What is wrong with the MDMA available today? - v2

[vash445]

https://pubs.acs.org/doi/pdf/10.1021/acsomega.1c05520?ref=article_openPDF

Yep, anhydrous raecemic MDMA hydrochloride does indeed form three identified polymorphs.

Also at least four hydrates.

Form III spontaneously converts to form I, Form II will convert to Form I under competitive equilibration conditions. In aqueous conditions, hydration occurs. As they point out, the well known Form I is the most stable.

It does seem to suggest all are readily soluble in water. Or, rather, all revert to Form I and then undergo hydration.

So I'm uncertain if this makes a blind bit of difference in the case of MDMA hydrochloride.

But it IS a viable way of obtaining a patent. I stand by that reading; that it's to get patent protection rather than having any real world advantage(s). Might be physically smaller, if that IS an advantage?

Different addition salts certainly DID alter the pharmokinetics of a related compound, but inherently changing the addition salt means the crystalline structure(s) will be different anyway. Maybe that's one reason why MDMA.HBr turned up on occassion? It's impossible to know why in most cases, but we just happened to get complaints so actually had to look into it.

If nothing else, the paper does demonstrate two less soluble impurities, 2-chloro and 2-bromo MDMA. Even a tiny amount of an impurity has the porential to wreck havok on crystalization.

I can only GUESS that 'moonrock' MDMA MAY be in an one of the less stable forms if seeding used a crystal of Form II or Form III, but in the presence of impurities? I don't know. Smaller WOULD be an advantage if it is to be smuggled.

I am aware of two cases where it mattered. The Ritonavir production-line suddenly began producing a much less soluble second form and manufacture was abandoned. The other was Rotigotine patches in which spontaneous polymorphic transition resulted in a less soluble form so a less active medicine. I don't say other examples simply don't exist, but those were the two that ended up in the news.

But I can follow the thinking...

Also my opinion on this is

Fast melt slow recrystallization does a few things smuggling space, if one pot or telescopic synthesis is done, it will be a good way to force a lot but not all impurities, Impurities also tend to be missed under basic spectre, speed of productionetc etc etc.

The real issue though is fast melt in an API setting is by in large not traditionally done.

Next when it came to ritonavir the most interesting thing is polymorph#3/ #4 madevia melt

Nobody knew about polymorph #3/4 until 2023/2024/ 2025/2026

Because fast melt can create more unknown polymorphs. And because maps to my knowledge has not fast melt recrystallization it does by in large add up

Two new polymorphs of piroxicam (Forms VI and VII) were discovered by melt crystallization and crystal structure prediction (CSP).

Surprisingly, even though melt crystallization has a long history, it has been employed less often in the search for new polymorphs than solution crystallization. Applications of melt crystallization to 21 highly polymorphic, well-characterized compounds with at least five ambient polymorphs revealed that melt crystallization afforded more than half of the known polymorphs and in many cases revealed new polymorphs not detected by other screening methods. A statistical analysis revealed that polymorphs grown from the melt have a greater propensity for high Z′ values, which are not easily accessible by other crystallization protocols and are often not detectable by crystal structure prediction methods. Melt crystallization within nanopores (8–100 nm) performed for 19 of the 21 compounds mostly resulted in polymorphs that dominated crystallization from the bulk melt at similar temperatures. The total number of polymorphs observed in nanopores was less than that observed during crystallization from the bulk melt, however, and melt crystallization under confinement revealed new polymorphs not detected by other crystallization methods.

Nonetheless, 24 years after the appearance of Form II of Ritonavir, scientists at AbbVie Inc. serendipitously discovered a new polymorph while studying the crystal nucleation of amorphous Ritonavir, and obtained the new Form III via melt crystallization. [9]

26-27 years 2 years after #3 form IV was found

The hydrogen-bonding network in Form IV differs from other forms, often characterized by alcohol-amide interactions. form 4 contains a trans carbamate configuration, like unstable forms 1 and 3, and unlike stable form 2. The hydrogen bonding network of form 4 is shown in Fig. 2. Consistent with the conformational similarity with forms 1 and 3, it has the amides forming a continuous hydrogen-bonded chain. However, there are also some notable differences. In form 1, the alcohol forms an additional intermolecular hydrogen bond with the nitrogen atom of the thiazole. In contrast, in form 4, the hydrogen bond is formed with one of the amide oxygen atoms. Meanwhile, form 3 displays a mix of the two: two of the four molecules in the asymmetric unit create the alcohol-amide hydrogen bond seen in form 4, while the other two form the alcohol-thiazole bond found in form 1. From this analysis, it appears that the more complete hydrogen bonding pattern contained in form 2, which is responsible for its stability, can only be obtained compromising the conformational energy and introducing the unstable cis carbamate configuration1

So, how many solid forms are still unknown?

Anyone who has tried to crystallise a stubborn compound will know that the mysterious business of coaxing molecules out of solution and into a regular solid array is very much a dark art. Not everything can be crystallised, and the structure you get if you do produce diffractable crystals is almost as much of a mystery. It’s still very hard to predict how organic molecules will pack in three dimensions, as James Mitchell Crow’s feature on crystal structure prediction explains.


Ritonavir form 4 could not be solved by the “gold standard” of single-crystal XRD, but a combination of 3D-ED with computational methods and experimental XRPD data produced an accurate solution and showed it is significantly less stable than forms 1 and 249. Being able to solve crystal structures for which single-crystal XRD is not an option is important from a risk assessment perspective. Often, high throughput experimentation finds new crystalline forms that are just seen as peaks on XRPD patterns, without the possibility of isolating them, solving their structures, and verifying their relative stabilities. This can cause significant concerns in drug development. Ritonavir form 4 ended up being unstable, but there are cases in which solving a crystal structure from a small sample size and therefore determining its relative thermodynamic stability is fundamental to quantify and assess risks. In this scenario, leveraging less traditional methods like 3D-ED or a combination of CSP and experimental data51–53 is the only option. This ability to characterize crystal structures from a small sample size can also have intellectual property implications54.

Finally, the work reveals the importance of determining structural disorder in crystal structures and quantifying its effects on the stability of polymorphs for a complete risk assessment on the polymorphic landscape of drug candidates. Disorder has a modest but not irrelevant stabilizing effect on ritonavir form 1 and particularly on form 4, and likely on form 3 too (where the effect was not computed), relative to ordered form 2. Crystalline disorder and its stabilizing effect are getting increasingly recognized in the solid-state community, and this study shows that this interest is well deserved.

 

[vash445]

https://pubs.acs.org/doi/pdf/10.1021/acsomega.1c05520?ref=article_openPDF

Yep, anhydrous raecemic MDMA hydrochloride does indeed form three identified polymorphs.

Also at least four hydrates.

Form III spontaneously converts to form I, Form II will convert to Form I under competitive equilibration conditions. In aqueous conditions, hydration occurs. As they point out, the well known Form I is the most stable.

It does seem to suggest all are readily soluble in water. Or, rather, all revert to Form I and then undergo hydration.

So I'm uncertain if this makes a blind bit of difference in the case of MDMA hydrochloride.

But it IS a viable way of obtaining a patent. I stand by that reading; that it's to get patent protection rather than having any real world advantage(s). Might be physically smaller, if that IS an advantage?

Different addition salts certainly DID alter the pharmokinetics of a related compound, but inherently changing the addition salt means the crystalline structure(s) will be different anyway. Maybe that's one reason why MDMA.HBr turned up on occassion? It's impossible to know why in most cases, but we just happened to get complaints so actually had to look into it.

If nothing else, the paper does demonstrate two less soluble impurities, 2-chloro and 2-bromo MDMA. Even a tiny amount of an impurity has the porential to wreck havok on crystalization.

I can only GUESS that 'moonrock' MDMA MAY be in an one of the less stable forms if seeding used a crystal of Form II or Form III, but in the presence of impurities? I don't know. Smaller WOULD be an advantage if it is to be smuggled.

I am aware of two cases where it mattered. The Ritonavir production-line suddenly began producing a much less soluble second form and manufacture was abandoned. The other was Rotigotine patches in which spontaneous polymorphic transition resulted in a less soluble form so a less active medicine. I don't say other examples simply don't exist, but those were the two that ended up in the news.

But I can follow the thinking...

But I can follow the thinking...

Perfect

Now then my guess is we actually have a polymorph #4 or something

Not that MDMMA or similar is possible

My meh came from safrole small batch after I handed off NMR confirmative safrole

But when it comes to super lab giant rocks that all test 99% by in large bulk of the market it's what I'm talking about....people who get under an oz might not encounter this product

Those that get 250g-200kg will definitely see this product.

Ritonavir can avoid form 4 and specifically make form 2 via ball mill during production. This would be a super lab path. Or continuous flow in partial segments.

The smaller DIY method I propose, post production is recrystallization with dH20. I'm pretty sure everyone will still encounter meh, but this product from what I can tell is not form 1,2,3. It doesn't really form back to 1 or 3 or whatever

But what it does is allow the bonds to be BROKEN, and when recrystallization is done under proper solvents, it will form back into its metastable form 1 by in large. I say this because I'm having issues crashing out this product and I believe the only stuff that by in large was crashing out was, the dH20 product.

I haven't proved it yet, but everything I posted here seems to line up with that. Comments 1-3 pages prior.

I and 1-2 others here on the page, hope to continue to refine and work on OTC methods and yields to confirm as such.

We hope that kykelon should be able to at least some extent will be able to detect these polymorphs with NMR using TOSY, COSY, etc etc even if these are not around. Solid-state NMR (ssNMR), particularly CP-MAS, is a powerful, non-destructive technique for polymorph testing. It distinguishes crystalline forms by detecting unique chemical shifts caused by differing molecular conformations and packing in the crystal lattice. ssNMR is exceptionally useful for detecting amorphous content and identifying polymorphs in finished drug formulations where excipients may interfere with other methods.

High-resolution Solid-State NMR (SSNMR) uses Magic-Angle Spinning (MAS) and Cross-Polarization (CP) to produce sharp, distinct spectra for different polymorphic forms.Unlike PXRD, which requires long-range order, NMR is sensitive to the local environment, making it ideal for characterizing crystalline-amorphous mixtures.

IDK analytics isn't my strong suit, hell I don't even think O-chem is either. But that's neither here nor there. I just know the "basics" depending who you ask XD

 

[Mohd Adeeb]

A lot of people feel that way, but it’s not always that something is “wrong” with MDMA itself. One big issue is consistency. What’s being sold isn’t always pure MDMA sometimes it’s mixed with other substances, or it could be something else entirely. That’s why experiences can vary so much from person to person. There’s also the factor of tolerance and expectations. People who’ve used it before might not get the same effects over time, which can make it feel like the quality has gone down. Overall, it’s less about MDMA being different today and more about unpredictable quality and individual factors.

 

[4DQSAR]

A lot of people feel that way, but it’s not always that something is “wrong” with MDMA itself. One big issue is consistency. What’s being sold isn’t always pure MDMA sometimes it’s mixed with other substances, or it could be something else entirely. That’s why experiences can vary so much from person to person. There’s also the factor of tolerance and expectations. People who’ve used it before might not get the same effects over time, which can make it feel like the quality has gone down. Overall, it’s less about MDMA being different today and more about unpredictable quality and individual factors.

Well, if you read the link in my previous post, you will note that impurities were now not so much artifacts of the synthesis but because QC is now 'good enough' rather than 'pure. The paper mentions two specific impurities but there are many. But if an impurity adds mass, simplifies production AND is accepted, that really IS 'good enough' for the market.

I would be surprised if APB homologues weren't being mixed in and of course they come with their own set of impurities.

But it's also the case that those who paid £20 for a Dove in 1988 forget that the drug was just part of the scene. But it's true that as quality dropped, K and C both began to replace MDMA. Mephedrone sort of helped for a few years but again, you cannot recreate a time and place. Not fourty years later.

 

[Kaden_Nite]

 

[vash445]

Well, if you read the link in my previous post, you will note that impurities were now not so much artifacts of the synthesis but because QC is now 'good enough' rather than 'pure. The paper mentions two specific impurities but there are many. But if an impurity adds mass, simplifies production AND is accepted, that really IS 'good enough' for the market.

I would be surprised if APB homologues weren't being mixed in and of course they come with their own set of impurities.

But it's also the case that those who paid £20 for a Dove in 1988 forget that the drug was just part of the scene. But it's true that as quality dropped, K and C both began to replace MDMA. Mephedrone sort of helped for a few years but again, you cannot recreate a time and place. Not fourty years later.

I doubt apb is being used

Labs came back as 50% purity

 

[vash445]

A lot of people feel that way, but it’s not always that something is “wrong” with MDMA itself. One big issue is consistency. .What’s being sold isn’t always pure MDMA sometimes it’s mixed with other substances, or it could be something else entirely That’s why experiences can vary so much from person to person. There’s also the factor of tolerance and expectations. People who’ve used it before might not get the same effects over time, which can make it feel like the quality has gone down. Overall, it’s less about MDMA being different today and more about unpredictable quality and individual factors.

What’s being sold isn’t always pure MDMA sometimes it’s mixed with other substances, or it could be something else entirely

Remember everything is being presented has been tested as MDMA. While some area might have added shit, or there was a time period of BZP. It still doesn't change the facts

That it's pretty easy to tell the difference between both a cathone, BZP, amph/meth or MDMA

And that if intentionally added chemicals, were present, labs should detect something

Considering how it's not uncommon for me to send it to 2-3 labs and

FTIR. RAMAN, paper spray mass spec, and GC/MS or similar is used. Something we be detected at one of the labs.considering I've had Xanax powder test with H20 peak at like 1% via paper spray mass spec... That's saying something

The smoking gun though is when people do have a magic batch and the hold heads from the 80-90s know. They know. Oh they know.

What we have is not people who have encountered isn't what's being sold isn’t always pure MDMA sometimes it’s mixed with other substances, or it could be something else entirely

While some impurities may play a role or ROLL XD

Giant ass rocks or giant shards of meth, just weren't a thing back then.

At most it was usually the size of sugar crystals

And typically the sparkling white snow.

While I don't doubt we have encountered fake stuff, I know I my self have encountered BZP that was restamped to avoid the neg pillreports.com lab test.

When you get involved with the rave scene, as old of some of us are.

And are willing to offer lab tested MDMA that's meh at $15g as a special in bulk

But $100g for "magic" and people that know know will go for the magic. And they say it's the best they had since the 90s even beating the "1 vendor that follows maps route"

It's still not 100% maps route, at least cGMP status. It's close... It's SOME OF THE BEST

But it is more like second place to both MAPS

And at least, what I have successfully recrystallized in small ammounts from meh.

The people that want the best, or close to it. Will be willing to pay $2800oz $100g on price breaks, they know what I got XD

 

[4DQSAR]

Put simply, other compounds are being misrepresented as MDMA?

Even my previous reference notes that ther method still produced a little 2-chloro MDMA and a little 2-bromo MDMA. Would the typical 'cook' remove what might be less than 1% of either in the product?

Impure compounds do not form neat, clean crystals, certainly any metastable polymorphs would spontaneously undergo translation to the lowest energy state, Form I.

Now, maybe it's possible for some even more obscure hydrates to exist, or for two or more anhydrous polymorphs to intercalate, but how on earth would you reliably prepare them? When an experienced researcher admits that the 'composition is uncertain', is that a limit of instumentation or because the hydrates intercalate?

Now ask if their is even a slight enantiomeric excess, the whole game changes again...

Shulgin identified:

MDMA.HCl anhydrous (Form I)
MDMA.HCl hemishemihydrate (0.25)
MDMA.HCl hemihydrate (0.5)
MDMA.HCl trishemihydrate (0.75)
MDMA.HCl monohydrate (1.0)

https://scispace.com/pdf/the-background-and-chemistry-of-mdma-4dwkznt8aw.pdf

Sci-Hub: are you are robot?

From a purely pragmatic position, people seeking to obtain a patent certainly DO go to the trouble AND if the anhydrous forms are significantly denser so less mass and bulk to smuggle, that might also be 'worth the squeeze'. But how many people fall into those two catagories?

Interesting, but not likely something most people need to know. What's that old enginering saying?

 

[vash445]

Put simply, other compounds are being misrepresented as MDMA?

Even my previous reference notes that ther method still produced a little 2-chloro MDMA and a little 2-bromo MDMA. Would the typical 'cook' remove what might be less than 1% of either in the product?

Impure compounds do not form neat, clean crystals, certainly any metastable polymorphs would spontaneously undergo translation to the lowest energy state, Form I.

Now, maybe it's possible for some even more obscure hydrates to exist, or for two or more anhydrous polymorphs to intercalate, but how on earth would you reliably prepare them? When an experienced researcher admits that the 'composition is uncertain', is that a limit of instumentation or because the hydrates intercalate?

Now ask if their is even a slight enantiomeric excess, the whole game changes again...

Shulgin identified:

MDMA.HCl anhydrous (Form I)
MDMA.HCl hemishemihydrate (0.25)
MDMA.HCl hemihydrate (0.5)
MDMA.HCl trishemihydrate (0.75)
MDMA.HCl monohydrate (1.0)

https://scispace.com/pdf/the-background-and-chemistry-of-mdma-4dwkznt8aw.pdf

Sci-Hub: are you are robot?

From a purely pragmatic position, people seeking to obtain a patent certainly DO go to the trouble AND if the anhydrous forms are significantly denser so less mass and bulk to smuggle, that might also be 'worth the squeeze'. But how many people fall into those two catagories?

Interesting, but not likely something most people need to know. What's that old enginering saying?

It's definitely enough to get tested in lab on lab seizures.

 

[vash445]

Put simply, other compounds are being misrepresented as MDMA?

Even my previous reference notes that ther method still produced a little 2-chloro MDMA and a little 2-bromo MDMA. Would the typical 'cook' remove what might be less than 1% of either in the product?

Impure compounds do not form neat, clean crystals, certainly any metastable polymorphs would spontaneously undergo translation to the lowest energy state, Form I.

Now, maybe it's possible for some even more obscure hydrates to exist, or for two or more anhydrous polymorphs to intercalate, but how on earth would you reliably prepare them? When an experienced researcher admits that the 'composition is uncertain', is that a limit of instumentation or because the hydrates intercalate?

Now ask if their is even a slight enantiomeric excess, the whole game changes again...

Shulgin identified:

MDMA.HCl anhydrous (Form I)
MDMA.HCl hemishemihydrate (0.25)
MDMA.HCl hemihydrate (0.5)
MDMA.HCl trishemihydrate (0.75)
MDMA.HCl monohydrate (1.0)

https://scispace.com/pdf/the-background-and-chemistry-of-mdma-4dwkznt8aw.pdf

Sci-Hub: are you are robot?

From a purely pragmatic position, people seeking to obtain a patent certainly DO go to the trouble AND if the anhydrous forms are significantly denser so less mass and bulk to smuggle, that might also be 'worth the squeeze'. But how many people fall into those two catagories?

Interesting, but not likely something most people need to know. What's that old enginering saying?

The new Form III was discovered by melt crystallization. This is the same method used by the University of Wisconsin group, headed by Lian Yu to discover new ROY polymorphs. Based on these observations it is clear melt crystallization should be included as a method for polymorph screening if the drug is stable enough to melt

 

[vash445]

"It’s some of the best me and a few friends have ever tried. And I was a raver in Dallas, Texas in the 90s."

I'll be willing to pay similar to the $20 doves if you needed to mark it up again

 

[vash445]

"I still have a beautiful looking clear crystal of the batch you were trying to recrystallize before you had this stuff. I only kept it because it’s one of the clearest MD crystals I’ve ever seen. I wasn’t particularly fond of the way that that stuff made me feel, but it looks amazing"

This was the dH20 batch

 

[vash445]

Put simply, other compounds are being misrepresented as MDMA?

Even my previous reference notes that ther method still produced a little 2-chloro MDMA and a little 2-bromo MDMA. Would the typical 'cook' remove what might be less than 1% of either in the product?

Impure compounds do not form neat, clean crystals, certainly any metastable polymorphs would spontaneously undergo translation to the lowest energy state, Form I.

Now, maybe it's possible for some even more obscure hydrates to exist, or for two or more anhydrous polymorphs to intercalate, but how on earth would you reliably prepare them? When an experienced researcher admits that the 'composition is uncertain', is that a limit of instumentation or because the hydrates intercalate?

Now ask if their is even a slight enantiomeric excess, the whole game changes again...

Shulgin identified:

MDMA.HCl anhydrous (Form I)
MDMA.HCl hemishemihydrate (0.25)
MDMA.HCl hemihydrate (0.5)
MDMA.HCl trishemihydrate (0.75)
MDMA.HCl monohydrate (1.0)

https://scispace.com/pdf/the-background-and-chemistry-of-mdma-4dwkznt8aw.pdf

Sci-Hub: are you are robot?

From a purely pragmatic position, people seeking to obtain a patent certainly DO go to the trouble AND if the anhydrous forms are significantly denser so less mass and bulk to smuggle, that might also be 'worth the squeeze'. But how many people fall into those two catagories?

Interesting, but not likely something most people need to know. What's that old enginering saying?

. A compound containing a three-membered aziridine ring system (23) was an uncommon impurity that has previously been reported by Palhol et al. [21]. Another compound containing an oxazolidine ring system (24) was an unusual find, but had also been previously reported as an impurity during MDMA synthesis [22]. The presence of the impurity N-cyclohexylacetamide (11) indicates that cyclohexylamine was used as the base during the nitroaldol addition reaction. ...
... The chlorinated impurities of the MDMA precursors can be considered valuable fingerprint molecules for this particular synthetic methodology. The compound 2-chloro-4,5-methylenedioxymethamphetamine (6-Cl-MDMA) (14) has previously been identified in two forensic analytical studies, one within an illicit batch of ecstasy pills seized within Scotland and the other within a drug user's urine sample in the Czech Republic [23,24]. In both cases it was hypothesised that the chlorinated analogue was a deliberately included adulterant and not an impurity generated during synthesis, however given our results this assumption may have been incorrect

 

[Allylbenzene]

No, I'm sorry, I have to call this out.

Tell me about it!

The notion somehow that "natural" is better than "man-made" is bullshit. First, it assumes that somehow mankind is unnatural. As if we aren't a natural part of this planet who evolved here.

A fundamental question is whether those designing a drug sufficiently understand the body and it's arguably unfathomable complexity. In that context most synthetic drugs are improperly designed (besides perhaps aspirin - and that's semi-synthetic anyway). Medicine is great no doubt but corporate medicine has many dysfunctional & hazardous nuances which necessitate acknowledgment.

There are some deadly poisonous fungi out there for example...
...
Lipitor and Zocor to control cholesterol levels and reduce risks of heart disease.

Ironically the 2 original statins are mycotoxins (monacolin & compactin aka lovastatin & mevastatin respectively). All subsequent statins share the same MOA. They're very effective at promoting heart issues and diabetes amongst other more serious issues. The malformed "cholesterol theory" is a shinning example of modern medicines ineptitude (more-so that of academia, specifically the corporate-led research element).

Prilosec and Nexium, proton pump inhibitors that give ppl relief from gastroesophageal reflux disease (GERD) and peptic ulcers.

PPIs are responsible for ample medical negligence, as are most prescription drugs. Doctors are legally obliged to use approved medications so it is what it is. PPIs interfere with proton-pumps in important places beyond the intended target area, besides their other issues.

These synthetic medicines play crucial roles in various medical treatments

Considering the problematic aspects of most (semi)synthetic medications, I'd interpret their application as normalised medical negligence justified "on sand". It's unwise to base decisions on foundations made of sand.

Eg - doctors simply follow the established guidelines and continue to prescribe statins. This despite the myriad papers popping up about the complete inadequacy of the "cholesterol theory". I was part of 2 support groups for those harmed by statins, some after a few months and others decades. Interestingly after speaking with many patients it was clear that many doctors & nurses seem well-aware that statins are often poorly tolerated and cause innumerable adverse effects.

...and have significantly improved healthcare outcomes.

The book "Death by Medicine" and others like it outline the unfortunate state of modern medicine and it's consistent ability to harm patients. Doctors are "just following orders" and the risk/benefit ratio is positive of course.

 

[unodelacosa]

A fundamental question is whether those designing a drug sufficiently understand the body and it's arguably unfathomable complexity.

I agree that biology is incredibly complex and no drug is perfectly designed in a complete sense. Unexpected effects do happen. But it's undeniable that modern medicines save more lives than not. Turning a corporate profit is not only the incentive that drives the discovery of new medicines, but, for any publicly traded company like Pfizer, Eli Lilly, Merck, Gilead, Johnson & Johnson, &c., the company has an ethical responsibility to shareholders to increase equity. This might seem distasteful, and I agree it has flaws, but when it comes to the development of ground-breaking new medicines, I have yet to see a better system that preserves an effective form of incentive for those involved in funding and execution.

In that context most synthetic drugs are improperly designed

Drug design isn't perfect, but medications are rigorously tested with increasing refinements. Many drugs are highly optimized through decades of research.

(besides perhaps aspirin - and that's semi-synthetic anyway).

"Synthetic" does not imply poor design, and "synthetic-v-natural" is not a meaningful safety distinction. "Semi-synthetic" is also a useless descriptor in this. Heroin, MDMA, and LSD are all semi-synthetic in that Heroin comes from poppy, MDMA from sassafras, and LSD from the ergot fungus that grows on rye. All Schedule I in the U.S. and the equivalent legality in other countries. Meanwhile, there are many deadly toxic, all-natural plants, like: Deadly Nightshade (A. belladonna), Water Hemlock, Oleander, Foxglove… plus Death Caps and Destroying Angel mushrooms, among others. Hell, smoking uncured tobacco can cause a fatal nicotine overdose…

Medicine is great no doubt but corporate medicine has many dysfunctional & hazardous nuances which necessitate acknowledgment.

I agree. There are definitely structural issues, like industry influence and overprescribing, that deserve scrutiny. This is also why we need impartial, apolitical oversight.

statins are mycotoxins … very effective at promoting heart issues and diabetes amongst other more serious issues.

While there is a slight uptick seen in diabetes onset, that correlation does not imply causation. Claiming statins promote heart issues is backwards. Statins are among the most well studied drugs in medicine and consistently show reduced risk of heart attack, stroke, and cardiovascular death.

The malformed "cholesterol theory" is a shinning example of modern medicines ineptitude (more-so that of academia, specifically the corporate-led research element).

The link between LDL and atherosclerosis isn't just a "theory". It's supported by multiple independent lines of evidence. Because HMG-CoA reductase determines cholesterol synthesis rate, its inhibition by statins decreases plasma LDL cholesterol and reduces atherosclerotic risk. Beyond lowering lipids, statins exhibit pleiotropic effects such as improved endothelial function and anti-inflammatory activity. Dysregulation or genetic variation in HMGCR influences susceptibility to metabolic and cardiovascular disorders, but let's not throw the proverbial baby out with the bath water. The link between LDL cholesterol and atherosclerosis is one of the most robust findings in medicine, supported by genetics, epidemiology, randomized trials and mechanistic biology. The underlying process is atherosclerosis: plaque build-up in the arteries.

PPIs are responsible for ample medical negligence, as are most prescription drugs.

This is not evidence-based, and I'm not sure where you're getting this notion of "most prescription drugs" being medically negligent. Medicines are approved based on risk–benefit analysis. Many save or extend lives dramatically (e.g., antibiotics, antihypertensives, insulin). PPIs do act on proton pumps beyond the stomach but clinical harm from this is limited and context-dependent with most associations being weak and observational, not causal.

Doctors are legally obliged to use approved medications so it is what it is.

You say that like it's a bad thing and like something cannot be both profitable and ethical to sell. I too bristle and am nauseated by the thought of the Pharmaceutical-Industrial Complex® preying on sick people with medical needs. But for instance, in the U.S. medications cost a lot more than they do elsewhere, and this is to offset the cost of pharmaceutical research & development. Other nations get bulk discounts on meds, but the upshot of U.S. meds is that the U.S. has more access to newly emerging medicines, which might not mean much to some people, but to someone dying of a disease that so far has resisted other forms of treatment, trying a new experimental medicine might be well worth the risk when one's time is short and their life is on the line.

Considering the problematic aspects of most (semi)synthetic medications,

This is an incorrect assumption, and "most" sounds to me like random conjecture.

I'd interpret their application as normalised medical negligence justified "on sand". It's unwise to base decisions on foundations made of sand.

Now there's some actual irony. It sounds like your view and opinion are being largely informed by subjective personal anecdote and some misleading information. Please don't take any of this personally, btw. I'm not criticizing you, just pointing out some flaws in this argument. Overall, I'm impressed with your grasp of the subject and knowledge, I just disagree with some of the conclusions you've made or sometimes jumped to, as it were.

Eg - doctors simply follow the established guidelines and continue to prescribe statins. This despite the myriad papers popping up about the complete inadequacy of the "cholesterol theory". I was part of 2 support groups for those harmed by statins, some after a few months and others decades.

Again: this is anecdotal evidence. Support groups naturally select for negative experiences, and they don't reflect population-level risk.

Interestingly after speaking with many patients it was clear that many doctors & nurses seem well-aware that statins are often poorly tolerated and cause innumerable adverse effects.

This is imprecise language: "many patients" (how many?), "it was clear" (to untrained non-professionals in the medical field?), "often poorly tolerated" (how often? is it a majority share of patients, or does it simply seem like that when you highlight a few specific cases?), "innumerable adverse effects" (how, and why, would that be "innumerable"? Sounds more like dramatic writing, no offense, but let's be careful not to get caught up in confirmation biases). Btw, I'm not like: "Yay, Big Pharma! Let's go Corporate America! Hooray for soulless crapital profits that exploit poor health among the peons!" Anywhere the profit motive crops up is worthy of scrutiny to protect against exploitation among other things.

The book "Death by Medicine" and others like it

Which others? More books by Gary Null? This seems like a potentially problematic last name entry for a database, doesn't it?

outline the unfortunate state of modern medicine and it's consistent ability to harm patients.

That book is 15 years old and is also driven by the profit motive. It's been widely criticized for misusing statistics, combining unrelated data, and inflating evidence of medical harm.

Doctors are "just following orders" and the risk/benefit ratio is positive of course.

I think you mean that the "risk/benefit ratio" is ≥1, meaning the risk outweighs the reward. If the benefit were greater, we'd get a proper fraction <1. Also, it's reductionist to claim that "doctors are just following orders", but this does sound very much like a Gary Null thing to say. What it ignores are other forces at play here, such as fear of malpractice suits, pressure from malpractice insurance providers, ethics, the Hippocratic Oath, autodidactic patients, and other considerations.

Anecdotal reports (like support groups) can highlight real issues but they don't reflect how common those outcomes are across millions of patients. I think the more accurate takeaway is that medications should be used thoughtfully and individually; not that most of modern medicine is fundamentally unsound and/or that doctors all mindlessly follow the orders of Big Pharma corporate overlords.

Regardless, I'm sorry you've been so negatively affected by statins and PPIs. This is why I think pharmacogenomics is the next big field that will dovetail genetics, technology, biology, medicine, pharmacology and commerce. I think companies in this field could be good opportunities for speculative investment … and thus the crapitalism machine churns on, right? Lol. You can't please everyone I suppose…

To tie it all in, I think there's a parallel between this and those who claim that something is wrong with MDMA despite having no concrete data, just anecdotes, subjective biases and random hypotheses built upon, to borrow your proverb, "foundations of sand."

 

[Allylbenzene]

But it's undeniable that modern medicines save more lives than not.

It saves many but also manages to do the opposite quite spectacularly, including reducing quality of life (see: medical negligence). Unfortunately medical negligence is often never recognised in the first place.

Turning a corporate profit is not only the incentive that drives the discovery of new medicines, but...the company has an ethical responsibility to shareholders to increase equity. This might seem distasteful, and I agree it has flaws, but when it comes to the development of ground-breaking new medicines, I have yet to see a better system

Making a profit is quite common for most ventures. Is it the only system you've experienced? It's the most pronounced one in most countries so for many people it's all they know. Many have come to enamour it which is understandable.

In that context most synthetic drugs are improperly designed
Drug design isn't perfect...

In hindsight I should've clarified re "improperly designed" - I meant based on an incomplete understanding of the body. As an analogy: a programmer must first learn how the OS works before writing kernel software otherwise the program might cause a crash or brick the hardware.

...but medications are rigorously tested with increasing refinements. Many drugs are highly optimized through decades of research.

Perhaps - but if the design rationale is misguided and/or the underlying mechanism inappropriate for the condition, then rigorously testing this medication is besides the point.

"Synthetic" does not imply poor design, and "synthetic-v-natural" is not a meaningful safety distinction.

I don't consider "natural" to be better than "synthetic". Shulgin made some excellent drugs, so has the botanical kingdom.

(besides perhaps aspirin - and that's semi-synthetic anyway).
"Semi-synthetic" is also a useless descriptor in this.

I described aspirin as "semi-synthetic" in the sense that salicylic acid is of botanical origin but acetyl-salicylic acid isn't (afaik).

Statins are among the most well studied drugs in medicine and consistently show reduced risk of heart attack, stroke, and cardiovascular death.

I'd award statins the prize of "drug with most manicured statistics" but I suspect SSRIs rival this. Besides, I made this thread which is dedicated to promoting awareness & harm reduction for statin users.

I'm not sure where you're getting this notion of "most prescription drugs" being medically negligent.

I was implying that "most" prescription drugs enable doctors to enact medical negligence. It's not necessarily their fault as they don't know any better. I'm referring to their education and training.

Doctors are legally obliged to use approved medications so it is what it is.
You say that like it's a bad thing...

It's just a neutral observation.

...and like something cannot be both profitable and ethical to sell.

Putting profit aside for a moment; with the toxicity/safety issues surrounding many prescription drugs I'd consider said drugs to be unethical for human use - but the standards by which drug companies and regulatory agencies abide by are unique.

I too bristle and am nauseated by the thought of the Pharmaceutical-Industrial Complex®...

I call it "corporate healthcare" but your label is also appropriate since it alludes to the involvement of the agricultural, food and cosmetics industries in their use of "safe" crop treatments and "safe" ingredients.

...preying on sick people with medical needs.

Unfortunately this practice seems quite commonplace and built-in to the MO.

Considering the problematic aspects of most (semi)synthetic medications
This is an incorrect assumption, and "most" sounds to me like random conjecture.

To rephrase what I wrote; most classes of prescription medications have problematic adverse effects, many of which are under-represented and under-reported in the literature. Classes such as antibiotics, ADHD stimulants, anti-epileptics, anti-hypertensives, anti-cholesteremics, anti-diabetics, analgesics, anti-depressants etc.

It sounds like your view and opinion are being largely informed by subjective personal anecdote and some misleading information.

It's mainly via insights gained from medical professionals, knowledge of how pharmaceutical companies operate and their track record, myriad studies (those on statin toxicity are always as 'entertaining' as they are bemusing) and an analysis of the "corporate healthcare ecosystem".

Again: this is anecdotal evidence. Support groups naturally select for negative experiences, and they don't reflect population-level risk.

Funnily enough, many of the group members were actively taking statins. A few long-term users were adamant they have zero side-effects. Others had stopped due serious damage. As I regularly explained on various posts, the negative effects of statins are indiscernable from regular ageing so most people don't notice anything.

Interestingly after speaking with many patients it was clear that many doctors & nurses seem well-aware that statins are often poorly tolerated and cause innumerable adverse effects.
This is imprecise language: "many patients" (how many?), "it was clear" (to untrained non-professionals in the medical field?), "often poorly tolerated" (how often? is it a majority share of patients, or does it simply seem like that when you highlight a few specific cases?), "innumerable adverse effects" (how, and why, would that be "innumerable"? Sounds more like dramatic writing

Several patients reported that their health professionals (doctors, nurses, specialists) are well-aware that statins are poorly tolerated and cause adverse effects. Since professionals (doctors, nurses, specialists) have a large patient throughput this gives them a somewhat unique overview of things. The patients in question were mainly from UK/EU/US/AU so at least some health professionals in those countries aren't surprised when patients report statin-related adverse effects.

Which others?

Other books by other authors.

Doctors are "just following orders" and the risk/benefit ratio is positive of course.
I think you mean that the "risk/benefit ratio" is ≥1

I was implying that the risk/benefit ratio positively justifies and supports the regulatory approval of a drug.

Also, it's reductionist to claim that "doctors are just following orders",

I was likening it to soldiers just following orders. Doctors are legally required to follow certain rules & regulations besides the other factors you mentioned. You can't blame doctors for working within the set legal framework, they're just doing their job (this is another neutral observation).

I think the more accurate takeaway is that medications should be used thoughtfully and individually

It is possible to use an inadequately designed medication in a thoughtful (and individual) way.

...random hypotheses built upon, to borrow your proverb, "foundations of sand."

To bring things back on topic, the [rhetorical] question is what type of quartz polymorph is this sand composed? Is "meh-MDMA" merely an internet-based phenomenon spurred on by impure or mislabelled product?

 

[unodelacosa]

It saves many but also manages to do the opposite quite spectacularly, including reducing quality of life (see: medical negligence). Unfortunately medical negligence is often never recognised in the first place.

Where do you live that this has become your view of hospitals? If a hospital wants to stay open, it has to protect itself against legal liability, potential lawsuits and claims of negligence. Prescribing a well known, thoroughly studied and approved medication with a percent of intolerance that sits below the established threshold is not, by any stretch of the imagination or loose legal interpretation, "medical negligence".

Making a profit is quite common for most ventures.

Yes, that's what business ventures are for.

Is it the only system you've experienced?

What, the U.S. system with its 50 separate state systems? That one? Or the experiences I've had in Canada and Mexico? I have complaints, no doubt, and I'm not here to defend the system from the many deserved criticisms people have for it. It's far from perfect but so is the economic system within which it sits. I don't think there's any simple fix. This issue is too complex.

It's the most pronounced one in most countries so for many people it's all they know. Many have come to enamour it which is understandable.

No one I know in the U.S. is enamored with U.S. healthcare. There's a reason Luigi Mangione has many fans, and it's not just his good looks. And please don't imply that I'm enamored either. Mostly I just want to caution people to think about the downstream effects radical changes to the system can bring about, many of them fairly unpredictable and influenced by social and political factors too often. I find science fascinating, including medical science, but that does not mean I'm enamored with the commercial for-profit aspects of commerce in a supply & demand economy and blase blah trickle down this that & the other Keynesian economics, woo³ U.S. hegemony. Nahmsayin'?

In hindsight I should've clarified re "improperly designed" - I meant based on an incomplete understanding of the body.

What are you basing this on? And let me ask you… do you have a complete understanding of all the electrical engineering/science that goes into running electrical power (what do you call it? "Mains" I believe) across a grid, through a transformer, into a building, to a specific wall and socket, through to a light switch? Can you describe all of that in great detail, and more importantly, do you need that "complete" knowledge before you can flip a light switch? No, you don't. You flip that switch so there's light, and then if you want to, you can use that light to read up on this subject, but so long as you can recognize a light switch, you can take action. So I don't think this "complete understanding" is a very useful metric, nor is anyone truly even close to this when you consider our biological complexity. This doesn't mean we should cease taking medicine though. It's a moving target and a work in progress. Maybe that's why they call it "practicing medicine", lol (I'm joking).

As an analogy: a programmer must first learn how the OS works before writing kernel software otherwise the program might cause a crash or brick the hardware.

This is a flawed analogy to compare biology with computer science, or more specifically comparing OS kernel software to a class of medication. Even within this analogy, the vast majority of medicine would be better seen as standard software. So like "meds" = "apps". Our bodies and the OS are fairly robust (unless they're old) and they have failsafes built in to protect against germs, bacteria, viruses, hacks, malware, &c. so unless the system is overwhelmed, and despite some performance impacts at times, things keep on processing as needed. As the hardware gets older, certain apps serve as patches, updates, and performance impact mitigators… idk, see this analogy kinda falls apart.

Perhaps - but if the design rationale is misguided and/or the underlying mechanism inappropriate for the condition, then rigorously testing this medication is besides the point.

Sure, if it's actually misguided or inappropriate, but you're not qualified to make that call, and neither are your handful of doctors + a stack of anecdotes a mile high. (☜ no offense) That's been my point in this thread: lay opinions and conclusions don't matter in this context (it's why these fields are regulated independently via qualified agents), and until we have more data collected from peer-reviewed studies with consistently repeatable results, everyone is just guessing and drawing hard conclusions from this guesswork is pissing into the wind.

I don't consider "natural" to be better than "synthetic". Shulgin made some excellent drugs, so has the botanical kingdom.

So did Dr. David Nichols whose research into psychedelics with his group at Perdue was used to deepen our understanding of Parkinson's and develop medications from this knowledge. You mentioned aspirin, but there's also penicillin, insulin, thorazine, mechlorethamine & other anti-cancer agents, AZT for the treatment of AIDS/HIV, ketamine (thanks to, and by way of, PCP) and birth control, among other important medications and medicinal breakthroughs.

I described aspirin as "semi-synthetic" in the sense that salicylic acid is of botanical origin but acetyl-salicylic acid isn't (afaik).

Aspirin is not considered semisynthetic despite salicylic acid having first been discovered in the willow tree. In industry, it is the product of "total synthesis" and has been for decades now. I'll admit, I had to look that one up to be sure, and I'll grant you that the definition of semisynthetic does not appear entirely static.

I'd award statins the prize of "drug with most manicured statistics" but I suspect SSRIs rival this.

And how do you propose these statistics are being "manicured" exactly? I think that's easy to say, but it's another thing to prove and quite another to condemn. I also think you're letting personal biases cloud your judgment when condemning statins, wholesale ignoring the proven good they do. That doesn't negate your experiences, I'm just looking at the big picture, so to speak.

I was implying that "most" prescription drugs enable doctors to enact medical negligence.

Strange rhetoric, "enable" and "enact". And why would a doctor want to "enact medical negligence"?

It's not necessarily their fault as they don't know any better. I'm referring to their education and training.

Well then how would that constitute negligence if they "don't know better" and what makes you think that you somehow do know better, despite lacking qualifications to do so, or at least a doctor's education and experience?

It's just a neutral observation.

No, it's pretty far from neutral in my opinion, not when you yourself have had negative experiences with a drug class and you're arguing that it's negligent simply for a doctor to prescribe statins despite their proven record of effectiveness, imperfect though it may be, like other medications.

Putting profit aside for a moment; with the toxicity/safety issues surrounding many prescription drugs I'd consider said drugs to be unethical for human use

Ok, well you're welcome to your opinion, but maybe don't be shocked when others disagree and point out the flaws in your logic and distortions in your perspective. Be careful you haven't slipped into the Dunning-Kruger effect thinking you understand the full scope of what you're talking about when you can't see the forest for the proverbial trees. "Unethical for human use" is not a well thought-out phrase here.

- but the standards by which drug companies and regulatory agencies abide by are unique.

I would imagine so. Medicine + pharmaceutical oversight require unique regulations. That makes sense to me.

I call it "corporate healthcare" but your label is also appropriate since it alludes to the involvement of the agricultural, food and cosmetics industries in their use of "safe" crop treatments and ingredients.

Well how do you mean "corporate healthcare" and as opposed to what? Public healthcare? Private healthcare? Self-employed healthcare?

Unfortunately this practice seems quite commonplace and built-in to the MO.

More like "built-in to the HMO", ehh? See what I did there?

Yeah well, in my more cynical moments, I consider that hospitals and medical practices are for-profit businesses, so I do recognize the point you're driving at, and I have plenty of my own criticisms of healthcare and personal stories of epic fail I've encountered in that field. But these are rather small gripes in the grand scheme of things. Modern medicine is goddamn wizardry in the way it combines technology, science, and practical application to our staggeringly complex biological systems and similar-though-unique biochemical makeup.

most classes of prescription medications have problematic adverse effects, many of which are under-represented and under-reported in the literature.

Is this just speculation or you have concrete evidence to back up these claims? Also, I'm sure you're aware of this, but in the U.S. pharmaceutical companies can advertise their products through television ads, posters, magazine ads, online ads, etc. The caveat is that they must also list any and all side-effects no matter how small of a percent occurrence that reaction is. And while I have no figures in front of me, my best speculation is that these adverse effects are most certainly neither underrepresented nor underreported.

It's mainly via insights gained from medical professionals, knowledge of how pharmaceutical companies operate and their track record, myriad studies (those on statin toxicity are always as 'entertaining' as they are bemusing) and an analysis of the "corporate healthcare ecosystem".

Funnily enough, many of the group members were actively taking statins. A few long-term users were adamant they have zero side-effects. Others had stopped due serious damage. As I regularly explained on various posts, the negative effects of statins are indiscernable from regular ageing so most people don't notice anything.

Weird conclusion. How about, different people respond differently to the same medication? "Indiscernible from aging" is a ridiculous claim.

Several patients reported that their health professionals (doctors, nurses, specialists) are well-aware that statins are poorly tolerated and cause adverse effects.

Still not delving into how often though or any actual figures.

Since professionals (doctors, nurses, specialists) have a large patient throughput this gives them a somewhat unique overview of things.

"Somewhat unique" is not a thing. Unique means "one-of-a-kind".

The patients in question were mainly from UK/EU/US/AU so at least some health professionals in those countries aren't surprised when patients report statin-related adverse effects.

Probably all health professionals know there's a risk of adverse effects, but when is that not the case? Try being a doctor.

Other books by other authors.

So in other words, you're bullshitting and basing your argument on Gary Null's profit-incentivized opinion.

I was implying that the risk/benefit ratio positively justifies and supports the regulatory approval of a drug.

Again: not a bad thing.

I was likening it to soldiers just following orders.

Yes, I'm aware of the simile you were attempting, but they're two entirely different things.

Doctors are legally required to follow certain rules & regulations besides the other factors you mentioned.

Well aware.

You can't blame doctors for working within the set legal framework, they're just doing their job (this is another neutral observation).

Then why are you claiming medical negligence? You're contradicting yourself here.

It is possible to use an inadequately designed medication in a thoughtful (and individual) way.

Again, you're not really qualified to speak on whether a medicine's design meets any definition of "adequate".

To bring things back on topic, the [rhetorical] question is what type of quartz polymorph is this sand composed? Is "meh-MDMA" merely an internet-based phenomenon spurred on by impure or mislabelled product?

None of this ties back to the thread topic, nor is that question actually rhetorical or relevant. The second question has already been answered, and the lack of coherence only underscores that while we can form whatever opinions we want, any opinion is only as good as the facts on which it is based. Perhaps stop letting Gary Null influence your opinion so much.

 

[ageingpartyfiend]

Thread still going I see...wild, also impressive

mdma....was an amazing drug a couple decades ago, became a pale imitation of itself around a period of time when it's primary precursor (forgive lacking science language) became much, much more difficult to source and the production process was changed. Correlation yeah, but ...

Have a look at footage of raves (uk in particular) in the 80's/90's. Have a good look at the dancing and in particular how the ravers look, their facial expressions, movements, and how they interract etc. Then find me any footage from say 2005 onwards with people looking/behaving similarly.

It says something to me anyway. Bravo everyone though - will check back in next year!

 

[notsmokeymcpot42088]

I am not picking up the cudgell on this debate but there is a few things I can add

I was implying that "most" prescription drugs enable doctors to enact medical negligence.

Strange rhetoric, "enable" and "enact". And why would a doctor want to "enact medical negligence"?

To make there life easier and because there is 0 risk. That one is simple.

Putting profit aside for a moment; with the toxicity/safety issues surrounding many prescription drugs I'd consider said drugs to be unethical for human use

Ok, well you're welcome to your opinion, but maybe don't be shocked when others disagree and point out the flaws in your logic and distortions in your perspective. Be careful you haven't slipped into the Dunning-Kruger effect thinking you understand the full scope of what you're talking about when you can't see the forest for the proverbial trees. "Unethical for human use" is not a well thought-out phrase here.

Are you saying there are no prescription drugs that are generally unethical for human use? Darvocet/APAP fits the bill but that is a lame example. Do we get to count things that use to be prescribed until we learned better? As that is sure to happen again and citing previous horrors would be easier admittedly

That aside I would just say look at the 'weaponization of antipyschotics' thread and the Sackler family thread for more.

I would agree that side effects are vastly underreported as well --- If I like the med I may not mention a side effect, I.E Itchiness with morphine (oh no) - I am sure there are many more reasons. Including what you can afford/what insurance covers etc.

Hospitals do work with a certain amount of infallibility -- especially if there is only one in the area. Kind of a position they are 'policing themselves/eachother' and we see how well that works in EVERY INSTITUTION.

I do agree with most of what I read though

 

[Didgital]

This video is pretty recent or I wouldn't share it... It covers some of what has been discussed here without getting seriously bogged down by conjecture.

I especially like the last 5 minutes.