefore a scheduling history is not available.

DMAA

In August 2012, the ACMS considered a delegate-initiated proposal to list DMAA in Schedule 9 of the Poisons Standard, following New Zealand's temporary Class Drug Notice of 8 March 2012 advising that DMAA would be classified as a temporary class drug (equivalent to Schedule 9). New Zealand's temporary prohibition of DMAA came into effect on 9 April 2012.

Members noted that: there was inadequate evidence to suggest DMAA's toxicological and pharmacological properties warrant a Schedule 9 listing. DMAA is not listed in either Schedule IV to the United Nations Convention on Narcotic Drugs, 1961 or in Schedule 1 to the United Nations Convention on Psychotropic Substances, 1971. There was a lack of supporting evidence to reach the conclusion that DMAA needs the same level of control as amphetamine. DMAA's toxicological properties meet the Appendix C (now Schedule 10) scheduling criteria. In the absence of a current accepted therapeutic use, the stimulant effect that can induce a psychoactive effect, its active promotion as a party drug as well as a sports supplement, the lack of evidence of dependence, the significant number of adverse events including cardiac, nervous and psychiatric disorders that have been reported with use of DMAA including cerebral haemorrhage and heart attacks and the high potential for misuse and abuse, the committee recommended that the substance be placed in Appendix C (now Schedule 10). Based on DMAA's toxicity, lack of data supporting long-term safety, wide variability in potency of different doses of DMAA and the high risk of use, misuse and illicit use, the delegate placed DMAA in Schedule 10 effective on 8 August 2012[7]. Reasons for the substance ban were published on the TGA website at: The TGA decision to ban DMAA.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 10 - Proposed New Entry

1,3-DIMETHYLBUTYLAMINE (DMBA) AND OTHER ALIPHATIC ALKYLAMINES WITH STIMULANT PROPERTIES INCLUDING 1,5-DIMETHYLHEXYLAMINE (DMHA) except when separately specified in these schedules.

Index - Proposed New Entry

1,3-DIMETHYLBUTYLAMINE (DMBA) AND OTHER ALIPHATIC ALKYLAMINES WITH STIMULANT PROPERTIES INCLUDING 1,5-DIMETHYLHEXYLAMINE (DMHA)
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4 methylhexane-2-amine, 1,3-dimethylamylamine, DMAA

Schedule 10

The applicant's reasons for the request are:

  • 1,3-Dimethylbutylamine (DMBA) is a structural analogue of 1,3-Dimethylamylamine (DMAA) which was previously included in Schedule 10 of the Poisons Standard. It is proposed DMBA be added to the same schedule as DMAA due their structural and pharmacological similarity and potential for misuse and potential to result in harm. DMBA is a stimulant with no known therapeutic use.
  • 1,3-Dimethylbutylamine (DMBA) has structural and likely pharmacological similarity with 1,3 Dimethylamylamine (DMAA). DMAA has been banned by regulatory agencies in United States of America (USA), United Kingdom, the Netherlands and Brazil because of its links to negative health events including as strokes, heart failure and sudden death. In 2012, Australia listed DMAA Appendix C (now Schedule 10). In New Zealand, DMAA was classified as a prescription medicine and it was noted that that it did not meet the definition of a dietary supplement. The applicant questions the classification of DMAA, given the deaths linked to DMAA internationally.
  • DMBA is prohibited from sport under the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods, due to its structural similarity to DMAA under category 'S6. Stimulants'.
  • DMBA appears to have become increasingly prevalent in supplements following the removal of DMAA from dietary supplements due to the intervention of food regulators in several countries. The effects of DMBA in humans have not been fully studied or clinically evaluated, and as such its efficacy and safety is unknown. Cohen, et al., (2014), called for regulatory agencies to act expeditiously to warn consumers and remove DMBA from supplements.
  • A review of reports in online forums states that users had a strong stimulant effect. Anecdotal side effects reported by users of DMBA included 'jitteriness (sic), rapid heartbeat, dizziness, headache, and a crash after it has worn off'. There were also reports of depression and anxiety.
  • Despite the lack of proof of the efficacy and safety of products containing DMBA they are readily available for purchase in Australian supplement stores and through online suppliers in Australia and overseas. Distributors are promoting products containing DMBA as supplement that improves athletic performance, increases weight loss and enhances brain function.
  • Supplement products containing DMBA have promoted or implied that DMBA, is a 'naturally occurring' botanical substance derived from Pouchong tea (Camellia sinensis). This claim has been proven to be false, an analysis of 25 authentic and commercial samples of Camellia sinensis tea leaves failed to detect DMBA.
  • DMBA is prohibited from sport under the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods, due to its structural similarity to DMAA under category 'S6. Stimulants'.
  • Since DMBA is a synthetically produced compound, the United States Food and Drug Administration (FDA) issued a warning in April 2015 that DMBA is not an approved dietary ingredient. The FDA determined products containing DMBA would not meet the definition of a “dietary supplement” and supplements containing DMBA are considered to be adulterated. The FDA has issued warnings, requiring manufacturers to immediately cease distribution and recover products containing DMBA already in the marketplace.
  • Supplement manufacturers appear responsive to regulatory initiatives to restrict the supply of substances by converting to analogues or substances of similar effects. When regulatory agencies banned DMAA from all dietary supplements, alternative pressor amines such as DMBA appeared on the market replacing DMAA supplements. This demonstrates the need to regulate to prevent other compounds of this class from being added as ingredients to supplements.
  • There are reports by supplement distributors online of plans to replace DMBA in supplements should DMBA be regulated in a similar way to DMAA. One of the suggested replacement substances is DMHA. Websites such as Herb Nutritionals and Mr Supplement have called DMHA a replacement for DMAA and DMBA. The websites also note that although there are unverified claims of the botanical nature of the compound, DMHA is likely to be synthetically produced.
  • Given its structural similarity to DMAA, the application seeks to list DMBA on Schedule 10. Should this not be considered appropriate, the application seeks to list DMBA in Schedule 4.
  • Given the evidence that more advanced analogues of DMBA, such as DMHA, and other aliphatic alkylamines with similar stimulant properties are reaching the market, the applicant also propose the scheduling apply to the class of substances. Scheduling of DMBA and its alkyl-analogues will protect public health from the potential adverse impacts of these unapproved substances. The adaptability of the supplements industry in developing chemically similar substances with similar stimulant like properties further underlines the need to be proactive and consider including an analogues clause that thereby schedules this class appropriately.
Australian regulatory information

DMBA and DMHA are not currently scheduled in Australia.

A search of the ARTG found no products containing DMBA or DMHA.

The Australian Sports Anti-Doping Authority (ASADA) has issued a warning to athletes, asserting that the presence of DMBA in a bodily sample collected during the competition period is an anti-doping rule violation and may attract a range of penalties including a 2-year ban from sport. If an anti-doping organisation can however demonstrate that the athlete intentionally took DMBA, the ban could be as high as 4 years.

International regulations
1,3-Dimethylbutylamine (DMBA)

DMBA is prohibited from sport under the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods, due to its structural similarity to DMAA under category 'S6. Stimulants'. WADA, noted that novel psychoactive substances (DMBA and DMHA) are derived from stimulants and marketed for these effects. The substances arrive on the market with little pharmacological data and the use of non-approved drugs in humans poses risks for health. Under the World Anti-Doping Code, use of these substances by athletes may result in ineligibility to compete in sport for up to 4 years. WADA confirmed DMBA is deemed to be a health risk given it is a non-approved drug with little pharmacological data regarding its effect on humans.

The US FDA issued a statement in relation to the inclusion of DMBA in dietary supplements[8] following warning letters to 14 companies sent in April 2015, where DMBA was considered an adulterant in 17 products. The US FDA considers any dietary supplement containing DMBA to be "adulterated".

In New Zealand, DMBA is classified as a psychoactive substance and its sale and supply are prohibited under the Psychoactive Substances Act.

1,5-Dimethylhexylamine (DMHA)

No information could be found regarding the status of DMHA in the USA. However, the US FDA website includes warnings regarding DMAA, DMBA and BMPEA (β methylphenylethylamine, reportedly sourced from Acacia rigidula) in Dietary Supplements[9]. None of these substances have been determined to meet the statutory definition of a dietary ingredient. The US FDA issued warning letters to 5 companies sent in April 2015 regarding BMPEA and Acacia rigidula[10].

No information could be found regarding the status of DMHA in New Zealand.

In Canada, DMHA is known as 'octodrine and its salts' and is listed as prohibited on the Health Canada Cosmetic Ingredient list.[11]

Substance summary
1,3-Dimethylbutylamine (DMBA)

Figure 1.2A: Structure of DMBA

Figure 1.2A: Structure of DMBA

DMBA, is an aliphatic amine stimulant that is structurally related to DMAA, where a butyl group replaces the amyl group. DMBA is commonly found in OTC supplements commonly described as 'pre-workouts' and 'fat burners'. DMBA has a molecular weight 101.2, and molecular formula C6H15N.

Some products market DMBA on labels as a compound extracted from Pouchong tea and infer that it is a natural product, rather than synthetic. This may imply safety for consumption. A similar marketing approach was used for DMAA as a geranium extract. However, Cohen, et al., (2014) noted 'we are unaware of any scientific evidence that DMBA has ever been extracted from any plant, while synthetic DMBA is easy to synthesise and widely available'.

DMBA belongs to the family of pressor-amines including DMAA, tuamine and propylhexedrine. The concentrations found in the supplements analysed strongly suggest DMBA is synthetically mass-produced to create pharmaceutical effects.

DMAA was listed in Schedule 10 in 2012. The use of DMBA and structurally related stimulants has generated concern in medical circles due to their amphetamine-like effect and possible health consequences. It appears manufacturers are intentionally including DMBA in sports supplements to restore, and possibly surpass, the effect generated by DMAA before its prohibition.

In the scheduling of DMAA in August 2012 the ACMS noted:

  • there are risks due to DMAA's toxicity
  • DMAA has no current accepted therapeutic use
  • DMAA has a stimulant effect which can induce a psychoactive effect
  • there are a number of significant adverse events including cardiac, nervous and psychiatric disorders that have been reported with use of DMAA including cerebral haemorrhage (stroke) and heart attacks
  • there is a wide variability in the potency of the different doses of DMAA

As DMBA is a new ingredient there do not appear to be any peer-reviewed studies assessing the pharmacology, toxicology, and safety of the compound.

1,5-Dimethylhexylamine (DMHA)

Figure 1.2B: Structure of DMHA

DMHA, also referred to as Octodrine, 6-methyl-2-heptanamine, molecular weight 129.3, has the following molecular formula C8H19N. DMHA is an α-adrenergic agonist and decongestant. The hydrochloride salt is crystalline and soluble in water, and the Merck Index reports LD50 in mice, rats (mg/kg): 59, 41.5 i.p. Websites report that DMHA is found in sufficient doses in nature, in particular in the Kigelia africana fruit and state that this allows it to be considered a dietary supplement and get approval from the relevant authorities[12]. Website product names that contain DMHA include Giant Sports Giant Rush.

There has been limited research regarding the harms and possible therapeutic benefits associated with the use of the substances proposed for scheduling. The potential side effects of this class of stimulants are wide ranging. Significant adverse events include cardiac, nervous and psychiatric disorders that have been reported with use of DMAA. As an analogue of this Schedule 10 substance, DMBA is believed to pose similar health risks.

The health risks from DMBA in pharmacological doses are unknown. DMBA has never been studied in humans. DMBA has pressor effects and DMBA should be considered an active pharmaceutical ingredient that requires rigorous clinical testing and evaluation prior to marketing.

These substances are being used by athletes and the broader community as a stimulant before physical activity. Supplements containing DMBA have been marketed to improve athletic performance, increase weight loss and enhance brain function.

Available information on pre-workouts and thermogenics suggest that this part of the supplement industry is expanding considerably in Australia.

DMBA can be included in sports supplements as part of a proprietary blend and as such product labelling usually does not specify the exact dosage per serving.

The study conducted by Cohen et al (2015) tested the relative concentrations of DMBA in a range of sports supplements sold in the USA ranging from 13 mg to 120 mg per serving. Based on the maximum daily number of servings some products allowed for a daily intake of up to 320 mg. As there has been no testing on the safety or efficacy of this compound it is unknown what level of intake (if any) would be safe. Australian supplement websites and internet forums report taking three to five times the recommended daily dose in one serving in order to experience the full psychoactive effect.

An analysis of numerous supplements on the Australian market produced data showed two products from the pre-workout and weight management category contained DMBA and DMAA at high concentrations and other products with low-level cross-contamination in complex botanical ingredients.

Due to the purported psychoactive properties of DMBA, it is used primarily as a stimulant to increase focus during workouts. It also has the potential to be used for other purposes and has been promoted as a study aid as its stimulant properties are reported to increase mental focus.

Pre-meeting public submissions

No submissions were received.

Summary of ACMS advice to the delegates

The committee advised that a new entry be created for 1,3-dimethylbutylamine (DMBA) and other alkylamines with stimulant properties including 1,5-dimethylhexylamine (DMHA) in Schedule 10, except when separately specified in these schedules, as follows:

Schedule 10 - New Entries

1,3-DIMETHYLBUTYLAMINE (DMBA) except when separately specified in these schedules.

1,5-DIMETHYLHEXYLAMINE (DMHA) except when separately specified in these schedules.

ALKYLAMINES WITH STIMULANT PROPERTIES except when separately specified in these schedules.

Index - New Entries

1,3-DIMETHYLBUTYLAMINE (DMBA)
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4 methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane Citrate (AMP Citrate)

Schedule 10

1,5-DIMETHYLHEXYLAMINE (DMHA)
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4 methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane Citrate (AMP Citrate)

Schedule 10

ALKYLAMINES WITH STIMULANT PROPERTIES
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4 methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane citrate (AMP citrate)

Schedule 10

The committee also recommended an implementation date of 1 October 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.

The reasons for the advice comprised the following:

  • There is a significant health risk.
  • DMBA is readily available in Australia despite lack of proof of efficacy and safety, and there is no current accepted therapeutic use.
  • DMBA is listed by ASADA and WADA in anti-doping rules. WADA considers DMBA to be a health risk due to little pharmacological data of its effects in humans and is a non-approved drug.
  • The potential for misuse and abuse is high.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACMS advice
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information
Delegate's interim decision

The delegate's interim decision is to create new entries for 1,3-dimethylbutylamine (DMBA) and other alkylamines with stimulant properties including 1,5-dimethylhexylamine (DMHA) in Schedule 10, except when separately specified in these schedules. The proposed Schedule entry is as follows:

Schedule 10 - New Entries

1,3-DIMETHYLBUTYLAMINE (DMBA) except when separately specified in these schedules.

1,5-DIMETHYLHEXYLAMINE (DMHA) except when separately specified in these schedules.

ALKYLAMINES WITH STIMULANT PROPERTIES except when separately specified in these schedules.

Index - New Entries

1,3-DIMETHYLBUTYLAMINE (DMBA)
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4-methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane Citrate (AMP Citrate)

Schedule 10

1,5-DIMETHYLHEXYLAMINE (DMHA)
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4-methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane Citrate (AMP Citrate)

Schedule 10

ALKYLAMINES WITH STIMULANT PROPERTIES
cross reference: 1,3-dimethylbutylamine, DMBA, octodrine, 1-aminoisoheptane, DMHA, 1,5-dimethylhexylamine , 4-methylhexane-2-amine, 1,3-dimethylamylamine, DMAA, 4-amino-2-methylpentane citrate (AMP citrate)

Schedule 10

The proposed implementation date is 1 October 2017, since this is the earliest possible implementation date.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • There is a significant health risk.
  • DMBA is a structural analogue of DMAA which was previously included in Schedule 10 of the Poisons Standard. DMBA is readily available in Australia despite lack of proof of efficacy and safety, and there is no current accepted therapeutic use.
  • DMBA is listed by ASADA and WADA in anti-doping rules. WADA considers DMBA to be a health risk due to little pharmacological data of its effects in humans and is a non-approved drug.
  • The potential for misuse and abuse is high.

Footnotes

  1. Scheduling delegate's final decisions: DMAA, August 2012
  2. DMBA in Dietary Supplements
  3. DMBA in Dietary Supplements
  4. BMPEA in Dietary Supplements
  5. Cosmetic Ingredient Hotlist
  6. Is this the new DMAA? and The New DMAA (DMHA / 2-Aminoisoheptane / Octodrine)

Book pagination