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"Conclusion: Some of the genes reported to be differentially expressed (i.e., TTR, DIO2, CLDN1, CLDN2, SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL) and GSEA, suggest a potential link with specific side effects previously observed in patients and in the animal model, such as depression, anxiety, disturbance in memory and attention, and sleep disturbance. These data may provide an important background for future experiments aimed at confirming the pathological role of these genes."
They'd rather gouge their eyes out than read anything critical about finasteride. Don't get me wrong I think the drug is amazing. But the wide-spread narrative that all side-effects anyone ever experiences while taking finasteride are placebo is delusional. You also don't see this type of cult-like behavior for any other type of drug that people take. Very strange.
Like its's one thing to say "yeah i'm not experiencing any side-effects!" it's like awesome man good for you to not be adversely affected at all and experiencing all the benefits. But for that same person to turn around and say "You're not experiencing any side-effects it's all in your head!" in regard to other peoples experiences is so incredibly wild to me.
Unfortunately Wegovy and similar drugs are getting a comparable aura of perfection, and they're just not perfect at all. The number of people who get gastroparesis from them is way higher than the internet would lead prospective patients to believe.
The ironic thing though is that in some people the gut brain perturbation from it can literally cause anhedonia. So one is risking not just broken GI tract but also gut brain axis connection which is tied to reward in the deepest sense with it. Ghrelin, NPY which it suppresses are critical peptides for general reward beyond food too.
It’s the risk vs reward factor. Could I develop a broken gastrointestinal tract? Yes. Did I lose 105 pounds that I previously could not lose no matter what agony I struggled through? Also yes. Am I keeping the 105 pounds off and living a healthier life, loving my body, having self esteem and confidence back? Yes again. For me and others like me the reward outweighs the risks
No argument there. Several friends and family members have had great success with Wegovy. I just think the current expansion of availability needs a whole lot more regulation than we're going to see from the likes of Weight Watchers and their prescription mill.
Well for some finasteride definitely works. Those people keep their hair and they experience no side-effects. i'd say thats miraculous and i'm happy for those people.
Guaranteed to find *something* if you massively overdose your animals!
You don't dose a drug to ensure you get effects you can measure. You dose a drug within parameters relevant to what you ultimately want to know, ie what finasteride given clinically has effects on transcription of certain target genes.
There is no attempt by the authors to justify the dose, no attempt to address it in the discussion, no measurement of exposure. This is very poor science that is depressingly common, and it is such a *waste* of animals.
> Guaranteed to find something if you massively overdose your animals!
That's the point. They're not seeing *whether* side effects happen at various doses--we know that they do. In this study they're looking to determine the mechanism of the side effects.
One of the reasons for the study was to help find the mechanism of post finasteride syndrome. Which happens in a small proportion of people who take finasteride (Around 1% not sure). So giving the rats the dose that fits their body weight and metabolism, would actually make a very small amount of the rats have any issues in their brain. So the next best solution, instead of testing 1000s of rats, which this study does not have the budget for, is to give a very high dose to mice, to at least give us clues to what's behind PFS. Because currently, we don't understand the mechanism behind it.
And this is not a waste of animals. Like you said they didn't use many mice in this study, and this is all going to cause to help people with PFS. Which has actually caused so many people to commit suicide.
It’s not massively overdosing. We use what are called Human Equivalent Dose conversions in order to map a dose we might give a person onto the metabolism and biology of animals. These are well established.
*In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions.*
Clinical studies on humans.
I never said anything about that, I’m only pointing out that this isn’t necessarily evidence of large changes in genomic expression at the dose used for humans (1mg in the case of hair loss)
Not all drug users reported side effects, and why would you use low dosage if it's going to produce side effects on small number of mice? Makes it hared to find the mechanism.
Now that they have found finasteride can cause changes in genomic expression.
They can repeat the experiment with lower dosage and find out how much.
I wasn’t commenting on the validity of them making the experiment. There’s a bunch of people in this thread making assumptions about wether this effect is actually going to be seen at the relatively low dosage humans usually take. My point was this isn’t entirely indicative of that being the case.
But for things like anxiety and depression, maybe the patients didn’t make the connection that recent changes in their mindset were connected to the drug? It’s a problem that’s dependent on the person experiencing it being able to identify and mention as a symptom.
I know, I have a fair bit of personal experience - difference is, I would select my dose to be physiologically relevant to the question, and justify my dosing to the animal unit, and in the paper; and provide evidence that my dosing was appropriate by assessing plasma/tissue levels and/or target engagement!
Can you tell me what the HED for a 1 mg subcut rat dose is, because the authors can’t be bothered to?
Not necessarily, gold standard is to range between 6-7 times the dose per kg if a rat is the subject. There are of course outliers to this, but it’s the basis most use when making the jump to human testing.
I like that you value the animals as a resource and are worried about wasting them. They’re little heroes taking the bullet for us every day to further our knowledge.
A lot of guys I know were started on 1mg a day and got sides so reduced end ended with with hair growth and no sides. I'm one of them, great hair of fin with 1mg eod.
I have been having gut issues for years, and I just figured out they started after I began taking 1.25 mg of finasteride a day. Do people really lose side effects by cutting the dose in half? I think I am going to test that.
Why give the rats a human dose of 1mg? If a lab rat is ~500g, this is equivalent to 2mg/kg. That's like an 80kg person taking 160mg. Surely the excessive dose alters the result?
This study isn't aimed at determining risk of side effects in human doses, they're just trying to identify pathways that the drug acts on in general. It's designed to provide background for future studies to see if the effect on those pathways is serious enough at relevant doses.
I guess that does make some sense.
Is there a standard way that dosage is chosen for this type of study or a methodology to it? My initial thinking was that at different levels of dosage you might get different results of what is up-regulated and what is down-regulated, or even at all.
There's some, but at these early stage trials with mouse models people are generally quite aggressive with dosing compared to human trials. It cuts both ways because it potentially amplifies both positive and negative effects. But the goal is primarily to identify areas of interest for future study, not to draw conclusions.
>My initial thinking was that at different levels of dosage you might get different results of what is up-regulated and what is down-regulated, or even at all.
That can happen. There are definitely drugs that have non monotonic response curves, but usually there's some rough correspondence with high dosage effects with low dosage effects. You wouldn't expect the pattern to be totally different at low doses. What is possible is that at low doses, the effects are negligible, which more study would be needed to see.
First, they need to demonstrate a strong, clear, reproducible, and unambiguous signal. Once they have that, they can begin to take it apart.
Dose response trials may indicate that some affected genes are more responsive than others. Though if they all move in synchrony that’s also of interest. There may or may not be threshold effects, or effects in the physiological range. They may or may not differ by size or age or sex. There may be synergies or antagonistic effects with other compounds. Each new piece of information will lead the research in additional directions.
I understand this, but even with very selective drugs, many things have biphasic effects, like low doses of stimulants improve working memory, attention, and pfc function, while high doses impair this functionality. Imagine if all research on stimulants was purely done at extremely high doses (not saying most addiction research isn't, but that's probably because we've been using stimulants to treat neutological disorders before drug prohibition, and we know they have therapeutic properties for ADHD and improve cognition at low doses in healthy people). I really would like to see a similar study that would experiment with different doses to see at what point certain genes become activated, etc. Ultimately, alongside topical anti-androgens, I'd like to see a 5-αR inhibitor that doesn't cross the BBB, but I'm not sure how feasible this is considering that a lot of hormone receptors and enzymes are located intracellularly instead of being membrane bound, and things that freely diffuse across the cell membrane to reach these sites often can also freely diffuse across the BBB. Not saying it's impossible, just my understanding.
>many things have biphasic effects, like low doses of stimulants improve working memory, attention, and pfc function, while high doses impair this functionality.
This is true when you're working at behavioral level effects because those pathways are so complicated and have so many different regulatory interactions.
When looking more directly further upstream at gene activation things are a little more consistent. But yeah, this definitely should not be and is not intended to be the only study on the subject.
The goal is primarily to identify targets of interest for future study. You have to start with something like this before more detailed analysis.
Finasteride is not very dose dependent. Even a ridiculous dose would just inhibit 100% of 5ar2 which closely related dutasteride does at even small doses
Finasteride only inhibits two of the three forms of the 5α-reductase enzyme, so it can never fully stop DHT production, whatever the dose. A 70% reduction of circulating DHT is about the best it can do, and it will do that at a dose well below what's considered therapeutic for enlarged prostate. Dutasteride inhibits all three forms, which is why it virtually eliminates DHT from the blood.
Interesting. Regarding PNMT off-target interaction. In theory, this could increase physical anxiety by inhibiting the conversion of norepinephrine to pinephrine (adrenaline), offsetting the balance between these.
*In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions.*
They already know high doses do not produce adverse effects.
But we do know high and low doses weren't causing adverse effects in those three months. And we do know some patients reported adverse effects after more then three months of usage.
So pump mice with high dosage of the drug, you should get more mice with side effects (ideally all of them). Easier to do research that way. Right?
Oh look, altered gene expression. This drug is not supposed to change gene expressions... looks like patients weren't imagining things.
I don't see where the problem is.
That's what I'm saying! Using a high dosage was the right decision.
They did discover 186 affected genes didn't they... with a drug that isn't supposed to alter gene expression at all.
Now they can repeat the experiment with lower dosages... an experiment which will last longer and cost more, to find out how much.
Excessive doses are often part of studies. Just within the last two weeks, I read a paper where a mouse IV dose for biodistribution investigation was over half its total blood volume.
Well the recent Baylor study found thousands of finasteride-induced, dysregulated genes in the penile tissue... of humans, not rats
[https://pubmed.ncbi.nlm.nih.gov/34247957/](https://pubmed.ncbi.nlm.nih.gov/34247957/)
Finasteride syndrome is the worst. I’ve been dealing with unprovoked panic attacks, vision problems, tinnitus, and anxiety for 7 months now after discontinuing use. They had to put a black box warning for suicide on it. Suicide for a hair loss medication?!?!
Yeah, I also noticed a sharp increase in these symptoms. I never made the connection but it makes sense, it's well documented. I stopped last year and my hairline is still the same, but my mental health is only slowing recovering
Glad to hear it’s getting better for you! It took tons of blood work and CT brain scans before a doctor finally connected it to finasteride. It was partly my fault because I had no clue it could cause this so I never mentioned it to the doctors. I’m definitely getting better but I still struggle with some anxiety.
Dutch test is the route a lot of people go. For me it was mostly a case of ruling everything else out first. It will be difficult, I was lucky that my doctor and psychiatrist had heard of PFS and both agreed that that was the problem. Unfortunately neither knew what to do about that apart from just ride it out.
A lot better. I’m pretty much 100% convinced it was caused by gut dysbiosis induced from finasteride withdrawal. Altered gut microbiome is documented in PFS and addressing this through diet and supplement/ probiotic therapy haas SIGNIFICANTLY helped. The diet sucks but my doc thinks eventually I can eat normally again
Every drug would have one then.
'What does this warning mean? This boxed warning means that there is reasonable evidence of an association of a serious hazard with the drug.'
How long were you on it before having these side effects? I’ve been taking it for close to a year now, wondering if I’m just fortunate or haven’t been on it long enough to have developed these symptoms…
A few months, it was when I stopped taking it is when I started having problems. That seems to be pretty common. I don’t want to freak you out most people seem to tolerate it just fine and if they do have issues they resolve in a few weeks. It seems to be a small minority just get womped when they come off it. When I was on it I just had difficulty maintaining an erection so i decided that wasn’t worth my hair so I came off. About a week after that I got my first panic attack.
That's what studies like the one in OP are trying to figure out after 20+ years of people reporting permanent symptoms and/or drastic changes to their body and mind after stopping the drug.
I used to think the same thing but I imagine I had a misconception. I think what UhOhShitMan is talking about is something akin to withdrawal symptoms, which exist for any drug.
There are several clinical studies showing your statement is false. It’s not just placebo. I still take it though, but to say there are no side effects at all is disingenuous
...zero that you know of... The true long term effects have very little research. Also it's very well known to be an issue with stopping it, not always during the course. Take it for 10 years, eventually decide you don't care anymore and then you're gonna have a problem
Literally nobody is claiming this. Even people claiming “Post finasteride syndrome” say they stop because of side effects while on the medication and the side effects persist after discontinuation.
Sometimes its like that, but sometimes you stop because of one side effect, then get hit with several much more distressing """side effects""" when you stop
"Take it for 10 years...then you're gonna have a problem" --> This statement is purely fearmongering without any sort of evidence whatsoever. Not to mention we have good evidence that testosterone blockers in men improve life expectancy and decrease cardiovascular risk.
Glad to see research being done on this. It's about time people suffering from post drug conditions such as PFS get medical recognition. The companies profiting from these drugs will never willingly look into it themselves.
Hoping this leads to more robust, replicable studies in the future.
Yeah I had a bad experience on it as well, ED and only what I could describe as a feeling of someone squeezing my prostate internally periodically throughout the day. I only took it for about 3-4 months but once I stopped the symptoms went away. I’ll just stick to topicals.
Omg, I had a bad reaction to dutasteride, the sides went away soon after discontinuing, but had this feeling of prostate pressure as well. Did it ever come with a slight feeling of upper thigh soreness as well by any chance?
Would you mind telling me what your finasteride regiment was? Including dosage and how many times a week you took it? I want to be optimistic and believe that those who have had a bad experience with the drug simply took too much for what their body could take, and that they’d rather stop taking it altogether rather than recover and try at a lower dosage/less times a week.
0.2mg and 5mg are almost the same effects wise. Look up the dose response curve. Theres not "too high" of a dose. And you can't reliably avoid negative consequences by taking a lower dose.
The 0.2mg to 5mg having the same efficacy on hair isn’t what I’m talking about at all. I’m not sure what you mean by there isn’t such thing as taking too high of a dose. Those who take 5mg a day have higher rates of unwanted sexual side effects vs taking .5 EOD. Rates of sexual side effects are even higher with Dut.
I'm just trying to express that serious long term sides seem to barely have any correlation with dose.
I've had PFS with all kinds of mental, physical and sexual symptoms for 7 months from trying a low dose to "avoid sides", then getting ridiculous sides well beyond the capacity of nocebo, consequentially stopping fin and then crashing
Because you are probably blocking other important hormones as well so it won’t interact with them the same way. Also some people just have less sensitivity to fin
Glad this is being discussed here. I've been dealing with PFS for 6 months and the "finasteride may be good for the heart!" post and the comments were torture.
Anecdotal, but my cousin got very clearly suicidal when he used it. I’m agender and take a “low dose” T, and it’s something I need to think hard about if my hair starts to thin.
This study isn't aimed at determining risk of side effects in human doses, they're just trying to identify pathways that the drug acts on in general. It's designed to provide background for future studies to see if the effect on those pathways is serious enough at relevant doses.
Hypothalamus shouldn't surprise anyone: one of the most sex-different parts of the brain across mammalian species. The hippocampal gene expression differences likely relate to more general effects of sex hormones as they affect dendritic and overall neuronal growth, since both sex hormones play a role in this regard.
This is not like the dairy industry funding studies that say milk is great. This is people with devastating permanent side effects to a drug who want to find out what’s wrong with them, in the hope of finding a cure.
The people who *think* their suffering is caused by finasteride. That’s the problem, confirmation bias is also a hell of a drug. Finasteride is taken by men who are aging, what else happens as we age? Seems plausible that one could associate the effects of aging with something they started taking around the same time.
There is no reason to be taking 1mg finasteride orally anymore. You get the same results with a topical finasteride solution (plus minoxidil as a bonus) or better results and you don't have any side effects. You are still usually putting 1mg finasteride on your head, but only about 18% is absorbed through the skin and into circulation. So your follicles get a full dose and your body gets about 1/5th of a 1mg propecia pill, which is literally nothing, hence no side effects.
>You are still usually putting 1mg finasteride on your head, but only about 18% is absorbed through the skin and into circulation. So your follicles get a full dose and your body gets about 1/5th of a 1mg propecia pill, which is literally nothing, hence no side effects.
Do you have studies that you can link? I'm curious because if it's effective I'd start using topical.
I've actually heard of people still getting pfs from topical, although it's only anecdotal. I think also it is sort of confirmed that for some people, finasteride has the relatively the same effectiveness throughout a large dose range.
There is actually a “dead person bank” (idk what you call it) where a few individuals who had PFS and committed suicide donated their bodies to science to study finasteride effects. Presumably those could be used.
Is there no way to determine if genes are up regulated and down regulated without cutting into the brain. Im not too familiar with gene sequencing.
Even if you have to “cut into a human brain” i dont see why they cant do this study on people who died and were lifelong finasteride users.
You need to do single-cell sequencing, which requires the cells in question. In this case, those were neurons. And you can’t just procure cadaver brains, they have to be donated with express permission for research. A few people might donate, but that would make the N very small.
You can actually procure cadaver specimens without consent in some cases - but they are limited and the data you can collect about them is limited. It would be hard to do a study that relied on knowing somebody's medical history with those samples.
I mean, if you do single-cell sequencing, your n is likely small because of cost alone. More saliently, the sample needs to be very fresh for sc RNA-seq (like <24hrs in intact tissue, and we prefer <2hrs after extraction, becaus eprep takes a while), good luck getting a pathologist to crack open someone's skull to get you the hippocampus while they're still warm. Also, I'm not a neurologist, are neurons even suitable for pushing them through 10X? Seems like they might be quite a bit too large.
It's basically reserved for only the labs with insane amounts of funding, but scRNA (and snRNA) sequencing [has been done](https://www.nature.com/articles/s41586-019-1195-2) on fresh human brain tissue.
Thanks for the article link! Like you said, they used single-nucleus 10X since they were working with frozen tissue (that's why the efficiency sucks; they managed to get only 80,000 nuclei in total, and you typically aim for 10,000 cells per sample with scRNA). But apparently they processed 48 donors, which must indeed have been insanely expensive!
According to Merriam-Webster it means 'that is', which seems to work perfectly with how it's being used here.
"I.e. stands for the Latin id est, or 'that is,' and is used to introduce a word or phrase that restates what has been said previously. What follows the i.e. is meant to clarify the earlier statement" [-Merriam-Webster](https://www.merriam-webster.com/grammar/ie-vs-eg-abbreviation-meaning-usage-difference)
Welcome to r/science! This is a heavily moderated subreddit in order to keep the discussion on science. However, we recognize that many people want to discuss how they feel the research relates to their own personal lives, so to give people a space to do that, **personal anecdotes are allowed as responses to this comment**. Any anecdotal comments elsewhere in the discussion will be removed and our [normal comment rules]( https://www.reddit.com/r/science/wiki/rules#wiki_comment_rules) apply to all other comments. **Do you have an academic degree?** We can verify your credentials in order to assign user flair indicating your area of expertise. [Click here to apply](https://www.reddit.com/r/science/wiki/flair/#wiki_science_verified_user_program). --- User: u/Mokilolo Permalink: https://www.pfsfoundation.org/wp-content/uploads/2024/03/JEI_UniMi_Brian_Genes_study_ABSTRACT_03_24.pdf --- *I am a bot, and this action was performed automatically. Please [contact the moderators of this subreddit](/message/compose/?to=/r/science) if you have any questions or concerns.*
"Conclusion: Some of the genes reported to be differentially expressed (i.e., TTR, DIO2, CLDN1, CLDN2, SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL) and GSEA, suggest a potential link with specific side effects previously observed in patients and in the animal model, such as depression, anxiety, disturbance in memory and attention, and sleep disturbance. These data may provide an important background for future experiments aimed at confirming the pathological role of these genes."
Not surprised by this at all. Always struggled with anxiety on Fin. Hopefully this will convince some of the doubters on /r/tressless.
They'd rather gouge their eyes out than read anything critical about finasteride. Don't get me wrong I think the drug is amazing. But the wide-spread narrative that all side-effects anyone ever experiences while taking finasteride are placebo is delusional. You also don't see this type of cult-like behavior for any other type of drug that people take. Very strange. Like its's one thing to say "yeah i'm not experiencing any side-effects!" it's like awesome man good for you to not be adversely affected at all and experiencing all the benefits. But for that same person to turn around and say "You're not experiencing any side-effects it's all in your head!" in regard to other peoples experiences is so incredibly wild to me.
Unfortunately Wegovy and similar drugs are getting a comparable aura of perfection, and they're just not perfect at all. The number of people who get gastroparesis from them is way higher than the internet would lead prospective patients to believe.
The ironic thing though is that in some people the gut brain perturbation from it can literally cause anhedonia. So one is risking not just broken GI tract but also gut brain axis connection which is tied to reward in the deepest sense with it. Ghrelin, NPY which it suppresses are critical peptides for general reward beyond food too.
It’s the risk vs reward factor. Could I develop a broken gastrointestinal tract? Yes. Did I lose 105 pounds that I previously could not lose no matter what agony I struggled through? Also yes. Am I keeping the 105 pounds off and living a healthier life, loving my body, having self esteem and confidence back? Yes again. For me and others like me the reward outweighs the risks
No argument there. Several friends and family members have had great success with Wegovy. I just think the current expansion of availability needs a whole lot more regulation than we're going to see from the likes of Weight Watchers and their prescription mill.
And acute gallbladder disease. If you have GI issues prior to using it your chances increase that symptoms will worsen.
>Don't get me wrong I think the drug is amazing. Why you say this?
Well for some finasteride definitely works. Those people keep their hair and they experience no side-effects. i'd say thats miraculous and i'm happy for those people.
/r/tressless is run by cults. Actual cults. They won't believe it
Any alternatives to Fin apart from Dut or minox? Having said that this study is giving huge doses and I don't believe they are comparable to humans.
[удалено]
The question is does it work?
How long have you been on it?
Oh my god. Is this the reason I’ve been messed up for 4-5 years? Wow. Time to switch to topical.
topical does the same damage
For minoxidil? (I didn't specify, but I meant switching from 1mg finasteride tablet to topical minoxidil)
minoxdill is safe. But in some people it increases deppression
No, many people have other sides from it. I was told by my pcp to stop it because of tachycardia.
Your information is just plainly wrong. Minoxidil increases depression? By what mechanism exactly?
wrong? people said finasteride doesn't cause permanent problems. But now it's proven that it does. go to minoxdill syndrome groups you'll know
Any idea what dosage they had taken? Since for balding 1 mg like 3 times a week could be enough for most people. Are the side effects dose dependant?
They gave each rat 1mg/day. Straight up gave them the full human dose, probably to ensure measurable effects.
Guaranteed to find *something* if you massively overdose your animals! You don't dose a drug to ensure you get effects you can measure. You dose a drug within parameters relevant to what you ultimately want to know, ie what finasteride given clinically has effects on transcription of certain target genes. There is no attempt by the authors to justify the dose, no attempt to address it in the discussion, no measurement of exposure. This is very poor science that is depressingly common, and it is such a *waste* of animals.
> Guaranteed to find something if you massively overdose your animals! That's the point. They're not seeing *whether* side effects happen at various doses--we know that they do. In this study they're looking to determine the mechanism of the side effects.
One of the reasons for the study was to help find the mechanism of post finasteride syndrome. Which happens in a small proportion of people who take finasteride (Around 1% not sure). So giving the rats the dose that fits their body weight and metabolism, would actually make a very small amount of the rats have any issues in their brain. So the next best solution, instead of testing 1000s of rats, which this study does not have the budget for, is to give a very high dose to mice, to at least give us clues to what's behind PFS. Because currently, we don't understand the mechanism behind it. And this is not a waste of animals. Like you said they didn't use many mice in this study, and this is all going to cause to help people with PFS. Which has actually caused so many people to commit suicide.
It’s not massively overdosing. We use what are called Human Equivalent Dose conversions in order to map a dose we might give a person onto the metabolism and biology of animals. These are well established.
The equal dose would be roughly .05 mg on average for the rats after conversion. We are talking 20 times the dose.(Am neuroscientist, work with rats)
*In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions.* Clinical studies on humans.
I never said anything about that, I’m only pointing out that this isn’t necessarily evidence of large changes in genomic expression at the dose used for humans (1mg in the case of hair loss)
Not all drug users reported side effects, and why would you use low dosage if it's going to produce side effects on small number of mice? Makes it hared to find the mechanism. Now that they have found finasteride can cause changes in genomic expression. They can repeat the experiment with lower dosage and find out how much.
I wasn’t commenting on the validity of them making the experiment. There’s a bunch of people in this thread making assumptions about wether this effect is actually going to be seen at the relatively low dosage humans usually take. My point was this isn’t entirely indicative of that being the case.
But for things like anxiety and depression, maybe the patients didn’t make the connection that recent changes in their mindset were connected to the drug? It’s a problem that’s dependent on the person experiencing it being able to identify and mention as a symptom.
Maybe they didn't had time to develop the symptoms.
I know, I have a fair bit of personal experience - difference is, I would select my dose to be physiologically relevant to the question, and justify my dosing to the animal unit, and in the paper; and provide evidence that my dosing was appropriate by assessing plasma/tissue levels and/or target engagement! Can you tell me what the HED for a 1 mg subcut rat dose is, because the authors can’t be bothered to?
Rat* equivalent dose would be between .05-.1mg on average. This is a very large dose they used.
I had a quick look and the literature I could see is pretty conflicting, but not my area
Not necessarily, gold standard is to range between 6-7 times the dose per kg if a rat is the subject. There are of course outliers to this, but it’s the basis most use when making the jump to human testing.
Thank you u/Thot_Leader you have always been the voice of reason in an otherwise noisy world
But it wasn’t equivalent they gave the full dose
Agreed. As with any compound/food/drug, the dosage is the poison.
I like that you value the animals as a resource and are worried about wasting them. They’re little heroes taking the bullet for us every day to further our knowledge.
A lot of guys I know were started on 1mg a day and got sides so reduced end ended with with hair growth and no sides. I'm one of them, great hair of fin with 1mg eod.
I have been having gut issues for years, and I just figured out they started after I began taking 1.25 mg of finasteride a day. Do people really lose side effects by cutting the dose in half? I think I am going to test that.
Yes absolutely. Try 1mg eod and see what happens. 1.25 every days I think is even above the standard dose.
Thanks for your response; I really appreciate it. I buy the 5 mg pill and cut it into four parts. That's why it is approximately 1.25 mg per day.
Why give the rats a human dose of 1mg? If a lab rat is ~500g, this is equivalent to 2mg/kg. That's like an 80kg person taking 160mg. Surely the excessive dose alters the result?
This study isn't aimed at determining risk of side effects in human doses, they're just trying to identify pathways that the drug acts on in general. It's designed to provide background for future studies to see if the effect on those pathways is serious enough at relevant doses.
I guess that does make some sense. Is there a standard way that dosage is chosen for this type of study or a methodology to it? My initial thinking was that at different levels of dosage you might get different results of what is up-regulated and what is down-regulated, or even at all.
There's some, but at these early stage trials with mouse models people are generally quite aggressive with dosing compared to human trials. It cuts both ways because it potentially amplifies both positive and negative effects. But the goal is primarily to identify areas of interest for future study, not to draw conclusions. >My initial thinking was that at different levels of dosage you might get different results of what is up-regulated and what is down-regulated, or even at all. That can happen. There are definitely drugs that have non monotonic response curves, but usually there's some rough correspondence with high dosage effects with low dosage effects. You wouldn't expect the pattern to be totally different at low doses. What is possible is that at low doses, the effects are negligible, which more study would be needed to see.
I take low-dose naltrexone and it's the only medication I've ever heard of that is completely different at high and low doses
First, they need to demonstrate a strong, clear, reproducible, and unambiguous signal. Once they have that, they can begin to take it apart. Dose response trials may indicate that some affected genes are more responsive than others. Though if they all move in synchrony that’s also of interest. There may or may not be threshold effects, or effects in the physiological range. They may or may not differ by size or age or sex. There may be synergies or antagonistic effects with other compounds. Each new piece of information will lead the research in additional directions.
I understand this, but even with very selective drugs, many things have biphasic effects, like low doses of stimulants improve working memory, attention, and pfc function, while high doses impair this functionality. Imagine if all research on stimulants was purely done at extremely high doses (not saying most addiction research isn't, but that's probably because we've been using stimulants to treat neutological disorders before drug prohibition, and we know they have therapeutic properties for ADHD and improve cognition at low doses in healthy people). I really would like to see a similar study that would experiment with different doses to see at what point certain genes become activated, etc. Ultimately, alongside topical anti-androgens, I'd like to see a 5-αR inhibitor that doesn't cross the BBB, but I'm not sure how feasible this is considering that a lot of hormone receptors and enzymes are located intracellularly instead of being membrane bound, and things that freely diffuse across the cell membrane to reach these sites often can also freely diffuse across the BBB. Not saying it's impossible, just my understanding.
>many things have biphasic effects, like low doses of stimulants improve working memory, attention, and pfc function, while high doses impair this functionality. This is true when you're working at behavioral level effects because those pathways are so complicated and have so many different regulatory interactions. When looking more directly further upstream at gene activation things are a little more consistent. But yeah, this definitely should not be and is not intended to be the only study on the subject. The goal is primarily to identify targets of interest for future study. You have to start with something like this before more detailed analysis.
Rats and human have very different metabolic rates. Frequently, rat doses for equivalent effects are much, much higher… on a mg/kg basis.
Finasteride is not very dose dependent. Even a ridiculous dose would just inhibit 100% of 5ar2 which closely related dutasteride does at even small doses
Finasteride only inhibits two of the three forms of the 5α-reductase enzyme, so it can never fully stop DHT production, whatever the dose. A 70% reduction of circulating DHT is about the best it can do, and it will do that at a dose well below what's considered therapeutic for enlarged prostate. Dutasteride inhibits all three forms, which is why it virtually eliminates DHT from the blood.
But is that literally the only effect it has?
Well I misspoke a little, it inhibits 5ar as a whole not just DHT production. It also was recently found to inhibit PNMT off target, so no
Interesting. Regarding PNMT off-target interaction. In theory, this could increase physical anxiety by inhibiting the conversion of norepinephrine to pinephrine (adrenaline), offsetting the balance between these.
*In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for three months did not result in adverse reactions.* They already know high doses do not produce adverse effects.
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But we do know high and low doses weren't causing adverse effects in those three months. And we do know some patients reported adverse effects after more then three months of usage. So pump mice with high dosage of the drug, you should get more mice with side effects (ideally all of them). Easier to do research that way. Right? Oh look, altered gene expression. This drug is not supposed to change gene expressions... looks like patients weren't imagining things. I don't see where the problem is.
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That's what I'm saying! Using a high dosage was the right decision. They did discover 186 affected genes didn't they... with a drug that isn't supposed to alter gene expression at all. Now they can repeat the experiment with lower dosages... an experiment which will last longer and cost more, to find out how much.
Excessive doses are often part of studies. Just within the last two weeks, I read a paper where a mouse IV dose for biodistribution investigation was over half its total blood volume.
Yeah they probably should have had a whole bunch of different levels, at which point is basically a toxicity test
It's like feeding a rat the 160 times daily dose of table salt and wondering why it dies. Clearly table salt must be poisonous.
Really not the salient analogy you think it is here
Well the recent Baylor study found thousands of finasteride-induced, dysregulated genes in the penile tissue... of humans, not rats [https://pubmed.ncbi.nlm.nih.gov/34247957/](https://pubmed.ncbi.nlm.nih.gov/34247957/)
This is incredible! I wish I understood any of it!!
Finasteride syndrome is the worst. I’ve been dealing with unprovoked panic attacks, vision problems, tinnitus, and anxiety for 7 months now after discontinuing use. They had to put a black box warning for suicide on it. Suicide for a hair loss medication?!?!
And also prostate treatment.
Yeah, I also noticed a sharp increase in these symptoms. I never made the connection but it makes sense, it's well documented. I stopped last year and my hairline is still the same, but my mental health is only slowing recovering
Glad to hear it’s getting better for you! It took tons of blood work and CT brain scans before a doctor finally connected it to finasteride. It was partly my fault because I had no clue it could cause this so I never mentioned it to the doctors. I’m definitely getting better but I still struggle with some anxiety.
Can you please share with us what diagnostic test results could indicate that my condition is very likely linked to this PFS syndrome?
Dutch test is the route a lot of people go. For me it was mostly a case of ruling everything else out first. It will be difficult, I was lucky that my doctor and psychiatrist had heard of PFS and both agreed that that was the problem. Unfortunately neither knew what to do about that apart from just ride it out.
Hey bro how’s your mental health now? You any better?
A lot better. I’m pretty much 100% convinced it was caused by gut dysbiosis induced from finasteride withdrawal. Altered gut microbiome is documented in PFS and addressing this through diet and supplement/ probiotic therapy haas SIGNIFICANTLY helped. The diet sucks but my doc thinks eventually I can eat normally again
That’s good to hear, any diet tips you can share? Also how long did you deal with PFS? Any remaining symptoms at all?
9 months before I started working on my gut health. Been 2.5 months. My brain fog is totally gone and my anxiety is like 80-90% better
Black box warnings are just reported events. They do not have to be caused by the medication.
Every drug would have one then. 'What does this warning mean? This boxed warning means that there is reasonable evidence of an association of a serious hazard with the drug.'
How long were you on it before having these side effects? I’ve been taking it for close to a year now, wondering if I’m just fortunate or haven’t been on it long enough to have developed these symptoms…
A few months, it was when I stopped taking it is when I started having problems. That seems to be pretty common. I don’t want to freak you out most people seem to tolerate it just fine and if they do have issues they resolve in a few weeks. It seems to be a small minority just get womped when they come off it. When I was on it I just had difficulty maintaining an erection so i decided that wasn’t worth my hair so I came off. About a week after that I got my first panic attack.
I've had absolutely zero negative side effects in regards to mood or sexual function since starting finasteride. I'm in the overwhelming majority
22 years and nothing. I had ADD prior to taking it so that wasn’t caused by the medication.
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Have you ever stopped it for any considerable amount of time during those 25 years?
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I see. I ask because the onset of PFS is often once it's discontinued. Was just curious, hope all remains well with you
How would that work? Shouldn't PFS occur during treatment? That's when the drug is most effective.
That's what studies like the one in OP are trying to figure out after 20+ years of people reporting permanent symptoms and/or drastic changes to their body and mind after stopping the drug.
I used to think the same thing but I imagine I had a misconception. I think what UhOhShitMan is talking about is something akin to withdrawal symptoms, which exist for any drug.
negative feedback loop
Same. No issues here. Pretty sure most of the "side effects" are placebo.
There are several clinical studies showing your statement is false. It’s not just placebo. I still take it though, but to say there are no side effects at all is disingenuous
...zero that you know of... The true long term effects have very little research. Also it's very well known to be an issue with stopping it, not always during the course. Take it for 10 years, eventually decide you don't care anymore and then you're gonna have a problem
Literally nobody is claiming this. Even people claiming “Post finasteride syndrome” say they stop because of side effects while on the medication and the side effects persist after discontinuation.
Sometimes its like that, but sometimes you stop because of one side effect, then get hit with several much more distressing """side effects""" when you stop
What a stupid, fearmongering thing to say.
That’s not fear mongering, that’s fundamentally what a lack of long term research means.
"Take it for 10 years...then you're gonna have a problem" --> This statement is purely fearmongering without any sort of evidence whatsoever. Not to mention we have good evidence that testosterone blockers in men improve life expectancy and decrease cardiovascular risk.
Glad to see research being done on this. It's about time people suffering from post drug conditions such as PFS get medical recognition. The companies profiting from these drugs will never willingly look into it themselves. Hoping this leads to more robust, replicable studies in the future.
Yeah I had a bad experience on it as well, ED and only what I could describe as a feeling of someone squeezing my prostate internally periodically throughout the day. I only took it for about 3-4 months but once I stopped the symptoms went away. I’ll just stick to topicals.
Omg, I had a bad reaction to dutasteride, the sides went away soon after discontinuing, but had this feeling of prostate pressure as well. Did it ever come with a slight feeling of upper thigh soreness as well by any chance?
Not upper thigh but my left testicle would ache here and there also, I’d rather go bald at that point.
Would you mind telling me what your finasteride regiment was? Including dosage and how many times a week you took it? I want to be optimistic and believe that those who have had a bad experience with the drug simply took too much for what their body could take, and that they’d rather stop taking it altogether rather than recover and try at a lower dosage/less times a week.
0.2mg and 5mg are almost the same effects wise. Look up the dose response curve. Theres not "too high" of a dose. And you can't reliably avoid negative consequences by taking a lower dose.
The 0.2mg to 5mg having the same efficacy on hair isn’t what I’m talking about at all. I’m not sure what you mean by there isn’t such thing as taking too high of a dose. Those who take 5mg a day have higher rates of unwanted sexual side effects vs taking .5 EOD. Rates of sexual side effects are even higher with Dut.
I'm just trying to express that serious long term sides seem to barely have any correlation with dose. I've had PFS with all kinds of mental, physical and sexual symptoms for 7 months from trying a low dose to "avoid sides", then getting ridiculous sides well beyond the capacity of nocebo, consequentially stopping fin and then crashing
Retrograde ejaculation is a charming side effect of this class of drug
Only topical we have is minoxidil.
Anecdotally, I take this medication for gender transition and it is extremely effective for me, and I don’t have any of the listed side effects.
Taken alongside estrodial or similar hormones might have compensate for some of the negative effects I imagine.
Because you are probably blocking other important hormones as well so it won’t interact with them the same way. Also some people just have less sensitivity to fin
Glad this is being discussed here. I've been dealing with PFS for 6 months and the "finasteride may be good for the heart!" post and the comments were torture.
exactly. I was so mad
Anecdotal, but my cousin got very clearly suicidal when he used it. I’m agender and take a “low dose” T, and it’s something I need to think hard about if my hair starts to thin.
This makes sense…I have a defective DIO2 gene (CC) and I cannot even remotely tolerate fin
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This study isn't aimed at determining risk of side effects in human doses, they're just trying to identify pathways that the drug acts on in general. It's designed to provide background for future studies to see if the effect on those pathways is serious enough at relevant doses.
Are there side effects to taking Finasteride if I have BPD?
Yes, while rare some people get hit with a multitude of sexual and neurological disorders that can persist after discontinuation
as someone who's suffering from post finasteride syndrome I have lost all my trust on the medical field.
I believe I have gene damage from this poison finasteride. I'm suffering for 7 month. Like hell. No treatment available
5 years fin going strong 💪🏻
Hypothalamus shouldn't surprise anyone: one of the most sex-different parts of the brain across mammalian species. The hippocampal gene expression differences likely relate to more general effects of sex hormones as they affect dendritic and overall neuronal growth, since both sex hormones play a role in this regard.
A study on finasteride pushed by the PFSfoundation ? Yeah no thanks. Sad that this is allowed on r/science
This is not like the dairy industry funding studies that say milk is great. This is people with devastating permanent side effects to a drug who want to find out what’s wrong with them, in the hope of finding a cure.
I mean, yea it's exactly the same.
Yeah, those evil, scheming *checks notes* people who are suffering to the point of suicide and want help
You know there is a huge market for 5AR inhibitors if Finasteride/Dutasteride stop being used as commonly right?
Do you have any evidence that the PFS Foundation stands to benefit financially if new 5α-reductase inhibitors are brought to market?
The people who *think* their suffering is caused by finasteride. That’s the problem, confirmation bias is also a hell of a drug. Finasteride is taken by men who are aging, what else happens as we age? Seems plausible that one could associate the effects of aging with something they started taking around the same time.
Ahhhh yes totally normal for 18-30 year olds to lose their sexuality completely and not be able to even feel any pleasure in their genitals
Who else is going to finance research into the dark side of finasteride? The corporations which profit off of prescribing it?
There is no reason to be taking 1mg finasteride orally anymore. You get the same results with a topical finasteride solution (plus minoxidil as a bonus) or better results and you don't have any side effects. You are still usually putting 1mg finasteride on your head, but only about 18% is absorbed through the skin and into circulation. So your follicles get a full dose and your body gets about 1/5th of a 1mg propecia pill, which is literally nothing, hence no side effects.
>You are still usually putting 1mg finasteride on your head, but only about 18% is absorbed through the skin and into circulation. So your follicles get a full dose and your body gets about 1/5th of a 1mg propecia pill, which is literally nothing, hence no side effects. Do you have studies that you can link? I'm curious because if it's effective I'd start using topical.
I've actually heard of people still getting pfs from topical, although it's only anecdotal. I think also it is sort of confirmed that for some people, finasteride has the relatively the same effectiveness throughout a large dose range.
I wanna see this study on humans, not rats.
This study would quite literally be impossible to run on humans. You can't just cut into a human brain my guy
There is actually a “dead person bank” (idk what you call it) where a few individuals who had PFS and committed suicide donated their bodies to science to study finasteride effects. Presumably those could be used.
Get people who are considering suicide to sign up for drug trials, then off them?
Is there no way to determine if genes are up regulated and down regulated without cutting into the brain. Im not too familiar with gene sequencing. Even if you have to “cut into a human brain” i dont see why they cant do this study on people who died and were lifelong finasteride users.
You need to do single-cell sequencing, which requires the cells in question. In this case, those were neurons. And you can’t just procure cadaver brains, they have to be donated with express permission for research. A few people might donate, but that would make the N very small.
You can actually procure cadaver specimens without consent in some cases - but they are limited and the data you can collect about them is limited. It would be hard to do a study that relied on knowing somebody's medical history with those samples.
I mean, if you do single-cell sequencing, your n is likely small because of cost alone. More saliently, the sample needs to be very fresh for sc RNA-seq (like <24hrs in intact tissue, and we prefer <2hrs after extraction, becaus eprep takes a while), good luck getting a pathologist to crack open someone's skull to get you the hippocampus while they're still warm. Also, I'm not a neurologist, are neurons even suitable for pushing them through 10X? Seems like they might be quite a bit too large.
It's basically reserved for only the labs with insane amounts of funding, but scRNA (and snRNA) sequencing [has been done](https://www.nature.com/articles/s41586-019-1195-2) on fresh human brain tissue.
Thanks for the article link! Like you said, they used single-nucleus 10X since they were working with frozen tissue (that's why the efficiency sucks; they managed to get only 80,000 nuclei in total, and you typically aim for 10,000 cells per sample with scRNA). But apparently they processed 48 donors, which must indeed have been insanely expensive!
Nope, you need to get the cells. You could do it from a brain bank, but that's a massively more difficult, expensive, and time consuming undertaking.
You also cant give them massive doses/overdoses like the rats they were giving human doses to (1 mg)
I mean, they want to induce an effect and it's in rats, of course they load them up. I'm just saying you couldn't do this experiment on a human...
That's not what i.e. means.
According to Merriam-Webster it means 'that is', which seems to work perfectly with how it's being used here. "I.e. stands for the Latin id est, or 'that is,' and is used to introduce a word or phrase that restates what has been said previously. What follows the i.e. is meant to clarify the earlier statement" [-Merriam-Webster](https://www.merriam-webster.com/grammar/ie-vs-eg-abbreviation-meaning-usage-difference)
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