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.

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 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:

Read more

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.

What was initially an inside joke at school took a turn for the worst. Around the age of 15, I started weightlifting, and ended up injuring my elbows and knees. To the point that it hurt to walk, so I limped instead. I even used crutches a few times.

I wasn’t sure what was the problem. Maybe I was lifting too often, or with poor form… which was probably true.

The exact chain of events is blurry, but at some point, I started to connect the dots between flexible joints and joint pain. It’s a common complaint of patients with hypermobile joint disorders — flexible joints tend to overextend and get injured, and are less capable of sustaining weight.

So my mother drove me to the hospital to see a doctor. I told him that my joints were in pain, and that I thought it was connected to the flexibility of my own joints. He was pretty convinced of the flexibility after a demonstration. The doctor, unfortunately, said there was nothing he could about the pain, that there was no cure for my condition.

I stopped listening after he said that. Later, my mom told me that he thought I did have some kind of hypermobility disorder. I haven’t bothered seeing a doctor about the issue since.

II.

Ehlers-Danlos syndrome (EDS) refers to 13 different connective tissue disorders, unified by joint hypermobility and strechy skin. Lesser-known complications incude cardiovascular failure, joint pain, and scoliosis. Some people with the disorder do not have the characteristic strechy skin. Treatments are limited in variety and efficacy — typically losing weight and strength training are encuraged; sometimes opioids are prescribed for pain, but doctors are generally wary of doing that. The disorder itself is genetic and incurable.

It also turns out that Ehlers Danlos syndrome is correlated with a variety of symptoms and medical conditions: narcolepsy, POTS, ADHD, autism, LGBT identification, MCAS, allergies, IBS, and dysautonomia. That covers, well, everything in the body — the brain, sex, cardiovascular system, gastrointestinal system, immune system, and nervous system.

Some of the effect sizes are large: 42.5% of EDS patients have a psychiatric diagnosis — the condition is most strongly associated with autism (7.4x) of all mental disorders. Transgenders are 132x (?) more likely to have a hypermobile joint disorder. Which replicates too — a different study found 17% of teenagers with EDS are trans.

Personally, I’m inclined to believe some of these associations are real. I have some of these comorbidities1, and so do my siblings. They also have flexible joints, but not to the same extreme. You could say they regressed to the mean.

It would also be surprising if mutations affecting collagen, the most common protein in the body, were specific to just joints and skin. It’s also found in the brain, gut, teeth, cornea, and spine. Name a random body part: it’s more likely than not that collagen is there.

There is a theory the correlations might be specific to clinical samples due to selection, but it’s hard to test that theory, since EDS is such a rare disorder. This has caused people to say there is “no evidence” EDS is associated with these conditions.

Bad evidence is bad, but it is still evidence.

Related: The Phrase “No Evidence” Is A Red Flag For Bad Science Communication

The critics of the comorbidity literature are essentially arguing that the symptoms of connective tissue disorders are limited to the skin and joints, even though there is connective tissue everywhere in the body. Which is a ridiculous null hypothesis. It’s not even a good alternative hypothesis.

III.

On reddit, people with hypermobility disorders report being ignored, belittled, or rejected by their doctors for seeking care. The r/ehlersdanlos subreddit even has posts that advise people on how to work with doctors to get medical testing:

70% of people diagnosed with a joint hypermobility disorder are women; about 95% (?) of the people seeking care for it are female. It’s an autosomically-caused disorder, so the true ratio is 50/50, but sex differences in musculature and the formation of connective tissue lead to the disorder having an exaggerated expression in women.

There’s another variable at play. I assume a lot of the other men with joint hypermobility did what I did: went to the hospital, got told the condition isn’t curable, and left. Women, on the other hand, are more likely to seek diagnoses and care for medical conditions in general.

The male strategy is definitely more culturally valorised. Is it better? Not really. Sometimes, not seeking medical care for uncertain or benign symptoms works: the symptom either doesn’t matter or it goes away on its own. Other times, it leads to late diagnoses or symptoms not getting proper treatment.

Ehlers Danlos Syndrome has acquired a reputation for being an “instagrammable illness”, one that people fake or aesthetise for attention. This has been invoked as an explanation for why hypermobile joint disorders have so many comorbidities.

The diagnostic environment for people with EDS is already complicated. Then you add in the instagrammable ilness stigma, which makes doctors suspicious of people seeking care for the condition, maybe for good reason.

These debates about the social dynamics of EDS bore me. Muddled by Judeochristian2 morals and idiots on the internet. Let’s pull out the economics.

A patient has physiological problems — pain or fatigue — perhaps caused by joint hypermobility. Incentives pull them away from the medical system because it does not reliably diagnose the condition or provide options for treatment. So people pivot to the internet to get what doctors normally give them: validation, information, and suggestions for treatment.

But it’s still the internet: full of hypochondriacs, grifters, false information, questionable anecdotes, and people who just want attention. That then affects the reputation of the disorder, which makes its diagnosis more difficult.

The fact that EDS is incurable, rare, and illegible enables people to fake it. So they do. Not much more depth to it than that.

In other words, Ehlers Danlos syndrome being a meme is downstream of economic incentives and the biological constraints of the disorder. Not random social trends, or evil people in a room full of smoke.

IV.

Oh, and I forgot to say. Ehlers Danlos Syndrome is a made up disorder.

Worse, it’s not even good at being a made up disorder.

It’s more analogous to ‘intellectual disability’, than something concrete like Down’s syndrome — except that it affects connective tissue and not the brain.

There is no consistency in what is and is not ‘Ehlers Danlos Syndrome’. If it was mutations in collagenous genes, then Alport syndrome would qualify. It’s not hypermobility: there are genetic disorders associated with hypermobility that do not form part of the EDS umbrella (e.g. Marfan syndrome). There are even types of EDS, like Musculocontractural EDS (mcEDS), that are associated with stiffer joints.

Maybe Ehlers Danlos syndrome is supposed to be an umbrella term for joint hypermobility disorders with specific causes that generalise past skin and joints — like brittle cornea syndrome. Using the intelligence analogy — joint hypermobility is analogous to having a low IQ, independent of whether there is a specific cause, like brain trauma or a chromosome deletion. Ehlers Danlos is more like Down Syndrome: not only do people with Down’s have a low IQ, but there is a specific cause (trisomy) and accompanying comorbidities, like obesity or a short neck.

This would make sense… if there wasn’t another vague diagnostic label under the EDS umbrella — hEDS. A joint hypermobility disorder with an unknown cause. Translated into English, it means “there’s something wrong with your connective tissue and we have no idea what it is”. And that still ignores the many disorders that feature joint hypermobility that are not categorised as subtypes of Ehlers Danlos syndrome.

A different way to see it: there are 28 different types of collagen. Coded by 44 genes and 2 pseudogenes. In total3, those genes add up to about 6,567,598 base pairs. Assuming ~95% of mutations are benign, that gives us 300,000 potentially causal variants — most of these will not vary in the general population, and if they do, only a few will have large effects. And then you have all of the genes that affect connective tissue that have nothing to do with collagen.

If so many genetic mutations and variants could affect the expression of connective tissue, the reasoning behind grouping a bunch of disorders under one label starts to look a little unreasonable.

‘Syndromic intellectual disability’ is a useful label, because it gestures at a problem (low IQ) and the suspicion of a single cause, without having to identify one. ‘Ehlers Danlos syndrome’ is not, because it is pretending to identify a specific cause without actually doing it. And everybody loses their minds: patients, doctors, medical researchers, and people on reddit.

V.

The beighton score is the IQ test of joint hypermobility. It involves testing whether the thumbs, elbows, knees, and spine can bend past a certain point, and adding up the nine tests into one score.

An OK idea which… somehow turned into the gold standard hypermobility test.

The biggest problem is that the expression of even a single type of Ehlers Danlos syndrome varies significantly. Among people with genetically confirmed cEDS, which supposedly causes generalised joint hypermobility, only 59% pass the beighton test:

They also reported the frequency of comorbidities. Based on a visual glance, they seem high, but not as high as the percentages in the comorbidity studies.

What’s the problem?

Circling back to the intelligence analogy, there is a consensus that an IQ test alone is awful at diagnosing intellectual disability. Not just among the people who are labelled as experts, but among the IQ-realist crowd as well.

Why? Well, it simply doesn’t work.

Let’s use 22q11.2 deletion syndrome (DiGeorge syndrome) as an example. In accordance with its name, it involves a deletion in part of the 22nd chromosome, which causes intellectual disability and some other comorbidites. These individuals score about 2 standard deviations below the average person on an IQ test.

The myth on the internet is that an IQ score of below 70 equals mental disability. If 70 was the cutoff, only half of the people who have the mutation would get diagnosed, and about 2% of the general population would be shoved into the same category; most of who do not have any specific problem, besides scoring poorly on a test.

Now, we circle back to Ehlers Danlos syndrome (this will happen many times). The reliability of the beighton test is mediocre — a meta-analysis of 24 studies found a mean inter-rater reliability of 0.75 — the authors of the publication thought that implied the beighton scale was a “highly reliable clinical tool”. An offensively incorrect interpretation4, which can be ignored for now.

When we are diagnosing people with Ehlers Danlos syndrome or another hypermobility disorder, we are dealing with outliers. Typically, outliers regress to the mean in a disproportionate way — this is called the winner’s curse in statistics.

This phenomenon makes it difficult to identify gifted students with IQ tests.

When using composite ITBS scores, which have a reliability of 0.98 (??): 50% of students who were labelled as gifted in 3rd grade would not have qualified as such, had they been tested in the 8th grade instead.

Part of this is that people have different developmental curves for intelligence, but it also has to do with the way cutoffs work. A test with a reliability of 0.9 will still misclassify 50% of the people who scored in the top 1%.

Doctors using beighton scores to diagnose Ehlers Danlos Syndrome are doing something far more ineffective: using a tool with a inter-rater (aka maximum) reliability of 0.75, to diagnose a disorder with a rarity of 1/5000.

My argument here isn’t that a lot of people are incorrectly diagnosed with hypermobility disorders by fluking the beighton, though I’m sure that happens. It’s that many people, particularly with forms of EDS that do not cause generalized hypermobility, are being screwed over by a simplistic and mediocre test.

In some cases, these missed diagnoses can make the difference between life and death. Vascular EDS in particular can lead to random arterial ruptures, which can be fatal; the life expectancy of people with the condition is about 50 years.

VI.

Medicine and psychiatry both have a problem where they want to merge classificatory and diagnostic labels. ‘EDS’ is a classification. ‘A mutation in the COL5A1 gene causing strechy skin and hypermobile joints’ is a diagnosis.

This also generalises to other debates in science — is chronic fatigue real? As a symptom, sure. As a disorder — chronic fatigue syndrome? The wrong question. If we can identify a causal pathway by which people have persistent fatigue, then why don’t we call that its own thing?

Then we have psychiatry. Is ADHD real? Or is it another way of reframing low conscientiousness/intelligence/energy/executive function, a personality type, or disliking rejection, spreadsheets, and school? Arguing ADHD is one of these things is kind of like answering the question “what do you want to be when you grow up?” with a colour. “I want to be red when I grow up” — “ADHD is executive dysfunction”.

ADHD is a classification used to identify problems that can be solved with stimulants.

There is an uncontested assumption in the EDS discourse that I have not seen other people highlight — whether knowing you have the disorder matters. Does knowing you have an uncurable, rare disorder actually help you? Making you feel special doesn’t count.

My vote is yes.

Let’s say God swoops down from the heavens to tell me my recurring joint pain is not caused by hypermobility.

Well, my joints are still in pain. What causes that then?

Maybe the pain is psychosomatic. Does knowing that matter? To me, it does.

What if the pain is caused by a different disorder, like rheumatoid arthritis? Well, that can actually be treated.

VII.

To have Ehlers Danlos Syndrome is to have a body that does not work, because of a disorder that does not exist. You can try going to a doctor — most of them will not know about the disorder. If they do, they might just assume you are malignering (aka a munchausen) from the get go. And if they do trust you, they are likely to use inadequate diagnostic methods like the Beighton score. And then, even with a diagnosis, there is little the doctor can do to help you, even if they care. Internet communities can give some useful information… but it’s still the internet. The truth of whether you have this nonexistent disorder will still matter to you, even if nobody understands why.

And that’s if you are lucky enough to live a developed country.

1

• Narcolepsy: probably. I have the sleepiness, hypnohallucinations, and disordered sleep. The condition accelerated around the ages of 16-20. Some symptoms, like sleepwalking and randomly falling into deep sleep, were there since I was young.

• ADHD: subclinical. Older sister, younger sister, mom, and all three of her siblings have it. Yes, all four.

• Autism: subclinical. The only psychiatrist I ever went to thought I had aspergers, but my mom pushed back against the diagnosis; it would have prevented me from going to private school (didn’t grow up in the US).

• Depression, anxiety, headaches: fortunately not.

• Allergies: cats, dogs, and probably pollen. Went into anaphylactic shock after chewing on a Brazil nut… it was so disgusting I spit it out and washed out my mouth. Some nuts really are too bitter to swallow. Dad (not hypermobile) and older sister also have problems with allergies. Thankfully, H1-blockers are highly effective and OTC.

• POTS: maybe. Ever since I was a child, I would occasionally see stars whenever I stood up. I thought that was normal, but it indicates a drop in blood pressure. My blood pressure off stimulants (~95/55) is very low. I’ve randomly fainted twice already. Sister was diagnosed with the condition; brother also faints a lot, but I don’t think he’s talked to a doctor about it.

• Tinnitus: when I was a child, I thought it was normal to hear buzzing in quiet environments. Apparently that’s, well, tinnitus. Not bothersome or particularly elevated though.

• Temporomandibular Joint Disorder: if I open my jaw far enough I hear some popping sounds. Not bothersome or notable. It’s also common in Latin Americans.

• Subluxations: they come and go. Just had a shoulder sublixation like three weeks ago.

• Wrist pain: used to have issues with it. I honestly think it was psychosomatic. My joint hypermobility is nonexistent in smaller joints; other people have reported similar experiences with gaming causing psychosomatic joint pain. Specifically, Mikyx (LoL player) reported having problems with wrist pain, which improved after reading a book about… back pain. From what I read, it identified the autonomic nervous system as being implicated in chronic pain. Don’t know if that’s actually true. My impression is that the author is saying “psychosomatic conditions cause chronic pain” in a scientific and emotionally acceptable way.

• IBS: used to have it. Changed diet. Went away. Don’t even remember what I changed, but I’m glad it’s gone. Maybe I shouldn’t ask too many questions…

• I noticed my right ring finger was deformed when I was 16 years old, and thought it was from playing video games or excessive computer use. Apparently, it’s called a swan neck deformity, a side effect observed in hypermobility disorders. Not sure if that is the actual cause though, since my small joints aren’t hypermobile.

The effect of paternal age on offspring attractiveness has recently been investigated. Negative effects are predicted as paternal age is a strong proxy for the numbers of common de novo mutations found in the genomes of offspring. As an indicator of underlying genetic quality or fitness, offspring attractiveness should decrease as paternal age increases, evidencing the fitness-reducing effects of these mutations. Thus far results are mixed, with one study finding the predicted effect, and a second smaller study finding the opposite. Here the effect is investigated using two large and representative datasets (Add Health and NCDS), both of which contain data on physical attractiveness and paternal age. The effect is present in both datasets, even after controlling for maternal age at subject’s birth, age of offspring, sex, race, parental and offspring (in the case of Add Health) socio-economic characteristics, parental age at first marriage (in the case of Add Health) and birth order. The apparent robustness of the effect to different operationalizations of attractiveness suggests high generalizability, however the results must be interpreted with caution, as controls for parental levels of attractiveness were indirect only in the present study.

The p-values check out:

Intuitively, the idea makes sense: older parents will have more genetic mutations, which will cause them to be less attractive to their peers.

The problem is that this could be confounding: that attractive parents have children at earlier ages. It’s an issue the authors were aware of, and tried to control for indirectly.

To test the extent to which confounding played a role, I checked the raw data of the Wisconsin Longitudinal Study, which had the yearbook photos of the participants rated by 12 different researchers on the basis of their physical attractiveness. It turns out that attractive people have kids at an earlier age. The magnitude of the correlation matches the one between parental age and child attractiveness, just in the opposite direction. And it’s not like the original correlation was strong to begin with.

It holds for both men and women:

The idea that older parents have more mutations, and that those genetic alterations have negative effects on the appearance of their children is not unreasonable. What is disputed is the extent to which that correlation is causally mediated.

Chater’s thesis is that the mind is flat — superficial, simple, and unpropositional.

We think we have unconscious beliefs, personality traits, or desires that inform our thoughts and actions. The author argues those things do not exist, and that our actions and thoughts are made up based on what we have experienced before. That we believe what we do because we chose to believe it at some point in the past.

In his own words:

We have all been victims of a hoax, perpetrated on us by our own brains. Our brains are spectacular engines of improvisation that can, in the moment, generate a colour, an object, a memory, a belief or a preference, spin a story, or reel off a justification. And it is such a compelling storyteller that we are fooled into thinking that it is not inventing our thoughts ‘in the moment’ at all, but fishing them from some deep inner sea of pre-formed colours, objects, memories, beliefs or preferences, of which our conscious thoughts are merely the shimmering surface. But our mental depths are a confabulation – a fiction created in the moment by our own brain. There are no pre-formed beliefs, desires, preferences, attitudes, even memories, hidden in the deep recesses of the mind; indeed, the mind has no deep recesses in which anything can hide. The mind is flat: the surface is all there is.

What he is really arguing in the book is something more complex: that the propositionality of the mind is specific to what is conscious. Everything else is a mish-mash of neural networks that do not adhere to strict logic, and change from moment to moment.

Specifically, propositional statements like “I hate my father” and “I am allergic to apples” may arise in the brain’s conscious experience, but not correspond to the brain’s structure. There is no set of neurons that encode axioms like “I hate my father”. What ultimately decides how you react to your father is dependent on the neurons and environment, not the conscious belief.

Beyond the rhetoric, Chater does make some genuine mistakes after he lays out his premises.

Chater believes all perception is inference. That is to say, perception constructs an interpretation of reality based on sensory inputs — it’s not the inputs themselves. He loves mental illusions, and likes using them to demonstrate this.

My favourite examples are impossible shapes: things which your mind can perceive, but are not logically possible according to the rules of this universe:

Here, we aren’t just seeing a bunch of black and white dots on a paper. It feels like we are actively constructing an interpretation of the image — a shape that feels coherent, even if it is not.

Another optical illusion that helps show perception is inference: the Bs are easier to see in the second image because the grey bars fill in the conceptual blank for us. Despite the fact the amount of optical information we receive is equivalent in both images.

Where this relates to his thesis, is that what you experience is not raw data: but an interpreted and processed version of it. Conscious perception is the output of the mental process — not the inputs or the process itself.

Chater then leads these illusions to another point — that perception can only focus on one object at a time. We think that we can perceive a whole image at a time, but only a clear subsection of it is seen at a time:

This can be experienced more directly in the following optical illusion. Darting one’s eyes throughout the grid causes the black dots to appear and disappear dpeending on where focus is placed:

This has been tested more rigorously with studies using computer vision. This involves a camera which tracks where people’s eyes are focusing at a given point. Some researchers then tried testing the limits of human vision by having a text that was written entirely in gibberish except for the fragment of the text the eyes were gazing at.

This is done by having the displayed text change depending on where the computer predicted the subject was looking — this is achievable with fast refresh rates and low latency. According to Chater, their study found that people don’t notice anything is amiss as long as the distance between the center of focus and the right side of the text window is 12-15 characters.

Big if true. I checked his source, and Chater is taking the study’s conclusions too far here. The authors were wrong too, to be fair. For reference, this is the abstract:

A computer-based eye-movement controlled display system was developed for the study of perceptual processes in reading. A study was conducted to identify the region from which skilled readers pick up various types of visual information during a fixation while reading. This study involved making display changes, based on eye position, in the text pattern as the subject was in the act of reading from it, and then examining the effects these changes produced on eye behavior. The results indicated that the subjects acquired word-length pattern information at least 12 to 15 character positions to the right of the fixation point. and that this information primarily influenced saccade lengths. Specific letter- and word-shape information were acquired no further than 10 character positions to the right of the fixation point.

Early psychologists noted that people could pick out words in their peripheral vision 2-3 lines above or below where they fixated their gaze. This study was trying to evaluate how wide vision was in an experimental environment where people are actively reading.

It did this by testing whether the participants — six high school boys — were really using their peripheral vision using computer vision. They used six different types of dummy text depending on their content and spacing, and also manipulated the window lengths from 13 to 100 characters.

They then assessed how easily they read based on what the computers inferred from their vision: how long they looked at characters, and how far their eyes jumped from character to character to continue reading. Empirically, there was no statistically significant difference in objective reading skill past a window span of 25 — which is where Chater got the figure ‘12-15 characters’ (25/2 = 12.5 =~ 12-15).

The obvious problem here is the lack of power: they had six participants. If one charts the relationship between window size and the length of people’s eye movements, one can infer at what point people stop using their peripheral vision to read. Visually, to me, it seems possible that there is a window size effect until 40 characters (remember to divide by 2).

Given there is intraindividual variability in visual span, it’s likely the average is lower, but the maximum is higher.

The same logic can be applied to how long it simply took them to read — we still get the same number: 40 characters. That correponds to 10 degrees of human vision on both sides, according to page 3 of the study. And that’s the amount of vision people use to read, not necessarily what people use to see. Though that does seem to be the case, coincidentally.

Looking back at the book, 10 degrees seems to be around where human vision starts turning into garbage; right before the pupil’s blind spot.

Chater then brings us to a different theory: the brain transforms inputs into outputs; we only see the outputs, not the inputs or the process involved. Our perception is not the raw data, but an interpolation and interpretation of it based on our cognition. Thoughts and physiological reactions can be observed, but what caused those things to occur cannot.

He makes some first-principles arguments for this being the case. If our brain is a network of billions of neurons, and we are only conscious of one thing at a time, then it must be unconscious of everything else. To him, what looks like multitasking — chewing gum and walking at the same time — is the brain carrying out automatic processes that do not require cognitive resources.

If we are conscious of one thing at a time, and the brain is a network of 100 billion neurons communicating by streams of electrochemical pulses, we must necessarily be unconscious of almost everything our brain does. This should not surprise us. As we have seen, we are only ever conscious of the results of our brain’s attempts to make sense of the world – or rather, to make sense of some small part of it. Yet these results arise from a hugely complex cooperative computation, the cycle of thought, involving a substantial fraction of those 100 billion neurons and drawing on vast amounts of information from our senses and our memories.

That does not mean the brain is oblivious to everything it is not attending to. Through peripheral vision, the brain can detect unexpected motion and pay attention to them when appropriate. Keeping these processes maintained does not require the brain’s global attention; it helps direct it.

He also notes that multitasking is impossible at the cellular level because neural transmissions would become jangled and confused:

“But it is hard to see how a vast population of interconnected neurons can coordinate on more than one thing at a time, without suffering terrible confusion and interference. Each time a neuron fires, it sends an electrical pulse to all the other neurons it is linked to (typically up to 1,000). This is a good mechanism for helping neurons cooperate, as long as they are all working on different aspects of the same problem (e.g. building up different parts of a possible meaningful organization of a face, word, pattern or object). Then, by linking together, cross-checking, correcting and validating different parts of an organization (the parts of a face, the letters making up a word), it is possible gradually to build up a unified whole. But if interconnected neurons are working on entirely different problems, then the signals they pass between them will be hopelessly at crosspurposes – and neither task will be completed successfully: each neuron has no idea which of the signals it receives are relevant to the problem it is working on, and which are just irrelevant junk. So we have a general principle. If the brain solves problems through the cooperation computation of vast networks of individually sluggish neurons, then any specific network of neurons can work on just one solution to one problem at a time.”

Personally, I buy it. I’ve played thousands of hours of League of Legends, and people definitely cannot look at two things at a time — they can’t look at both the minimap and the lane.

The theory is literally false, in the sense that the brain can engage in multiple processes at a time, figuratively true in the sense that one process must dominate at all times.

Some of Chater’s thoughts on emotions are interesting. He thinks that emotional states are something that are inferred based on context, not felt. For example, our interpretations of what a man feels depends on what we see in his surroundings:

This politician looks angry alone, but elated with others:

The author1 extrapolates from there to argue that our own interpretations of our emotional states are confounded by the context. This is the most boring part of the book, so I’ll skip2 over it. In my opinion, emotions aren’t real in some strict sense, but that doesn’t have to do with the structure of the mind. The emotions are the map, physiology is the territory; the fact that emotions don’t exist is besides the point. They are descriptive labels.

Now we get to one of Chater’s biggest theories: the brain is always improvising.

My objection: if everything is improvising, then nothing is. Improvising, as a term, only makes sense when it can explain some human behaviour but not all of it.

Let’s say I want to kiss my older sister on the forehead. I drive over to her house and then do it. Chater will have you think that, because there isn’t a book in my brain commanding me to kiss her, that I improvised that action. That’s nonsensical. If she pulled a gun on me and told me to leave, I probably wouldn’t kiss her. Otherwise, it’s a pretty fixed event. Literally true, figuratively wrong.

Now, what if I just slid over to her house, had no pre-existing plan to kiss her on the forehead, and did it anyway. I’ll grant that is an improvisation, but when you strech the definition of that word to include literally everything you do, it loses its meaning. A theory of everything explains nothing. The word is used for rhetorical purposes in the book, to argue that humans are shallow.

If everything is improvising, then reading directly from a script must be too.

In a physical sense, it is impossible for the brain to be living anywhere but the moment. We only think it does not because we can remember the past, and weigh future outcomes as well as past experiences into our decisions.

The frame of improvising misleads us into thinking we are evanescent and can do anything, ignoring how much human phenotypes are stable and genetic: the 75% heritability of intelligence and personality traits, the consistency of our food preferences. Variety often hides consistency — one day I read the g-factor, then I read Metamorphosis, and then Fate/Stay Night. All different materials, but read.

Chater acknowledges the consistency of human behaviour, using the metaphor of water channels. Our thoughts are water, and they flow through the channels that already exist, and then the water flowing through the channels cuts through them:

Thoughts are like water droplets finding their way from high ground to the sea, following the channels in the landscape, whether gullies, streams or river valleys. And, in its passing, each droplet cut those channels just a little more deeply. The landscape, then, is partly a history of past water flow, as well as a guide for how water will flow in the future. In the same way, our mental life follows channels carved by our previous thoughts, and traces of our present thoughts and actions will shape how we think and act in the future.

Which is rather odd: this metaphor illustrates depth, not shallowness. It would be shallow if the landscape before the water arrived was flat, but it clearly is not. In this metaphor, it is genes that affect the distribution of the density of dirt across the mind’s landscape, the landscape’s shape, and the rate at which channels atrophy when no water runs through them.

Chater then builds on his theory that brains constantly improvise. More accurately, that humans are dispositional and cannot live anywhere but the present. But basically, he then concludes that explanations are unreliable, made up in the moment, and unreflective of mental depth.

I once read a philosopher argue that people had really shallow understandings of how the world around them worked. That they couldn’t even explain how a simple zipper did. Which is the most worthless thing I’ve seen written. You don’t need to know how zippers work, you just need to know that they close when you tug up, open when you tug down.

Chater appears to form part of this tradition.

“Whether explaining how a fridge works, how to steer a bicycle, or the origin of the tides, we have a feeling of understanding which seems wildly out of balance with the mangled and self-contradictory ex­planations we actually come up with.”

When we are asked for an explanation of something, the answer will necessarily be incomplete. If I am asked why I love my parents, I can say “many reasons” or “I don’t know”. These are true answers, but not meaningful ones. The inaccurate, abritrary nature of explanations is only a bug if you expect them to be something else.

The author cites Gazzaniga’s research3 to argue that human explanations are ad-hoc and nonsensical. This involved studying split-brain patients, who had the connections between their left and right brain severed as a treatment for epilepsy. This somehow didn’t have noticable effects on their cognition or lifestyle.

The left side of the brain controls and receives stimuli from the right side of the body, and vice versa. So my man Gazzaniga decided to see what happened when the left side of the brain was forced to explain the unexplainable: behaviour that originated from stimuli it received from the left side of the body — which is connected to the right side of the brain. It turns out that, when that happened, the split-brain participants would just make up the explanations for their unexplainable behaviour.

Consider a particularly striking study by one of the pioneers of split brain research, the psychologist and neuroscientist Michael Gazzaniga. He simultaneously showed a split-brain patient, P.S., different pictures on the left and right halves of the visual field.2 The left-hand picture was a snowy scene; the brain’s cross-over wiring pipes this information through to the visual cortex of the right hemisphere. The right-hand picture was a chicken’s foot, which is sent to the corresponding area in the left hemisphere. Like most of us, P.S.’s language-processing abilities are strongly concentrated in the left hemisphere; the right hemisphere, in isolation, has minimal linguistic abilities. P.S.’s left hemisphere was able to report what it could see – and fluently describe the chicken claw, but P.S. was unable to say anything about the snowy scene that the right hemisphere could see.

What this research is showing us is that the quality of our explanations deteriorates when we are forced to explain what we can’t. This doesn’t necessarily hold for anything besides that. My inuition is that the explanations we make for why we make large decisions influenced by multiple variables (e.g. relationship breakups, career changes) are incomplete. Otherwise, I think they can work. “Running an errand” is a good explanation for being in a car.

Chater builds from that faulty premise to argue that those arbitrary explanations we make up in the moment create our long-term preferences and behaviour. To make this claim, he cites what he calls “choice arbitrage studies”. These involve asking people to choose between two objects. Once they make their selection, they are intentionally presented with what they did not choose, and asked to explain why they chose it.

One example involves getting people to choose which woman they are more attracted to, and then are asked to explain why they prefer the other. In this experiment, many of the participants then began to explain why they made that choice, citing reasons like their hair colour, earrings, or face shape.

I have no reason to think the study did not happen as he describes it; where I differ is interpretation. In that image, the proctor is presenting two women who share a lot in common: race, hair colour, and apparent age. People would probably notice the trick if that was not the case, and they would be more likely to make a choice based on stronger preferences.

It also might be the case that the subject chose one at random, so they didn’t notice the trick. Or maybe they thought something was wrong when the proctor falsified their choice, but felt constrained by the structured environment, and had no incentive to introduce social friction by asking if the proctor was mistaken. Or maybe they felt something was wrong, but thought it was unlikely that the proctor would trick them or make a mistake.

Chater also presented a more interesting study to argue this was the case: they had Americans fill out a form about their political beliefs before the 2008 election. On half of the forms, there was an American flag in the corner. Those who had the flag on the form were more likely to agree with right wing political attitudes.

When they tracked the participants’ votes in the presidential election, they found that people who had the flag in the form were more likely to vote for the Republican party.

Chater then argues that is evidence of his hypothesis, that our in-the-moment choices are arbitrary and possible to manipulate. And that would be true… if that flag priming study actually replicated.

It did not.

So maybe it is possible to trick subjects with these cute experiments, but the explanations those people made didn’t actually track to the creation of new preferences or identities. So much for Chater’s thesis, then — the mind is not flat.

That’s the end of the argument, logically.

Not the book, though. Chater then argues the unconscious exists the way psychoanalysts or common folk think it does. By unconscious, he means a part of the mind that has beliefs, desires, thoughts, and identities that is hidden from our conscious experience.

I think this is necessarily true if you conclude that the propositional character of our conscious experience does not apply to raw sensory data or our unseen cognitive processes. I don’t know if that’s Chater’s argument (I don’t understand it), but it’s fair if that is the case.

Concretely: we have a mental surface: thoughts, actions, sensory perceptions, and feelings which can be consciously observed. Then, we supposedly have some sort of unconscious mind underneath that surface: motives, thoughts, feelings, and identities that we do not know, but affect our consciousness.

Chater astutely notices this analogy tricks us into thinking what is conscious is like what is not. That the ice above the water is the same as the ice beneath it. That the consistent and clean thoughts we see on the surface generalise to what is underneath.

But the vision of the iceberg, with its vast dark mass hidden below the water, hides an important but entirely flawed assumption. In an iceberg, the material that is above and below the waterline is precisely the same – ice is ice, whether deep beneath the waves or sparkling in the sunlight. And, for this reason, it seems only natural that what is hidden can be made visible and what is visible can be made hidden – it is still the same ice whether we lift it from the waters or plunge it into the depths. The metaphor suggests that the very same thought could be either conscious or unconscious – and could jump between the two states. Accordingly, a thought that was previously unconscious might be brought into the light of consciousness (whether through casual introspection, intense soul-searching or years of psychoanalysis).

In that regard, I don’t think Chater was radical enough. You might think you have a conscious drive to “satiate thirst”, but you have only inferred it based on patterns of behaviour and physiological signals. You can’t see a neuron or set of neurons in your brain that activate when you need water.

Every single drive, fear, and desire you have is unconscious. Nothing is being repressed, just ignored or unrecognised. The only way you can learn anything about yourself appears to be… introspection.

Chater does not like introspection as a word or concept. He never says this so nakedly, but its clear from his writing. A problem I see is that intropsection isn’t really one thing. One kind — noticing emotions — is plainly useful. Causal accounts of why these emotions occur: environmental factors or one’s personality — are useful for self-interpretation, but often wrong.

People are almost always unwilling to admit to being wrong, especially if it’s about something as personal as the self. People are often highly overconfident in their interpretations of themselves, and are unwilling to revise them.

Much error can come from taking your thoughts too seriously; even the eminent and talented philosopher Bertrand Russell did — he went on a bike ride and somehow realised that he no longer loved his wife Alys. What followed was an unhappy marriage that eventually broke apart.

The philosopher, logician and political activist Bertrand Russell writes memorably of a moment of apparent emotional insight in the autumn of 1901: ‘I went out bicycling one afternoon, and suddenly, as I was riding along a country road, I realized that I no longer loved Alys. I had had no idea until this moment that my love for her was even lessening. The problem presented by this discovery was very grave.’

For Russell, this thought was no mere creation of the moment (perhaps a product of a frustrating morning’s work, or the aftermath of argument); instead, he interpreted it as an indisputable revelation, breaking through from a hidden subterranean emotional world. This proved to be a disastrous interpretation, at least for their relationship, which foundered rapidly, though not leading to divorce until twenty years later. Of course, the marriage might have failed in any case, but once Russell had received, as he saw it, a damning and final verdict from the ‘inner oracle’, he became utterly convinced that the relationship was dead. And with that belief firmly established in his mind, there was probably little hope.

Russell, here, is assuming the mind works in syllogisms: I either love or don’t love my wife. It doesn’t. You have a dispositional attitude towards your wife, and could feel anything towards her in the moment. During that bike ride, he might just be in a bad mood, and a thought just sprung into his head. It didn’t need to be taken seriously.

Chater’s ultimate argument is that a unified, stable self does not exist. That feels like the biggest clam he makes in the book, the most derivative of his premises, but it’s also the most reasonable conclusion to make. Great philosophers like Hume, Nietzsche, or Buddha noticed the same thing. In a way, Chater is still right — the mind has no propositional and unchangeable depth.

Where I would push back is that this model of the human brain, in a weird way, opens itself to more depth that the alternatives. The incoherence and evanescence of mental depths is not evidence of its absence, or of it not being worth wondering about. People do have genetically-determined personality traits which will reliably affect how they act and feel. They have beliefs… held loosely or in contradiction with others.

So

The mind is a woman and she has B-cups.

I read the entire book, some sections of it twice. If you can get me to do that, you are entitled to at least a 6/10. I give the book a 9, and it's earned a place on my sidebar. The book is great at taking bad ideas and tearing them down — Freudian nonsense, identitarian self-modelling, multitasking, and whatnot. The model he replaces it with is good, but incomplete and sometimes plainly wrong.

The most useful information in the book:

1. Perception is inference.

2. The mind can only focus on one thing at a time.

3. Only the outputs of the brain can be observed.

4. Self-explanations are necessary, but shouldn’t be taken too seriously.

5. Minds are dispositional, not propositional.

6. There is no stable, coherent self.

7. The unconscious has no desires, beliefs, or deep hidden self.

Chater unredpilled me on self-deception. People don't need to trick themselves because there is nothing to trick. The paradigm of self-deception assumes there is a way people can find the answers that explain their own behaviour — that must be overidden. It doesn't exist.

What happens is that, when people are asked about their behaviour in a socially sensitive context, they default to defensive and benign answers. The answers aren’t lies because they often do not know the answer, unless their behaviour was planned or highly deliberate. The anwers they provide aren’t necessarily wrong, they just happen to be what people are incentivised to share. The Elephant in the Brain is the fact we think we are righteous individuals in the first place.

Many other schools of philosophy do not survive the scrutiny of flatism. Psychoanalysis is the most obvious one. Rational econometric models of human behaviour fall out of favour, as brains are not propositional. Modern beliefs about a true self or even nonexistent one look flimsier.

The worst conclusion you could make based on this book is that, because you don’t have mental depth, that you can become anything. That if you keep working hard at math or being a good person, that you can become those things. That if you keep eating potatoes and convincing yourself you like them, you will. It’s the kind of logic your parents used to get you to participate in extracurriculars you didn’t care about.

Genes are real. Persistent environmental effects are real. Free will is fake. Case closed.

In second place would sit the idea that, because our explanations can be faulty and selective, that they must always be. Not exactly. Somebody asked to explain why they are in a bed at night could say they desire to sleep; it wouldn’t be wrong. The problem lies with wanting explanations to do things they cannot.

Beyond that, there is a scientific consensus that they cause dementia in the long term.

It’s incorrect.

This is one of the biggest academic blind spots I’ve seen in my life. Anti-cholinergics are not a well-known drug class, but they are taken by about 25% of the general population; more common than anti-depressants.

These drugs are thought to cause dementia for multiple reasons. One of them is that some anti-cholinergics block1 the M1 receptor, which can then cause the brain to produce less α-secretase and more α/β peptide; α/β peptide accumulates into amyloid plaques, which cause cognitive decline. Essentially:

Drug → M1 receptor block→ more α/β peptide →amyloid plaques → cognitive decline (specifically Alzheimer’s)

The amyloid hypothesis of Alzheimer’s has attracted some doubt. One of the researchers who published papers that influenced the theory was found to have committed tons of fraud; some of the papers were retracted. Prior to this finding, there were people who were skeptical of the theory, noting that many of the drugs based on it failed FDA trials, while the others that were approved were not related to it.

The presence of amyloid plaque is still a pretty strong predictor of the disease. There is almost no overlap in the amount of plaque in Alzheimer’s patients and similarly aged controls who have no dementia. At least, in some parts of the brain:

It seems that the plaques themselves don’t cause cognitive decline, it’s the tau tangles. One study reports baseline amyloid plaque levels had no statistically significant association with declines in future test scores, but tau tangles did:

The statistical reasoning here is faulty. Within people who had elevated amyloid plaque levels (A/β+), the association between plaque and cognitive decline was not statistically significant, but it was in the expected direction. They claimed to correct the association between tau tangle baseline levels and cognitive decline for plaque levels in their regression model, but it doesn’t look to me like they did.

It seems that, at the early stage of Alzheimer’s disease, α/β plaques are more present than tau tangles, and both predict the future levels of tau tangles. Once the disease gets going, plaque becomes less relevant and tau starts dominating2:

I suppose this explains why drugs that were developed based on the theory were so unsuccessful. By the time somebody is diagnosed with dementia, they already have plaques and tau tangles in their brain. Preventing the creation of plaque doesn’t deal with the tau tangles that are directly driving the cognitive decline.

Overall, the plaque/tau theory of Alzheimer’s holds up reasonably well to scrutiny.

There are also a few other mechanisms by which anti-cholinergic drugs could affect dementia. People adapt to the effects of anti-cholinergic drugs by upregulating the receptors that are blocked and/or increasing their sensitivity; if we believe the plaque/tau hypothesis, then the tolerance effect should theoretically counterbalance some of the effect of M1 blockage.

Use of anti-cholinergics could also lead to selective synaptic pruning, where cholinergic neurons are selectively disconnected by the brain due to lower activity. Not implausible, but hard to test.

The hypothesis that these drugs cause dementia is sensible in the way the diet-heart theory is. It’s rational, but some of the theoretical mechanisms by which they do involve lots of mechanistic causal chains, which imply an uncertain and attenuated effect size.

What I mean by this, is that if A has a 0.5 SD effect on B, and B has a 0.5 SD effect on C, the effect of A on C is 0.25; not 0.5. In this hypothesis, there are a total of five steps between anti-cholinergic drug intake and cognitive decline: drugs → M1 blockage → α/β peptide upregulation →formation of plaques →tau protein accumulation →cognitive decline. If any one of these effects don’t exist, or if the drugs have effects in the opposite direction that counteract the main chain, the theory flies out the window.

Oh, and those studies people cite to argue that M1 receptor blockage is associated with α/β peptide and amyloid plaque? Most of it is literally in mice. I found one human study that finds M1 agonists reduce AB peptide levels by 20%; it’s a p < .004 with 19 people. I guess that’s not terrible.

When it comes to observational data on this topic, this study stands out as being particularly large and high quality:

• Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. doi: 10.1001/jamainternmed.2019.0677

Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

Their results:

Pretty unambiguous as far as statistics go, the lower 95% CIs are far away from 1.

The elephant in the room: people experiencing cognitive decline need medications to control the symptoms: insomnia, psychosis, urinary incontinence, and such. It just so happens that a lot of the drugs prescribed to treat these symptoms are also anti-cholinergics, so it’s not surprising the users are more likely to experience dementia later.

The other issue is that not all of the anti-cholinergics were even associated with future cognitive decline. The anti-histamine variants were hardly correlated with future cognitive decline, as were the antiemetics, muscle relaxants, gastro antispasmodics, antiarrythmics, and bronchodilators — when you adjusted for the effects of taking other drugs.

I’ve seen it argued that this is because the “strong anti-cholinergics” are the ones that cause dementia, but the weaker ones do not. This is not borne out in the data. For example, benadryl is strongly anti-cholinergic — but the other anti-histamine drugs they lumped it with are not associated with cognitive decline.

Perhaps they accidentally lumped benadryl with anti-histamines that are less potent or do not get into the brain’s blood, so the real effect got lost in the mess. Here’s the problem: every single anti-histamine that they used in their study — Azatadine, Brompheniramine, Chlorpheniramine, Clemastine, Cyproheptadine, Hydroxyzine, Trimeprazine — was a first generation variant that does cross into the brain. The fact these drugs are not assoicated with dementia is quite telling.

Researchers try to overcome this with case-controls, examining long term use before diagnoses, or controlling for demographic/SES variables. “Controlling for variables” is overly maligned in statistics, but this is a uniquely egregious case — they aren’t controlling for the thing that matters: existing cognitive decline and genetic/environmental predisposition.

Cognitive decline is also a long term process. It can start as early as people’s 30s:

I checked the drugs they evaluated in that observational study: some of them don’t even cross the blood-brain barrier. Glycopyrrolate (bronchodilator), Ipratropium (bronchodilator), Propantheline (gastro antispasmodic), Trospium (bladder control drug), Flavoxate (bladder control drug), and Butylscopolamine (gastro antispasmodic) are all below-the-neck drugs.

Out of the gate, the anti-cholinergic drug hypothesis looks sketchy.

I found a similar Swedish study that was published recently, focused on vascular dementia. I looked at their table3, and it turns out they found the same thing: anti-depressants, anti-spasmodics, anti-epileptics, anti-psychotics, and anti-parkinsons drugs with anti-cholinergic properties were all associated with cognitive decline; everything else was a null.

A nonlinear dose-response relationship with all-cause dementia was found for the cumulative use of strong anticholinergics (e.g., 1–89 DDDs: AOR, 1.10 [95% CI, 1.08–1.12]; ≥1095 DDDs: AOR, 1.66 [95% CI, 1.55–1.79]), notably within the class of urinary antispasmodics, antihistamines, and psychotropic drugs. In contrast, a subtle association lacking a dose-response pattern was observed for weak anticholinergics (e.g., 1–89 DDDs: AOR, 1.11 [95% CI, 1.08–1.13]; ≥1095 DDDs: AOR, 1.01 [95% CI, 0.98–1.03]). The associations with strong anticholinergics were more pronounced in men, younger people, those diagnosed with vascular dementia or Lewy body dementia (versus Alzheimer’s disease), and those with milder-stage dementia.

Consistent with the drug-specific effects found earlier. Out of curiosity, I checked the UKBB study on the same topic: it found associations between dementia and anti-depressants, anti-epileptics, diuretics; no for everything else. Antipsychotics had a positive, but statistically insignificant relationship.

Coincidentally, it seems like all of the drugs you would expect somebody experiencing early-onset cognitive decline — anhedonia (treated with anti-depressants), psychosis (treated with anti-psychotics), loss of dexterity (trated with anti-parkinson’s), and urinary issues (treated with anti-spasmodics) — to be taking, all just happen to be associated with future dementia.

People have tried testing the theory in more creative ways: one of them involved examining the effect of taking hypertensive drugs that had anti-cholinergic side effects on dementia. They found nothing.

Studying the effect of duration of treatment on prognostic outcomes using real-world data is challenging because only people who survive for a long time can receive a treatment for a long time. Specifying a target trial helps overcome such challenge. We aimed to estimate the effect of different durations of treatment with antihypertensive drugs with anticholinergic properties (AC AHT) on the risk of vascular dementia and Alzheimer's disease by emulating a target trial using the UK CPRD GOLD database (2001-2017). Comparing treatment for 3-6 years vs ≤3 years yielded null results for both types of dementia. Comparing a longer duration of treatment, >6 years vs ≤3 years, yielded a 10-year risk ratio of 0.69 (95% CI, 0.54-0.90) for vascular dementia and 0.91 (95% CI, 0.77-1.10) for Alzheimer's disease. For illustration, we performed an analysis that failed to emulate a target trial by assigning exposure categories using postbaseline information, obtaining implausible beneficial estimates. Our findings indicate a modest benefit of longer duration of treatment with AC AHT on vascular dementia and highlight the value of the target trial emulation to avoid selection bias in the evaluation of the effect of different durations of treatment. This article is part of a Special Collection on Pharmacoepidemiology.

If anything, it looks like the drugs helped. Which isn’t surprising, since the cardiovascular system is also implicated in cognitive decline. It led to a stronger reduction in vascular dementia4, which is caused by repeated strokes; the effect on Alzheimer’s was protective but not statistically significant.

This study is the nail in the coffin on anti-cholinergics and dementia. They compared the effect of anti-cholinergic bladder drugs to a drug that aided in bladder control but had no cholinergic properties — miragebron. In comparison to people who used mirabegron, anti-cholinergic users were less likely to get dementia.

Compared with non-use, ever use of anticholinergic bladder drugs was associated with an increased risk of dementia, with an incidence rate ratio of 1.44 (95% confidence interval (CI) 1.40 to 1.48). The incidence rate ratio increased with increasing cumulative drug use, from 1.31 (95% CI 1.27 to 1.36) for 1-90 defined daily doses to 1.68 (1.59 to 1.76) for >365 defined daily doses. Compared with non-use, all types of anticholinergic bladder drugs were associated with increased incidence rate ratios for dementia: tolterodine 1.43 (95% CI 1.38 to 1.49), solifenacin 1.37 (1.29 to 1.46), trospium 1.52 (1.37 to 1.67), and fesoterodine 1.48 (1.26 to 1.74). The increased risk of dementia with use of anticholinergic bladder drugs was not seen when compared directly with the use of the β3 agonist mirabegron (incidence rate ratio 0.82, 95% CI 0.74 to 0.92), irrespective of the type of anticholinergic drug.

The abstract is a little confusing. Fortunately, their figures are not. They conducted the regular, observational analysis first, and found a positive correlation between anti-cholinergic drug intake and future dementia.

According to this table, using an anti-cholinergic bladder drug for only 1-90 days is associated with a 31% increase in the risk of dementia. If that’s a real effect, surely the power users who took anti-cholinergics daily for 30 years would be totally cooked? What about those teenagers who megadose them for fun?

They then ran the analysis which anti-cholinergic bladder drugs to the non-cholinergic variant, Mirabegron. Anti-cholinergic drugs had a protective effect on dementia.

I checked the supplement, and there was no statistically significant difference in all-cause mortality.

Not only are the associations between anti-cholinergic drugs and dementia dependent on the specific drug type, if we evaluate drugs that have been shown to relate to dementia in multiple studies — it turns out it’s still confounding.

Now, we pivot to in-vitro.

I found one nice study that did it — examining the effects of anti-cholinergic drugs on neurons when they were grown outside of the human body. Theoretically, if they are harmful in humans, we might see their effects take place in artificial cultures as well. It turns out that some of the anti-cholinergic drugs had measurable toxic effects:

We treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.

We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1‐42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments.

All three anti-depressants showed robust cytotoxic effects (poisonous to cells). One of the anti-muscarinics (bladder control drugs) showed a slight toxic effect, but it might have been a mere statistical fluke:

When it came to the development of amyloidic plaque, which likely contributes to cognitive decline, Oxybutynin (bladder control drug) showed up as a contributor to its formation. They couldn’t detect changes in tau protein formation; in some cases, this might have been because of the toxicity of some of the medications.

Some of these results in-vitro match the observational study — both methodologies agreed that the antihistamine and antispasmodic drug variants had no measurable effect on cognitive decline. It’s hard to compare the two methods, since they aren’t always using the same drugs, at the same doses.

Besides these studies, I didn’t find much of value: one study that examined effects of anti-cholinergics in 55 year olds on dementia found a p = .04 and a p = .01; an AI prediction study that was able to reliably predict Alzheimer’s diagnoses using medical records, anti-cholinergic drugs only came up in the top 20 factors once (other drugs like benzos came up more often); and some other observational studies that said the same thing.

One could argue that, because cholinergic drugs are meant to treat Alzheimer’s, that means that anti-cholinergics must have the opposite effect. And they are — in the short term. And it’s not like cholinergics are that effective — according to the largest meta-analysis, the effect they have on cognition in people with AD is about 0.33 standard deviations5; similar to the effects of a generic stimulant on cognitive ability.

So

The answer is no, anti-cholinergic drugs do not cause dementia6.

The big problem with the theory is that it is too general. In some cases, anti-cholinergic drugs have protective side effects, like the anti-hypertensives, so it would be crude to hypothesise they are pathogenic. “Don’t eat yoghurt because it has saturated fat”. Some anti-cholinergic drugs don’t even cross the blood brain barrier, so it’s not mechanistically possible for them to cause dementia. I guess it’s great marketing for other drugs that don’t have this effect.

The mechanistic reasoning behind the theory is not irrational, but it’s flimsy in the sense that it relies on believing in the existence and importance of 4th order effects. There’s also reason to think obesity and the cardiovascular system are implicated in dementia, if this is the case, then drugs that affect these systems should naturally affect dementia as well. Also, a general example of why I dislike mechanistic arguments in medicine.

Anti-cholinergics kind of suck as a drug class. They make you tired and dull, but if you take them to sleep, then the quality of your sleep decreases. As such, pharmacists try hard to get these drugs to not cross the blood-brain barrier.

The reason I was interested in this research is that I take benadryl, an anti-cholinergic drug, as a sleep aid. I doubt I’d ever actually develop dementia due to my family history, unless I live to be over 100 years old — that’s when the real decline starts.

3

Table:

If people respond to price signals, then they respond to social signals too: approval, embarrassment, exclusion, and disapproval. Game theory then organises how people act when they are uncertain, being watched, and watching others.

A good example of its application: Werner on The Origins of Wokeness. Previous theorists argued that it originated from philosophy, the long march through the institutions, or WEIRD morality. Werner, on the other hand, argues that increased diversity in American elite spaces resulted in larger returns to signalling woke beliefs — which indicate that somebody is more able to cooperate with different types of people.

In this case, I deem its use appropriate. The status economics theory explains why woke beliefs are typically uncorrelated/positively correlated with intelligence, why wokeness escalates (race → sex → sexuality → gender), historical timing, and relative absence in East Asia.

Status economics takes behaviour that was previously considered irrational, moral, or unexplainable and attempts to explain it through a different lens. Low quality luxury goods? Status. Medical tomfoolery? Status. Art? Status. Altruism? Status. Education? Status. Politics? Status. People not consciously thinking about status when they engage in these activities? Self-deception.

It’s hard not to emphasise self-deception as foundational. When people are consciously living life, they rarely think about wanting to dominate others. Sometimes even when they are pressured. For status economics to be plausible, we must have a theory as to why people’s stated motivations do not map to their drives and actions.

I don’t think it originated1 from one person, group, or ideology. In terms of communities, status economics is currently popular in economics, tech twitter, the rationalist community, and the online right.

The appeal of status economics is evident. A lot of times, it just works. It discourages the convoluted psychiatric stories and common sense. It explains the unexplainable.

Where does it err?

Status Economics degenerating into metaphysics

Platonism for the elites is an insult.

In the myth of Plato’s cave, we have men casting shadows on the wall with clay figures — what they perceive with their raw senses. People can choose to leave the cave and find themselves in the rest of the world — the world of Platonic forms, ideas.

The application is clear. In status economics, morality and irrationality are shadow explanations for human behaviour; status is the true substrate behind everything. The appeal of Gnosticism — Marxism, Christianity, The Red Pill — is intuitive. The masses are a bunch of cattle and your third eye sees the truth behind everything. It makes you feel better than other people.

To divide the world into a “true” and an “apparent” world, whether after the manner of Christianity or of Kant (after all a Christian in disguise), is only a sign of decadence,—a symptom of degenerating life. The fact that the artist esteems the appearance of a thing higher than reality, is no objection to this statement. For “appearance” signifies once more reality here, but in a selected, strengthened and corrected form. The tragic artist is no pessimist,—he says Yea to everything questionable and terrible, he is Dionysian2.

The idea of a true and apparent world — in other words, the world has layers — is true on a figurative level. There are lenses, frames by which sequences of events can be radically reinterpreted. The issue lies in reificiation — thinking that the layers are not mere appearances as well.

The core tenets of the school — that pretending not to care about status is itself a status play, and that self-deception is psychologically real — makes the theory unfalsifiable. If people are overtly competing over status, that proves our theory. If people are not overtly competing over status, that proves our theory — they are just self-deceived.

It is falsifiable at the group level — see social signalling vs human capital models of education — but unfalsifiable at the individual level. The theory can explain what attracts people to education in general, but can’t explain the motivations of particular people.

Unfalsifiable theories are not necessarily wrong. They are dangerous. If you take them too seriously, it is impossible to test them. “All true beliefs are falsifiable” is not even a falsifiable statement3.

Another note on ‘not caring about status’ — I don’t take this literally. Figuratively, what is meant is that this person is playing with their cards face up. What they appear to be is what they are, uninterested in playing elaborate games, comfortable to carry themselves through their own values.

Take Frank Herbert promoting Dune as an example. Is he making a play for status? Definitionally, yes — he is vying for attention and desirability. But there is something reductive about claiming that selling Dune is about status — it’s like saying he’s doing it to enable capitalism, promote satanism, or feel good. It’s an empty explanation.

Motive vs method

This is where we get to separating motives, mediums, and products; status economics often confuses these things. Dune was probably written tons of reasons — boredom, money, fame, self-expression, mastery, and connecting to people. Writing and publishing a novel involves dealing with a social world with its own signals and incentives; if people like it, then the author is rewarded with attention/money/etc.

Presumably, if somebody is willing to put in the effort to publish and sell a novel, they have financial or social motives; likely both. That’s not a bad thing, but that doesn’t necessarily mean that was the only reason for having bothered to write one in the first place. It also doesn’t mean that they were just chasing “status” in the broader sense — they might enjoy attention, but not prestige; desirability, but not credibility.

What I am getting at is essentially this question: do we want power for its own sake, or is power the way humans accomplish goals?

The question is definitionally absurd; if we take cause and effect for granted, evertything is power. The distinction still functions in a utilitarian way. Are social resources valuable for their own sake, or are they only useful instrumentally?

When a business attempts a viral marketing strategy, they are essentially pursuing a type of status — attention. But are they pursuing status for its own sake? Perhaps, to an extent, but surely money is also a motive. But then you could ask why they want money…

What even is status?

Another massive issue; status is not one thing. I define ‘status’ as power through perception, what power people have as a function of other people’s beliefs.

I consider status to come in nine different forms:

• Prestige: who is considered admirable?

• Legitimacy: who reigns supreme?

• Credibility: who is considered believable?

• Immunity: who is allowed to get away with violating rules?

• Leverage: who can impose costs and benefits?

• Attention/clout: who commands attention — cognitive fixation?

• Fame: who is remembered?

• Desirability: who is wanted?

• Access: who is allowed opportunities and resources?

Multidimensionality can be pedantic, but this frame solves a lot of the weird questions; for example, are young people low or high status? The answer: young people are more desirable, rule-immune, and are given more opportunities; but they have less leverage, credibility, and legitimacy. This also works for other debates about whether men vs women have more power. Often groups differ in which social currencies they possess.

Unfortunately, this does not go without saying: what is “high status” is individually dependent. People pay attention to, appreciate, and approve different things. These individual-level tendencies can result in aggregate effects at the group level, but many times, it’s not necessary to get most people’s approval/attention to get what you want. Only about 0.25% of the global population has bought Dune, the best selling scifi novel of all time4.

The opacity of human motivation

Is “status” a good explanation for human behaviour?

My vote is no. I think it’s a good explanation for macro-level weirdness: luxury goods, religion, altruism, ideology, and even some medical practices. Otherwise, I think it’s at best an arbitrary explanation and at worst a terrible one.

An explanation is not just a model. It’s a theory for why something is occurring and not something else. The apple fell because of the Earth’s gravitational pull, not because I sneezed before I saw it.

So, why do I like playing competitive video games? I will admit — winning feels good; losing feels bad. But why am I playing competitive video games… and not something else? Why am I not rapping, playing sports, or tasting wine? Why do I keep my childhood belongings? This is where status loses: it can explain why people play games, but it cannot explain why people pick them. The idea that art is about status is grotesque; it is to say that sex is about burning calories.

If something explains everything, then it explains nothing.

Regarding introspection: it’s easy to see emotions, thoughts, and perceptions. The mind is not flat, but it can only see the output of its depths, not the depths themselves. The machinery that creates thoughts/emotions cannot be accessed by the conscience and must be inferred; inference is unreliable. In a weird way, all desires are definitionally unconscious. This is why, I think, self-deception works. It’s not trickery if everything is hidden.

We often do not want things because of what they are, we want them because of what they represent5. Allow me to explain: we have base needs such as thirst, hunger, tiredness, sexual appetite, and bodily integrity. People then make demands of others to satisfy those needs: flirt, buy food, and request quiet. Our linguistic and cognitive maps of the world enable us to satisfy these base drives — we fear men with guns because they threaten our bodily integrity; we like sushi because it will satisfy our hunger. Sometimes we want to want things.

At times, these cognitive maps and demands of the world falter. and we want things that things that do not satisfy our bodily drives as much as we think they do, or at all. This is where unwholesome desire, taṇhā, comes from. The Buddhists were right to reject it.

When people seem to do and want irrational things that are connected to social mechanisms — farm attention from Neo-Nazis on twitter, buy luxury goods, or participate in religion — the easy explanation is just status. Sometimes that is the answer. Other times, the motivation is to satisfy desires that have stayed unsatisfied, and our unreliable linguistic maps have determined those are the answer.

Taking the psychoanalysis further, a lot of status economists are fans of Girardian desire, the idea that a lot of human motivation is mimetic. I’ve never read Girard, but I’ve seen some of that in myself; we were all teenagers once. The idea is cool, but bad as an explanation for human behaviour — what made something popular in the first place, is the more interesting question. It’s definitely overextended, for example, to explain what body types people find attractive.

There are other times where the answers are not that deep. Why do people like playing Skyrim? Lacanian desire? Mimesis? Need for community and affiliation with successful products? Maybe it’s just… fun.

Status Economics — current status?

Status economics is useful. It breaks us from the trance of gnostic explanations of behaviour, exposes that all social relationships are transactional under pressure… until it degenerates into its own gnosticism.

The school explains human behaviour well at the macro level, inconsistently at the micro level (this is true for economics in general). Humans have layered motivations and respond to some social incentives, not others. At the aggregate level, social incentives will reliably shift behaviour. “Status” is also a compresion word, which makes it useful in language but tenuous as a concept.

There’s also another question. If I dislike status economics as it is currently applied, what theory of human behaviour should replace it?

I am fine with nothing.

This will probably be the last article I write on the social status question. I’ve already written on the issue far too frequently, though I posted about it again since my opinions changed (of course!).

I was 15 years old.

Some adults came to my high school and encouraged us to do strange stuff in front of everybody else at the assembly hall. I volunteered. And I did not have a good time; so did a friend of mine, who left before everything was over. I then went to find her, and she was (also) having a panic attack. We then went to hide in one of the classrooms and listen to music with some friends and my older sister.

My homeroom teacher found us, and I ended up talking to her about what happened in the office. I ended up crying, if I recall. Just before I left, she told me something along the lines of “if there is anything you need me to do, just ask”. She said it in, what I interpreted as, a suggestive tone. This woman was in her late 30s or 40s.

I would be inclined to brush it off… if she didn’t mention in a groupchat1 that she would date one of the students there if she wasn’t his teacher. And if she didn’t hang up my drawings in her office. She also mentioned in that groupchat that she hadn’t had sex in a while.

This woman was… odd. She was too lazy to send my brother’s high school transcripts to universities, until my mom screamed at her. She seemed to disliked women. She was a libertarian (of course!) and would argue about politics with me in school.

And no, I did not have sex with that woman. I do still think about her, though.

The question is, why do these people want to have sex with minors or students, and not adults?

The case of men doing this is not so mysterious. Maybe they want to have sex, think it’s possible a long term relationship could develop, or just happen to like somebody who is under 18. Women doing this is weirder. If they just wanted to have sex, they could ask random men or hire prostitutes. Young men generally don’t go for older women when they want longer-term relationships.

The idea people initiate these types of relationships for the purposes of power is true for a few cases, but far too reductive. I could believe it’s a misguided attempt to be exploitative. The fact of the matter is that, if the student/child feels pressured, they can admit to the relationship, and result in their partner losing their position of authority or suffering legal consequences.

The meta-answer: they cannot find adults that are suitable replacements, because if they could, they obviously wouldn’t be doing what they are doing. Relationships with teenagers could also provide them things relationships with adults can’t: sexual validation, the dynamic, lower stakes, and the taboo element.

Beyond that — I think these types of offenders are strongly motivated by loneliness.

Evidence

Pedophiles are more introverted and neurotic than regular people.

Accordingly, they are more likely to have fewer friends, and be less likely to psychologically tolerate their lack of them. They don’t have lower levels of conscientiousness, which seems believable, since most pedophilic crimes are premeditated.

Fortunately, we have another study of the personality traits of sex offenders — 32 child molesters, 26 sexual offenders against adults, 31 regular prisoners, and 42 controls:

The pedophile personality profile2 replicates, and regular sexual offenders have similar personalities to them: low extraversion and high neuroticism. Still no difference in agreeableness, a point against the power explanation.

Beyond that, there’s a qualitative study of 10 English women who had sex with male teenagers when they were in a position of authority. Their research suggested that they did not have exploitative motivations, and were more motivated by low self-esteem, issues with their own relationships, and a desire for intimacy. Generally, I don’t trust qualitative research, but this seems fairly credible to me.

There are various typologies of offenders: those with preferences for teenagers/children, situational offenders, and repressed offenders (those who fail with adults). There is something here, but I think the independence between these categories is questionable: why, exactly, do some people prefer minors in the first place? It’s not impossible that personal circumstances and failures with adults could subconsciously raise attraction to minors. People are often attracted to things based on what they mean, not what they are.

Oh, and there is evidence that teacher misconduct regarding students is becoming more common over time. In 2004, 9.6% of students claimed to have been sexually harrassed/abused by educations; in 2023 11.7% claimed to be.

So

There is no one reason why somebody decides to try to have sex with a teenager, though one thing unites all cases: they chose a teenager over an adult, or loneliness. I think a lot of the reasons people espouse out: a lack of morality or desire for power, are framed incorrectly or too reductive. They’re making choices under uncertainty and incentives.

Unfortunately, it is necessary to say that dating a 6 year old and a 15 year old is not the same thing. I’m not talking about morality, or even about harm. The thing about harm-based theories of rules is that there are lots of harmful things people are allowed to do, so something being harmful isn’t a good theory as to why things are not allowed. In terms of ethics, there is a clean difference: some people would privately excuse dating a 15 year old, but almost never a 6 year old. The whole field of “sexually unallowed behaviour” has a lot of issues with categories and words getting mixed up, leading to tedious definitional discussions.

And no. I don’t support removing the age of consent3. And I think rape is bad.

Ideally, the age of consent would be the same as the age of voting, graduating, and working. I think we could design society in a way where people graduate from high school at 15, but #wecanthavenicethings.

2

More: pedopophiles and those who actively abuse children are more neurotic than the regular person:

Non-offending pedophiles (NM) and healthy controls were unlikely to have been abused by an older person when they were a child. Offending pedophiles (FM), on the other hand, were much more likely to have been abused (according to them… at least).