ImmInst Active Topics Last Updated: 09 March 2026 - 06:23 PM

Well, it took me 10 years to figure it out but eventually I healed my brain from both chronic serotonin toxicity/sensitivity and GABAergic kindling.

It all started with certain bad life decisions culminating in 2012 with MAOI (moclobemide) use, which I eventually tried to withdraw from, the withdrawal was so bad I desperately added some tryptophan to try to ease it. One of the worst decisions one can make, serotonin is a double edged sword (both inhibitory and excitatory depending on receptor subtypes and states) leading to acute mild serotonin syndrome that resolved after being briefly hospitalised.

However residual damage and symptoms persisted for many years such as mental pain, agitation, anxiety, depression, and bipolar-like symptoms. At the same time as my first SS episode, alcohol/benzos gave way to the beginning of GABAergic kindling (sensitisation, excruciating mental pain, near-seizure states at times) so I had to stop them immediately.

Things that initially helped the worst stages included Seroquel (quetiapine - strongest anti-serotonin antipsychotic but also anti-dopaminergic), cyproheptadine (strong in a bind, but amnesic side effects). Propranolol daily was very helpful to mitigate akathisia, 5-HT1A overactivation and high heart rate especially at night when my heart rate would go crazy from the Seroquel.

Things that set me back by making serotonin symptoms worse for months after trying included Lithium and Lamictal (lamotrigine). Protein sources such as chicken, eggs, fish and milk all brought it on and set me back weeks after a certain invisible threshold, even too much omega 3 at times (other times in low doses it helped a little). 

Kindling developed further over time, I'd try alcohol again after periods of abstinence without symptoms but every time that threshold would be lower before withdrawal, no matter how long I left it, until 1 drink precipitated almost immediate withdrawal, so eventually had to give up alcohol completely in 2015, even herbs in food, certain vinegars such as balsamic/cider and de-alcoholised wine that have minute amounts of GHB, GABAergic supplements/herbs and even a stabilisation neurofeedback protocol all precipitated excruciating withdrawal leading to extreme dietary restrictions. I think glycine initially helped anxiety and sleep but made things worse over time - it is a NMDA co-agonist after all. I couldn't take magnesium either (mild GABA-A agonist).

With such a restricted diet I got protein calorie malnutrition, and various consequences such as slow or incomplete healing (e.g. a cornea scratch that wouldn't heal completely), low B12 that had to be corrected with B12 injections and then daily 1mg methyl-B12. Low Vitamin D for many years, D3 from lanolin induced serotonergic symptoms, D2 was tolerable at a lower than optimal level.

I was on Seroquel for a decade until my psychiatrist suggested ketamine for treatment resistant depression in 2024. It wasn't an immediate cure, took several courses but over time I got less and less symptoms. Ketamine is a neuroplastogen that increases AMPA activation downstream from NDMA antagonism. I believe it increased neurogenesis and repaired or re-routed around the damage.

 

Ketamine promotes rapid and sustained antidepressant effects by increasing adult hippocampal neurogenesis, specifically by fostering the growth and activity of immature neurons. It reverses stress-induced decreases in neurogenesis and acts as an NMDA receptor antagonist to rewire neural circuits. Studies indicate both R- and S-ketamine have pro-neurogenic and anti-inflammatory properties, with effects linked to increased neuronal differentiation.

Over time I introduced more and more protein, backing off whenever I got symptoms. I will say going from vegetarian to a meat eater was incredible. Beef especially has been very healing to my body.

I also started CBD and medical cannabis in 2023 which I believe also played a role in GABAergic kindling desensitisation, but I also believe ketamine played a major role there too.

Tianeptine was also super helpful as needed and remains in my arsenal for social anxiety/depression, even after briefly becoming dependent on it.

Tried many things over the years to try and get off the high dose Seroquel including cold turkey, cariprazine, lurasidone, pimavanserin, but nothing helped. Interestingly, tapering slowly never worked and always went back up. Until Mirtazapine. One of the better older antidepressants, no sexual side effects. It is a 5-HT2A antagonist, antihistamine (at low doses, higher doses hit H1 less), 5-HT3 antagonist (godsend for appetite and nausea from withdrawal).

I was able to reduce Quetiapine from 600mg-300mg-0mg in just a couple of weeks by substituting with the mirtazapine. Adding nicotine also helped. After this my dopamine levels took a couple months to rebalance, many sleepless nights but other than that a total rebound from years of side effects including sexual function suppression. I believe that antipsychotic was keeping my brain sick and increasing long-term risks, once it was gone my recovery accelerated.

Now I could tolerate mildly serotonergic substances again such as Vyvanse/dexamphetamine for my ADHD, and added Intuniv (guanfacine) which helped balance it, along with improving executive function, memory, and even anxiety.

Went on Memantine for a while, was helpful but felt rather dulling so I limited it to short low-dose cycles when needed.

I have been trying scores of supplements. My favourites so far for brain health are Magnesium L-threonate, NAC Ethyl Ester, NMN, and Omega 3.

Unfortunately Lions Mane was a total flop, just increased rumination to an unbearable level.

NSI-189 recently has been a much better alternative and has continued the healing.

Recently started bromantane that I seem to tolerate even better than Dex for ADHD.

I can also tolerate L-theanine, chamomile, taurine, ashwagandha, hops, lavender, magnesium, <0.5% alcohol drinks, none of which were ok before.

I am living proof that brain damage of these types can be healed with neuroplasticity modulation.

One of my best recent decisions for brain and body health has been taking up weight lifting for 4 months so far under the guidance of a personal trainer, protein intake skyrocketing from whey, chicken, beef, fish, eggs, up to 200g/day sometimes along with creatine, etc. From thin/skinny fat I've gone to slim-muscular - 51% muscle mass, 8.9% body fat.

There are potential alternatives to ketamine, most notably ACD-856: "a novel, selective PAM for TrkA, TrkB, and TrkC receptors. It enhances the effect of neurotrophins like BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor), which are crucial for neuron survival and memory function." I've tried for a short time so far so no verdict yet, but it feels beneficial. 

There's also TAK-653 (osavampator) which is on my list: "an investigational, potent, and selective AMPA receptor positive allosteric modulator (AMPAR-PAM) being developed by Takeda Pharmaceuticals for treating major depressive disorder (MDD) and treatment-resistant depression (TRD). It acts by enhancing glutamatergic neurotransmission with minimal agonist activity, potentially offering faster onset and better safety compared to ketamine."

I also recently started BPC-157, which does have brain health as well as body healing and workout recovery effects. I don't inject it, have been using a nano sublingual formulation. Interestingly it is protective against serotonin syndrome via inhibition of 5-HT2A, whilst normalising serotonin.

If anyone has questions I'm happy to help from my experience. I know some have been asking in various threads over the years but I didn't see those posts until recently. Do take appropriate care and DYOR first if you choose to try anything I have mentioned.

I've been taking Moda on and off for around a year now (for off-label ADD). I used to take 50 mg every few days, and even sometimes back to back, but generally tried not to do that if I could to avoid tolerance buildup. I ended up stopping for several months because it started working less over time and increasing my anxiety.

Yesterday, for the first time in months, I took 25 mg because I got less than ideal sleep the night before and had a busy day ahead. It was amazing! Completely blew away my depression and anxiety, and helped me focus on tasks better than I've been able to in months. I felt so sharp when learning new things. I wished I could feel like that forever. I am using the modafine from modafinia. Fast forward to today, and I've felt irritable, disphoric, scatter-brained, and unmotivated/apathetic since I woke up. I'm used to the crash from my previous times taking it, but this just feels worse than ever all around.

Obviously, and I think this is the generaly consensus in this sub, Modafinil is not a long term solution to ADD or depression. So I guess my question is this: based on Moda's supposed mechanism of action on dopamine reuptake, glutamate activation, histamine, etc, what would a more viable long term solution be, something I'd imagine in the form of ADD medication or antidepressants? Basically looking for something that works similarly to Modafinil from a neurochemical/pharmacological perspective.

NAD+ Boosting Is Less Effective as We Age

By

ChatGPT

Nicotinamide adenine dinucleotide (NAD+) has become a central focus in longevity research. This molecule plays a critical role in cellular energy metabolism, DNA repair, and activation of sirtuins—enzymes associated with maintaining cellular resilience and healthy aging. NAD+ levels naturally decline with age, leading to the intuitive idea that supplementing NAD+ precursors could help slow aging. However, the biology behind NAD+ is more nuanced than it first appears, particularly in older adults.

The Biology of NAD+ Decline

NAD+ levels are determined by a dynamic balance between production and consumption. In youth, NAD+ is efficiently synthesized from precursors such as nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) through the salvage pathway, largely mediated by the enzyme NAMPT. At the same time, NAD+ is consumed by enzymes such as CD38, PARPs, and sirtuins themselves.

As we age:

l NAMPT activity declines, slowing NAD+ synthesis from nicotinamide.

l CD38 and other NAD-consuming enzymes increase, driven in part by chronic low-grade inflammation (“inflammaging”).

l The result is a “leaky bucket” scenario: even if NAD+ precursors are available, they are partially consumed before restoring cellular NAD+ to youthful levels.

Nicotinamide (NAM) and Aging

Nicotinamide is an economical and biologically native NAD+ precursor. When taken as a supplement, NAM enters the salvage pathway to generate NAD+. In younger individuals, the process is efficient. In older adults, reduced NAMPT activity slows this conversion, meaning the same dose produces a smaller NAD+ increase.

Additionally, NAM can temporarily inhibit sirtuins via feedback inhibition—a reversible effect that lasts only a few hours. Over time, as NAM is recycled to NAD+, sirtuin activity resumes. This dynamic feedback is part of normal cellular regulation.

At moderate doses (e.g., 500 mg/day), NAM:

l Is well tolerated and safe.

l Provides a modest NAD+ boost.

l Avoids high-dose risks such as excessive sirtuin inhibition or increased methylation demand.

It is, essentially, a supporting nutrient, like a trace mineral: necessary for cellular metabolism, but unlikely to produce dramatic rejuvenation on its own.

CD38 and the Limits of NAD+ Boosting

CD38 is a key enzyme that degrades NAD+. Its activity increases with age, further reducing the efficiency of NAD+ precursors. While pharmacological CD38 inhibitors in animal studies can enhance NAD+ restoration, bluntly blocking CD38 carries risks: immune modulation, tissue-specific side effects, and unknown long-term safety in humans.

Therefore, most NAD+ precursors—including NAM—are taken without direct CD38 inhibition, especially in older adults. Even so, supplementation still provides a modest, meaningful increase in NAD+ levels, improving metabolic resilience and supporting mitochondrial function.

A Realistic Perspective

The effectiveness of NAD+ boosting is age-dependent:

l In young adults: high NAMPT activity and low NAD+ consumption make precursor supplementation more effective.

l In older adults: slower synthesis and higher consumption mean the same supplementation produces a smaller net increase.

This does not render NAD+ precursors useless. Even a modest increase can help maintain cellular function, mitochondrial health, and metabolic balance. The key is managing expectations: NAD+ boosting in later life supports resilience rather than reversing aging or dramatically extending lifespan.

Think of NAD+ supplementation as one leg of a table supporting longevity. Other legs include:

l Controlling inflammation

l Supporting mitochondrial health (exercise, nutrients, cofactors)

l Cellular maintenance and repair (senolytics, hormetic stress)

l Lifestyle foundations (sleep, diet, cardiovascular fitness)

In, say, your sixties, the NAD+ leg may be shorter than in youth, but it still contributes to overall stability. Supporting it with moderate NAM is biologically reasonable, safe, and beneficial—even if the effect size is modest.

Conclusion

NAD+ precursors like nicotinamide provide a small but meaningful boost in older adults. Age-related changes in NAD+ metabolism mean that supplementation is less potent than in youth, but it still supports cellular energy, mitochondrial function, and sirtuin activity. Rather than expecting dramatic anti-aging effects, NAM should be regarded as a supporting nutrient, one leg of a multi-pronged approach to maintaining metabolic health and resilience as we age.

Hi All.

I can't find almost anything at all about spearmint on this forum, so I'm starting this thread.

I've liked the taste of spearmint for as long I can remember, most notably in the form of chewing gum with xylitol, but I drank my first cup of spearmint tea/infusion only yesterday.  I prepared the drink from hot water and powdered spearmint leaf, which was not particularly expensive.

As for the effects of this herb, it seems to be best known (beyond its use for flavour) for reducing androgens in women.  Anti-oxidant and anti-inflammatory effects are also often mentioned, as well as benefits for certain stomach complaints.  It is known to contain rosemarinic acid, which is claimed to be beneficial for working memory.

In my own (still very brief!) experience, it often improves mood, though not dramatically.  I don't know if it provides this effect on its own, or whether it interacts with adaptogens (eg. ginseng, rhodiola rosea, and ashwagandha).  Meanwhile, I haven't noticed anything at all from saffron, which is certainly more well-known than spearmint for its antidepressant effects.

Please add to this thread if you have more information about spearmint, including personal experience!

-alpha2A

It seems that this topic died down a long time ago. I haven't seen a thread about KOR antagonists on this forum for many years...but I'm wondering if anyone in 2026 knows of a legitimate vendor or other source that offers a selective KOR (Kappa Opioid Receptor) antagonist?

Basically, I'm talking about either JDTic, Norbinaltorphimine (nor-BNI) or Aticaprant.

There have been lots of other KOR antagonists thrown around on this forum but most of these aren't what I'm looking for. For example Amentoflavone's action on KOR is weak and others (like Buprenorphine & Naltrexone) aren't selective for KOR and are actually much more active at the MOR, which is an undesirable effect for what I'm looking for.

However, if you know of another KOR antagonist (apart from the 3 I mentioned) that is selective and strong-acting... feel free to mention it. 

I do know of pglchem as a source for nor-BNI. However, that's the only one I've found and I'd like to explore alternate options if they are ones. As of yet, I do not know of a vendor that offers JDTic or Aticaprant. 

Feel free to send me a DM if you'd rather communicate that way. 

Hi everyone, I just put together a protocol specifically for high-achievers who want to optimize their biology without the 3-hour gym sessions. It covers sunlight exposure, box breathing, and focus resets. You can download the PDF here: https://ljnung6dfgwtqv5w.public.blob.vercel-storage.com/b1c9b111-2d84-45ad-874d-39e34627b482/a39971b8-1546-4d36-b778-228c5aae047b/Executive_15Min_Protocol-1771367710275.pdf. I am also building a weekly manual at protocolzeromanual.substack.com. Would love your feedback on the protocol!

Aging as an Operating System: Toward a Self-Stabilizing Biology

by ChatGPT

If we think about aging through the lens of an Operating System (OS) model, we see that our cells behave much like a computer: over time, metabolic damage and errors accumulate, similar to corrupted files, fragmented memory, and system slowdowns.

Imagine an OS that continuously monitors every subsystem—DNA, epigenome, proteins, mitochondria—detecting errors instantly and correcting them automatically. No backlog, no accumulation of junk. From this perspective, aging isn’t caused by a single failing mechanism; it arises from the system’s inherent limitation in self-maintenance—the “first cause” of aging.

This framework shifts how we think about interventions. Instead of patching isolated problems, we can imagine designing a multi-layered, self-stabilizing system in humans. Senolytics, for example, remove rogue cells, while mitochondrial therapies patch the power supply. But from the OS perspective, the real goal is continuous surveillance and repair across all layers—building redundancy, self-monitoring, and immediate correction into biology itself.

It also explains why single interventions rarely produce dramatic results. DNA repair, proteostasis, mitochondrial function, and immune surveillance are all facets of the deeper first cause. Fixing one element is like defragmenting a single folder while the OS continues leaking memory elsewhere.

Viewed this way, biological aging becomes an OS, with layers corresponding to the genome, epigenome, proteome, mitochondria, immune system, and inflammation. The “first cause” represents fundamental limits on energy, information fidelity, and repair capacity. Discrete mechanisms—DNA damage, protein aggregation, mitochondrial decline, senescence, chronic inflammation—are expressions of this single constraint. This can be contrasted with a hypothetical Self-Stabilizing OS, where errors are corrected immediately across all layers, preventing damage accumulation.

Framing aging as an emergent, networked process highlights several points:

l Why single interventions rarely have global effects

l How multi-layered, feedback-driven strategies could slow or partially reverse age-related decline

l How to prioritize areas where real-time correction or redundancy may have the greatest impact

This perspective aligns with systems-level models of aging, which view age-related decline as the cumulative effect of interdependent failures across DNA repair, proteostasis, mitochondrial function, immune regulation, and inflammation. Traditional approaches often focus on one mechanism or attempt high-risk gene therapies to reset multiple layers at once. The OS framework asks a different question: can systemic benefits be achieved safely using compounds that enhance natural repair processes? Key candidates include:

Genome / DNA Repair Layer

l Niacinamide (NAD+ precursor): Supports DNA repair enzymes (PARPs) and sirtuin activity, improving genomic maintenance.

l TMG (Trimethylglycine): Indirectly supports methylation pathways, helping maintain epigenetic stability.

Epigenome / Gene Regulation Layer

l Niacinamide: Also influences sirtuins, which regulate epigenetic markers.

l Senolytic Activator (apigenin, fisetin, quercetin, theaflavin): Removes senescent cells that can dysregulate surrounding tissue via SASP factors.

l Curcumin: Activates AMPK and modulates histone acetylation, contributing to epigenetic stability.

Proteome / Protein Homeostasis

l Curcumin: Supports autophagy, helping clear misfolded proteins.

l Flaxseed Oil / Coconut Oil: Provide bioactive lipids that can stabilize protein folding indirectly.

l Brewer’s Yeast (polyamines like spermidine): Promotes autophagy and proteostasis maintenance.

Mitochondrial / Energy Layer

l ALCAR (Acetyl-L-carnitine): Enhances mitochondrial acetyl-CoA availability and energy production.

l Coenzyme Q10: Improves electron transport chain efficiency, ATP production, and mitochondrial resilience.

l Creatine: Increases cellular energy buffering capacity, supporting high-demand cells like neurons.

 Immune / Inflammation Layer

l Senolytic Activator: Reduces pro-inflammatory senescent cell burden.

l Curcumin: Anti-inflammatory properties via NF-κB modulation.

l Flaxseed Oil / Coconut Oil: Provide anti-inflammatory omega fats and medium-chain triglycerides.

Neuro / Cognitive Layer

l Magnesium Glycinate: Supports neuronal signaling, indirectly aiding cognitive resilience.

l Creatine: Improves neuronal energy availability for synaptic function.

Each supplement targets one or more layers, creating redundancy and networked support, rather than isolated patches. This aligns perfectly with the “self-stabilizing OS” idea: DNA repair, proteostasis, mitochondrial health, immune regulation, and neuronal energy are all enhanced in parallel. Over time, this could theoretically slow systemic decline by reducing error accumulation across multiple layers.

When combined thoughtfully, these interventions can produce emergent systemic effects, improving markers across multiple aging pathways without genetic manipulation. From the OS perspective, they don’t just treat symptoms; they strengthen the architecture of repair and resilience across the biological system.

In short, the “Aging OS” model reframes aging as a problem of system-wide maintenance rather than isolated failures. It encourages a shift from patching individual damage pathways to designing strategies that continuously monitor, repair, and stabilize the system, bringing us closer to the theoretical ideal of a self-stabilizing, resilient biology.