> Several classes of opioids have been shown to cause neuronal degeneration
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?
That's an excellent question, and an area of active research. It differs a lot by drug, though, because of their affect on different signaling systems, different neurons, and due to indirect damage to the brain from effects elsewhere in the body:
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.
Wow, that's a really great summary, thank you! If you wouldn't mind, I am very curious about two things:
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?
So, my interest in these drugs is primarily from a therapeutic standpoint, so those without therapeutic effects are less within my wheelhouse. My ignorance caveated, I'll say with a grain of salt:
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.
Are animals in his studies which show damage injected with doses which are comparative to what humans inject, adjusted for weight? Or are they using much larger doses?
>Alcohol, on the other hand, is a glutamate blocker, which increases sensitivity to glutamate signals.
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.
I'm a big fan of Stahl's Psychopharmacology. Since pretty much every illicit drug has a legal equivalent, but the legals are better studied, you'll probably find that a good source. If your primary interest is illicit drugs, though, I don't have a good suggestion - it's not the sort of book too many careers are built on.
This might be the third or fourth time I've been asked so I'm going to write about it on my website tomorrow and share it here once I'm done. Apologies.
I'm interested too; feeling described to a T by your post. I struggled heavily with focus issues as a child / teen but it was never diagnosed far enough to try and medicate me out of it. As an adult with improved awareness of my attention issues, the prospect of pursuing a prescriptive fix that might just make me feel worse is intimidating.
I got diagnosed with ADHD at 31 and got a prescription for methylphenidate (Ritalin is the most known brand name for this)
I think medicine should be used as a last resort and it is not a "fix" or "solution". Dealing with my ADHD is still a daily struggle and I didn't transform into a better person by taking the medicine
What it did was to turn my experience of my life from a large overwhelming interconnected problem into small doable issues. It made me able to pick up each of the many broken aspects of my life, fix it, and move on to the next
I'm afraid of the notion, I often hear, where medicine "fixes" something. My ADHD didn't go away with the medicine, but it did make me able to take responsibility for my own life and feel confident enough in myself, that I don't want to apologize for needing a different environment to be productive
The good thing about methylphenidate is that it works quickly (20 minutes or so after taking it), so you know pretty quickly if it's a good fit. It wears off after 4-8 hours depending on the formulation, so if you feel worse it'll only be for a short period
For me, my add has been made much better with aggressive weight training. I started doing "Starting Strength" and transitioned into the Texas method but three pretty heavy workouts a week really helps.
Normally I feel like I see the world through the narrow end of a funnel. When I get done with a big workout, somehow for the next day or so my brain is chilled out and I can concentrate again. After two days or so I start to regress a bit but another bout of lifting resets me.
I only really need medicine during periods of bad health or incredible personal stress now.
Interesting, I've recently started committing to a hard 10-minute workout each day of the week, and it's been helping me focus through my ADD a lot better too. I feel so much more alive.
I've also picked up meditating 10 minutes a day and that's been helping as well, but I don't think as much.
I've got a theory about why it works. Basically you're tiring out parts of your brain when you exercise and activating others. Somehow that regulates the neurotransmitters at the heart of add for a while. If I only lightly exercise, I don't get the same effects. The workout has to be strenuous and I need to feel like I worked both body and mind (finishing that last rep under heavy load takes willpower and concentration).
I bet that HIIT could be as effective as weights for me because the curative part seems to come from exhaustion and exercise of will.
Meditation may or may not be as mentally strenuous, I am not really familiar with it.
Yes, if TSLA is 1% of S&P500, short $1,000 of TSLA shares for every $100,000 of SPY you own. And then dynamically hedge as the price fluctuates. This doesn’t really work unless you can borrow on margin for cheap and have lots of money (unless you can short partial shares, lol)
Not saying it’s a good idea, only that it’s possible
There are a lot of illusory ideas out there for beating the market. But I do believe there’s at least one way to do so without any special expertise, and that’s to studiously avoid being sucked into the frenzied, speculative bubbles that seem to reliably take hold of a significant fraction of the population.
In an efficient market, one might expect the smart, rational players to correct these bubbles. But once they’ve sold all their own holdings, you’re left with a Winner’s Curse [1] dynamic where the most (irrationally) optimistic investors are the ones ultimately setting the price. And essentially the only way the rational players can affect things from there is through short-selling, thereby risking running afoul of Keynes’ famous adage about the market remaining irrational for longer than they can remain solvent.
Thus there can fairly regularly arise situations in which somewhat common knowledge has it that some asset is overvalued, without the price of that asset collapsing. Until eventually it does.
It seems to me, then, that it’s not so foolish to attempt to get some of the diversification benefits of an index fund, while avoiding particular components whose valuations seem to defy rationality.
Per Ray Dalio's "Holy Grail" math, supposedly you'd buy the top 7, 15, or 20 uncorrelated equities from the S&P 500, and capitalization-weight them yourself by hand.
Everyone please be careful buying puts if you're not doing it for insurance against current holdings. If you're buying anywhere outside of the .30 delta and less than 21 days until expiration (even then) you're probably buying a lottery ticket.
The average person would be better off buying 10 x $5 scratch off lottery tickets tomorrow and accepting the result... than buying a far out of the money short dated put.
I’m sure there are broad market Vanguard ETFs out there that won’t have Tesla in it and will make no changes based on this announcement. This is really just ETFs that track S&P 500.
This is stupid. I've seen 0 signs of this as the FAANG company I work at (my gauge being our internal forum). Absolutely 0 mention of this. No mentions from coworkers, friends, etc.
> and it the only company with increase in # of deliveries among the 10 largest autos globally
I'm sure others have commented, but this is some real silly logic. Yes, going from (fake numbers) 100k -> 110k cars sold is a lot easier than going from 1M -> 1.1M.
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?