Ketosis Mimetics brief FAFO report
This is the next in a series of rescued old drafts I've been finding and finishing. Even when I initially wrote the draft I was intending to make it brief and without the kind of scientific deep dive I normally do. Coming back to it I was tempted to flesh out all the details on these interventions, but in the end I decided to leave it as more of a "notes" post. I'll probably come back in depth on some, but not all of these.
As promised in my retatrutide post, I wanted to give a brief summary on some substances I have delved into in the past. Rather than do my typical behaviour of publishing nothing unless it's comprehensive, I'm just going to put these here for posterity, and maybe I'll flesh some of them out later.
Contents
Exogenous Ketones
IV NAD+
Nicotine
DNP (2,4-dinitrophenol)
Bremelanotide (PT-141)
Retatrutide
CoSci Presentation
Exogenous Ketones
KM marker/mechanism: ketosis (but how depends on which type)
There are many formulations with advantages and disadvantages based on how the substance gets converted to ketone bodies. I would count medium chain triglycerides as the lowest tech / earliest example of this, whereas the newest innovation is the bioidentical offered by American Ketone and Kenetik.
Proposed uses:
- extra fuel in endurance exercise
- prevent "flu" during keto-adaptation
- neuroprotection / cognitive rescue in conditions ranging from TBI to neurodegeneration to mood disorders
- helping to heal tissue in "autoimmune" (don't get me started) or connective tissue disorders
- Ease fasting by providing brain energy
Biggest controversies / criticisms
"Cannot help with weight loss because you're adding calories!"
Not really how weight loss works. Insofar as exogenous ketones can lower blood sugar, they can probably tilt metabolism in a way that's favourable for that if used in conjunction with a ketogenic diet or fasting.
My experience in a nutshell
Have tried many of these over the years with curiosity about mood/cognitive effects, as a fasting aid, as potential improved fat loss. No significant benefits noticed, except increased energy while fasting and increased mental sharpness, but both frustratingly inconsistently.
My bottom line opinion without explaining (against all instincts!)
Very useful in getting ketone bodies into the system quickly. This is especially relevant for brain issues probably including insomnia. I have had some form of this in the cabinet at all times for decades in case of TBI.
IV NAD+
KM marker/mechanism: Increased NAD or NAD/NADH ratio
A longevity marker among other things, high NAD+ has even been attributed by some as the master mechanism by which KDs exert their magic on epilepsy.
Proposed uses:
- "longevity"
- addiction recovery
- cellular repair
- energy, especially in the brain
- antioxidant / anti-inflammation
Biggest controversies / criticisms
Speculative.
My experience in a nutshell
Did many IVs over the course of several months in the hopes that it might turn around my post-infectious fatigue and fat-loss resistance. Health improved somewhat over that period, but it's difficult to attribute to the NAD, especially since I never had acute improvements in energy or any other qualitative experience in the hours or days following an infusion. I've also tried several oral forms with no effect that I could discern.
My bottom line opinion without explaining (against all instincts!)
Probably overrated. My thought is that it's too far at the end of the pathways that really matter, or maybe it just doesn't get where it needs to go by that route.
Nicotine
KM marker/mechanism: Increased lipolysis via AMPK
Nicotine is, in my opinion, a wonder drug whose reputation has been smeared by the effects of smoking. In addition to aiding fat loss through enhanced body fat access, it seems to have cognitive benefits and potential therapeutic use in endometriosis. However, the evidence on these is not well established.
Proposed uses (but these are considered speculative):
- fat loss (but only if lipolysis is your bottleneck)
- cognitive rescue
- treatment of UC and endometriosis
Biggest controversies / criticisms
It is believed to be addictive, although this is counter to my experience and that of some others I know.
My experience in a nutshell
Tried low to moderate doses via patch and lozenge. I felt some cognitive stimulation, but no change in weight or ketosis levels.
My bottom line opinion without explaining (against all instincts!)
I think this might be very helpful in people with impairments in fat release, or in ruling that out.
DNP (2,4-dinitrophenol)
KM marker/mechanism: mitochondrial uncoupling
This is a significant effect of ketogenic diets that is probably part of the small "metabolic advantage" often observed.
Proposed uses:
- fat loss
- prevention of chronic disease / neurodegeneration
Biggest controversies / criticisms
Will kill you if you're careless.
Seriously, I expect a huge amount of flack for even mentioning this one, and I studied it for many months before attempting it last spring [Sentence originally written in April 2025]. I feel confident that I've read every paper and news bulletin in the English speaking world relevant to the topic going back to its discovery, not to mention countless anecdotes from intrepid bodybuilders. It deserves a series of posts--on mitochondrial uncoupling itself, the mechanisms, the failure modes, the safety issues, the interactions with carb ingestion, and much more--which I intended to do the year before I initally wrote this draft, a year and a half ago. If anyone tries this without extreme due diligent research of their own, I take no responsibility. Just don't do it.
But I will state that there plainly are safe doses, and the fatality problem appears to be from people who cannot control the desire to try to lose fat as fast as possible, or who cannot understand about giving it enough time to build up in the bloodsteam before adding more. If you're impatient or desperate or not extremely well versed in biochemistry, forget about it.
My experience in a nutshell
Took a low dose for a little over a week, by which I mean less than the most conservative doses used in papers and online fora for fat loss, but higher than the microdoses suggested for preventing chronic disease. After several days I had no apparent fat loss and crippling fatigue. This and other experiments I've tried to no avail (eg nicotine), make me believe that my symptoms are largely from the fat oxidation side: it's probably not low lipolysis, and if low dose DNP made me tired without fat loss or increased ketones (as total fasting often has) then as far as I can tell I was just somehow unable to generate enough energy from fat despite both demand and substrate.
My bottom line opinion without explaining (against all instincts!)
Don't do it. Forget I mentioned it. However the studies around it are informative around the phenomenon of mitochondrial uncoupling, and I'll probably write more on that.
Bremelanotide (PT-141)
A derivative of melanotan designed to selectively affect a smaller subset of receptors, bremelanotide does not have the tanning effect, but retains the libido effect and the appetite suppression.
KM marker/mechanism(?): activates melanocortin receptors (MCRs)
This is a bit confusing, because the evidence is actually against KDs activating MCRs.
It used to be presumed that ketogenic diets activated MCRs as part of the mechanism of increased energy expenditure and appetite control. Normally MCR activation would happen via Pro-opiomelanocortin (POMC) to produce α-MSH, which then activates these receptors. However, in mice, the opposite occurs--POMC is actually reduced on ketogenic diets!
With a little more examination, it appears that acute rises in ROS are what elevate POMC. This might mean that calorically restricted KDs and KDs in non-human animals don't activate POMC, but fully fed KDs in humans do. After all, ROS is the one satiety signal I know of that transcends the glucose-fatty acid context test.
As an aside, I have long hinted at my belief that broader MCR activation (the ones that result in tanning with melanotan) was the mechanism behind better sun tolerance on keto and Carnivore, rather than linoleic acid (LA) depletion. Given that people giving up LA seem to get this benefit keto or not, and since I learned that MCR activation is questionable on KDs, I'm much less sure about that. If it contributes, it must be through satiety, which, admittedly, keto usually excels at. And to wit, LA depletion ought to improve ROS signalling, so even that avenue could potentially be explained via POMC. Open question.
Proposed uses:
- improved libido in erectile dysfunction and hypoactive sexual desire disorder
- currently in trial as an adjunct to Tirzepatide for fat loss
Biggest controversies / criticisms
As per above, this may be only a ROS/satiety mimetic which would be independent of metabolic mode.
My experience in a nutshell
Tried this to see if it would affect fat loss. No discernible effect for me on that. The libido effects were underwhelming, because it seemed completely local: my groin area was more pleasantly sensitive to touch or pressure, even from clothing, but I was not more aroused in a brain/"desire" way, if you see what I mean. It didn't have a full body effect; it was superficial. Anyway, that wasn't why I was trying it. While I did have reduced libido during my sickest times, it was mainly a matter of just not having the energy to feel into it, and PT-141 did not change that.
My bottom line opinion without explaining (against all instincts!)
Maybe a red herring.
Retatrutide
I have written about this in detail previously The mechanism is glucagon recepter agonism.
Proposed uses:
- Fat loss
Biggest controversies / criticisms
- It's a triple agonist including GLP1 receptors, and may have some appetite suppression effects which have negative consequences when they are discordant with actual energy need, including potential loss of lean mass. This seems to especially happen at higher doses. People on Reddit often report taking higher doses than they probably need in order to get to the appetite suppression they assume they need, but probably usually don't.
My experience in a nutshell
In late 2024 I started becoming increasingly desperate for a solution to my fatigue and fat gains, and went back to fasting even though it hadn't worked for me before. After months of extreme intermittent dry fasting routines that left me exhausted and accounted for only very slow, minor losses; and having looked into it enough to be fully intrigued, I finally decided to try retatrutide.
It took a couple months to get up to a dose that was clearly working for me (6mg). I think it took about 5-6 months to get back to what I had previously considered my ideal weight. But my proportions weren't right. Since I had gone through the insult of menopause during my illness, I wondered whether HRT would help correct that. My HRT mishaps are another story, but in the end neither estrogen nor the GH secretagogue tesamorelin (renowned for visceral fat reduction) significantly altered my new shape, which may be partly attributable to midsection fat and/or loose skin acquired while unhealthy that doesn't want to go anywhere.
The fat loss superpower of retatrutide engaged my curiousity about its limits, and I spent some months at the end of last year sporadically eating things I hadn't dared to in decades: salads, sandwiches, porridges, cakes. Reta permitted them all. But in the end I simply didn't feel as good eating those things as when I eat just meat. So inevitably I drifted back to eating Carnivore almost all of the time, with occasional merely low carb days, because it seems like I can. Meanwhile, I dropped the dose lower and lower and took it less and less frequently. I took a few 2mg doses over the summer.
My current deal with myself is that if I cross back up above 128 lbs, I'll take another 2mg dose that week. But it hasn't come up since I made that decision in early September.
My bottom line opinion without explaining (against all instincts!)
Retatrutide definitely has ketosis mimicking effects, probably directly at the fat oxidation step via glucagon receptors, since fat oxidation has seemed to be a clear bottleneck for me and retatrutide worked. It couldn't have been merely an appetite suppression effect, since I previously ate less with worse results many times. But on the flip side, I may have drifted into getting appetite suppression at times, which I consider dangerous, and I'm glad to be essentially off it at this point.
CoSci Presentation
At CoSci this year, I presented on ketosis memetics using a framework of bottlenecks where impairment in specific functions could make the ketogenic metabolism difficult to get into. Latest word suggests it will be released this month. I'll link it here when that happens!