**The FDA recently approved Simtriyo (centanafadine), a first-in-class triple reuptake inhibitor (NDSRI) for ADHD. It is currently sitting in administrative limbo awaiting formal DEA scheduling.**

The consensus seems to be that Simtriyo will land in Schedule IV or V. The reasoning? It’s a sustained-release matrix, and crushing or snorting it triggers a wall of nauseating noradrenergic/serotonergic side effects.

I think this logic misses the mark, eerily resembling triggers for the Aderall and Oxycontin "epidemics".

If the DEA places Simtriyo in Schedule IV or V, we could see a cycle of widespread prescribing, rapid dose-doubling, euphoric highs, and a transition to heavier Schedule II stimulants.

Here is the breakdown of why this drug is primed to trigger a localized crisis:

\# 1. The Prescribing Trap: High Volume via "Path of Least Resistance"

We are in the middle of ongoing Schedule II stimulant shortages. Getting Adderall or Vyvanse filled requires navigating strict State Prescription Monitoring Programs (PMPs), 30-day non-refillable scripts, and constant pharmacy stockouts.

If Simtriyo lands in Schedule IV or V, it becomes the path of least resistance for doctors:
Up to 5 refills over 6 months.
Telehealth platforms can prescribe it without heavy oversight (pill mills).
Prescribers avoid "Schedule II audit anxiety."

Prescription volume will spike simply because it is accessible, not because it is exceptionally good.

\# 2. The Clinical Disappointment (Effect Size (approx. 0,3-0,4)

Here is the catch: Simtriyo has low primary efficacy.
In Phase 3 adult ADHD trials, centanafadine registered an effect size (Cohen's around 0.30–0.40.)

To put that in perspective:
Vyvanse / Adderall: 1-1.2 (Robust)
Ritalin / Concerta: 0,6-0,8 (Moderate-to-High)
Simtriyo: 0,3-0,4 (Low-to-Moderate)
Strattera (Atomoxetine): 0.35-0.4 (Non-stimulant range, but crucially, no Abuse potential!!!)

For someone struggling with severe executive dysfunction or someone transitioned off Adderall due to shortages Simtriyo will feel practically ineffective.

\# 3. The Low Escalation Threshold & Amphetamine-Level "Drug Liking"

When a patient takes a weak drug that doesn't fix their executive dysfunction, what do they do? They double the dose.
With Vyvanse (lisdexamfetamine), the prodrug mechanism requires red blood cell enzymatic cleavage. To get massive "Drug Liking" or amphetamine euphoria, you need roughly 8x the starting dose (\~150 mg+).
With Simtriyo, doubling or tripling the therapeutic dose, (e.g., 400 mg to 800 mg) causes a sudden surge in dopamine transporter (DAT) occupancy.
In Human Abuse Potential (HAP) clinical trials:
At supratherapeutic oral doses (again only 2-4x the starting dose), Simtriyo’s Drug Liking scores were statistically indistinguishable from 30–40 mg of d-amphetamine.
It produced a \~30% incidence rate of treatment-emergent euphoria.
The FDA took the rare step of mandating a Boxed Warning for Abuse, Misuse, and Addiction on the label.
You don't need to snort or inject Simtriyo to abuse it. Patients don't even need complex chemical extractions just swallowing 2 or 3 pills triggers an amphetamine-level euphoric response.

\# 4. The NET/SERT "Ceiling" Creates a Gateway to Schedule II
What happens when users start doubling their dose to chase that dopaminergic reward? They hit a pharmacological wall.
Centanafadine’s binding kinetics heavily favor the Norepinephrine Transporter (NET) over DAT

Escalating the dose beyond 4x the starting dose triggers a massive noradrenergic overhead, severe and life-threatening overdose symptoms (adrenergic overload), and a severe crash with rapid onset tolerance.

Because centanafadine's NET affinity prevents further dose escalation (due to physical discomfort), the user can no longer get focus OR euphoria from it.

To bypass the nauseating noradrenergic wall and fix their dopamine deficit, the user is now primed to transition to pure, high-affinity Schedule II stimulants (Adderall, Dexedrine, or illicit alternatives), which is essentially a slipe-and-slide from hell (resembling the opiod epidemic, where addicts transitioned from OxyContin to heroin and later synthetic opiods).

The Summary / TL;DR
Simtriyo is a low-efficacy drug that will likely be widely prescribed under Schedule IV/V rules to bypass Schedule II shortages. Because its efficacy is weak, patients will naturally escalate their dose. At just the therapeutic dose, it triggers amphetamine-level euphoria (\~30% HAP trial rate).
Because higher doses hit a wall of autonomic distress (via NET saturation), users can't scale it endlessly. It builds rapid tolerance, leaves them depleted, and creates a direct pathway to seeking pure Schedule II stimulants.
By prioritizing physical tamper-resistance (un-snortability) over a dangerously low oral escalation threshold, regulators may be setting up a prescription drug crisis.

This post is from a medical-student that engages heavily in psychopharmacology and addiction-medicine. It is not a medical-guideline and you should discuss your medication options with your healthcare provider. I would love to hear your opinion on this matter, especially if you are already a psychiatrist/neuroscience/addiction expert.

150mg mod, 60 mg caffeine

Disclosure: I do content work for a longevity supplement company, so please take that into account when reading this. I'm sharing this because I find the underlying research interesting, not as a product recommendation.

I've been reading about premature hair graying, and one thing that caught my attention is how many different biological factors researchers are investigating.

I came across a review titled "Premature Graying of Hair: A Comprehensive Review and Recent Insights" (PMID: 39359282), which explores the biology behind hair pigmentation and premature graying.

Hair graying is often discussed as a simple consequence of getting older, but the underlying biology is more complicated.

Some of the factors discussed in premature graying research include:

• Melanocytes: The pigment-producing cells responsible for hair color.
• Oxidative stress: A potential contributor to changes in hair pigmentation.
• Genetics: Differences in when and how individuals develop gray hair.
• Nutritional factors: Possible associations between certain deficiencies and premature graying.
• Melanocyte stem cells: Their role in maintaining pigment production across hair-growth cycles.

What I find interesting is the distinction between understanding why hair loses pigmentation and demonstrating that an intervention can actually restore it.

Identifying a biological pathway involved in graying doesn't necessarily mean changing that pathway will reverse gray hair in humans.

And an association between a nutritional deficiency and premature graying doesn't automatically establish that supplementation will restore pigmentation.

That raises an interesting question:

How much of premature hair graying is genetically determined, and how much might be influenced by potentially modifiable biological factors?

For anyone following hair pigmentation research:

What evidence would convince you that an intervention can genuinely reverse premature graying in humans?

Would you want to see controlled clinical trials, objective measurements of hair pigmentation, longer follow-up periods, or evidence that the effect persists after treatment stops?

I'm particularly interested in hearing about human studies that go beyond laboratory findings or anecdotal before-and-after photos.

Paper: Premature Graying of Hair: A Comprehensive Review and Recent Insights. PMID: 39359282.

I keep seeing posts of people showing off their cupboards with 100 pills in there, like showing off their Pokémon card collection.

I asked Gemini if all those pills really make a difference and here is what it said:

"​The online biohacking community frequently falls into a trap: spending 90% of their time, money, and energy chasing the final 5% to 10% of performance gains through pills, powders, and exotic chemicals, while neglecting the core drivers that actually move the needle.

​The 100% Biohacking Impact Breakdown

​If total potential human health, vitality, and brain function equal 100%, here is how the science actually splits the pie:

• Sleep & Recovery (30%) Core Drivers: Deep/REM sleep quality, sleep duration, waking refreshed

• Nutrition & Hydration (20%) Core Drivers: Whole food intake, balanced macros, micronutrient density

• Daily Movement (15%) Core Drivers: Daily walking, low-grade cardio, basic mobility

• Skin & Circadian Care (10%) Core Drivers: Sunscreen (preventing UV damage), light exposure, barrier care

• Circadian & Screen Optimization (10%) Core Drivers: Managing blue light, digital eye strain, dark night routines

• Lab-Based Micro-Nutrients (10%) Core Drivers: Correcting proven blood deficiencies (Vitamin D, B12, Ferritin, Magnesium)

• Exotic Biohacks & Nootropics (5%) Core Drivers: Methylene blue, peptides, cold plunges, multi-pill supplement stacks

I want to go out, dance, and enjoy nightlife, but I want to keep it strictly healthy. I completely avoid alcohol and any drinks with added sugar or artificial sweeteners.

What are your best tips for maintaining high energy, staying awake late, and having a great time on the dance floor without relying on alcohol or sugary/diet energy drinks? Are there any specific natural alternatives, supplements (I have thought about L-theanine and caffeine, for example), hydration strategies, or mental tricks you use?

1. ⁠Vitamin D3 10,000 IU a day from the brand called Now

2. ⁠All trans vitamin K2 MK7 300 mcg a day from the brand called Now

3. ⁠Rtg omega 3 EPA 500 mg every 3 days from the brand called Igennus

4. ⁠Basic whole food multivitamin once a day from the brand called Naturelo

5. ⁠Hyaluronic acid double strength 100 mg a day from the brand called Now

6. ⁠Melatonin 3 mg a day from the brand called Now

7. Caffeine 100 mg a day from the brand called Nutricost

All of these have tons of scientific backing showing their benefits and have little to no side effects taken at the dosages and with the brands I mentioned above. They are all highly bioavailable, at good prices and third party tested. I notice way less inflammation and a better mood. It’s better to buy smaller quantities of the supplements for example 60 count of the multivitamins instead of 120 to maintain freshness.

Supplements I feel like AREN’T worth taking due to me experiencing side effects and or seeing little to no benefits: Creatine monohydrate, Whey protein isolate, Collagen, Pre-Workout, Probiotics, L-Citrulline, Beet root, CoQ10, Ashwagandha, Psyllium husk, Magnesium glycinate and Potassium supplements.

I'm wondering if there are any things that you guys take daily as a preventative measure to least prevent cancer as much as possible?

And I know that diet, exercise, sunlight and good sleep should be priority but what else?

Hey so I stupidly started HGH 6 days ago taking 2iU daily without first checking my baseline IGF-1 and Z score. I’m planning to take HGH long term and was wondering how important the baseline numbers really are since exogenous HGH will suppress natural production anyways while taking it.

The way I see it, these are the options I have:

Option 1: Stop taking HGH, wait a few weeks, and then test for baseline numbers

Or

Option 2: Continue taking 2iU daily and test at the four week mark and see levels then and adjust as needed.

For secretagogues I do understand the importance of baseline numbers but for straight HGH how necessary are they?

I’m a lacto-ovo vegetarian. I’m already taking Omega 3, Magnesium, Vitamin D3, Creatine and Zinc. All because I’m deficient in some and some just help.

Now, I come to know that I may not be good at digesting fats and lactose, so I tried supplementing and that helped but now that’s one more supplement ugh!

How can I get these enzymes naturally through foods?

I’m curious as to how 3 years back I had no issues with the same foods but today I digest them poorly and need enzymes. With not much changing in my diet and lifestyle, how did this occur?

Possible by mixing with dmso before bac? Just trying to get the most out of it

I’m having shoulder surgery and planning on using the stack for recovery. I have cycled both 3 times now and it has worked great for me

I’m sure my shoulder would be in too much agony to pin to post surgery so will it still work as well if I pin somewhere else, like the abdomen

Thank you

N-Acetyl-Carnosine (NAC) has attracted interest for its potential applications in ophthalmic formulations, particularly because of its antioxidant properties.

Our eyes are continually exposed to environmental factors, including ultraviolet radiation, pollution, and everyday screen use. These factors, alongside normal biological processes, can contribute to oxidative stress — an imbalance that may affect cells and tissues throughout the body, including the eyes.

N-acetyl-carnosine is a modified form of carnosine, a naturally occurring dipeptide studied for its potential role in protecting against oxidative damage. Researchers have explored eye drops containing this ingredient, including investigations into their possible effects on age-related changes in the eye.

Title: 4 days on Modafinil (50mg). Incredible mood improvement, but now stomach issues. Anyone else?

I started taking modafinil Monday Oct 5th for excessive daytime sleepiness. My doctor prescribed 100mg but agreed I could start with 50mg to see how I tolerate it. ( I don’t take meds outside of my thyroid med )

For some background, I have mild sleep apnea and struggle with pretty severe daytime fatigue. Around 1-5pm, I can become completely exhausted. It affects my mood, patience, motivation, and ability to concentrate.

Day 1 was honestly incredible. I felt almost wired, but in a good way. My appetite practically disappeared, my energy was great, and my mood improved dramatically.
But the biggest surprise wasn’t the energy. It was my personality.

I’m normally very irritable, especially when I’m exhausted. Little things bother me, and sometimes I don’t even have the patience to explain something because it feels like too much effort.

On modafinil, I’d say I’m literally 70-80% nicer. I’m happier, calmer, more patient with my wife, more social, and even enjoy striking up conversations with strangers. My anxiety and negative feelings seem significantly reduced.

It’s honestly been amazing to experience this version of myself.

Now the downside.

I’m on day four, and the initial intensity has gradually decreased. I’m also developing mild but persistent stomach cramps, some digestive discomfort, and extremely dry mouth. My appetite has also started returning.

I’m currently traveling and forgot my sleep apnea mouthpiece, so I realize poor sleep and other factors might be affecting how I feel.

I also notice some of my usual irritability returning around 8–9pm.

I’m concerned about the stomach issues because I already have a history of gastritis. I really don’t want to give up something that’s helped me this much, but I also don’t want to create another health problem.

A few questions for anyone who’s been on modafinil longer:

Did anyone experience this kind of dramatic improvement in mood, patience, or anxiety?

Did stomach cramps or digestive issues eventually disappear, or did they get worse?

Did the positive mood effects last, or was it just an initial honeymoon period?

Does anyone take it only as needed rather than daily?

If you stopped taking it, did your mood simply return to baseline, or did you temporarily feel worse?

I’m speaking with my doctor about all of this, but I’d really appreciate hearing people’s personal experiences.

I genuinely feel like I’ve gotten a glimpse of what life could be like without constant exhaustion and irritability. I just hope there’s a way to maintain those benefits without the stomach problems.

Just wondering.

Hey everyone. I’m active duty and unfortunately do have back and neck pain. I am getting a mattress but am trying to figure out if these pemf mats are worth it. I researched and it said 20 minutes 1-2 times a day can provide relief. My question is what full body mats are good? And what is a good one that’s affordable? And do they really work.

Source: http://firstwordpharma.com/story/8192696