Pharmacology Methylone is better than MDMA change my mind

[4DQSAR]

Certainly - one needs to be careful with AMT and particularly 7-methyl AMT. Upjohn's research revealed that the addition of that 7-methyl increases it's monoamine release and reuptake activity by an order of magnitude.

Did you know that in the late 1980s when MDMA was finally brought under legal control in the US, someone spotted that AET was still legal AND commercially available? The individual in question actually sold AET AS MDMA and by all accounts, nobody realized he had misrepresented the product. After his eventual arrest, he was able to fight his case in court and be found not guilty. Not deterred he went straight back out and carried on. Arrested again he was informed by the judge that IF he was ever caught selling AET again, he WOULD be convicted of several civil offences.

But the irony is that the makers had noted how unexpectedly popular AET was with a handful of customers (the guy using multiple names/bank accounts) and the put the price up x10!

I LOVE the fact that the guy had managed to find a loophole. I'm all for loopholes rather than breaking the law.

Now here is the thing. The CsA laws instituted in the US deal with SPECIFICALLY the indole nucleus and use Markush descriptions to make all derivatives of tryptamine automatically illegal. BUT that doesn't cover modifications to the indole. Now I certainly wouldn't want to test that in a court but the CsA laws also specifiy that an analogue mus possess 'similar or more potent' activity than a NAMED drug.

So here is my question. If you synthesize a compound that is chemically related to hallucinogens BUT is an entactogen, is it controlled by the CsA laws? Again, not one I would wish to test but I didn't write the laws and clearly whoever did.... wasn't expert in the field.

Remember when someone was selling the benzofuran analogue of 5-MeO DMT? I forget the name they used and reports weren't great but to the best of my knowledge, it was never actually controlled.

Most nations use caselaw so if someone is found not guilty, defence councils can cite the case as part of the defence. My guess is that is why VERY FEW people have ever gone to court if they were accused of breaking the UK's PSA laws. Sadly nobody repoerted on the cases but it's my impression that the CPS has decided to offer defendants extremely leanient sentencing to avoid it winding up in a court room. Because the moment one person is found not guilty, that opens the door to a defence.

I don't KNOW the above, it's just my impression. IF anyone knows more, I would love to hear about it.

 

[4DQSAR]

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You can see how (S)-AMT is a substructure of LSD but as we know, only one of the four enantiomers of LSD is psychoactive. So my simple logic was to test if AMT likewise was optially active. It IS. That done a simple referral to both the Roussel-UCLAF and Upjohn patents.

People have asked why (R)-7-methyl AMT hasn't turned up as an RC, especially given it's relatively high potency and similarity to MDA and MDMA. The answer is simply that the intermediate 7-methyl-1H-indole-3-carbaldehyde is difficult to make and once you resolve the product, you end up having to throw half if it away. IF someone were to offer 1-(7-methyl-1H-indol-3-yl)propan-2-one, a chiral reductive amination would make it facile.

BUT on reflection, it's SO potent that the racemate has a window where it's active as an entactogen BUT not psychedelic. Problem is, if someone takes a second dose and EVERYTHING changes ;-)

 

[someguyontheinternet]

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You can see how (S)-AMT is a substructure of LSD but as we know, only one of the four enantiomers of LSD is psychoactive. So my simple logic was to test if AMT likewise was optially active. It IS. That done a simple referral to both the Roussel-UCLAF and Upjohn patents.

People have asked why (R)-7-methyl AMT hasn't turned up as an RC, especially given it's relatively high potency and similarity to MDA and MDMA. The answer is simply that the intermediate 7-methyl-1H-indole-3-carbaldehyde is difficult to make and once you resolve the product, you end up having to throw half if it away. IF someone were to offer 1-(7-methyl-1H-indol-3-yl)propan-2-one, a chiral reductive amination would make it facile.

BUT on reflection, it's SO potent that the racemate has a window where it's active as an entactogen BUT not psychedelic. Problem is, if someone takes a second dose and EVERYTHING changes ;-)

LSD is a really interesting compound to me, it has that same pharmacophore as tryptamines but the structure is rigid and typically has far greater affinity than any tryptamine off the top of my head

I think the rigidity keeps it in a more optimal configuration for binding, and possibly imparts some metabolic resistance

 

[Shinji Ikari]

I liked methylone a lot in 2009/2010. I grabbed a 10g bag just before it was banned in the UK and haven't encountered it since. It's more forgiving than MDMA but I definitely had a good long bout of the sads at the end of that binge.

I don't know what the benefit over MDMA would for therapeutic use. I'm terms of effects it's just MDMA but less and I don't think MDMA is generally considered to be neurotoxic when taken on its own at normal doses. Methylone is only "safer" when you're abusing it (and it'll still pickle your brain when you smash it, can confirm) which is kind of moot in a therapeutic context.

I still like methylone though. Would love to see it make a comeback. I can't see that ever happening though. It's rise in popularity to begin with coincided with a global MDMA drought and with real MD readily available nerds like us are the only ones who would ever seek it out.

 

[4DQSAR]

What I found most interesting was overlaying LSD with the NBOMe compounds. That ortho methoxy benzyl moiety PERFECTLY overlays the diethylamine moiety of LSD. Even the lone-pairs of the oxygen align. The 2,5-dimethoxy overlays the N of the indole and encompasses the 5-MeO of the more potent tryptamines. The 4 (para) substitution of the PEAs/NBOMes perfectly overlays, you guessed it, the 7 position of the indole ring.

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It's really difficult to explain a 3D structure using a 2D image but I've drawn LSD and underneath it a compound that is half way between LSD and the NBOMe. What I can't do is show the benzene ring of the NBOMe rotated by 90 degrees as all you would see is an edge. But the two classes overlay and what is extremely useful is that it highlights the key moieties.

In essence the diethyl is merely space-filling with a hydrophobic group. As you know there are quite a few other amides that are also active and the key thing that all possess is an ability to fill the same pocket.

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I realize that the above is the BEST explaination of what 7-methyl AMT actually DOES. It perfectly overlays p-methyl amphetamine. As you noted, it's very important to carefully test to confirm the safety profile of 7,a-DMT (7, alpha dimethyl tryptamine) but in essence, it's a reasonably selective serotonin reuptake inhibitor. 7-methyl AET WAS tested by Upjohn but was shown to possess MAOI activity. I discussed this with David Nichols a few years ago and he mentioned that the reason the alkyl was made longer was to suppress 5HT2a affinity BUT he also noted that the longer alkyl chain was a core reason for the compound having significant MAOI activity.

I would be prepared to bet that even racemic 7,a-DMT will have a window between it's entactogen activity and it's psychedelic activity given that it's seratogenic activity is an order of magnitude larger than AMT but I underline the fact that unlike MDMA, increasing the dose would significantly alter the subjective effects.

It just seems crazy to me that a simply VAST number of different tryptamines have become RCs but the only indole substitution is the 5 methoxy...

 

[4DQSAR]

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I ABSOLUTLY promise this is my last word on the topic.

3-Methoxy-4-methylamphetamine - Wikipedia

en.wikipedia.org

More accurately, 7,a-DMT overlays the above compound. While the Wikipedia entry is for the raecmic compound, I am prepared to bet that one enantiomer is responsible for 5HT2a affinity, the other for seotonin modulation. Nichols produced the compound he abbreviates a MME. Page 304 states:

'Racemic MMA proved to be as potent as MDMA or (+ )-MBDB in drug discrimination assays in rats trained to discriminate MDMA or (+ )-MBDB, respectively. Surprisingly, both enantiomers of MMA had nearly identical potencies, similar to the racemate, in substitution tests in ( + )-MBDB-trained rats. Perhaps most exciting was the finding that MMA lacked serotonin neurotoxicity.'

https://bitnest.netfirms.com/external/DrugDes.Disc/9.299

Pihkal notes:

'Some years ago a report appeared in the forensic literature of Italy, of the seizure of a small semitransparent capsule containing 141 milligrams of a white powder that was stated to be a new hallucinogenic drug. This was shown to contain an analogue of DOM, 3-methoxy-4-methylamphetamine, or MMA. The Italian authorities made no mention of the net weight contained in each dosage unit, but it has been found that the active level of MMA in man is in the area of 40-60 milligrams. The compound can apparently be quite dysphoric, and long lived.'

Now my point here is that Shulgin does not claim to have tested MMA and rather than a 3-methoxy, 7,a-DT has pyrrole ring of the indole system that places a nitrogen over the spot where the 3-methoxy would sit. Now it's simply impossible to extrapolate the subjective effects of 7,a-DMT but as I have previously mentioned, it appered to be significantly more potent than MDMA so one presumes more potent than MMA. I believe the key to this is that the aromatic indole system keeps the bioisostere of the methoxy planer to the benzene ring in the same way that bromo butterfly keeps the system planer.

So has the PEA homologue ever been made? No would appear to be the answer. I thought I had heard of 'hemi fly' compounds but no.