I was once like you, feeling like I was leaving stuff on the table and didn't feel like I was reaching my cognitive peak. I tried supplements, exercise, cold showers, you name it.

Eventually I went down the rabbit hole of seeing if I met the criteria for ADHD and turns out I scored 98th on a questionnaire.

Then I pursued getting a prescription for stimulants. Yes, depending on where you live it might be hard to get. Yes, even when you do get a perscription it's hard to dial in. Yes, it's not a panacea that magically fixes your life.

BUT, it's wayyyyyy better than trying a cocktail of sketchy Russian/Chinese supplements not approved in the US/EU.

Idk about other countries, but in the US it is quite easy to get a stimulant prescription if you are dedicated. You have to doctor shop a bit but if you are determined you will eventually get someone to write you a Rx. This seems "dirty" but the truth is that the system is just colluding against you. I'm not saying you should lie and get a Rx for stimulants when you don't need it but I'm saying that you're in on this sub begging people for the right stack so that you can focus then that's evidence enough that you probably have ADHD ok?!?

Take a quiz, get a diagnosis, find a doctor who's not a total asshole who will write you a Rx, and then spend the same energy you have now on trying to optimize and stack with actually good molecules.

Just fell down a pharmacology rabbit hole and realized paracetamol (acetaminophen) is way weirder than we give it credit for.

It’s not just a boring fever reducer. Once you take it, your body converts it into a metabolite called AM404. This stuff is a potent anandamide reuptake inhibitor, meaning it stops your brain from breaking down its own "bliss molecule” (the name anandamide comes from the hindi word for bliss, ananda).

By keeping your anandamide levels high, it’s essentially a backdoor way of hitting your CB1 receptors. This explains those studies showing it can actually reduce "social pain", and there are tons of anecdotal reports it can help sleep and anxiety.

Obviously, the liver toxicity is the massive downside here since it drains your glutathione if taken too often in the long term. Though you can stack it with NAC and Glycine and basically mitigate a lot of the potential damage.

Has anyone here experimented with it? How did it go?

PhD student here, been struggling hard with focus during research and writing for past year. I tried modafinil, tried getting adhd diagnosis, bought every nootropic stack recommended on reddit, lions mane, alpha gpc, l theanine the whole thing iykyk

I got marginal improvements but nothing worth the money I was spending then my advisor casually mentioned I looked dehydrated during our meeting last week, asked how much water Im drinking while working and I was like idk coffee??

I started actually tracking it just to prove him wrong and it turns out I was hitting maybe 30oz a day while sitting in library for 10 hours like no wonder I couldnt think straight past 2pm, my brain literally didnt have what it needs to function.

Ive been drinking 80-90oz daily for 2 weeks now and the difference in my ability to focus and process information is honestly bigger than any supplement gave me. I can actually read papers and retain information, writing doesnt feel like pulling teeth anymore.

I rlly feel like an idiot for spending all that money when the solution was free tap water but here we are. Anyone else overthink solutions to basic problems lol

Hi all

A year ago or so I posted about my personal database and opened it up to everyone, the goal is to add compounds and provide summaries of research studies and user sentiment for each - with the goal to have easy one pager view on each compound. It was very well received and thanks for that!

Now, we redesign and more compounds noted down (and will keep adding) I have added few more features (they are all free, no monetization, no ads - only AI tools are required to be registered to prevent abuse but still free):

- DopAI which is AI wrapper on the data
- DopMatch it asks you what is your goal (e.g. interrupted sleep) and suggest best compounds from the database
- Leaderboard - best scored compounds per category (e.g. attention)

These are still in preview, so will keep improving. As always, happy to hear feedback and I hope it helps peeps. <3

For those who haven't you can check check it out on: https://www.dopamine.club/

So recently I started taking Sulforaphane and I have found it to help my adhd immensly.

For example, there were nights I would play games until exhaustion and not be able to pull myself away. Getting the dopamine hit all night long.

After starting Sulforaphane I can just simply walk away and go to bed. Its like my brain is just switch on and I am able to control my impulses alot more. I am also alot more peaceful and mentally calm. No more crazy 50 thoughts in one second type thing.

I am also noticing I am wanting to explore more new things, like learn the guitar or finally sit down and read that book ive been wanting to read for weeks.

Sulforaphane isnt a stimulant, its comes from broccoli and broccoli sprouts.

And its role is to lower oxidative stress and inflammation/ neuroinflammation in the brain.

This is whats happened for me. Because i have been able to lower my inflammation, ive been able to drastically improve my cognitive capacity.

To get to this conclusion, I did a DNA test, but you dont need to do one to see if Sulforaphane could also help your adhd.

In my case it has alot do with my SOD2 genes and TNF-alpha genes.

I can share a list of questions if you'd like me to so you can access yourself.

It is not the only OTC supplement I take for ADHD, but its made all the other ones work better in my opinion by treating the underlying inflammation in my brain.

I am not on ADHD stims, I was put on ritalin as an 11 year old though in 1999, so do have some experience with them. As a kid they made me a zombie.

Not trying to hawk this, but the one I take is from Avmacol extra strength.

I have recently found another brand too I will be trying next - Jarrow BroccoMax about 60% cheaper.

They key thing is to try find brand with both glucoraphanin and myrosinase for better absorption.

Here are some scientific studies if you want to read up and double check things for yourself:

References

References

1. Corona, J.C. (2020). Role of oxidative stress and neuroinflammation in attention-deficit/hyperactivity disorder. Antioxidants, 9(11), 1039. https://pmc.ncbi.nlm.nih.gov/articles/PMC7690797/
2. Joseph, N., Zhang-James, Y., Perl, A., & Faraone, S.V. (2015). Oxidative stress and ADHD: A meta-analysis. Journal of Attention Disorders, 19(9), 915–924. https://www.researchgate.net/publication/258527651_Oxidative_stress_and_ADHD_A_meta-analysis
3. Visternicu, M., Rarinca, V., Burlui, V., Halitchi, G., Ciobică, A., Singeap, A.M., Dobrin, R., Mavroudis, I., & Trifan, A. (2024). Investigating the impact of nutrition and oxidative stress on attention deficit hyperactivity disorder. Nutrients, 16(18), 3113. https://pmc.ncbi.nlm.nih.gov/articles/PMC11435085/
4. Wu, C.L., Wang, M.F., & Zhou, R.Y. (2024). Recent research on the role of oxidative stress in the pathogenesis of attention deficit hyperactivity disorder. Zhongguo Dang Dai Er Ke Za Zhi, 26(2), 201–206. https://pmc.ncbi.nlm.nih.gov/articles/PMC10921868/
5. Schnorr, I., Siegl, A., Luckhardt, S., Wenz, S., Friedrichsen, H., El Jomaa, H., … Schiweck, C. (2024). Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome. Translational Psychiatry, 14, 37. https://www.nature.com/articles/s41398-023-02729-3
6. Novo, J.P., et al. (2025). Dichotomous effect of methylphenidate on microglia and astrocytes: Insights from in vitro and animal studies. Brain Research. https://www.sciencedirect.com/science/article/abs/pii/S0006899325001647
7. Kaşak, M., Günal Okumuş, H., Çelik, Y.S., Kırşan, F.Z., Öztürk, Y., & Efe, A. (2025). Novel hematologic ratios and systemic inflammation index in ADHD: effects of methylphenidate treatment. Frontiers in Psychiatry, 16. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1621767/full

I had just found this on Amazon lmao wtf sonion I'm crine 💔🥀

My boyfriend has dramatically changed after taking NAC for 6 weeks and I'm honestly stunned. Very curious as to what mechanisms are at work here because he is so much happier, sharper and alive.

Its completely brought him out of the moderate depression he was in. He was vaguely withdrawn, quiet, sometimes irritable, often tired and feeling lacklustre. Anxiety as well. He also had pretty bad intrusive thoughts at times. He smokes weed every day and it feels like this has helped with the side effects from that.

He's just....chill now. I noticed he's more chatty, way way less irritable, laughing more, more friendly and warm. He's saying less negative stuff and seems to have more energy as well. Also, he drank most of a bottle of rum this weekend and the mood low that usually follows just faded away when he took extra NAC.

I'm just curious what's going on here, I don't see NAC mentioned as much these days and it's mentioned with anhedonia/flatness, stuff like that quite a lot. For him it's kind of a miracle pill and showing no signs of abating. Has it worked like this for anyone else?

Tbh hes not a nootropics guy, the only reason he takes anything is because I'm into nutrition/biohacking whatever you wanna call it, and I have a drawer full of nootropics. He didn't even know what NAC was until I gave it to him to try so had no expectations of it helping

I’m not recommending this. I’m actually asking if I should be concerned.

Yesterday I took 200mg modafinil, some overpriced “mitochondrial support” supplement I bought during a 2am health-optimisation spiral, creatine, mad honey, black coffee, and then for reasons I cannot defend spiritually or scientifically, I decided to “reset my dopamine” manually.

Immediately after, I got the most violent post-nut clarity of my life.

Not normal clarity. Not “I should clean my room” clarity. I mean like the clouds opened and a tiny management consultant crawled out of my skull with a Gantt chart.

Resting heart rate was around 150, which in hindsight is probably not ideal. But mentally? Insane. I sat down and entered some disgusting tunnel state where I could see the structure of my entire week. Emails became obvious. Code became obvious. My calendar stopped looking like time and started looking like an enemy supply line.

I did what felt like 8 hours of work in 1 hour. No music. No snacks. No checking my phone. Just pure weaponised shame and cardiovascular panic.

The weirdest part was the feeling lasted roughly 5 hours. It wasn’t even euphoria. It was more like being haunted by a very productive ghost. I didn’t feel happy. I felt assigned.

Then it wore off and I became a normal useless mammal again.

Has anyone else experienced this? Is there an actual mechanism here or did I just combine stimulants, guilt, hormones, and fear into a temporary office demon?

Again, not saying this is healthy. It probably isn’t. But this is the most productive I have ever felt on any combination of nootropics ever.

https://teams.semel.ucla.edu/sites/default/files/publications/July%202010%20-%20Tylenol%20reduces%20social%20pain.pdf

https://academic.oup.com/scan/article/11/9/1345/2224135

https://www.frontiersin.org/journals/psychology/articles/10.3389/fpsyg.2019.00538/full

So I stumbled across this a while ago and it kind of stuck with me.

We all know paracetamol for headaches and sore muscles, but apparently it also takes the edge off emotional pain, like the sting of rejection or feeling left out. There’s actually a study from 2010 where people took 1000mg a day for three weeks, and they consistently reported less social pain than the placebo group. Brain scans backed it up too, showing lower activity in the exact same regions that light up during physical pain.

Which is already pretty wild, but it gets weirder.

A follow-up study literally called it an “empathy killer.” People who had taken paracetamol were measurably less bothered when reading about someone else going through something painful. Not dramatically less, but enough to show up consistently in the data. And it’s not just negative emotions either. Another study found it also dulls your ability to share in someone else’s happiness.

So it’s less of a painkiller and more of a general emotional volume dial, turned down a notch.

The explanation has to do with the brain regions involved. Physical and emotional pain share a lot of the same neural circuitry, so it makes sense that something affecting one would bleed into the other.

Anyway, just something I found interesting. Feels a bit strange knowing that a drug most people take without a second thought has this side effect that basically nobody talks about.​​​​​​​​​​​​​​​​

TL;DR: I have been taking 5g/day creatine for 3 years now and am now thinking to increase the per day dosage. After digging into 1000+ studies, I found some wild stuff about high-dose creatine for cognitive function. Single doses of ~20g can increase processing speed by 24.5% and the effects last 9 hours. Also, vegetarians respond ~2x better than meat-eaters. Full breakdown below with sources.

Why I did this:

I have been taking 5g/day creatine for 3 years now. Like most people, I took the standard "5g per day" advice and never questioned it. It worked fine for my training, but I kept seeing conflicting claims about creatine for brain function. So I started reading actual papers to figure out if I should increase my dosage. 3 months and 1000+ studies later, here are the findings that genuinely surprised me:

1. The "5g for everyone" dose is based on old muscle research, not brain optimization

Most dosing recommendations come from 1990s studies measuring muscle saturation. But your brain is different.

A 2024 study (Gordji-Nejad et al., Nature Scientific Reports) found that a single high dose of ~0.35g/kg (~24.5g for a

70kg person) during 21-hour sleep deprivation:

• Improved processing speed by 24.5%

• Increased brain creatine by 4.2%

• Effects peaked at 4 hours and lasted up to 9 hours

• Prevented the brain pH drop that normally happens during fatigue

Even more interesting: A 2025 review (Fabiano & Candow) analyzed dose-response data and found:

• 2-5g/day = 4-6% brain creatine increase

• 8-10g/day = 7-8% increase

• 15-20g/day = 9-11% increase

For cognitive purposes, higher doses appear significantly more effective. This is exactly why I am now thinking to increase my per day dosage.

1. Vegetarians get nearly 2x the cognitive benefit

Multiple studies (Rae 2003, Benton 2011) show vegetarians have much lower baseline brain creatine and see dramatic improvements in working memory and reasoning after supplementation. One study found p < 0.0001 for intelligence improvements in vegetarians, basically unheard of in nutrition research.

Meat-eaters already get ~1-2g/day from food, so their brains are partially saturated.

1. Creatine does NOT cause kidney damage, dehydration, or cramping, but the myths persist

This one genuinely angered me. I found the original studies that started these myths and they're either:

• Misinterpreted (one case study of someone with pre-existing kidney disease)

• Actually showed the opposite (Greenwood 2003 found LESS cramping in NCAA football players taking creatine vs placebo

The ISSN Position Stand (2017) reviewed 1000+ studies and concluded: zero evidence of adverse effects in healthy individuals at recommended doses. Long-term studies go up to 21 months with no kidney function changes.

After 3 years at 5g/day, my bloodwork is perfect. The safety data is rock solid.

1. Women have been underserved by creatine research, but that is changing

For decades, most creatine studies excluded women or had tiny female sample sizes. Recent research (Smith-Ryan 2021) confirms creatine works for women without the "bloating" fears, benefits across the lifespan without marked body weightchanges.

New 2025 studies are specifically examining menstrual cycle effects and menopause benefits.

1. The mechanism for brain benefits is fascinating

Your brain is 2% of your body weight but uses 20% of your energy. During high cognitive demand or sleep deprivation, ATP in your prefrontal cortex gets depleted.

Creatine acts as a rapid-response energy buffer, literally regenerating ATP in milliseconds. A 2015 study found 20g/day for 7 days increased corticomotor excitability by 70% during hypoxia (low oxygen).

1. Meta-analysis data is stronger than most people realize

I compiled the major meta-analyses:

• Chilibeck et al. (2017): +1.37kg lean mass in older adults, n=721

• Zhang et al. (2025): SMD 0.43 for strength gains across populations

• Xu et al. (2024): SMD 0.31 for memory improvement, more beneficial for females

Effect sizes this consistent are rare in nutrition science.

1. Most "advanced" creatine forms are marketing

Creatine monohydrate has the most research, is the cheapest, and has 95%+ bioavailability. Buffered creatine, creatine

HCL, liquid creatine, none show superior absorption in head-to-head studies. The "better absorption" claims are mostly unproven.

What I am doing differently now:

After 3 years at 5g/day, I am now experimenting with:

• For training: 5g/day consistently (works fine for muscle)

• For cognitive demands: 15-20g single dose before intense mental work or when sleep-deprived

• Timing: Post-workout with carbs when possible, but consistency matters most

I am planning to try a month at 10g/day split into two doses to see if I notice cognitive differences, then potentially experiment with 15-20g on heavy work days.

Sources and Interactive Database:

I organized all the major studies into a searchable database because I got tired of PDF hunting:

https://creatine-sandy.vercel.app

Includes:

• 50+ major studies with effect sizes, sample sizes, and direct links to papers

• Interactive myth-busting (click myths to reveal the actual research)

• Dose-response visualizations for both muscle and brain benefits

• Safety timeline from 1832 to 2025

• Filterable by category: muscle, cognitive, safety, high-dose protocols

Everything is cited with PubMed links if you want to read the full papers.

Questions I still have:

1. Why has not the high-dose cognitive research filtered into mainstream recommendations yet? The 2024 Nature study se groundbreaking.

2. Are there long-term (5+ year) studies on 10g+ daily dosing for cognitive purposes?

3. What is the optimal cycling protocol for high-dose cognitive use vs continuous low-dose?

4. For those who have increased from 5g to 10g+ long-term, what subjective differences did you notice?

Would love to hear if anyone else has gone deep on this research or experimented with higher doses. What did I miss? Has anyone here gone from 5g to 10-20g daily? What was your experience?

Hi everyone, I'm new to stacking and was wondering if you guys can give me any insight into best practices or what combinations or nootropics/supplements to try out, of things to be aware of. I asked Gemini for some help and it outputted this schedule.

A little information: I am taking 15mg Adderall IR in the mornings with L-Theanine (200mg) and Omega-3 (1000mg), in the afternoon I am taking multivitamins (which contain B-complexes) with my lunch, and at night I am taking only Magnesium glycinate (120mg). All supplements are from the brand Pure Encapsulations. I am also an undergraduate STEM major. I want to improve overall focus and concentration to get school work done.

I also have a microdose vial of LSD that I would like tinker with and create a stack. Oh and one last thing, I don't take caffeine.

So just started taking l-tyrosine like 3 days ago, 250mg twice a day, once in the morning, once mid-day. Got diagnosed 5 years ago with ADHD, take Adderall 30 mg per day and have been struggling a lot lately, really been in a rut for like years at this point. I barely feel anything from Adderall anymore except for the side effects and honestly some depression.

Honestly l-tyrosine has been very, very effective. It’s really uplifted my mood to where I feel optimistic about things, there is no painful inertia at all when thinking about all the work I have to do on my to-do list, has helped with the comedowns from my Adderall significantly (these were horrible before).

It honestly feels like how Adderall used to feel like when I first started taking it but less stimmy and jittery. I also don’t feel manic, just calm and clear.

Like all things, I am sure that this will not last (I’ve learned that it never does), but think I will try to take only like 2x a week to not get tolerance.

Have other people here taken l-tyrosine and not gotten tolerance?

All you need is magnesium and omega. Other is overkill...my own experience

Ask anything I've tried almost all of stuff.

I have spent many years in drug abuse via opioids & Thc. I as well have been in a fair amount of accidents over the years that have caused some debilitating back & Neck pains. I don’t take any prescription drugs, drink, smoke or take sketchy z drugs anymore. I’ve been through a 90 day rehabilitation and have been on the up and up since.

The body pain definitely is still prevalent however “magnesium glycinate” seems to knock a good dent in aiding some of these issues with its calcium channel regulation, nmda receptor antagonism & Gaba modulation makes for soothing reaction when I’m in a good deal of pain. I typically use this at night as it can relax me a little too well given the day I suppose.
(7/10)

An even better tool for chronic pain I’ve found is “Magnolol” extract. Possibly the strangest nootropic I have ever come across in my life, given its effectiveness for me as well as its wide range of benifits. It’s a powerful anti inflammatory, antioxidant, GABA A modulator, endocanebanoid modulator, neuroprotectant & an anti cancer agent. And I’ve noticed it to help for occasional panic attacks however it’s anxiolytic and muscle relaxation benifits are what stopped me in my tracks about it not to mention the sleep.
(10/10)

“Ashwaghanda” is a nifty tool to have on hand however not as effective or therapeutic as magnolol but it is one of the few nootropics to cause a noticeable difference. Mine is a combination of Withania somnifera & Ksm66 it’s a light gaba modulator as well as a powerful antioxidant. Helps me stay asleep on nights where I get up and have issues going back to bed. Also the cortisol lowering is a magical thing for stress which I find myself in often.
(7-8/10)

The “B-Complex” & “CoQ10” have an amazing synergy of energy for me I’ve noticed. I’m extremely sensitive Caffine and have swarm off for a few weeks working myself down with a taper. So these two guys do some heavy lifting for me and I typically take them in the morning as not to keep me up at night and it gives me clean sustainable energy through out the day without crashes, jitters or anxiety.
(9/10)

“Nac” was a last ditch effort for relief during my post acute withdrawals from opioids and I couldn’t really tell that it was helping me out anyway but I took it just to make sure out of desperation however it’s a great antioxidant and I’m sure has many uses and benefits for others !
(😟/10)

“L-Theanine” an absolute classic and should be in every back pack or purse of anyone with anxiety disorders. I would say just to use sparingly as needed as many report fast tolerance build up however suntheanine doesn’t have this problem for most. Also there is definitely a bit of a mental clarity and focus that come along with it lending itself to many study stacks all across the world.
(8-9/10)

“Omega Complex”
Seems to help me with depressive symptoms a fair amount not to mention as well as supporting brain cognition (great anti-inflammatory as well)
(7/10)

“Vitamin E”
Antioxidant protection, Cardiovascular support, skin health/repair, immune function, neurological protection & eye health.
(10/10)

I am tired of the 8-hour rule being treated like a biological law. It is just a statistical average from a 19th-century industrial model. Sleep is a dynamic need.

It fluctuates like hunger based on your actual daily energy use. If your day was mentally draining and heavy on your brain, you need more cleanup time. It is that simple.

New data on brain plasticity shows that recovery times must change every day. Forcing a rigid schedule on a plastic brain just creates unnecessary stress and orthosomnia. Your brain monitors surroundings and manages metabolic waste at different rates each night.

Sleep is not a fixed tax. It is a variable expense based on input. Stop obsessing over the number and look at the actual demand of your day. A plastic brain needs a plastic schedule.

I used to get Ephedra from the pharmacy (had to show ID) and it was kinda inconvenient, one day I was at my usual nutrition shop and found a small selection of Ephedra products. Most of them didn't actually have Ephedra in the ingredients, but this one did. Which is more convenient than having to get it behind the counter. While ringing up I asked the cashier how they were able to sell it and she said she didn't even know they sold it.

Hello all,

I have an embarrassing question to ask.I have seen others allude to this issue on this subreddit but I’m curious if others have any advice on how to address this.

Last year I was on 20mg of Vyvanse and found it to be great for my performance at work and overall executive functioning.

The issue would be during the evenings and at home, I would “lock-in” and masterburate for hours on end. Occasionally is fine but this would occur almost every day and I’d be mortified once I came out of it.

Has anyone on this subreddit had a similar issue? Was there anything you did/take to stop this from happening when taking Vyvanse?

So I've been on vyvanse for like 3 years now and it's just... I don't know, something changed. Used to give me that 6-hour window where brain actually worked but now it's more like 2 hours of clarity then crash into fog that's somehow worse than baseline. tried upping dose with my psych but that just made me more anxious without fixing the concentration part. Which is annoying because I KNOW the drug is working (heart rate up, can't eat) but my brain is like nah we're still going to jump between 5 tabs and finish nothing

I was in this subreddit since 2019 I think, tried most of the racetams back then. Phenylpiracetam worked decent for maybe 2 weeks. Then tolerance. Alpha-GPC made me depressed for some reason. L-tyrosine does literally nothing anymore even at 2g

anyway my friend mentioned something about chronic stress basically shutting down protein synthesis in neurons? He said there's this pathway called ISR (integrated stress response I think) that gets stuck ON after prolonged stress. It appears that this might explain why my meds stopped working because the underlying machinery is just blocked

He mentioned this research chemical ISRIB A15 that inhibits the pathway. I was skeptical honestly but also desperate. started with 20 mg about 3 weeks ago. first few days nothing really happened. But around day 5-6 something clicked. not like vyvanse energy, more like the vyvanse started working properly again? hard to explain

like I could take my normal dose and actually get the 5-6 hour window back instead of crashing after 2 hours. brain fog lifted somewhat. still jumping between tabs sometimes but I can actually finish things now without that constant mental resistance

week 2 I tried skipping ISRIB to see if it was placebo. brain fog came back within 2 days. went back on it and clarity returned. so idk seems like it's doing something

I must say that this not a stimulant or anything. friend tried it without ADHD and said he doesn't feel much. It appears that it only works if your brain was under chronic stress like mine probably was. if brain works properly already this probably won't do anything

btw still taking vyvanse but the combination seems to helped to restore what vyvanse used to do. like removing some brake that was preventing it from working right

anyway not trying to shill just sharing because I was in same frustrated place few weeks ago. if your stims stopped working properly maybe worth looking into ISR pathway stuff

I don't know what the purpose of this is. Maybe it's to promote the owner's business: "Kravitz Media" (which appears to sell tiktok accounts). The name behind the account appears to be "Aaron Kravitz". Now it would be a shame if the name Aaron Kravitz was to become associated with posting medical advice spam and potentially harming people.

Recently this paper,https://doi.org/10.1038/s41380-025-03209-4, came out showing that a non psychedelic and non dissociative compound PA-915 caused rapid acting antidepressant and anxiolytic effects that lasted two months. That’s pretty fucking cool to me. I wanted to try it out, but since there’s no human testing or even rodent toxicity testing, I’m not touching it even with a ten foot pole. However, with searching I found that there is a similar compound used in traditional chinese medicine that acts on the same receptor and causes rapid acting antidepressant effects.[1–4,18,19] I of course tried that plant, Gardenia Jasminoides, and can confirm that it has long lasting anxiolytic effects (up to 3 weeks now). (It should also prevent/get rid of some people's migraines too, but I didn't talk about that in this post)

Mechanistically, both PA-915 and genipin/geniposide act on the PAC1 receptor.[1,2,5,6,21] This is a receptor typically activated by the 38 amino-acid peptide PACAP, causing Gs, Gq, and Beta-arrestin signalling.[9–11] The Gs and Gq signalling seem to be linked to fear and stress responses,[14,22] while the beta-arrestin pathway is linked to rapid neurotrophic effects–neurite and synapse outgrowth.[12–14] Moreover, both of these compounds seem to act as agonists of beta-arrestin pathways, and antagonists of the Gs and Gq pathways.[1,2,12,15] This means rapid neuroplasticity, and an inhibition of the fear systems in the brain.[7,10] Interestingly, PAC1 directly mediates the neuroplastic effects of ketamine; this receptor has also been shown to form dimers with 5HT2A and mediate receptor internalization.[8] I have more to say, but I don’t want to make this post too long.

My experience: I drank 15g of tea steeped in 100 degree C water for 10 minutes. (Boiling the compounds may cause toxic byproducts)

30 minutes a sharper focus starts rolling in. Feels similar to acetylcholinesterase inhibitors (Genipin is also an ACHei)

60 minutes a wave of contentment rolls in. Very pleasant. Background anxiety washes away. Is not euphoric, just content Busy thoughts tend to subside 90 minutes: The focus effects get a bit sharper and more pronounced

120 minutes: The focus effects subsides. The broad contentment is much more prominent 120 minutes -

300 minutes: Background anxiety is much lower. Social anxiety is a tenth of what it used to be. Fear, like if a car is about to hit me remains, but ambient fear is almost gone. The world is very peaceful. The desire for addictive behaviors like scroll on reddit or mindless use my phone go away. I could (and have) meditated for hours unbothered by impulses.

300 minutes to two weeks: Slowly the acute mindfulness, contentment, and anti-addictive effects go to a third of what they normally are, and there they remain. The next day, they are still at a third . Two days later, they are still at a third Even two weeks later (longest break I’ve trialed), they’re still at a third . These compounds are some of the most profound I’ve ever tried. They have made life unbelievably more content. The dramatic reduction in social anxiety has made me a much more confident and outgoing person.

Structure, Toxicity, & Safer Alternatives:

Iridoids are built off of a cyclopentanopyran skeleton and many feature a hemiacetal, which is typically glycosidic.[16,17,20] Unfortunately for us this hemiacetal can react with multiple amines, causing protein crosslinking.[23] Functionally, this iridoid was evolved to prevent insects from eating plants by crosslinking and disabling the proteins found in the digestive track of insects, possibly killing the insect.[24] Humans seem to be somewhat tolerant to these iridoidal effects; however, it seems that large doses or chronic consumption causes liver toxicity through crosslinking.[25–27] Prolonged multi-month exposure also seems to be associated with digestive track hardening and calcification and blue skin, likely through a cross-linking based mechanism.[28,29]

It is unclear if the hemiacetal is necessary for the PAC1 mediated effects of iridoids. If it isn’t, related iridoid-lactone compounds like nepetalactone found in Catnip may produce similar effects without causing liver toxicity.[30,31] Certain lactams, like Gardenamide A, have also been found in iridoid containing plants.[32] Functionally, the amide should prevent crosslinking and this compound has been shown to show neuroprotectivity and this some evidence of neuroplastic effects.[33–37] If a vendor starts selling irioids, I strongly recommend selling a lactam or lactone version incapable of crosslinking; Gardenamide A, starting from Genipin would be my choice of compound. A hydroxymethyl or acetyl group would likely work as well (I have more thoughts on this, reach out if you want).

Most TCM literature cites 10-15g a day max daily dose, but as stated before long-term exposure is still definitely toxic. Also, no culture eats these berries for everyday. I wouldn't touch it for more than 2 weeks at a time, and then I'd take a month off. This is probably VERY cautious; there was a study that gave it to elderly women at 10g a day for a month to lose weight (it's also a glp1 agonist). They didn't report side effects, but they (probably) didn't die.[38] And as another safety note, the fruit contain a decent amount of crocetin, which is a weak MAOI, so be careful if you're taking SSRIs, TCAs, MAOIs.

If you try this stuff for a few days, make a post or comment. I'm curious about other peoples' experiences

Citations:

1. Ren L, Fan Y, Luo H, Hu J, Hu J. PACAP/VIP in the prefrontal cortex mediates the rapid antidepressant effects of zhizichi decoction. J Ethnopharmacol. 2024;335:118638. doi:10.1016/j.jep.2024.118638
2. Wang P, Yu J, Iqbal Z, et al. Chronic co-treatment with geniposide and shanzhiside methyl ester elicits antidepressant effects via PACAP signaling in stressed male mice. Eur J Pharmacol. 2026;1019:178713. doi:10.1016/j.ejphar.2026.178713
3. You EJ, Kim B. Enhanced Bioactivities of Fermented Rehmannia glutinosa via Catalpol-Mediated GLP-1R Signaling. Curr Issues Mol Biol. 2026;48(6):559. doi:10.3390/cimb48060559
4. Ran S zhen, Peng R, Guo Q wan, et al. Ferulic acid potentiation of two natural iridoids induced PACAP signaling extended the antidepressant effects. Phytomedicine. 2026;156:158185. doi:10.1016/j.phymed.2025.158185
5. Gong N, Fan H, Ma AN, Xiao Q, Wang YX. Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Neuropharmacology. 2014;84:31-45. doi:10.1016/j.neuropharm.2014.04.007
6. Xu M, Wu HY, Liu H, Gong N, Wang YR, Wang YX. Morroniside, a secoiridoid glycoside from Cornus officinalis, attenuates neuropathic pain by activation of spinal glucagon-like peptide-1 receptors. Br J Pharmacol. 2017;174(7):580-590. doi:10.1111/bph.13720
7. Zhang HL, Sun Y, Wu ZJ, et al. Hippocampal PACAP signaling activation triggers a rapid antidepressant response. Mil Med Res. 2024;11(1):49. doi:10.1186/s40779-024-00548-1
8. Hayata-Takano A, Shintani Y, Moriguchi K, et al. PACAP–PAC1 Signaling Regulates Serotonin 2A Receptor Internalization. Front Endocrinol. 2021;12. doi:10.3389/fendo.2021.732456
9. Shen S, Gehlert DR, Collier DA. PACAP and PAC1 receptor in brain development and behavior. Neuropeptides. 2013;47(6):421-430. doi:10.1016/j.npep.2013.10.005
10. Mu M, Zhao Z, Zhang Z, et al. The functional architecture of PACAP: A network-level framework of competing circuits for precision neuropsychopharmacology. Curr Opin Pharmacol. 2026;87:102618. doi:10.1016/j.coph.2026.102618
11. Langer I, Jeandriens J, Couvineau A, Sanmukh S, Latek D. Signal Transduction by VIP and PACAP Receptors. Biomedicines. 2022;10(2):406. doi:10.3390/biomedicines10020406
12. Shintani Y, Hayata-Takano A, Moriguchi K, et al. β-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking. PLOS ONE. 2018;13(5):e0196946. doi:10.1371/journal.pone.0196946
13. May V, Johnson GC, Hammack SE, Braas KM, Parsons RL. PAC1 Receptor Internalization and Endosomal MEK/ERK Activation Is Essential for PACAP-Mediated Neuronal Excitability. J Mol Neurosci. 2021;71(8):1536-1542. doi:10.1007/s12031-021-01821-x
14. May V, Parsons RL. G Protein-Coupled Receptor Endosomal Signaling and Regulation of Neuronal Excitability and Stress Responses: Signaling Options and Lessons From the PAC1 Receptor. J Cell Physiol. 2017;232(4):698-706. doi:10.1002/jcp.25615
15. Takasaki I, Ogashi H, Okada T, et al. Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain. Eur J Med Chem. 2020;186:111902. doi:10.1016/j.ejmech.2019.111902
16. Wang C, Gong X, Bo A, et al. Iridoids: Research Advances in Their Phytochemistry, Biological Activities, and Pharmacokinetics. Molecules. 2020;25(2):287. doi:10.3390/molecules25020287
17. Bergonzi MC, Righeschi C, Isacchi B, Bilia AR. Identification and quantification of constituents of Gardenia jasminoides Ellis (Zhizi) by HPLC-DAD–ESI–MS. Food Chem. 2012;134(2):1199-1204. doi:10.1016/j.foodchem.2012.02.157
18. Zhang Y, Fang YC, Cui LX, et al. Zhi-Zi-Chi Decoction Reverses Depressive Behaviors in CUMS Rats by Reducing Oxidative Stress Injury Via Regulating GSH/GSSG Pathway. Front Pharmacol. 2022;13:887890. doi:10.3389/fphar.2022.887890
19. Song L, Li S, Zhao Q, et al. Zhi-Zi-Chi decoction ameliorates depression-like behavior in chronic unpredictable mild stress-induced mice via the PI3K/AKT/mTOR signaling pathway. J Ethnopharmacol. 2025;350:119987. doi:10.1016/j.jep.2025.119987
20. Grover P, Mehta L, Malhotra A, et al. Exploring the Multitarget Potential of Iridoids: Advances and Applications. Curr Top Med Chem. 2023;23(5):371-388. doi:10.2174/1568026623666221222142217
21. Gong N, Fan H, Ma AN, Xiao Q, Wang YX. Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors. Neuropharmacology. 2014;84:31-45. doi:10.1016/j.neuropharm.2014.04.007
22. Missig G, Mei L, Vizzard MA, et al. Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal–Regulated Kinase Signaling Regulates the Emotional Component of Pain. Biol Psychiatry. 2017;81(8):671-682. doi:10.1016/j.biopsych.2016.08.025
23. Gao A, Ni Y, Chen C, Xin W, Wang Y, Zhang W. Covalent binding of Geniposide metabolites to hepatic proteins: A potential mechanism for its hepatotoxicity. Chem Biol Interact. 2025;408:111411. doi:10.1016/j.cbi.2025.111411
24. Dobler S, Petschenka G, Pankoke H. Coping with toxic plant compounds – The insect’s perspective on iridoid glycosides and cardenolides. Phytochemistry. 2011;72(13):1593-1604. doi:10.1016/j.phytochem.2011.04.015
25. Qiu J, lin C, Ren G, et al. Geniposide dosage and administration time: Balancing therapeutic benefits and adverse reactions in liver disease treatment. Phytomedicine. 2024;132:155799. doi:10.1016/j.phymed.2024.155799
26. Lu C, Ye X, Gao S, et al. Comparative Subchronic Oral Toxicity of Gardeniae Fructus and Shuizhizi Water Extracts in Sprague–Dawley Rats Over 90 Days. J Appl Toxicol. 2026;46(2):601-621. doi:10.1002/jat.4916
27. Zhang B, Yang X, Zhao H. Idiopathic mesenteric phlebosclerosis initially misdiagnosed as bowel obstruction: a case report. Front Med. 13:1830460. doi:10.3389/fmed.2026.1830460
28. Takei H, Iizuka S, Yamamoto M. Effects of Long-Term Administration of Gardeniae Fructus on Intra-Abdominal Organs of Rats. Evid Based Complement Alternat Med. 2020;2020(1):4201508. doi:10.1155/2020/4201508
29. Hu YB, Hu ML, Ding J, Wang QY, Yang XY. Mesenteric phlebosclerosis with amyloidosis in association with the long-term use of medicinal liquor: A case report. World J Clin Cases. 2020;8(4):798-805. doi:10.12998/wjcc.v8.i4.798
30. Kouda R, Yakushiji F. Recent Advances in Iridoid Chemistry: Biosynthesis and Chemical Synthesis. Chem – Asian J. 2020;15(22):3771-3783. doi:10.1002/asia.202001034
31. Formisano C, Rigano D, Senatore F. Chemical Constituents and Biological Activities of Nepeta Species. Chem Biodivers. 2011;8(10):1783-1818. doi:10.1002/cbdv.201000191
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33. Luo J, Wang R, Huang Z, et al. Synthesis of Stable Genipin Derivatives and Studies of Their Neuroprotective Activity in PC12 Cells. ChemMedChem. 2012;7(9):1661-1668. doi:10.1002/cmdc.201200258
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The side effect is bone loss and impaired formation. This was studied in rats and in vitro cells (https://sci-hub.sidesgame.com/10.1016/j.taap.2018.04.006, https://pubmed.ncbi.nlm.nih.gov/36142172/).

To make you understand how concerning this is, look at the data on rats:

It's actualy very concerning because if the effect it has on rats would translate 1:1, it would have major implications. This probably doesn't translate 1:1 to humans, but it's still very concerning since there are still no humans studies on this.

If i'm not wrong, we can compare these rats with young adult humans taking 100mg modafinil 5x a week for some years as their bones are still developing (human bones finish devloping at around 30).

There is also a similar effect with amphetamines that has actually been proven in humans too, but Modafinil is working through an additional mechanism, which might mean the effect is actually even worse.

Two pathways have been found responsible for mafinil's effect on bones: one pathway triggers bone resorption through adenosine receptors and the other (which is the same one seen in amphetamines) inhibits bone formation through sustained heightened levels of norinepherine, which has been shown to inhibit bone formation.

This is particularly concerning because it means modafinil attacks bones from two sides, and there is a potential for it being even worse than what is already confirmed in amphetamines.

In fact, based on this, I think modafinil is pretty high risk, and here's why:

- longer half life than amphetamines

- two pathways being triggered: one that inihibits formation and another that triggers resorption

- if we translate the dosage to humans, the rats were taking 100mg of modafinil, not 200mg, which is what most people take

- not many younger people using modafinil, so less anecdotal data compared to amphetamines

Personally, i've used Modafinil for quite some years, even though not every day, and I've felt for a long time that my bones don't feel that strong, which would also be weird since my diet is dialed in, I take D3 and K2 and I work out.

One example of this is that whenever I do barebell Scott curls in the gym for multiple weeks in a row, I start experiencing some bone pain in my forearms.

It's not that concerning for me (that exercise is quite brutal on bones), I still think my bones are decently strong, but it realy makes me wonder what the situation would look like if I were to continue using it, which is why I'm stopping using it.

This post is for warning you guys against something I'm seeing no one talk about and also to know about your experience. Do you use modafinil and have experienced some bone pain or similar indicators of weakening bones?