The grand (and still largely unsolved) challenge is not killing them, it‘s sparing the rest of the body while doing so.

https://www.youtube.com/channel/UCBbnbBWJtwsf0jLGUwX5Q3g

It's a wild and highly resistant world we don't know nearly enough about.

I think this paper's intentions was merely to understand it all better (which is a great thing0, while most people are taking issue, or at least providing much needed context, with an article suggesting some utility in fighting cancer.

Question for you - is this "brain damage" that I often hear results from taking a particular drug the result of intentful downregulation of certain neuronal receptors (e.g., meth -> too much dopamine in synapse -> downregulate dopamine receptors), or is the drug actually killing brain cells/neurotoxic?

1. E.g., cocaine as a strong vasoconstrictor can directly cause cerebral ischemia, causing hypoxic damage to the brain. Acute hypoxic damage is relatively uncommon, but atrophy due to chronic hypoxia is more common. Because the bulk of atrophy in chronic coke users is in some of the most hypoxia-sensitive areas of the brain, it might be the primary mechanism of damage.

2. Opioids can do the same via respiratory depression, even though blood flow to the brain is not impaired. Chronic opioid abusers tend to dose themselves into respiratory depression - and post-mortems show their brains to have ischemic neural damage.

3. Seizures are intrinsically neurotoxic. Damage from other sources (such as above) predisposes to seizure, which can have effects on the remainder of the brain.

4. We generally suspect there is more cell death than downregulation of neuronal receptors. When we look at the basal ganglia of chronic drug users (the dopaminergic neurons involved in the 'reward' circuit), we find atrophy, suggesting actual neuronal loss.

4b. What type of regulatory (e.g., down regulation) change occurs depends on the drug. Some drugs imitate an existing signal (e.g., opioids), so downregulation would be the homeostatic response. Coke and ecstasy stimulate dopamine release and serotonin release respectively, so we can expect a downregulation in receptors, but we may also see an upregulation in the transmitting cell in response to increased "release this signal" demands. Even that depends on the drug in question - amphetamine prompts dopamine release, so the releasing cell runs low and may increase storage levels. Coke prevents reuptake of dopamine, so active concentrations are up but the releasing cell doesn't see a change in its internal dopamine storage levels. Alcohol, on the other hand, is a glutamate blocker, which increases sensitivity to glutamate signals.

5. Opioids have been shown to be directly neurotoxic. It's unclear on whether this is a significant contributor above and beyond the respiratory depression in real life settings. In the lab, though, heroin, heroin metabolites (6-mono-acetyl morphine and morphine), fentanyl, have all been shown to be directly neurotoxic, though not all equivalently so.

6. MDMA is also shown to be directly neurotoxic, and (at least in a rat model) MDMA metabolites are more neurotoxic than MDMA itself.

7. Adulterants, through their toxic effects, also directly fuck up tissues. We see increased activation of cell-suicide pathways when heroin is induced, but we also see that the degree of activation is inversely proportional to the purity of the heroin.

I can probably go on for a while. I'm sorry if the above is a bit rambly, I didn't really stop and outline it as an essay. I hope that sheds some light, though.

First, what's your opinion on alpha lipolic acid and MDMA neurotoxicity? Given its popularity and its rising use it'd be great to have a simple way to prevent MDMA-induced neurotoxicity, and ALA is pretty widely available and relatively cheap, but there doesn't seem to have been much research on its use in humans.

And second, how bad are the neurotoxic effects of these drugs? The internet has anecdotes in all directions, from people claiming serious issues from only a few low doses of (cocaine/opiates/MDMA/etc) to people claiming no issues whatsoever from significantly more extensive use at higher doses. I realize that every person is very different, and this is a sort of "how long is a piece of string" question, but what is your personal feeling? More and more college students are experimenting with MDMA and cocaine especially - do you think a few low doses cause serious permanent damage, or do you think the neurotoxicity wouldn't be serious enough for concern, or somewhere in the middle?

1. We have a shitty understanding of chronic MDMA toxicity in human beings. Rat and primate models of MDMA differ in the primarily damaged pathways (non-human primates it has a pronounced effect on serotonergic cells; in rats it has a pronounced effect on dopaminergic cells). It's also a "dirty" drug, in that it hits a number of different receptor types - which means its downstream effects are going to be in a bunch of different pathways. And even those receptors are dirty - the serotonin 2A receptor that MDMA hits is involved in a wide variety of cellular functions.

Beyond that, we do know that a number of MDMA metabolites are directly capable of forming free radicals (such as quinone and thioester compounds), and oxidative damage is a serious problem in any cell tissue, but especially in brain, where cell replacement is generally too slow to matter. In rats, we've directly observed the production of compounds due to free radical exposure after MDMA injection, strongly suggesting that that is a mechanism of damage in the brain. (We also find that in rats that over-express copper superoxide dismutase, an antioxidant mechanism, there's resistance to MDMA toxicity.)

MDMA has also been shown to induce neuronal apoptosis that is inhibited by serotonin2A blockage, but... serotonin2A has such a wide variety of effects, I won't even guess as to what the direct pathway of that interaction is, much less how to block it.

ALA is a fine anti-oxidant. However, I wouldn't put my eggs in that basket, for the following reasons:

1. Anti-oxidants mitigate the damage of oxidizers, the way that cops on the street mitigate street crime. Some of the cops are gonna do stuff you don't like (we also depend on free radical mechanisms for destroying nascent cancer cells and bacteria - ALA doesn't discriminate); some of the criminals are going to slip by anyway (oxidizing damage will continue to accrue, if slower).

2. ALA to my knowledge has been studied to the extent of "we gave rats ALA and MDMA for two weeks, and the ALA group seemed to have less grossly visible brain damage." I expect diminished brain function long before we have significantly detectable anatomic changes. (There's also a tiny crap study or two showing it didn't have any protective benefit at all, but I tend not to lean on 'tiny crap studies'.)

3. ALA as a protective mechanism relies on oxidation being the main mechanism of damage. It might be; we don't know. If the main mechanism of damage is serotonin-pathway-driven apoptosis, or serotonin-pathway-driven neuronal structural change, or dopaminergic-pathway-etc. then ALA will not play a meaningful role in preventing long-term damage. It would just be hitting entirely the wrong mechanism.

Bottom-lining it: if a patient said "I'm definitely going to do MDMA and you can't talk me out of it, should I take ALA to try and mitigate the harm?" I'd say yes, sure, it's not likely to do meaningful harm if you're not on it for years (or don't have a disease that causes you to have an impaired oxidative immune function.) If a patient said, "I'm curious about MDMA but only if I can do it safely, can I do it if I take it with ALA?" my answer would have to be, "There's no good evidence that ALA is protective, and several mechanisms of damage besides the one that ALA acts on. If you're not comfortable doing MDMA without ALA, I wouldn't do it with ALA."

As to how bad the effects are:

No one really knows. My professional opinion is that most of the low-grade effects are likely to be behavioral/psychiatric, and due to our generally poor ability to quantify and track psychiatric symptoms, and the social confounders that accompany drug use, we're unlikely to have any good idea about what their adverse effects are. My most honest answer is a profession of ignorance.

My personal opinion is that, assuming someone is healthy and doesn't have any particular underlying risk factor, almost none of these drugs are going to do meaningful neurological harm if done a couple of times. My bigger concern lies in (a) people with underlying psychiatric risk factors, (b) in combinations (alcohol + coke + etc.), and (c) non-neurological effects.

Opioids can absolutely kill you stone dead the first time you take them - but not from its neurotoxic effect. Given the spate of fentanyl being cut into the street drugs these days, and unregulated dosing, it's the one drug I'd tell people to stay away from like their life depends on it. Though obviously if you're taking a prescription pill one time at low dose, it's a different story.

Is there more information or sources you can share on that? I'm interested because 1) I'm close to someone who suffers from both alcoholism and an eating disorder, and 2) I worry about excess amounts of glutamate on the brain.

There's a lot to go through.

I took a Biopsychology of Drugs class in college and found it fascinating. Do you know of any good (text)books on the subject?

edit: actually only sections of it are available online. The book isn't hard to find, though.

[1] https://stahlonline.cambridge.org/common_home.jsf

I think that it's possible but unlikely that loperamide is having a unique effect, because (a) they've shown that it's operating via the ATF4 mechanism, which is the same mechanism we see in other opioids (and multiple other drugs), and (b) loperamide's activity has generally been pretty well characterized and it doesn't really stand out (it's by no means a new drug - I remember taking it as a generic twenty years ago.)

I'll admit it's possible in the broad sense because ATF4 isn't some super-specific pathway. It's a stress response signal. So while I think (b) above makes a unique mechanism unlikely, (a) by itself isn't a slam-dunk - there are a lot of stress signals that induce cell death when they get amped up enough, and can inhibit cell death if blocked off.

just playing devil's advocate for the paper -- I happen to agree with witty's original comment thesis (except for the argument based on the authority of the journal it was published in)

From the paper:

> We previously screened a library containing autophagy-inducing compounds and identified the Food and Drug Administration-approved drug loperamide (LOP) as potent inducer of ACD in the glioblastoma multiforme (GBM) cell line MZ-54 [7]

7: Zielke S, Meyer N, Mari M, et al. Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells. Cell Death Dis. 2018;9:994

Probably because it's what they were studying which led to the analysis? A drug doesn't have to be unique to be important in understanding side effects...or off-label use if that's how you want to think of it.

Getting funding to study all of them at once is more challenging, so it shouldn't be a surprise that it's constrained to one.

It's like a study finding that "opioid X" gets you high via mu-opioid receptors. It's not really a finding; it's the null hypothesis.

More likely it's a liability check. The null hypothesis characterization is incidental.

People do get high on immodium [0]. With huge doses, but still.

0: https://www.forbes.com/sites/robertglatter/2018/01/31/fda-cr...

I always worried about the diarrhea problem that would justify such a purchase, but I guess this explains it.

This is wild. I had no idea! How does one even discover that?

[1] https://www.sciencedirect.com/science/article/abs/pii/S07356...

"Morphine is protective against doxorubicin-induced cardiotoxicity in rat" https://pubmed.ncbi.nlm.nih.gov/17988779/

"Morphine enhances doxorubicin-induced cardiotoxicity in the rat" https://pubmed.ncbi.nlm.nih.gov/24531975/

I feel that there should be a special name for this kind of publications they are so common: https://www.ncbi.nlm.nih.gov/pmc/?term=cancer+cells+in+vitro

Where he reviews a paper that shows in 2 males, loperamide lead to cardiac arrhythmia and death. The doses they took arent clear but it's in the heroic range. (50x-100x 'normal')

If you're desperate to get off opiates and unwilling to do suboxone or methadone, I'm not sure a doctor, if you can afford one, would even mention loperamide.

Edit: I don't mean this in a gatekeeping way, I honestly was just curious to hear an example of how this happens. Do people outside tech have someone in tech mention the site to them? Do they browse and just read the fraction of articles that aren't about something software related?

I got to HN itself ... I don't know how. I delete my account about once a year to try and limit my breadcrumb trail, so I can't really look backwards and say how long I've been here, or what may have gotten me here. IIRC, it was probably due to chasing articles on startups/entrepreneurship, as I seem to think that was over-represented in my early HN reading. But it's probably been about a decade, so take that with a grain of salt.

2. Many people have areas of interest outside of their profession.

(3 minutes of searching got me Con Kolivas, and "ck" sounds familiar so that might be him.)

edit: now I see heavyset_go has commented about the same.

I can't speak for the original poster but I think HN users are attracted to complexity and raw truth. Medicine and programming have a lot in common in that regard.

An example is the discovery and isolation of insulin [0]. Banting barely convinced somebody to give him lab space for 2 measly months. He then experimented with tying off the ducts of dog pancreases or removing the pancreases altogether. He realized he could keep a severely diabetic dog alive with injections from another dog's pancreatic juices. There was some drama around the subsequent purification of insulin and the Nobel Prize.

The full story almost sounds like software hacking and startup drama.

[0] https://www.sciencehistory.org/historical-profile/frederick-...

The idea that there is or ever will be a "cancer cure" is a popular misconception. There are hundreds--if not thousands--of cancer variants. The more targeted the treatments are, the fewer patients any one treatment can help. It takes a decade or more and hundreds of millions of dollars for each targeted treatment. There's still an enormous need for broad-spectrum treatments in addition to targeted ones.

It's conceptually similar to the mRNA covid vaccine. The framework has been figured out and tested, then it's only a matter of days to create the vaccine once you have the target genetic signature.