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 α-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 α-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-β-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 α-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, α-phthalimidopropiophenone (see below)	R1 = Me R2 = H R3 = H R4 = H
α-phthalimidopropiophenone Note: found in products from the Internet	R1 = Me NR2R3 = phthalimide R4 = H
Methcathinone (Class B) Ephedrone α-methylaminopropiophenone	R1 = Me R2 = Me R3 = H R4 = H
N,N-Dimethylcathinone Metamfepramone Dimethylpropion Note: encountered in seizures	R1 = Me R2 = Me R3 = Me R4 = H
Ethcathinone Ethylpropion N-ethylcathinone 2-ethylamino-propiophenone Sub Coca II Note: encountered in seizures	R1 = Me R2 = Et R3 = H R4 = H
Diethylpropion (Class C) Diethylcathinone Amfepramone	R1 = Me R2 = Et R3 = Et R4 = H
α-Pyrrolidinopropiophenone α-PPP Note: encountered in Germany	R1 = Me NR2R3 = Pyrrolidinyl R4 = H
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
α-Pyrrolidinobutiophenone α-PBP Note: no seizure or user reports but listed on Wikipedia and in a patent	R1 = Et NR2R3 = Pyrrolidinyl R4 = H
α-Pyrrolidinovalerophenone α-PVP α-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
Mephedrone 4-Methylmethcathinone 4-MMC Sub Coca I Note: most frequently encountered cathinone derivative	R1 = Me R2 = Me R3 = H R4 = 4-Me
4’-methyl-α-pyrrolidinopropiophenone MPPP Note: seizure report from Germany	R1 = Me NR2R3 = Pyrrolidinyl R4 = 4-Me
4’-methyl-α-pyrrolidinobutiophenone MPBP Note: seizure report from Germany	R1 = Et NR2R3 = Pyrrolidinyl R4 = 4-Me
Pyrovalerone (Class C)	R1 = n-Pr NR2R3 = Pyrrolidinyl R4 = Me
4’-methyl-α-pyrrolidinohexiophenone MPHP Note: seizure report from Germany	R1 = n-Bu NR2R3 = Pyrrolidinyl R4 = Me
Methedrone 4-methoxymethcathinone PMMC bk-PMMA Note: encountered in seizures	R1 = Me R2 = Me R3 = H R4 = 4-MeO
4’-Methoxy-α-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
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)
Methylone 3,4-Methylenedioxymethcathinone bk-MDMA Note: encountered in seizures	R1 = Me R2 = Me R3 = H R4 = 3,4-methylenedioxy
Ethylone 3,4-methylenedioxyethcathinine bk-MDEA Note: encountered in seizures	R1 = Me R2 = Et R3 = H R4 = 3,4-methylenedioxy
3’,4’-methylenedioxy-α-pyrrolidinopropiophenone MDPPP Note: seizure reports from Germany and Denmark	R1 = Me NR2R3 = Pyrrolidinyl R4 = 3,4-methylenedioxy
Butylone β-keto-N-methyl-3,4-benzodioxyolylbutanamine bk-MDBD Note: seizure reports from 7 countries	R1 = Et R2 = Me R3 = H R4 = 3,4-methylenedioxy
3’,4’-Methylenedioxy-α-pyrrolidinobutiophenone Note: no seizure reports, but mentioned in Wikipedia and in patent	R1 = Et NR2R3 = Pyrrolidinyl R4 = 3,4-methylenedioxy
Pentylone β-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
Methylenedioxypyrovalerone MDPV Note: encountered in seizures	R1 = n-Pr NR2R3 = Pyrrolidinyl R4 = 3,4-methylenedioxy

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

This was an essay I wrote last year about the ethics involved with curing the ageing process. A worthy topic of discussion, I hope you’ll agree. I thought it was alright, so here it is, sans references.

“O brave new world that hath such people in’t!”

One way to define ageing is an increased chance of dying as time progresses as a result of cumulative natural changes and degradation of the body. Therefore a cure for ageing wouldn’t simply be a cure for all of the most common diseases associated with old age, such as cancer, heart disease and so on, but rather a cure for the underlying cause of the body being more susceptible to those diseases. Even if we could cure cancer or heart disease, the disease itself may not kill you, but something else would, as the body would still have accumulated years of stress and damage making it increasingly more likely to fail. Instead, a cure for ageing itself would mean prevention (and even reversal) of the ageing process, ensuring a state of perpetual youth for those that partake.

As such, the incredibly complex ethical considerations for such a cure are echoed throughout a number of social and political issues, calling into question the rights of the current generation over future generations, the rights of the individual versus the rights of the society and the purpose of life itself.

Overpopulation

The primary concern that springs to the mind of most people when the topic of curing old age is discussed is overpopulation. Already, the population is growing exponentially, even when the majority of people are dying before they reach 100. If people are living for double that amount of time and reproduction continues at its current rate, surely we will run out of room sooner than if people were dying before 100? It follows then, that we would exhaust that same amount of habitable space even quicker should life expectancy be increased further, to say 500 or in the thousands, provided that the rate of childbirth remained the same.
This idea of cramped living conditions conjures up an image of Victorian style slums or today’s “High Density Living” solution to the same problem in Hong Kong, where the concept of your own space outside has almost disappeared. Not only does that sound uncomfortable with a diminished sense of privacy, but the more people there are in any given area, the more easily and more likely it is that infectious diseases will spread. So how can this problem be resolved? By drastically reducing the birth rate.

Controlling Birth Rate

It would appear that the only option besides killing a large proportion of the population every so often is to place a limit on the rate of child birth for society as a whole. On the surface, this suggests that the generation that decides not to have children so they can extend their own life are making an immoral selfish choice, but let us first take a look at how society handles this issue today.

In 2004, the average number of children per married couple in the UK is approximately 1.8. It is important to realise that this is not a physical limit imposed by the human body, but an amount which is convenient. With the use of birth control and abortions, we can decide when it would be appropriate for us to have a child and how many children we have overall. The point here is that by choosing when to have a child based on factors such as financial stability, we already are being selfish when it comes to reproduction. The world at present is rife with examples of people putting their career (and hence their own satisfaction and financial gain) ahead of their future children, which we do not tend to see a problem with. This hypocrisy extends even further when it comes to the stigma of underage pregnancy – if we as a society should selflessly put our potential offspring before ourselves, surely we should be reproducing as early as possible, no matter what the cost to ourselves? Apparently not. What may seem selfish to some may be perfectly acceptable to others. Unfortunately, it is never clear where the line should be drawn with most ethical dilemmas, and this is no exception.

Selfish or otherwise, there are other pressing matters relating to this kind of population control that must also be discussed. For example, who decides who should reproduce and when? Even China’s notorious “One Child Policy” is not enough to curb population growth. According the British Medical Journal in 2006, “China still has one million more births than deaths every five weeks”, so to prevent overpopulation, the average number of children per family would have to be reduced to far less than one to even keep the population growing at the same rate as China’s is now. Since it’s not possible for every family to give birth to a rather low percentage of one child, the responsibility of deciding who could reproduce and when would have to fall to someone, or some specified group of people, leaving the potential system open to all manner of imperfections. This could include bribery, blackmail, human error and any other form of corruption, which is particularly important with matters as fundamental as this. My lack of faith in humanity being able to think up and implement the perfect system for this situation is still not the most important concern, however.

Assuming that some method of control was necessary and in place, some people would simply not be permitted to reproduce for the interests of society. Not just limited to one child, but not at all. Currently, though, people who decide not to have children, or limit the number they have, retain their right to choose, no matter who may think it immoral; but if society decided the majority wanted to live forever, and the right to reproduce was something worth sacrificing, the choice would then belong to the society and not the individual. Many people see the point of life as having children, and could imagine life as worthless and hollow in hindsight should they not have had their children. The idea of potentially removing what point a lot of people saw in life from those people is one big step up from allowing people to choose when they have children themselves.

Equality & Prejudice

A further ethical topic in need of discussion is just how widespread this cure for ageing would be. The two factors that determine just how far we can expect this cure to reach are choice and availability. The former addresses the question of whether or not the choice would be left up to the individual or decided by the majority.

If it is a majority that decide the fate of quite possibly all of human kind, this decision and all of its implications as outlined here could have a profoundly negative impact upon that minority, however small in number they may be. That minority that would have normally refused treatment if the decision was up to the individual could still be forced not to reproduce by the government for example, as mentioned previously. If the majority voted against it, there would no doubt be ways that particularly rich and powerful people could still acquire the treatment.

If the decision was left up to the individual, some people opting for extended life and others not, it is easy to see how society as we know it may be torn in two in a fashion not too dissimilar to Aldous Huxley’s Brave New World: a completely state-controlled “utopia” on one side, and the “savages” on the other, who opt out of the apparent benefits that such advances may bring. It is not too far fetched to imagine health care for the elderly refused with treatment being the only option, or perhaps a lack of work or housing. We already fear prejudice and ill treatment as a result of genomic sequencing, something that can be kept a secret, but whether or not you’ve taken a cure for ageing could not be hidden. There is an incentive for companies to hire employees who have taken the treatment over people who have not – no pension plans, a reduction of staff turnover, a continued increase in skills without the need to retrain new people. One person doing one job for 150 years will likely be a lot better at that job than someone who has done it for only 50 years, so why wouldn’t companies discriminate against those that opt?

The second factor, availability, needs to be thought about at an international level. Already, the availability of drugs in industrialised nations far exceeds that of developing countries, with over a third of the world’s population having no access to essential drugs. There is no reason to suggest availability of a cure for ageing would be any different, driving the wedge between the rich and poor even further. A possible result could be war for land or resources between both sides of this divide once the need for population control and limited space become a factor for those with the cure.

Dying Peacefully

One topic we’ve not touched on so far is death. If we remove the natural cap that the aging process forces upon us, then there won’t necessarily be a maximum age we can live to. However, death from anything not related to age would still occur. Currently, we think of death as an inevitable natural process although the causes of death can be many and varied. When asked to think about death and how they would like to die, the majority of people hope for a peaceful death during their sleep, at the end of a long and fulfilling life, and without pain. As we’ve already discussed, how fulfilled your life may be could already be compromised by denying you the right to bear children, so what about the rest of our ideal scenario? A long life? Yes. But pain-free in your sleep? That’s another story.

After dying of old age, the only causes of death that remain involve accidents, murder and other diseases that can affect anyone, not just the elderly. Discounting instantaneous (but still gruesome) death, any other situation in which a life is about to be ended will undoubtedly be accompanied by fear and pain. This is not to suggest that fear and pain are not part of dying of old age, but any hopes of peacefully dying in your sleep would be shattered. As people get older, the thought of death becomes more and more a factor in their life as something they have to come to terms with, but this will no longer be the case. Death will only be associated with terror and pain; with lying in hospitals fed through a tube; certainly without peace.

Legalising and actively supporting euthanasia, on the other hand, would be the only acceptable solution to this problem. Only then would the problem of the perception of death being necessarily negative be alleviated, but this raises yet more ethical problems, particularly among religious communities.

Conclusion

A cure for old age may bring with it the promise of an undefined limit to humanity’s lifespan, allowing us to do more than we ever thought possible; read more books, watch more films, and finally build that shed you’ve been talking about, among other things. On the surface, this seems idyllic, but only when you begin to scratch the surface do you reveal a swamp of ethical concerns that muddies this picturesque vision of the future. Living forever may require our lives to change so significantly that life might not be worth living in the first place.

It would seem that having our cake and eating it is simply not feasible. Would you really want to live forever if you could never eat cake again?

***

I’d love to hear your comments and opinions.