• 0.1%: life changing positive experience

• 39.9%: positive, but not life changing experience

• 10%: nothing happened

• 39.9%: negative, but not life changing experience

• 0.1%: life changing negative experience

According to this information, the expected value of trying LSD is close to 0.

What happens to the anecdotal reports?

The 0.1% who had their lives transformed are probably going to tell everybody about it, and probably are much more likely to continue using psychadelics or engage with the community.

The 0.1% who had their lives ruined might rant about it on the internet or disclose it to a few trusted friends, but they are going to be relatively quiet.

The 99.8% who had mundane experiences will have various things to say.

But people have a tendency to misinterpret what happens to them, and so a small proportion of the people who had mundane experiences might think that it changed their life anyway. And this fraction might even be larger than the amount of people who actually did have life changing experiences on LSD.

So, if ~80% of the people in psychadelic communities say that the drugs changed their lives for the better, that’s not good evidence of the drug having high value in the abstract, and it might be the case that most of those people didn’t even have transformative experiences.

People from psychadelic enthusiast groups are also a selected bunch. If you find normal people on prolific who tried psychadelics, you typically find they say psychadelics had a much less positive effect on their lives, and report lower levels of extraversion/agreeableness/openness

There’s also a status game going on here. You have a bunch of people who say X drug changed their life, and if you are skeptical of their report, they can always say “ok but have you tried it though”. And to some extent, you can’t really say they are wrong. And then people have a tendency to make identities out of drug use, so if you have doubts about how safe or effective psychadelics are, people whose identities are based on psychadelics are… not going to be happy about that. Regardless of their intellectual understanding of anattā and their control over their 8th chakra.

I am doing something a little sneaky here. Making up a statistical distribution and then fitting it to a bunch of observations is… not proper mathematics. What I am trying to articulate is this: the fact that people who love psychadelics say psychadelics are great means very little. They could have negative or positive value in the aggregate regardless of what people say about them; they are a selected and unreliable group.

II.

I have never tried any psychadelic. But I have had about a dozen episodes of sleep paralysis, typically accompanied by a full blown hallucination; and maybe a few dozen more mundane auditory/visual hallucinations when transitioning between sleep states.

The worst experience was waking up completely paralysed, and seeing my father try to rape and kill me. I felt quite a bit of fear, despite knowing he was a hallucination, and when he disappeared, the fear disipated quickly. About 5 minutes later, I walked up to my dad’s house to eat breakfast.

A fallacy I often see normal people make is thinking that negative, intense, or out of the ordinary experiences must have some deeper meaning or effect on people. Maybe they just don’t.

I don’t think life changing experiences are impossible at all. Environmental effects account for about 50% of variance in the distribution in the average phenotype, and if the effects of those experiences follow a power law, then it follows that there are experiences that contribute disrpoportionately to somebody’s self.

I just don’t see why we have to assume that any experience that is intense or out of the ordinary must have a transformative effect on people; or a better question: why we must assume that transformative experiences have to be intense or out of the ordinary to be legitimate.

A nice study on child abuse and psychopathology: adults can report subjectively how much abuse they thought they suffered as a child, and there can also be court records of that abuse. Occasionally, these differ: sometimes because adults lie, and sometimes because abuse is not reported to authorities.

Statistically, psychopathology tracks subjective reports of abuse, not court records.

If we look at people who were actually abused as children, not just people who hallucinated the abuse, it looks like what happened did not substantially affect their personalities. That doesn’t mean that the abuse didn’t feel bad, or that it wasn’t abuse, just that most people just move on with their lives, regardless of whatever they think, or others do.

VI.

Hallucinations and dreams don’t have inherent meanings. Humans are bundles of cells and neurons that fire off signals that give them conscious experiences; the mind is flat. The exact process by which those experiences come about is completely unseeable.

That isn’t to say they are random. I assume, for example, that if you scientifically studied people’s dreams: neurotic people would have more negative and intense dreams, sexual dreams track sexual orientation, and extraverted people are more likely to have dreams that revolve around other people. The extent of people’s visions is determined by what concepts they understand and their memories.

Meaning and causality are not the same thing. Let’s say somebody has a dream that their girlfriend chased them around with a boquet of flowers. A Freudian would invent some kind of schizophrenia about how the flowers symbolise approval, and running away from your girlfriend carrying flowers means that your mother was neglectful and that you aren’t willing to let your girlfriend replace the emotional hole she left.

Causal inference is different. Maybe you dreamt about flowers because you had been thinking about them recently, or because you went to a garden the other day. A dream about your girlfriend chasing you could mean various things: maybe the chasing was playful and it is a sign of good health; maybe you want to leave, and the chasing is linked to you feeling like you are less involved than her. Or maybe it was because you just been watching Mirai Nikki before bed. It could be due to various different causes. Hallucinations and dreams are overdetermined, and it’s difficult to tell what psychological processes contributed to their generation; even if they are non-random in an obvious sense.

III.

From what I have heard from others, psychadelics cause people to think things are more meaningful in general, regardless of how mundane or irrelevant they are; a trip to the bathroom feels like a quest to toss the ring of power in mount doom.

Going through that might be a fun experience, but it’s also coincidentally exactly the type of drug that would be most likely to trick somebody into thinking they went through something incredibly transformative that did absolutely nothing.

Likewise, there are also large differences in how capably people can act when under the influence of drugs, or when they are withdrawing from them. As a kid, I would have found it hard to believe that Stephen King wrote several of his novels while he had a severe alcohol and cocaine addiction; as an adult, I totally do.

So when an alcoholic says that they can drive better than the average person on 8 drinks, they might not even be wrong. It’s easy to brush this off as making excuses or special snowflake logic, but the fact of the matter is that everybody really is special in their own way.

But that’s a “bad story”, because people aren’t aware of how well they can tolerate drugs; kind of like how self-reports of attractiveness and intelligence are weakly correlated with the real measures. All of the people who think they can function on drugs and resist addictions take them; some of them do, and the rest become, well, junkies. So anti-drug messaging often devolves into universalist negative messages, even when they aren’t accurate.

Fiction has a tendency to moralise: to want to send a message. As such, the depiction of drug use is often selective: it depicts addicts who destroy their lives or die from overdoses, or it shows people living it up and having fun, managing to live normal and functioning lives regardless. It also has a tendency to underreport the mundane stories: accidentally buying counterfeit drugs, underdosing, or somebody getting lazy and not taking drugs after their plug pulls a no-show.

As such, it’s actually pretty difficult to depict how drug use works in fiction accurately: if 10% of opioid users are addicts, 10% just use them for fun, 50% try them and quit, and maybe 30% use them for medical purposes — a story could accurately detail what life is like for a person in each of these categories, while still failing to tell the full story.

Stories of people on drugs often underreport how often people try to mitigate side effects by changing doses or switching drugs. Maybe somebody notices that they are getting a little too happy on oxycodone, and they ask their doctor to switch them to buprenorphine, an opioid with a lower liability to addiction. They do it… and it works.

But that’s another bad story, because the message is suddenly that buprenorphine was a better treatment than oxycodone for this specific patient. Stories about specifics are hard to market.

II.

Another thing. Drugs also have this nasty habit of working. I mean, that is kind of what they do by definition: “A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect”.

When I started having trouble staying awake and focused in college, I looked at different explanations and solutions: not sleeping like a degenerate, quitting caffeine, and different supplements/lifestyle choices. None of them worked. Then I tried drugs, and suddenly I could stay awake for 16 hours a day.

II.

Story time. One time, I took 300mg of modafinil out of curiosity, and ended up getting extremely over-stimulated. A friend of mine was going through some rough stuff, and for some reason, I started to get really suspicious of him, and started accusing him of lying. He kept frame and sent me proof he wasn’t. I then did a double-take, and started to feel really embarrassed. Then I remembered.

I apologised mid-conversation and we went on with our lives.

I suspect that the ability to function interpersonally and productively on drugs is a function of being aware of A. how you feel in the moment, B. what dose/drug you are taking, and C. what main/side effects that drug has. At the time, I don’t think that I knew how large the effects of modafinil on personality were, and how they scale with dose.

Strangely enough, I think that maintaining function on drugs requires a certain level of self-denial. Let’s say I take adderall and go on a walk. I cross by somebody and our shoulders brush. And then I get an urge to punch them in the face. The rational thing to do is to think: “you are not tolerating the adderall well and that is not a good idea”. But will you? Some people will. Some people will not.

IV.

The Wolf of Wall Street is an interesting film. It was accused of glamorising drug use; the writers and some of the actors denied that, but I think it did something different. It portrayed drug use fairly realistically. I guess, it isn’t realistic for cocaine to immediately stimulate people, but that’s mostly just plot physics.

The movie is basically about a group of some capable but degenerate financebrtos who do drugs while they work and party. They also do illegal stuff to make money. And they manage to succeed anyway. Despite using drugs? Because of the drugs? My vote is that the drug use is incidental, that they probably would have done equally well without being degenerates.

The same goes for the illegal activity — it was probably helpful at first, but then they had moments where they could have stopped and gotten away with it, and retired with a decent amount of money. And they kept doing it, and they went to jail.

But that’s not really the relevant question here. The film portrays both the benefits and costs of using drugs: cocaine makes them feel great, quaaludes make them high, and they also make them do crazy and humiliating things. In terms of causality, the story itself doesn’t seem to be leaning one way or the other.

But the master variable here is the choice. These characters are smart people. They are not even addicts. They are choosing the drugs and crime lifestyle because, frankly, that is the way they wanted to live life. They are the masters of their own fate.

V.

Stories about drug addiction are boring. Girlfriend is being annoying? NEED DRUGS. Need to get to work? WHERE’S MY FIX. Bored? CALL THE PLUG. The addiction totalises everything they do in life. I guess it is a story that should be told and read a few times, but it gets old. Fast.

Drug abusers, on the other hand, are interesting. The drugs do affect what they do, but because they aren’t always on/withdrawing, they have a life and personality independent of them. What they are doing is a function of their own choice and ignorance.

The only times I’ve really felt any dread over aging or “old” were when I got rejected from graduate school (twice), and realised how old I would be until I had a real career, assuming I stayed in academia. That is, until I started taking bodybuilding seriously (8 months ago?).

The first thing I noticed was how rapidly I was making gains in strength, despite the fact I was gaining lean mass slowly; I learned later that it’s essentially impossible to make large gains in muscle past the beginner phase without steroids.

And then a thought crept into my mind: what if I died without ever getting jacked? I am 26. I maybe have 15 years left of peak-level physiology for building muscle; what if I live those through those years and just never do it, or just die before getting there?

I would watch people and think: ‘this person will die, probably in agony, and this is how they are spending their life’. Those animals can argue about whether Sydney Sweeney is a white supremacist. I am getting on gear.

So I went online and found places I could buy steroids. There was a problem: I am poor. And I have a feeling that saying “hello my mormon dad, can you lend me $400 so that I can buy steroids” is not going to go very well. There is also something undignified about asking your dad for money to buy steroids. So I decided to wait until I could actually afford it.

So I waited… and I never bought them. I don’t even want to buy them anymore. There isn’t really any one reason. Part of it is that I stopped thinking about death every 5 minutes. Part of it is that I am short and have an effeminate face; I would look ridiculous if I got extremely jacked.

It is true that I have not moved from 62kg for like 3 weeks after quitting reta… but I have faith. Worst case scenario, I buy mass gaining powder.

The gist

The frame with which steroids are spoken of is rather suspicious. Athletes looking for a zero sum, competitive edge at all costs. Superficial and vain bodybuilders. Macho men with body dysmorphia. That only people who are irrational or under pressure would bother using them.

Looking through the literature, two things seem pretty clear: that the health risks of using steroids are overblown, and that they are also highly effective at building muscle in a short amount of time. There are ways the side effects and risks can be mitigated, but they can’t be eliminated: steroids can always be misdosed or laced. And some people, physiologically, can’t tolerate them even at appropriate doses.

Post cycle therapy or hCG is basically mandatory. Not just for harm reduction, but for managing symptoms of steroid withdrawal and holding on to gains after ceasing usage. Blood work is useful, but it’s not as crucial, especially for people using safer steroids or lower doses.

The science of steroids

…is pretty unambiguous. Steroids build muscle really well. Not creatine or caffeine well. Well, as in, they work as well as weightlifting alone.

The dose-response relationship indicates that testosterone supplementation starts having large effects on gains around 300mg/week , which is around when testoserone levels rise relative to the baseline1.

It is the norm for muscle mass gains to be lost after steroids are discontinued. Prescriptively, this does not need to be the case.

When people naturally gain muscle through resistance training, if they keep exercising, they keep their gains. No increase in the production of testosterone is necessary; natural testosterone levels hardly correlate with muscle mass. The fact that extremely high testosterone levels build muscle does not imply that said levels are necessary to retain their gains.

There’s nothing magically different about muscle gained on steroids vs muscle gained naturally; the same pathways and physiology are responsible for both.

Steroid-induced gains typically peter out in academic studies and sometimes in bodybuilders because people do not do enough resistance training to maintain them; this is also the case for people who start resistance training and discontinue it.

The other reason steroids can disappear is that endogenous testosterone production naturally downregulates natural production, and said downregulation persists for some time after the testosterone clears from the blood.

The solution to downregulation is to either take a moderate dose of steroids, or do post-cycle therapy (PCT) after the steroids clear the blood. This involves using drugs like HCG, clomiphene, enclomiphene, and aromatase inhibitors to ease the transition from a steroid cycle to natural testosterone production; hCG can also be used on cycle to maintain testicular function.

HCG and clomiphene/enclomiphene are used to achieve the same output: kick off natural testosterone production, but through different pathways — HCG mimics LH which directly stimulates the testes; clomiphenes block estrogen receptors, which stimulates the production of LH and FSH. Aromatase inhibitors are typically only used when the ratio of testosterone to estrogen is too low.

V.

All steroids fundamentally work the same way. They activate the androgen receptor.

Beyond DHT, testosterone, and nandrolone, synthetic steroids have been developed, with the goal of desirable effects of steroids, while eliminating the undesirable ones. Typically, people run them with a testosterone base because they also downregulate the production of testosterone.

Sometimes, these synthetics have their own idiosyncratic effects. This is particularly notable when it comes to effects on lipids — winstrol infamously decreases HDL by a large amount, contributing to atherosclerosis.

That said, most of the differences in effects between synthetic anabolic steroids can be reduced to 5 components:

1. Ratio of anabolic/androgenic activity. The higher, the better.

2. Agonising other receptors, such as the progesterone and estrogen receptors.

3. Whether or not the steroid aromatises into estrogen. At high enough doses, this can lead to gyno (bitch tits) or water retention.

4. Whether the steroid is converted into DHT by 5α-reductase. DHT is highly androgenic relative to its anabolic effects.

5. 17α-alkylation — a chemical manipulation made to synthetic steroids that allows oral steroids to survive metabolism in the liver, but also makes them toxic.

Generally, bodybuilders prefer steroids that are anabolic, selective to the androgen receptor, non-aromatising, non-toxic, and do not get converted into DHT. Predictably: anavar, primo, and nandrolone are the most popular synthetics; with the nuance that anavar is toxic to the liver, primo’s anabolic/androgenic ratio is a little low, and nandrolone is harder to tolerate than the other two. Unfortunately, these are also the steroids that are most frequently counterfeited.

III.

Traditionally, when people think of the undesirable side effects of steroids, they think of aggression, androgenisation, gynecomastia, and organ toxicity (liver, heart, and lipids). All of these effects can be actively mitigated or avoided by supplementing with certain drugs (e.g. hCG), avoiding the bad steroids (e.g. trenbolone) which actually do make people aggressive and hairy, moderating dosages, and cycling off.

Empirically, testosterone supplementation has mild side effects at normal doses (200-600mg) — a nice review on this. The side effects that were more common in people on testosterone were changes in lipids, decreased testicular size, and nipple sensitivity. Nothing too extravagant.

There’s another review on the side effects of taking oxandrolone (anavar), an oral steroid. Most at daily doses of 10-20mg, with one study going as high as 80mg, taken for 8 weeks to 5 years. Again, fairly mild, with the exception of liver toxicity.

The elevated presence of musculoskeletal complaints in the placebo and treatment groups is due to the fact that anavar is sometimes used as a medication to treat burn victims, people with HIV, or spinal injuries.

The idea that testosterone and most steroids (besides the really strong ones) cause aggression is a myth. (Edit: conveniently, Cremieux just posted a literature review on the question)

Some anabolic steroids aromatise into estrogen, which causes gynecomastia, the growth of breasts in men. This can be avoided by taking aromatase inhibitors or avoiding steroids that aromatise. Because of individual differences in baseline estradiol levels and responses to steroids, it is typically recommended to do a hormonal blood work while doing an intense or complicated cycle of anabolics.

The androgenous effects of steroids are easy to target individually. Finasteride and other medications can help deal with hair loss. Accutane prevents acne. When it comes to androgenisation, holistically, the only two solutions are taking lower doses or steroids with lower levels of androgenic activity.

The question of toxicity is a little opaque — part of the reason steroids are unhealthy is that androgenisation slowly kills people; eunuchs lived 15 years longer than regular men in historical Korea, though I have my doubts about whether that difference is entirely downstream of hormones or even physiology.

Some steroids have toxic effects on the liver. They’re fairly uninteresting. Anavar, for example, has effects on biomarkers than are indiciative of liver toxicity, but they reverse once people stop taking the drug for 4 weeks.

Synthetic steroids also have effects on lipids, which aren’t well understood. Generally, they are negative — they increase LDL and decrease HDL. This is also true for normal testosterone. The exact effect of this on cardiovascular risk is hard to quantify, but my intuition is that it is not that large. Most people with persistently poor lipids do not develop cardiovascular disease until they are older; the effect of transiently low lipids must be assumed to be even weaker.

In terms of black swans, there are some case studies of bodybuilders who died at young ages, typically of heart attacks. The doctors know which steroids are present in the blood at the time of death, but not how often they were taking them, or even which ones. So it’s difficult to make judgements about the extent to which steroid use contributed to said deaths.

PED advocates have accurately argued that no drug is really safe, that steroids are not an exception to that rule, and that anabolic steroids are relatively benign compared to alcohol and tobacco. Many normal drugs have their own black swans: there is a one in a million chance that certain antibiotics can cause Steven Johnson syndrome — where part of your skin peels off and dies.

Humans have a long history of accepting enhancements that come with risks: adderall, laser surgery, orthodontics, and vaccines. Many of these things are controversial, but they don’t arouse the same passion that steroids do. As such, the stigma around steroids has little to do with something as abstract2 as health, or with human enhancement more broadly.

Personally, I think that trenbolone (anabolic steroid) is more dangerous than alcohol. I can’t prove it, since trenbolone’s scientific evidence is limited to… rats and cows. Most anabolic steroids, besides testosterone, anavar, and nandrolone have surprisingly little empirical evidence in favour of their efficacy. To believe in steroids, is to believe in stories, myths, and legends. You might not believe in those things. But the WADA definitely does. Good luck getting into the olympics on tren.

…So can steroid use be rational?

No. You can’t write down the positives and negatives of taking steroids onto a spreadsheet and make a mathematical decision. People have to make decisions on their feelings and intuitions. Sometimes, those feelings don’t work and people make bad decisions. But that’s not a reason to not make decisions based on feelings. There is no other alternative.

My own verdict on steroids is that the black swan type side effect are massively overrated, and basically nonexistent in people who use them responsibly. The negative effects of using them chronically — androgenisation and the gradual attrition of one’s health — are probably underrated, and should be studied more deeply.

The one thing I will say is that our culture underrates trying, doing something to see what will happen. When it comes to anything — careers, hobbies, foods, or lifestyles. People systematically overestimate the permanence of choices, and underestimate their ability to adapt.

The transformative element of life is always overrated. A body count of 20 does not irrepairably damage a woman. Addicts relapse. Lost weight finds a way to come back. The best predictor of future behaviour is previous behaviour.

Promises of eternal damnation or enlightenment can never be fulfilled. You can find that depressing, or you can take advantage of the fact that nothing is permanent. Cynicism never runs both ways.

1

Receipt:

II.

Marathon runners, who do prolonged but low intensity exercise, do not gain much muscle size or strength from running Neither do farmers, who work hard for long hours, but do not regularly deal with heavy loads. Resistance training is effective at inducing gains in size and strength in comparison to other activities because of the larger loads.

Progressive overloading — incrementally increasing the difficulty of workouts over time — is also essential in the development of hypertrophy and strength. It’s also broadly true for other domains of life: growth is driven by a pressure to improve.

These statements are uncontroversial. Where bodybuilders disagree is whether higher volumes (sets + reps) of lifts or higher intensities are more effective at increasing strength or inducing hypertrophy.

Intensity, in bodybuilding, is poorly defined: some people think of it in terms of subjective experience, some use it as a synonym for load size, and others think of it mathematically. I define it as how close a person gets to momentary failure, how far they took their body to its physical limits.

Scientists speak of this debate as if it were happening in a vaccum. Intensity (proximity to momentary failure), volume (sets + reps), and load (total weight lifted) are dependent — they cannot be evaluated in isolation. Somebody who adds more reps to the same 40lb dumbell curl exercise is getting closer to momentary failure. It’s also harder to sustain the same amount of reps after multiple sets, and increasing sets also increases proximity to failure. It’s the year/cohort/age problem of physique science.

People have tried to solve this by asking people to lift with one rep in reserve, that is, the person lifts until they think they are 95% done. The problem here is that I think, broadly speaking, people’s bodies are capable of more than they think, and can kick in to a different gear when they are under enough pressure or motivation. So the people who try to lift until 1 rep in reserve could reasonably be lifting anywhere between 0-5 reps in reserve, which introduces measurement error, which causes regression to the mean, which causes false positives.

So not only is the debate conceptually confusing; the empirical evidence that would be necessary to solve it basically can’t exist.

III.

Speaking practically, lifters are a heterogeneous group: 6 year olds exercising with their parents, 80 year old women, unemployed 19 year olds, and 23 year olds on trenbolone. These people do not have the same bodies, motivations, and incentives.

Personally, I have genetically gifted muscles, but hypermobile joints and bizarrely small wrists: 5.9 inches, about the size of the average woman’s. My muscles can go much father than the rest of my body, when it comes to doing most exercises.

If I try to train to failure in any exercise that involves substantial wrist strain, I am setting myself up for failure. If a muscle can’t perform an exercise, it might tear or strain, but they recover quickly because they are vascularised; that is not the case for bones and joints. It doesn’t matter if it is the “right” way to do things. My heart also recovers rapidly from intense exercise, so it doesn’t make sense for me to have long intervals between sets, even if they maximize gains for the average person.

A 39 year old CEO with 5 children might get more gains by spending an additional 15 minutes at the gym, but his time might not be best spent doing that. Maybe he would prefer to spend more time with his children, or work harder on his business.

VI.

And that’s not the end of it. Mentzer also accurately captured a different problem: that there are three types of muscle movements: concentric (the muscle contracts), isometric (the muscle does not move), and eccentric (the muscle expands). For example, in dumbell curls, the upwards movement is concentric, the stagnant motion is isometric, and the downwards motion is eccentric.

In the dumbell curl, it is more difficult to raise the weight than to keep it still, and more difficult to keep it still than to lower it because of the way gravity works. Bodybuilders failing at raising the weight likely could continue to keep it still, or at least lower it. A momentary failure to complete an exercise does not imply a maximisation of intensity.

To ameliorate for this issue, he typically had his clients do regular exercises until they tired, and then he assisted the concentric movements of their last few reps, so that they could exhaust their eccentric and isometric capacities.

So how do you actually train then?

My intuition is that an optimal workout would combine three different types of exercises: low load + high rep sets and high load + low rep sets.

Weightlifting with a low load initially recruits type 1 muscle fibers, which are weaker, but more energetically efficient. Over time, those fibers get exhausted, and the type 2 fibers get recruited. Higher loads instantly recruit the type 2 fibers due to strength demands. Combining these two maximises the amount of fibers that are subject to hypertrophic stimuli.

It’s probably best to wait until a muscle recovers to train it; this is because it is still undergoing hypertrophic stimulation, and the amount of work it can generate in a given session will be lower if it is not fully recovered. How quickly recovery happens depends on the intensity of the training and individual; the heuristic seems to be 1-2 days for smaller muscles like calves/forearms/abs/, 2-3 days for triceps/biceps/delts, and 2-4 days for pecs/biceps/thighs/back.

What do I actually do?

Strict every-other-day (EOD), maybe 2 upper body days for every full-body day. High loads and average volume.

I like EOD because it stabilises unhelpfully high or low motivation, preventing both overtraining and laziness. At first, my joints found it hard to keep up with that much volume, but with time, I adapted and am basically fully rested whenever I walk into the gym.

Further reading

Performative Bafflement

Recovery after workouts

Recovery is the single most important + neglected area of training I see out there among otherwise disciplined athletes…

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2 years ago · 1 like · 3 comments · Performative Bafflement

Performative Bafflement

Dan Lieberman's Exercised review

This is the big one - 2700 pages in my e-reader, and I had more than a hundred bookmarks…

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2 years ago · 8 likes · 18 comments · Performative Bafflement

Performative Bafflement

A comprehensive guide to hypertrophy

Renaissance Periodization's Scientific Principles of Hypertrophy is a pinnacle achievement, one of those magnum opuses that stands apart in depth, rigor, and breadth, unchallenged on a mountain peak of sweet gains, surrounded by tiny yappy foothills of influencers and youtube stars and also-rans with their own slapdash, misinformed, and scarcely researc…

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2 years ago · 10 likes · Performative Bafflement

My mom was kind of right though. I had an eating disorder. Just… a different one: I was eating too much and unable to stop myself from doing so. I wasn’t even technically overweight, but I was heavier than I would like to be for the sake of aesthetics, health, and pain management. Like, semantically, it’s disordered, and it has to do with eating. So it’s an eating disorder.

The cure to obesity is just… dieting. Mass in = mass out. Exercise can help, but it’s less effective because the body downregulates energy consumption to compensate, and it’s harder to adhere to consistently, especially if you are just doing it to lose weight.

The catch is that dieting sucks, and I’m tired of pretending otherwise. Personally I’ve found that it’s easiest to eat less when you buy foods that are filling (high protein/fiber) and less palatable/tasty. Eating those foods every day is boring.

I guess I could make a list of ~1000 different foods, categorise them by taste/nutrients/cost/obesenogenics/health, and then write an excel function that gives me the optimal diet that is not too obesinogenic, tasteless, or expensive.

But I don’t want to do that. I don’t want to turn my life into a spreadsheet that commands me to buy a list of foods and eat them at specific times so that I can stay at a healthy weight without having to eat potatoes and salad every day. I just want to go to the supermarket and buy stuff I actually want to eat. That’s the dream, and GLPs are the ultimate cheat code.

II.

So I bought some retatrutide and injected 0.5mg — like 10x less than the average person takes. And I got super nauseous for the entire day, and most of the week; I took it after eating which apparently is a bad idea. So I took 0.25mg on an empty stomach and I still felt nauseous throughout the week.

Eventually, after microdosing for a few weeks, my body adapted to the drug. And I was like “ok, I guess it’s time to start titrating up, most people are fine on doses much higher than what you are taking”. I scaled up to 3mg and I started tweaking, deadass. My heart had trouble handling workouts and I regularly felt nauseous.

The catch? The stuff really worked. I lost weight. The pain went away.

Life is just better on GLPs.

There is no cost to being thin. When I buy food, I don’t need to think about whether I am going to eat it compulsively and gain weight. Any time I am hungry, I can eat with zero worries about becoming overweight again. All of the background noise, habits, and thoughts that accumulated in my brain for the purposes of being lean were no longer useful, and went away. Before taking retatrutide, I had to tolerate the discomfort of being a little hungry to lose weight. Now, I don’t. Genuinely life changing.

Once I had dropped down to 62kg, I recorded myself doing knuckle pushups, and looked at the video. First thought that came to my mind: are those my ribs???

I thought it over, and realised: ok, maybe it might be time to stop taking retatrutide.

Most people report that, after they stop using GLP drugs, that their hunger comes back and they naturally regain weight. So I decided to titrate down to 0.25mg, and eventually even started taking 0.125mg.

A few days or weeks later, I am in the bathroom, I look into the mirror, and I am staring back at a balenciaga model. A fraction of a second later, I realise that was me. I didn’t look bad, or even good for that matter. Just different, I guess.

So, eventually, I decide to quit retatrutide and start bulking at 62kg. 3 weeks later, and it looks like… I still weigh 62kg.

You can’t be serious man.

IV.

On the side effects3: the entire internet and my family told me that GLPs were dangerous, that I would become a skeleton, that my muscles would disappear, that my pain would get worse, that my bones would fall apart, that my gut would get destroyed, and that my grey market reta would be either counterfeit or laced with fent.

Did any of that happen? No.

My experience with using any drug or medication is basically the same: people always massively inflate the risks, particularly of addiction or mortality; nothing ever happens, as they. But the frequency and severity of undesirable, transient side effects is somehow underestimated; like if you look at scientific publications or trials on any drug, the most common outcome is that they report most people don’t have any side effects at all, and the ones they have are benign. But then, when I actually take a drug, I almost always have 2-4 different side effects and sometimes even a severe one.

Both me and my dad are unusually sensitive to drugs, but I have a feeling that statistics tend to underestimate the frequency of side effects, either because the participants don’t notice them or because the researchers don’t bother looking. Specifically, for GLP drugs, I don’t think the trials are checking for psychological and hedonic side effects, and it seems like most people who take them report feeling flatter or more controlled in terms of personality.

Hot take: almost all of the side effects of GLP drugs can be chalked up to what they do to the gastrointestinal system, and what weight loss does to people.

People have complained that GLPs cause muscle loss, bone loss, and “ozempic face” — a gaunt face with less fat on it. Well, that’s what happens when people eat less calories than they use. Your body loses mass everywhere. Predictably, GLP drugs and natural weight loss results in the same ratio of muscle/weight loss.

GLP drugs make people feel nauseous and can cause vomiting or diarrhea, but that’s because they shift a person’s satiety towards fullness. If people feel too full, nausea kicks in as a downregulation mechanism, and their gastrointestinal system becomes stressed. In that regard, the main and side effects of GLP drugs can’t be separated.

One exception to this rule is lower impulsivity. I haven’t noticed this much, though I didn’t have a lot of issues with that to begin with. Others report that their compulsive gambling, drinking, and shopping dropped as much as their compulsive eating did.

I’m not so certain this is a purely benign and positive effect. There is purpose to the part of our brain that is hedonistic and compulsive. The cycle of life: boredom →wanting→striving→achieving→satisfaction→boredom — that is the human experience, and I embrace it. What I like the most about retatrutide is that I can eat palatable foods without having to weigh in concerns about weight gain. Everybody else seems to be glad that these drugs make you want to eat palatable food less.

Personally, in terms of side effects, the most notable and severe one was nausea. When I was taking 2-3mg, my affect was slightly blunted and I felt less compelled to do things. I also can’t tolerate 2mg of nicotine gum anymore, and I actually vomited once when I chewed it for like 2 minutes or something. My gag reflex has permanently gotten more sensitive.

While I was on modafinil + reta, I would feel nauseous and odd after I went for a hard rep in the gym; after quitting and switching to amph, that doesn’t seem to happen.

V.

In terms of anecdotes: Cremieux reports that he lost weight on semaglutide, and when he stopped, he didn’t regain his hunger, and actually wants to gain weight. Scott Alexander said like a year ago that when he stopped taking tirz, his appetite came back (saw him a few months ago and he looks relatively thin, so gj).

Statistically, most people will regain weight after they stop taking GLPs, but it seems like there are a decent number of people (like me and Crem) where the effect of the drug on weight maintenance may be permanent.

VI.

I think most Americans have an eating disorder: 75% of Americans have BMIs over 25, ~2% develop anorexia at some point of their lives, and a decent proportion of Americans with normal BMIs are skinnyfats — not the pinnacle of healthy eating.

In terms of health, there are diminishing returns to reducing BMI below 26 for most people. Some people, like myself, are in weird positions where their optimal BMI is somewhere between 19-22 because they are 26 year olds with knee pain. Those are the exceptions.

The negative effects of being underweight on health are massively overstated and statistically confounded: disease makes people thinner and kills people, but being thin itself isn’t a massive factor in death, as long as you stay above 17 BMI or so.

In terms of aesthetics, the consensus seems to be that the most attractive female BMI is between 17-20; for men, the optimal body fat % is between 10-15%. About 4% of women actually fall in that BMI range, and a similarly low fraction of men have a body fat % that low:

The vast majority of Americans would aesthetically improve by using GLP drugs; even the people who are really lean would still find it easier to lose and maintain weight.

I’ve seen people complain about the cultural effects of the drug, that it encourages shallowness or certain beauty standards. Personally, I like being hot, and I like looking at hot people. I don’t think about it too much, and I wish other people were more like me.

The catch is that few of those people will actually end up using them. It’s superficially easy to order peptides on the internet, buy the necessary materials, and start injecting them into yourself. Not something most normal people are willing to do.

The case for GLP drugs being OTC seems pretty clean to me. It is possible to OD on them — just like people can overdose on caffeine or benadryl. They have side effects and can be dangerous… like every single drug that does something to the body. The benefits, on the other hand, are undeniable: easy weight loss as cheap as $10 a month.

III.

While I was on retatrutide, I got seriously into weightlifting. I’ve gotten really strong. In percentile terms, I’m stronger than the average guy now4, even though I am at the 7th percentile of weight for American men and my frame (besides shoulders5) is the size of the average women’s. I’ve gotten shredded, but I have yet to ascend to the status of jacked.

The idea GLP drugs make you weaker is true, in the sense that they cause people to eat in a calorie deficit, which causes them to lose lean mass, which, well, makes you weaker. But if you ignore that, I actually think the drugs make you stronger: GLP/GIPs eliminate fat deposits in your muscles and increase your insulin sensitivity which, theoretically, should make them stronger per unit of weight.

III.

Before GLPs hit the market, I had been following the obesity debate for some time. People have many explanations as to why it’s so difficult to lose weight and stay that way.

There’s the epigenetic theory, which is that being overweight rewrites genetic expression of fat tissue, even after the fat has been lost. This would explain, for example, why 80% of weight that is lost is regained after 5 years.

Another is that evolutionarily, we’ve been selected to prevent hunger more than overeating, so our bodies systemically make us feel more hungry than we need. People who feel too much hunger can lose weight through pain tolerance, but find it difficult to maintain that level of deliberate effort for years.

Trying to find the one theory that explains obesity is like trying to find a universal theory to explain hair loss or childlessness. We can, however, find a theory as to why obesity is high or rising in every country.

My theory is the problem is processed food. Specifically:

• Processing that improves the taste and palatability of food.

• Cooking.

• Low fiber and protein content.

• Softness

• + some people naturally have different appetites due to physiological differences in digestion and brain function. The heritability of BMI is 50-70%, though I don’t think that weight or even physiological set points are heritable the way people think they are, like the way intelligence or facial structure is genetic.

The evidence? The evidence doesn’t matter. ‘Just take GLPs’ is the new strategy for managing weight, at least for the large majority of people who respond to the drugs.

Let’s say we pull out the truth machine, and it can give us a final answer to why everybody is getting so fat. Regardless of what its output is: seed oils, sugar, microplastics, or an evolutionary mismatch + genetics — the answer is the same. Injecting yourself with Chinese peptides.

VII.

I have no issue with people who dislike GLPs due to concerns about safety or uncertainty, which are understandable. They are new, powerful drugs. People dooming about the observed side effects are simply uninformed, which isn’t much of an indictment either. Life is full of fallibilism. For all I know, I could be wrong too. Discussing the side effects of any drug is boring to me, because there is a very simple solution to them: just stop taking them.

I would be disappointed if it turned out to be true that these drugs suppress compulsive behaviour across the board. Some of history’s greatest geniuses were not calculating, cautious people. They were people who did what they did out of compulsion. Nietzsche and Kafka were like this. The difference between compulsion and motivation does not exist, compulsion is what we call motivation we dislike.

“Don’t take drugs because you might miss out on becoming a world class philosopher” — not exactly the best argument. What I am pointing at more generally is that impulsive behavour is often counterproductive, but that the same machinery that produces those impulses also is what makes us tick and enjoy life. GLPs help a lot with regulating appetite, but they also come at a cost in terms of physiology and hedonics.

I suspect many critics of these drugs dislike them because of moral and social anxieties they cannot or do not want to articulate. People feel like taking them is cheating, that their existence removes a criteria by which they could judge and filter people.

Taking GLPs is only cheating if the game you are playing is ‘sink as much displeasure into losing weight as possible’. Are glasses and washing machines cheating too?

And it’s not like there aren’t millions of ways character can be read other than weight; are we really so stupid that we need people to be fat to discriminate? It’s not like it was ever good as a signal of anything — it hardly correlates with intelligence or social class; barely with personality, believe it or not. The signal in the noise is a little stronger in women, but muted:

Not a fan of the term “zero sum mindset”, but it applies to many critics of GLP drugs.

Conclusion

I took GLPs and I turned into a shredded balenciaga model. I felt nauseous, even when I took low doses, and my affect changed substantially when I took just 3mg. I didn’t even enjoy taking them. Was it worth it? Absolutely, probably the best purchase I have ever made. I really do care that much about looking good, and managing appetite and pain in the pre-GLP era really was that bad.

Sourcing

The cheapest place to buy GLP drugs is peptaura, which connects Western buyers to Chinese suppliers, cutting the costs of them by an order of magnitude. Their current prices:

• Retatrutide: as low as $0.54/mg — $4-20 per month.

• Tirzepatide: as low as $0.33/mg — $4-20 per month.

• Semaglutide: as low as $0.48/mg — $0.5-13 per month

I would recommend taking tirz; it’s highly effective and easier on the heart than reta.

BAC water can be ordered on peptaura; everything else — alcohol wipes, reconstitution syringes, peptide case, and insulin syringes — can be bought on amazon.

I’ve also from kimerachems, nuscience, and nextgen with no issues.

Personal update

My sleeping condition6 has gotten worse. Modafinil isn’t strong enough to work anymore, and it made me nauseous when I exercised. So I switched back to amph, unfortunately psychs can’t prescribe me normal adderall7 until I get a sleep study done, and who knows when that will be. Just taking 20-40mg per day orally. Not something I want to do permanently, but it’s working well for now — I can stay awake for 16 hours again.

Still unemployed. I still have 2-3 months before my dad gets tired of me and ships me back to the tax haven8, so we are fine for now. I’ve been laserfocused on a specific thing which has consumed 8-14 hours of attention per day.

3

Details:

Trizepatide and semaglutide are well-tolerated, ignoring the gastointestinal side effects. Retatrutide in particular is different, because it is also a glucagon agonist.

In retatrutide’s trials, these are the side effects that were reported more often in the treatment group than the placebos:

A lot of these seem either benign (feces hard, headache), statistically dubious (erectile dysfunction), or downstream of the gastrointestinal effects (abdominal pain, gastro reflux) — which can be ameliorated by starting with low doses.

One trend I see is that people on retatrutide seem to report more psychosomatic sensations and pain — particularly allodynia, pruritus, and sensitive skin. I think it’s possible this is caused by people not psychologically adjusting to their lighter and smaller bodies, but I wouldn’t count on it.

Another is more colds and respiratory infections. If you are predisposed to these, you might want to watch out for that; personally, I rarely get sick.

Interestingly, more people in the retatruitide groups report both hypotension and hypertension. People might respond to the drug in different ways.

Of note were reports of cardiac arrythmia in people who took high doses of retatrutide:

Some other side effects of retatrutide worth reporting:

Lower blood pressure

More favourable lipid profiles; barring a temporary drop in HDL cholesterol.

Higher heart rate

The nausea side effect can easily be dealt with by starting with a very small dose and then gradually increasing it. Even high doses of GLPs can be taken without the undesirable nausea this way:

Starting with a lower dose hardly shifts the amount of weight lost:

My personal advice is to scale the dose depending on how nauseous you feel. Start with 1mg. If you feel too nauseous, take half the dose the next week; if you feel a little nauseous, stay on the same dose; and if you feel no nausea, double the dosage. I’d recommend against taking more than 8mg of retatrutide, personally, as it can have bad cardiac effects.

After graduating from college, I started helping people write research papers, whether it was doing the data analysis, writing the drafts, or communicating with peer reviewers. I did this for three years, from 2023-2025. I stopped doing this after a change in circumstances and motivation; I no longer wanted to go to graduate school or become an academic. I would prefer to work in the private sector.

I was hired this year to write a website for some vacation homes, which was completed several weeks ago. I had no prior experience in this field. I would prefer not to post it due to concerns about privacy; I am related to the employer.

I have been blogging as a hobby ever since I was in college, and have been doing so for about 4 years. I’ve written about many topics: psychology, education, genetics, intelligence research, philosophy, and medicine.

The best work I have done is my meta-analysis of 1517 correlations between family members in phenotypes, all of which I collected by hand. I also wrote a followup post on the nature-nurtue debate: arguing that it’s essentially impossible to make an unbiased estimate of heritability, but that the bulk of evidence suggests that twin studies generally make for acceptable estimates of the true heritability of traits.

My greatest strength is the ability to do work that other people do not want to do because it is tedious or uncomfortable. I can also learn how to do things on my own.

Experience

Currently, I have a Bachelors in statistics, 3 years of experience in technical writing/data analysis, and 6 months of experience in website development.

I am most skilled at data analytics: data preprocessing, analysis, visualisation, reporting, and interpretation. I can also write and code.

Here are 6 publications where I did both the writing and data analysis:

• Predictors of Interracial Dating

• Who Believes It’s the Government’s Responsibility?

• International Cross-Temporal Meta-Analysis of Assortative Mating for Educational Attainment

• The Relationship between Intelligence and Ideological Views

• Psychometric Analysis of the Multifactor General Knowledge Test

• International meta-analysis of differential fertility for intelligence

Contact me at sebjenseb@gmail.com or on substack if you are interested.

The problem is that all of these medications kind of suck. A decent amount of people either can’t tolerate them or don’t want to take them due to concerns about side effects.

Minoxidil has low tedious and is often discontinued or not adhered to. Topically, it needs to be applied 1-2 times a day for effects to materialise and it takes a long time for its effects to become visible. Oral minoxidil is an option, but its side effects on the heart and body hair are stronger. The drug was initially approved to lower blood pressure, but people found that it increased hair growth, so it became primarily used for that purpose. Topical minox made me faint twice1, though this is not a common experience.

For what it is worth, anagen claim to have developed an extended release version of oral minoxidil that retains the hair growth side effects but not the cardiovascular ones. They’re pretty honest about the available evidence regarding its safety.

The way finasteride and dutasteride work is by inhibiting 5ar, which processes conversion of testosterone into DHT, which has a lot of downstream effects; one of them being decreasing hair loss. Some guys can tolerate it well, but it makes others moody/depressed or less sexually functional.

In some cases, it’s been observed that the side effecs of these medications are permanent — leading to the term post-finasteride syndrome. We don’t really know why it occurs. Personally, I felt off when I took oral finasteride, and I felt fine after I started using it topically.

Men with 5ar deficiency give us the opportunity to evaluate what, exactly, it is like to live life on permanent finasteride/dutasteride. The boys are often raised as girls, as their genitalia is ambiguous at birth. In Europe, these children often continue to identify as women after puberty; in China and the Dominican Republic, they almost always socially transition.

As adults, these men do not bald and have lower levels of body hair — implying that DHT is necessary for androgenetic alopecia (male-pattern baldness). A qualitative study of men with this mutation finds that they are attracted to women and have a libido, despite the lifelong absence of DHT. This leads me to believe that post-finasteride syndrome is either psychogenic, or only occurs in men with rare genetic or physiological characteristics.

The science of hair loss (skip if bored)

People have various theories and mechanistic explanations for what causes hair loss. In my opinion, they don’t matter. If a drug finds results, then it finds results.

The most common causes of hair loss include androgenetic alopecia — the classic male/female pattern baldness; alopecia areata, an autoimmune disease that causes patchy hair loss; and telogen effluvium, broad thinning of hair believed to be caused by mental and physical stressors like anxiety or pregnancy.

Causal factors underlying alopecia areata and telogen effluvium often spontaneously fade; androgenetic alopecia tends to be progressive and lifelong. As such, “hair loss treatments” and “treatments for androgenetic alopecia” have become almost synonymous.

Other acknowledged causes of general hair loss include:

• Fungal infections

• Traction and friction (e.g. from ponytails or socks)

• Pregnancy

• Obesity and high blood pressure

The causes of androgenetic alopecia are a little more controversial: it is known that DHT is a necessary factor in its progression. It’s also not sufficient for balding to occur; some men do not appear to bald at all, despite not being 5ar deficient. If you look at the comorbidities of androgenetic alopecia: smoking, drinking, having poor sleep, high blood pressure, or obesity — the case for it being entirely DHT/gene driven looks very weak.

Androgenetic alopecia is highly heritable, but I always thought that was a weak argument in favour of the immutability of hair loss (without drug intervention, that is), or whether androgens are the “root cause” of the condition. Eyesight quality, athletic ability, and obesity are also moderately to highly heritable — but mutable2.

Hair treatments are mechanistically divided into ones that promote the growth of new hair, and others that prevent the loss of current hair. In practice, empirically distinguishing between these effects is rather difficult; the consensus seems to be that finasteride/dutasteride is better at retaining hair, while minoxidil is better at growing it.

Hair loss comes in progressive stages: first the hair the follicle produces becomes smaller, then it stops growing hair, and then the follicle dies or connective tissue grows over it. Thinning is highly reversible, nulled growth is somewhat reversible, and dead follicles generally don’t grow back. The research on this is iffy, as there are individual differences in the ability to regrow hair; the heuristic is that hair loss is irreversible after 5 years of local baldness.

The nice thing about hair loss literature is that it is uses standardised, legible outcomes that can be easily replicated from study to study. There is no self-reported hair loss scale, researchers just measure the density of hair and where they fit on the norwood scale. Sussing out what works and what does not is easy.

The holy grail: topical fin/dut

Finasteride and dutasteride are typically taken orally, but they can also be applied topically. Topical 5ar inhibitors are even more effective than oral ones, because their effect is localised to the scalp. Particularly, when it comes to improving hair counts:

For the highest dose of topical dutasteride (0.05%), the effect size on hair count is 0.8 SD after six months; for hair width, it was 1.2 SD. The 0.01% and 0.02% solutions are about half as effective for growing hair, and a little less effective for increasing its width3.

The devil in topical 5ar inhibitors comes with the dosage. Ideally, you would want to take enough dutasteride to get a positive effect, but not so much that it starts leaking into your blood and messing with your systemic hormones.

The study I cited seemed to find that, at the highest dose, topical dutasteride hardly leaked into the blood4:

They said that they could reliably measure dutasteride levels in the blood starting at concentrations of 50.125 pg/ml. Most of the time, levels were below that range. The maximum observed value in the study was 2555.2 pg/ml ; a normal dose of oral dutasteride (0.5mg/day) leads to an average stready state of 40 ng/mL — which is 20x higher than the maximum value observed in 0.05% topical dutasteride, and about 2000x higher than the mean value observed.

Topical finasteride in concentrations of 0.25% has also been studied. Even though very little of it leaked into the blood5, it did end up inhibiting DHT as much as oral finasteride when multiple doses were administered:

A followup study found that the DHT decrease in the blood from topical finasteride (0.25%) was attenuated when smaller doses of the serum were applied, but the effect on the scalp was basically the same6:

Some guys combined these studies and a few others into a convenient chart:

Because dutasteride inhibits DHT more than finasteride, I’d consider it better for topical use, but worse for oral use. It also has a much longer half life than finasteride, so it takes longer for the effects of the medication to wear off after discontinuation.

Overall, based on that information, it looks like the optimal topical dose per day is about ~0.5mg of finasteride/dutasteride; for a 0.25% drug concentration, that would be 0.2 mL per day; for a 0.05% concentration, that would be 1 mL per day. I typically spray ~0.5mL of liquid on hair per day, so I adjusted the dutasteride dose to 0.1% of the liquid.

Sourcing

Anagen claim to have perfected the science of topical 5ar with their precision dutasteride formula. Personally I wouldn’t recommend the 0.3%7 dose since it’s too high and would probably affect serum DHT. 0.03% should be safe and effective.

There is also the DIY degen route, which I took of course. I bought two bottles of more.hair MH1, which has 10% DMI, which should be enough to dissolve a small amount of either finasteride or dutasteride. I’ve bought 1g of research grade dutasteride and plan to dissolve a small fraction of it it in one of the bottles to see what happens.

The MH1 formula is nice in its own right. The bottles are aesthetic and the spray feels 100x better than dripping minoxidil on your hair and rubbing it in. I also wrote in a nonsense address the first time I ordered, so the post office couldn’t deliver; the customer service people were nice enough to re-ship.

I’m not sponsored by any of the companies I mentioned, and I have a feeling that the owners of both companies would disagree with a lot of what I said in this post.

Alternative treatments (e.g. caffeine, adenosine…)

Caffeine

There is one study of the effect of caffeine shampoo (alpecin) which finds positive effects on hair growth comparable to minoxidil. Visually, the differences look statistically significant across time8, but they didn’t explicitly test for it, which is disappointing. They claimed that the differences in subjective measurements of hair loss were statistically significant, however.

One of the authors on the paper is Adolf Klenk, who is an employee of Kurt Wolff, who designed the alpecin formula. Generally I find these kinds of social/financial tie arguments tedious, but it is something worth weighing into the equation. Unfortunately, this is the only empirical study on caffeine I found.

There’s some mechanistic logic by which caffeine could cause faster hair growth, which makes some sense to me, though I am not liable to trust this kind of reasoning.9 Caffeine also seems to work in vitro; a finding that replicates.

Adenosine

There’s a meta-analysis on it that finds no effect, though the authors chalked that up to low power and bad sample sizes. I didn’t read it, and I was inclined to trust it. Their confidence intervals are wide enough to accomodate for a realistic, small effect.

Fortunately, there’s a high quality study that looks at both the mechanistic pathways by which topical adenosine could improve hair growth. They claim that some of the ways it could work are shared by minoidil, but a few are not: interaction with the androgen receptors and a few pathways: Hippo and Wnt, which supposedly control cell growth and renewal.

Given that it interacts with both androgenic and growth pathways, it could potentially both prevent hair loss and promote hair growth.

Like proper scientists, they tested their hypothesis. Adenosine helped grow hair, by a margin far beyond statistical significance.

The effect size for hair density was about 0.45 SD in 4 months (compared to 0.4 for minoxidil). In terms of hair thickness, the effect size for adenosine was 0.63 SD compared to 0.3 for minoxidil.

I’m a little hesitant to jump on the 'adenosine works’ bandwagon after just one study, but it’s a pretty good one, and the p-values in it are pretty low. There’s an in vitro study on adenosine does find positive effects on hair growth, but I’m not sure how well the in vitro →in vivo effects translate in this particular domain.

Microneedling

I honestly have no idea if it works. My intuition is that microneedling alone probably doesn’t, but combining needling + ingredients enhances the effects of them.

The original study on dermarolling and hair growth had a terrible p-value (0.04) and the meta-analysis finds no statistically significant effect when only microneedling is done, and extremely large heterogeneity between studies.

Normally, this is enough evidence for me to toss the towel and give up. But then, the authors found out that if you pool all of the studies together, the effect of microneedling looks statistically unambiguous, even when compared to topical minoxidil alone.

Part of this, honestly, might just come from minoxidil sucking — it doesn’t work that well, and it promotes shedding at first.

Summary

Topical finasteride/dutasteride are the holy grail in terms of safety and efficacy, but the evidence for their efficacy isn’t as solid as it is for oral delivery. Adenosine probably works.

In terms of effect size, topical fin/dut > oral fin/dut > adenosine > minoxidil.

No opinion on whether 5ar inhibitors can work on women. I’ve heard different opinions, both positive and negative in terms of safety and efficacy.

I have no idea if microneedling or other alternative treatments (e.g. caffeine, peptides) work. Because the evidence for these compounds is often ambiguous or of low quality, people have overcorrected into thinking they are useless, which is a little hasty.

From a personal standpoint:

There’s basically two groups of people looking into hair loss research. One of them is older guys who have already lost a decent amount of hair. The other is young guys who want to tackle the problem before they get too bald.

I don’t like giving advice, especially not advice that I cannot take myself. But if you are past a norwood 3, I would recommend looking into a hair transplant. My dad got one a few months ago, and it seems to be going well. From what I can see, he went up 2 stages on the norwood scale to a NW2. He got it in Spain, his country of residence.

If you are sub norwood 3, don’t bother with a hair transplant. Topical finasteride/dutasteride should be enough to prevent further hair loss, and minoxidil/adenosine/caffeine can help regrow hair that was previously lost.

Right now, my hair seems to be following the classic jewish pattern of recession around the temples (aka the vegeta or dracula hairline); my dad also lost hair this way. Fortunately, this means I only have to apply hair serum to basically two spots on my head if I want to keep it.

Further reading:

• Are finasteride and dutasteride irreversible?

• Derek (More plates more dates) on the genetics of hair loss and prevention.

• The Ultimate Hair Loss Flowchart

• Scalp tension theory

• Post finasteride syndrome: the case for it being psychosomatic

• Post finasteride syndrome: possible biological pathways

• OTC minoxidil far less tolerated than pharmaceutical minoxidl.

Other treatments that I heard about, but didn’t research:

• PP405 (massive hype)

• RU58841 (hype)

• Bimatoprost (FDA approved)

• GT20029

• TB500

• GHK-cu

• BPC-157

• Keratin

• HGH / GH secretogues

• Ketoconazole (didn’t notice anything, personally).

• Vitamin C (didn’t notice anything, personally).

• Castor/rosemary oil.

• Melatonin

• Levocetrizine

• Fecal transplants

• Laser therapy

• Rezpegaldesleukin (for alopecia areata)

Anagen also have a tier list for hair loss treatments in terms of how solid the evidence is for their efficacy.

3

Receipt:

4

They also measured T/DHT levels, not a lot of changes

5

Receipts:

6

p-values for the ratio of scalp/serum DHT

9

Tweet:

But I did.

III.

Semax is a first line treatment for stroke in Russia. It’s also been used to attempt to prevent cognitive decline in mice, treat optic nerve disorders, and gastric ulcers (?). There is some evidence of nootropic effects in animals and mice, and some evidence of weak anesthetic effects, but only when taken through an injection.

Mechanistically, it’s a peptide which mimics part of adrenocortocotropic hormone, without its activity as a steroid and cortisol releasant. The research is dominated by two clinical groups: Gusev/Skvortsova and Ashmarin/Myasoedov/Dergunova/Dolotov.

The most commonly reported side effects are a headache, nasal irritation/metallic taste if snorted. Given it upregulates BDNF activity, it’s possible that it could contribute to seizures. Otherwise, it’s a well-tolerated substance. Drug interactions are unknown.

Mechanistic and animal evidence (skip if bored)

A peptide that is believed to have neuroprotective, neurorestorative, anti-depressant, and axiolytic effects. Nobody really knows how it exactly works; the dominant theory is that it raises Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF) expression, and changes neurotransmitter activity.

There are theories on what BDNF exactly does; an easy way to judge it is to see what happens to the body when the BDNF, or its receptors, start to malfunction.

In the case of the NGF gene, there is a mutation which leads to Hereditary Sensory and Autonomic Neuropathy type V (HSAN5), a type of congenital insensitivity to pain. The gene produces a protein called NGFβ which prevents neurons from dying and allows them to differentiate; a mutation causes it not to bind to its receptor properly, causing pain neurons to die. No intellectual disability is observed.

Then we have the NTRK1 gene, which codes a receptor for NGF. The same congenital insensitivity to pain is observed, but with varying levels of intellectual disability, depending on the specific mutation.

Mice who have their BDNF gene knocked out have less norepinephrine and dopamine in their brains, though the difference depends on the specific area; it’s often a lethal mutation. In humans, there is a disorder called WAGR syndrome which is associated with a deletion of part of the 11th chromosome, where the BDNF gene happens to sit. People with the mutation have intellectual disability, less sensitivity to pain, high appetite, the absence of an iris, and kidney tumours.

The GWAS evidence paints a similar picture.

Variants of the BDNF gene are associated with: altered body mass, smoking rates, blood lipid measurements, blood pressure, educational attainment, bone density, chronotype, and mathematical ability.

For NGF, it’s: blood pressure, migraine disorders, endometriosis, angina, height, memory performance, pain, schizophrenia, red/white blood cell counts, Alzheimer’s disease, and osteoarthritis.

These are just associations, of course; it doesn’t necessarily imply causality, and it doesn’t even take into account up or down regulation. A few internet searches told me the current theory about down/upregulation of these genes is associated with:

Upregulation of NGF: migraines, endometriosis, pain, osteoarthritis

Downregulation of NGF: schizophrenia, alzheimer’s

Upregulation of BDNF: hypertension, denser bones

Downregulation of BDNF: obesity

From what I can see, upregulation NGF probably increases IQ, but it also makes people feel more pain; upregulating BDNF increases blood pressure, but strengthens your bones and protects against obesity. Double edged swords.

Independent of BDNF, semax interacts with pain in other ways — it’s an enkephalinase inhibitor, though it’s unclear exactly which enzymes it inhibits. It might be the case that, because semax is degraded by enkephalinases, it competes with its metabolites (like opioids) and causes them to be upregulated.

In fact, the study that found semax did this also noted that it had the strongest effect, out of the other seven enkephalinase inhibitors (leupeptin, puromycin, D-PAM, N-CMPL, Selank, Semax and bacitracin) they tested. I’d argue it’s rather concerning Semax, at a high enough concentration, almost completely inhbiits those enzymes in the body.

That puts semax in a weird place where it likely upregulates the expression and survival of neurons that cause pain, but also increases the amount of enkephalin peptides in the body, which make it respond differently to pain.

This effect is hypothesised to cause anti-depressant, anti-anxiety, and pain-relieving effects — particularly for chronic pain. They’re considered safer and less addictive than traditional painkillers; particularly, they do not cause respiratory depression.

Let me use Racecadotril as an example, which is used as an anti-diarrhea medication. There is no documented case of an overdose or pathological drug interactions. The most common side effects are headaches and rashes; fairly benign. Painkilling effects haven’t been reported, probably because the drug doesn’t cross the blood brain barrier.

In terms of empirical evidence, most of the enkephalinase inhibitor literature is in animals; there’s a few human studies1.

Instead of doing the dirty work and going through the animal and human literature… I could also cheat. And look at the genes.

Well, we’ve got a problem. Neprilysin, an enkephalinase inhibitor, is actually very useful: it breaks down amyloid beta peptides which are implicated in Alzheimer’s disease. Mice with a knockout MME gene that prevents them from synthesising neprilysin show signs of early onset Alzheimer’s. So even if semax might protect against cognitive decline due to BDNF and NGF upregulation, it might also contribute to the buildup of AB plaques.

In terms of GWAS evidence, it appears that missense mutations to the MME gene are associated with cluster headaches, probably one of the worst disorders on the planet — they’re also called suicide headaches. They also found links between this gene and Alzheimer’s disease, testosterone levels, blood pressure, and yes — pain. Specifically, back pain and neuropathic ocular pain.

I looked through the other genes that code for enkephalinase inhibitors, and I tallied whether they were associated with any medical conditions associated with pain:

• ANPEP: no.

• DPP3: osteoarthritis

• CPA6: no.

• LNPEP: no.

• ACE: no

Well, that’s kind of anti-climactic. I still feel a lot less pain on them, so I think I’ll keep using them.

Semax also interacts with serotonin and dopamine. When rats take semax, more 5-HIAA, a metabolite of serotonin, is observed in the striatum of rats who took semax; but not more DOPAC, a metabolite of dopamine.

Although semax didn’t change concentrations of DOPAC, a metabolite of dopamine, it did magnify the dopaminergic effect of d-amphetamine.

Human evidence

There’s a Russian meta-analysis on how effective it is for the treatment of strokes. It’s pretty good, so I didn’t have to do the hard work of doing everything properly myself. I read it to the best of my abilities using google translate. From what I can gather, all five authors (Shmonin, Verbickaya, Soloveva, Malceva, Melnikova) work in St. Petersburg — either at a local medical university, or Saint-Petersburg City Hospital №26. They don’t seem to be part of any of the main research groups.

They found 8 studies and excluded 5 based on a point system involving 17 questions2.

This here is a plot of the effect of Semax on the NIHSS, a stroke severity scale (0-42), on the 10-14th days of treatment. In people with moderate (1.1.2) and severe (1.1.3) strokes, Semax (Семакс) works better than the placebo (плацебо). The fact that they observed anything resembling an effect for minor strokes (1.1.1) is… impressive.

The effect sizes here are actually compressed because of restriction of range — by separating people into different groups, the effect sizes are artificially attenuated. The standard deviation of the NIHSS is about 7, meaning that Semax delivers a roughly d = .28 benefit on stroke protection. That’s pretty good.

The high heterogeneity — variation in effect sizes between studies — is traditionally a red flag, but note that we are talking about strokes here: the severity of them varies massively. The average stroke is pretty tame (7/42 on the scale), but if a group is made up purely of people with bad strokes, the standard deviation of the stroke scale will be higher. If I had to guess, the effect would be closer to 0.5 when controlling for restriction of range.

The standard errors are also very low in comparison to what you would expect from the NIHSS’ standard deviation, but I think that’s because they are using paired differences, not normal cohen’s d measures.

This meta-analysis also studied the effect of semax on other scales, like the Rivermead Mobility Index or Rankin Scale; they found the same highly impressive and super statistically significant results3.

So yeah. The meta-analysis was well-done and its results look clean to me. The only black mark I see is that the highest quality study according to the inclusion criteria — Скворцова (editor) Стаховская (first author) et al 2011 — was not included. I’m not sure why that is the case. I found said study they did not include. Weird; it was a positive result, and it looks like it serves as the official guidelines for the drug in Russia.

The study evaluated the effect of taking semax (placebo, 6mg, 12mg, and 18mg per day) for 5 days on 160 participants who had undergone moderate or severe strokes. They evaluate the effect of Semax on stroke patients using various scales: Orgogozo, Scandinavian, Barthel, and a custom scale they developed. They also evaluated several biomarkers in the heart, brain, and blood.

Patients who received semax were more likely to survive and have good recoveries, particularly if they were given high doses (12/18mg) of Semax.

This is a chart of stroke severity scores — the cells vary by patient group (severe vs moderate), dose (placebo, 6mg, ...), scale (original, Scandinavian, …), and day (6 vs 30):

All the statistics here look very clean to me. 6mg/day does not appear to be an effective treatment for strokes — 12 or 18 is required.

The following chart was hard to read for me, but it appears that patients who took Semax had biomarkers in their cerebrospinal fluid that suggested lower levels of inflammation — less IL-1β, IL-8, and C-reactive protein. They had more TGF-β, Il-10, and TNF-α — though the results here were not as decisive.

They also studied cGMP levels — it seems Semax only lowered them in patients with severe strokes, and the p-values here aren’t as convincing. Especially since the effect only appears in a split subgroup.

It also appears that patients who are given Semax have less autoantibodies:

Statistically, this study looks fine. It has a few p-values in the 0.001-0.05 range, but that is to be expected from the small sample size, and the wide range of outcome variables reported.

From the little I could uncover online, there doesn’t seem to be any suspicious financial or social links between these researchers and the developers and companies behind Semax. The first author is L.V. Stakhovskaya, a Russian neurologist — didn’t find anything interesting. The editor of the paper, Skvortsova, is a Russian politician who started her career as a stroke researcher. Her most common co-authors are mostly biologists or people interested in longevity.

[Skvortsova was] Born into a family of doctors, a physician in fifth generation,^[1] She graduated from school with a gold medal in 1977. In 1983, she graduated from training at the pediatric department of the Second Moscow Medical Institute (today called Russian National Research Medical University). In 1988, she graduated from the same department and received her PhD. From 1988 to 1997 she worked as Medical Laboratory Assistant and associate professor. In 1999, she became one of the founders of the National Association for the Fight Against Stroke. Since 2005, she was director of the Research Institute for Stroke in the Russian National Research Medical University. In July 2008, she was appointed Deputy Minister of Health and Social Development of the Russian Federation. On May 21, 2012, she was appointed to the role of Minister of Health of the Russian Federation in Dmitry Medvedev’s Cabinet. At the Seventieth World Health Assembly on May 11, 2017, she was elected 70th President of the World Health Organization,^[2] and only Ukraine protested her nomination.^[3] She has emphasized the importance of healthy lifestyles and noncommunicable diseases.

On 15 January 2020, she resigned as part of the cabinet, after President Vladimir Putin delivered the Presidential Address to the Federal Assembly, in which he proposed several amendments to the constitution.^[4] She was appointed as the Director of the Federal Medical-Biological Agency on 22 January.^{[citation needed]}

So, it looks like semax helps people who had strokes. Whether it works as a nootropic in normal, unhealthy people is a different question.

There’s one study on Semax’s effects on cognitive function in tired people. They had 16 power plant operators were administered with either semax or a placebo. They underwent a cognitive task where they memorised a set of numbers, and then were told to press the spacebar as fast as possible when one of those numbers appeared. They did that 160 (?) times.

When they were not fatigued, both groups perfomed perfectly. When they were tired after their shifts, the placebo group started to make more mistakes; the effect of fatigue was attenuated in the semax group. The effect looks pretty large (d > .5?).

It also influenced people’s EEG readings. Higher levels of alpha frequencies; lower theta and delta frequencies.

Jensen, in the g-factor, claims that the frequency of alpha waves correlates with IQ, with reported correlations ranging from 0 - 0.6; he wasn’t confident in the idea himself:

Among the simple, nonaveraged EEG waves, the frequency of the alpha wave has most often shown correlations with IQ. These range between zero and about + .60. The alpha rhythm consists of relatively intermediate brain waves, in the range of 7.5 to 12.5 Hz, that occur when the subject is in a state of relaxed wakefulness, with eyes closed. The alpha frequency in Hz is usually averaged over a number of one-second intervals selected at random from an EEG recording that can last several minutes. The studies of the correlation between the alpha frequency and IQ are consistent only in showing a positive relationship, that is, higher IQ is directly related to a higher alpha frequency. This suggests a relationship between alpha frequency and IQ. The cause of the relationship is unknown, but hypotheses, such as more sustained attention in high-IQ subjects, have been suggested. Beyond that fact, however, the literature seems too chaotic to warrant averaging the results of many studies. Their methodologies are far from standardized and the various methodologies are seldom replicated. The results of all these studies probably reflect “ method variance” as much as anything else. The unsystematic nature of this particular body of EEG research on alpha waves (and other nonaveraged brain waves) increases the risk of a statistical Type I error in drawing conclusions from a meta-analysis of all the available evidence.

I found a rat study on the nootropic effect of semax, but the p-values were whatevers. If the effect exists, then intranasal administrations require lower doses than intraperitoneal injections.

If we use the 6.2x conversion factor and a human weight of 70kg, then the ideal subQ dose of semax is somewhere between 170 and 500 mcg; without it, its 1000-3500 mcg.

Intranasal semax had no effect on pain sensitivity; injected semax appears to have a mild but real pain-relieving effect.

Another study also found that semax changes the perception of pain in animals, at two different doses — 0.05 and 0.5mg/kg in rats.

In the first chart, we see that semax partially neurtralises the effect stress has on attenuating pain, when it is taken before the stressor, in a dose-dependent fashion.

When semax is injected after the stressor, the low dose attenuates the effect of stress, but the high dose magnifies it:

Too tired to look at other studies. Maybe I should take semax… xaxaxaxaxa

Summary

Semax’s evidence base looks pretty good to me. There’s evidence it alters brain physiology in animals and humans and allows people to recover from strokes. Whether it works as a nootropic agent, however, is still up for debate.

The evidence on alleviating depression/anxiety or increasing cognitive function entirely limited to animals, with the exception of one study finding positive effects on counteracting the effects of mental fatigue. From what I gather, it seems that the only effect semax has on healthy animals is better cognition; the behavioural and emotional effects only appear in damaged ones.

Sourcing

Read more

The skeptics lost. Effective nootropics exist, particualrly in the form of stimulants and catecholaminergics. Drugs that help maintain cognitive function past reproductive years almost certainly exist, but I don’t know of one that has been proven to be highly effective.

Traditionally, the case against nootropics has rested heavily on the Algernon’s argument: that nature has already picked most of the low-hanging fruit, so traits like intelligence are already heavily evolutionarily optimised.

Whether the argument is true or false does not really matter. Using this logic to refute the existence of effective nootropics is nonsense. It’s the same idea that makes people think that businesses don’t work because markets are efficient — and they aren’t.

Many of the other objections raised against nootropic research: small effects, animal studies, and Russian science — do not hold up to scrutiny. The only real indictment of the field and movement is the focus on intelligence.

I.

IQ tests estimate general ability based on measurements like knowledge, memory, or mathematics. A drug might make people better at focusing on things in the moment, but worse at recollecting. This will worsen their performance on general knowledge and vocabulary subtests, but imporve it in other aspects.

Most studies of nootropics don’t even use complete IQ tests; they measure attention/focus rather than general ability, which is rather unfortunate. From this observation, many intelligence researchers have incorrectly claimed that nootropics are not effective, because there is “no evidence” their effects are ‘g-loaded’, that is to say, due to increases in general intelligence.

Let us imagine for a second there was a drug that increased general ability. If you administered an IQ test to people who hadn’t and had taken the drug, scores on subtests would not improve across all subtests. Becoming 20% more intelligent in one second does not magically increase your vocabularly or knowledge about the world; and it is these tests that are best at measuring intelligence.

The utility of g-theory is rather questionable when it comes to approaching drugs. If a stimulant made people better at focusing, then it’s possible that it could increase their vocabularies over time, as they attend to a greater quantity of words they do not understand. It’s not like a little focus hurt anybody.

II.

Intelligence is overrated, but it’s underrated when it matters — for economies. For nootropics, it works because it is one of the few cases where more of a trait is always better1. The value of intelligence decreases with age, as execution becomes more dependent on concepts already learned, rather than pure g. Neuroprotection, on the other hand, becomes more valuable with age; sadly, drugs that have been proven to slow or prevent cognitive decline are generally lacking in terms of evidence.

I’m not convinced I’d even notice a 15 IQ improvement, if it didn’t change how I feel.

One could ask then: why care about marginal improvements to a trait that does not even matter that much?

Mathematically, 1 IQ point translates to an increase in lifetime earnings of 50,000$, so a drug that increases IQ by only one point breaks even as long as it costs less than $100 per month to use; assuming young dosing that continues into adulthood.

At the group level, even a 3 IQ point boost has a large effect. Empirically, an increase in national IQ is associated with an increase in GDP per capita of 9.1%. If we assume half of that effect is causal from IQ→GDP per capita; if the national IQ of the USA increases from 98.7 to 101.7, then its GDP per capita would go from 84,000 to 96,000.

IIII.

The evidence for many drugs, particularly novel ones, rests on animal studies. These have been traditionally brushed off as useless, which is irrational. All “proven” nootropics that have effects on people’s minds — alcohol, caffeine, nicotine, amphetamines — have the same effects on animals. They are extremely useful for looking at receptors, blood-brain barriers, analogous traits, and toxicity.

The value of human studies comes from evaluating effects on traits subjective experience, socialisation or language that don’t translate well to animals, or calibrating doses. Most nootropic studies in humans don’t even study these traits.

Few drugs and interventions have effects in animals, but not humans. Caloric restriction is a genuine example that has to do with animal size and lifespan. Arsensic is considered a carnicogen in humans, but not animals.

Empirically, in drug research, translation from animal to human studies is pretty good. The problem comes with approving drugs based on animal studies — this could be due to problems with safety, efficacy, or tolerability in the drug, or incompetence/inefficiency within the FDA.

We assessed the proportion of therapeutic interventions advancing to any human study, a randomized controlled trial (RCT), and regulatory approval. We meta-analyzed the concordance between animal and human studies. The risk of bias was probed using a 10-item checklist for systematic reviews. We included 122 articles, describing 54 distinct human diseases and 367 therapeutic interventions. Neurological diseases were the focus of 32% of reviews. The overall proportion of therapies progressing from animal studies was 50% to human studies, 40% to RCTs, and 5% to regulatory approval. Notably, our meta-analysis showed an 86% concordance between positive results in animal and clinical studies. The median transition times from animal studies were 5, 7, and 10 years to reach any human study, an RCT, and regulatory approval, respectively. We conclude that, contrary to widespread assertions, the rate of successful animal-to-human translation may be higher than previously reported. Nonetheless, the low rate of final approval indicates potential deficiencies in the design of both animal studies and early clinical trials. To ameliorate the efficacy of translating therapies from bench to bedside, we advocate for enhanced study design robustness and the reinforcement of generalizability.

The internet is generally skeptical of the Russian nootropics, claiming there is “no evidence” they work. Actually, there is a ton of it. It just happens to be written in Russian, and most of it is in animals. I don’t speak Russian, but I do speak statistics.

There’s also an implicit idea among many people that Russian research is bad. I haven’t worked at Russian universities, so I can’t speak anecdotally, but there’s no data that suggests it is uniquely awful. Plagiarism rates in Russia are relatively high, though I would consider that a relatively minor infraction — I should note they county self-citations. Though, I assume that fraud rates are higher in countries with higher levels of plagiarism.

From what I see on the internet, Russian academic misconduct is heavily concentrated around faked/ghostwritten/plagiarised dissertations and duplicated papers to boost citations.

If we are talking about fraud that actually matters — in medicine — Russians are pretty tame. Per capita, they are on par with the United States and most European countries in terms of retractions.

Another red flag people commonly raise in research is research groups — like that Croatian one that is behind a lot of the BPC-157 research. Personally, I don’t think this is necessarily a bad thing. If anything, it makes me less likely to believe that the research is fraudulent; people like this draw attention, and their collaboration raises the stakes of what they are doing. If they just wanted to publish or get titles, they would plagiarise or do less glaring research.

It would still be best to see if a drug has positive results outside of a particular group, of course; I think it would be more likely that a research group would suffer from group-think or ignoring a bad side effect, and it would be less likely that they would commit deliberate fraud, given more people are involved.

VV.

IQ tests, despite their flaws, are generally much better than anything else psychology has to offer. Scales of depression, for example, are not great. TLP notes that most of the effect Zyprexa has on alleviating depression comes from changing sleep and appetite:

Take the simple example of depression, as measured by the popular Hamilton Scale. The scale measures insomnia and weight loss, but not hypersomnia and weight gain. Using this scale, a patient who sleeps too much and eats too much is less depressed than someone who sleeps too little and has lost weight. And, any drug that fixes sleep and makes you gain weight has an advantage over drugs that don’t. In fact, a third to half of the improvement on the Hamilton could be accomplished by improved sleep and appetite alone. Go Zyprexa.

Predictably, we’ve made the most scientific progress in things we can measure: blood pressure, glucose, obesity, genes, and muscle mass. Drugs that improve things that are difficult to measure — sleep, gut health, mood, and pain — sometimes still have effective options, but they typically come with more side effects or uncertainty in terms of potency.

An effective treatment for autism probably exists, but it’s too hard to evaluate, because social cognition is difficult to measure, and autism also carries a lot of quality of life and compounding effects. Worse social skills lead to less frequent and high quality interactions, which then make developing and expressing those skills more difficult. People couldn’t treat typhoid before they had anti-biotics. To know that anti-biotics could work, we had to be able to see bacteria. Happiness looks like a complete black box, even if you account for the difficulty of defining it.

There is, indeed, a problem of conceptualisation. Personality, psychiatric disorders, attention, intelligence, memory, wakefulness, affect — these aren’t independent factors. Drugs frequently affect multiple of traits at once, even after accounting for the problem of categories.

Improving personality and affect is far more valuable than improving intelligence. Everybody, to some degree, is rate-limited by intelligence; people’s specific limitations in personality vary based on the individual. The average person would have far more to gain from improving their 2 worst personality traits than getting a 15 point boost to IQ.

III.

A common thread I see in drugs that have evidence for improving cognitive ability is that they are all stimulants. This doesn’t particularly surprise me; there are reasons to think that the human body would not want to chronically upregulate neural activation.

When it comes to tolerance upregulation, I am an advocate of cycling; that the ideal stimulant protocol would involve taking modafinil one day, then taking an XR amphetamine, then a day of caffeine/nicotine, and then the cycle is repeated. This would make it so the different pathways by which stimulation is downregulated are diffused, so that the maximum benefit from each is achieved.

VII.

For reference, this is how I interpret effect sizes:

In statistics, the p-value determines the probability of observing an effect as or more extreme than the one observed given a model; usually a null hypothesis — that there is no effect. The p-value does not estimate the probability that the null hypothesis is true. Because of widespread p-hacking, even very low p-values can’t be trusted, unfortunately.

There is much more to interpreting scientific studies than these two numbers: methodology, publication bias, blinding, fraud, and whatnot. On the subject of blinding: it’s not possible to do blinded studies with real drugs; arguably not even necessary.

X.

When I look at nootroptics, I will be assessing:

1. Whether the substance does anything.

2. What that is, or is supposed to be.

3. Whether taking it is worth it, the relevant side effects, and evidence regarding changes in intelligence or mental state.

Some drugs are so popular and established that there is basically no point to studying them, at least, not in the same way we research other drugs. Caffeine clearly keeps people awake, but it’s not clear if it makes people smarter. Among these, I name: Caffeine, Nicotine, Amphetamines, Modafinils, Alcohol, Opiates, Cocaine, Hallucogenics, Benzos, Ketamine, MDMA, and Cannabis.

It’s fairly uncontroversial, scientifically speaking, that sleep-deprivation reduces cognitive performance. Anybody who has been sleep-deprived before, meaning everybody, can tell you the same thing. As such, I’ll take for granted that any drug that keeps you awake will make people smarter at the aggregate level, even if it’s not a strict nootropic.

‘X drug vs Y drug’ debates can get fraught by comparing doses. 50mg of bromantane might get beat by 10mg of adderall, but maybe 200mg of bromantane beats 10mg of adderall. Bcause of that, I consider the best drugs to either be ones that are so well-tolerated that taking high doses isn’t obstructive; or ones with a dose-response effect.

Tolerance and dependence probably exist for every drug; at what point the tolerance kicks in, and how brutal the dependence is differsfor every drug. Drug dependence is expensive, uncomfortable, and psychologically pessimistic. Which was why I quit stimulants when I was around 23-24. Later, I accepted I had a body that did not work on its own, so I started using them again.

Even drugs like modafinil induce tolerance, even though scientific literature claims they don’t — my lived experience, and that of others, says the opposite.

Many studies restrict themselves to healthy participants, and people are quick to dismiss findings from any study that doesn’t do the same. “X supplement does nothing to people who aren’t deficient” is a bad critique if 40% of people have inadequate intake. A perfect, ideally healthy person would have an IQ of 10000 and not bother with nootropics. We take drugs because we are unhealthy.

Further reading:

• Creatine (gwern’s take)

• Bromantane

• Caffeine

• Modafinil (gwern’s take)

• Amphetamines

• Nicotine (gwern’s take)

• Semax

• On stimulant tolerance

• The algernon argument (disagree with the framing of evolution)

Brief thoughts on a few nootropics

Bacopa monnieri

One of the most studied natural nootropics, which is believed to augment memory.

There’s a systematic literature review on the supplement. Large effect. Can’t say I trust it. Better meta-analyses find that modafinil has little effect on cognition in healthy people, but they found a large one (d = .77) here.

Maybe it works, maybe it doesn’t. Not personally interested in it.

Cerebrosylin

Meme peptide. An accurate, but pedantic review on the issue: its empirical studies are often conducted by the manufacturer of the drug and it has few null results. It has not been approved by the FDA. We don’t even know what cerebrosylin contains. The ingredients it is supposed to contain might not even cross the blood-brain barrier.

Oh, and a lot of cerebrosylin research is simply fraudulent.

The funnel plot for its effect also looks pretty ugly, indicative of publication bias.

Pitolisant

More commonly known as wakix. It’s an inverse agonist to the H3 receptor (type of histamine receptor). It got approved by the FDA for treating narcolepsy.

My intuition regarding every single drug that intends to improve wakfulness is that they all work. Evaluating wakefulness in other people, or yourself, is pretty easy and straightforward. Never tried it, but I will if I get a narcolepsy diagnosis.

• “It just works”: tesamorelin

• Efficacy, at a cost: MK-677

• Efficacy, but of uncertain safety: CJC with DAC

• Safe, possibly effective: ipamorelin, CJC with no DAC

Besides directly supplementing with growth hormone, drugs can also target ghrelin or GHRHR receptors to cause the body to naturally release growth hormone. Most of its effects are mediated through IGF, which causes bone growth, fat loss, muscle repair, connective tissue repair, and neurotrophy.

The GH itself also increases water retention, which can lead to increased blood pressure, joint pain, and muscle pain. It also increases insulin resistance.

Growth hormone has traditionally been used as a performance enhancing drug, but its rather overrated in that regard. It might not even make people stronger — it makes people lose fat and gain lean mass, but the gains in lean mass do not translate to improved strength.

The kind of people who would find GH or its alternatives valuable are people who want to recover more quickly or have low baseline levels of IGF.

How much is too much?

The evidence GH and IGF increase the risk for cancer and death is pretty solid.

Knocking out the genes that promote GH signalling is one of the most effective interventions for raising the lifespan of mice. People with acromegaly, which causes chronically elevated GH and IGF, typically live about 10 less years; GH deficiency does not appear to have a marked effect on lifespan. People with Laron syndrome, which causes insentivity to GH, have been observed to rarely have cancer.

In normal humans, IGF levels range from 150-400 ng/ml:

People with acromegaly typically have IGF levels in the 400-800 ng/ml range1, which eventually causes the development of several health problems, like sleep apnea or high blood pressure.

Normal people can have IGF levels in that range and remain asymptomatic, but that’s likely because their levels eventually regress to the mean. Even if normal humans can be found with naturally high IGF levels, that doesn’t necessarily mean those levels are safe.

Empirically, IGF is a good candidate for a trait that shows antagonistic pleiotropy: it has positive effects in the youth, but more negative effects in the elderly:

The age x dose interaction suggests that low IGF-1 is bad regardless of age; something the anti-PED people will never tell you:

Genetically, high IGF levels are only robustly associated with colorectal cancer in the UK biobank and Japanese biobank. These correlations, including the genetic ones, are probably confounded by other factors that are hard to control for. That said, I still think it’s still pretty likely that chronically and unusually elevated IGF does drive cancer risk and mortality.

Summary:

Tesamorelin

Gold standard. It secretes GH through the GHRH receptor; half life of 30 minutes.

It’s been demonstrated to reduce visceral fat in FDA trials.

At doses of 2mg/day, it increased IGF levels by about 60-100%2 in this study:

They didn’t specify how long after injecting this was; a different one finds a similar increase in IGF levels by 181 ± 22 (ng/mL) 20 hours after the same dose (2mg) of tesamorelin had been administered.

Tesamorelin is pretty well tolerated; side effects include joint pain, muscle pain, and injection site reactions. The joint and muscle pain probably come from retained water putting stress on the muscles and connective tissue. Presumably, if used for enough time and at high enough doses, it would also increase the risk of

People have taken 2mg/day of this drug for as long as 26 weeks, causing their IGF levels to increase by up to 100%, with none of these complaints. About 2.5% of young adults have IGF levels of 300-400, which is similar to what the average person would achieve from a 2mg dose of tesamorelin. The optimal dose is probably lower than that.

This drug doesn’t seem to affect insulin resistance much, not in the FDA trial3, or in a small sample of diabetics.

Interestingly, this absence of effect is due to its reduction in visceral fat, which improves insulin resistance. People who did not lose >8% of their visceral fat on the drug had higher resting glucose levels, while the responders didn’t change:

MK-677

Another option is MK-677, a ghrelin analogue which can be taken orally. Its half-life has been cited to be 5 hours, and it elevates IGF for 24 hours, so it only needs to be dosed daily. The empirical evidence it works is fairly undeniable.

Despite being considered highly potent, it doesn’t even raise IGF as much as 2mg of tesamorelin does, and the effects of it taper off with time:

It also stimulates appetite, which many people find difficult to tolerate. It has few benefits over other options, besides the fact there is extensive empirical evidence that supports it, and the fact that it can be taken orally. It also increases growth hormone levels for longer than other secretogues, so more its negative side effects — water retention, joint/muscle pain, and tingling — should be expected.

CJC

CJC is a fragment of GHRH which stimulates the release of growth hormone. When the DAC component is added, its half-life is increased from 30 minutes to about 7 days. In this formation, it has been demonstrated to increase IGF levels for a week using only one dose:

The GH increases that it causes are also more erratic, leading to higher pulsatile increases as well as higher chronic levels. The community seems to think this is better, as it leads to less receptor desensitisation and IGF-mediated downregulation.

They also ran a second study where they had some people take weekly doses, and found that low doses could deliver the same IGF increase as tesamorelin:

CJC with DAC was pretty well-tolerated at low doses, but 100% of the subjects who took the 125-250mcg/kg doses experienced diarrhea and flushing. No consistent changes in glucose or lipid levels were found.

Bryan Johnson had a bad experience with CJC-DAC. He found that it increased his fasting blood glucose by 20%, insulin resistance by 50%, and reduced his REM sleep by 23%.

CJC, no DAC

The DAC component can be removed, which gives the drug a shorter half life; it’s been cited to be 30 minutes, but there is no original source for that claim. The drug itself originates from an attempt to increase Sermorelin’s resistance to degradation, which has a half life of 12 minutes. Realistically speaking, the half life of CJC with no DAC could be anywhere from 10 minutes to a week.

There’s no real evidence CJC works in this formulation, but there’s also no reason to think it doesn’t. We do know that tesamorelin, which has a short half life, and acts on the same receptor — does work. So, I think the null hypothesis is that this peptide does too, though there is still a chance it doesn’t.

My main concern is that it’s underdosed. All of tesamorelin’s studies are using 2mg, while the community typically recommends CJC doses of 100-500mcg.

There’s no real reason for this. Tesamorelin is 1.5x heavier than CJC with no DAC4, but that doesn’t justify a 10x difference in dosage.

Ipamorelin

This drug sits in a similar situation to CJC with no DAC. There’s no real evidence it works in humans, but it theoretically should. Its half life of 2 hours is decent, and it targets the same receptor that MK-677 does. It’s highly selective, and hardly acts on prolactin or cortisol.

One of the first ipamorelin studies supposedly found no increase in IGF levels, which is correct, but the sample size here is only 16; it’s not large enough to detect a small effect. Though, it is large enough to detect a large one.

The half-life of ipamorelin is also shorter in rats (30-60 mins) than humans (120 minutes), so it’s not clear if the results can be cleanly ported over. My intuition is that the devil is in the dosage.

The specter of European nihilism haunting peptides

The question people want answered is “does X work?”

The answer the internet gives is usually something along the lines of “this drug failed Y trial so it does not work” or “this drug was approved to do YZ so it does it better than other drugs of its class”. None of these claims follow from their premises. Tesamorelin, for example, was trialed for visceral fat loss, but that’s a general feature of any drug that increases GH and/or IGF.

The way these drugs work is by increasing the frequency/peak of GH pulses. Which then increases IGF, which is what does most of the heavy lifting in terms of physiological changes. Demonstrating that a drug increases IGF, or even GH, in my opinion, means that it almost certainly works — the devil is in the dosage, after that point. 100mcg of ipamorelin might spike GH, but maybe for not enough time to elevate IGF enough to produce physiological changes.

People have different thresholds of evidence when it comes to rating GH alternatives; the yardstick I use is whether they improve IGF, which is the most important thing that GH does. When it comes to instutitions and scientific consensus, it’s FDA trials + status or bust.

I’ve heard that the GHRH receptor reaches saturation at 1mcg per kg of body weight. Regardless of whether this is true, this does not mean that diminishing returns kick in around 50-100mcg. High doses also increase the amount of time that the human body is exposed to the peptide. This is particularly relevant for these drugs, as they are functioning by increasing GH, which rises and falls in spikes that can’t be cleanly predicted from the dose itself.

Using adderall as an example:

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The convention is for protein doses to be weight normalised, which is fine as a heuristic, I suppose. It falls apart when it comes to individuals. A 6'5’’ 170lb new lifter with a large frame will need a higher dose of protein than a 5’9’’ 170lb man who has been training for 5 years, as the taller man will be gaining more muscle mass.

II.

First, there is the question of how much protein our body naturally uses. If we look at mortality curves, protein intake taps out at around 15-18% of the body’s calorie intake1, about 106g per day for the average person:

Maintaining muscle mass will be useful for longevity, but less so than repairing the gut or carrying out the body’s instructions. A fraction of that longevity-maintenance dose will go to increasing muscle mass, but I doubt increasing protein intake beyond that does absolutely nothing.

The dosage can also be estimated mechanistically. The maximum possible amount of muscle that can be gained in a year varies by drug use, training level, and genetics; I’d peg it to be about 5kg in people who are not using PEDs; Mentzer says a realistic estimate for most people is 2.5kg per year. I should note that traditional estimates of maximum muscle mass gains are inflated by the usage of noisy body fat measures and using lean mass as a proxy for muscle mass.

Muscle is about 20% protein by mass, so a person who is gaining 5kg of muscle in a year will be gaining 2.7g of muscle protein per day. Based on tracing studies, only about 15% of injested amino acids are deposited in the muscles. Add that 2.7/0.15 to 106, and that gives us an estimate of 124g.

This estimate doesn’t account for the metabolic overhead of amino acids being used for other reasons besides hypertrophy in muscle, the fact that existing muscle fibers need to be repaired, and that some of the protein in the longevity-maintenance dose of 106g does get used in hypertrophy.

II.

We can also look at this empirically. The largest meta-analysis to date does find a positive effect of high protein diet on gains in lean body mass, and that the effect depends on the dose and the study. The average intervention period in the study was about 4.5 months, and they found an aggregate effect of protein supplementation on lean mass of 0.5kg.

The grouping is a little convoluted. Essentially:

• A: all studies, no adjustments

• B: resistance training studies only, no adjustments

• C: no resistance training studies only, no adjustments

• D: all studies, adjustments for age, sex, intervention period, and resistance training (not sure what this means in this context)

• E: resistance training studies only, adjustments for age, sex, intervention period, and resistance training

• F: no resistance training studies only, adjustments for age, sex, intervention period, and resistance training

• G: all studies, adjustments for age, sex, intervention period, and resistance training, weight change

• H: resistance training studies only, adjustments for age, sex, intervention period, and resistance training, weight change

• I: no resistance training studies only, adjustments for age, sex, intervention period, and resistance training, weight change

Controlling for weight change here is probably a bad idea here, which is what charts g/h/i do, because its evaluating change in mean fat free mass as an outcome. So it’s answering a different question: how much lean mass is lost relative to how much weight is.

In the studies that involve resistance training, we do not see any tapering off in effects at high doses. It’s possible that this is due to differences in effects between people: that new lifters and people with large frames gain muscle mass faster, so they require relatively more protein. Or, it could be the case that more is better no matter what. It’s hard to tell.

As such, the most informative charts are e and f. It turns out that the effect of protein intake attenuates in people who are weightlifting; it’s probably more valuable in people who are cutting.

VV.

And then we have the biomechanical studies. The one that spawned the ‘muscle saturates at 30g of protein’ meme is… actually, pretty well designed.

They had 48 volunteers assigned to 4 different doses (0, 10, 20, and 40g) of protein after engaging in a leg workout; they had eaten a breakfast with protein in it prior to this. Going from 0→40g of protein intake stimulated muscle synthesis as much as resistance exercise.

The difference between the 20g and 40g doses wasn’t statistically significant, but I think this is a simple power failure. A similar study which evaluated the difference between 20g and 40g doses of protein did find a small improvement in going from 20 to 40:

The charts are slightly overselling the effect of protein on hypertrophy. Resistance training will increase muscle synthesis over a longer period of time than protein. It’s also likely that the effect of protein on muscle synthesis taps out after a certain periodic or daily dose.

I’ve also heard about the idea of an anabolic window, where protein ingested near a workout is more hypertrophic than that ingested farther away from it. The idea seems sensible, but the magnitude of the effect and the size of this window are unknown, as of yet. Both [1, 2] of the most recent meta-analyses on the issue have found nulls, when total protein intake is controlled for. My intuition is that the effect does exist, but the window is far larger than commonly thought, like maybe 12-72 hours in terms of size.

Summary

From what I can tell, protein intake does contribute to increased levels of muscle synthesis, but it’s probably not as necessary or effective as is commonly thought. Studies that evaluate the effect of protein intake post-exercise are more encouraging in their results, but do not

The heuristic I would use, when it comes to optimal protein intake for preserving and increasing muscle mass, is calculating the calories the body spends in a day, multiplying by 0.15 (maintenance) and dividing by 4 (g→calorie) to get the longevity-maintenance dose. Then, I would add the 2g of protein added to the muscle every day, divide by 0.15 as not all dietary protein is funneled into muscles, and multiply as 3x to account for metabolic overhead and inefficiency.

For me, that would be a total of 115g of protein per day.

1

Some replications:

Kawasaki aging project:

People with obstructive pulmonary disease:

Koreans:

Ignoring these people’s unique circumstances would be a little mean, wouldn’t it?

From our premises, we can conclude that supplementing creatine almost certainly improves cognitive performance at the population level.

The better question is in who, and by what magnitude.

The skepticism toward creatine supplementation is warranted — the studies on it are often of low quality, we don’t know what the dose-response effect of brain creatine is on IQ, and we don’t know which people would improve by supplementing it, but it’s gone a little out of hand. Not knowing isn’t the same as knowing a not.

As far as I can tell, creatine is innocent until proven guilty. Even if I knew it didn’t improve IQ, I would still take it because of its effect on athletic performance. So, personally, I’m not interested in tearing the literature apart or running my own studies on it; though I would encourage other people to do the dirty work.

III.

There might be publication bias in the literature too, according to a correspondence between gwern and a scientific researcher:

Publication Bias

The common publication bias checks like the funnel plot are useless with 3 studies. As it happens, there is no need to do any hypothesis-testing here: Ling (personal communication 2013) mentions that 2 student theses were done involving creatine supplementation & cognition with apparently uninteresting results, but did not have any copies and the university library had not retained any; this is prima facie publication bias. Hence, we know that the meta-analytic results are biased upwards by publication bias.

The base case in meta-analyses seems to be that the observed effect is about a third of the size when it is replicated in a follow-up study. Even meta-analytic correction methods overestimate the effect.

I think it’s fair to give creatine the same treatment. This is the latest meta-analysis:

Sixteen RCTs involving 492 participants aged 20.8–76.4 years, including healthy individuals and patients with specific diseases, were selected. Creatine monohydrate was the form used in all included studies. Creatine supplementation showed significant positive effects on memory (SMD = 0.31, 95% CI: 0.18–0.44, Hedges’s g = 0.3003, 95% CI: 0.1778–0.4228) and attention time (SMD = −0.31, 95% CI: −0.58 to −0.03, Hedges’s g = −0.3004, 95% CI: −0.5719 to −0.0289), as well as significantly improving processing speed time (SMD = −0.51, 95% CI: −1.01 to −0.01, Hedges’s g = −0.4916, 95% CI: −0.7852 to −0.1980). However, no significant improvements were found on overall cognitive function or executive function. Subgroup analyses revealed that creatine supplementation was more beneficial in individuals with diseases, those aged 18–60 years, and females. No significant differences were found between short- (<4 weeks) and long-term (≥4 weeks) interventions for improving cognitive function. Low-to-moderate risk of bias was found, and no significant publication bias was detected. The GRADE assessment indicates that the certainty of evidence for memory function is moderate, suggesting a reasonable level of confidence in the positive effects of creatine on memory. However, the evidence for processing speed, overall cognitive function, executive function, and attention is of low certainty, indicating that further research is needed to confirm these potential benefits.

They found no effect on overall cognitive performance… which could easily be a power failure. Just look at that confidence interval:

They didn’t find any publication bias using the egger’s test; again, based on the gwern correspondence, it sounds like it definitely exist. They just couldn’t prove it.

If we average out the effects on their outcome variables: general ability, executive function, trail making test, attention, stroop test, memory, processing speed, and reaction time (meaningfully different from processing speed) — we get (0.51+0.01+0.31+0.31+0.21+0.03+0.32+0.34)/8 = 0.26. Divided by 3, we get 0.086. That sounds fair to me.

V.

Oh: that big “more is better for creatine” study? Written by the guy serving on the scientific advisory board for AlzChem, which manufactures creatine. I generally find arguments based on social/fincancial ties tedious, but I find this specific case a little suspicious.

The effects of bromantane last for 10 hours, and the lethal dose in animals is around 8g/kg; the conventional dose in humans is 50-200mg. It’s not something patients will overdose on.

The only country that has approved it as a treatment is Russia — for neurasthenia, aka chronic fatigue. Predictably, most of the scientific literature on bromantane was written in Russia, so the drug hasn’t been able to diffuse to the West.

The history of bromantane’s development is encouraging. It all starts with an antiviral, amantadine, that was developed to treat influenza. They found out by accident that the drug was also a dopaminergic stimulant. This led to the development of bromantane, a drug that lies in the adamantane family — drugs typically used to treat viral infections or neurodegenerative diseases.

Does it actually work?

Pharmokinetics in animals (skip if bored)

The dominant theory as to why bromantane works is by upregulating dopamine synthesis, similar to the way MAO-A inhibitors work, but without the drug interactions and side effects that make them unpopular.

This paper is foundational to that theory. They essentially tested all of the hypotheses of the theory: whether bromantane changes gene expression, whether it increases dopamine, whether it changes neural activity, and whether the change of neural activity holds when blocking the activity of dopamine.

They tested the gene expression effect by seeing whether bromantane elevates the gene expression of tyrosine hydroxylase, which is what synthesises catecholamines like dopamine, relative to a control gene (Hprt). They had rats take bromantane, and sacrificed them at different time intervals, and checked the expression of these genes in the ventral tegmental area (VTA). These were their results:

These p-values are awful, but I still believe the result. These are separate groups of rats, and in each one, the gene expression of TH was higher than that of the control gene.

In what I believe to be different rats, they checked whether levels of dopamine and L-DOPA were higher in the rats that took bromantane. The finding here is a little dodgier, statistically, but it’s not terrible. They are reporting lots of outcomes, but they are still testing different groups of rats at each time interval.

They also checked dopamine levels in other regions of the brain, which also give positive results. As with the prior chart, it’s hard to write these off as false positives because there are so many positive effects here; regardless of p-values.

In some of these groups, particularly the 30/90 min groups, levels of dopamine appear to be lower. This might be because bromantane releases dopamine in addition to upregulating the synthesis of it. Because this paper is looking at how much dopamine is in the whole tissue, it can’t examine the localised concentration of dopamine outside the cells. Given the drug is not well studied, I’d caution against any particular interpretation of how or why it works.

A theory as to how memories are created and skills are aquired is the transformation of short-term potentiation (STP) into long-term potentiation (LTP). A STP is a neural firing that occurs once, then returns to baseline; an LTP is a neural firing that maintains itself.

In the prior study, they cut out a slice of the rat brains, and stimulated them with electrodes — which is called tetanisation. The rats who were administered bromantane (black circles) had stronger and more durable synaptic responses than those administered with DMSO (controls, grey circles).

The elevation in synaptic strength in that study was not due to the bromantane itself; they did a second study where they administered bromantane to the rats but didn’t administer a neural shock. In this group, no elevated synaptic strength occured (black triangles).

They then tested whether adding a dopamine D1/D5 blocker, SCH23390, affected the results. It appears that administering bromantane with the blocker attenuated the rise in synaptic strength, but didn’t completely eliminate it, relative to the control group that was given DMAO and the tetanisation. Potentially, it could be because dopamine is a precursor to norepinephrine, which is implicated in neuroenergetics and perception of novelty.

There are other studies that evaluated the effect of bromantane on dopamine synthesis and gene expression (#1, #2), as well as ones that find anti-inflammatory effects. Frankly, what exactly bromantane is doing in the brain is not as interesting to me as the actual evidence regarding whether it works.

The human studies

One small study found that Bromantane reduced how much anxiety patients fell, but the placebo did not. 8/15 subjects in the placebo group eventually dropped out, but none of the 15 in the bromantane group did. The dose of 100mg was considered optimal for all patients except for 2 — one who opted for 50, and another who opted for 150.

In this chart, the black line with diamonds denotes the effect on anxiety and the grey dotted line with the square denotes the effect on alleviating fatigue. From the text, I can’t tell if these are clinician-rated or patient-rated.

Bromantane improved performance on global cognitive performance by about 1 standard deviation, though I assume that figure with be a third or fourth lower in a replication attempt.

There is a much larger study and frequently cited study on bromantane… that has no control group. I don’t think this is that bad. It’s a stimulant — people will know if they are on it. A placebo would only be useful for cataloguing what natural improvement would look like.

Statistically, the result looks fairly undeniable. The patients got much better during the 30 day period they were taking bromantane:

The problem here is that, even after the patients discontinued the drug, the majority of the patients improved in terms of mental health. According to both themselves, and the clinicians.

It’s unlikely that bromantane does much more besides upregulate dopamine synthesis, perhaps norepinephrine and adrenaline indirectly, and improve the immune system. There’s little reason to think that the effects of the drug are permanent. There is a small drop-off in efficacy after the patients discontinued the drug, but the overall story points to remission + nonpharmacological improvement.

Overall

I think bromantane works, but is generally overrated. It has a nice niche as a stimulant that does not increase anxiety, otherwise, it’s outclassed.

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That question doesn’t interest me, but I’ll explain the logic. When we run studies on people who take caffeine, we generally see lots of mental improvements. Why these happen is not clear: perhaps it is an improvement that tapers off as the drug is cleared from the body:

Or it is reversing a pathology that stems from the body’s adaptation to caffeine:

When effect sizes are compared in people who takes lots of caffeine vs not so much of it, they are not the same. They lean towards the reversal hypothesis: caffeine consumers’ mental alertness and reaction time reverts to baseline when they take caffeine.

The problem here is that these are not randomly assigned groups. People who take lots of caffeine might be taking it because the drug has a stronger effect on them, or because they tolerate it well. Notably, levels of anxiety are unchanged when caffeine-takers take caffeine.

This is a debate that can’t be evaluated cleanly with a small study or even a meta-analysis of them. Cross-sectional, observational evidence that control effectively for demographics/genes would be very useful here — like the type of studies that evaluate the objective effects of ADHD medications on outcomes like car crashes or crime, but a little different. It’s perhaps not even a good question to answer with science: people who do well on caffeine should take it, and people who don’t shouldn’t.

I.

There are two good meta-analyses on the effects of caffeine.

The first is an analysis of the effect of caffeine on healthy, rested adults. Not exactly a representative population, but it will do for now. It found roughly identical effects for both reaction time and accuracy:

Results: Thirty-one trials with a total of 1455 participants were included in the meta-analysis. Significant effects in favor of caffeine were found for both accuracy, g = 0.27, and reaction time, g = 0.28. Subgroup analyses showed that higher doses of caffeine (≥ 200 mg) improved both reaction time and accuracy more than lower doses, but whereas a positive linear dose-response relationship was found for reaction time, a quadratic relationship was found for accuracy. The effect of caffeine was not related to differences in habitual caffeine consumption, task complexity, or which attention network was taxed.

Their supposed quadratic effect is nonsense; the p-value (0.032) of it is frankly is laughable. Pooled together, I think they would find a dose-response effect that tapers off after 200-300mg.

They tested for publication bias, but didn’t find anything statistically significant. Visually, it does look like it exists; the studies with higher effect sizes have smaller sample sizes. The priors for it existing are pretty high.

I’d guess that publication bias is inflating the meta-analytic effect size by 0.1-0.2; I think it’s fair to say caffeine’s effect on cognition in healthy people is in the 0.1-0.3 range at high (200-400mg) doses.

A second meta-analysis assessed the effect of caffeine on treating sleep deprivation, which they defined rather loosely. Averaging all of their effect sizes yields an aggregate effect size of d = 1.08, aka 16 IQ points.

Caffeine is widely used to counteract the effects of sleep loss. This systematic review and meta-analysis examined the impact of acute caffeine consumption on cognitive, physical, occupational and driving performance in sleep deprived/restricted individuals. 45 publications providing 327 effect estimates (EEs) were included in the review. Caffeine improved response time (44 EEs; g = 0.86; 95 % CI: 0.53–0.83) and accuracy (27 EEs; g = 0.68; 95 % CI: 0.48–0.88) on attention tests, improved executive function (38 EEs; g = 0.35; 95 % CI: 0.15–0.55), improved reaction time (12 EEs; g = 1.11; 95 % CI: 0.75–1.47), improved response time (20 EEs; g = 1.95; 95 % CI: 1.39–2.52) and accuracy (34 EEs; g = 0.43; 95 % CI: 0.30–0.55) on information processing tasks, and enhanced lateral (29 EEs; g = 1.67; 95 % CI: 1.32–2.02) and longitudinal (12 EEs; g = 1.60; 95 % CI: 1.16–2.03) measures of vehicular control on driving tests. Studies also typically indicated benefit of caffeine on memory (25 EEs), crystallized intelligence (11 EEs), physical (39 EEs) and occupational (36 EEs) performance. Ingestion of caffeine is an effective counter-measure to the cognitive and physical impairments associated with sleep loss.

I looked at their funnel plots, and it looks like a few of the effect sizes may be inflated by publication bias or small study effects. Among these, I count response speed and maybe vehicular control. That said, I think it’s still likely that the overall effect is high.

It’s been estimated that 30% of American adults are sleep-deprived; I assume severe cases are closer to the 1-10% mark. If that is the case, I’d say the overall effect size of caffeine is 0.24 (0.2*0.95+1.08*0.05).

It’s extremely effective at what it does, which is keeping people awake. So much that it’s possible to pull an all-nighter with no effort as long as the drug is active in the body. It’s said to be a fairly popular drug at the White House. Joe Rogan and Sam Altman have said positive things about it.

It’s been approved by the FDA to treat various sleep disorders; since it’s a controlled substance, a prescription or a grey market source are necessary.

In terms of statistical effect size, it’s surprisingly low. It decreases sleepiness in narcoleptics is about 0.61 SD on the ESS scale. I assume that people who have actually tried the drug would have a different opinion — myself included.

In terms of cognitive enhancement? A disappointment. The best meta-analysis on the drug’s effect finds an overall effect of d = .12, and it barely crossed the threshold of statistical significance.

Said meta-analysis was restricted to healthy adults. Presumably, it improves cognitive function more in people with sleep deprivation, just like adderall does.

People have studied its effects on chess performance, along with caffeine and ritalin. Overall, it didn’t have an effect on winning. It made people make better moves, but it took them longer to make decisions, so they lost on time more often. The effects cancelled each other out. The exact implications of this are unclear to me: it could be that the drugs made them smarter, but caused them to take more time to make decisions independently of that. Or a dozen of other interpretations.

Modafinil’s side effects are weak and easy to ignore. There’s a 1/1,000,000 chance of getting a Stevens-Johnson reaction, which causes a fraction of your skin to die. They say you can avoid the headaches by taking choline, but I haven’t tried that myself.

The drug does build up tolerance. When I first started taking the drug, it felt extremely strong, and a ~300mg dose gave me bad anxiety. I fixed that by taking 50-100mg instead. Over time, I started having to take the normal dose (200mg) to get the same effect on wakefulness. Even on an appropriate dose, I felt less empathetic and more extraverted. Kind of like amphetamines, but a more muted effect.

Sourcing

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• Enclomifine: increases testosterone while preserving testicular function, but increases estrogen more than TRT. Looks promising for people with secondary hypogonadism, where the testes can naturally produce testosterone, but the pituitary gland is dysfunctional.

• Kisspeptins (10, 54, and TAK-448): awful. Downregulate hormones into oblivion or have awful half lives.

• Tongkat ali: probably does nothing.

The existing competition, sadly, looks pretty weak.

Enclomiphine

Enclomiphine (enclo1) antagonises the estrogen receptor, which causes the body to produce more testosterone. Because the cause of increased testosterone is not endogenous, it doesn’t result in down-regulation. It’s well-tolerated2. The statistical support for its effects is undeniable: it increases total testosterone by 273 ng/dl; as well as free testosterone, DHT, LH, FSH, and estradiol3 (unfortunately).

It doesn’t decrease sperm counts, unlike testosterone replacements:

Sounds great, though it’s already possible to maintain testicular function and testosterone production on steroids if HCG is taken alongside it.

Unfortunately, the Committee for Medicinal Products for Human Use recommended against using it as a treatment for low testosterone levels, aka male hypogonadism.

The CHMP noted that although the studies showed an increase in testosterone levels with EnCyzix, they did not look at whether EnCyzix would improve symptoms such as bone strength, weight gain, impotence and libido. In addition, there is a risk of venous thromboembolism (problems due to the formation of blood clots in the veins) with the medicine. Therefore, the CHMP was of the opinion that the benefits of EnCyzix did not outweigh its risks and recommended that it be refused marketing authorisation.

The drug went down the institutional rationalisation pipeline: ambiguous evidence is bad, bad evidence means no evidence, and no evidence means it doesn’t work. That really hurt the drug’s reputation.

Their reasoning was that there was lots of evidence the drug increased testosterone levels, but no evidence that it alleviated the symptoms of low testosterone (?). Particularly, the committee was concerned that its activity as an anti-estrogenic would change body physiology in other ways that would make it possibly doesn’t have the desirable effects of testosterone.

I’d actually predict the opposite to be the case: traditionally the complaint about exogenous testosterone is that it converts into estrogen, and it taxes the body’s natural testosterone production. Enclo antaogonises estrogen receptors, so the downstream estrogenic effects of T are mitigated, and the T increase is downstream of natural processes.

They also saw three cases of deep vein thrombosis (DVT) in the treatment groups; none in the placebo group. Given the number of events they tracked, it wouldn’t be out of the ordinary for a difference like this to emerge due to statistical randomness; the observed rate (0.9%) in the treatment group is hardly different from the rate in the general population (0.08-0.2%).

That said, DVT can be caused by using TRT, so it’s not implausible that enclo also causes it. Though, it’s rather unfair that this drug got shanked for being a risk in DVT, when the first line treatment for male hypogonadism also has this risk. Oral contraceptives, surgery, and chemotherapy are all considered risk factors in DVT — I don’t see any bans against these treatments.

People have raised concern about enclo potentially harming bone density. Traditional TRT raises bone density. The effect of SERM drugs on bone density is more ambiguous; one clinical trial was conducted to evaluate exactly that, and its results were never posted.

One study found that clomiphene — a more estrogenic and less pure version of enclomiphene — decreases bone density in the spine, but not the hip:

The p-value for the decrease, 0.0089, is low, but still potentially a fluke. Especially since statistics can be selectively reported.

A different study finds the exact opposite effect in some hypogonadal men who were treated with the same drug:

Figure 2 shows the outcomes of bone densitometry over the study period. Mean ± SD T scores for femoral neck/lumbar spine at baseline were − 2.1 ± 1.7/ – 3.2 ± 2.2. These values improved signifi cantly ( P < 0.01 for both sites) over time, with scores at 1, 2 and 3 years being − 1.2 ± 1.2/ – 1.6 ± 1.8, 1.3 ± 1.6/ – 1.6 ± 1.2 and − 0.9 ± 1.2/ – 1.1 ± 1.0, respectively. In all, 28% of patients had

One possible explanation is differences in study populations. In the first study, most of the men had normal levels of bone density, and only a third had any osteopenia at all; in the second study, which found a positive effect, almost 75% of the men had osteopenia.

There’s other studies that find evidence that SERM drugs have positive effects on bone density in women with pre-existing osteoporosis:

Overall assessment

Enclomiphene looks like a promising alternative to testosterone that doesn’t damage the testes, but a relative absence of human data and institutional backing hurts the drug’s credibility.

It demonstrably has a different hormonal profile than testosterone, which could plausibly change its downstream effects on musculature, bone density, and sex drive. An aromatase inhibitor possibly needs to be taken alongside it to mitigate its increase in estradiol.

Kisspeptins

Kisspeptin-10 actually does increase total testosterone levels. There’s a problem: it has a very short half life: 4 minutes.

So people have pivoted to using kisspeptide-54 instead, which has a half life is 30 minutes. This makes it so its hormonal effects are able to last longer than a few hours.

There’s then another version of this peptide, MVT-602, which has a half life of about 3 hours. It’s currently in clinical trials for female infertility and hypogonadism.

This version of the drug was shown to be unsafe in clinical trials for prostate cancer. 80 healthy men took TAK-448 (old name for MVT) for 14 days, and it was found that natural production of testosterone and LH was downregulated to dangerously low levels within a week. The effect stopped after the subjects discontinued the drug.

They found the same thing in rat studies. The decline likely happened because kisspeptins work through LH, which are subject to receptor downregulation.

Overall assessment

Nope. There’s a marginal chance Kisspeptin-54 works, but I wouldn’t bet on it.

Tongkat Ali

Ran the stats on this one years ago. Turns out the meta-analytic effect that some researchers found is due to publication bias.

2

Adverse events. The patient who died of a stroke had untreated atrial fibrillation, somebody in the placebo group

3

Receipts:

Predictably, sentiment on these drugs is highly polarised. If we look at the empirical data, the case for them looks good. Studies that evaluate the effect of ADHD medications, including amphetamines, on symptom scales of ADHD find large improvements — on the scale of about d = 1.

Critics of amphetamines pivot by arguing something else: the side effects aren’t worth it, they are over-prescribed, or they make people less creative.

Statistically, it seems that when people with ADHD get treated with medications, they have better real world outcomes in terms of criminality, car crashes, and unintentional injuries. With another catch: their efficacy in observational data seems to be decreasing as time as gone on, as people have been diagnosing the condition more liberally.

III.

Overall, the current literature also suggests that amphetamines are effective nootropics.

There’s an unreleased meta-analysis which suggests the benefits of stimulants that treat ADHD on cognitive test scores are larger in people with ADHD or with sleep deprivation, with a small (d = .14) effect in normal people.

This is consistent with the decline in the observed efficacy of ADHD medications as the condition has been diagnosed more liberally.

Positive effects have replicated in larger samples: people with medicated ADHD scored higher on the Swedish SAT than those without medication. This was even the case when the same person was observed over time (d = .11). It’s not a large effect, but it does show that the benefit of the drug generalises to tests beyond the traditional attention/executive function measures.

Adderall is well-tolerated and has few side effects at appropriate doses (5-30mg). It’s addictive, and a controlled substance in most countries.

III.

What ADHD exactly is doesn’t matter. Its symptoms: forgetfulness, lack of focus, poor performance — are legible and easy to measure, so effective and safe treatments for them were found early.

The fact that adderall is a net cognitive benefit suggests to me that the average person has subclinical ADHD; the population’s bell curve is shifted too much in the ADHD-direction. It’s been observed that people with the trait have higher rates of fertility, despite arguably having a disability.

I took adderall for a few months and did not get addicted, but I found the drug extremely totalising. I felt great while on it, but crashed when the effects wore off and built up dependence. I also noticed that I was still functional when I was withdrawing, so I quit. I’ve never gotten addicted to a drug, so I am a bad example in this particular case.

It’s also not true that ADHD treatments make people shorter. People with ADHD have always been shorter than the average person, before the drugs for it got approved.

Overall:

• Adderall and most other ADHD medications work. Among these I include atomoxetine, methylphenidate, dexmethylphenidate, serdexmethylphenidate, bupropion, clonidine, guanfacine, viloxazine, and all amphetamines.

• Drugs that work aren’t necessarily good. The ones with extended release profiles and smaller highs will have lower liabilities for addiction and dependence. Specifically: vyvanse, XR adderall, bupropion fit this description.

• Amphetamines are well-tolerated, but addictive, mood-altering, and highly totalising.

In the scientific literature, what caught my attention was a large meta-analysis on the effect of nicotine on cognitive performance. It was incorrectly executed, so I decided to run on my own. Several of the studies reported multiple effect sizes from multiple groups, so I tracked them. I divided the sample sizes by the number of effect sizes that were reported for each individual group, to get an estimate of the effective sample size of each study.

The aggregate effect size is about 0.38 SD, translating to 6 IQ points.

There is no dose-response relationship.

The quick-and-dirty meta-analytic effect is 0.33. The existence of it was extremely unambiguous (p < .0001).

Random-Effects Model (k = 84; tau^2 estimator: REML)

  logLik  deviance       AIC       BIC      AICc   
-53.6688  107.3375  111.3375  116.1752  111.4875   

tau^2 (estimated amount of total heterogeneity): 0.1178 (SE = 0.0320)
tau (square root of estimated tau^2 value):      0.3432
I^2 (total heterogeneity / total variability):   62.10%
H^2 (total variability / sampling variability):  2.64

Test for Heterogeneity:
Q(df = 83) = 255.1649, p-val < .0001

Model Results:

estimate      se    zval    pval   ci.lb   ci.ub      
  0.3250  0.0508  6.3939  <.0001  0.2254  0.4246  *** 

---
Signif. codes:  0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

I tested for moderators; none of them were significant in the aggregate: dose, smoking status, or domain of cognition.

Mixed-Effects Model (k = 84; tau^2 estimator: REML)

  logLik  deviance       AIC       BIC      AICc   
-46.0473   92.0946  116.0946  143.5801  121.2946   

tau^2 (estimated amount of residual heterogeneity):     0.1155 (SE = 0.0342)
tau (square root of estimated tau^2 value):             0.3399
I^2 (residual heterogeneity / unaccounted variability): 60.32%
H^2 (unaccounted variability / sampling variability):   2.52
R^2 (amount of heterogeneity accounted for):            1.91%

Test for Residual Heterogeneity:
QE(df = 73) = 216.0037, p-val < .0001

Test of Moderators (coefficients 2:11):
QM(df = 10) = 12.2553, p-val = 0.2683

Model Results:

                                           estimate      se     zval    pval    ci.lb   ci.ub    
intrcpt                                      0.3758  0.1788   2.1018  0.0356   0.0254  0.7262  * 
smoking_statusSmoker                         0.2308  0.1140   2.0247  0.0429   0.0074  0.4542  * 
dose_mg                                     -0.0150  0.0099  -1.5103  0.1310  -0.0344  0.0045    
domainAlerting attention-RT                  0.0017  0.2076   0.0082  0.9935  -0.4052  0.4085    
domainFine motor                            -0.1482  0.2320  -0.6390  0.5228  -0.6029  0.3065    
domainLong-term episodic memory-accuracy    -0.1982  0.2106  -0.9411  0.3467  -0.6109  0.2146    
domainOrienting attention-accuracy          -0.0517  0.2740  -0.1887  0.8503  -0.5888  0.4854    
domainOrienting attention-RT                 0.0655  0.2159   0.3034  0.7616  -0.3576  0.4887    
domainShort-term episodic memory-accuracy    0.0902  0.2133   0.4231  0.6722  -0.3278  0.5083    
domainWorking memory-accuracy               -0.3580  0.2436  -1.4694  0.1417  -0.8355  0.1195    
domainWorking memory-RT                     -0.0367  0.2328  -0.1577  0.8747  -0.4930  0.4196    

---
Signif. codes:  0 ‘***’ 0.001 ‘**’ 0.01 ‘*’ 0.05 ‘.’ 0.1 ‘ ’ 1

I averaged all of the effect sizes of the individual publications to estimate publication bias. The regression test suggested that if there was any publication bias, it was likely negative — people wanted to report nulls more than positive effects.

#Meta-analysis with aggregated effect sizes
Random-Effects Model (k = 41; tau^2 estimator: REML)

  logLik  deviance       AIC       BIC      AICc   
-18.3017   36.6034   40.6034   43.9812   40.9278   

tau^2 (estimated amount of total heterogeneity): 0.1088 (SE = 0.0344)
tau (square root of estimated tau^2 value):      0.3299
I^2 (total heterogeneity / total variability):   75.42%
H^2 (total variability / sampling variability):  4.07

Test for Heterogeneity:
Q(df = 40) = 182.8701, p-val < .0001

Model Results:

estimate      se    zval    pval   ci.lb   ci.ub      
  0.3769  0.0616  6.1155  <.0001  0.2561  0.4978  *** 

##### Regression test for publication bias

Regression Test for Funnel Plot Asymmetry

Model:     mixed-effects meta-regression model
Predictor: standard error

Test for Funnel Plot Asymmetry: z = -0.5439, p = 0.5865
Limit Estimate (as sei -> 0):   b =  0.4960 (CI: 0.0497, 0.9422

So, it does seem that the effect of nicotine on intelligence is real, just not exciting — maybe an increase of 3-8 IQ points. I should note that, if the effect is indeed generalised. The effects of it on real world outcomes and broader cognitive function haven’t been studied very well, so it’s difficult to tell how much the cognitive enhancement generalises.

Other notes

• Nicotine, through smoking, increased performance on the Raven’s test by 6 IQ points, but the effect barely passed significance testing.

• Nicotine reduces insepction time by about 0.5 SD (good), and the study had low p-values in the 0.001-0.01 range. Seems legit.

• One study claims nicotine increases mental speed, but not performance on intelligence tests. I’m not inclined to put much weight into this finnding, as they had just 55 subjects. The effects of amphetamines on IQ/SAT type tests, for example, are very small (d = 0.05-0.15), but probably real.

IIXI.

Traditionally, the extent to which a trait is genetic is assessed using the heritability statistic, which denotes the extent to which variation in a trait is caused by genes. This is estimated using pairs of twins or family members of different relatedness.

If members of a household are all similar to each other, regardless of their genetic similarity, then it will be concluded that the trait is strongly downstream of a shared environment; if people in the same household don’t tend to share a trait, it is concluded that it’s downstream of the unshard environment; and if similarity in a trait tracks genetic similarity, it’s concluded to be highly heritable. Most traits are caused by all three of these factors.

Proxies for athletic ability tend to be highly heritable: 85% for height, 80-90%1 for reaction time, 55% for BMI, 60-80% for bone density, 50-70% for VO2% max, and 50-70% for measures of strength:

Twin studies are not exactly the most uncontroversial scientific method. I think they, and family/adoptee studies like them, are generally defensible. These estimates of heritability vary little, if at all, between countries. It doesn’t when it comes to height2 or education, though the heritability of BMI does have a little international variation.

Athletic improvement is a multi-stage process. First, people have to be motivated to get better in the first place. Independent of motivation, some people train in more efficient and functional ways, take different drugs, and have different diets. Finally, people’s bodies respond to training and diet in different ways.

When focuing on the genetics of athletic ability, people seem to hyperfocus on the last stage — the differences in bodily responses to training — and ignore everything that comes before it. The problem here is that everything is heritable — a finding so uncontroversial, it’s been called the first law of behavioural genetics. The heritability of people’s persistent interests is about 66%, and the heritability of dietary habits is about 30%.

In the field of intelligence enhancement, an argument called ‘Algernon’s argument’ — that if there was an easy way to optimise intelligence, nature would have already found it. This logic fails incredibly badly for athletics. Steroids are even more effective than resistance training for building muscle; 50% of olympic athletes admit to being on performance enhancing drugs, despite their illegality. Even legal supplements like protein, creatine, beta-alanine, and caffeine have small to moderate effects on performance. Eating protein and supplementing creatine have basically zero undesirable side effects; the case of caffeine is more debatable.

III.

So, let me be clear. The idea that racial groups that evolved separately for 50,000 years have completely identical genetic predispositions to physical abilities is insane.

The idea that the causes of racial or international differences in sports performance are strongly downstream of environmental or cultural factors is not, though.

Empirically, international differences in grip are massive. The difference in strength between Polish or Swedish men (45kg) and Pakistani men (~22kg) is 23kg, equivalent to 2.6 standard deviations. That’s comparable to 6.5 inches in height, $200,000 in salary, or 39 IQ points.

Now, if we look at the grip strength of South Asian men who live in Britain — not just ones who were born there, but who just live there, the picture is very different. Their grip strength is only 6kg lower than that of British whites:

Because of differences in sample composition, it’s difficult to make exact comparisons between South Asians in Britain and those in South Asia. After making a few assumptions3, I estimated the between-group heritability of grip strength between Northern Europeans and South Asians — in their respective countries — to be 16-28%. Much lower than the heritability of strength at the individual level, which is closer to 60%

As much of a meme ‘variance within vs between’ has become in behavioural genetics because of one specific and infamous example, the idea still applies in the wild.

A little known fact — Chinese youth are now as tall as their American counterparts:

XAXA.

Differences in athletic performance between countries and races has attracted quite a bit of popular and academic attention. Genetics are a hazy explanation for these differences. Sometimes accurate, other times nonsensical.

Those advocating for the hereditarian explanation cite radical overrepresentation of East African runners in endurance competition, or that of West African runners in spriting. Similarly, one could bring up examples that support evironmentally-downstream views: despite the fact that only 11% of the Moroccan diaspora lives outside of Morocco, 73% of the country’s world cup team was born abroad.

The case of Kenyan endurance runners is interesting — it’s clear there are some genetic advantages at play: evolved respiratorial efficiency due to living at high altitude, and an ectomorphoic build that is more suited to running: better at dissipating heat, lighter on the knees.

There is also a cultural factor: there is a tradition where Kenyan schoolchildren run to school, and are incentivised to compete in athletic events. Still, those traditions and environmental factors wouldn’t exist without the genetic advantages; genetically gifted Kenyans are probably more likely to take advantage of them.

Powerlifting, on the other hand, favours more mesomorphic physiques, which are more common in Europe. Predictably, weightlifting is dominated by whites; Korean bodybuilders, believe it or not, are pretty good too. On a per capita basis, Eastern Europeans and people from the Caucasus fare the best.

Kenyans in endurance running remind me of the phenomenon of Koreans in League of Legends (LoL), the most popular esport — meaning competitive video game. Of the top 50 pro players with highest tournament winnings, 56% were born in Korea, 28% were born in China, 14% were born in Europe, and 1 was born in Taiwan. Even ignoring their overrepresentation relative to the global population, South Koreans only constitute 3% of the entire East Asian population; there are as many East Asians living abroad as there are living in South Korea.

European and American LoL teams frequently import Korean players because they’re much better. There is no scramble for racially Asian players who grew up in the West.

In Dota 2, Koreans make up a total of 0% of the top 50 highest paid players ever. Not because they lack a Dota 2 gene, but because the game isn’t popular there. In physical sports, it’s often difficult to separate a region’s cultural preference for a sport and their talent for it. In gaming, it is possible to separate the two, and it’s easy to see that the preferences have a massive impact on national overrepresentation.

Koreans were incredibly dominant in the early days of Starcraft — as in, maybe only 2-5 of the top 50 players in that time were non-Koreans. They fell off after other games became more popular and Western players started getting better; now Korean and non-Korean players are roughly at parity with each other.

Unsurprisingly, hereditarian explanations for differences in ability between nations are unpopular in the esports scene, even among professional players and staff.

Explanations for Korean dominance in esports vary. So far, I’ve seen the following theories: Koreans are better at handling criticism from other players or coaches; Koreans are able to practice against better players — particularly, this is an explanation for why the gap is so large, not why it appeared in the first place; IQ; better internet and lower ping in Korea; and cultural factors surrounding competition and the serious nature of gaming in Korea.

The difference in practice environment seems like a believable explanation as to why the gap is so large — one of the best Western Starcraft players, Naniwa, would say that, when he travelled to Korea, he would fair poorly against even B-tier Korean players. After a few weeks, he would rapidly improve, and become competitive with the top Korean players.

There’s definitely something to the IQ story, but it is a bad explanation for Korean dominance in particular. South Korea is a coutnry with a national IQ of 103, and is better than America, Europe, and China, which all have national IQs in the 95-100 range, and vastly larger populations. So much larger that not even the tail-effect argument makes any sense, mathematically. Ethnically, most of the players on Western teams are either white or asian; there’s a surprisingly large number of Turkish and Arabic players too.

Then we have the overrepresentation of black athletes in the NFL and NBA.

Statistically, 70% of NBA players were black in 2023; in 2019, 59% of the NFL was.

If we look at the general population, black people are more athletic than whites: 1kg higher in grip strength and higher bone density. To actually test whether that causes their overrepresentation in sports would require a precise estimation of race differences in athletic ability for that particular sport in a large, nationally representative sample — which doesn’t exist, to my knowledge. And then we still have the issue that, even if we have that measurement, there’s no guarantee that the difference is due to genes.

If we assume that the overrepresentation is due to group differences in athletic ability relevant to the sport — which I don’t believe, we can calculate the athletic advantage black people have over the rest of the American population.

14,000 professional athletes are employed in the USA, and there are 90 million Americans between the ages of 20 and 40 — that’s z = 3.544. It’s a little difficult to make a z-score here, because there is selection for the particular sport too. Given black people are 13% of the US population, the advantage in athletic ability in basketball would have to be d = 0.73; for football, it would have to be d = 0.545.

Those aren’t trivial differences, by any means. Black people are the same height as whites, and are not much stronger than them — their grip strength is only 1kg (d = 0.22) higher. Their specific build — tall and lean — is definitely more suited to basketball; in football, it would depend on the position.

Discussions over what the null hypothesis should be, what qualifies as evidence, and what qualifies as good evidence — frankly — don’t interest me. It’s a boring debate.

XIII.

People have noted that ethnicities genetically adapt to their environment: Tibetans have a gene that make them better at tolerating environments that lack oxygen; the Bajau people have enlarged spleens that allow them to tolerate long periods of diving.

Genes have been identified with non-negligible effects on performance in sports, such as the ACTN3 gene, where the RR and RX polymorphisms correlate with better performance in sports that require sprinting or power; the XX polymorphism correlates with better performance in endurance. Only 1-3% of black people have the XX genotype, 18% of whites do, and 25% of asians do.

After screening 476 initial registrations, 25 studies were included in the final analysis (13 different countries; 14,541 participants). In power athletes, the RX genotype was predominant over the two other genotypes: RR versus RX (OR 0.70; 95% CI 0.57–0.85, p = 0.0005), RR versus XX (OR 4.26; 95% CI 3.19–5.69, p < 0.00001), RX versus XX (OR 6.58; 95% CI 5.66–7.67, p < 0.00001). The R allele was higher than the X allele (OR 2.87; 95% CI 2.35–3.50, p < 0.00001) in power athletes. Additionally, the frequency of the RR genotype was higher in power athletes than in non-athletes (OR 1.48; 95% CI 1.25–1.75, p < 0.00001). The RX genotype was similar in both groups (OR 0.84; 95% CI 0.71–1.00, p = 0.06). The XX genotype was lower in power athletes than in controls (OR 0.73; 95% CI 0.64–0.84, p < 0.00001). Furthermore, the R allele frequency was higher in power athletes than in controls (OR 1.28; 95% CI 1.19–1.38, p < 0.00001). Conversely, a higher frequency of X allele was observed in the control group compared to power athletes (OR 0.78; 95% CI 0.73–0.84, p < 0.00001). On the other hand, the frequency of the RR genotype was higher in power athletes than in endurance athletes (OR 1.27; 95% CI 1.09–1.49, p = 0.003). The frequency of the RX genotype was similar in both groups (OR 1.07; 95% CI 0.93–1.24, p = 0.36). In contrast, the frequency of the XX genotype was lower in power athletes than in endurance athletes (OR 0.63; 95% CI 0.52–0.76, p < 0.00001). In addition, the R allele was higher in power athletes than in endurance athletes (OR 1.32; 95% CI 1.11–1.57, p = 0.002). However, the X allele was higher in endurance athletes compared to power athletes (OR 0.76; 95% CI 0.64–0.90, p = 0.002). Finally, the genotypic and allelic frequency of ACTN3 genes were similar in male and female power athletes.

An ACTN3-downstream theory would predict black people to be poor endurance runners and asians to be good ones. In practice, this isn’t true because black people have ectomorphic physiques which are better suited to running.

Black people also have fewer repeats of the CAG polymorphism on the androgen receptor gene than whites, which has been hypothesised to cause higher androgen sensitivity.

There are locker room theories about national/ethnic differences in sport performance being downstream from willingness/ability to use steroids and their physiological response to them. Empirically, hispanic and black teenagers are about equally likely to claim they use anabolic steroids… if they are straight.

I assume the elevated rates of steroid use in sexual minorities are due to normal teenagers lying about their behaviour for fun.

If we’re talking about differences in the USA, then rates anabolic steroid use do not explain race differences in athletic performance, but perhaps their response to them at the top level could. It’s not inconceivable, however, that access to more and better performance enhancing drugs in the Soviet Union contributed to their success in weightlifting.

Contrary to popular belief, race differences in total testosterone are minimal, if they exist at all:

This evidence only refutes the insane version of the theory, which is that genes play zero role in race differences in athletic ability. Not the empirically supported one — that environmental factors play a large role in international differences in athletic ability, or that there are race differences in sports selection that are caused by cultural factors.

It’s notable that sports dominated by black people tend to be those that require less equipment and money: running, basketball, and football; the only exception is weightlifting, where white performance is higher due to differences in physical morphology. The racial demographics of boxing in the USA shifted over time: it was first dominanted by Jews — no joke — in the early 1900s, then Irish and Italian, and now black and hispanic. This tracks poverty more than any real biological difference.

In fact, Jews entered the ranks of American boxing in large numbers and by 1928, were the dominant nationality in professional prizefighting, fol¬ lowed by the Italians and the Irish. Ten years later, Jews sank to third place, preceded by the Italians and the Irish. When World War II ended and the G.I. Bill of Rights and other avenues of advancement became available, boxing was no longer attractive to the Jews as participants. By 1950, there were virtually no Jewish boxers, and their number has been minuscule ever since. A similar decline occurred among Jewish trainers, but Jewish managers, promoters, and matchmakers continue to maintain a presence.

The traits that cause differences in performance like height or bone density are polygenic. As such, the same will be true for genes that cause differences in performance in sports.

Normally, when talking about the subject of race and athletics, people attack the idea of racial categories, and how well they map on to genetic differences. It is true, for example, that there is more genetic diversity in Africa than outside of it. The fact of the matter is that people dislike racial categorisation because they find it uncomfortable for social and emotional reasons, not because of any scientific or statistical beliefs. If accuracy was the only objection, then they would call for more genetically-informed racial terminology, and they… don’t.

If we want to complain about broad and cloudy concepts, the obvious culprit here is the idea of ‘athletic ability’, not race. Sometimes, the traits that make you good at one sport are antagonistic to what makes people good at others; some muscle fibers are optimised for strength, others are optimised for endurance.

People with hypermobile joints are much more suited for dancing than long distance running; bone density prevents injuries, but makes swimming more difficult; muscle fibers are optimised for strength or endurance; lanky people are better at running; stocky people are better at weightlifting. Professional athletics is looking for a microniche where your body performs 0.2% better than other athletes.

XIY.

To summarise, I think the most clear genetically caused group-level advantages are differences in frame type: the tall and narrow frame of Africans make them better runners, while the compact frame of Europeans make them better powerlifters.

The causes of their relative representation rates in complex sports: tennis, soccer, combat sports, basketball, and football — is more debatable. This is where, I think, cultural selection becomes a much better explanation. The endurance and reaction time of whites might be an advantage in tennis, but so would the speed and power of a black person. The fact that great tennis players tend to be white is probably because most people who play tennis are, well, white.

I.

Regarding my father’s inability to build muscle; Jews and American Indians aren’t exactly the most stereotypically athletic ethnic groups. If we look at statistics on differences in grip strength between races, Hispanics only trail whites by 4lb — 0.37 standard deviations. So my dad rolled the wrong genes at an individual level.

Otherwise, my dad is athletically gifted and active. I haven’t beat him in tennis a single time, and he often plays with people 10-30 years younger than him. He is 55.

The only edge I have on him, controlling for age, is hypertrophy and reaction time. The advantage doesn’t map on to a difference in the ACTN3 gene; we both have the endurance variation.

I have my own athletic limitations: AMPD1 deficiency and joint hypermobility. I checked my dad’s genome, and he carries an allele for the former disorder — which is recessive. He complains that his joints are too stiff, not too flexible.

Funnily enough, AMPD1 deficiency is 3x more common in white gentiles than Jews, and even rarer in American Indians.

The common thread in our athletic strengths and weaknesses is not race, or even genes for that matter. There isn’t even one.

1

Increases after correcting for the unreliability of reaction time:

set.seed(1)

n_black <- round(38929319 / 10)
n_white <- round(223553265 / 10)

black <- rnorm(n_black, mean = 0.54, sd = 1)
white <- rnorm(n_white, mean = 0, sd = 1)

both <- data.frame(
  race = c(rep("Black", n_black),
           rep("White", n_white)),
  performance = c(black, white))


##dawdaw
#awdawd
#awda##

nfl <- both %>% filter(performance > 3.51)

nfl %>% group_by(race) %>% summarise(n = n())

5828/10855

####################

n_black <- round(38929319 / 10)
n_white <- round(223553265 / 10)

black <- rnorm(n_black, mean = 0.73, sd = 1)
white <- rnorm(n_white, mean = 0, sd = 1)

both <- data.frame(
  race = c(rep("Black", n_black),
           rep("White", n_white)),
  performance = c(black, white))


##dawdaw
#awdawd
#awda##

nba <- both %>% filter(performance > 3.51)

nba %>% group_by(race) %>% summarise(n = n())

10671/15623

BPC-157 likely works as a healing agent, but it might cause anhedonia and cancer. Whether it should be taken depends on the situation at hand. In terms of what parts of the body the drug acts on, perhaps the better question to ask which ones it does not heal — there are studies that find positive effects on joint, muscle, and even gut recovery.

Low doses (0.1-123mcg/day) are likely sufficient for humans; the conventional doses (200-1000mcg per day) that are recommended online are much higher than the ones used in animals, controlling for body weight. Multi-day dosing could potentially increase the drug’s potency.

About 20% of people on reddit who took BPC-157 report anhedonia — the inability to feel pleasure or pain — as a side effect. It’s possible that BPC-157 interacts with catecholaminergics (SSRIs/NDRIs/etc), and counteracts their effects, potentially inducing anhedonia or withdrawal. I took it while on adderall, and that might have factored into the anhedonia I got from it. I quit, and it went away. (Edit: I started taking it again in the form of 1mg of KLOW/day for a week, and I didn’t experience the anhedonia again).

Most people report the side effect being temporary; a few say it was permanent.

The science

BPC-157 is a peptide that acts as a broad-spectrum healing agent. It can be taken orally or injected into the body; it’s considered to effectively repair ligaments, muscles, bones, skin, the gut, and much more. We don’t know how BPC-157 works. Most of the theories (e.g. VEGF activation, NO-1 modulation), involve the compound activating receptors that lead to the the body spending more resources on healing itself. We don’t know if the body even makes BPC-157; the peptide itself is derived from a protein found in gastric juice — which doesn’t leave the digestive system.

Human studies on the compound itself are bad, typically containing no control group or an extremely small number of subjects. Dosages, drug interactions, effect sizes, and side effects have not been documented. Typically the recommendation online is to take 200-1000mcg of BPC-157 daily, cycled for 4-8 weeks, then 2-4 weeks off. Quite a large dose compared to what the animal literature uses.

There’s several justifications that one could make for that dose. If there is a dose-response relationship between the peptide and its effect, then it would be ideal to take a higher dose. It’s possible the pharmacokinetics of the drug differ significantly between humans and animals, making it so humans require larger doses for comparable effects.

These are not bad ideas; the recommended doses are still absurdly high.

Let me pull up a few rat studies. In this one, doses as low as 10ng/kg — 0.7 mcg in humans — are as effective as doses of 10 mcg/kg. That’s a 1000x difference.

The context here is that they disconnected the muscle and bone in the quadriceps of some rats. Apparently, an injury that does not heal on its own in their species; adding BPC-157 to their water reattached the muscle to the bone.

A different study on healing severed achilles tendons in rats found something similar, though the rats in the control group also healed eventually. It sped up the healing process by about 10-20%, in all doses except for 10 pg/kg, which was completely ineffective.

BPC-157 research is infamously concentrated in a Croatian research group led by Sikiric, the developer of the drug. A boring criticism; there are also studies conducted by people outside that circle that also find positive results.

A Korean study administered some rats a single injection of saline, BPC-157, or morphine. 60 minutes later, they either injected them with formalin (toxin) or made a small cut to their hind paws — a 2x3 study design. They sowed up the incisions and treated with anti-biotics. They then monitored their responses to pain over the next seven days.

Rats treated with BPC-157 had more blunted responses to pain, indicating either a better recovery or an anesthetic effect. Rats treated with morphine fared better after it was administered, then worsened, probably because of withdrawal.

In the formalin test, rats treated with BPC-157 flinched less than those administered with saline 10 minutes after the formalin was injected; but not 10-60 minutes later (in phase 2).

There existence of a dose-response effect here looks quite ambiguous, despite the statements of the authors. It also might be the case that the dose-response effect differs between effects — the anesthetic and therapeutic ones — assuming they exist in the first place. The doses of BPC-157 used here are also quite high, above when you would even expect the dose-response effect to appear.

It’s pretty clear BPC-157 works in animals, it would be overkill to go through more studies. There is still the question of human extrapolation, whether doses in rats generalise to people.

Typically, humans are given lower doses of drugs than rats are, due to their lower relative surface area and slower metabolism. The FDA’s heuristic is that, for coverting rat/mouse drug doses to humans, the amount must be 6.2-12.5x lower controlling for body weight. This is not necessarily the case for BPC-157, but there is no particular reason to think that it does not.

In rats, the bioavailability of BPC-157 is 14-19%; within beagle dogs it’s 45-51%. Rats are more genetically similar to humans than dogs; regression-to-the-mean logic implies it’s likely that the human bioavailability is higher than the rat one. Unless BPC-157’s effects within humans differ significantly from those observed in rats and mice, it’s possible that doses as small as 0.1 mcg1 are effective in humans.

Which is insane, and likely wrong, but keep in mind that BPC-157 is a compound that activates receptors. It’s unlikely it does the dirty work of repairing the body itself.

My intuition is that the rate limiting factor in the efficacy of BPC-157 is the volume of injected liquid, not dosage. At the 0.01-0.05ml range, it becomes more difficult to reliably control the volume due to various factors: dead space in the syringe, the precision of human muscles, and slanting (e.g. one part of the liquid being on the 4 unit bar, and the other part being on the 2 unit bar).

Most BPC-157 vials have a volume of 3ml and 5-10mg of peptide powder. This means that, realistically speaking, the smallest consistently injectable dose of BPC-157 is somewhere between 30-100mcg depending on the vial and syringe. Unless the solution is deliberately diluted by removing reconstituted peptide and replacing it with BAC water.

Ignoring the constraints of injecting, I’m not really sure what the optimal dose is. If we assume a worst case scenario: the human bioavailability is 10x lower than in rats, the surface area conversion factor doesn’t apply, and maybe humans even have some unique quality that makes the drug 10x less effective — that gives us a worst-case dosage of 62-123mcg2. Still much lower than what people tend to use.

My intuition regarding the dose-response effect is that injecting more is not better. Even when people have severe and urgent injuries like gunshot wounds, there is little the body can do to speed up the recovery process. Even with all the drugs, energy, and water in the world. Releasing more healing signalling molecules should theoretically redirect more resources towards the injury, but the thing is that it seems the signalling can only do so much. Gunshot wounds take at least several weeks to heal, even with state of the art medical care and optimal health.

There is also the question of dosage frequency. People typically recommend daily doses + cycling the drug. I don’t think this is necessarily ineffective, but the drug clears from the body pretty quickly; the half life is lower than 30 minutes… in rats and dogs. People who want stronger effects might find better results from dosing 3 times a day rather than 3x as much at once.

Cancer

BPC-157 is a generally well-tolerated drug. Humans taking it report few side effects, and neither do studies on animals. A lethal dose has not been established.

One of the major concerns with the drug is that it causes cancer. BPC-157 is an angiogenic drug, which means that it contributes to the formation of new blood vessels. Theoretically, these could latch on to new tumours and contribute to their growth — causing cancer.

Some anti-cancer drugs, like Axitinib, treat cancer by doing the exact opposite of what these peptides do: inhibit angiogenesis through the VEGFR pathway (however that works). Many other cancer treatments are angiogenic inhibitors, for that matter.

Things that have been proven to cause cancer in humans are almost always shown to be carcinogens in animals. So much, that some scientists think that all human carcinogens also cause cancer in animals. I’ve heard some say that arsenic causes cancer in humans but not animals, but that’s it. That said, there is no evidence (not saying bad evidence!) BPC-157 causes cancer in animals. It’s all theoretical.

No evidence does not mean an absence of effect here; testing for carcinogenic effects properly requires a specialised methodology due to the fact most animals have shorter lifespans. In some cases, animals (e.g. mice) genetically altered to have cancer mutations or the implantation of tumours into animals to see if the cancer grows.

Some people have claimed that BPC-157 is an anti-cancer drug. That’s not necessarily false, but there is no good empirical evidence to support that claim:

The comment by Sikiric et al. cites “anti-tumor potential” yet offers no published in vivo tumor-growth or metastasis studies. A single melanoma cell-line experiment from 2004 [8] (unreplicated) is insufficient to support anticancer claims, while pro-angiogenic signaling remains a plausible tumor-promoting hazard. To date, no published in vivo data demonstrate that BPC 157 inhibits tumor progression, reduces tumor volume, or suppresses metastasis.

In line with this, in the comment, the authors claim that oncologic risks are “entirely excluded,” yet they fail to cite a single in vivo study involving solid tumors. Paradoxically, their own previous work demonstrates BPC 157 activates angiogenic signaling—precisely the kind of mechanism known in oncology to potentially support tumor growth. The study by Kang et al. [9], which was cited by the group of Sikirc et al. as a solid confirmation of in vivo anti-tumor activity mediated by BPC peptide, primarily focused on alleviating symptoms of cachexia and inflammation in tumor-bearing animals, rather than inhibiting tumor growth or destroying cancer cells. Therefore, such studies cannot be interpreted as the evidence of BPC 157’s antitumor activity but rather as a potential supportive effect on the overall condition of the diseased organism.

I’d say it’s likely BPC-157 causes cancer; we don’t have the proof it does yet.

Anhedonia

Imagine if there was a drug that turned you into the king of the world, but removed your ability to feel anything. Would you take it? I assume not.

The argument about BPC-157 potentially causing cancer dominates scientific discourse, but people who actually take the drug seem to be complaining more about anhedonia. Particularly, when they take it with certain medications; the common link I see between them is that they are catecholaminergics: adderall, SSRIs, and whatnot.

The “experts” claim that there is “no evidence” that BPC-157 causes anhedonia. Of course there is no scientific evidence it does. Where are the human studies?

I took BPC-157 for about a week, in the form of KLOW: a combination of GHK-cu, BPC-157, TB-500, and KPV. Took it because of struggles with chronic knee pain + a subluxated shoulder. Tried various doses out of curiosity — 66mcg, 132mcg, and 625 mcg (intramuscular, into deltoid). Didn’t notice any differences in effects.

Felt great on it, regardless of the dose. Nasal passage was clearer, pain/fatigue improved, and it was just easier to move my body. The shoulder seemed to start recovering faster, but it’s hard to tell because of the way recovery works.

Unfortunately, I felt anhedonic. I quit. I recovered within a week.

I was also taking adderall at the same time. I quit that too, as a precaution.

Many such cases. Somebody asked about said side effect on reddit, and people commented on whether they got it. 17 said yes, 58 said no; 9 were complicated cases.

That means 20% of people in the thread who took BPC-157 reported anhedonia. A large number; you’d struggle to find a figure that high, even for something like SSRIs.

Apparently for some people, the anhedonia is permanent (!). One of the worst side effects you could get from any drug. Even worse than getting cancer — at least you can still enjoy life.

Generally, I’m pretty skeptical of cases like these. It could be an attribution error, where the permanent side effect was caused by something else. It could be psychosomatic: people getting in their own heads about whether they are experiencing something so much that they actually experience it. That doesn’t mean the drug didn’t cause anhedonia; it just did it through a different causal pathway.

Here’s the problem. Now you know you could get anhedonia from taking BPC-157. So if you take it, you will monitor your body to check if it happens to you. The problem is that a lot of things that are enjoyable are that way because you aren’t checking yourself. You become absorbed. Asking yourself whether you like a video game pulls you out of the trance, and makes the magic disappear. But if you don’t check yourself, you could be wrecking yourself. Quite the catch 22.

When I was on BPC-157, sometimes I would just stare at a computer screen, wanting to care about something, but I couldn’t. I was worried about whether I permanently damaged, and didn’t even feel any dread about what I did. I just felt empty.

I checked out some of the animal studies on how BPC-157 interacts with amphetamines and hedonic responses. It seems that BPC-157 counteracts some of the effects of amphetamines on rats, including repetitive behaviour; it also seems to heal disruptions in behaviour caused by chronic amphetamine use.

So maybe the anhedonia wasn’t caused by BPC-157 itself, but by nullifying the effects of adderall, which then sent me into withdrawal — which caused the anhedonia.

I am not here to give medical advice — I do not have a medical license — but if you also have chronic pain caused by joint hypermobility, it’s unlikely that BPC-157 or anything in KLOW will fix it. It may do so temporarily, but it would be unwise to take a drug that may cause cancer for your whole life, even if it is cycled.

BPC-157 Adverse Event Database

Anthonystaj has developed an adverse event database for BPC-157 by mining every single reddit thread that mentioned the drug. In total, 1370 users reported 4254 side effects. Half of them were neurological:

Anhedonia was at the top of the list, when it came to psychiatric side effects:

Of these neurological cases, 29 showed rechallenge data: the side effect came back with use:

The legal question

I think BPC-157, and all peptides like it, should be legalised anyway. No matter how dangerous. Logic is simple: before legalisation, main and side effects can’t be proven the same way. If it’s legalised, and it’s dangerous, the danger will show up in the data. Then we can make them illegal. That is the meaning of accelerationism.