wittyreference

Some cells never divide, and so theoretically shouldn't become cancerous. They still happen though: myocardium tumors shouldn't happen, but hey, rhabdomyoma. In that case, it's more likely in youth / congenital, because it had to happen via inherited defect rather than one that accrued through cell replication in your lifetime. It is rare, though, and ridiculously rare in adults. Still, "on a long enough timeline...". I mean geeze, let a guy get a tiny bit poetic.

Other cells don't have DNA and don't reproduce, so they shouldn't be eligible (red blood cells.) They still fall into a grey area though: the RBC itself will be dead soon enough and never leave behind cancerous progeny. On the other hand, your bone marrow can absolutely lose its mind and pump out the equivalent of a red blood cell mass, a condition known as polycythemia. You can also have RBCs turn cancerous before they become fully mature and shed their DNA. The erythroblast stage - the late stage of RBC development, the last stage before it chucks its nucleus and becomes disposable - can develop into a leukemia.

Our reproductive system generally keeps its genetic payload cells in stasis for the lifetime, so it doesn't accrue replication errors, as well as sitting behind a protective wall (e.g., the Blood-Testis Barrier) similar to the one that protects the brain. Even in stasis, though, damage accrues - the age of the parent has a direct impact on the likelihood of various congenital disorders.

(a) True cancer cures will be more dynamic than cutting bits off, like very sophisticated immune therapies, or

(b) We'll get really good at replacing cut off bits.

Solid cells generally sit on a foundation called basement membrane. Tissue invasion means "fuck basement membrane, I'm cutting through it and getting into the sewer pipes (blood vessels) below!"

This actually has two consequences. One is that, well, it's not really cancer until it can escape its original confines - then it's just a pre-cancerous growth. There are a lot of cellular proliferative conditions that will get big, but never go anywhere (e.g., uterine fibromas). These can still cause problems due to displacement of normal tissues, but not of the "I'm all over the body and munching happily away" variety.

The other implication of this step, though, is another type of immortality. Being detached from the basement membrane is one of those cell suicide signals we discussed earlier. So if you can successfully invade the membrane and dig into tissue, the implication is "I'm no longer sensitive to the basement membrane's cell-death signals." These signals overlap and tie into the cell-suicide signals mentioned above. None of these things are completely walled off from the others.

(6) Limitless replicative potential.

Normal cells are limited in their ability to replicate. Every time they do, there is a bit of their DNA that degrades on the ends. In order to compensate, there's a little end-cap, like the plastic aglet on a shoelace, that is there to be sacrificed. Those are called telomeres. Cancers will develop runaway enzymes for restoring those telomeres, so that they never run out of runway for cell replication.

There are other mechanisms in there that make it more complicated, though - we know this because some creatures have much longer telomeres than we do, but not proportionately more cancer (rabbits, if memory serves.)

This also gives rise to some of the weirdness in cancer research. We need immortal cell lines to do standardized research (so everyone is using the same baseline), but by being immortal they are fundamentally abnormal. The HeLa (Henrietta Lacks) cell line of recent fame is one of these immortalized cell lines. (Worth noting: at least in my lab, it wasn't hard to immortalize a cell line if needed. HeLa was unique only in that it was used early enough to become ubiquitous and set a standard - not that there's anything otherwise noteworthy about that particular handful of cells. They're the USB of cells.)

(7) Avoiding immune destruction.

There's overlap between all of these categories. Some of the ways your immune system kills pre-cancer cells are the pathways we broke above: the immune system might trigger apoptosis directly or indirectly, for instance. A cell-killer (CD8+ cytotoxic cell) will attack with an enzyme called 'granzyme', that explicitly tries to trigger apoptosis!

But there are other ways for the immune system to kill, and to be evaded. For instance, cells all express what's called "MHC 1". It's like the inspection sticker on your car. It take samples of intracellular proteins and shoves them up onto the cell surface for inspection by the immune system. If they're unusual, the immune system binds to them and kills the cell. So, not surprisingly, there are some cancers that downregulate MHC 1 - parking your car in your driveway so no one sees the expired sticker. This is common, I believe, in lung cancers. You can also see defects in the machinery that gets proteins to MHC 1; you can increase expression of "come hither" signals for immune suppressing cells (e.g., Regulatory T Cells, and Myeloid-derived suppressor cells); or secretion of immune suppressing molecules directly (e.g., TGF-Beta, IL-10, and VEGF). If VEGF sounds familiar, I should point out it's the signal for growing new blood vessels above.

(That's not a coincidence. Healing a wound requires quieting the inflammation that preceded the healing.)

New research in cancer vaccines is focusing on how to either restore the immunogenic environment, or to use alternative pathways. For instance, the toll-like receptor pathway doesn't usually play much of a role in developing cancer, so it's usually intact - so one of the new strategies that's being worked on is how to activate that pathway in response to cancers. And, we have drugs that target some of the elements here! For instance, those T-Regs express the cell surface marker CD25, which we can hit with a drug called daclizumab (I hope I got that spelled right - small molecule and monoclonal names are all gibberish.)

(8) Tumor-Promoting Inflammation. This wasn't a separate hallmark when I was a wee baby: the inflammatory signals promote cell proliferation, they can make blood vessels leaky, they can make blood vessels dilate (the combination means lots of yummy blood to feed a tumor). Inflammation also brings in lots of tumor-killing signals. "Tumor-promoting inflammation" is basically "everything I described above." So, I don't know, maybe something unique has been found here over time that I missed out on as the field evolved? Or not - all of these have grey areas of overlap.

(9) Genome instability and mutation.

Cancer cells, by virtue of shedding their DNA-protecting mechanism (cell death if the DNA is damaged too much) and going into rapid division, break the absolute shit out of their DNA. Not just the run-of-the-mill "oh, mutations accrue" type of breakage. I mean chromosomes are breaking and reattaching and breaking again, centromeres are all over the place, it's a shit show. This is a normal karyotype (image of the chromosomes as a whole): https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.scienc...

This is the karyotype of a breast cancer cell: https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.resear...

This "genome instability" doesn't just allow for rapid evolution - the fact that it can exist without the cell suiciding is a great big flag that this cell has very serious immortality mechanisms in play already.

(10) Deregulated cellular energy metabolism.

All of the stuff regulated above? It regulates, and is regulated by, cellular energy metabolism (which also feeds into various other type of macromolecule metabolisms - so when energy is dysregulated, it's like saying "our entire supply-side market is broken.") Which means dysregulated growth, dysregulated proliferation, etc. This is also a really core pathway - you can't fuck with such elemental life-or-death metabolic pathways without breaking stuff or killing stuff. By the time a cell can dysregulate these pathways (excess free radical generation by way of energy pathways is one of those cell suicide triggers, for instance), it's already shed a lot of its suicide signals and it's just burning through energy without heed for the tissues around it.

I hope that helps.

So, this is just a conceptual schema, and not a hard-and-fast rule. It was first published by Robert A. Weinberg in 2000 as "the six hallmarks of cancer", as an attempt to distill down everything we knew about cancer genesis into something we could understand as a model. He's considered the grand high poobah of oncogenetics. There've been people fretting at the details of his model since then, so it's grown a bit.

Also worth noting that this model was basically built on solid tumors. Liquid cancer (cancers of the blood - e.g., leukemia) have a different, more poorly studied path, though the broad brush-strokes seem to be the same.

The original model was: -Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential

The version that I learned in grad school was up to 8 hallmarks. Apparently it's evolved a bit more since then, and the most recent version being bandied about is:

-Evading apoptosis -Self-sufficiency in growth signals -Ignoring anti-growth signals -Autonomous, ongoing angiogenesis -Tissue invasion -Limitless replicative potential -Avoiding immune destruction -Tumor-promoting inflammation -Genome instability and mutation -Deregulated cellular energy metabolism

Honestly, I'm not sure the ten hallmark model really adds anything - I'd argue that the four additions fall neatly under the old six. But whatever - it's just a model, and doesn't change the granular reality at all.

To summarize each of the hallmarks in brief:

(1) Evading Apoptosis. Cells have a number of mechanisms that basically say "something's off here, I should kill myself now."

For instance, when DNA repair enzymes get upregulated, so does p53 - if p53 tips over a key value, it starts setting off the suicide pathway. So, "too much DNA damage" = "cell offs itself rather than propagating damaged DNA." There are actually a bunch of proteins in the cell see-sawing here, in response to internal and external signals, and if the "kill yourself" signal tips the see-saw, the cell dies.

Pretty much any mutation in the cell suicide pathway predisposes to cancer. For instance, an extrinsic trigger of apoptosis is binding of what's called the FAS Ligand to the FAS Receptor (a big part of how immune cells regulate their own suicide, to prevent auto-immunity.) A mutation in FAS Ligand, or FAS Receptor, or anything downstream of them, will predispose to autoimmune disease and cancer.

Another one is the anti-apoptotic protein BCL-2, which you'll find overexpressed in something like half of all cancers.

Since cancer development triggers so many "kill me now!" signals, turning this pathway off is a hallmark of cancer development. The cancer will usually do so through a combination of over-expressing anti-apoptotic proteins, and under-expressing pro-apoptotic proteins.

Do we make use of this knowledge for therapy? Sure do. One therapy is a BCL-2 inhibitor, Venetoclax. Methotrexate, which slows down cell proliferation, also causes adenosine accumulation that can trigger apoptosis. These drugs have varied benefits: when you target the specific broken pathway in the cell, they're excellent (e.g., BCL-2 in CLL). Cancers are good at evolving around these therapies though, so they're not used as mono-therapy.

(2) Self sufficiency in growth signals. Normal cells don't just grow on a whim - they require signaling from cells around them and from distant parts of the body, to ensure things are kept regulated. Once a cell starts generating its own growth signals, though - like an army in revolt, giving its own orders - then you're on the path to cancer. This is one of the key mutations that gives rise to the "atavistic cell" description of cancer - they've thrown off their shackles, and become wild cells again! Well, not really - even wild cells are careful about when to expend the resources to proliferate. Bacteria commonly depend on their neighbors - using whats called quorum sensing molecules - to control their growth. Heedless, runaway growth is not the norm even in 'wild' cells.

(3) Ignoring anti-growth signals. Most everything in the cell is the process of see-saw balances: there are always signals pushing in each direction, compensating biochemical pathways, and shifting balances. Growth is no exception: how the cell acts is in response to a whole bunch of pro- and anti-growth signals, and most of the time it moves in the direction that they're pressured to by the consensus.

Well, if one of the hallmarks of cancer is like an army giving itself orders (independence from external growth signals), another is the active refusal to heed anti-growth signals (shutting down lines of communication with the Joint Chiefs of Staff). This may be because key anti-growth receptors are broken; it may be because something downstream of those receptors is broken. The key is, though, that between "I'll tell myself when to grow" and "I don't care what anyone else says to the contrary," the cell is now positioned to grow and grow and grow.

(4) Autonomous Angiogenesis.

Tissues need oxygen and nutrients and stuff. However, that stuff really only travels a tiny distance from the smallest blood vessels - capillaries - because it has to leave the capillaries via diffusion, and the time for something to travel by diffusion increases as the square of the distance. So, going 4mm will take 4x longer than going 2mm. Forget about feeding tissues 1cm away from a capillary - it's not happening. Usually, outside of embryogenesis, blood vessel construction is rare - it happens when a blood vessel is damaged, and it secretes growth signals to build a new vessel. (In fact, in a well regulated environment, this is often followed by signals to kill some of the new vessels, too - which is why a fresh scar is red and angry, but an old one is pale and avascular. The blood vessels that came in to supply immune cells and fibroblasts actually regress.)

So, anyway, here's our tumor - replicating like wild, if it can, not caring if it grows too far from a capillary. One of the consequences is rampant cell death. Tumors aren't healthy, they're usually riddled with dying cells. Another consequence is shifting to anaerobic metabolism - which, yay, don't need blood supply so much. But it's also massively less energy-efficient than oxygen, so any tumor cells that can make use of oxygen supply will tend to outreplicate those that can't.

So what happens? Almost inevitably, they start secreting stuff like VEGF (vascular endothelial growth factor) to grow their own blood vessels. These vessels are messy and leaky and prone to breaking, but they're so much better than nothing, and our tumor is off to the races.

Do we target angiogenesis in therapy? Yeah, there's a shit-ton of drugs that inhibit angiogenesis (you might have heard about bevacizumab a lot lately - we've also given it to Covid patients at high risk of hospitalization, since nothing in the body ever only has one effect).

I'll continue in another post; I'm not sure if HN has length limits.

You've got it essentially correct, it's just that every metabolic pathway is in a dynamic equilibrium. So let's say you do deprive the body of fresh glucose intake. While liver is turning fat into ketone bodies, and brain and skeletal muscle are digesting those ketone bodies, at the same time that TCA cycle that is now getting fed ketone bodies is going to push back upstream to tilt 'eat sugar' (glycolysis) a little bit more towards 'make sugar' (gluconeogenesis); meanwhile, other ketone bodies (dihydroxyacetone) are going to plug right into the gluconeogenic pathway.

The body will be making glucose where it can, because, if I recall correctly, red blood cells can't make use of ketone bodies, full stop. Some level of production must be maintained.

Which, in the body's parlance, is 'starvation'. If red blood cells are going hungry, from the body's perspective, there's a serious problem. But that's part of the difference between true ketosis and a ketogenic diet - the latter continues glucose intake, with a preference towards stimulating ketogenesis. The former is "oh fuck where's the glucose why can't I use the glucose aaaaaah!"

I gotta go refresh this now - you're painfully reminding me of how long it's been since I reviewed biochem.

It's fair to say that it's a "failure of immunity," though it's a bit more varied than that. You might have started with a failure of the immune system, in the sense that something like autoimmune proliferative syndrome means cells that should be committing suicide aren't, and so eventually you have cancer. More common is a "normal" immune system, and a cancer cell lineage that evolves to be invisible to it.

Either way, it's fair to say that normal cells and cancer cells are divided by the fence of "immunity," and cancer doesn't happen until the cancer cells hop the fence or the fence falls down.

I suspect the fear -> cortisol -> immune suppression -> cancer pathway is probably, quantitatively, pretty small.

Stress does have negative effects on the immune system, in the broad sense, but granularly it gets more complicated. For instance, one of the key cells involved in keeping cancer at bay is the CD8+ cell. While total CD4/CD8 t-cell counts seem to trend down when cortisol trends up, CD8 T-cell counts actually trend up.

We know that Natural Killer T-cell activity drops in response to cortisol, in isolation, but that it has differing effects on NK cells in different organs. In some organs, it had no impact at all, due to shielding by other inflammatory signals.

It's probably true that there are some people who, if they didn't stress out about getting cancer, wouldn't have gotten cancer. I suspect that number is very, very, very low, though, and I'd certainly never tell a patient (or believe about a patient) "if they'd had different thoughts, they wouldn't have cancer."

I can't rule it out as never having happened. It's not physically impossible. But, compared to all of the other things that play a role in cancer development, it's probably not worth mentioning.

(I feel like I should clarify on the first paragraph: in short, every cell is somewhere on the continuum between 'normal cell' and 'cancer cell'. The only difference between the two is time. Like that Palahniuk quote, "On a long enough timeline, everyone you love is dead"? Well, "on a long enough timeline, every cell is a cancer cell.")

1. We do attempt to attack cancers by reducing their available energy. That's why, at one point, a major field of research in cancer therapeutics was interfering with angiogenesis, because cancers will secrete messengers that help grow them dedicated (if crappy, low-quality) blood vessels. The issue with "starving" them more starkly is that they're very good at getting a share (e.g., forcing the body to supply them with blood vessels), so you're going to be hitting other labile tissues as fast or faster (skin, GI mucosa, blood and immune cells.)

Another way of targeting their rapid metabolism is pointing our therapy at cells with high replication rates. A number of our cancer therapeutics are aimed directly at cells that are currently replicating, which should selectively hit cancer cells (though again, it hits skin, GI mucosa, blood and immune cells, etc. because they're also high-turnover cells.)

We use methotrexate to interfere with DNA synthesis, thus reducing the rate of replication altogether (in cancer cells, as well as.... above).

The problem is, besides the dose-limiting toxicities of all of these things (because targeting metabolism hits all high-metabolism cells), is that cancer cells are really good at developing resistances. So, for instance, if you starve them of blood supply, they'll switch to anaerobic metabolism of glucose. If you starve them of glucose, well, you can't really - I'll discuss that below. If you give them methotrexate or other nasty drugs, they alter the cells' native drug-efflux pumps to target those drugs better and pump them right out of the cell. Cancer cells have a broken mechanism for protecting DNA - the result is really high rates of cell death among cancer cells, and also really rapid evolution.

In terms of starving cells of glucose: glucose is the least common denominator of cellular metabolism. It's the primary food source for the brain. Different cells have different receptors for absorbing it, with different levels of affinity. If you're running low, pretty much every cell in the body that can will kick up metabolic products to the liver to turn into glucose it can share with the bloodstream - because the best receptors in the bloodstream for picking up glucose belong to the brain. You'll starve, or poison, the brain long before you manage to starve out a cancer. (Yes, Ketone bodies are a thing, but that happens alongside your body mobilizing everything it can to feed the brain, not instead of.)

We also can't 'see' all the tumor. The way cancers actually develop is you have an abnormal cell A, which grows into a tiny nest. These are below detection in any practical clinical way, and we don't want to treat them because they're ridiculously common - your immune system wipes them up. If we tried to detect and treat them all, we'd kill everyone with side effects long before we prevented a fatal cancer.

Out of the bunches of these that develop and die, or develop and go permanently quiet, one gets active enough to start seeding tumor cells into the blood stream. Most of those cells will die, too, because blood is rough for cells not built to withstand it. Most of these are going to be undetectable in any way, and do nothing to people.

(Every time I say something is undetectable, I mean "Except for high precision laboratory experiments used to detect just such things").

Eventually a tiny pre-pre-tumor will start seeding cells into the blood stream that can survive the blood. These will get seeded effing everywhere. Most of these are permanently quiescent and do nothing, ever. They exist at the level of single cells - we can't see them. They don't do anything, metabolic activity very low, so we can't target them.

Once in a blue moon you get one seeded that is actually metabolically highly active. Or maybe it mutates into metabolic activity later. Most of those die.

Once in a blue moon, one of these will live enough to start replicating for real. Most of those get wiped out.

And once in a blue moon, they start replicating for real, and develop immune evasion, and you have something that becomes a cancer, maybe. Or it gets triggered by something external and becomes a cancer. There's a "seed and soil" element here. It'll often start seeding back into the blood stream.

By the time you have a detectable mass, your entire body has been seeded with these cells, most of them both un-image-able and un-selectively-treatable. Luckily, the overwhelming majority of these cells - lots of nines - won't do jack. Of the trillions that will seed your body, if we stimulate them just right, you might get a couple of new tumors, or none at all.

We know this because we learned that tumors benefit from circulating inflammatory markers early in modern oncology. When a surgeon took out a tumor, not infrequently, a patient would come in a year later with a new one or two that weren't previously detectable. We eventually learned that the inflammatory growth signals that come with surgical trauma can provoke an otherwise sleepy tumor cell into metabolic activity.

Which is a roundabout way of saying "cancers are more metabolically varied than the late, aggressive stage of the process we usually refer to as 'cancer' would suggest."

That being said, if you could inject something directly into the tumor (rather than the bloodstream would prioritize sending said poison pill glucose to the brain or liver) and take advantage of its metabolism, that would be great. We do kind of do that: we implant radioactive pellets directly, with the added benefit that we know it won't affect much tissue outside of the immediate area.

I hope my answer was actually useful in providing some biological context? I'm afraid I might have just word-vomited instead of being helpful.

It's not close to even 'relatively' being new. I was giving cancer talks that made mention of it back when I worked in cancer bio, just about 16 years ago now. I didn't come up with it, and it wasn't new then. I used it in talks to laymen, to give a very abstract idea of how cancer worked. But it fell into the category of "lies we tell children," because it was only true in the most abstract way, and utterly incorrect once you dug into any details.

The reason cancer bio people dislike it is because it's only true at the 10,000-foot, highly abstracted level. When you start digging into the granular level, its testable predictions rank between 'falsified' and 'irrelevant'. It doesn't produce any alternative lines for thinking about treatment, causality, etc. Especially given that the progress of a single cancer tends to be all about their interaction with the multicellular milieu - e.g., developing immune evasion, which isn't at all an "atavistic" trait, although it's one of the core hextad that defines malignant development. (On the contrary, it comes built-in for normal cells - they're now developing a novel immune evasion, to hide their newly altered antigens from the immune system).

e.g., "Cannot help but switch to previous single-celled metabolism" doesn't follow in any meaningful way from the thesis of atavistic traits. In fact, it doesn't predict at all the relationship between tumor size, distance from vascular supply, and anaerobic metabolism. "Cells without controlled growth will outgrow their vascular supply, requiring a transition to anerobic metabolism" does, however, and predicted the relationships we see. It's not "cannot help but engage with less efficient metabolism", it's "transition to relying on the only metabolism afforded to a highly-dysregulated cell that is not responsive to environmental signals that normally trigger or withhold growth." Normal unicellular organisms are responsive to those signals.

Yeah, I don't hate it - it's a cute metaphor. It's a nice way of thinking of cancer at the 10K-foot level. It's just also wrong at any closer level of inspection than that, which is why people whose job is to be elbow-deep in all of the nitty-gritty details of cancer can't help but look at it and go "please stop wasting my time."

I can't say that I did it without trepidation or concern of stigma, but I was surprised at the degree to which that fear was unjustified. In hindsight, I don't know whether I was over-exaggerating the feared stigma in keeping with our cultural expectations, or as an expression of the depression itself. Either way, I can tell you that the experience was painless. Getting appropriate medication also made a world of difference, to such a degree that nowadays, when things deteriorate, I can qualitatively recognize "those" thoughts and feelings as not belonging to my normal palette, though there are grey areas that sometimes sneak up on me.

I don't speak up on my behalf, as you're right - I'm just a stranger on the internet, and we'll forget about each other soon enough. I'm speaking up on behalf of the people in your life that you're currently telling yourself will be better off without you. Because they won't be better off, and they'll carry the pain of your absence as a wound that doesn't heal.

There are signs of people not being a high suicide risk, despite depression and overt claims of suicidality. This post is the absolute opposite of that - if you were with me in the clinic right now, I'd consider you an incredibly high risk of an actual suicide attempt. Please, please, please, please reach out to a professional and friends for help. Please.

I'm really glad that it's finally come to fruition, but I definitely feel a bit of regret that I have come to embody the "ideas are cheap, execution matters" truism.

If not for that, it would indeed be decades-old egg on their face. I think they’ve done a fair job of freshening up that egg, though.

Just saying.

There's a lot to go through.

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.

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.

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.

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.

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.

AKA, drug belonging to [drug class] that kills [neuronal tissue] will also kill [bad neuronal tissue] through same mechanism as [general drug class].

The key question is "if putting a shit-ton of opioids (which already cross into the brain) in cancer patients doesn't already meaningfully treat this condition, why do we imagine that delivering the same class of drug past the blood-brain barrier suddenly will?"

Having worked in a breast cancer lab once upon a time, I can tell you: because run-of-the-mill cell biology doesn't get grant funding if you don't attach "early cancer diagnostics" or "potential cancer treatment" to the grant application.

1. Loperamide is not unique. I don't know why these researchers have singled it out. Is it because they heard there's an opioid that doesn't get you high? It only avoids getting you high because it doesn't get into the brain. IF you deliver it to the brain to treat a brain tumor, it will get you high.

2. Patients with GBM already get a shit-ton of opioids for pain, which do cross the blood-brain barrier. Is there any reason at all to imagine that this opioid, using the same mechanism as other opioids, if delivered the area other opioids already reach, will have a different outcome?

3. I don't understand why identifying that loperamide causes cell death via ATF4 is even worth publishing. "Opioid that causes cell death uses same mechanism as other opioids that induce cell death"? Maybe I'm missing something here?

4. This was published in Autophagy. Which is another way of saying it wasn't novel enough to be published anywhere anyone reads. Which is why this is a university press release, and not a discussion by anyone else.