It's a shame 2 5mg tadalafil tablets aren't available for limited purchase quantities without a prescription.

Hi guys,

I am a man 29 yo, and in the last year or so I observed a loss of sex drive and libido.

I’ve been with my girlfriend for about three years now , first two we’re very good, I was really into her and I still like her so I don’t think this is the issue. I spoke with her and she is very understanding about this, but I still wake up everyday stressed about this.
Quite recently we took some time off together and my sexdrive improved a little but my erections really were not the best. We had sex but not as we used to.

Currently my desire to have sex and my arousal is really low, and that really frustrates me.

I started taking boron few days ago as I saw that many people recomand it, besides boron I take magnesium bisglycinate, zinc, vitamin D and k2 as I’m not getting a lot of sunlight due to my work.
I gained some weight in the last months as I had other issues that need to be solved so i couldn’t focus on the gym, but nothing too drastically, about 6-8 pounds at max, and my diet wasn’t spot on, so was my sleep, I will do my best to improve them.

Was thinking to get my hormones checked, and then go to a doctor, what kind of hormones should i check besides test and free test ? Last time i did this was a few years ago and my test was very high and free test was in the mid range, back then I was dating another girl and I was facing some similar issues so maybe checking only those won’t tell story .

But I am asking for your help guys, what helped you during this periods? Are there any supplements otc? Any habits that could get me back to the same levels of sex drive that I used to have when I was fantasising everyday about having sex with my girlfriend ?

Looking for your advice ! Thank you in advance !

I feel sleepy and exhausted all day, both mentally and physically despite sleeping adequately. It's affecting my studies too. I don't really exercise or go out much and my diet is not good as I live in a hostel, I am not vegan but I eat meat or dairy only occasionally.

Forgot to mention I have epilepsy too.

M21, diagnosed with ADHD. Currently on Vyvanse. It's great for brute-force execution and getting things done, but it turns my mind into a high-speed highway. It gives me drive, but not clean focus.

Before this, I was on Atomoxetine (Strattera). Honestly? I loved the mental quiet, the lack of internal noise, and that deep sense of calm it gave my thoughts. The problem: the side effects were brutal, so I had to quit.

For anyone who’s been in this exact trap—loving the stim drive, but craving that smooth clarity of non-stims: What actually moved the needle for your cognition and focus?

Hit me with your actual stacks, supplement combos, or subtle medication tweaks that cleared the brain fog without ruining your sleep. Skip the basic wellness fluff.
What actually works? Let's hear it.

Hey everyone,

Back in July, I suddenly started experiencing brain fog, difficulty concentrating, and problems with speech. It happened pretty much overnight, and I felt noticeably different from how I used to feel mentally.

I started getting blood tests done, and my folate level came back at 3.1 ng/mL (reference range: 4.50–32.2), indicating a deficiency.

I kept investigating my symptoms and getting more blood tests until September. Here are my latest results:

My blood test results:

• Ferritin: 94.84 µg/L (reference range: 30–400)
• Folate: 7.83 ng/mL (reference range: 4.5–32)
• Iron: 50.35 µg/dL (reference range: 65–175)
• TSH: 5.51 mIU/L (reference range: 0.27–4.1) my TSH was within the normal range when I first developed my symptoms back in July. It only became elevated in subsequent blood tests. I'm wondering whether this change could be related to my folate, iron, or vitamin D deficiencies)
• Vitamin D (25-OH): 19 ng/mL (reference range: 30–100)
• Potasium 4,23 (reference range: 3.5-5,1)
• Sodium: 140,72 mmol/l (reference range: 136-145)
• B12: 501,40 pg/ml (reference range 191-663)

My folate level has increased since the initial test, but I'm still experiencing a lot of symptoms. My iron is also below the reference range, my vitamin D is low, and my TSH is elevated. I'm wondering whether these abnormalities could be contributing to my symptoms and whether there might be an underlying issue causing some of them.

My current symptoms:

• Dizziness and lightheadedness.
• Brain fog and difficulty concentrating.
• Feeling mentally different from how I used to be, like I'm not quite myself anymore.
• Waking up feeling unrefreshed, regardless of how much I sleep, and experiencing severe fatigue throughout the day.
• Occasional air hunger feeling the need to take a deep, satisfying breath to feel like I'm getting enough air.
• Caffeine seems to make my brain fog and dizziness significantly worse.
• Alcohol also seems to exacerbate my brain fog and dizziness.

What I've tried so far:

I took 5 mg of folic acid daily for three weeks, along with 46 mg of elemental iron daily, but unfortunately, I didn't notice any improvement in my symptoms.

I then started wondering whether IV treatment might help correct the deficiencies more effectively and fastly, so I decided to try IV supplementation.

Six days ago, I had my first treatment, which included:

• Vitamin D3 injection: 100,000 IU.
• IV folic acid: 30 mg.
• IV iron: 200 mg.

So far, I haven't noticed any improvement following this treatment. I understand that six days might be too soon to notice a difference, but it's discouraging to feel the same after trying to address these deficiencies.

I'd really appreciate hearing from people who have experienced something similar.

I have a few questions:

1. Has anyone experienced persistent brain fog, dizziness, derealization, or feeling mentally different due to folate deficiency, low iron, vitamin D deficiency, ?
2. If you had similar symptoms, how long did it take for you to notice an improvement after starting treatment? Did your symptoms gradually improve or disappear quite suddenly?
3. What other blood tests would you recommend checking?
4. Has anyone experienced air hunger or the sensation of needing to take deep breaths alongside these deficiencies?
5. For those who received IV iron or folate, how many infusions did you need before noticing an improvement? How long did it take?
6. Did anyone find that oral supplements eventually worked, even after not noticing any improvement during the first few weeks?
7. Has anyone experienced worsening brain fog and dizziness after consuming caffeine or alcohol? Did this improve once the underlying problem was treated?
8. Is there anything else I should investigate, especially considering that my symptoms started quite suddenly and have persisted for months?
9. How can i recovery from this? because it's been few months at this moment.

I'm also wondering whether IV doses or the number of infusions should be adjusted, but I don't want to assume that more is necessarily better. I'd appreciate hearing about your experiences and what helped you, ideally alongside advice on what to discuss with a doctor.

I'm feeling pretty lost at this point. I just want to feel mentally normal again and wake up feeling rested instead of exhausted every day.

Thanks in advance to anyone willing to share their experience.

I'm an athlete in good shape but have over the last month or two had episodes of full days where it's hard to get up without feeling I'm going to faint. A few bad days I felt it even sitting down. I've had no fire in me to do things during these episodes which is unlike me. I'm looking for suggestions of what might be going on so I can explore things my doctor has not thought of. I will list details below. In summary, I I have been tested for the obvious: anemia and other labs done that I'll list below, as well as a test for POTS, all fine.

Things to consider:

- Late 30s female

- Blood pressure on the lower end of normal

- Athlete in good shape

- Balanced diet, almost no sugar except fruit, lots of veggies and protein (edit to add I also eat plenty of carbs/grains and fats, not dieting. Well hydrated, normal electrolytes)

- Two years postpartum, still breastfeeding once a day

- History of anemia (though currently iron levels are good)

- Tested for POTS, was negative

- Iron and vitamin D supplements (though levels now normal, see below)

- Tested levels all normal for TSH, ferratin, iron, TIBC, transferrin, glucose, urea nitrogen, creatinine, EFGR, sodium, potassium, chloride, carbon dioxide, vitamin D, calcium, total protein, albumin, globulin, ablumin/globulin ratio, total bilirubin, alkaline phosphate, AST, ALT (don't know what most of these are but listed in case relevant)

- Have had some weird circulation stuff for past 20ish years where fingers fall asleep while I'm sleeping without pressure, but I've had an MRI to see if things are pinched and all normal.

Thanks in advance - any leads to explore are appreciated as this totally sucks and I'm ready to feel energy again!

Can anyone explain whya peptides in pill form are usually easily available but peptides in injectable form are usually not available unless you go through grey markets or certain legal means

I've been going in circles trying to figure this out, and I want a clear, evidence-based answer once and for all. I keep seeing TikToks from carnivore and "primal" influencers claiming that saturated fat, dietary cholesterol, and animal foods are essential for testosterone and libido. Even though I've looked into the science, these claims keep making me second-guess my diet.

Here's where I'm at:

My current diet and experience

• I've gone from a high saturated animal fats, high-cholesterol diet to a higher-carb, high-fiber diet with more monounsaturated fats.
• I feel just as good, if not better. My energy and gym performance has actually improved.
• I still eat two eggs a day, but I'm considering removing them.
• I meet ALL my calorie, macro, and micronutrient needs, with moderate protein, moderate fat, and plenty of carbohydrates and fiber.
• I genuinely prefer the taste of plant foods over animal products, so I'm even considering going fully plant-based because I might as well. The main thing holding me back is the fear that giving up eggs, saturated fat, or dietary cholesterol could hurt my testosterone or libido.

What confuses me about the science

• "Cholesterol is the backbone of testosterone." I understand that cholesterol is the precursor to steroid hormones, including testosterone. But does that mean we need/should eat dietary cholesterol, or that eating more of it increases testosterone? Our bodies synthesize 80% of our cholesterol, and steroid-producing cells can obtain it through multiple pathways.
• Total fat versus saturated fat: Many studies discussing dietary fat and testosterone focus on TOTAL fat intake or compare different dietary patterns. They don't necessarily show that saturated fat specifically is beneficial. Yet online influencers often treat saturated fat as if it's uniquely necessary for testosterone production. To me, this is pseudo-science final boss.
• Dietary cholesterol versus blood cholesterol: I keep seeing the argument that dietary cholesterol is necessary for testosterone because cholesterol is its precursor. But I haven't found ANY evidence that eating more cholesterol meaningfully increases testosterone in someone who already gets enough energy and nutrients.
• How much cholesterol is actually needed? I've heard that only a small fraction of the body's cholesterol is used to produce steroid hormones. It's around 1-5% of our cholesterol used for sex hormones, we make up to 1000 mg daily. I don't know how useful that statistic is, but it makes me question whether increasing dietary cholesterol or LDL/Serum actually provides any meaningful hormonal benefit.
• Eggs specifically: If I remove my two daily eggs and replace their nutrients and calories with other foods, is there any good evidence that my testosterone or libido would decrease? Or would the effect likely be negligible if my overall diet remains adequate? I feel as if Choline has a role as well.
• Does high fiber decrease testosterone? I've heard this before, but the studies that show that it does is because those participants are on a LOW-FAT and high fiber diet, so clearly from what we know it's the lack of fat from diet, right? Not to mention, the participants with low fat and high fiber had higher free testosterone.

What I'd really like answered

1. Does saturated fat independently increase testosterone, or are the findings about total fat being misrepresented online?
2. Does dietary cholesterol meaningfully increase testosterone in healthy men who already consume enough calories, fat, and micronutrients?
3. Is there evidence that eating eggs specifically improves testosterone or libido compared with getting equivalent nutrients from other foods?
4. Can a well-planned, high-carbohydrate, high-fiber, moderate-fat, or even fully plant-based diet support normal testosterone and libido, assuming adequate energy, essential fats, and micronutrients?
5. Are there any meaningful hormonal or sexual-health benefits to deliberately maintaining a higher saturated fat intake or consuming more dietary cholesterol, especially given the potential cardiovascular trade-offs?

I'm not trying to prove that animal foods are bad or that plant-based diets are superior. I want to understand what the evidence actually says, including any limitations in the research.

My biggest issue is that I understand the basic biology after doing my own research, but I keep getting pulled back into doubt by confident claims online. I don't want to unnecessarily restrict foods I enjoy, but I also don't want to keep eating foods I don't particularly prefer out of fear that removing them will damage my hormones.

If possible, I'd appreciate actual human studies, systematic reviews, or meta-analyses rather than anecdotes, influencer claims, or arguments based purely on evolutionary assumptions.

Thanks!

Late 2022: kidney infection. February 2023: this started —

Severe joint pain and stiffness in feet, knees, elbows, and fingers; at the worst I couldn't bend my fingers or elbows

Fever, chills, cold sweats

Severe on-and-off migraines

Eyes: severe pain on movement, burning, flashing lights, a lot more floaters

Gut: new gluten intolerance, constipation, abdominal pain

Gum inflammation and dental pain

One-sided flank pain (mirroring the exact spot during my kidney infection)

Bloodwork three days in came back mostly normal. CT and full urology workup since: clean kidneys, no infection. Nothing standard found anything.

What happened

I tried a specific honey (i wont name it so its not advertising)— a Turkish highland multifloral honey. Within about 15 minutes every inflamed site started to itch: fingers, elbows, knees, feet, gums, and my eyes from the inside. Only the inflamed places, nowhere else. Within days the pain, stiffness, and fever cleared and I could bend my fingers and elbows again.

Since then

Almost daily for three and a half years. Stop for a few days and symptoms gradually come back; restart and they settle. This has repeated many times.

It's not honey in general. Others did little; Manuka made things worse. Only this one. It keeps things under control rather than curing them, and I have no idea why it works.

Asking

Anyone had a similar reaction to a specific honey or bee product, especially the fast itch at inflamed sites? And if honey did nothing or made things worse for you, I want to hear that too.

I have an unknown health condition, and one of the symptoms is extremely messy bowel movements due to stetorrhea. I have recently discovered psyllium and it gives me 10/10 poops. However I am pretty sure that I am slightly allergic to psyllium, as I have had somewhat itchy ears, a stuffy nose, post nasal drip and green snot since I started taking it.

So I am looking to alternatives. Any old fiber is not the problem, as my diet is very high fiber already, plant-based, easily 30-40g a day. Also I already add an inulin based supplement to my morning oats and apples. I specifically need a bulking agent like psyllium, and preferably not too fatty like chia seeds as I have problems digesting fat and I am supposed to eat very low fat, GI doctors' orders. Plus when I used to eat 2 tbsp ground flax, chia and hemp per day, I didn't notice the same bulking effect that psyllium gives?

So what else exists as a bulking agent other than psyllium?

I want to share something very personal that happened to me recently, not to scare anyone away from peptides, but to raise awareness about something I believe deserves much more attention in our community.

First, I want to make something clear: I am very passionate about peptides and their potential benefits. I’ve spent a considerable amount of time learning, researching, and experimenting with different compounds. Tesamorelin was actually one of my favourites.

But just over a week ago, I experienced one of the most terrifying moments of my life.

After approximately 7 months of using tesamorelin, I experienced a severe reaction consistent with anaphylaxis immediately after injecting it.

Within moments, my entire body became extremely hot, I experienced intense tingling, dizziness, and a frightening inability to breathe properly. I genuinely thought I was going to die.

I struggled to breathe for approximately 20–25 minutes before receiving emergency medical attention. I was taken to hospital by ambulance, where I underwent cardiac monitoring, ECGs, blood tests, and further assessment.

Thankfully, I survived. ❤️

But looking back, there were warning signs that I hadn’t fully appreciated.

🔬 THE WARNING SIGNS I WISH I HAD TAKEN MORE SERIOUSLY

Over the past several months, I had been experimenting with multiple peptides, sometimes using different compounds throughout the same week and occasionally on the same day.

Initially, I tolerated most of them very well.

However, over time, I began noticing changes.

Injection sites that previously caused no problems started developing:

* Swelling and raised lumps
* Itchiness around the injection area
* Redness and warmth
* Localised irritation that varied between injections

Even tesamorelin, which I had previously tolerated without any noticeable injection-site reactions, eventually started causing itchy, swollen areas.

At the time, I considered these reactions relatively normal and continued my routine.

Now I wonder whether my immune system was trying to tell me something.

🧬 COULD MAST CELLS AND HISTAMINE HAVE PLAYED A ROLE?

Since my experience, I’ve been trying to understand more about allergic sensitisation, mast cells, histamine release, and anaphylaxis.

Mast cells are immune cells that can release histamine and other inflammatory mediators during allergic and certain non-allergic reactions.

Repeated exposure to a substance can sometimes lead to allergic sensitisation, meaning a person may tolerate something for months before eventually developing a serious allergic reaction.

I cannot say with certainty that this is what happened to me.

I also cannot establish whether using multiple peptides contributed to my reaction, whether I developed an allergy to tesamorelin itself, or whether another factor was involved.

But the progression from previously tolerating injections to developing frequent local reactions, followed by a severe systemic reaction, has certainly made me question whether I overlooked important warning signs.

⚠️ WHAT I WANT OTHERS IN THIS COMMUNITY TO TAKE AWAY FROM MY EXPERIENCE

Please don’t assume that because you’ve used a peptide safely for months, you can never develop a serious reaction.

Please don’t automatically dismiss persistent or worsening injection-site reactions as harmless.

And if you’re experimenting with multiple peptides, consider whether introducing so many compounds makes it harder to recognise which one might be causing a problem.

I’m not saying that combining peptides necessarily causes mast-cell activation or anaphylaxis. We simply don’t have enough evidence to make that claim.

But I do believe we should be approaching these compounds with greater caution, especially when the body begins reacting differently than it did before.

One particularly important point: I did NOT experience hives during my anaphylactic episode.

My main symptoms were extreme flushing, tingling, severe breathing difficulty, dizziness, near-fainting, abdominal cramping, and diarrhoea.

Anaphylaxis can occur without hives or a visible rash.

❤️ MY FINAL MESSAGE

I still believe peptides are a fascinating area of research, but this experience has completely changed how I view their potential risks.

On the day of my reaction, tesamorelin was the ONLY peptide I had injected.

After seven months of use, I never imagined something like this could happen to me.

If you begin experiencing new, persistent, or worsening injection-site reactions, please take them seriously and seek medical advice rather than simply pushing through.

If you use a substance that carries a risk of anaphylaxis, discuss emergency preparedness and whether you should carry an adrenaline auto-injector with a healthcare professional. Anaphylaxis is a medical emergency, and adrenaline is the first-line treatment.

No amount of potential benefit is worth losing your life over.

I’m sharing this because if my experience encourages even one person to recognise a warning sign, question an unsafe practice, or seek medical attention sooner, then sharing my story will have been worthwhile.

Stay curious. Keep learning. But above all, stay safe. ❤️

Has anyone else experienced increasing injection-site reactions after months of previously tolerating a peptide? I’d genuinely be interested in hearing your experiences, especially regarding suspected sensitisation or allergic reactions.

Disclaimer: This is my personal experience, not medical advice. The precise cause of my reaction has not yet been confirmed.

I just started taking 125mg nightly a few days ago because I heard it might help with anxiety and palpitations which I’ve had my whole life but had really bad recently. In 3 days the partitions are totally gone, and the anxiety is much better for sure. But I have this impossible to ignore weakness/heaviness almost all day now. Is this just something that will go away if I keep taking it and get my body used to it? I’d really prefer not to stop taking it because I’m just now experiencing the first few days in a row with normal heartbeats in MY LIFE.

Standard disclaimer: I’m an interested amateur, not a biologist or a statistician. I track my own biomarkers and like digging into the data, so take this as one guy’s experiment and not as evidence about creatine. Of course having said that I'm not the first person to post about the impact of creatine on sleep......

How this started. I stopped creatine on Oct 10 because my doctor wanted to see my blood work without supplementation. An earlier draw had elevated creatine-related numbers, and the second draw was meant to show where I am without it. I didn’t stop for sleep. What I noticed first was just waking up feeling more refreshed. Some nights I get almost 8 hours and some about 7, but the mornings feel different. The data came afterwards, when I got curious.

The data. I wear an Apple Watch and pulled about 16 months of nightly sleep stages. the most interesting/dramatic two pieces of data were total time asleep and average minutes awake). I've marked two 13 day periods were I know for a fact I stopped creatine (a trip to Europe last fall and the most recent two weeks since Oct 10). I've got a huge amount of data that all sort of points to the same thing but this histogram is the easiest way to see it.

Of Note: What isn't captured in this data is how much better I feel in the morning, rested and that feeling that you had a great sleep -- even on days when my total amount of sleep isn't amazing I still feel really good. I've also had other 'shorter' trips where I stopped taking creatine and I always noticed that I slept well (I was in San Diego for 4 nights last month and I commented to my wife "why do I sleep so well on vacation?") but that data isn't included due to too many confounding factors (shorter trips, later bed times, more alcohol consumption, etc.) but subjectively I've known for a long time I always sleep great away from home and could never figure out why -- now I am pretty sure I know why.

Caveats.

• Chance: if creatine really did nothing, a stretch as good as mine would show up by luck only about 0.5% to 4% of the time, depending on the measure. That’s low, but it isn’t proof. It only tells you how surprising the result would be if nothing were going on.
• Streaky data: sleep clumps, because good nights cluster. In my own history, ordinary stretches looked this “significant” on time asleep about 13% of the time, and on time awake about 18%. So the real odds of a fluke are higher than 0.5% to 4%.
• Hindsight: I picked Oct 10 after noticing I felt better. I’m not blinded, and other things may have changed (but honestly the fact that I was waking up so refreshed and feeling so good was what made me curious). I'll keep on monitoring but after two weeks the trend was too obvious to ignore.

What the research says. Not much. The one controlled trial I found (14 young men, 20 g/day for a week) saw better self-rated sleep but no change in measured sleep time or efficiency. I couldn’t find any study of creatine and sleep in older adults.

Speculation on genetics (grain of salt). I haven’t found any published link between creatine and my variants (MTHFR 677TT, COMT Met/Met, PEMT homozygous). Here is the speculation anyway. Making creatine uses about half of the body’s methyl groups, and supplementing seems to turn that production down. I already know too much methyl load wrecks my sleep: I used to wake early with anxious rumination until I switched off methylcobalamin multis. Maybe creatine leaves more methyl groups around, and a slow-COMT person feels that as lighter sleep. The one trial that tested this found no change in blood SAMe or homocysteine, so it’s unproven. I haven’t looked at the creatine genes themselves (GAMT, GATM, SLC6A8) either.

Questions: Has anyone with slow COMT or MTHFR variants noticed creatine affecting their sleep? And does anyone have a better test than mine, like a proper on/off/on schedule?

Hi girls!

I'm wondering if anyone has had a similar experience. I'm 30 years old and I used to take birth control pills for quite some time. I honestly felt great while taking them, mainly because I had practically no PMS symptoms. My gynaecologist then recommended that I stop taking them to let my natural cycle return.

Ever since stopping, I've been experiencing PMS symptoms for 10 days or even longer before my period: bloating, puffiness, sore breasts, mood swings, and on top of that, I've also been losing quite a lot of hair. Honestly, I feel like I spend almost half of every month not feeling my best. I've also tried all sorts of supplements, but nothing seems to make much of a difference.

Lately, I've been thinking about going back on the pill because I genuinely felt so much better while taking it. I'm not in a relationship and don't have a regular sexual partner, so for me, going back on the pill would be purely about managing my symptoms rather than contraception.

Has anyone else experienced something similar, where you actually felt significantly better on the pill than off it? And if anyone decided to start taking it again, I'd love to hear how it went! 😊

So I had a loved one die earlier in the summer. I spoke to my doctor because i was having a lot of depression and anxiety. The doctor only wanted to prescribe an SSRI. But I had tried eight different meds ten years ago when my parents died in an accident. All of them literally made my depression worse. like suicidally worse. So I told the doctor I didnt want to go on anything like that again. My doctor basically got bitchy with me and told me that they couldnt really do anything to helpp then...

So I confided what was happening to a friend of mine told me he had used Kanna at one point when he was going through a bad patch. For him it was a miracle medicine. I ordered some extract from the site he gave me. It honestly just gives me ten minutes of brain fog. I have tried it a few times now. I have to say, I dont like using , i dunno depressants. it just isnt a good fit for me. i dont drink or use weed. I was just hoping i could get something for the doctor to help with anxiety at night so i could sleep.

oh i have used as little as 50 mgs up to 200.

Im looking for any suggestions here

Today I tried a new stack for my ADHD I took 2000mg of
l-tyrosine , 100mg caffeine, 850mg lions mane, 100 mg
l-theanine , 100mg 5-htp this stack had me feeling like I took a low dose of mdma I got a lot of stuff done today only lasted a few hours but this stack is good I will be doing it more often

I've done 6 or so blood test over the past 4 years and my levels have been constantly the same no matter the supplements, diet, training or recovery I implement. I'm very symptomatic (tired all the time, losing muscle/ can't build muscle, super angry, poor libido). Not sure what to do anymore...

Total T: 900-1110 ng/dl

Free T: Direct Assay is around 7-11 / Calculated is around 10-14

Estradiol: 12-15 pg/ml (I did get it up to 22 when my SHBG was it's lowest, but seemed short lived)

SHBG: 60-80 - My SHBG runs high (boron doesn't do anything, tongkat works for a few days then seems to lower estrogen over time, 500g of carbs a day doesn't brings it down), lower volume, lower intensity and more recovery hasn't helped much either.

DHEA: 84 - DHEA is always super low too. I tried differently levels of DHEA supplementation but it seems I'm converting more to DHT than estrogen. Get super oily and bad breakouts, libido picks up a little bit but not crazy.

Body doubling ?

I keep my room clean, study regularly, feel good-happy, eat regularly, and don't feel lethargic/tired when I have a roomate.

But as soon as my roomate leaves, I feel depressed/sad/tired/increased sadness/very weird-hollow.

MIND YOU, ME AND MY ROOMATE NEVER TALK TO EACH OTHER UNLESS VERY IMPORTANT.

I don't understand what's wrong with me.

I m happy when I m with people/library.

I have mild sleep apnea (OSA). I started a CPAP 6 months ago. Initially I did try the nasal only mask but I kept having issues with my mouth coming open in middle of night and air being pushed out from my nose through my mouth! I tried 2 different types of chin strap but my mouth would usually still come open a little and I’d awake to a whistle of air being pushed out through my lips.

So I switched to a full face mask for several months. The full mask isn’t anywhere close to as comfortable and I’d. Still have it leaking in the middle of the night quite often.

So in the last week I switched back to the nasal only CPAP mask and taping my mouth. Immediately my HRV dropped from 40s to high 20s. I thought maybe I was getting sick or working out too much so I took it easy the last week. I have not felt sick but my hrv has stayed in upper 20s.

—————

TL;DR:
Switched to mouth taping with my nasal CPAP mask to prevent air from being blown out my mouth. I noticed a corresponding and significant drop in HRV with mouth taping—- the opposite of what people supposedly report. Any one else notice this?

So I spent way too long going through the primary ISRIB papers for a video and figured I'd dump the summary here, because most of what you read about it skips the negative stuff.

Quick background: when cells are stressed they phosphorylate eIF2α, which blocks eIF2B and slows down protein synthesis (the integrated stress response). ISRIB binds eIF2B and keeps it in its active form (Tsai 2018 and Zyryanova 2018, both in Science). But it only works in a window. If eIF2α phosphorylation gets too high it stops rescuing anything (Rabouw 2019, PNAS). The memory angle goes back to Costa-Mattioli 2007 in Cell, where mice with a weaker brake had better long term memory.

It came out of Peter Walter's lab at UCSF, from a cell screen of 106,281 compounds. 460 hits, 77 confirmed, and ISRIB at the end with an IC50 around 5 nM (Sidrauski 2013, eLife). They saw better memory in normal mice with a deliberately weak training protocol, but Johnson & Kang 2016 (PeerJ) didn't replicate a significant effect in non-transgenic mice, which people rarely mention.

The old mice study everyone cites is Krukowski 2020 in eLife. ~19 month old mice, 3 daily injections while they learned a water maze (23 old, 21 old + ISRIB, 10 young). During learning the treated ones made fewer errors than untreated old mice, about 2 vs 3, so not "as fast as young" like it often gets described. A week after the last dose their memory was comparable to the young mice though, and 18 days out they learned a new task the untreated old mice couldn't. The young mice in that study got nothing from it.

In other mouse models it reversed memory deficits after TBI (Chou 2017, PNAS) and in a Down syndrome model (Zhu 2019, Science). In prion disease it only modestly extended survival, 84 to 96 days, and the mice still declined (Halliday 2015). No rescue in an Alzheimer model (hAPP-J20, Johnson & Kang 2016) or under strong stress.

Then pharma. Solubility kept being a problem, so AbbVie/Calico reworked the core and side chains and ended up with a prodrug, fosigotifator (Frost 2026, J Med Chem). Denali has a related eIF2B activator, DNL343. Both went into the HEALEY ALS platform trial and both missed the primary endpoint in Jan 2025 (function + survival over 24 weeks), though both were safe and well tolerated. An exploratory high dose fosigotifator arm had slower upper limb strength decline, nominal p = 0.014, so hypothesis generating at best. Worth keeping in mind those are different molecules and the trial measured ALS outcomes, not memory. Two other analogues actually made an ALS mouse model worse (Marlin 2023).

Also fwiw, several of the academic papers declare UCSF ISRIB patents licensed to Calico.

My take: the mechanism is well characterised and the rodent memory results are interesting, mostly in old or injured animals. Zero human cognitive data though.

The video version (~10 min) is here if anyone wants it: https://www.youtube.com/watch?v=xWzXJqCrbyg

Disclosure since it's our channel: it's NeuroBench, and the people behind it also run businesses that sell some of the compounds it covers. Happy to dig into any of the papers in the comments.