Saturday, 23rd September 2017

Cathinones

Naphyrone (NRG-1)


Naphyrone, known by the trade name NRG-1, was classified as a Class B controlled drug with effect from 23rd July 2010[i].

 

It is a naphthyl analogue of Pyrovalerone that acts as a triple monoamine reuptake inhibitor[ii], producing psychostimulant effects[iii].  The substance enjoyed a brief period of popularity in 2010 following the scheduling of mephedrone, for which it was marketed as the ‘legal’ replacement.

 

The Advisory Council on the Misuse of Drugs (ACMD) considered the substance among other legal highs in July 2010[iv]., noting “it is important to distinguish between naphyrone (the subject of the ACMD’s advice) and NRG-1; a branded product which may contain naphyrone or any number of other cathinones, legal stimulants (caffeine) or other active and inactive constituents. The branded product NRG-1 cannot be presumed to be naphyrone.”

 

Chemistry & Composition

Brandt et al[v] analysed ‘second generation’ legal highs following the ban on mephedrone on 16-4-10, finding “Overall, the purchased products consisted of single cathinones or cathinone mixtures including mephedrone, butylone, 4-methyl-N-ethylcathinone, flephedrone (4-fluoromethcathinone) and MDPV (3,4-methylenedioxypyrovalerone), respectively. Benzocaine, caffeine, lidocaine, and procaine were also detected. The emphasis was placed on 'Energy 1' (NRG-1), a product advertised as a legal replacement for mephedrone-type derivatives usually claiming to contain naphyrone (naphthylpyrovalerone, O-2482). It was found that 70% of NRG-1 and NRG-2 products appeared to contain a mixture of cathinones banned in April 2010 and rebranded as 'new' legal highs, rather than legal chemicals such as naphyrone as claimed by the retailers. Only one out of 13 NRG-1 samples appeared to show analytical data consistent with naphyrone. These findings also suggest that both consumers and online sellers (unlike manufacturers and wholesalers) are, most likely unknowingly, confronted with the risk of criminalization and potential harm.”  Brandt et al[vi] later noted the presence of different stereoisomers of the drug.   A drug users forum published a batch analysis of NRG1 on 14-6-10[vii] finding a roughly even mixture of MDPV and suspected fluorinated cathinone (4-FMC, 3 FMC or 4-FMC, flephedrone)

 

The ACMD report warned “The majority of samples purported to contain naphyrone which have been analyzed to date contain other materials such as mephedrone, butylone and other related compounds. However, it is highly possible that the chemists who supply the legal high websites are ‘dumping’ their old stocks of cathinones (which are now controlled by the generic classification) under the trade name naphyrone (NRG-1). This is fraught with potential problems (see below), particularly if genuine naphyrone becomes more widely available as the dose required is ten-fold less than for mephedrone and this could lead to a significant risk of overdose.”

 

Dosages of Naphyrone

The ACMD considered the effects of Naphyrone likely to resemble those of cocaine, based on relative levels required for inhibition of enzymes breaking down dopamine, noradrenaline and serotonin[viii], but around 10 times as potent weight for weight as cocaine.  User-forum posts have recommended dosages as low as 1mg (more typically 20-30mg) and purchase of milligram-sensitive scales in order to weigh out dosages accurately, and have cautioned against use without accurate weighing of dosages due to the high potency and risk of overdose.  The ACMD noted “The potency of naphyrone is such that users only require a dose of approximately 25mg to have an effect. Since this dose is a very small amount it is unlikely that users will be able to, with any accuracy, measure out this amount.”

 

Effects of Naphyrone

There are no scientific papers reporting effects of naphyrone in humans or laboratory animals.  The drug-users forum only provided a single report[ix] of a male taking 200mg of the powder (miscalculated dose which was supposed to be 20mg) and reported “rapid heartrate and slight euphoria. Very thirsty” after one hour, “stomach cramps/discomfort” after 90 mins and “mood changed drastically and mindset was not normal… felt depressed and very unhappy about life. Just wanted to crawl in bed and sleep” after 2 ½ hours.  After 24 hours he reported “bad back pain, leg pain. Feels like body aches similar to… fever. Mindset returned to normal, though… not immediately interested in dosing again because of the horrible comedown experience”  There were 131x replies to a post for NRG1 experiences (most probably not referring to naphyrone), 56x providing data on dosages and effects, several posters remarking on the unpleasant taste of the drug.  Positive reported effects included alertness and talkativeness, buzz/rush/stimulation/increased energy, euphoria, increased focus/concentration, a space/trippy sensation, increased awareness (e.g. of music).  Negative effects most commonly reported were insomnia, increased heart rate, anxiety, paranoia, jittery/fidgetiness, breathing difficulties (tight chest), panic, bruxism, sweating/body temperature fluctuations, stomach cramps etc, comedown effects included lethargy, depression, headache and exhaustion.

 

The ACMD warned that compounds with naphthyl substituents are generally avoided in medicinal chemistry due to their potential risk as carcinogens, from metabolism to a highly reactive naphthalene epoxide[x] and carcinogenicity of related compounds in animal tests[xi][xii].

 

Forum users made each other aware of the risks of mixing naphyrone, a potent MAO inhibitor, with mephedrone or other stimulants “Bioassays have shown that if taken alone, NRG-1 produces a long-lived but somewhat subtle high… If other amphetamines/cathinones/etc are taken while the reuptake inhibition of this compound is still active, then potency is increased as is the level and duration of undesired residual stimulation… Translation: taking NRG-1 and then mephedrone? Don't expect to sleep for 36 hours.”

 

The IDMU 2010 survey found only 8x individuals who reported having used NRG1 or Naphyrone at some point (write-in options under other drugs or other herbs and plants), with an average rating of 2.88/10 (a very low rating where 5 is broadly neutral), however four respondents gave the worst possible rating (0/10) and two strong positives (8-9/10) including the user who reported ‘napherone’ sic.  This would suggest most of those who had used the drug had had strongly negative experiences with it.

 

Summary – Naphyrone & NRG1

The limited evidence available suggests Naphyrone to be effective as a stimulant in dosages much lower than commonly found with recreational users of street-level amphetamine, cocaine or mephedrone.

 

Products sold as NRG1 when tested in the period following the UK ban on Mephedrone rarely contained naphyrone as claimed on the packaging, several samples were found to contain a mixture of MDPV and fluorinated cathinones.  This misrepresentation first became known to the ‘research chemical’ using community with access to user-forums in mid-June 2010.

 

The effects of Naphyrone appear to be similar to those of classical stimulant drugs, user reports confirm the high potency (of some NRG1 samples) compared to mephedrone which it replaced, and the resultant risk of accidental overdose.  Anxiety/paranoia, insomnia and tachycardia were the most commonly reported symptoms, however breathing difficulties were reported by a number of users.  The drug polarises opinions with some users relishing the high potency and efficacy and others very concerned about the health risks and giving the drug a low rating.


[i] http://www.homeoffice.gov.uk/drugs/drug-law/naphyrone/

[ii] Meltzer PC, Butler D, Deschamps JR, Madras BK. [2006] 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem. 49(4):1420-32.

[iii] Advisory Council on the Misuse of Drugs [2010] Consideration of the naphthylpyrovalerone analogues and related compounds.  London: Home Office 7 July 2010 - http://www.homeoffice.gov.uk/publications/drugs/acmd1/naphyrone-report

[iv] Advisory Council on the Misuse of Drugs [2010] Consideration of the naphthylpyrovalerone analogues and related compounds.  London: Home Office 7 July 2010

[v] Brandt SD, Sumnall HR, Measham F, Cole J [2010] Analyses of second-generation 'legal highs' in the UK: initial findings. Drug Test Anal. 2(8):377-82

[vi] Brandt SD, Wootton RC, De Paoli G, Freeman S. [2010] The naphyrone story: The alpha or beta-naphthyl isomer? Drug Test Anal. 2(10):496-502.

[vii] http://www.drugs-forum.com/forum/showthread.php?t=132067

[viii] Rothman, R.B., Baumann, M. H. [2003] Monoamine transporters and psychostimulant drugs. European Journal of Pharmacology. 479: 23-40.

[ix] http://www.drugs-forum.com/forum/showthread.php?t=123121

[x] Clayson, D. B., Jull, J. W., Bonser, G. M. [1958] The test of ortho hydroxylamines and related compounds by bladder implantation and a discussion of their structural requirements for carcinogenicity. British Journal of Cancer. 12: 222-230.

[xi] Howe, R. [1965] Carcinogenicity of ‘Alderlin’ (pronethalol) in mice. Nature. 207: 495-496.

[xii] Stapleton M.P. [1997] Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology. Texas Heart Institute Journal. 24: 336–42