1.5. alpha-Pyrrolidinovalerophenone (alpha-PVP) and related substances methylone and synthetic cathinones

On this page: Referred scheduling proposal | Scheduling application |Current scheduling status | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACMS advice to the delegates | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

Scheduling application

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

Schedule 9 – New Entries

The delegate’s reasons for the request are:

• Synthetic cathinones (also known as substituted cathinones or cathinone derivatives) are derivatives of cathinone, a monoamine alkaloid found in the khat plant (Catha edulis), which are often referred to colloquially as "bath salts". Synthetic cathinones elicit a variety of amphetamine-like and/or 3,4-methylenedioxy-methamphetamine (MDMA)-like physiological, subjective, and behavioural effects.
• Synthetic cathinones act predominantly as central nervous system stimulants. Stimulants mediate the actions of dopamine, norepinephrine and/or serotonin, mimicking the effects of traditional drugs such as cocaine, amphetamine, methamphetamine and ecstasy.
• Cathinone and its related substances have the potential to be misused and abused. Synthetic cathinones include alpha-PVP and methylone.
• Synthetic cathinones are the β-keto (βk) analogues of a corresponding phenethylamine. Cathinone itself is β-keto (βk) amphetamine, 2-aminopropiophenone or, more formally, 2-amino-1-phenyl-1-propanone (IUPAC systematic name). The group includes several substances that have been used as active pharmaceutical ingredients (API) of medicinal products, e.g. amfepramone (diethylpropion).
• Use of synthetic cathinones has been associated with sympathomimetic toxidrome.
• Most of the unregulated cathinone derivatives (synthetic cathinones) that have been marketed in are ring-substituted and first appeared in drug markets in the mid-2000s. The most prevalent of which appears to be mephedrone (4-methylmethcathinone).^[28] In 2005, methylone, an analogue of MDMA, was the first synthetic cathinone reported to the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA). In 2007, reports of 4-methylmethcathinone (mephedrone, currently in Schedule 9) use emerged, first in Israel and then in other countries and regions, including Australia, Scandinavia, Ireland and the United Kingdom.^[29] Mephedrone was reportedly first synthesised in 1929.^[30]
• The most commonly available cathinones sold on the recreational market in the period up to 2010 appear to be mephedrone (captured under the Schedule 9 entry, 4-methylmethcathinone) and methylone (unscheduled). These products are usually encountered as highly pure white or brown powders. Ring-substituted cathinone derivatives are claimed to have effects similar to those of cocaine, amphetamine or 3,4-methylenedioxymethamphetamine (MDMA/ecstasy), but little is known of their detailed pharmacology.
  • Methylone (unscheduled) is one of the most popular products with stimulant effects. Methylone is a synthetic cathinone and an alternative of MDMA. Methylone in most cases is taken orally or by insufflation. Methylone is also part of a party liquid.
• Synthetic cathinones were associated with nearly 23,000 emergency department visits in the United States in 2011,^[31] and have been implicated in multiple deaths.^[32]

Current scheduling status

Cathinone

alpha-Pyrrolidinovalerophenone (alpha-PVP)

alpha-PVP, also known as alpha-pyrrolidinopentiophenone, is not specifically listed in the Poisons Standard. It is structurally related to, but not captured by, pyrovalerone (Schedule 4), prolintane (Schedule 4), 3,4-methylenedioxypyrovalerone (MDPV, Schedule 9) and cathinone (Schedule 9).

Methylone

Methylone is not specifically listed in the Poisons Standard. Methylone is structurally related to, but not captured by, the Schedule 9 entry for MDMA (differing only by a single beta-ketone). Methylone is also chemically related to several other cathinones and amphetamines already included in Schedules 9 and 8.

Related substances listed in the Poisons Standard

Scheduling history

alpha-PVP

alpha-PVP, also known as alpha-pyrrolidinopentiophenone, has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Cathinone

In August 1986, the Drugs and Poisons Schedule Committee (DPSC) considered a Schedule 9 entry for cathinone in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP) under Psychotropic Substances. It was discussed after a notification from the Secretary-General from the United Nations.

In November 1986, after review of the States and Territories, the DPSC agreed to add cathinone into Schedule 9 of the SUSDP.

Methcathinone

In November 1998, the National Drugs and Poisons Schedule Committee (NDPSC) agreed to the inclusion of methcathinone in Schedule 9 due to its potential as a problem drug.

Methylone

Methylone has not been previously considered for scheduling. Therefore, a scheduling history is not available.

4-Methylmethcathinone (mephedrone)

In June 2010, the NDPSC decided to create a new entry in Schedule 9 for 4-methylmethcathinone (mephedrone). The committee agreed that 4-methylmethcathinone, as a derivative of methcathinone, is captured by the Schedule 9 entry for methcathinone. The committee further agreed that it would be appropriate to create a new entry for 4-methylmethcathinone in Schedule 9 to clarify that this substance is indeed a prohibited substance.

3,4-methylenedioxypyrovalerone (MDPV)

In October 2011, the Advisory Committee on Medicines Scheduling (ACMS) considered an application to include MDPV in Schedule 9 of the Poisons Standard due to it being structurally related to cathinone and MDMA. The ACMS recommended that MDPV be included in Schedule 9, with a cross-reference to 3,4-methylenedioxypyrovalerone, due to its potency and its associated dangers with heavy and repetitive use.

Australian regulatory information

Alpha-PVP, methylone and cathinone are not an excipient or active in any medicines on the ARTG.

According to the TGA Ingredient Database, prolintane is available for use as an:

• Active ingredient in biologicals, export only and prescription medicines;
• Excipient ingredient in biologicals, devices and prescription medicines; and

There are no recorded adverse event reports for any related substances on the Database of Adverse Events Notification (DAEN) - Medicines.

International regulations

United Nations (UN)

Cathinone and methcathinone are listed in Schedule I of the UN 1971 Convention on Psychotropic Substances. Amfepramone and pyrovalerone are in Schedule IV of that Convention, but other derivatives are not under international control. A few synthetic cathinones are controlled in some Member States under drug control or equivalent legislation, for example:

• Mephedrone (Belgium, Denmark, Germany, Estonia, Ireland, France, Italy, Lithuania, Romania, Sweden, Croatia and Norway);
• Methylone (Denmark, Ireland, Romania and Sweden);
• Butylone (Denmark, Ireland, Romania, Sweden and Norway);
• MDPV (Denmark, Ireland, Finland and Sweden); and
• Flephedrone (Denmark, Ireland and Romania).

Mephedrone is controlled under medicines legislation in Finland and the Netherlands. By Council Decision of 2 December 2010, 4-methylmethcathinone (mephedrone) was submitted to control measures in EU Member States (2010/759/EU).^[33]

United Kingdom (UK)

Generic control in the UK covers a wide group of cathinone derivatives. In the UK, the 31 March 2010 report of the UK Advisory Council on the Misuse of Drugs – Consideration of the cathinones indicated that the harms associated with mephedrone and related cathinones were commensurate with the amphetamines and the substances in Class B. This UK report, defines cathinone derivatives generically as follows:

1. by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents;
2. by substitution at the 3-position with an alkyl substituent;
3. by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure.

Present UK controls include:

• Cathinone (Class C), methcathinone (Class B), diethylpropion (Class C) and pyrovalerone (Class C) are controlled under the Misuse of Drugs Act 1971. However, other derivatives and analogues are not presently controlled (including mephedrone).
• Although the paragraph 1(c) of Part 1 (Schedule 2) of the Misuse of Drugs Act 1971 offers some scope for the control of substances which are structurally related to the phenethylamine backbone, it is primarily concerned with ring-substituted amphetamine-like compounds. Specifically, no mention is made of the presence of any substituents (other than hydrogen) at the β-carbon of the phenethylamine backbone (cathinones all possess a β-ketone oxygen).
• Irrespective of whether controls for the cathinones are implemented under the Misuse of Drugs Act 1971, the rapidity and easy availability of mephedrone and other cathinones (including websites set up so that vendors that can deliver to individual addresses) does raise the question of whether other legislation and regulation should be available.

United States of America

In the USA, alpha-PVP (also known as alpha-pyrrolidinopentophenone) is reported by the US DEA to be a synthetic cathinone and was temporarily placed in the US Schedule 1 of controlled drug substances in March 2017. After consideration of the relevant matter presented as a result of public comment, the scientific and medical evaluations and accompanying recommendations of the Department of Health and Human Services (HHS), and the DEA's consideration of its own eight-factor analysis, the DEA finds that these facts and all other relevant data constitute substantial evidence of potential for abuse of 4-MEC, 4-MePPP, alpha-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and alpha-PBP. As such, the DEA is permanently scheduling them as controlled substances under the Controlled Substances Act.

See also the DEA warning in relation to synthetic cathinones.

Canada

Schedule I of the Controlled Drugs and Substances Act:

• Methylenedioxypyrovalerone (MDPV), its salts, derivatives, isomers and analogues and salts of derivatives, isomers and analogues

Schedule III of the Controlled Drugs and Substances Act:

• Cathinone ((-)-α-aminopropiophenone) and its salts
• Methcathinone (2–Methylamino–1–phenyl–1–propanone) and its salts

New Zealand

Substance summary

Synthetic cathinones are chemically similar to cathinone, which comes from the khat plant (Catha edulis). Khat is a shrub grown in East Africa and southern Arabia, and people sometimes chew its leaves for their mild stimulant effects.

Synthetic cathinones are included in a group of drugs that concern public health officials called "new psychoactive substances" (NPS). NPS are unregulated psychoactive (mind-altering) substances that have become newly available on the market and are intended to copy the effects of illegal drugs. Some of these substances may have been around for years but have re-entered the market in altered chemical forms or due to renewed popularity.

The most well-known synthetic cathinone is mephedrone (4-MMC or meow meow), although there are several others, including methylone, alpha-PVP, methedrone, naphyrone, butylone and MDPV. These substances reportedly produce similar effects to methamphetamine and MDMA (ecstasy).^[34] Synthetic cathinones have only been used as street drugs since the 2000s.^[35]

Until recently, these drugs were available under the guise of 'research chemicals' or 'plant food', either online or in shops which sell legal highs.

Table 1.5.4: Chemical properties of cathinone and some synthetic cathinones

Chemical	CAS number	IUPAC and/or common and/or other names	Molecular structure and weight	Structure
Cathinone	42542-10-9	1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine (IUPAC); Mandy, MDMA, Molly, ecstasy;	C11H15NO2 193.2 g/mol
Mephedrone (4-methylmethcathinone)	1189805-46-6	2-(methylamino)-1-(4-methylphenyl)propan-1-one (IUPAC); M-CAT, HSB 7979, Meow Meow, Bounce, Bubbles;	C11H15NO 177.2 g/mol
Methylone	186028-79-5	1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (IUPAC); BK-MDMA, HSB 7997, M1;	C11H21NO
Pyrovalerone	3563-49-3	1-(4-methylphenyl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC);	C16H23NO 245.4
Prolintane	493-92-5	1-(1-phenylpentan-2-yl)pyrrolidine (IUPAC); Catovit;	C15H23N 217.4 g/mol
3,4-methylenedioxypyrovalerone (MDPV)	687603-66-3	1-(1,3-benzodioxol-5-yl)-2-pyrrolidin-1-ylpentan-1-one (IUPAC); MDPV, MDPK;	C16H21NO3 275.3 g/mol
General chemical structure of a cathinone derivative showing substitution patterns

Cathinones act as central nervous system stimulants, although the potencies of the cathinones are generally lower than their amphetamine congeners. This may be due to the increased polarity conferred on a cathinone by the presence of a β-keto group reducing their ability to cross the blood-brain barrier.

Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine. Synthetic variants of cathinone can be much stronger than the natural product and, in some cases, very dangerous.^[36]

Cathinone is structurally very similar to amphetamine (1-phenylpropan-2-amine), differing only in the functionality present at the β-carbon. Cathinone possesses a ketone oxygen at the β-carbon; cathinone can therefore be considered as the 'beta;-keto analogue' of amphetamine. The molecular architecture of 2-amino-1-phenyl propanone (cathinone) can be altered to produce a series of different compounds which are closely structurally related to cathinone. Together these are known as the 'cathinones', 'synthetic cathinones' or 'cathinone derivatives'.

The basic cathinone structure can be altered in a number of predictable ways, such as the inclusion of additional functionality to the aromatic ring (ring substitution, R₁), N-alkylation (or inclusion of the nitrogen atom in a ring structure, R₃ and R₄), and variation of the (typically alkyl) α-carbon substituent (R₂). Multiple modifications may be present in a single derivative. Cathinones are all usually N-alkylated (or the nitrogen is incorporated into a ring structure, typically pyrrolidine) and many also bear ring substituents.

Pre-meeting public submissions

Three (3) public submissions were received that opposed the proposal for for alpha-PVP and related substances (cathinones and methylone), instead suggesting that a Schedule 9 entry may be more appropriate. The main points opposed to a Schedule 4 entry and in support of a Schedule 9 entry were:

• Methylone (MDMC) and alpha-pyrrolidinovalerophenone (alpha-PVP) are synthetic psychostimulants associated with overdoses, suicides and illicit use.
• The poisons information centres and clinical toxicology units around Australia continue to be contacted for advice on poisonings from these agents. Features of these poisonings include agitation, tachycardia, hypertension and in severe cases delirium, aggressive behaviour, hallucinations, hyperthermia, cardiac dysrhythmias and seizures. Deaths have occurred due to alpha-PVP toxicity.
• Cathinones, MDMC and alpha-PVP have no currently established therapeutic value and have demonstrated high risks of dependency, abuse, misuse and illicit use; and possess a significant toxicity profile which fits the criteria for inclusion in Schedule 9. Schedule 4 and Appendix D are not appropriate.
• Cathinones are illegal in many other countries such as the United States of America, the United Kingdom, Sweden and New Zealand.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegates

The committee recommended that new Schedule 9 entries be created for alpha-PVP and methylone in the Poisons Standard, and the current Schedule 9 cathinone entry be amended as follows:

The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

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; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

1. the risks and benefits of the use of a substance:

• Risks: These classes of substances collectively are associated with considerable toxic effects as evidenced by reports of mortality and poisons data. Risks of consumption by humans are significant.
• Benefits: There was no benefit of use found.
• the purposes for which a substance is to be used and the extent of use of a substance:
• No established therapeutic purpose or use (except cathinone-structure medicines are already included in Schedule 4). There is evidence these substances are used as recreational drugs worldwide, including in Australia, with consequent significant public health harm.
• Readily available in internet and retail stores.
• the toxicity of a substance:
• Significant stimulant and psychoactive effects. Human use has resulted in death.
• Toxic effects include agitation, tachycardia, hypertension, delirium, aggression, hyperthermia, cardiac arrhythmias and seizures. There has been reported mortality in Australia and internationally. With mephedrone in particular, there are deaths reported in England, Scotland, Wales and Sweden.
• the dosage, formulation, labelling, packaging and presentation of a substance:
• N/A – generally 'white powders'.
• Doses of MDPV reported as 5 mg or less, mephedrone as 200 mg or more with repeated redosing up to 1-2 g per 'session'.
• the potential for abuse of a substance:
• Animal studies indicate many cathinone substances have addiction potential.
• any other matters that the Secretary considers necessary to protect public health
• Alpha-PVP, methylone and some synthetic cathinones are already controlled through misuse of drugs legislation across Australia.
• Increasingly, there are similar controls internationally.

Delegate's considerations

The delegate considered the following in regards to this proposal:

• Scheduling proposal
• ACMS advice
• Public submissions received
• Section 52E of the Therapeutic Goods Act 1989
• Scheduling Policy Framework (SPF 2015)

Delegate's interim decision

The delegate’s interim decision is create a new Schedule 9 entries for alpha-pyrrolidinovalerophenone and methylone, as well as amend the Schedule 9 entry for cathinone. The proposed Schedule entries are:

The proposed implementation date is 1 June 2018. This is the earliest practicable implementation date.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of the substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of the substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

1. the risks and benefits of the use of a substance:

• Risks: These classes of substances collectively are associated with considerable toxic effects as evidenced by reports of mortality and poisons data. Risks of consumption by humans are significant.
• Benefits: There was no benefit of use found.
• the purposes for which a substance is to be used and the extent of use of a substance:
• No established therapeutic purpose or use (except cathinone-structure medicines are already included in Schedule 4). There is evidence these substances are used as recreational drugs worldwide, including in Australia, with consequent significant public health harm.
• Readily available in internet and retail stores.
• the toxicity of a substance:
• Significant stimulant and psychoactive effects. Human use has resulted in death.
• Toxic effects include agitation, tachycardia, hypertension, delirium, aggression, hyperthermia, cardiac arrhythmias and seizures. There has been reported mortality in Australia and internationally. With mephedrone in particular, there are deaths reported in England, Scotland, Wales and Sweden.
• the dosage, formulation, labelling, packaging and presentation of a substance:
• N/A – generally 'white powders'.
• Doses of MDPV reported as 5 mg or less, mephedrone as 200 mg or more with repeated redosing up to 1-2 g per 'session'.
• the potential for abuse of a substance:
• Animal studies indicate many cathinone substances have addiction potential.
• any other matters that the Secretary considers necessary to protect public health
• Alpha-PVP, methylone and some synthetic cathinones are already controlled through misuse of drugs legislation across Australia.
• Increasingly, there are similar controls internationally.

Footnotes

28. The Europe Monitoring Centre for Drugs and Drug Addiction – Synthetic cathinones drug profile.
29. Kelly, J.P. "Cathinone derivatives: A review of their chemistry, pharmacology and toxicology", Drug Testing and Analysis 3 (2011): 439-453.
30. Saem de Burnaga Sanchez, J. “Sur un homologue de l’ephedrine”, Bulletin de la Société Chimique de France 45 (1929): 284-86. [4] Meyer, M.R., Wilhelm, J., Peters, F.T., Maurer, H.H. "Beta-ketone amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone and methylone" in urine using gas chromatography-mass spectrometry, Analytical and Bioanlytical Chemistry 396 (2010):1225–1233.
31. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality Drug Abuse Warning Network (DAWN). (2013). "Bath salts" were involved in over 20,000 drug-related emergency department visits in 2011.
32. Maskell et al., "Mephedrone (4-Methylmethcathinone)-Related Deaths", Journal of Analytical Toxicology 35(2011)188-191.
33. The Europe Monitoring Centre for Drugs and Drug Addiction – Synthetic cathinones drug profile