Much of the effects of any intoxicant are culturally constructed. Alcohol is widely known for causing aggression, but this effect doesn’t seem to exist in cultures without that association. Nor does it exist in double-blind studies, yet the placebo group becomes more aggressive.

You can start with two chemically identical intoxicants, and either by marketing or random path dependencies one gains a reputation in the subculture for making people go crazy. You can bet that large number of people are going to act wild on it.

This is no different than the reputation different types of alcohol have garnered. Gin makes people mean. Whisky makes people emotional. Tequila makes people party like crazy. It’s all ethanol, but those cultural preconceptions become self-fulfilling prophecies.

In many ways that makes these rumor filled, science light, unsubstantiated media stories about “this is the most dangerous drug ever” incredibly irresponsible. The stories themselves create the cultural preconditions around encouraging more self-destructive behavior among users. This isn’t even just drugs. Look at the moral panic over Four Loko. The same cocktail of ethanol and caffeine has been consumed as amaro and coffee by rich women since time immemorial. Yet it never caused moral panic until the “wrong type of people” started consuming it.

I agree that the gin->mean, whisky->emotional, etc, is all bunk. But I'm still convinced there's a link between alcohol and violence. If nothing else, the lowered cognitive function and reduced inhibition would mean more opportunity to be angry, and less self control.

Like, a drunk person might misinterpret someone accidentally bumping into them as aggression. And would be less likely to suppress the urge to respond in kind.

You're describing the stereotype of a mean drunk. In reality, there's also the happy or the sentimental drunk. They might just laugh it off or smile big and hug the person bumping into them.

For sure, alcohol reduces inhibitions. If you're a naturally chip-on-the-shoulder kind of person, alcohol will turn you into a certified jerk. Alcohol can turn other kinds of people into lovable fools as well though.

I didn't think the bar was to describe something that was true for everyone. I suspect what I described is true for many, across many cultures. I've also seen people I would have characterized as mild-mannered act much differently with alcohol in them. I don't think it's just strictly amplifying existing traits.

Reduced inhibition does not support the thesis of increased agression, unless you define aggression to refer to "aggression shown".

But I'd overall turn the 'cultural' aspect a little further even. I think I have observed a couple of times people to consume alcohol in order to be able to transgress cultural norms because the cultural norms themselves are 'parametrised' for the sober-drunk states.

I.e. get into a fight sober? Could be unacceptable even to someone who wants to get into a fight. After 4 beers? May be perfectly fine for your peer group. Same goes to other things, like dancing, approaching strangers, etc.

What I really found interesting for example is, in my abroad term in Canada. The sober Canadian society was overall friendly and polite, definitely friendlier than in my German home. People held up doors for me (a 20 something man, felt really weird and unexpected), you got compliments for what you wore (never happened to me in Germany), etc. pp. But this radically changed in the 'drunken space' where people were a lot more aggressive and fights were much more the norm.

> Reduced inhibition does not support the thesis of increased agression, unless you define aggression to refer to "aggression shown".

So... the normal definition that everyone already uses?

>Reduced inhibition does not support the thesis of increased agression, unless you define aggression to refer to "aggression shown".

I mean overall increased opportunity for violence. Less inhibition might mean I'm more likely to say "fuck off" to someone rather than just think it. Which could lead somewhere.

That's indicative of underlying aggression and can't be extrapolated to other cultures.

I guess, but I'm curious what culture has no aggression at all.

Probably depends on how specific you get with the term aggression

It sounds like there's a suggestion that cultures where alcohol has no notable effect on overall violence. I'm curious what culture that is.

look at japan. Salarymen get shitfaced on the regular, but you don't hear about drunken street fights in Tokyo do you?

I don't hear about drunken street fights in the US either, probably because I don't consume the local media and street fights don't make it to the international news section.

idk maybe mormon culture?

Where in canada were you? I've lived here my whole life and never experienced anything like this. And I've been to Germany, out drinking with Germans, a handful of times and never felt any material difference in demeanor between partying with those folks and with canadians.

If you have to fake being sorry about everything, eventually that pent up frustration has to come out :P

I’m just a sample of one, but I’m way more likely to flip my shit when sober — all my fights or verbal altercations I have in fact been sober.

Granted, I’ve been diagnosed with various mental health disorders related to emotional regulation, so perhaps this is dependent on individual brain function.

Of course. Not everybody is going to get violent. And it won’t affect everybody the same. But it does feel like it really brings out the violence in people who maybe are already prone to that type of behavior. In your case it may do the opposite.

I think you're still describing a cultural cause here.

Responding to perceived aggression with your own aggression is not a given. It's a culturally decided response, not an instinctive one.

A good christian is supposed to respond to aggression by "turning the other cheek" and not responding at all. A strict, honor based society might say the only way to respond to aggression is by killing that person.

Western culture falls in between these two. Reduced inhibition simply makes your judgement of the consequences worse so people usually make the choice they want to make (shaped by their culture) and just don't think though what it could mean.

But we wouldn't say that Japan is more of a Christian culture than the U.S., or that the U.S. is more of an honor culture than Japan.

I understand the sociological theories you are referring to, but I'm not sure how useful they are.

You are probably right in your assertion regarding alcohol, however I suspect it may be possible that there are other compounds unique to various flavors of liquor which may influence the overall effects in various ways. These compounds may not be perceptably psychoactive on their own.

The same goes for strains of marijuana, beyond THC and CBD other psychoactive compounds are inconsistently present with uncertain psychoactive effects (if any). Further there may be complex nonlinear interactions (e.g. two compounds produce no effect but adding a third can change the experience, particularly if you consider reaction products from combustion).

In any case the uncertainty is good for marketing.

> One theory is that much of the meth contains residue of toxic chemicals used in its production, or other contaminants. Even traces of certain chemicals, in a relatively pure drug, might be devastating. The sheer number of users is up, too, and the abundance and low price of P2P meth may enable more continual use among them. That, combined with the drug’s potency today, might accelerate the mental deterioration that ephedrine-based meth can also produce, though usually over a period of months or years, not weeks.

These are the theories mentioned in the article referenced in the comment you replied to. It might be the meth itself. Gin, whiskey, and tequila are different colors, and it's not because they are compositionally identical.

> Look at the moral panic over Four Loko. The same cocktail of ethanol and caffeine has been consumed as amaro and coffee by rich women since time immemorial. Yet it never caused moral panic until the “wrong type of people” started consuming it.

You’re not entirely wrong, but a splash of liqueur into a small cup of coffee is pretty different from dissolving caffeine pills in tall boys of malt liquor.

Substitute "PBR hard coffee," then.

Malt liquor drink, 30mg caffeine. Tastes like Yoo-hoo.

PBR hard coffee (and similar products) are comically expensive for what they are which means the wrong people don't buy them which means the avoid the stigma.

That's true. I own a bar, and PBR HC is our most expensive-cost drink in a can. It's roughly double a Guiness, which used to hold that title.

It’s also not sold in 32 oz cans at 8-12% ABV in addition to the 3-4 cups of coffee worth of caffeine.

> In many ways that makes these rumor filled, science light, unsubstantiated media stories about “this is the most dangerous drug ever” incredibly irresponsible. The stories themselves create the cultural preconditions around encouraging more self-destructive behavior among users. <

What about krokodile?

What about it?

Desomorphine is not any more inherently dangerous than other opioids (so, still quite dangerous of course).

The synthesis pathway that Krokodil producers used are quite bad and unrefined, but quite surprisingly do work and does appear to produce desomorphine.

The problem was the producers were usually addicts who then injected the reactions solvent mixture, rather than extracting their product.

Did they separate the culture link from a potential genetic link? Maybe the association exists in a culture because it is a real effect, it just differs between groups.

I've heard (purely anecdotal) rumors that North Korea basically runs on Meth. I'm not sure if that is true but I suppose it would explain a lot.

NK has a lot of meth because the government started producing it for export in the 90s, and in the 2000s it became a sort of cottage industry and culturally normalized.

https://www.bbc.co.uk/news/world-asia-58838834

https://www.nytimes.com/2019/02/12/world/asia/north-korea-cr...

Imperial Japan was heavily dependent on amphetamines for wartime production and military stamina, and even gave the drug a patriotic-sounding name. It is definitely a useful tool for a totalitarian regime.

Not sure how this is related to my comment...?

Alcohol effects some subgroups (like Asians) differently so why not have more complex behaviors as genetic as well?

> It’s all ethanol

I used to believe that. It seemed obvious to me and a phd chemist friend of mine that - as you say - the different reputations were a cultural/social creation. The drink itself was just different amounts of ethanol.

Then one day that chemist friend of mine decided to get a bottle of Hornitos Reposado. We usually preferred a good bourbon or weird herbal stuff[1]. We drank most of the bottle, but that wasn't unusual for us at the time[2]. We were intending on a normal evening of video games. MTG, and/or VtES. Instead... we ended up spending the evening having the stupidest, most aggressive, pointless, childish, "macho" argument of our lives. It was shockingly out of character for us. The amount of ethanol consumption wasn't large, and we drank it at a normal rate. Both of us had been a LOT drunker in the past. The only significant difference was our unusual choice of tequila.

While I agree that the cultural preconceptions are probably responsible for most of the effect, there is at least some truth behind the reputations of different types of alcoholic beverages, because the actual drink isn't just ethanol. The different brewing/distilling/aging processes produce different amounts congeners[3][4]; their psychological effects might be small, but small effects amplified through social mechanisms are how "culture" is created.

> In many ways that makes these rumor filled, science light, unsubstantiated media stories about “this is the most dangerous drug ever” incredibly irresponsible.

Hear, hear!

> moral panic over Four Loko ... amaro and coffee

Yah, people have probably started putting whisky (Irish or otherwise) in their coffee the morning after they invented the whisky. Also, you probably have to drink the entire giant can of Four Loko to get the same caffeine in a typical cup of coffee.

> Yet it never caused moral panic until the “wrong type of people” started consuming it.

It's disturbing how often this kind of bs ends up just being a fancy form of racism/sexism/${targeted_group}ism

[1] e.g. Pernod, Herbsaint, Chartreuse

[2] Yes, we were regularly drinking WAY too much. 375ml/day/person minimum. WAY WAY WAY too much...

[3] https://en.wikipedia.org/wiki/Congener_%28beverages%29 "These substances include small amounts of chemicals such as methanol and other alcohols (known as fusel alcohols), acetone, acetaldehyde, esters, tannins, and aldehydes (e.g. furfural)."

[4] Also, the different amounts of sugars means different effects on bloodsugar/insulin/etc. The resulting effects are probably complicated and difficult to explain, but their contribution to the different reputations might be larger than we expect.

I saw a similar post that claimed the new meth caused psychosis and hallucinations, etc. I don’t know much about meth itself but I do know about Adderall. When you take the normal dose (10-30mg) it can cause some euphoria but for the most part it helps you focus, gives energy (makes you more happy, talkative.) But when it is abused (60+mg) it can cause serious psychosis with all kinds of mental side effects. I image than the new meth is just extremely strong and so for people who are used to doing (or seeing others do) a weaker type it would seem to be a completely different drug. At least this is my theory, since as you said there isn’t any evidence there is a new type of meth, just a stronger type.

Yeah it's all very straightforward when you look at usage patterns. Often meth abusers will smoke multiple points across a day (a point = 100mg). As a result they stay awake for days straight, don't eat, and often will engage in enormously risky sexual behavior (this is the dirty secret of AIDS btw...it arose in the context of the "party and play" gay subculture where people would smoke meth or other drugs and have sex for hours and hours and hours straight with many, many different partners...but I digress)

The infamous "meth mouth"? That's caused by not sleeping and by just overall letting one's life go to shit. Amphetamines do suppress saliva production, so they aren't great for teeth, but it's 95% the lack of sleep and other associated behavior patterns.

I've taken pharmaceutical adderall (which is 75% d-amp and 25% l-amp btw), and pharmaceutical dextroamphetamine (100% d-amp), and illicit, presumably cartel-sourced, and presumably very pure d-methamphetamine. When taken orally, d-meth is, in my opinion, simply a superior ADHD drug (it is much more dopaminergic than amphetamine, yet causes less peripheral stimulation, so you get a much more favorable ratio of positive cognitive effects to negative peripheral effects).

However, the moment someone starts taking (especially smoking, since the RoA of any drug makes a massive difference in addiction, doubly so for meth) hundreds of milligrams, it becomes a completely different drug. It becomes super deleterious to health through the sleep deprivation and risky behaviors alone. Furthermore meth has a unique property that amphetamine apparently doesn't, which is that it can become directly neurotoxic in large doses (meth has some serotonin release, like a much, much weaker form of MDMA, whereas amphetamine has virtually none, so it's possible that that's the mechanism). This is why in the research literature there's a lot about methamphetamine "neurotoxicity", but the papers conveniently omit that if taking oral doses comparable to what's given for ADHD, it's not neurotoxic whatsoever (and frankly may be neuroprotective, especially against traumatic brain injury).

So yeah, your analogy to Adderall is spot on. I've often seen people derisively refer to Adderall or other amphetamines by saying "we're basically giving kids meth!". Which is true in a sense, except it's really the other way around: meth is really not very different from Adderall. If someone were to smoke 100mg+ of amphetamine, their body would break down the same way it does in a meth user, except possibly for the direct neurotoxicity effect I mentioned.

Great writeup!

Just adding on: Other key differentiator between recreational and therapeutic amphetamine usage is the pharmacokinetics: Vyvanse is the best in this regard - it’s actually an amphetamine prodrug that gets converted to amphetamine in the bloodstream over the course of ~2 hours, giving a very smooth release. Adderall achieves a similar end (to a lesser degree) by combining equal ratios of four different amphetamine salts with various absorption rates to smooth out the serum concentration curve. Dexedrine and Desoxyn I believe are both single salt compounds, and thus have a slightly higher risk of dependency due to their sharper peaks. Of course, other RoAs like smoking or injecting amphetamines recreationally take the effect to a whole new level with even sharper curves, dramatically raising the chances of addiction and negative side effects.

Totally agreed. Expanding a bit on some of the stuff you mentioned:

Vyvanse hits C_max around 3 to 3.5 hours. But you'll hit the maximum "acceleration" (as opposed to "velocity") around 1-2 hours like you said.

Fun fact: Vyvanse was basically designed to have more meth-like pharmacokinetics, since meth also takes about 3-3.5 hours to peak in the blood. Having done both lisdexamfetamine and d-methamphetamine orally, the C_max numbers in the literature are definitely correct because those numbers line up perfectly with when I subjectively peak.

> Adderall achieves a similar end (to a lesser degree) by combining equal ratios of four different amphetamine salts with various absorption rates to smooth out the serum concentration curve.

Yup, and I forget the exact mechanism but I have seen a paper arguing that the 75:25 ratio actually does improve the efficacy. Although I can't remember what the mechanism actually was...

> Dexedrine and Desoxyn I believe are both single salt compounds, and thus have a slightly higher risk of dependency due to their sharper peaks

Correct, both are 100% d-enantiomer, and both due have somewhat sharper peaks as a result. Although to elaborate AFAIK Vyvanse is really the only super unique one. Adderral does/should have a slightly smoother peak but largely the levoamphetamine seems to serve to up the norepinephrine-y effects (that is to say, the "I need to be doing something right now" effects, whereas dopamine is moreso the "once I start something I can keep doing it" effects).

Also methamphetamine in particular when taken orally is very vyvanse-like, as I mentioned above. So it's really exclusively with the fast RoAs like smoking or injecting it where you get the really crazy instant spike. (That last sentence is just from my general understanding, I've never taken meth in a non-oral RoA so I can't speak from experience)

Adding on: the problem with vyvanse is that there's no way to mess around with the dosage to get it "just right."

It's like a more strict version of extended release (EX) and timed release formulations (there's a difference!).

Vyvanse is metabolized to d-amphetamine in your blood cells (the specific mechanism escapes me right now), unlike the regular non-prodrug versions which get "metabolized" first in your stomach and intestinal tract, and then your liver.

However, there is a set speed that vyvanse gets converted into free-circulating d-amphetamine, determined by how quickly (or slowly) your blood cells metabolize it. Unlike regular d-amphetamine, where the speed, and effect, can be "messed" with (or rather "tuned") on a variety of factors, such as:

0. Carbohydrate intake (regular, non-fructan and non-galactin, carbs get released into the bloodstream and trigger an insulin release response, which also happens to dull the effect of excitory neurotransmitters)

1. Stomach pH (acidicity == lesser effect, basicity == higher effect. E.g. drinking orange juice with d-amphetamine will lessen its effect, while taking tums will increase its effect, many times TOO much)

2. Certain liver enzyme inhibitors (mainly those in black pepper and grapefruit/pomegranate) will decrease the rate of amphetamine clearance, thereby intensify its effects

3. Caffeine (will potentiate amphetamine)

4. Personal physiology (not much you can do except play around with dosage and the aforementioned 4 factors)

Now, with the regular IR version, you can take more or less (1-5mg here and there) depending on your specific circumstances to get into the "right" spot where you're not overly or under stimulated, but just enough to be in that Goldilocks zone of flow.

However, with the ER version you lose the ability to get your "Goldilocks Dosage." You can still play around with the aforementioned factors, but this time you're restricted to a specific dosage now (say 5mg) and a specific dosage in some set amount of time later (say another 5mg, about 4-6 hours later).

Yet, with vyvanse you get even less of an ability to play around with the dosage. Take 60mg, and your body will slowly metabolize it to a set amount per hour, regardless of almost anything you can control. If that amount/hour rate doesn't coincide with your Goldilocks zone, you're shit out of luck -- and Vyvanse will not "work" for you.

There's so much more that goes into this, but I've frankly written way too much of an essay at this point.

Thank you for in-depth explanation. Is there a book or some website where all this knowledge of ADHD medication usage nuances is collected in one place? Like a missing ADHD manual?

Ironically, erowid and other "drug" related forums contain the best "practical" knowledge and nuances of actually having to take the medication. They're not scientific or robust, but they are empirical. That's why most pharmacists and prescription-writing physicians will look at you funny (or get combative) if you tell them generic brand X isn't as effective/good as generic brand Z for you.

On paper, each generic must pass some bio-equivalency test with the FDA. Most of the time all that means is "we at generic brand X ran our own experiments and concluded that we show similar blood concentrations of drug A, to Brand-Name Z." And then every professional involved in that supply chain writes it off as "basically the same," excluding all the little implementation/manufacturing details that go into each specific producer, much less factory (quality control is frankly disturbing in many of these plants).

You won't find a lot of practical information written within scientific literature, aside from basic chemistry/biology (the low-level details). Most of the time the researchers running these experiments have done less research and have less hands on experience than the people who have to use this medication on a daily basis. Many times reading the scientific literature is just a rabbit hole that leads to nowhere, except feeling like "you're on to something."

Apologies for the rant.

I remember reading a very big thread about MDMA on Bluelight [1]. They were trying to figure out why the MDMA manufactured today is very different empirically compared to the MDMA manufactured in the 80s. Lots of very interesting chemistry discussion One thing I particularly remember is somebody bringing up the example of their cat. Their cat had some digestive issue and couldn't poop so it was prescribed medicine. One brand of medicine worked wonders for the cat, while a generic brand didn't work at all. Both were supposed to be the same exact molecule!

[1]: https://www.bluelight.org/xf/threads/what-is-wrong-with-the-...

Not that I know of. One of the side effects of amphetamine usage is compulsively researching details about amphetamine, so that’s where my knowledge comes from :)

Certainly need to read some of the research literature and places like /r/DrugNerds (that community is super legit). The public health/doctor-y type websites are the worst for actually getting info since they never go into details and often give bad advice, so I’d stay away from the “traditional” resources if you’re trying to go deep

Yep. It's why I switched from Vyvanse (lisdexamfetamine - basically just d-amp bound to lysine which is then metabolized into d-amp during digestion) to IR generic Adderall (a mix of d-amp and l-amp).

Any unwanted effects (insomnia if I take it too late, etc) are almost entirely due to the l-amp, but the slow release of Vyvanse made it essentially impossible to titrate and my options were either to take a dose so low it wasn't effective or deal with regular insomnia due to lingering amphetamine effects into the evening.

I guess ideally I'd have IR d-amp but I assume it's considered too "abusable" so it's rarely prescribed. Meanwhile, my whole goal is to get useful effects without taking enough to feel like I'm tweaked out or high.

I had the same experience with vyvanse. Insomnia and ADHD medication are a dangerous combo -- one that's hardly recognizable until it's too late.

In my experience, I've had to run the gamut on all the "other" ADHD drugs (ritalin, adderall, d-amphetamine ER, etc.) and then prove they weren't effective, for my insurance to finally approve it. I've heard of some people even going so far as to get prescription meth (desoxyn) because nothing else would work! Strange world.

I've stopped taking meds entirely. I don't know if it's because I'm getting old, and even a "low" dosage (5-10mg) makes me feel very uncomfortable, or if it's because I've used a lot of different slavic nootropics and neuro-regenerative peptides (e.g. semax/NASA, BPC-500, etc.), but I just do not have any tolerance for it anymore.

Fortunately, this loss of tolerance coincided with the ability for me to function very well on simple caffeine alone.

> Insomnia and ADHD medication are a dangerous combo

A few months ago I started taking 15mg diphenhydramine every night just to make damn sure I always get enough sleep. I had taken it occasionally in the past, but didn't like the lingering effect it had the next morning. Then I had a conversation with my sister, who said that she takes it every night for the antihistamine effects after a doctor told her it's fine. The morning after effects seemed to fade (or I got used to them) pretty quickly once I started regular dosing.

Of course I have mixed feelings about ratcheting up the number of medications I'm taking daily, but to be fair OTC allergy medicine is a far cry from using something like Ambien or benzos to manage insomnia.

> slavic nootropics and neuro-regenerative peptides (e.g. semax/NASA, BPC-500,

more info?

Apologies; I confused BPC-157 with TB-500, and made a horrible amalgamation.

What do you want to know? Do you have some specific goal you want achieved or curiosity that you would like satisfied?

It's been a bit since I've been involved with these things. Most of it is underground, but I can give you a quick rundown.

BPC-157 and TB-500 are regenerative peptides. BPC-157 seems to be more "global" and neuro-involved throughout the body, while TB-500 is more local and structural (joints, tendons, etc.). BPC-157 also has a (prolonged) effect in some that negates the effects of amphetamines. Subcutaneous injections of BPC-157 have helped get rid of my recurring ganglion cysts and golfer's elbow.

Semax would fall under "slavic nootropics," along with Selank, and if I remember correctly Epithalon. All have "sub-versions" of varying efficacy. F.e. all have "N-Acetyl" and "N-Acetyl Amidate" versions. NASA would be the shortened version of "N-Acetyl Semax Amidate" -- which in my experience is the "strongest." With NASA, while I was injecting it subcutaneously it brought a sort of structure to my mind I hadn't had since I was a child. It's like feeling everything is falling into place, and a loss of the feeling of helplessness.

If you've ever used noopept, it's like that except with more real and long-lasting effects. I would liken it to bromantane, too.

If not, it's difficult to explain what they are, because they're such a different class of drugs that there's no reference point to base their effects off of. Imagine that you have a drug, but instead of giving you a few hours of a noticeable "high" or "low," instead you get a small, but perceptible shift in how you view the world, and how you filter all the information coming in. Like a micro-micro-micro dose of LSD. No high, no impairment, just a beneficial "shift" in your perception that lasts for an indeterminate, but long time.

A few of my friends were career-researchers and likened these effects to be genomic (subtly altering the expression of genes all around the body) rather than physical (that is, simple physical reactions like consuming more electrolytes would cause you to hold more water, and become bloated, because electrolytes attract and "hold" water; or how drunkenness is simply a temporary shift in the delicate GABA/glutamate balance in your brain). The purely "physical" drugs require constant re-dosing to be effective, while the more genomic ones (such as peptides) can have long-lasting effects even after they've been ceased.

Looks like there's NASA sold in spray form, how would that compare in efficacy to subcutaneous injection?

Seems to act differently depending on route of administration. If you've ever had weed, it's like edibles (injecting) vs. smoking (nasal).

Intranasal is more cerebral, "in your head" type of effects.

Subq is more bodily, "all around your body" type of effects.

If you're looking at it as a nootropic, I would recommend the spray. It feels similar to prozac and wellbutrin, if they weren't so terrible.

If you're looking at is as an anodyne or body-anxiolytic, I would recommend subq. If feels like baclofen.

I guess I'm a little confused by your answer - are peptides nootropics or sensation-type experiences? I guess I perceive nootropics as like "become smarter" or "having better recall" but this answer makes it seem like a recreational time bound physical experience? I also could see how the mental and physical have blurred boundaries.

I'm nodding off right now, so my verbal fluency is off. I think I was trying to make an analogy on how their effects differ, not on how their effects are.

For example, with eating weed, you get bodily sensations, and so its effects are more on your body, i.e. physical; while with smoking weed, the "sensations" are more in your head, and mental.

Likewise, with injecting NASA, the effects seem to be spread around your body and more "physical"; while administering NASA intranasaly, the effects are more mental, and focused "in your head."

The route of administration changes the expression of the drug on your body and mind. Dependent on that, it can either be a nootropic (nasal route) or akin to a mild and sensationless (compared to painkillers like opiates) muscle relaxant (subcutaneous).

It's difficult to explain, because the effects are so mild and without the normal "Oh, I'm on drugs. I can feel it" sensations, that you can only see them in hindsight (in my case, by perusing old journal entries).

Are there short and long term benefits as far as memory and what not?

Uncertain. Likely nothing noticeable.

Only thing in the vein has been a better ability to plan, reason about in my head, and make use of visualization to reason about problems (and their solutions).

I’ve been on Vyvanse for a couple years now, and while I was titrating up the dosage I got into the habit of “spreading out” the capsule by opening it up and taking half about three hours apart. The idea was to make sure that the peak effect occurred at the right time. I recently discovered that this probably served no purpose whatsoever, and taking the entire pill at once produces pretty much the exact same overall effect profile.

> Vyvanse is metabolized to d-amphetamine in your blood cells

Do you have any more information about this? Can't find it on google - would be very interesting if its true but I'm a bit skeptical - I've never heard about blood cells being a primary site of drug metabolism.

A search turned up:

> "Lisdexamfetamine dimesylate is converted to dextoamphetamine and L- lysine, which is believed to occur by first-pass intestinal and/or hepatic metabolism."

(https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/02...)

According to this, sounds like its mostly intestines and liver, which is much more typical for drug metabolisms.

Old FDA data.

Here's the latest: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/02...

> 12.3 Pharmacokinetics

> Metabolism Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells after oral administration of lisdexamfetamine dimesylate. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes.

EDIT: A better one: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257105/

~30 year old article on how red blood cells metabolize many classes of drugs: https://onlinelibrary.wiley.com/doi/pdf/10.1002/bod.25100904...

Basically, RBCs have lots of enzyme systems that serve (in part) to protect the important parts (e.g. haemoglobin) from oxidation. Put a bunch of lisdexamfetamine in the blood, and the RBCs will gradually hydrolyze it to cleave off the l-lysine and leave d-amph.

Very interesting, thanks!

Meth causes your mouth to produce to less saliva which removes the bacteria moderating ability of your mouth.

Combine that with also constricting the blood vessels of your gums, and you get a great mix of infection of dying tissue.

It's a myth. I have met hundreds, maybe thousands of long term addicts of meth, crack, and heroin... Lifestyle addicts suffer from massive tooth decay & dental problems, in similar proportions, regardless of which drug they were using.

Whatever the pharmacological impact of meth usage on oral health, it's pretty clear to me that it's a much smaller factor than the general gone-to-hell life of a full time addict.

The 'dirty secret' you refer to (1) is mostly wrong because partying with LSD was popular in the early 80s, not meth, and (2) the gay community is and always has been very up front about risky behaviors and how to minimize the risks. Just because you're unaware of something doesn't make it a secret.

In the American urban gay community, neither LSD nor meth were nearly as popular as prescription amphetamines (pills) until the 1990s, when bathtub meth (crank) manufacturing really took off. They were all always available, but the pills were so cheap & easily obtainable that they were a natural favorite.

MDMA/"Ecstasy" was quite popular in the 80s ("mollie" today), as well as Amyl Nitrite/"poppers"/"rush". The club drugs.

All other literature have told me exactly the contrary in terms of attitudes concerning risk. So, do you have a non politicized source for your statements?

My somewhat large reading about this and some real life knowledge says this is a very true POV.

Amphetamines also cause capillary vasoconstriction which eventually kills off your gums

Pharmacologically, amphetamines are no worse on your mouth than regular nicotine or caffeine usage. And while cigs & coffee aren't necessarily good for your oral health, they also don't generally cause major gum disease and tooth loss.

"Meth mouth" is mostly caused by neglect, not the biological effects of amphetamines. Long-term heroin & crack users suffer the same kind of severe tooth decay as meth addicts. If you smoke meth every day, but still somehow manage to brush & floss your teeth every day, your oral health won't be any worse than the average American.

That's incorrect, at least in the case of cigarettes. According to the CDC, you have twice the risk of gum disease if you smoke versus nonsmokers. They also state that the more you smoke and the longer you smoke, the greater your risk. That doesn't directly imply a causal link, but it sure winks really obviously in the direction of one.

https://www.cdc.gov/tobacco/campaign/tips/diseases/periodont...

For some perspective, "Twice the risk of gum disease" is pretty tame. Try losing 90% of your adult teeth... That's the level of dental prohlem that lomg-term addicts have to deal with, after 5-10 years of street life. Smoking cigarettes doesn't even come close.

This "new meth" thing seems like a PR push by government contractors. It's redolent of the UK "skunk" scare (it's not the pot you used to smoke, mommies and daddies - it's special pot that will definitely make your children think they can fly and jump out of windows, and become prostitutes to pay for more.)

What makes you say that?

I'm not 100% sold on it yet, but my city has always been "welcoming" to homeless folks and it has never been a huge problem. Now it looks like an actual zombie apocalypse out there in some parts, and there are periodically meth busts of hundreds of pounds in just random apartments, not even kingpin types.

Combined with the anecdotal evidence from social workers, there's a whole lot of smoke out there that the "new meth" theory might explain.

As the article points out, the big change is in the production levels and the price. If meth is cheap and every dealer is flooded with it, more people are going to be using it and in higher quantities that will produce more visible (and negative) effects.

The random apartments are probably stash houses used for storage of bulk quantities that would be broken down and distributed to dealers.

Yes because what people are taking now is super pure and potent where before what was common was “dirty” meth.

> government contractors

I’m not sure I follow? I know drug fear-mongering is a favorite tactic of politicians but I’m not sure I understand what government contractors have to do with it. Are you alluding to private prisons? Or perhaps some other piggy-back industry that I’m unaware of?

It sounds like someone just watched Breaking Bad.

More that breaking bad was picking up the story that was taking place at the time when sourcing their material. There's been a lot written about the superlabs in Mexico that produce hundreds of pounds of pure product a batch. There are probably thousands of facilities like this now making this P2P cook at industrial scales.

> When you take the normal dose (10-30mg) it can cause some euphoria but for the most part it helps you focus, gives energy (makes you more happy, talkative.) But when it is abused (60+mg) it can cause serious psychosis with all kinds of mental side effects.

Background: I'm prescribed 20mg/day of extended release Adderall, via a legitimate ADHD diagnosis. If we take the article's "meth is 2x as potent as Adderall" statement at face value, that would mean I'm taking 10mg equivalent of meth per day.

Now, since part of the reason I take this medication is to remember to take my medication (a joke, yes, but not without its kernel of truth!), I've accidentally double dosed myself before. I've also done the same previously when I was prescribed instant release Adderall. In either case, I've never experienced anything like a euphoric high, but I have experienced the kind of "uselessly driven"/tweaker sort of side of it. And, let me tell you, I do not like it when that happens. Although I'm in no hurry to find out, I honestly find it hard to imagine what the high must actually be like in order for people to voluntarily subject themselves to the negative effects of this drug. And, I don't even exceed the therapeutic range when this happens!

I wish there was some way to actually understand why people abuse meth without actually smoking meth myself, which I'm unwilling to do, for obvious reasons.

This is off the top of my head, so no citations, but d-methamphetamine is something like 30% more potent than d-amphetamine. The fact you're taking Adderall makes the comparison more complicated though because you're not taking d-amp. In general d-amp is 3-4x more cognitively powerful than l-amp. So we can consider l-amp to be about 25% the potency of d-amp, except IIRC the 75:25 d-amp:l-amp ratio of adderall synergizes a bit, so let's say that d-amp is ultimately 2.5-3x as strong as l-amp.

Your 20mg of XR addy is equivalent to 10mg IR and another 10mg taken roughly 4 hours after, but let's forget the XR part and just assume it's a 20 IR for convenience (it doesn't change the math anyway, just the pharmacokinetics).

20mg IR Adderall is 15mg dextroamphetamine and 5mg amphetamine. That's about 17mg dextroamphetamine equivalent. Given my estimate of d-meth being 30% more potent than amphetamine, you're taking an equivalent of about 13mg of d-methamphetamine a day.

> In either case, I've never experienced anything like a euphoric high, but I have experienced the kind of "uselessly driven"/tweaker sort of side of it. And, let me tell you, I do not like it when that happens.

See you're amphetamine tolerant. Give your 20mg dose to an amphetamine naive individual, and they will get the euphoria for the first couple days at least of taking it. The euphoria quickly fades, though.

You are correct that when you overdose and aren't stimulant naive, you often end up with mostly the downsides with little upside. There's not too much value in pushing the body past its "equilibrium" level of stimulation (in your case 20mg XR).

> Although I'm in no hurry to find out, I honestly find it hard to imagine what the high must actually be like in order for people to voluntarily subject themselves to the negative effects of this drug. And, I don't even exceed the therapeutic range when this happens!

> I wish there was some way to actually understand why people abuse meth without actually smoking meth myself, which I'm unwilling to do, for obvious reasons.

Have you ever done MDMA? That makes it easy if you have, because MDMA is like a way gnarlier version of methamphetamine: it's shorter lasting and releases WAY more serotonin while still being very dopaminergic. Methamphetamine, taken in oral doses enough to get you slightly tweaking but not at a crazy level, is kind of like 10% of the sensation of "rolling" (rolling means being quite high on mdma) while feeling like a smoother, less physically tweaky version of Vyvanse, which itself is a smoother, less physically tweaky version of adderall.

(For context, when comparing adderall to dexedrine to vyvanse, adderall is by far the tweakiest due to the l-amp. Personally, I'm a dextrorotatory supremacist so I won't touch the l enantiomer with a 10-foot pole)

If you've never done methylynedioxy-methamphetamine, and you clearly haven't done regular methamphetamine, you likely don't "know" what serotonin feels like, unfortunately. But the TLDR is methamphetamine is a smoother and somewhat more dopaminergic version of amphetamine, with the added bonus of some minor (significant when you're smoking it though) serotonin release as well, whereas amphetamine has almost no interaction with serotonin to the best of my knowledge.

Thank you!

I hadn't expected anyone would answer my comment, much less that anyone would provide a concrete reference point that was actually within my experience. I have used MDMA and experienced the high you're describing. For reference, I was high enough that I felt it certainly would not have been a good idea to try driving my car anywhere, but not so high that I felt taking my dog for a walk around the block would have been at all risky.

I found it pleasant, and wished it would last longer, but I don't think it's anything I'd go for if i were only 10% as intense and came with all the twitchy/tweaker effects. The jaw clenching I got from MDMA was more than enough of that.

But, as far as this:

> See you're amphetamine tolerant. Give your 20mg dose to an amphetamine naive individual, and they will get the euphoria for the first couple days at least of taking it. The euphoria quickly fades, though.

When I said "never," I meant "never." I didn't experience it the first time I took amphetamine, the second time, or this morning.

I have experienced some mild euphoria from prescribed dosages of opioids in the past, and, as I mentioned, I've experienced the high of MDMA, so, I think I have some sort of reference point here, although I'm sure they're very different highs.

Maybe it's because the starting dosages my doctors had me trying out initially were very small. Maybe it's because that initial dosage was 10-15 years ago, and I don't really remember it well (which would imply it wasn't very memorable). Or, maybe I did experience some euphoria, but just couldn't classify it as such because of my limited drug experience thus far.

In any case, as you said, I am not amphetamine-naive anymore and certainly don't get high off my medication at prescribed dosages, or even somewhat higher than prescribed dosages.

Again, thank you for helping me understand a bit of the appeal of smoking meth, without actually smoking meth. :-)

> but I don't think it's anything I'd go for if i were only 10% as intense and came with all the twitchy/tweaker effects. The jaw clenching I got from MDMA was more than enough of that.

While we don't know the exact MoA of the jaw clenching, it's likely a form of excitoxicity, presumably a result of excess glutamate firing. This is why high-bioavailability magnesium, such as a chelated magnesium glycinate, helps a lot with the jaw clenching while rolling.

In other words, it's not the serotonin itself that causes the jaw clenching, AFAIK. The "10% of rolling" was me describing just the serotonin dimension of the mdma vs meth experience, not that it would be 10% of the rolly feeling with 100% of the clenching etc :P

> When I said "never," I meant "never." I didn't experience it the first time I took amphetamine, the second time, or this morning.

Very interesting! I definitely have experienced the euphoric high before, but only when starting prescription amphetamines. Yeah, it may have been that you started with a low enough dose, or just that your neurochemistry is pretty resistant to it.

The reason I mentioned the tolerance thing is because there's a common ADHD myth that if someone has ADHD that amps won't get them a euphoric high, and rather will just "calm them down". But in truth anyone can get the euphoria, and most of the "difference in how ADHD people respond to stims" is just an artifact of them having tolerance. It is of course true that ADHD medication can and often does make ADHD people feel more "calm" due to the greater cognitive control etc, but it's not necessarily true that they/we can't actually get "high" off it.

> Again, thank you for helping me understand a bit of the appeal of smoking meth, without actually smoking meth. :-)

Any time :P I've never smoked it myself but having taken it orally for years, as well as having vaporized DMT many a time, I think I have a pretty good imagination for what it would feel like :P

Another factor is just sleep deprivation. It's been shown that sleep deprivation increases the likelihood of mania, hallucinations and psychosis. You force someone to stay awake long enough, they will inevitably act crazy. Amphetamine users tend to go on binges and stay awake for days. Keep taking drugs until they pass out from exhaustion.

It's even more silly a claim because P2P based syntheses have been in common use for many decades. They were especially popular amongst the Hells Angels' chemists. I'm not sure what their final reductive amination step was, but I'd guess Al-Hg amalgam & methylamine.

From what I've read of schizophrenia[1] it is highly inherited and unlikely that any drug would cause it. A sufficient amount of stress is known to trigger or quicken the emergence of schizophrenia in people already predisposed to it.

When it comes to studying this, you have to separate out:

* The high rates of drug abuse by people with mental illness.

* The correlation drug use with other sources of stress. Drug use may not be the source, but a result of the source. (But I think we can all agree drugs probably aren't happening matters.)

* Misdiagnosis of temporary drug-induced psychosis as a permanent, incurable mental health illness.

* Race, sex, age, and location, since this all affect the normal rates of schizophrenia for each population group.

OR:

* Show a significant increases in rates that can't be explained by the above. (If this rate tripled, it's pretty clear something bad is happening.)

Very few studies do this, because it is very difficult and there is little incentive to do high quality research.

1: I'm bipolar which is sometimes considered to be on the same spectrum

Maybe it doesn't cause permanent psychosis but people do become psychotic due to it and need to spend the night cooling off in the psych ED.

You are severely underestimating the power of these drugs. Anyways, most people do and usually find out the hard way.

Really interesting read. Thank you for sharing. For some reason this sort of information about street drugs and science/culture surround it fascinates me.

you might enjoy this then:

https://en.wikipedia.org/wiki/Hamilton%27s_Pharmacopeia

Xylene episode shook me to my core

You must mean the Xenon episode.

si

The author does bring up l-meth. I'm taking them at their word that l-meth is an isomer of d-meth and is created in P2P synthesis, but that seems at least plausible.

It doesn't seem to be common in the legal markets, and especially not at the kind of doses addicts would be exposed to.

From Wikipedia on Levomethamphetamine:

> In larger doses (more than 20 mg/day), it loses its specificity for MAO-B and also inhibits MAO-A, which increases serotonin and norepinephrine levels in the brain.

So there is a difference in response at higher doses. I would expect that addicts could be exposed to much more than 20mg/day, which begs the question of whether we even know what several hundred milligrams a day could do.

That's without getting into method of consumption. I'm not a chemist, but would we expect both isomers to break down under heat the same way? Or is the l-meth potentially being converted to something different than d-meth when smoked?

If the issue is the quantity, I would have expected schizophrenia to be constantly present. There's a fixed upper limit on how much people can do in a day, and overdoses have always existed, so there have always been people teetering on the edge. The amount heavy users use hasn't changed, there's just more heavy users and more users in general.

There doesn't seem to be debate that P2P processes create l-meth and d-meth, and that l-meth was less common in earlier versions.

I also don't think there's a debate that l-meth and d-meth have different effects. They're both used in prescription drugs, and those drugs are not interchangeable. You can't treat ADHD with l-meth, and you can't use d-meth in segiline.

None of that is conclusive. It could still be the quantity, or even something we haven't though of like an interaction between meth and fentanyl (which started its rise around 2015). I just don't think the evidence is so weak that we can discard the potential that l-meth is involved.

> I'm not a chemist, but would we expect both isomers to break down under heat the same way? Or is the l-meth potentially being converted to something different than d-meth when smoked?

Methamphetamine is very, very stable. It stays as methamphetamine when it's vaporized, regardless of whether we're talking d-meth or l-meth.

> There doesn't seem to be debate that P2P processes create l-meth and d-meth, and that l-meth was less common in earlier versions.

Not quite. p2p done naively creates racemic meth, yes, but the modern methods, which have been used for years, purify that to enantiopure d-methamphetamine. They do this by bubbling d-tartaric acid through the racemic mixture, which separates the two enantiomers thus yielding the desired pure d-meth.

Furthermore, historically racemic meth was much more common. AFAIK the infamous "shake and bake" technique creates racemic meth. I do know that there is a pseudofed route that yields d-meth, but I think it's different than shake and bake. So don't quote me on this paragraph, but at a minimum we know that in the last several years, almost all meth seized in the US is highly pure/potent d-methamphetamine. There is less l-meth than ever.

> I just don't think the evidence is so weak that we can discard the potential that l-meth is involved.

On the contrary, the evidence is so weak that we literally can discard that l-meth is involved. First of all l-meth is better studied than you say. I would bet to approve the l-methamphetamine-based vics vapo inhaler they had to at least do animal models with large amounts of pure l-meth.

Second of all, and this is what blows the giant hole in your argument, there is no surge of l-meth. There is less l-meth than there has ever been in the history of methamphetamine.

Thirdly - this ties into the second point - you seem to thikn that getting racemic methamphetamine is something particular to the p2p method. It's not. As a general rule, synthesis of any compound yields the racemic version (if we're talking a compound with two enantiomers). This is definitely true for meth, where almost every method yields racemic meth. AFAIK there's a pseudoephedrine route that yields straight d-meth, but like I mentioned above the current state of the art is just to do a big p2p synth route and then separate out the d enantiomer specifically.

> AFAIK the infamous "shake and bake" technique creates racemic meth

the shake and bake method uses "sudafed"/pseudoephedrine. therefore, it will produce d meth

> This is definitely true for meth, where almost every method yields racemic meth

not quite true, because the main precursor pseudoephedrine already had the correct stereochemistry in place. you would actually have to do effort to racemize that asymmetric carbon. But it is true that if your precursors are racemates or not asymmetric and you are not using some fancy asymmetric catalysis or tedious resoltuion your product will be racemic. An example of a racemic meth synthesis that does not involve P2P is direct amination of allylbenzene.

Thanks so much for your correction/insight here. My chemistry knowledge is pretty weak - and extra rusty - so that was very helpful.

It seems to me that the Elephant in the room is not the racemic composition of meth, or purity, but composition and nature of the remaining impurities.

Do you know if these are well understood and tracked over time?

I can't rule it out, but it's unlikely. Unless the meth cooks are doing something really bizarre, it's unlikely anything in the synthesis route produced as a side product is going to be as biologically potent as the meth itself. (This is not true for other street drugs, see MPTP). P2P Meth synthesis is pretty simple and straightforward if you have the reagents, it's Organic Chem 2xx-3xx level stuff. And it is really easy to crystallize to high purity.

I think it's actually the opposite of impurities. The tech and supply chains have gotten so good, the purity had gone way up and the cost down, that people are just using way more of it.

> There are claims that this new form of meth is chemically different in some what that started creating schizophrenia around 2017.

You are off by 8+ years ... P2P made meth became mainstream after 2008 because that is when Ephedrine was banned in Mexico [1].

[1.]https://www.justice.gov/archive/ndic/pubs31/31379/meth.htm#:....

OP is debunking the same claim you are.

Extremely good analysis. I was also skeptical of the original podcast.

It’s also possible that the impurities themselves were making it easier on the body(for whatever reason they could signal liver to produce more enzymes that were the ones to break down meth or clear it’s harmful metabolites etc)

P2P synthesis was the standard until it became hard to get (controlled) and that's when ephedrine and pseudoephedrine reduction became popular, despite much higher precursor cost. The reduction pathway is also easier, but because it's so much easier, It's likely much dirtier, since so little care is needed to "succeed." Now that Sudafed and ephedrine Diet pills are controlled, and can't be bought retail by the 1,000 lot, the balance has tilted back to the original precursor.

Thank you for doing the research and writeup.