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The ACMD’s Mephedrone Report Part II

By John Clarke

This post con­tains the important annexes from the ACMD’s report on mephed­rone and related cath­inones. You can read the main body of the report here: The ACMD’s Mephed­rone Report Part I. The ori­ginal pdf is linked to at the end of this post.

I’ll prob­ably write a few com­ments about the entire report in my next post, whenever that may be. Anyhoo…

Annex A. Recommendation For The Generic Control Of The Cathinone Derivatives

Scope of a generic definition

The ACMD here set out recom­mend­a­tions on the range of com­pounds that should be included in a generic defin­i­tion for the control of cath­inone deriv­at­ives under the Misuse of Drugs Act 1971.

It was pro­posed that the scope of com­pounds covered by generic control should be much wider than the 6 ring sub­sti­tuted com­pounds listed in Table 1 (annex A) and wider than the 10 com­pounds reported to the EMCDDA since 2006.

The scope should include all cath­inone deriv­at­ives that have been found in seizures and col­lected samples together with com­pounds that have not been encountered but have misuse poten­tial. This includes cath­inone deriv­at­ives with and without ring sub­stitu­ents and with side chains longer than those usually encountered in the phen­ethyl­amine drugs.

The scope should also include any sub­stances known or believed to be pro-​​drugs, i.e. sub­stances that are meta­bol­ised to a known active sub­stance (for example GBL is con­verted in the body to GHB).

The generic defin­i­tion should not include those sub­stances already con­trolled under the Misuse of Drugs Act, i.e. diethyl­pro­pion (Class C), cath­inone (Class C), meth­cath­inone (Class B) and pyro­va­lerone (Class C). Finally the defin­i­tion should not include any sub­stances, e.g. bupro­pion, that are ingredi­ents of legit­imate phar­ma­ceut­ical products or that have other legit­imate uses.

The struc­ture of cath­inone deriv­at­ives is rep­res­ented by the gen­er­al­ised struc­ture below:

Figure 1: Gen­er­al­ised struc­ture of cath­inone deriv­at­ives
where,

R1= single alkyl group [but not H]
R2= H or alkyl
R3= H or alkyl or
[NR2R3] = pyrrolidino or phthalimido or other ring structure
R4= H (no sub­stitu­ents) or
= one or more of alkyl, alkoxy, alkyle­ne­dioxy and halide whether or
not further sub­sti­tuted with an other uni­valent substituent

The phthalimido group has so far only been encountered in the com­pound a-​​phthalimidopropiophenone. This sub­stance has been found in a capsule in com­bin­a­tion with 2-​​fluoromethcathinone and in cap­sules con­taining a mixture with 4-​​methylmethcathinone, N-​​ethylcathinone, and caffeine.

The reason for adding a-​​phthalimidopropiophenone is not clear. It may have been added delib­er­ately, perhaps as a pro-​​drug for cath­inone, but there is no inform­a­tion about its phar­ma­co­logy or meta­bolism. This sub­stance is also an inter­me­diate in the syn­thesis of cath­inone and N-​​alkyl deriv­at­ives of cath­inone. It could there­fore be present unin­ten­tion­ally as a residue of an inter­me­diate, the product of a failed chem­ical syn­thesis, or even the miss-​​labelling of an intermediate.

In addi­tion to com­pounds with the gen­er­al­ised struc­ture in (Figure 1, Annex A) the phenyl ring can be replaced with a naph­thyl ring (e.g. Figure 2, Annex A) or with a thiophene ring. The naph­thyl ana­logue of pyro­va­lerone (Figure 2, Annex A) is avail­able on the Internet and is being retailed as “NRG-​​1”. These com­pounds cannot easily be included in a generic defin­i­tion for the cath­inone deriv­at­ives having the gen­er­al­ised struc­ture in Figure 1, Annex A, but they could be con­trolled as named sub­stances or by one or more sep­arate generic defin­i­tions. The ACMD intend to review these sub­stances and provide further advice at a later date.

Figure 2: Naph­thyl ana­logue of pyrovalerone

The sys­tem­atic chem­ical name for the struc­ture in Figure 2, Annex A is 1-(2-naphthyl)-2-(1-pyrrolidinyl)-1-pentanone and altern­ative names include naph­thylpyro­va­lerone, naphyrone and O-​​2482.

Appendix I, of this Annex includes all the cath­inone deriv­at­ives, with the general struc­ture in Figure 1, Annex A, that have been encountered in seizures and col­lected samples, sub­stances that are already con­trolled, ingredi­ents of known phar­ma­ceut­ical products, sub­stances avail­able via the Internet and sub­stances that are listed in Wiki­pedia. However, the market for cath­inone deriv­at­ives is still evolving and new sub­stances will con­tinue to appear.

Many cath­inone deriv­at­ives are men­tioned in patents for phar­ma­ceut­ical applic­a­tions but the only known non-​​controlled cath­inone deriv­ative with a mar­keting author­isa­tion appears to be bupro­pion, an ingredient of ®Zyban.

Some cath­inone deriv­at­ives are men­tioned in patents for non-​​pharmaceutical applications.

A structure-​​based search of the 12th Edition of the Merck Index (1996), carried out pre­vi­ously by Dr Les King, found no con­ten­tious compounds.

Inter­est­ingly, a recent patent (WO PCT 2010006196) relating to water puri­fic­a­tion mem­branes men­tions the com­pound in Figure 3 below, which is closely related to methylone (bk-​​MDMA). This com­pound would be included within a generic defin­i­tion since the term methyl­e­ne­dioxy can have two mean­ings. However, com­pounds ana­logous to those in Figure 3, Annex A are unlikely to have any com­mer­cial uses.

Figure 3: 3,4-methylenedioxy-N-methyl-ß-keto-amphetamine

Structure Activity Relationships

Cath­inone deriv­at­ives have a range of effects (e.g. stim­u­lant, empath­ogen and antidepressant).

The cath­inone deriv­at­ives without ring sub­stitu­ents (e.g. diethyl­pro­pion, meth­cath­inone, buphed­rone, N,N-dimethylcathinone) are mostly stimulants.

Most of the cath­inone deriv­at­ives encountered as legal highs are ring sub­sti­tuted com­pounds with a sec­ondary amino group (R2 = methyl or ethyl and R3 = hydrogen) or with a cyclic amino group (NR2R3 = pyrrolidino group or phthalimido group). These sub­stances are primarily stim­u­lants, with varying degrees of empath­o­genic effects (i.e. similar in effects to MDMA). Ring sub­stitu­ents (R4) have included alkyl, alkoxy, methyl­e­ne­dioxy and halide.

The side chain sub­stituent (R1) has mostly been a single alkyl group. However there are examples with allyl (an alkenyl) and pro­pargyl (an alkynyl) groups and also examples with a second alkyl group attached to the same carbon atom as R1, but these com­pounds are not within the pro­posed scope.

No haloalkyl sub­stitu­ents (e.g. tri­fluoro­methyl –CF3 as found in piperazine deriv­at­ives) in the ring (R4) or on the side chain (R1) have been encountered or reported in the lit­er­ature. However, replace­ment of the ring methyl group, as in mephred­rone, with a tri­fluoro­methyl group is likely to produce sub­stances with similar activ­ities. It is recom­mended there­fore that haloalkyl sub­stitu­ents be included in the generic defin­i­tion for ring substituents.

Cath­inone deriv­at­ives with a primary amino group (i.e. no N-​​alkyl sub­stitu­ents) are rarely encountered, pos­sibly because of their instability. There are only two known examples, bk-​​MDA (known to sub­sti­tute for MDMA in rats) and cath­inone (a stimulant).

The NR2R3 amino groups reported in the sci­entific lit­er­ature have included alkylamino (R2 = alkyl, R3 = H), dial­kylamino (R2 =alkyl, R3 = alkyl), the cyclic pyrrolidino group and a large number of other cyclic amines. However, for the pyro­va­lerone ana­logues an increase in size of the nitrogen con­taining ring from a five-​​membered pyrrolidine ring to a six-​​membered piperidine ring res­ulted in a sub­stan­tial loss in binding potency. There are also examples of N-​​allyl, N-​​propargyl and N-​​cycloalkyl substituents.

The anti-​​depressant drug bupro­pion has a tertiary-​​butyl group on the nitrogen atom and several other sub­stances invest­ig­ated for their poten­tial as smoking ces­sa­tion drugs also have a bulky alkyl group on the nitrogen atom, e.g. tertiary-​​butyl, iso-​​propyl or cyc­loalkyl, or the alkyl amino group is replaced by a cyclic piperidino group (a cyclic amino group with 6 membered ring).

Salts, stereoisomers, esters and ethers

Cath­inone deriv­at­ives with the gen­er­al­ised struc­ture in Figure 1, Annex A, all have an asym­metric a-​​carbon atom giving rise to R and S stereoisomers.

With the excep­tion of the phthalimido deriv­at­ives, all cath­inone deriv­at­ives have a basic nitrogen atom and can there­fore form salts.

There is no defin­i­tion of esters and ethers in the Misuse of Drugs Act 1971, but from a chem­ical per­spective esters usually only applies to deriv­at­ives of acids with a hydroxyl group, and deriv­at­ives of alco­hols and phenols. Like­wise ethers usually only applies to deriv­at­ives of alco­hols and phenols. On this basis the cath­inone deriv­at­ives would not form esters or ethers.

However, keto com­pounds, R1R2C=O, can form ketals, R1R2C(OR’)2, which argu­ably might be described as a special form of an ether. Ketals of cath­inone deriv­at­ives have been dis­cussed on drug forums in the context of a pro-​​drug and are men­tioned in the sci­entific lit­er­ature, usually as a means of pro­tecting the keto group during chem­ical syntheses.

Generic definition for the control of cathinone derivatives

The ACMD have con­sidered a number of options for the control of cath­inone deriv­at­ives, including listing of named sub­stances, several generic defin­i­tions and com­bin­a­tions of these approaches.

Taking into account the ACMD’s con­sid­er­a­tion of the scope, together with struc­ture activity rela­tion­ships and pre­val­ence of known cath­inone deriv­at­ives, the fol­lowing generic defin­i­tion is recommended:

Any com­pound (not being bupro­pion or a sub­stance for the time being spe­cified in para­graph 2.2) struc­tur­ally derived from 2-​​amino-​​1-​​phenyl-​​1-​​propanone by modi­fic­a­tion in any of the fol­lowing ways, that is to say,

  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.

Notes

  • the parent com­pound is cathinone
  • “any” is taken to mean one or more

Com­ments

This is a defin­i­tion that includes all per­muta­tions for the three sub­sti­tu­tion areas, i.e. in the ring (R4), in the side chain (R1) and on the nitrogen (NR2R3).

  • All the cath­inone deriv­at­ives would be in the same Class which would result in some anom­alies for com­pounds already controlled.
  • Includes all the com­pounds in Appendix 1.
  • Includes primary amines without ring sub­stitu­ents (no known examples, except cath­inone which is not included within the scope of this definition).
  • Includes ring sub­sti­tuted primary amines (bk-​​MDA is the only example).
  • The term “cyclic struc­ture” has a very wide scope (e.g. all ring sizes, all het­ero­cyclic nitrogen com­pounds and struc­tures with ring substituents).

Appendix 1

Cath­inone
(Class C)
beta-​​keto-​​amphetamine

Note: only encountered in Khat although it has been encountered as the pro-​​drug, a-​​phthalimidopropiophenone (see below)

R1 = Me
R2 = H
R3 = H
R4 = H
Cathinone
a-​​phthalimidopropiophenone

Note: found in products from the Internet

R1 = Me
NR2R3 = phthalimide
R4 = H
a-phthalimidopropiophenone
Meth­cath­inone
(Class B)
Ephed­rone
a-​​methylaminopropiophenone
R1 = Me
R2 = Me
R3 = H
R4 = H
Methcathinone
N,N-Dimethylcathinone
Metam­fe­pra­mone
Dimethylpropion

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = Me
R4 = H
N,N-Dimethylcathinone
Eth­cath­inone
Ethyl­pro­pion
N-​​ethylcathinone
2-​​ethylamino-​​propiophenone
Sub Coca II

Note: encountered in seizures

R1 = Me
R2 = Et
R3 = H
R4 = H
Ethcathinone
Diethyl­pro­pion
(Class C)
Diethyl­cath­inone
Amfepramone
R1 = Me
R2 = Et
R3 = Et
R4 = H
Diethylpropion
a-​​Pyrrolidinopropiophenone
a-​​PPP

Note: encountered in Germany

R1 = Me
NR2R3 = Pyrrolid­inyl
R4 = H
a-Pyrrolidinopropiophenone
Buphed­rone
2-​​methylamino-​​1-​​phenylbutan-​​1-​​one

Note: no seizures reported to EMCDDA but is avail­able via the Internet and user reports are on drug forums.

R1 = Et
R2 = Me
R3 = H
R4 = H
Buphedrone
a-​​Pyrrolidinobutiophenone
a-​​PBP

Note: no seizure or user reports but listed on Wiki­pedia and in a patent

R1 = Et
NR2R3 = Pyrrolid­inyl
R4 = H
a-Pyrrolidinobutiophenone
a-​​Pyrrolidinovalerophenone
a-​​PVP
a-​​Pyrrolidinopentiophenone

Note: No seizures reported to EMCDDA, but meta­bolism study by Germany, as a result of 2 seizures, in Germany and Netherlands.

R1 = n-​​Pr
NR2R3 = Pyrrolid­inyl
R4 = H
a-Pyrrolidinovalerophenone
Mephed­rone
4-​​Methylmethcathinone
4-​​MMC
Sub Coca I

Note: most fre­quently encountered cath­inone derivative

R1 = Me
R2 = Me
R3 = H
R4 = 4-​​Me
Mephedrone
4’-methyl-a-pyrrolidinopropiophenone
MPPP

Note: seizure report from Germany

R1 = Me
NR2R3 = Pyrrolid­inyl
R4 = 4-​​Me
4’-methyl-a-pyrrolidinopropiophenone
4’-methyl-a-pyrrolidinobutiophenone
MPBP

Note: seizure report from Germany

R1 = Et
NR2R3 = Pyrrolid­inyl
R4 = 4-​​Me
4’-methyl-a-pyrrolidinobutiophenone
Pyro­va­lerone
(Class C)
R1 = n-​​Pr
NR2R3 = Pyrrolid­inyl
R4 = Me
Pyrovalerone
4’-methyl-a-pyrrolidinohexiophenone
MPHP

Note: seizure report from Germany

R1 = n-​​Bu
NR2R3 = Pyrrolid­inyl
R4 = Me
4’-methyl-a-pyrrolidinohexiophenone
Methed­rone
4-​​methoxymethcathinone
PMMC
bk-​​PMMA

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = H
R4 = 4-​​MeO
Methedrone
4’-Methoxy-a-pyrrolidinopropiophenone
MOPPP

Note: seizure report from Germany

R1 = Me
NR2R3 = Pyrrolid­inyl
R4 = 4-​​MeO
Bupro­pion
(Zyban – medi­cinal product in UK)

Note: To be excluded from control. No reports of abuse)

R1 = Me
R2 = t-​​Bu
R3 = H
R4 = 3-​​Cl
Bupropion
Flephed­rone
4-​​Fluoromethcathinone
4FMC

Note: encountered in seizures. The 3-​​fluoro and 2-​​fluoro isomers have also been found in products from the Internet.

R1 = Me
R2 = Me
R3 = H
R4 = 4-​​F
(also 2-​​F and 3-​​F)
Flephedrone
Methylone
3,4-Methylenedioxymethcathinone
bk-​​MDMA

Note: encountered in seizures

R1 = Me
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Methylone
Ethylone
3,4-methylenedioxyethcathinine
bk-​​MDEA

Note: encountered in seizures

R1 = Me
R2 = Et
R3 = H
R4 = 3,4-methylenedioxy
Ethylone
3’,4’-methylenedioxy-a-pyrrolidinopropiophenone
MDPPP

Note: seizure reports from Germany and Denmark

R1 = Me
NR2R3 = Pyrrolid­inyl
R4 = 3,4-methylenedioxy
3’,4’-methylenedioxy-a-pyrrolidinopropiophenone
Butylone
ß-keto-N-methyl-3,4-benzodioxyolylbutanamine
bk-​​MDBD

Note: seizure reports from 7 countries

R1 = Et
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Butylone
3’,4’-Methylenedioxy-a-pyrrolidinobutiophenone

Note: no seizure reports, but men­tioned in Wiki­pedia and in patent

R1 = Et
NR2R3 = Pyrrolid­inyl
R4 = 3,4-methylenedioxy
3’,4’-Methylenedioxy-a-pyrrolidinobutiophenone
Pentylone
ß-​​Keto-​​methylbenzodioxolylpentanamine
bk-​​Methyl-​​K
bk-​​MBDP

Note: no seizure reports, but men­tioned in Wiki­pedia and in patent.

R1 = n-​​Pr
R2 = Me
R3 = H
R4 = 3,4-methylenedioxy
Pentylone
Methyl­e­ne­di­oxypyro­va­lerone
MDPV

Note: encountered in seizures

R1 = n-​​Pr
NR2R3 = Pyrrolid­inyl
R4 = 3,4-methylenedioxy
Methylenedioxypyrovalerone

Annex B & C

…Aren’t really worth including here. They contain a list of ACMD members and a list of organ­isa­tions and indi­viduals who sub­mitted evid­ence included in the report. Go and read it in the ori­ginal pdf if you want to. Go on! Go and bloody read it!

Annex D. Letter From The Advisory Council On The Misuse Of Drugs To The Home Secretary

22nd December 2009

Dear Home Secretary,

Re: ACMD con­sid­er­a­tion of mephed­rone (and related cathinones)

The ACMD wrote to you in March to explain that it would be pleased to accede to the Government’s pri­or­ities that your pre­de­cessor set out in her letter of 13 March 2009. Con­cerning the issue of ‘legal highs’ the ACMD has provided advice on the syn­thetic can­nabinoid receptor agon­ists (Spice), 1-​​benzylpiperazine, GBL and 1,4-BD all of which we note will be con­trolled in the legis­la­tion on the 23rd December. In the ACMD’s letter of 30 September 2009 it was explained that we would next provide you with advice on the cathinones.

Despite the dif­fi­culties of the last 2 months the ACMD is com­mitted to providing you with advice on the cath­inones. Although atten­tion has focused on mephed­rone, five other syn­thetic psy­cho­active cath­inone deriv­at­ives are also widely avail­able. The ACMD explained in a pre­vious letter to you that it has con­cerns about the apparent pre­val­ence and poten­tial harms of these com­pounds. Much has been made of these com­pounds in the media over recent weeks; we find it of concern that this may have had the con­sequence of bringing such drugs to the atten­tion of a wider demo­graphic sooner than may have been the case.

The ACMD under­stand that mephed­rone, amongst other cath­inones, is being mar­keted as a variety of appar­ently ‘benign’ products e.g. bath salts or plant food. Whilst the poten­tial harms of these drugs are not yet fully known, it is apparent that the selling of such unreg­u­lated pre­par­a­tions in a form that they are clearly unin­tended for could have serious public health implications.

The ACMD is mindful that, after recent events, our stat­utory mem­ber­ship require­ments need to be ful­filled before providing formal advice, according to the require­ments of the Misuse of Drugs Act 1971. However, the ACMD would like to assure you that it will seek to provide you with such advice at the earliest pos­sible oppor­tunity on this important issue.

I would be willing to discuss the issue of the cath­inones and, more broadly, new psy­cho­active sub­stances (‘legal highs’) and the timing of advice with you.

Yours sin­cerely,

Pro­fessor Les Iversen
(on behalf of the ACMD)

***

The ori­ginal (bor­ingly formatted) report can be found here: ACMD-cathinones-report.pdf

2 Responses to The ACMD’s Mephedrone Report Part II

  1. Sharon says:

    you twa are some­thing special. My key­boared is very stiicky, ent any comment further.

    I

  2. Steve Chapman says:

    Inform­ative, beau­ti­fully illus­trated and a joy to read. Having read the ori­ginal report, this is an inspiring example of vastly improved, elegant inform­a­tion design. Well done.

    May I link to this page from my site?

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