Under the previous system, if the British Government wanted to ban a drug, they had to consult their gaggle of scientists, doctors and other assorted experts collectively known as the ACMD, ignore their views, sack them for objecting to being ignored, appoint a new panel and then do what they were always going to do by banning the drug anyway. This circumvented cumbersome bureaucracy, and also allowed ministers to transcend any remaining ties to objective reality by applying such bans to chemicals the existence, let alone the effects, of which had not yet been proven.

Methoxetamine, purportedly synthesised by the intentionally mysterious underground chemist ‘M’, has emerged in the past two years as a “bladder-friendly” alternative to ketamine, but is more widely known for raising the stupid-drug-name bar which everyone thought had peaked with “meow meow”, being dubbed “mexxy” and “roflcoptr”. Needless to say, the putative toxicology information presented to promote the drug is highly questionable, as should be obvious

More recently methoxetamine has got the British tabloid press frothing after its alleged involvement in the death of two people. Needless to say the postmortem revealed both had methoxetamine and alcohol in their blood at the time of death. At the time of writing, no move has been made to ban alcohol.

Methoxetamine is the first substance to be banned under what’s called a ‘temporary class drug order’, a new measure enshrined in legislation in November 201. Making a substance subject to an order effectively bans it for 12 months, offering the government the welcome opportunity to ban the banned drug all over again in a years’ time.

This isn’t how they put it. In their words the introduction of an order is to allow time for the ACMD to perform tests and decide whether it should be permanently controlled. During this time the manufacture, supply and consumption of such a substance subject to an order, the effects and impact of which are necessarily unknown, is punishable by prison sentences up to 14 years and an unlimited fine, the current penalty imposed for supplying class B drugs such as amphetamines.

But perhaps after said testing period the ban might be lifted? Current Home Secretary Theresa May recently announced in somewhat less than neutral terms, an upcoming review of legislation concerning ketamine, stating that the review was prompted by “heightened public concern about the popularity and potential harms of ketamine” and considering the last major report into the legal status of a controlled substance resulted in cannabis being re-upgraded to a class B drug against the advise of the ACMD, it is looking unlikely that a radical rethink of drug-policy is taking place by our elected leaders in Westminster Palace.

This time the ACMD implicitly admit that methoxetamine appears to be more dangerous than ketamine and with the review of ketamine looking likely to result in an upgrading, the carefully charged words spoken at the start of the ban set the tone for when in 12 months time, methoxetamine is permanently controlled.
Since ketamine was made a class C drug in 2006, its use has risen dramatically indicating that the ban has made no impact on use and has actively driven people onto what the ACMD believe is an even more harmful drug, methoxetamine. As such, the decision not to let methoxetamine remain legal will, at best, have no impact on trends of use and at worst drive users to increasingly unsafe substances.

This seems as good a time as ever to remind you that prior to his election, David Cameron actively spoke out against the absurdity of the war on drugs. I await his intervention on this matter imminently.

[This article was written for Synchronium.net by slicedmind, who runs an esoteric music blog here and, well, lets just say, owes me big time.]

Post from: Synchronium

Mexxxxxxxxxxxxxxy

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Photography II

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These past several months have seen me busier than ever with mountain after mountain of business-related crap to climb; each bite-size chunk of finance-related bullshit being as boring to write about as it is to chew through, so I’ll spare any further details.

As I’ve mentioned before, Coffeesh0p is about to relaunch after being completely overhauled. This also means a tonne of new products and a tonne of new pictures to be taken for the site. Turns out it would cost far more to get someone else to take these photos than the cost of a new camera, so  in the interest of fiscal responsibility, I’m now “into photography”.

There’ll be lots of great product photos on the new site when it launches, but in the mean time, here’s some of my favourite photos taken in a personal capacity (click each for a larger version):

The University of Birmingham

Pylon & substation

Green & purple laser

Lake at night

Amanita muscaria

Hyde Park, London

Birmingham Christmas Market

If you think they’re not shit, there are loads more here: http://www.flickr.com/photos/synchronium/page1/

As always, your opinions welcome in the comments below.

Post from: Synchronium

Photography

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(Until 3 PM tomorrow (Monday afternoon), we’re giving away 1g samples with all orders over £30)

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Squidgy Black

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Here’s the first part of the report, formatted and presented in lovely HTML (Annex 2 will be posted up soon.):

Consideration of Desoxypipradrol (2-DPMP) and related pipradrol compounds

Letter To The Home Secretary From The ACMD

1. Background

In October 2010 the ACMD recommended to the Government that, 2– diphenylmethyl-piperidine (2-DPMP, here referred to as desoxypipradrol), which was being marketed at that time as “Ivory Wave”, should be subject to an immediate ban under the Open General Import Licence (OGIL). This advice was accepted by the Government and a ban was implemented on 4 November 2011

Published data on the effects of 2-DPMP are limited, although research on derivatives of desoxypipradrol show that they exhibit a cocaine-like binding profile (Schmitt et al., 2008).

Currently, there is no known medicinal use for this compound, although it was originally developed by Ciba-Geigy (Novartis) in 1953 to be used to wake patients following anaesthesia (Belucci, 1955).

This compound is related to pipradrol, a previously-licensed medicine for treatment of Attention Deficit Hyperactivity Disorder (ADHD), obesity and narcolepsy. Pipradrol is classified under the Misuse of Drugs Act as a Class C substance. Pipradrol still used is some countries, but its use is limited due to its abuse potential; it is a dopamine and norepinephrine reuptake inhibitor.

Pipradrol and its desoxy form have structurally related pyrrolidine analogues (see below) such as diphenylprolinol (diphenyl-2-pyrrolidinylmethanol, D2PM), for which there have been a number of recorded cases of cardiovascular and neuropsychiatric toxicity associated with recreational use (Lidder et al., 2008, Wood et al., 2008, Wood et al., 2011), and 2-diphenylmethyl-pyrrolidine, currently marketed, along with D2PM and various analogues, as chemical reagents for use as chiral catalysts in organic synthesis (Bertelsen et al., 2005, Sigma-Aldrich, 2007).

The two pairs of materials differ only by the size of the nitrogen-containing ring. Diphenylprolinol and its desoxy form have a five-membered (pyrrolidine) ring, while pipradrol and its desoxy form have a six-membered (piperidine) ring. It seems that the two desoxy forms have particularly long-lasting effects as their structures are resistant to metabolism, meaning that they have longer half-lives in the body. A common feature of these compounds is that they are structurally related to ß-phenylmethylamphetamine, which is also a potent stimulant with a long half life. However, these compounds differ from ß-phenylmethylamphetamine in that the nitrogen atom is linked to the a– methyl group by two or three carbon atoms to form a ring.

Various analogues of these compounds have been investigated and found to have stimulant properties (Isbell, 1970 and US Patents). Simple modifications, for example, addition of halogen, alkyl or alkoxy groups on one or both of the phenyl rings or addition of alkyl, alkenyl, haloalkyl and hydroxyalkyl groups on the nitrogen atom have been reported to produce compounds having a stimulant effect on the CNS, which could lead to a range of “designer” forms.

Other modifications that have been reported in the literature include replacing the piperidine ring with an azepane ring (7-membered ring), a morpholine ring or a pyridine ring (Winthrop, 1961; Enyedy, 2003). The piperidine ring has also been modified by substitution in the ring with an hydroxy group (Nodine, 1960), fusion of the piperidine ring with a benzene ring (Winthrop, 1961) and by substitution at the nitrogen atom with an ethano bridge to form a bicyclic ring system (Wikipedia, 2011).

Almost all of the analogues investigated are structurally related to the 2-isomer of desoxypipradrol, with 2 carbon atoms between the phenyl rings and the nitrogen atom. The only exceptions being the N–haloalkyl derivatives of desoxypipradrol and the pyridine analogue in which the 2-, 3– and 4– isomers were all reported to be active. No examples were found of compounds related to 1-diphenylmethylpiperidine (N–diphenylmethyl– piperidine).

Whilst, it should be possible to distinguish between pipradrol isomers using techniques such as NMR, in the long term it would be support forensic analysis to have reference standards of all the pipradrol positional isomers. The ACMD recommends that the Home Office considers commissioning the production of standards through the Forensic Early Warning System.

2. Use and prevalence

The National Poisons Information Service in Edinburgh highlighted that a number of individuals had presented to the Royal Edinburgh Infirmary in the summer of 2010 following their use of desoxypipradrol with symptoms that were similar to amphetamine toxicity, but with predominant neuropsychiatric features including:

• Hallucinations
• Paranoia
• Severe Agitation

In some patients the symptoms were still being manifested 5–7 days after ingestion and some patients presented directly to psychiatric services, bypassing A&E. There were approximately 12 cases over this period. It was subsequently reported that 4 out of 5 of the Edinburgh cases in whom confirmatory toxicological screening was carried out were positive for desoxypipradrol in urine/blood confirming exposure.

The number of patients presenting after confirmed ingestion of desoxypipradrol after the summer of 2010 has dramatically reduced in Edinburgh with no cases in 2011 and data from the National Poisons Information Service (NPIS) suggests that there has also been a significant reduction nationally. However, as noted below cases of diphenylprolinol (D2PM) toxicity continue to occur.

So far 3 deaths have been linked to the use of desoxypipradrolb(awaiting final reports).

Data provided by the Home Office Centre for Applied Science and Technology (CAST) under its Forensic Early Warning System (FEWS) reported one sample of 2-DPMP (from a head-shop), 10 samples of D2PM and 4 samples of desoxy-D2PM (from test purchases) during the pilot study.

LGC Forensics reported those samples of “Ivory Wave” it had seen in 2009–2011 contained different active ingredients including the cathinone MDPV (methylenedioxypyrovalerone) then, after this became controlled, naphyrone, and when this too was controlled, desoxypipradrol. More recently, diphenylprolinol has begun to appear in “legal high” products.

Desoxypipradrol has been found as a white powder that is generally taken by nasal insufflation (sniffing the powder into the nose) or swallowing after wrapping the powder in a cigarette paper (“bombing”) to avoid any unpleasant taste.

It is considered that 2-DPMP and its related compounds, as captured under the generic definition (see recommendation), have potential social harms. It appears to the ACMD that such harms are likely in relation to the impairment of function through drug use (mood disorders, changes to lifestyle), loss of relationships and the potential harm to others (directly and indirectly).

3. Preclinical Data

In the 1950’s, Ciba-Geigy investigated the effects of desoxypipradrol, amphetamine and d-methylamphetamine on small animals (report kindly provided by Novartis). The LD₅₀ is the dose, which kills 50% of the animals:

Table 1. Toxicity of desoxypipradrol and other compounds, measured as LD₅₀, to small animals.

(*iv – intravenous, sc – subcutaneous, po – orally)Table 1 shows that desoxypipradrol is, in many cases, more toxic than amphetamine and d-methylamphetamine.

The Ciba-Geigy report (from the 1950s) also noted that desoxypipradrol:

produced a marked central arousal in various, non-anaesthetised animals, consisting initially of general agitation, subsequently a greater degree of increase in co-ordinated motility, heightened reflexes, compelled movements and relatively slight respiratory stimulation.

This was easily discernible objectively in the normal mouse with the aid of the cage movement registration method. With this method the individual movements are registered directly and added up by means of a totaliser.

Figure 1. Effectiveness of desoxypipradrol in stimulating activity in mice when when administered subcutaneously (heavy line) or orally (thin line)
(Figure reproduced with kind permission of Novartis)

The data show that desoxypipradrol is effective as a stimulant in doses comparable to those for amphetamine or methylamphetamine – from 1 mg/kg upwards. For the purposes of its research at the time, Novartis recommended an initial human dose of 1mg or less, (ca 0.014 mg/kg). Anecdotal information would suggest that the human dose is only a few mg, with 10mg or more being considered harmful.

Experimental data supplied by Dr Colin Davidson (St Georges, University of London, 2011) demonstrated that desoxypipradrol potently stimulated dopamine release from rat brain slices in vitro. Dopamine release was measured from the region of the nucleus accumbens, using carbon fibre microelectrodes and fast cyclic voltammetry to electrically measure the oxidations of dopamine. The rate of recovery of stimulated dopamine release also allowed measurement of the action of the drug as an inhibitor of the dopamine reuptake mechanism. Dopamine release in the nucleus accumbens is considered to be a key target for psychostimulant drugs.

Figure 2. Effect of desoxypipradrol (10uM) on dopamine efflux in rat nucleus accumbens

It also proved possible to compare the potency of desoxypipradrol with the psychostimulant drug cocaine in the brain slice preparation. The results (Figure 3) indicate that desoxypipradrol is both more effective and more potent than cocaine in stimulating dopamine release and in inhibiting its reuptake.

Figure 3. Comparison of potencies of desoxypipradrol and cocaine in releasing dopamine, and inhibiting inactivation in rat brain slice preparations (C. Davidson, unpublished)

The results both from Novartis and from Dr Davidson indicate that desoxypipradrol is very potent and comparable to amphetamine or methylamphetamine in its potential to cause acute toxicity.

The available human data also show it to be a long-lasting substance, capable of eliciting agitation lasting for several days after a single dose.

In addition to the reports of toxicity associated with the use of desoxypipradrol noted above, there have also been reports of significant toxicity associated with the recreational use of the related compound diphenylprolinol (D2PM). In addition, reports from forensic providers suggest that D2PM has replaced desoxypipradrol in many “Ivory Wave” products. The clinical toxicology service at Guy’s and St Thomas’ Hospital in London have documented 6 cases of analytically confirmed D2PM toxicity: 1 case in 2008 and 5 cases in 2010 / 2011 (Lidder et al., 2008, Wood et al., 2008, Wood et al., 2011). In these cases patients have presented with a variety of symptoms including:

• chest pain
• agitation
• anxiety
• insomnia
• hallucinations
• paranoia

In many of these cases patients have had ongoing features, in particular neuro-psychiatric features such as anxiety, insomnia and paranoia for up to 48–96 hours after use of D2PM.

4. Recommendation

The ACMD advises that the harms of desoxypipradrol are commensurate with other Class B drugs and recommend that it is controlled under the Misuse of Drugs Act 1971 as a Class B substance and in Schedule 1 of the Misuse of Drugs Regulations 2001 (as amended). Furthermore, we recommend that the structurally related compounds diphenylprolinol (diphenyl-2-pyrrolidinyl-methanol, D2PM) and its desoxy form 2-diphenylmethylpyrrolidine are similarly controlled under the Misuse of Drugs Act 1971 and scheduled under the Misuse of Drugs Regulations 2001 by virtue of a generic definition (see Annex 1 of the report) to ensure that desoxypipradrol and related compounds, e.g. diphenylprolinol, diphenylmethylpyrrolidine, are fully captured (see Annex 1 & 2).

The ACMD understands that desoxypipradrol and its related compounds do not have any medicinal uses; however, the ACMD has not formally consulted with the industry.

The proposed generic definition includes desoxypipradrol and those analogues most likely to be produced as alternatives. Some of the compounds that fall within the scope of the proposed generic definition contain a hydroxy group, which can be converted to an ester or ether. Such compounds may have similar pharmacological properties to the parent compound and therefore it is recommended that esters and ethers of these compounds are also subject to control under the Misuse of Drugs Act, 1971.

Whilst, ideally, any generic definition would include all possible positional isomers, this may mean that non-active compounds would also be controlled. Further, a definition to cover all of these potential analogues is feasible, but it would be very complex and possibly difficult to understand.

Under the definition that the ACMD propose at Annex 1 esters and ethers of pipradrol would not be controlled. This is because pipradrol is specifically excluded from the generic definition and therefore paragraph 2A would also not apply to pipradrol. For consistency the ACMD advise the inclusion of esters and ethers of pipradrol by moving pipradrol from Schedule 2 Part III paragraph 1(a) to paragraph 1(b) so that paragraph 1(d) regarding esters or ethers would apply to pipradrol.

The ACMD further advise that stereoisomers should be controlled by Schedule 2 Part II paragraph 2. The three main drugs, desoxypipradrol, diphenylprolinol (D2PM) and
2-diphenylmethylpyrrolidine all have stereoisomers and most of the compounds covered by the generic definition will also have stereoisomers.

5. References

1. Bellucci G. (1955); (2-Diphenylmethyl-piperidine hydrochloride and the methyl ester of 2-chloro-2-phenyl-2-(2-piperidyl)-acetic acid), drugs with waking effect in anaesthesia. Minerva Anestesiologica 21: 125–8.
2. Bertelsen S, Halland N, Bachmann S, Marigo M, Braunton A, Jørgensen KA. (2005); Organocatalytic asymmetric a-bromination of aldehydes and ketones. Chemical Communications 4821–4823.
3. Enyedy IJ, Sakamuri S, Zaman WA, Johnson KM, Wang S. (2003); Pharmacophore-based discovery of substituted pyridines as novel dopamine transporter inhibitors. Bioorganic & Medicinal Chemistry Letters;13:513–517.
4. Hoffmann K, Heer J. (1958); 2-Diphenylmethyl-piperidine compounds. US Patent 2,826,583.
5. Hoffmann K, Heer J. (1958); Piperidines and their manufacture. US Patent 2,849,453.
6. Hoffman K. (1962); 1-Ethyl-2-diphenylmethyl-piperidines. US Patent 3,048,594.
7. Hoffmann K, Heer J. (1960); Substituted 2-diphenylmethyl-piperidine compounds. US Patent 2,957,879.
8. Isbell H, Chrusciel TS. (1970); Dependence Liability of Non-Narcotic Drugs. Bulletin of the World Health Organisation; 43: Supplement, pages 76–77.
9. Lidder S, Dargan P, Sexton M, Button J, Ramsey J, Holt D, Wood D. (2008); Cardiovascular toxicity associated with recreational use of diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]). Journal of Medical Toxicology; 4(3):167–9.
10. Nodine JH, Bodi T, Slap J, Levy HA, Siegler PE. (1960); Preliminary trial of a new stimulant SCH 5472 in ambulatory patients with depression, exhaustion, or hypersomnia syndrome. Antibiotic Medicine and Clinical Therapy ; 7:771–6.
11. Novartis (1955) Information on Prep. No. 14?469 (desoxypipradrol), a new synthetic stimulant with central point of application.
12. Schmitt KC, Zhen J, Kharkar P, Mishra M, Chen N, Dutta AK, Reith ME. (2008); Interaction of cocaine-, benztropine-, and GBR12909-like compounds with wild-type and mutant human dopamine transporters: molecular features that differentially determine antagonist-binding properties; Journal of Neurochemistry 107: 928–40.
13. Sigma-Aldrich Co. (2007) “Organocatalysis”, Chemistry files, vol 7, No.
14. Wikipedia entry for AL-1095. <http://en.wikipedia.org/wiki/AL-1095>; 2011 [accessed 25.08.11].
15. Winthrop SO. (1960) a-(3-Morpholyl)-benzhydrol and its salts. US Patent 2,947,749.
16. Winthrop SO. (1961); 3-Benzhydrylmorpholine and salts thereof, and method of preparing said compounds. US Patent 2,993,895.
17. Winthrop SO, Humber LG. (1961); Central Stimulants. Cyclized Diphenylisopropylamines. Journal of Organic Chemistry 26: 2834–6.
18. Wood DM, Davies S, Puchnarewicz, Holt DW, Dargan PI. A case series of individuals with analytically confirmed acute diphenyl-2– pyrrolidinemethanol (D2PM) toxicity. Manuscript submitted for publication.
19. Wood DM, Puchnarewicz M, Holt DW, Ramsey J, Dargan PI. (2011); Detection of the precursor benzophenone in individuals who have used legal highs containing diphenyl-2-pyyrrolidinemethanol (D2PM). Basic & Clinical Pharmacology & Toxicology; 109 (Suppl. 1): 86.

Annex 1

Proposed generic definition

Any compound (not being pipradrol) structurally derived from piperidine, pyrrolidine, azepane, morpholine or pyridine by substitution on a ring carbon atom with a diphenylmethyl group, whether or not the compound is further modified in any of the following ways, that is to say,

1. by substitution in any of the phenyl rings to any extent with alkyl, alkoxy, haloalkyl or halide groups;
2. by substitution on the methyl carbon atom with an alkyl, hydroxyalkyl or hydroxy group;
3. by substitution on the ring nitrogen atom with an alkyl, alkenyl, haloalkyl or hydroxyalkyl group.

Post from: Synchronium

Ivory Wave Destined For Class B

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–> Coffeesh0p’s New Logo <–

Please leave any feedback in the comments below.

Post from: Synchronium

New Coffeesh0p Logo

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The problem is, I’m crap at designing stuff. I love the thought of designing, but I always end up combining every single style I think looks good into some big casserole of a layout. So to force myself to not do that, I need a bit of help from you.

If you could please leave a comment with two or three words to describe the blog, that would be awesome. As I have no  idea how other people perceive this site, I think finding out would be a useful first step, then I can work on designing something around a couple of those themes.

So, if you wouldn’t mind…

Post from: Synchronium

A Kick Up The Arse

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And this is the result:

I bet René Descartes is rolling in his grave.

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Weed Maths

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Or at least, how to light a cigar under some kind of awesome cocktail!

The wife & I have just got back from the Dominican Republic where we celebrated our first anniversary. Got tonnes more work to do though, but I’ll try and update this blog again soon!

Post from: Synchronium

How To Light A Cigar Underwater

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Watch it Immediately.

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The Best Clip Ever

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