[amanaplanacanal]

Likely all amphetamines are neurotoxic the same way MDMA is, but we still use them for many things, including adhd. As a wise man once said, the dose makes the poison.

And as we know alcohol is carcinogenic and there is no known safe dose, but people still drink.

[cess11]

One of the main hypotheses is that concurrent release of neurotransmitters can cause dopamine to be reabsorbed into serotonin vesicles where the 'wrong' MAO enzyme breaks it down, releasing hydrogen peroxide.

Another hypothesis is that the human serotonin systems, specifically the prefrontal cortex, are relatively young and not evolved to take a beating, unlike the 'fight-and-flight'-related dopamine systems.

One indication that this might be the case is differences between people that use amphetamine regularly through nasal or oral routes compared to people using MDMA in a similar manner, where the latter group typically suffers more obvious neuronal damage faster. Amphetamine needs to be taken at very high doses to affect the serotonin transporter, so you'd typically see this in users mainlining lots of it.

As far as I know you don't see the same mental and neuronal risk profile with e.g. 6-APB and similar benzofurans that David Nichols lab produced in the nineties, as with MDMA. They are also not as subjectively rewarding and 'fun' as MDMA, indicating that the dopamine release plays an important part in this regard.

'The dose makes the poison' is usually credited to Paracelsus, late 1400s, early 1500s. Whether he should be considered wise is a matter of debate, Francis Bacon disagreed and argued against Paracelsus and the rosicrucians that did consider him to be.

Edit: Should probably add that methamphetamine is a much more potent serotonergic agent than amphetamine, and in some societies 'amphetamine' or 'amphetamines' tend to actually mean meth because that's what's available to them.

[_bin_]

There are a lot of possible mechanisms:

- mitichondrial inhibition

- hyperthermia

- excitotoxicity for DA at least

- hyperthermia speeds up redox cycling of dopamine quinones

- more quinones due to all your dopamine unprotected by vesicles

- metabolic impairment means harder to regenerate NADPH/make glutathione

- probably others I can’t remember at the moment.

You may notice many of these “synergize” in a way that’s particularly bad for the user.

It’s really not worth touching for anyone outside a clinical setting.

[cess11]

Someone else said that all amphetamines are likely to be neurotoxic the same way MDMA is. I responded that they don't have to be.

Why did you take this as an invitation to do a purely theoretical exercise in listing possible mechanisms for neurotoxicity? At the very least you ought to have anchored your reasoning in actual risky MDMA use, what people actually do, instead of just ranting out words that could scare a layperson. I.e. behaviours that are common, like combining MDMA with alcohol, or dopaminergic psychedelics like LSD and 2C-B, or forgetting to drink water, or whatever that isn't pseudo-academic stuff like 'sped up redox cycling of dopamine quinones'.

I also think you should have taken the time to show that you have an understanding of why millions of people disagree with you. In my opinion it would also be prudent to compare the risks you see with other neuronal risks, like living in an environment with ICE exhausts or having kids and suffering sleep deprivation for years on end or just plain old poverty. The latter is shown to, on average, have detrimental effects on the brain that can be clearly visible in medical examinations, unlike sporadic, responsible use of MDMA.

[_bin_]

This is a weirdly defensive answer. I didn't attack you personally, I brought up well-founded risks.

Your suggestions, while interesting, don't remove these risks. Yes, certain types of abuse make it worse: dosing higher, polydrug abuse, hot environments, and dehydration are all ways to damage your brain further. However, use of MDMA in an ideal sense probably still causes some level of damage.

https://pubmed.ncbi.nlm.nih.gov/16472832/

2mg/kg dose, so ~160mg for an adult human. More importantly rat to human is usually a 6ish HED factor so that’d be <30mg. In reality metabolism, brain volume, etc all matter but this is not an even remotely safe drug.

This isn't a "purely theoretical exercise", most of those are established mechanisms of amphetamine toxicity. This isn't "listing possible mechanisms", this is sharing salient info of risks of which possible abusers (given the nature of the thread and discussion so far) should be aware.

I'm sure as heck not "ranting out behaviors that would scare a layperson". Most of what I listed is pretty comprehensible with a grasp of high school chem and bio. Most of the information for this is freely available online. The information we have should scare a layman out of use, and probably someone with a greater background, too.

Whatabout-ing with sleep deprivation or similar doesn't make sense to me either. Did I say that was good or healthy? Bad things stack. Your body doesn't keep a record where it says "you've accumulated 10% damage from an un-fun cause like exhaust or sleep deprivation, so now you get to experience 5% damage from a fun cause like molly." That's just a really weird way of thinking about this.

People are within their moral rights to run the risk but I don't understand this defensiveness that it's somehow a good or smart risk to run for the average case of abuse.

[cess11]

It's as if you didn't read my comment. I said nothing about risk mitigation.

I find it unethical to try to scare people away from recreational drug use, for several reasons. One being the inherent distrust of their ability to form their own opinions, another the kind of linguistic gatekeeping involved where scientific information is withheld through the use of professional or academic vocabulary, and yet another that I don't believe that it works, in my experience it has more often than not the opposite effect and enables or fuels harmful behaviour.

Where do you live, is it actually true that they teach neuroscience in highschool there or did you just make that up? Or do you think one can do a risk assessment from your comments without having a scientific understanding and mental model of the nervous system in general, and the central nervous system in particular?

We know from a lot of informal experimental data that sporadic, responsible MDMA use is, on average, very safe. It's likely to be safer than a long term weed habit, which carries a risk of damaging the heart and things like bronchitis, besides the contamination risks which are relatively hard to test for.

Also, it's not "whatabout-ing". Without a frame of reference the risks you bring up are meaningless to most people and useless in regards to policy. To judge whether you want to take the strictly neurotoxic risks involved in dancing on MDMA you'd need to understand how it compares to other factors in your life. In practice few people go about it in this way, however, and for good reason because the immediate risks involved in going to roll at a rave like party are of a quite different nature. Things like traumatic injury from a fall or sexual abuse or financial harm or the psychological effects of mistaken intimacy with strangers or somesuch.

Having fried a piece out of n thousand axon terminals isn't really a concern to most users, and compared to the drudgery of everyday life it likely feels like a low price to pay for many people. To convince them that this should be their primary concern requires another strategy from you..

[_bin_]

You’re mis-framing this as “scaring”. It’s not. I am talking about real risks that inform my choice not to take drugs because the info available tells me MDMA is significantly too risky.

If you’re suggesting marijuana is also unsafe, I strongly agree. Smoking anything is a risk and more importantly THC is shit for your brain, pro schizophrenic, turns people into lazy fattys, etc. I never have nor will I ever touch THC, absent perhaps light usage for pain if I get cancer or something.

Where I live my high school bio and chem classes gave more than enough foundational knowledge to understand this. It’s not actually that complex and all the remaining info is freely available online.

The risk of molly has little to do with other risk factors besides eg interactions. You fail to understand that risk and damage are the sum of all your risks and damages, not the single highest value. Things stack up.

If your assertion is “frying a little piece of their brains is fine”, I think that’s an extraordinarily reckless thing to do. Adults may have the right to do so, but I will not stop telling them that they are doing so, because most abusers are either unaware or minimize and deny so they can feel good about their abuse.