Is Ketamine Neurotoxic? | Hacker News Reader

Is Ketamine Neurotoxic?

desmolysium.com

201 pointsamadeuspagel228 comments

Regardless of the answer to the question posed here keep in mind that high powered psychiatric interventions can be very effective, even if they don't last forever. Whether it's ketamine or electroconvulsive therapy - it's certainly better than suicide. At least promise yourself to try such things first (in a hospital setting! yes they have those in hospitals in developed countries) before you make the conclusion that your life has become too painful to live it.

PS. there are many other treatments that doctors may give you before reaching for the big guns; those can be very effective too.

>PS. there are many other treatments that doctors will give you before reaching for the big guns; those can be very effective too.

This part can sometimes be difficult if you are in crisis. There’s lots of other options like you mention but they tend to take longer to see an effect. Ketamine can be very immediate in that regard. I remember it being like a light switch and thinking “wow this is how others must feel!”. And just seeing, even once, that it is at least chemically possible for your own brain to work/think like that can be very inspiring and hopeful esp when it feels like it hadn’t been worked correctly for a long time (or ever)

How would you compare this feeling with taking psilocybin?

My personal experience. With ketamine you can see/feel your problem outside of you in many ways. With psilocybin you can dive straight into problem's answer.

Both ways can terrifing. Also It can be unpleasant or rewarding.

If that makes sense.

Thanks. Some day I will have the courage to try. Until then Erowid

The DeepMind researcher's letter elsewhere in this thread suggests to me that ECT is infinitely worse than suicide.

I don't think he really blames ECT for what has happened to him. It's more like "ECT didn't fix it either", which is a possibility - ECT isn't a guaranteed cure. For example:

> They [the NHS] couldn’t prevent this. Hundreds of hours of therapy couldn’t prevent this. A large network of friends and family checking in with me constantly over the last year didn’t prevent this. Psychiatric hospitals certainly couldn’t prevent this. ECT couldn’t prevent this. The only person who could have prevented this was me.

And the memory loss he's talking about (which is indeed a common side effect of ECT) doesn't seem to be as severe as he claims to be. For one he is actually able to recall the events of his life well enough to write this letter. For another he has abused ketamine to the point of having a month long psychosis episode that ended in involuntary stay in a mental hospital, which could have had its own effects. For yet another depression itself slowly erases memories.

Someone close to me did ECT for half a year after ketamine (in a clinical setting) became less effective.

The memory loss was worse than they were led to believe: near-dementia levels of short-term memory loss during treatment, and still now a year of missing memories from around the time of treatment.

The treatment itself left them without time or energy to do anything whatsoever on the days of treatment, and still weakened on the days off treatment.

And, it did seemingly nothing to address their depression.

So, YMMV.

I’m not sure what this means, but it’s not true. I have met people that are happy to be alive after ECT

When it comes to anything depression related, you should never rely on anecdotes alone.

The world is a big place. Many people have tried depression treatments. You can always find someone who had a very negative experience with something.

For a counter-anecdote: I know someone whose mother was deeply suicidal and unable to function for years. Eventually they tried ECT and it was the turning point in her depression. This was decades ago and she’s still doing okay today.

Do not let internet anecdotes steer depression treatment. ECT is an extreme example. I’ve seen countless people who avoided any depression medications for years because the internet told them SSRIs were evil drugs, only to experience life changing results for the better when they finally listened to their doctor and accepted treatment.

> PS. there are many other treatments that doctors may give you before reaching for the big guns; those can be very effective too.

Further, everyone reacts differently to different treatments. It's very, very common to need to try several things out (or even come back to things in different combos) to find the one that works best for you.

Heck, sometimes during the course of treatment a drug that didn't previously work for you will start working as intended.

I had a happy evening last July.

> However, the average ketamine “user” consumes 500-1000mg of ketamine per day

This is an outrageous claim with no citation. I'm a regular user, and this is roughly what I consume per month, if I'm going hard

It feels like a low-quality article in which the author is writing about a scientific topic but has no qualifications or expert knowledge (and therefore making wrong conclusions due to their lack of understanding around the research they cite). I don't understand why people feel the need to publish such blogs.

Agreed. It's an absurd dose assumption. According to Erowid, a common dose is 30 mg to 75 mg.

I spent some time reading papers about ketamine before, and it seemed that all the negative side-effects (like bladder damage) are only ever observed in extreme cases where someone takes massive, abnormal doses for an extended period of time. I think it is not relevant to the vast majority of recreational users.

I once did 75mg in a session and left with the feeling that that was way too much. I can't fathom 500.

Stupid raver trick layout a line of K like it's coke and snort it.

I thought that was the normal way. I guess that makes me a stupid raver? I was introduced by a hippie I met in the woods.

Definitely on the high side, but I'm guessing they mean "chronic abusers" rather than just "user". The serious ketamine addicts I knew when I was younger took the drug every single day, and multiple times during the day. I think that figure seems right, since a single large line can be north of 200mg.

I know: it's insane that someone would do that much ever, let alone every day, but I assure you that it happens.

>I'm guessing they mean "chronic abusers" rather than just "user".

It's a critical distinction to make. With everything we put in our body it is often 'the dose makes the poison'. The way the article is now, it's something skin to propaganda saying that beef causes death because there are some 600kg McDonalds addicts having heart attacks

Tolerance buildup is such an economic pain in the ass innit? Abuse vs use I guess. I know a lot of people who do ket but very few who do lines of it.

I haven't had good experiences with being a tranquil horse but I used to smoke a lot of weed when I was younger, I still smoke but much less and it's crazy how non linear it is, I subjectively feel like I'm probably 1/3 as high on average as I was five years ago but I spend maybe 20x less on weed.

It's also worth noting that ketamine does appear to increase neural plasticity and can promote the formation of new synaptic connections (synaptogenesis), particularly in areas of the brain involved in mood regulation.

That being said, I too have experienced tolerance with ketamine infusions- even with a month between doses. Always found it a bit troubling and I'd rather not have to continue to increase the dose.

The article talks about that. That's just not true in medical literature

Although everything seems to be researched thoroughly there are many mistakes. Mistakes that are pretty basic (like Venlafaxine having it's origin in an amphetamin instead of tramadol) and lead me to the assumption of sloppy work. In addition study results are stated as facts whereas reproducibility is very poor in psychiatry.

In addition microdosing escitalopram at like 2,5mg/d seems like it is mostly placebo. When introducing a drug there are dose response studies done, that determined that ESC needs 10mg for most people to be effective against depression. Same with 2,5% of the starter selegiline dose.

I think the texts of this author need to be viewed with much caution.

> However, the average ketamine “user” consumes 500-1000mg of ketamine per day, which is 100-300x as much as therapeutic use (0.5mg/kg)

For users weighing one kilo. For users of a more normal weight, you’re off by an order of magnitude.

The author clarifies later that the listed therapeutic dosage is weekly rather than daily, so that's 3500-7000mg/week versus 35mg/week for an average person (from a quick Google, 70kg).

Not sure where the 300x is coming from, since that's an average body weight.

1g/day is a pretty extreme dose, even disregarding that most users don't consume it daily.

It is however not unheard of, or even uncommon. With moderate tolerance, binging a couple of hours will reach the 1g threshold quite quickly.

Ketamine tolerance upon continued use can reach some really wild levels. I’ve worked with people who reported that a 1g single dose nasally won’t get them properly high.

Wow, I googled and the dose for horses is about 2 to 5 mg/kg

It should be noted that in this example we are comparing insufflation vs injection, which has a very different bioavailability and effect on the body.

I think for therapy with humans it is also given as a nasal spray.

Oh definitely, I thought about writing about it but omitted it, I should have added it earlier

It’s the same dose (per body mass!) for humans, and ketamine is heavily used in human medicine for similar reasons. The main difference is that for horses it’s mostly used as an anesthetic, while for humans it’s also used at lower doses as an analgesic (pain reliever).

When I severely dislocated my shoulder the hospital sedated me with ketamine and propofal. They'd already given me the max dosage of morphine and fentanyl to get me to be able to barely sit up for an X-ray.

So I'd say it's used in humans for anesthetic too.

And guys, I'd the doc says after your first dislocation you should have the surgery to prevent it from happening again, you should listen to them so you don't spend a night in excruciating pain three months later.

For what it's worth, when I came too I felt like I was black out drunk, not a good experience for a previous alcoholic

Yeah but I mean, 1g is a 200kg human dose in the best case. That's a lot

Yeah, I'm not sure that 'weekly' is true either, most of the research I've done says 0.5mg/kg is a single 'dose', rather than anything timebound. A lot of the protocols seem to indicate that twice weekly is the most common dosing, but it depends on the usage:

https://www.drugs.com/dosage/ketamine.html says 1-4.5mg/kg for anaesthesia, with more as needed to maintain

https://reference.medscape.com/drug/ketalar-ketamine-343099 says 0.5mg/kg for depression off label, repeated twice weekly.

https://dancesafe.org/ketamine/#:~:text=30-60%20mg says that the common recreational dose is 30-60mg, so the number mentioned by the author is between 50 and 250 'bumps' a week? I'm not familiar with ketamine usage, but that seems to be a very high number.

ROA (route of administration) also matters, and those figures you've given appear to be a mix of IV (intravenous) and IM (intramuscular) injection doses.

Many recreational users insufflate (snort) ketamine, and that ROA has much lower bioavailability than IM or IV - IIRC, it's something like 20% for insufflation, 80% for IM, and 100% for IV. Thus, you need a much higher dose for snorting.

I agree. The article is unclear though.

For recreational users snorting (I think it's 'insufflate', rather than insulate), the DanceSafe link is clear that that's the method (it says 'snort 30-60mg').

As you say, you'd expect users to need a much higher dosage for snorting than IV.

Either way, the article has since been silently updated to remove the 100-300x claim that I took issue with, so either I, or someone else, managed to get the point across to the author.

> I think it's 'insufflate', rather than insulate

Haha, auto-correct strikes again!

There are many things wrong with the claim, but even the math doesn’t make sense.

0.5mg/kg for a 70kg person would be 35mg, which is not 100-300X less than the 500-1000mg number.

The claim isn’t even close to mathematically correct. It’s also easy to find clinics giving IV or IM doses at significantly higher rates.

This entire article does not leave a good impression, to be honest. It feels like the author started with one conclusion and then made assumptions to fill in the blanks to write the article.

That's a therapeutic dose for users weighing one to two tonnes. I don't think they're off by any orders of magnitude.

They are confusing oral vs. IV. There are different amounts of ketamine used for different ROA's. Typical dose for prescribed lozenges is 200-250mg.

Now it says:

> However, a heavy ketamine “user” often consumes multiple grams per week, which is a lot more than therapeutic use (0.5mg/kg about once per week to every other week).

Ketamine Georg, who consumes 420 kg of Ketamine per day, is an outlier and should not be counted.

You can (try to) consume 420 kg of Ketamine one day, but you surely won't be able to repeat it the next day...

https://en.wikipedia.org/wiki/Spiders_Georg

I'm finding this draft article pretty confusing, and am not sure why it's shared in its current state. I think it should also cite sources.

> "However, the average ketamine “user” consumes 500-1000mg

My impression was that the majority who try ketamine do it a handful of times in their whole lives, usually <200mg.

They almost certainly mean habitual user.

For anyone interested in the therapeutic (or otherwise) use of ketamine, I strongly recommend the autobiography of John Lilly, the neuroscientist who developed the sensory deprivation tank. His discussion of ketamine-aided spiritual entity discovery and dolphin communication are enlightening.

https://archive.org/details/scientistnovelau00lill/page/n5/m...

I spent some time around a ketamine abuser and it was shocking how he seemed like… at one point he was a very capable and knowledgeable person and how much was just gone.

I know a person who was doing it a lot and then stopped. It seems that at least the illusions of grandeur and the usual spiritual nonsense are not a permanent thing.

Reading through the article and comments, it seems like there's a lot of confusion about what is considered "a user" and what typical dosages are. Obviously, a rave fiend who used to do MDMA twice a week and coke at least 5 and then moved to K would consume, completely disregarding this health but still staying conscious enough to continue dancing on a dance floor. At the same time, a tech worker who does Yoga, goes to Burning Man every year and have a long and productive relationship with psychedelics probably does a very K every 1-2 years in the right set and setting, but consumes a dose high enough to venture deep into the K-hole to seek some mystical answers — just as he does the same with DMT and other exotic Shulgin creations.

From the anecdotal data (including the tragic suicide note that pops up on HN every now and then) and sporadical research, it's very unclear how much danger does the second scenario actually entail.

> Nonetheless, it’s widely recognized that individuals who occasionally use ketamine find they need significantly higher doses than when they first started, even after prolonged periods of abstinence.

Sorry for the slight divergence from the focus on ketamine, but more generally, does anyone know if this applies to other medications that alter the brain's function?

I've noticed the same phenomenon with the adderall I am prescribed for ADHD, and despite the tolerance buildup and the offer from my psychiatrist, I refuse to bump up the dose further due to fears of long-term changes in the brain. Honestly, I'm considering ditching it altogether after about a decade of prescription because I become more paranoid over time about unknown, long-term effects. Posts like this about ketamine don't help my suspicions.

>Sorry for the slight divergence from the focus on ketamine, but more generally, does anyone know if this applies to other medications that alter the brain's function?

Tolerance is a phemomenon where after using a drug regularly for enough time, you will eventually need higher doses to achieve the same effect. A tolerance effect exists for many classes of medication, but in this case there is something specific to Ketamine.

With Ketamine, it can (reportedly) be much harder to reverse this built-up tolerance. That's what they mean by "even after prolonged periods of abstinence". Heavy abusers of Ketamine report having stopped for several years, and finding that the tolerance comes right back the first time they use it again.

With stimulants, this tolerance goes down after a period of abstinence (e.g. switching to a n̶o̶n̶-̶s̶t̶i̶m̶u̶l̶a̶n̶t non-amphetamine ADHD medication like Metylphenidate for a few weeks is known to lower tolerance to other ADHD drugs).

I would generally not worry about tolerance to stimulants at prescribed doses. You should try to avoid taking medication you don't need, but if you need the stimulants to function, the cost/benefit of stimulant medication for ADHD is highly favorable. Even if there is a slow tolerance effect, it can be reversed.

Taking stimulants for ADHD is not dangerous like taking Ketamine for partying is dangerous. Stimulants have the highest efficacy of any known drug in psychiatry. The medical interventions with the lowest NNT are things like insulin for diabetus, or not very far down, stimulants for ADHD. It's more than fine.

Methylphenidate is a stimulant medication [0]. Maybe you meant something else, like atomoxetine?

[0] https://en.wikipedia.org/wiki/Methylphenidate?wprov=sfti1#

You're right, of course. There is a difference between methylphenidate and other amphetamine-class stimulants for ADHD, but I didn't know what to call it.

I should have said it's not a direct agonist. Instead of directly causing dopamine release, it acts as an allosteric modulator on DAT to affect reuptake.

I had a study in mind that found switching to MPH was effective at lowering the equivalent dose (the tolerance did not carry over), but my Googling is failing me right now. Appreciate the correction.

Thank you for the clarification. I didn’t know about the differing mechanism, and you’ve sent me off on a research rabbit hole. Always a happy result of an HN thread. I appreciate your follow up!

I looked into this a while back, and found some reviews from some branch of the Canadian health authorities, that said that euphoric effect of methylphenidate fades more with tolerance than the therapeutic effect.

So you will still be getting some adhd related benefits from it, even if you're not feeling that little rush that you felt when you first started taking it.

Like the other commentator, I do like to skip some days occasionally (mostly on weekends). I usually see on day 1 that I was most definitely getting some benefit from it the day before, even when it didn't feel like it.

In general you should listen to your doctor for these things; if they say that an increase in dosage is recommended, listen to them. Although I am not very sure about the word "offer". What do you mean "offer" from your psychiatrist?

If you are worried about long term effects of stimulant medication (which is a very valid worry), you may want to ask your doctor for an intermittent schedule. Sadly, as we know, many of us need the medication to function reasonably in daily life. However, if you are building tolerance to the medication, it is probably worth it.

I think the Sackler family destroyed most people's trust regarding listening to their doctor about their prescriptions. You can't really come back from that...

Doctors themselves are at least partially, if not mostly, responsible for that lack of trust. The Sacklers might have been pushing on the doctors but the doctors were the ones writing the prescriptions and ultimately responsible for the health of their patients.

The Sacklers gave docs the wrong guidance on how habit forming it is. A doctor is busy and needs to be able to trust the experts- those who make the drug.

As someone who has been medicated for mental illness for several decades and went through this dance countless times, I can assure you that this is the worst advice to give somebody.

Psychiatrists aren't evil, of course, but they're not going to tell you (or are always aware) of all the minutia of long term effects treatment can have.

It is up to the patient to decide if the risk is worth it to them.

The adage of trust but verify applies here as well. You should start with the assumption that they know more than you, trust, but they can still make mistakes or have gaps in knowledge that could be very impactful to you, so verify.

>Psychiatrists aren't evil, of course, but they're not going to tell you (or are always aware) of all the minutia of long term effects treatment can have.

This, I help a family member with their medication and occasionally they'll have side effects that are obviously a direct result of one or more of the medications and the doctors will often ignore that until it's brought up over multiple appointments, even then they often want to add an additional medication to the 6-7 they already prescribe instead of working to lower dosages of the ones causing issues.

My brother was on ADHD meds most of his early life and started having heart issues that doctors seemed to have no ability to figure out, despite it being one of the listed side effects of his medication.

I have a friend who is pretty convinced that his wife won't live much longer because the dose of her medications is one that is known to cause liver and kidney damage long term.

You also regularly see psych patients gain tons of weight in a short amount of time from some of the medications like Seroquel, but the typical doctor response is "better to be fat than dead" while totally ignoring the long term health issues, including things like depression that the medicine was original prescribed to treat, stemming from ongoing unregulated weight gain.

People really need to advocate for themselves and often aren't in a place to do so.

^ horrible advice here. In general you should take agency of your oqn health. Educate yourself and make informed decisions instead of relying on the advice of a doctor who may or may not be confident and may or may not give any kind of a shit about you.

In my case, doctors recommended that I "just keep taking xanax until I feel better" which ended in a 24+ hour blackout. So yeah, dont necessarily just listen to your doctor

No, it is not horrible advice, it is good advice. If you have no confidence in your doctor, choose a better doctor. If you cannot trust any doctor, fair enough; do whatever you like.

Well we will agree to disagree ut far too many times ive seenpeople prescribed contraindicated meds because the doctor wasnt paying attention and the patient wasnt aware enough of their own healthcare to even list the pills they were taking daily.

Certain doctors will keep ramping up your adderall script until your on 200mg a day. No one needs that shit. Its horrible for you. So to just say "listen to your doctor, they know best!" As a general statement is asinine

When it comes to things like this, as cliche as it may sound, your best bet is to probably bring up those fears with your psychiatrist to evaluate the pros/cons with them.

Like most things, there is most likely a tradeoff - but your doctor also most likely prescribed the dosages based on the pros outweighing the cons, but only you can bring up how you feel about specific cons to the doctor.

If you give it a break the adderall tolerance goes away. It’s good to regularly skip days. Ketamine abuse is particularly dangerous compared to so many things, particularly amphetamines taken at therapeutic doses which is safe to the level of no particularly clear long term effects.

> Ketamine abuse is well known to cause widespread cognitive and neurological impairment. However, the average ketamine “user” consumes 500-1000mg of ketamine per day, which is a lot more than therapeutic use (0.5mg/kg). One glass of wine per week is surely different from a gallon of vodka per day.

Author is mistakenly comparing oral vs. IV routes. Of course the amounts are different because metabolism is different. How can they pontificate and make such a mistake?

All drugs build up resistance, making a increasging of dosage necessary, and dosage maketh the poison.

You might start out with a PTSD-tracking app, pumping a microdose of Keta via a insulin-pump every time the eldritch horror of reality hits you again and again, but you will still need to crash out of it regularly ever n months.

Its a high-functioning half-life, but preferable to the alternatives?

Regarding lesions, a recent pair of articles about Ibogaine.

https://pubmed.ncbi.nlm.nih.gov/39981248/

https://pmc.ncbi.nlm.nih.gov/articles/PMC11303312/

Well I’m convinced at least that there is potentially a significant danger. I’ll stick to microdosing shrooms.

Crazy I took it on a few evenings over the last few years and he just takes it every day/week?

For sleeping? Relaxing?

>At recreational doses

>already after three months of high-dose ketamine use

Recreational?

lots of compounds are neurotoxic when taken in large doses, but completely safe when taken in lower doses. This isn't really surprising

The point here is that the majority of people who take Ketamine take way more than the safe dosage especially when taken recreationally (without a physicians oversight).

With many drugs that are used both therapeutically and recreationally, it is the case that the average recreational dosage is much larger. Ketamine is an exception here, as therapeutic doses are actually quite high. The common mistake here is to equate intravenous dosage with intranasal dosage, when the bioavailability differs significantly between these routes of administration. And that's not even considering that most reported recreational dosages are wrong due to cutting agents.

There certainly is recreational abuse with very large dosages, but I don't think it's fair to claim that the majority of users fall into this category.

Is it not assumed all recreational drugs cause or have the chance to cause damage to the body?

I always assumed it was a trade off of some temporary fun for x% damage to the body or x% increased chance of disease.

The majority? I doubt that claim.

All things are not necessarily equal in this regard. NMDA antagonists, of which ketamine is one, are well-known for their neurotoxic potential.

are everyday people even prescribed Ketamine in the USA?

Or is it just people that can afford to buy it outright from a non=pharmacy source?

I'm in Medicaid in Utah. I'm taking 70mg in a hospital setting once per week for about 7 to 10 weeks combined with therapy.

Medicaid copay is only $20.

It’s the rich people.

There are startups.

Ketamine taken under the supervision of a physician is an effective treatment. I have seen its effects with my own eyes.

Do not fuck around with street drugs. If the FDA didn't approve it, there could be anything in it.

not a neurologist but pretty sure your "gut feeling" isn't science.

Everything acting on the brain is neurotoxic at sufficient doses. However, I would be far more worried about cardiovascular effects, for which life threatening complications are much more immediate.

Ketamine is widely used and it's very difficult to find deaths. Sure, one can die by taking it and getting in a hot tub or using it with other drugs. But on its own its safety profile is better than acetaminophen.

Acetaminophen is often chosen as a suicide drug because of its narrow therapeutic index. I don't think that means abuse of ketamine is that safe, having administered a lot of it. The effects at anesthetic doses are pretty spectacular.

Why aren't there huge numbers of deaths attributed to ketamine if it's unsafe? Ketamine is quite popular. When you look at opioids it's easy to find fatal overdoses.

I agree for opioids. And I'm certainly not saying there are 'huge numbers of deaths' linked to ketamine. Maybe specialK is popular where you live, but here long term ketamine habits seem quite rare, based on my totally unscientific impression. I also think ketamine abuse isn't very much studied, at least compared to more popular drugs. What I'm saying is that while a short term stint into ketamine probably isn't a big deal, I expect long term use with higher dosage ('ketamine hole', tolerance and all that) to be more dangerous. Having your blood pressure peak in the 250's can't be that safe when you start aging.

I can recommend everyone to read Felix Hill's suicide note on the topic. He was a scientist in DeepMind: https://docs.google.com/document/d/1-jBoSEVlryiX1IaSzV4vKuih...

Reading this, I couldn't help but think that I am the failed version of this guy. My life mirrors his, except mine is shittier in every way. I did not go to any fancy universities. My math career went nowhere. My deep learning career isn't going anywhere, probably. My h-index isn't even a quarter of his. My only gf left me after a week. My childhood was riddled with family illness. My mother died too soon. And I even look like an uglier version of him.

And I have been managing depression since 16 (I'm in my early 30s). But, I have always questioned whether I really have depression or whether I am justifiably upset at how shit my life is. I cannot imagine being him and being depressed. But I understand that some people have everything, except happiness and peace of mind. It's so confusing.

Thankfully, I don't mess with drugs.

I’m sorry you feel the way you do. Reading through your post, it is deeply rooted in your view of yourself. When I turn too far inward I can relate. It’s hard because your writing indicates you like to think and analyze, and you have embraced the “warm blanket” of self loathing since it is very comfortable for you.

I hope you don’t find what I'm about to say glib. I don’t mean it that way. I truly believe that you can find meaning through shifting your focus from inside to outside yourself. I say this only because this has benefits to me. I realize that may not mean it works for you, but I hope it will.

Try giving freely of your talents to others. You mention your math career. Try finding people who struggle with math and tutor them. For free. Start slow & easy, and focus on their growth not yourself.

I also encourage you to unplug and find ways to reconnect with nature. Walks where you do nothing but notice the colors of the flower petals, or the rippling of the water. No distractions. Just practicing on focusing outward with no expectations.

I hope you can find some meaning in this crazy life. Sometimes I resort to a pascal style wager - this is by definition my only shot at life, so why not try and see what happens?

You're on point. Really if you look at all the religions and creeds that have stood the test of time, they all kind of shift focus away from satisfying your ego so much. It's so easy for the mind to rationalize this or that as a failure, given enough time to neurotically brood. Even if you're actually in a very good spot in life.

> > Really if you look at all the religions and creeds that have stood the test of time, they all kind of shift focus away from satisfying your ego so much

For the modern day atheist person the formula for happiness could also be

1) Ignore risks

2) Ignore complexity

3) Ignore higher levels in all domains, pretty much disregard classifications better/worse of sorts.

What you also have is a poignient self-awareness. You've struggled, in both the sense of having challenges and in working against them. I'm certain someone important has defined a meaningful life in that way.

The linked note conveyed a world view that felt transactional, low in dimensionality, self-focused. Which isn't to criticize so much as empathize. I understand your comment, but perhaps you have it better than you realize.

Depression is a very real, very serious thing of course

BUT feeling like a failure is 100% incorrect thinking because you are basically using the ridiculous weight of others to judge yourself

Society is weird-AF, do not subject yourself to others judgment, ever

Way easier said than done but "don't do that"

If you haven't hurt anyone you've never done anything wrong.

It is amazing how things change as we get older, perspective is EVERYTHING

Dude; how can you say you are a failure in your early 30s? You have just finished being a kid and learned to navigate the adult work. You still haven't done anything worthwhile, and you're about to start. You have just finished the tutorial to life, and now are facing the question of now what?

Sincerely, a late 30s guy that has been through a massive burnout, mid life crisis and journey to discover myself in the past 5 years.

Millions of people have been through the same in the whole of history. Many have left notes about their experience for posterity. Time to hit the library, my friend.

(The things that have helped the most have been, in no order: talk therapy, solitude, the Tao Te Ching, Alan Watts, Camus, Nietzsche, and many more, rediscovering my long lost teenage dreams, understanding that nature is a crucial part to mental sanity and restoration)

Take care, and good luck.

Really ironically all of life up until 30 is kind of following a general script that's handed to you. And that kind of lets you get out of your own head, in a lot of ways. Then when you're ~30 and you have skills, you have some resources, and you understand pitfalls of life... there isn't much more of a set script left except the wife + kids + white picket fence script. And it takes some effort to figure out how/what your autobiographical script will be. (writing this as a 32 year old who hasn't figured it out)

Vigorously seconding this as an enby in xir early 40s who's only just figuring a lot of shit out and still has so very much left to go. So much left to discovery and explore about xirselves, too.

Seconding that entire list of recommendations, as well. Xe haven't really touched the Tao Te Ching specifically but, speaking as a secular materialist post-theist, tarot and oracle decks have served xe incredibly well as introspective tools. Consider the Oblique Strategies deck if you want to sample a similar experience.

Wishing you luck!

> Vigorously seconding this as an enby

Respectfully, I'm not sure what gender identity has to do with midlife crisis. Happens to every human that has ever lived past a certain age.

I think it’s relevant because, stereotypically, men and women tend to display them differently. I’m curious how it would present in a non binary manner - perhaps that would be the most “true” of them, breaking free of norms?

Indeed. Only cracked xir enby trans egg shortly before hitting thirty.

But xir midlife crisis had far more to do with an abusive ex, "normative" but foolish financial choices, and other mental health issues.

The gender matters were and continue to ground xe more than not: They're an undeniable, celebration-worthy facet of xir identity and a regular source of joy. Gender euphoria is a thing! If you're cisgender but have found deep affirmation in an especially gendered outfit (e.g. a tuxedo or cocktail dress) then you've had a taste of what it's like to go beyond your baseline gender contentment. Hope that helps!

Thanks for the informative reply!

Xir pleasure!

Yeah, but Alexander the Great conquered the world by the age of 18 or whatever, and look how he turned out. Am I a better man than him?

Alexander the Great inherited most of his success from his father. Although a competent and ambitious commander, he would have been a nobody if his daddy hadn’t been Mr. big shot.

And yet most people who inherited the same as he did would have done nothing of note with it and faded into obscurity. Like most of the Macedonian kings before and not long after.

Reality is complicated...

Sorry, who in Ancient Greece inherited the same position as Alexander did? Philip II was a one of a kind, once in 20 generations kind of guy.

https://en.m.wikipedia.org/wiki/Expansion_of_Macedonia_under...

Many people have inherited great power and wealth and squandered it. That's the default case.

Philip inherited too. He built on his father's very considerable success, just like Alexander built on his father's.

Amyntas III -> Philip II -> Alexander III

They're a dynastic set. There's not a lot of sense in separating and comparing them.

But in terms of lasting impact, it's not even close. Philip II exerted control over Greece for a brief time but didn't change much. Alexander changed the entire world permanently.

Just another reason to consider oneself damaged goods, no big shot daddy and not being born a king.

lol.

There are plenty of cases of people who rose through the ranks to become powerful beyond anyone’s wildest dreams.

Adolf Hitler, maybe the most famous example.

Sure, but if you think you are inferior on a personal basis, and inferior on a situational basis, that doesnt boost self esteem.

> Alexander the Great conquered the world by the age of 18 or whatever

He was also, by all accounts, a twat. He killed his friends in bouts of rage. He was a brilliant strategist, but he did not really build anything that lasted. Some slivers of his empire survived, but not because of his actions. He might have lived the life he wanted, we will never know for sure. But I would much rather live the life I have, however imperfect it might be.

> Am I a better man than him?

Are you happy? Do you make other people happy? Do you support or help other people when they need, or side by them when they want? Those are more important metrics than the surface area conquered at the cost of tremendous suffering.

We remember people for their accomplishments, not because they were good as human beings.

He wasn’t a brilliant strategist. He got lucky and was an absolute monarch.

I can accept that, depending on where you put the limit between tactics and strategy. He was good at wining battles and campaigns. He was bad at picking people to run the countries afterwards.

No question that he was both lucky and a despot.

1. He never lost a battle and conquered more territory than anyone in history, all while leading from the front. He's considered the greatest military leader in history by most every other great military leader in history (are you a better judge?)

2. Many of the Diadochi (his bros) went on to great success, and he picked all of them.

People love to be contrarian but it can get ridiculous. Claiming that Alexander the great wasn't actually so great is just boring.

Maybe not, but it's okay to not be the very best, and it's okay to fail. And it's especially okay when comparing ourselves to one of the few dozen names from before the Julian calendar that everyone still remembers to this day!

You're in good company, because the other ~100% of us are also imperfect and make mistakes all the time.

Weight the good more favorably than it sounds like you've been doing.

You take the "bad with the good" just the same as you take the "good with the bad."

And here you have your first true quest: questioning the meaning and value of comparison.

Life is not a race. There is no prize at the end. In a long enough timeline, nobody will remember you, nor Alexander the Great. What is the point then of your life? What is your goal?

Seek to answer this question, and proceed.

From time to time I think most, ambitious, people fall into this trap.

The issue is that these are positional goods. Per definition there can only be a single person who is the top contributor of a field of research.

Every time I fall into this trap I separate out what is positional goods and what is valuables to me. And then I very deliberately convince myself that it is not worth it to chase positional goods for the sake of doing so.

Said in other words: Do research because you like it, not because of the acknowledgement that follows on.

(As a side effect many will find that they indeed do not care doo much about research)

Well put. Chasing positional goods seems inherently vacuous and lacking in satisfaction. It surprises me that anyone thinks that recognition alone is enough to sustain interest in an academic or research career (or other areas like acting). Looking at who succeeds it seems to be people for whom the recognition is an afterthought.

Research is also very taxing on the mind. I'm not sure I could do it for a whole career, as enjoyable as it has been.

depression isn't about quality of life, the disease depression not the effect depression anyway. Depression as a response to environment doesn't respond super well to medication either. Depression the disease process that triggers depressive pathways without the environmental triggers is a different animal entirely.

You’re alive. Just getting through the day should be counted as a great success for pretty well everyone.

Me too... Maybe that's why his note resonates with so many people

That’s really heartbreaking to read, especially the underlying sense of shame. I feel for him.

Lamotrigine is worth checking out for those who never tried it. Antidepressants never worked for me either. But, Lamotrigine eliminated the worst of my depression and constant ideation. Apparently, it rarely works for people, but when it does, it works really well (see past HN comments containing “Lamotrigine”).

Wow that hits hard.

Anyone that resonates with that letter, please speak to someone. If you're a male in the UK there's Andy's man club[0], which is just a group of normal guys who chat about life - including mental health. You'll hear first hand how close a lot of them came to tapping out but made it through and are glad they did. No matter how bleak it seems, there is a route to something that resembles happiness... you might just need a helping hand from others to get there.

[0] https://andysmanclub.co.uk/

Not quite sure why he thought ketamine would be safer than LSD. Maybe because the local pharmacy carries it?

My first thought too. Don't know if it would have made any difference in the end result but LSD and Psilocybin Mushrooms are ranked much safer than Ketamine and unlike Ketamine, aren't addictive.

When I saw the Psychedelics headline I was expecting these two plus maybe DMT. Some people consider Ketamine as psychedelic drug but it's really a dissociative drug.

Physician supervised ketamine therapy has worked wonders for people with PTSD, at least one of whom I know personally.

Otherwise, street ketamine can be adulterated with anything. It is dangerous.

ketamine has become a very popular party drug in the UK so the stigma might have been significantly less, and therefore the perception of safety

well, LSD is not safe either. Of 3 people I took it with, in high dose, for various reasons, only one of us left the encounter better off and largely unscathed. Professional psychiatric help doesn't have great odds either but they're significantly better than an anecdotal 1/4, and when things go wrong people tend to know why and how to help. Leave the research and unproven chemicals to the researchers I guess?

What happened to the other 3?

It varies, some more benign, like short term legal trouble from acting out while on it, while another went down a darker path, like re-joining a cult they'd left. Perhaps what I view as darker path is their light path though, from what I've seen they seem happy.

And this is why just fucking with the genome via crispr to birth “smarter” babies is such a bad idea. I’m thinking of this recent hacker news post linking to “how to make superbabies”: https://news.ycombinator.com/item?id=43158387

(To be clear I’m not saying Felix was gene edited by birth, but rather there may be correlations between the genetic markers that “improve intelligence” and depression)

I came across this the other day. Super tragic. I'm not a user of these substances but I'm not against them either, but this was a dark perspective that I'd never heard of.

Thanks for sharing

The man had all the knowledge necessary for recovery, but faith without works is dead. Happiness cannot be caught directly, it comes to us only as a byproduct through thinking of others and what we can do for them rather than of thinking of ourselves or comparing ourselves to others. Then, following up that right thinking with unselfish constructive action. I have found in my experience this to be an un breakable law of the universe, as true as gravity, and frankly speaking, equally as probable as all things subatomic…

> un breakable law of the universe

That is precisely the case, for the simple fact that we human beings must live in groups, where we each do different tasks that enable the whole to function.

That is why narcissists are NEVER happy. They are simply reaping what they've sown.

All these people that think earning money will make them happy are ASLEEP to the fact that we can choose to ignore the truth you have realized. A human being must consciously WAKE UP to the fact that we must choose to help others become happier if we are to become happy.

The cool part, because I'm a nerd, is that it's mathematical at heart, as most everything is in this wonderfully constructed universe.

You can be happy thinking of yourself; you just might be branded a megalomaniac.

Fucking hell

Fucking hell indeed. I couldn't read the whole thing, only the first couple of pages.

I have read that Ketamine destroys grey matter. Is that true? Elon certainly makes it look true.

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Is it actually known if he regularly uses ketamine? I have seen lot of claims but never any source.

https://www.youtube.com/watch?v=NH4_rcq4jgQ Bloomberg

https://www.youtube.com/watch?v=SC2Z0mb1W2A interview

But I'm sure he uses in moderation, he's a very balanced and stable guy. Definitely not enough to cause bladder issues.

> But I'm sure he uses in moderation, he's a very balanced and stable guy.

This is a joke, right?

It's funny either way, isn't it? Just in very different ways...

Poe's law is dead.

I don't follow world events too much. I know who Elon is, but I have no idea about his personality and stability. I consider myself pretty sensitive to sarcasm over the internet, but I completely missed that.

I don't really mind not understanding that joke, since I don't really care about internet celebrities anyway, but that's an example how someone (hopefully) averagely smart can miss a joke like that.

Is the man who's seemingly acting as the 2nd in command of the current president of the US really a "internet celebrity"? That feels off.

I mean, it's possible he's lying about it for street cred?

But he has claimed to take it: https://www.cnn.com/2024/03/18/tech/elon-musk-ketamine-use-d...

He's claimed a lot of things. Pick pretty much any neurodivergency, and it seems like you can find an interview where Musk claimed he hasn't been diagnosed, but he's totally got it.

Except hypochondria, obviously.

I don't think it's productive to try and armchair-diagnose him (although it is fun). Maybe, someday, a court-appointed psychologist will give us an official answer.

>Maybe, someday, a court-appointed psychologist will give us an official answer.

At some level of wealth, in modern-day America, the idea of a court appointing a psychologist against someone's wishes and this actually being enforceable becomes fanciful. Even the idea of punishing such a person for any crime short of publicly documented ritual murder is dubious. I don't know if Elon reached that level of wealth, but I suspect he has.

Strong pedophilia accusations could still undo such people, publicly even if maybe not at court, and all things and products they ever touched. Even nazi lovers have kids and (mostly) feel paternal/maternal instincts.

Who knows where we will be in 2-3 years though.

I mean, Trump palled around with Epstein, bragged about barging into teenage women's dressing room while they were naked and described "sex" as the thing him and his daughter have most in common.

I don't know that it would be a deal breaker to his cult

> Maybe, someday, a court-appointed psychologist will give us an official answer.

This stinks way too much of USSR/RF treating political enemies as mentally ill. El Doge is clearly an issue we Americans need to address but the entire point is to make sure America does not become yet another tyranny.

I’m not sure “taking drugs” is a neurodivergency.

But the reason he's taking them? (ok, depression may not be neurodivergency but you get my point. I'm only really commenting on the reliability of Musk's claims about himself).

Okay, that's fair.

He also claimed to be top 100 diablo 4 gamer.

Maybe he hired a professional to do Ketamin ?

Don Jr?

That’s a good point. It’d be one of the few truths he publicly states.

[flagged]

You started a hellish generic flamewar tangent with this comment. Can you please not do that on HN?

This is in the site guidelines: https://news.ycombinator.com/newsguidelines.html.

On the plus side it appears to reverse the effects of balding.

Not if you look at the evidence.

Been seeing a lot of these in the news lately.

Will it soon be a crime to criticize 'El Doge' online...

[flagged]

Don't forget really bad jokes, such as making your product line spell out se*y and naming stuff after memes.

Bring back dorky middle-school sense of humor Musk. I’m fine with S*XY and fart mode and even flamethrowers. If you can find a history of Musk headlines through the years you see that almost everything before 2018 is just dorky engineer stuff and jokes, and then post-2018 it’s mean and destructive.

Does anybody know what happened around that time, ie some personal tragedy?

At the end of 2019 the TSLA stock price took off. Maybe it went to his head a little?

There was a pretty big epidemic of internet poisoning around that time that was followed immediately by COVID.

Other people noted a lot of things. Another is that he traveled to Shanghai to set up a gigafactory.

> such as making your product line spell out se*y

Especially with exterior designs ranging between boring and ugly.

One time I took side views of each of them and scaled them all to the same size based on wheelbase. They're literally all the same design, just stretched. That's why they look so bad, in the same way a corvette would look bad stretched into an SUV.

> roman salutes

It's worth noting that the Romans never did this. There was a fairly brief period in the 19th century where it was kind of a pop-culture Roman thing (it showed up in plays about Ancient Rome, that sort of thing), and then it was adopted by various nationalist groups, including the Italian fascists, and, ultimately, the Nazis.

Unless you're a theatre fan who's been in a coma for the last 150 years, though, it's a fascist (or Nazi) salute; the use of the 'roman salute' term is (potentially accidental; I think maybe some people do think it was a real thing) sanewashing.

TIL about the term 'sanewashing'; thanks, I'll definitely use that.

In exchange, I offer a cool word I learned yesterday: The Broligarchs.

> the use of the 'roman salute' term is (potentially accidental; I think maybe some people do think it was a real thing) sanewashing.

It's used because YouTube and tiktok will demonetized you for saying Nazi.

TikTok, in particular, has pretty aggressive live stream killing policies. It's lead to weird things like streamers saying "grape" for "rape" and "unalive" for "kill".

Huh, I actually didn't know that (as a certified Old Person I use neither on a regular basis). That maybe does explain why people are doing it to some extent. Talk about unintended consequences...

The Bellamy salute on the other hand was actually used to accompany the US Pledge of Allegiance 1892-1942: https://en.wikipedia.org/wiki/Bellamy_salute

>Later, during the 1920s and 1930s, Italian fascists and Nazi Germans adopted a salute which was very similar, which they attributed to the so-called Roman salute, a gesture that is wrongly thought to have been used in ancient Rome. This resulted in controversy over the use of the Bellamy salute in the United States. It was officially replaced by the hand-over-heart salute when Congress amended the Flag Code on December 22, 1942.

In other words, when people decided "fuck that, I dont want to look like a Nazi" they did something different.

Which is precisely why what Musk did was a Nazi salute. Because we know not to do them for fear of being mistaken for a Nazi. The deniability is implausible at this stage.

He did it twice. And I’m up to counting four more republicans who have done it since, not just caught in an awkward still with their arm out, just full-on did the thing in front of people on purpose. At least one of them at CPAC the other day.

At least they’ve cut through any doubt about how to treat their entire party in a hurry. Anyone still with them is in-fact a nazi.

>I’m up to counting four more republicans who have done it since

Names?

Bannon

Oh, bloody hell, totally forgot about him. Has he emerged from his lair again? Would've assumed he was in disgrace after defrauding all those Trump fans.

Like, he literally did an affinity fraud on Trump supporters. Have they actually forgiven him?!

s/autistic roman/nazi/

Please don't use "autistic" as a slur.

i very much don't use "autistic" as a slur, my comment was a riff on how Muskites tried to defend the salute https://time.com/7208614/elon-musk-nazi-salute-reactions-deb...

It was a nazi salute.

In other words, when people decided "fuck that, I don't want to look like a Nazi" they did something different.

There is no plausible deniability; it was a nazi salute.

And Elon has had enough media exposure and training to know how it would be perceived. He knew what he was doing. We know what he was doing. He knows we know what he was doing.

Twitter guy had lost his cred with all his nazi twitter followers (the ones he retweets from time to time when they have spent enough time licking his behind) after the H1B visa kerfuffle. They were all thrilled he was heiling away on the national stage.

The amount of cowardice in US politics is astounding. And I don't mean the republican part, because to be a coward with regards to beliefs you must actually believe something.

Well said. On the other side it's very sad and true, that the consequences can be global in special individual cases.

not to get too political, but Emusk is reported to be on it, not sureyou go

It is not neurotoxic, in fact, it is the opposite due to it being an NMDA receptor agonist (neuroplasticity). I thought we have known this for a long time. It could be, in very high doses. Just like you can die from water intoxication too.

Ketamine is a NMDAr antagonist, not a NMDAr agonist. Strong agonists can cause excitotoxicity whereas strong antagonists can cause shrinkage.

Agreed, it was a typo.

You might want to take a look at https://pmc.ncbi.nlm.nih.gov/articles/PMC3713393/.

In animal models it also seems like the dopaminergic effects are strong enough to cause midbrain downregulation and lower dopamine neuron density. If you've ever taken ketamine recreationally you've likely noticed the very strong dopaminergic effects, though maybe not been able to classify them as such.

Interesting, thanks. Whilst ".2G Twice a week, for 6 months" doesn't strike me as a lot- could be someone who just goes clubbing twice a week- apparently enough to cause brain lesions. Anyone know if the study is reputable, or could answer the question whether the "lesions" could be something like regions of the brain responsible for/exacerbating mental issues which have been altered by the treatment- ie, the method of action for treatment.

You are more likely to get brain lesions from DXM, called Olney's lesions, but it could happen from any NMDA receptor antagonists.

I have taken smaller, and larger doses of ketamine before, I personally did not experience the claimed strong dopaminergic effects.

What was I supposed to experience for this dopaminergic effects? Maybe I could tell you.

At dissociative doses ketamine typically induces a strong feeling of expectation, of something fantastic or important being imminent, things like that. To some people this takes a religious form, like (almost) coming into communication with some ethereal being or (almost) reach some mystical insight.

It can cause a strong urge to redose.

Do you recognise any of this?

I went into a k-hole (a few times) where I was seeing myself from the outside (with all my flaws and faults being shown to me), and I remember my then-girlfriend slipping away from me and I tried to grab into her but she slipped away, and I remember being locked in time (not sure how to explain it). I did DXM too, that was less clean than ketamine and DXM had more of an alienish-vibe to it and I ended up watching Stargate Atlantis on it, that was fun, but ketamine had me self-reflect quite a lot.

About expectations & imminent, it made me want to change the way I live as I am pretty much a reclusive.

I wish I could explain it better but I really can't. I never felt an urge to re-dose, however.

lol, what?

NMDA receptor agonists can be directly neurotoxic. See, e.g.: https://pubmed.ncbi.nlm.nih.gov/9109508/

Also: https://www.mdpi.com/2039-4713/15/1/12

> "Normal NMDA receptor (NMDAR) function is essential for neuronal development and higher brain functionality, while its inappropriate stimulation results in neurological deficits."

I made a typo, it is a NMDA receptor antagonist.

Additionally, I can find sources supporting my claim, too.

> Results in rodent models indicate that a single dose of ketamine induces robust markers of neuroplasticity in depression-relevant brain regions, including increased BDNF release and the stimulation of mTOR signaling in the PFC [23, 24]. In addition, ketamine induces an increase in synapse number and function in the PFC, reversing the loss of specific synapses by stress, an effect that seems necessary for the persistence of its antidepressant-like behavioral effects.[1]

[1] https://www.nature.com/articles/s41398-023-02451-0

From Wikipedia:

> Ketamine is under investigation for its potential in treating treatment-resistant depression. Ketamine is a known psychoplastogen, which refers to a compound capable of promoting rapid and sustained neuroplasticity.

Additionally: https://www.resetketamine.com/blog/2021/6/2/ketamine-and-its...

Additionally #2: https://pmc.ncbi.nlm.nih.gov/articles/PMC8190578/

Additionally #3: https://www.sciencedirect.com/science/article/abs/pii/S01656...

> Ketamine (NMDAR antagonism) and classical psychedelics (5-HT2AR agonism) trigger a long-lasting state of enhanced glutamate-driven neuroplasticity in frontocorticolimbic pyramidal neurons.

Your counterclaim is based on the unsupported assumption that a substance having relatively high neurotoxic potential means that it cannot induce neuroplasticity. The two are not mutually exclusive, and in the case of the substance in question, it is well known to have both high neurotoxic potential, as all strong NMDA antagonists do, as well as the ability to induce increased neuroplasticity.

Yes, you are pretty much correct.

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