Epistemic status: very speculative. This is mythmaking: you’ve been warned.

Ra is the Sun God

The Egyptian god Ra was a symbol of divine kingship, all-powerful and all-seeing.  He’s a good metaphor for a certain kind of psychological phenomenon that involves thought distortions around authority and legitimacy.  A new demon, if you will, in the grimoire that includes Moloch and Azathoth.

The idea of a malign Establishment is somewhat convergent:

The Establishment (attributed to Henry Fairlie in 1950’s Britain, talking about an informal social network of power among prominent, well-connected people)

The Man (e.g. Yippies, Burning Man)

The Combine (Ken Kesey)

Moloch (Allen Ginsberg)

The Beige Dictatorship (Charles Stross)

The Cathedral (Mencius Moldbug)

The Mandarins (Megan McArdle)

Not all of these ideas are coterminous with Ra, or identical to each other.

What they have in common is that the Establishment is primarily an upper-class phenomenon, that it is more about social and moral legitimacy than mere wealth or raw power, and that it is boringly evil — it produces respectable, normal, right-thinking, mild-mannered people who do things with very bad consequences.

What Ra is not

The usual pitfall when using poetic language to define egregores is making them too broad.  There is not one root of all evil that causes all the ills of the world.

Ra is not simply conformity, simply authoritarianism, or simply power-seeking.  Ra is not the same as “bureaucracy” or “capitalism” or “fallen human nature” or all the myriad reasons why your idealistic goal might fail.  Ra is not “everything that is wrong with people who disagree with me.”

As a social phenomenon, Ra is responsible for some dysfunctions in the democratic modern West; it is not, for instance, what was going on with the Nazis, or with terrorists, or with communist revolutionaries, or with the Confederates in the American Civil War.  Ra is not driving people who want to take over the world for some fanatic goal. It’s more like a dissipating, entropic motion, a process that corrupts institutions.

But it’s not merely the most commonly claimed drivers of institutional decay, like “knowledge problems” or “coordination problems”.  People who participate in those problems are following rational self-interest, but wind up contributing individually to collectively harmful outcomes.  Ra is something more like a psychological mindset, that causes people to actually seek corruption and confusion, and to prefer corruption for its own sake — though, of course, it doesn’t feel quite like that from the inside.

Ra is a specific kind of glitch in intuition, which can roughly be summarized as the drive to idealize vagueness and despise clarity.  I’m going to try to define it by extension, using examples from my and others’ personal experiences.

Ra is about generic superlativity.

You know how universal gods are praised with formulas that call them glorious, mighty, exalted, holy, righteous, and other suchlike adjectives, all of which are perfectly generic and involve no specific characteristics except wonderfulness?  That’s what Ra is all about.

The worship of Ra involves a preference for stockpiling money, accolades, awards, or other resources, beyond what you can meaningfully consume or make practical use of; a felt sense of wanting to attain that abstract radiance of “bestness”.

A featureless, powerful organization, something with a name like “Acme Corp”, whose activities you can’t pin down, is archetypally Ra.  Especially if it’s associated with markers of excellence (e.g. very smart high-achieving employees) or fully general capabilities (eg the most powerful computers in the world). OpenAI has a lot of this quality, as does Google, as did Enron before its collapse, as do top management consulting firms and investment banks and Ivy League schools. Effective Altruism, when it’s just “a movement for generic optimal goodness”, has a lot of this quality.  When an organization seems shiny, full of the best and brightest, and is presumed to be potentially good at everything, it is appealing in a very Ra-flavored way.

In my mind I synaesthetically imagine Ra as radiant white light and smoothness (as in “futuristic” computer graphics, or as in mirror-like glossiness.)

Ra is evident in marketing that is smooth, featureless, full of unspecified potential goodness, “all things to all people,” like Obama’s 2008 campaign.  (Note the logo, with its smooth gradient and radiant white sun.)  Apple’s design is also very Ra.

Ra is about legitimacy.

When someone is willing to work for prestige, but not merely for money or intrinsic interest, they’re being influenced by Ra.  The love of prestige is not only about seeking “status” (as it cashes out to things like high quality of life, admiration, sex), but about trying to be an insider within a prestigious institution.  Not only “people like and respect and desire me” but “this abstract, objective Thing full of goodness has sanctioned me.”  People with money or charisma but no prestige read as sleazy (e.g. gamblers, gurus) while people with status and prestige/insiderness read as legitimate (e.g. the rightful king or official priest or licensed professional.)

Ra involves seeing abstract, impersonal institutions as more legitimate than individuals. For instance, I have the intuition that it is gross and degrading to pay an individual person to clean your house, but less so to hire a maid service, and still less so if a building that belongs to an institution hires a janitor.  Institutions can have authority and legitimacy in a way that humans cannot; humans who serve institutions serve Ra.

Seen through Ra-goggles, giving money to some particular man to spend on the causes he thinks best is weird and disturbing; putting money into a foundation, to exist in perpetuity, is respectable and appropriate.  The impression that it is run collectively, by “the institution” rather than any individual persons, makes it seem more Ra-like, and therefore more appealing.

Ra causes avoidance of challenging regulators and establishment hierarchies in significant excess of the actual legal and reputational costs of doing so.  Not just caution, but a sort of unbounded over-caution that makes you willing to throw huge amounts of value away to reduce already small risks.  Selfishness can motivate caution and even conformity; Ra-worship motivates sacrificing excess value to institutions you view as more legitimate than yourself.

Once, the CEO of a hedge fund and a friend of mine were in a heated argument, and the CEO finally pushed his point home by saying “200 PhDs work for me, so I know what I’m talking about.”  This is argument by legitimacy.  It’s just saying “because my institution has piled up a lot of excellence in one place, I get to talk and you have to shut up.”  It’s not an argument from expertise like “My 200 physics PhD’s agree with my point about physics” would be. It’s not even a direct power claim like “My 200 armed security guards will make you shut up.”  The guards would be a practical threat; the PhD’s really aren’t.  But they would be, to someone who believed that they granted legitimacy, that the accumulation of PhDs proved that the CEO had more right to speak and think.

Ra defends itself with vagueness, confusion, incoherence — and then anger.

“Respectability” turns out to be incoherent quite often — i.e. if you have any consistent model of the world you often have to take extreme or novel positions as a logical conclusion from your assumptions. To Ra, disrespectability is damnation, and thus consistent thought is suspect.

Vagueness, mental fog, “underconfidence”, avoidance, evasion, blanking out, etc. are hallmarks of Ra.  If cornered, a person embodying Ra will abruptly switch from blurry vagueness to anger and nihilism.

I have, in Ra-influenced moods, had the intuition “I don’t know if it’s possible to be a consistent economic agent [i.e. von Neumann-Morgenstern] and still be good.” Consistency implies the potential for disobedience. Consistency means you might not be recruitable or available to arbitrary purposes.  It’s the opposite of malleability.  Ra wants its worshippers to be always available, always malleable; and calls it “wicked” to have resistance to that.

One friend of mine discussed having a conversation about the future of humanity with someone, getting the strong sense that this person was being evasive and switching between viewpoints, and also that underneath the evasiveness there was a negative-utilitarian belief that humanity ought to be annihilated. And she worried that if she pushed too hard on insisting the other person make a coherent argument, that he would double down on the negative utilitarianism and become vindictive about it.  This is prototypical Ra behavior.  Smooth, soft vagueness that, when challenged, collapses into angry nihilism.

One symptom of Ra is being offended or upset when friends and allies are not doing things associated with power and status.  Actual insecurity and anger at the sight of someone doing their own thing, behaving in ways that don’t bring them closer to the center of coolness/shininess/power/etc.

Nastasya Philipovna, in The Idiot, demonstrates this kind of anger; when she meets the man who embodies her moral ideal, instead of reaching out to him as a lover, she is outraged that he’s being shabby and noble and ignoring the “way of the world”, and she actively ruins his life. It’s not that she doesn’t appreciate goodness; it’s that it freaks her out.  People ought not be that good. It disturbs the universe.  Myshkin is missing something — it’s not clear what, because if you look at his words and actions explicitly he seems to be behaving quite sensibly and moderately — but he’s missing some intuition about the “way of the world”, and that enrages everyone around him.

I remember being angry at a coworker, once, for attempting to sell a product to big pharma companies, because he was thinking of them too lightly, not appreciating the awesome majesty of the pharma companies that we were barely worthy to submit our ideas to.  He seemed not to understand the unspoken “way of the world”, and that made me angry.  That was classic Ra thinking on my part.

Ra is involved in the sense of “everyone but me is in on the joke, there is a Thing that I don’t understand myself but is the most important Thing, and I must approximate or imitate or cargo-cult the Thing, and anybody who doesn’t is bad.”  E.g. having the intuition that the power to make successful companies lies in things like “complex sales”, without understanding how complex sales works on a nuts-and-bolts level.  If you just associate complex sales guys with power and success, if you have the feeling that they probably know how to become an insider even if you don’t, then you’re engaging in Ra thinking.

Ra causes persistent brain fog or confusion, especially around economic thinking or cost-benefit analysis or quantitative estimates.  E.g. for a while I had a block around the question “How much would it cost to outfit a biology lab?” and thought that this was literally impossible for me to discover the answer to because the information would only be available to properly credentialed biologists or pharma company employees.  I had a weird aversion to seeking information or thinking directly about the problem.  Another time, I had a block around answering the question “How many lives would be saved if all men got HPV vaccines?” because it was epidemiology and people were talking about publishing the results in a journal and I felt unworthy as a non-academic to submit journal articles, so I procrastinated and didn’t even try to do Fermi estimates on the question.

Ra tends to cause confusion and brain fog around modeling preferences, particularly two or more independent agents trying to negotiate mutually beneficial solutions.  When Ra is active, you’ll see a persistent disposition, in otherwise intelligent people, to misunderstand trade or negotiation scenarios as dominance/submission scenarios.

Ra may cause blurriness around objectives. In Drucker’s Management, the purpose of a business (or nonprofit or government agency) is explicitly not to maximize profits or shareholder value, or to produce the best widgets or save the most lives, but to fulfill its function.   But what does that even mean?  It means something like the preservation of the organization — but it’s not specific.

There’s a disinclination to get specific about numbers or negotiations or goals or arguments.  And then an angry sense that people who do get specific are “doing it wrong” or “bad people” and deserve harshness.  An intuition that the really important things in life, the true “ways of the world”, are hidden or mysterious, always unspoken, and must be respected.

Ra hates communication and introspection.

Ra causes a disinclination to express oneself. An impression that a person who is unknown or mysterious is more attractive or favorably received than a person who is an “open book.”  A tendency to prefer private and off-the-record communications. There are many non-Ra reasons for secrecy, privacy, or reservedness (e.g. spies, shy people) — the core Ra quality is not merely the concealment but the idealization of the invisible, an intuition that people who display a smooth surface to the world are better.

Glamour is a related idea (see Virginia Postrel), in particular the glamour of “mystery and illusion.”  Glamorous things or people are idealized precisely because the details are airbrushed out.

There’s also a preference not to engage with people authentically — i.e. being more comfortable asking someone for a pre-packaged response (like “give me money” or “sign this petition”) than asking them to have an open-ended conversation with you.

Ra promotes the idea that optimal politeness conveys as little information as possible. That you should actively try to hide preferences (because if you shared them, you’d inconvenience others by pressuring them to satisfy your preferences).  That all compliments are empty pleasantries.  There’s an interpretation of “politeness” that’s anti-cooperative, that avoids probing for opportunities for genuine mutual benefit or connection and just wants to make the mutual defection process go as smoothly as possible.  Ra prefers this, because it’s less revealing, commits you less, doesn’t pin you down, allows you to keep all your options open and devote everything to the pursuit of Ra.

Ra is involved in intuitions about silence or absence being ideal.  A blank sheet of paper is more beautiful than any art you can put on it, because the art is potentially flawed, while blankness is flawless.  Blankness leaves all the options open. See also The Whiteness of the Whale.

People who write a lot, or enjoy discussions, or spend a lot of time on introspective “inner work”, tend to be less Ra-oriented.  Blogging is very anti-Ra.  Having opinions and making essay-style arguments, for all the flaws of that medium, does promote some degree of coherence and specificity, and promotes people sharing their inner lives.  Having a coherent, specific, shareable inner life means you’re less malleable, less blank, and Ra insists that people’s inner lives be completely malleable and blank.

I’ve had my writing criticized because “when you give your opinion, it sounds like you think you’re smart”.  And I’ve spent a lot of time feeling ashamed of “thinking out loud” in public, because it tarnishes the glossy facade that it’s easy to feel obligated to put up.  I’ve also had my more mainstream, Ivy League friends express surprise that I cared at all or made the slightest effort for friends in trouble.  Being committed or involved in people’s lives is also messy and doesn’t permit the preservation of a flawless impression.  Expressing yourself, thinking speculatively, and relating to people are shameful to the Ra-worshipping mindset, because all mental and emotional resources must be channeled into the quest for prestige.

Gruad Grayface, in the Illuminatus! Trilogy, is one of many figures representing “the Man” or malign technocratic authority, and he is accused of setting people against each other, making them unable to empathize across demographic lines (men and women, black and white), because if they communicated with each other they would realize that they were natural allies and none of them benefited from Gruad’s tyrannical rule.

There’s a persistent theme in the 60’s counterculture ethos that if people just communicated authentically, it would make a big difference to the world. And while this sounds like a platitude, I think it might be an important truth about the nature of Ra. See “The Sound of Silence.”  See Leary’s exhortation to “find the others.”  See the dystopia of perfect conformity that is Camazotz, which is vanquished by human flaws and by the love of specific people. Understanding that everyone has an inner life and nobody is smooth and blank is the antithesis of Ra.

Ra is fake Horus.

Originally, the Egyptian falcon-god Horus was the god representing the Pharaoh’s sovereignty.  The notion of Horus as the pharaoh seems to have been superseded by the concept of the Pharaoh as the son of Ra during the Fifth Dynasty.

Horus was supposed to be literally the Pharaoh; that is, there’s some actual dude in charge, a god-king.  Ra, by contrast, is “father of the Pharaoh”, the un-look-at-able “power behind the throne.”  Instead of sovereignty that rests in an individual, Ra represents the abstract supreme to which the king is subordinate.

If Horus, the far-sighted, kingly bird, represents “clear brightness” and “being the rightful and just ruler”, then Ra is a sort of fake version of these qualities.  Instead of the light that distinguishes, it’s the light too bright to look at.  Instead of clear brightness, it’s smooth brightness.

Instead of objectivity, excellence, justice, all the “daylight” virtues associated with Horus (what you might also call Apollonian virtues), Ra represents something that’s also shiny and authoritative and has the aesthetic of the daylight virtues, but in an unreal form.

Instead of science, Ra chooses scientism.  Instead of systematization and explicit legibility, Ra chooses an impression of abstract generality which, upon inspection, turns out to be zillions of ad hoc special cases.  Instead of impartial justice, Ra chooses a policy of signaling propriety and eliteness and lack of conflicts of interest. Instead of excellence pointed at a goal, Ra chooses virtuosity kept as an ornament.

(Auden’s version of Apollo is probably Ra imitating the Apollonian virtues. The leadership-oriented, sunnily pragmatic, technological approach to intellectual affairs is not always phony — it’s just that it’s the first to be corrupted by phonies.)

Horus is not Ra.  Horus likes organization, clarity, intelligence, money, excellence, and power — and these things are genuinely valuable. If you want to accomplish big goals, it is perfectly rational to seek them, because they’re force multipliers.  Pursuit of force multipliers — that is, pursuit of power — is not inherently Ra.  There is nothing Ra-like, for instance, about noticing that software is a fully general force multiplier and trying to invest in or make better software. Ra comes in when you start admiring force multipliers for no specific goal, just because they’re shiny.

Ra is not the disposition to seek power for some goal, but the disposition to approve of power and to divert it into arbitrariness. It is very much NOT Machiavellian; Machiavelli would think it was foolish.

Ra corresponds to a stage in the corruption of organizations.

Thomas W. Lamont is an excellent example of Ra.  He was a banker at JP Morgan in the 1930’s who was famously gifted at communication, very much one of the club (Harvard and Exeter), somewhat “idealistic” but in a very vague sense that mostly amounted to rationalizing whatever power structure was nearby.  He ended up making major loans to militarist Japan and Mussolini, and was a major apologist for them right up until the situation became intolerably obvious; at which point without any apparent sense of shame he gave up on them, after making sure his friends were taken care of (e.g. negotiating a Morgan banker’s release from Italian imprisonment).

Lamont’s communication to the Japanese and later to Mussolini was all “I know you mean well but it’s getting harder to defend you, here’s some suggestions for how to clear up the obvious misunderstanding.”  He’s not a cynical power-seeker in these letters; he’s genuinely righteously indignant at people doubting his “ideals.”  There’s no master plan to gain power for himself or for an ideology he supports. He just seems to think “clearly the people gaining power must be good!”

The Lamonts of the world generally show up after the founding generation, after people like J. Pierpont Morgan himself, who was a genuine innovator who developed “modernization” techniques to make the businesses he took over profitable.  Vague objectives are only possible once institutions that steadily produce value have already been set in motion.  You see Ra-like figures at around the peak of an institution’s flourishing, when it’s begun to be possible to capture value without producing any, but before the decline is so severe that overtly exploitative behavior is socially acceptable.  Ra has a quality that’s triumphalist and slightly disconnected from reality — “Our institution is so powerful and wonderful that its proper sphere is the whole world!  And its job is to perpetuate its own flourishing!”

Ra is easy to overcome

As forces in the human psyche go, Ra is a pretty mild one. It’s not a powerful biological drive like aggression, or a difficult-to-treat problem like depression, or a highly optimized energy-saving structure like the standard cognitive biases.

Ra is hard to pin down, but vulnerable to open communication and introspection.  If you can talk and think about what you want, or how you feel, or why you believe what you do, and you don’t dodge the question, Ra will dissolve like mist. The illusion of smooth impersonal perfection doesn’t survive long after you get to know particular human beings. The subjective impression of something being like a vague glowy ball of positive affect doesn’t survive explicit discussion or analysis.  The sensation of total unknowability doesn’t survive the attempt to actually find things out.

It’s so faint and wispy that many people might say “Ra doesn’t have any part in my life!”  And you might be right.  Or it might be hidden in hard-to-find places, in certain questions you don’t ask and tasks you delay starting. It’s very, very rare for people to say “yes, I totally experience these things.”  But if you notice them, and are aware that they don’t make sense, then the fog yields to sunlight.

Cross-Sex Hormone Therapy: Female Hormones

Scope Of Report

For the purposes of this report, we’re looking at cross-gender hormone therapy for assigned-male-at-birth individuals — that is, estrogen and anti-androgens, as they are generally taken by transgender women and others seeking to feminize their bodies.  I’ll look into the evidence for the medical and psychological risks and benefits of these drugs.

Bottom Lines

  • hormone therapy consisting of estrogen and an anti-androgen is mostly safe: the biggest risk is cardiovascular problems
  • the anti-androgen cyproterone acetate is riskier than other anti-androgens: it’s associated with venous thromboembolism, hyperprolactinemia, and possibly impaired mood and cognitive ability. It can be substituted with spironolactone, or in some cases with no anti-androgen at all.
  • hormone therapy for trans women improves mood and agreeableness, reduces gender dysphoria, and has some feminizing effects on appearance
  • hormone therapy does change brain size but doesn’t impair cognitive performance
  • trying to get an “androgynous” outcome by taking anti-androgens without estrogen is a bad idea and does cause cognitive impairment and depression.

Risks of Hormone Therapy: Venous Thromboembolism

The most common risk of hormone therapy in trans women is venous thromboembolism. This is when a blood clot in a vein breaks loose and travels in the blood; if it reaches the lungs it is called a pulmonary embolism and can be very dangerous. About 5% of people with venous thromboembolisms die.[1]

In the largest study, 1076 individuals, the rate of venous thromboembolism is 1%; smaller studies find 5-6% rates.[2]  Some small studies (162 individuals) suggest that transdermal estrogen has less risk of venous thromboembolism than oral estrogen.

The risk of venous thromboembolism is also elevated in hormonal birth control, which, like hormone therapy, contains female hormones.  Current users of estrogen-containing birth control have about double the yearly risk of venous thromboembolism of female non-users. Birth control containing the progestin cyproterone acetate is associated with 1.88x the venous thromboembolism risk of birth control with other progestins.[3]  This is relevant because cyproterone acetate is also an anti-androgen sometimes used in cross-gender hormone therapy; avoiding cyproterone acetate could reduce the risk of venous thromboembolism.

Risks of Hormone Therapy: Osteoporosis

Estrogen is associated with osteoporosis: 25% of 100 transgender women had osteoporosis after more than 10 years of HRT, whereas transgender men did not.[2]

Risks of Hormone Therapy: Hyperprolactinemia

The anti-androgen cyproterone acetate can cause hyperprolactinemia.

High levels of the hormone prolactin can cause symptoms such as breast discharge, erectile dysfunction and reduced libido, infertility, breast growth, decreased body hair and muscle mass, and headaches. (Not all of these may be undesirable for trans women, of course.)  It is not otherwise dangerous, and can be treated with dopamine agonists such as bromocriptine.

In a total of 1109 trans women across six studies, there were elevated prolactin levels in 19.5%. [5]  Trans women on hormone therapy have much higher rates of migraine than the baseline population: 26% out of 50, as opposed to a baseline rate of 6%.  This may be due to higher prolactin levels.[6] 14/47, or 30% of trans women reported new sources of pain after going on hormones, in particular headaches, breast pain, and musculoskeletal pain.[7] This may also be a result of hyperprolactinemia, or it may be related to other hormonal-balance issues (women generally are more pain-sensitive than men.)

Cyproterone acetate increases prolactin levels; spironolactone does not. (p = 0.0002).[8]  Avoiding cyproterone acetate seems likely to reduce the risk of hyperprolactinemia.

Risks of Hormone Therapy: Infertility

Estrogen therapy usually eliminates the production of sperm.  In 7 out of 10 trans women on estrogen, there was no spermatogenesis.[53] A single male given estrogen had a pronounced drop in sperm motility and density by 4 weeks of estrogen treatment, though it did recover after discontinuation of treatment.[54] As of 2009, there have been no studies of restoration of spermatogenesis after prolonged treatment with estrogen. [52]

Benefits of Hormone Therapy: Improved Mood

Hormone treatment (transdermal estradiol + cyproterone acetate) reduced anxiety and depression scores (p < 0.001) in a cohort study of 107 trans women.[16]

Estrogen has a complex relationship to mood even in cis women.  One credible model is that estrogen fluctuations (for example, around the menstrual cycle, or around the start of menopause) cause mood disorders.  Increased vulnerability to depression in women begins with puberty and ends with menopause, though the perimenopause period is associated both with new onset of depression and increased depression symptoms. [17]  For this reason, estrogen supplementation in cis women is sometimes an effective treatment for mood disorders associated with hormone fluctuations. Estrogen has been consistently shown to be effective as a treatment for PMS, for postpartum depression, and for the milder mood problems associated with menopause, but not with severe menopausal depression or non-reproductive-related major depressive disorder.[18]

Higher doses of estrogen, on the other hand, tend to make mood problems in cis women worse. 3 mg estradiol vs. 2 mg estradiol in HRT for perimenopausal women significantly (p < 0.001) increased tension, irritability, and depressed mood, and decreased friendliness. [19] In postmenopausal women treated with 2 mg/day estrogen or placebo for three months, there was no difference in baseline mood, but the estrogen-treated group had stronger negative emotion responses to a social stress test.[20]  Chronic administration of E2 to ovariectomized female rats and mice at much higher than physiologic doses increases anxious and depressive behaviors.[21]  It’s not clear how this translates to trans women, but it may be preferable to err on the side of lower estrogen doses when possible.

The anti-androgen spironolactone is used to treat symptoms of PMS in cis women, such as irritability, depression, feeling of swelling, breast tenderness, and food craving. Unlike other anti-androgens such as cyproterone acetate or finasteride, it has not been connected with negative effects on mood or cognition.[22]

Benefits of Hormone Therapy: Reduced Gender Dysphoria

Cross-hormone therapy resulted in less body uneasiness in trans women, in a study of 125 subjects.[23]  Adolescents (mean age 17) treated vs. rejected for cross-sex hormone therapy had less gender dysphoria at follow-up in both groups, but significantly less in the treated group.  The treated group were more satisfied with their bodies.[24]

Benefits of Hormone Therapy: Higher Agreeableness

Androgen deprivation and estrogen supplementation in males (e.g. treated for prostate cancer) correlates with higher agreeableness on the Big Five personality test.[25]

Benefits of Hormone Therapy: Altered Sexual Patterns

Estrogen treatment inhibits sexual activity, spontaneous erections, and nocturnal penile tumescence.[4]   Androgen deprivation therapy in cis men (as part of treatment for prostate cancer) consistently causes reduced libido and lower frequency of early morning erections, p < 0.0001.[51] However, trans women have no higher rates of hypoactive sexual desire syndrome than cis women[47]; it may simply be that estrogen causes a more female-typical sex pattern.

Benefits of Hormone Therapy: Physical Appearance Changes

Estrogen and anti-androgens reduce hair on the trunk and limbs, but don’t completely remove it on the face; electrolysis or shaving is still usually necessary.[26]

Breast growth is usually present, with a mean hemicircumference of 18 cm after a year of hormone therapy — this is still a few centimeters less than the mean for cis women.[26]  Most trans women are dissatisfied with the final size of their breast development.[30]

Hormone therapy significantly (p < 0.01, Cohen’s d = 1) improved the “physical appearance score” for gender compatibility of transgender people, a composite made of hair, facial hair, larynx, voice, figure, height, skin, hands/feet, muscularity, chin, nose, jaw, speech, and gestures/movement.[27]

Breast growth, redistribution of body fat, and decrease in muscle mass begin at 3-6 months and peak at 2 years; decreased hair growth begins at 6-12 months and peaks at >3 years.[28]

Trans women, compared to cis men, had similar BMI but higher body fat percentage: 29% vs. 21%, p < 0.001. They also had lower grip, biceps, and quadriceps strength (p < 0.001).[29]

Non-Effects of Hormone Therapy: Cognitive Ability

A study of 35 trans men and 15 trans women at the beginning of hormone treatment, as well as 20 control (cis) men and 20 cis women, found that the trans men’s spatial rotation ability increased during 12 weeks of hormone treatment, while the trans women’s spatial rotation ability slightly declined (p < 0.01), from an average score of 101.9 to 98.5, or a 3% drop.  In this study, trans women were treated with with 100 ug/day of ethinyl estradiol and 100 ug/day of cyproterone acetate.[31]

A study of 51 trans people given hormone therapy and 29 cis controls found no effect on cognitive abilities of hormone treatment over the course of a year. Trans women were given 100 ug/day of oral ethinyl estradiol.[32]

A study of 103 trans women, treated with conjugated equine estrogens or ethinyl estradiol, and in some cases cyproterone acetate and/or medroxyprogesterone acetate, found a slight improvement in digit span after going on estrogen (6.70 on estrogen, 6.00 off estrogen), and a slight improvement in a visual recall test after going off estrogen, but mostly found no effect on a large battery of cognitive tests.[34]

The anti-androgens leuprorelin, goserelin, and cyproterone acetate, when given to men with prostate cancer, caused a drop in one or more cognitive tests in 24/50 men randomized to active treatment, compared to none of the men randomized to placebo.[33]  However, when men treated with anti-androgens were subsequently given estrogen, their memory performance improved.[50]

It seems likely that estrogen has little or no effect on cognitive abilities. Cyproterone acetate taken alone has a negative effect on cognition in cis men, and may contribute to a slight drop in spatial rotation ability in the context of hormone therapy for trans women.

Non-Effects of Hormone Therapy: All-Cause Mortality

In a retrospective study of 816 trans women and 293 trans men, all-cause mortality was not different than in the general population.[47]  In a long-term follow-up study of 2236 trans women and 876 trans men, there was no elevated mortality compared to the general population.[49] In a cohort study of 966 trans women and 365 trans men, the trans women group had 51% higher mortality than the general population, due mostly to suicide, cardiovascular disease, AIDS, and drug abuse; but the use of estrogen among trans women was not an independent predictor of mortality generally or of any cause of mortality except for cardiovascular disease. In other words, trans women are an at-risk population for problems like suicide, drug abuse, and AIDS, but hormone users are at no higher risk than non-users.[48]

Neutral Effects of Hormone Therapy: Brain Morphology

Men and women have structural brain differences. Men have larger brain volumes (and smaller ventricles) than women; they have larger hypothalamuses; and they have a higher fraction of white matter relative to gray matter.

In a study of eight trans women and six trans men, receiving estrogen and cyproterone acetate, and testosterone, respectively, as well as 9 cis male and 6 cis female controls, the trans women had significantly reduced brain and hypothalamus volume, while the trans men had significantly increased brain volume.  Brain volume decreased by a mean of 25 mL in trans women, from 1300 mL to 1275 mL, or about a 2% drop, leaving brain volume somewhere between that of cis men and cis women.[35]  Another study, of 15 trans men on testosterone and 14 trans women on estrogen and an anti-androgen, found that testosterone increased cortical thickness while estrogen and anti-androgens decreased it and increased ventricle size.[36]

While brain volume correlates with IQ,[37] and while some studies find slightly higher mean IQ in men than women (about 3.63 IQ points, extrapolated from the differences in SAT scores in a sample of 100,000)[38], the more common position among IQ researchers is that there are no significant sex differences in mean IQ.[39]  It’s not at all clear that hormone therapy’s effect on shrinking brain volume significantly impairs cognition.

Nonstandard Cases of Cross-Gender Hormone Use

Anti-Androgens May Not Be Necessary

Lower estrogen doses (0.625 mg conjugated estrogen daily) without cyproterone acetate, given to trans women, are sufficient to keep estrogen levels in the normal range for premenopausal women.[9]  7/10 trans women on estrogen alone, without anti-androgens, had testosterone levels drop into the normal female range.[10]  Given that anti-androgens, particularly cyproterone acetate, are responsible for many of the negative side effects of hormone therapy, taking estrogen alone may be a lower-risk approach to hormone therapy.

Risks of Anti-Androgens Without Estrogen: Depression and Cognitive Impairment

Men being treated for prostate cancer are regularly given anti-androgens to suppress the tumor. These men experience significantly elevated rates of anxiety and depression. (This is in contrast to trans women given anti-androgens along with estrogen, who generally experience significant psychological benefit.)

Chemical castration in men significantly reduces estrogen and testosterone levels, and causes significant increases in depression and anxiety scores (though generally subclinical.)[11]  Compared to controls, prostate cancer patients treated with anti-androgens had significant drops in spatial reasoning and executive function, more depressed mood and irritability, less energy and vigor.[12]

The anti-androgen finasteride, given to men as a treatment for hair loss, produced depressive symptoms in 64% of users and 0% of controls; finasteride users reported sexual dysfunction, problems with attention and memory, anxiety, depression, and suicidality.[13]  A prospective study on finasteride found that it increased scores on the Beck depression inventory (p < 0.001) and HADS depression scores (p = 0.005)[14]

Cyproterone acetate in men treated for prostate cancer is associated with declines (compared to placebo) in attention and memory.[15]


Tamoxifen is an selective estrogen-receptor modulator; its primary use is as a breast cancer drug, but it also prevents gynecomastia related to estrogen or anti-androgen use.[40]  It might in principle be possible that if one combines tamoxifen with estrogen, one can get some of estrogen’s feminizing effects without growing breasts, but I couldn’t find any case studies of this being done successfully.

Tamoxifen taken alone does not have feminizing effects on men.  It increases both serum estrogen and testosterone levels in men, and increases sperm count.[41]

Female Hormone Use in Men

Male cross-dressers do sometimes use female hormones, and in past decades the social concept of “transgender” was less sharp than it is today. In early-1990’s radical contexts, “transgender” was considered an umbrella term that would include transvestites, drag queens, feminine gay men, butch lesbians, and other gender-nonconforming people who would not usually be considered “trans” today.[43]

In a 1992 sample of 1032 male cross-dressers, 43% said they “would like to use” hormones and 9% had used or were using hormones; in a 1972 sample of of 504 male cross-dressers, 50% said they “would like to use” hormones and 9% had used or were using hormones. However, the majority of these people viewed themselves as “a man with a feminine side” rather than “a woman trapped in a man’s body,” and did not plan to live full-time as women.[42]

From a biological standpoint, there’s no strong reason to believe that hormones would have different effects depending on whether they’re taken by a person who identifies as trans or not.  Men given estrogen for medical reasons (coronary heart disease) had similar side effects as trans women do, including breast tenderness and growth, testicular shrinkage, sexual dysfunction, and depression upon discontinuing estrogen,[44] but there was no evidence of psychological disturbance as a result of taking estrogen.[45]




[2]Weinand, Jamie D., and Joshua D. Safer. “Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals.” Journal of Clinical & Translational Endocrinology 2.2 (2015): 55-60.

[3]Kwan, Marie, Judly VanMaasdam, and Julian M. Davidson. “Effects of estrogen treatment on sexual behavior in male-to-female transsexuals: experimental and clinical observations.” Archives of sexual behavior 14.1 (1985): 29-40.

[4]Lidegaard, Øjvind, et al. “Hormonal contraception and risk of venous thromboembolism: national follow-up study.” Bmj 339 (2009): b2890.

[5]Bourgeois, Anne Laure, et al. “Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance.” Annales d’endocrinologie. Vol. 77. No. 1. Elsevier Masson, 2016.

[6]Pringsheim, Tamara, and Louis Gooren. “Migraine prevalence in male to female transsexuals on hormone therapy.” Neurology 63.3 (2004): 593-594.

[7]Aloisi, Anna Maria, et al. “Cross-sex hormone administration changes pain in transsexual women and men.” Pain 132 (2007): S60-S67.

[8]Sofer, Yael, et al. “SAT-0111: High Prolactin Levels in Transsexual Women Are Related to the Anti-Androgen Treatment Modality.”

[9]Cunha, Flávia Siqueira, et al. “MON-595: Low estrogen doses are effective to keep estradiol and testosterone serum levels at normal premenopausal women in male-to-female transsexuals.” (2013).

[10]Spratt, Lindsey V., et al. “OR42-2: Efficacy of Testosterone (T) or Estradiol (E2) Therapy without a GnRH Agonist or Progestin to Suppress Endogenous Gonadal Activity in Transsexual Patients.” (2014).

[11]Almeida, Osvaldo P., et al. “One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men.” Psychoneuroendocrinology 29.8 (2004): 1071-1081.

[12]Cherrier, M. M., S. Aubin, and C. S. Higano. “Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non‐metastatic prostate cancer.” Psycho‐Oncology 18.3 (2009): 237-247.

[13]Ganzer, Christine Anne, Alan Roy Jacobs, and Farin Iqbal. “Persistent Sexual, Emotional, and Cognitive Impairment Post-Finasteride A Survey of Men Reporting Symptoms.” American journal of men’s health 9.3 (2015): 222-228.

[14]Rahimi-Ardabili, Babak, et al. “Finasteride induced depression: a prospective study.” BMC Pharmacology and Toxicology 6.1 (2006): 7.

[15]Green, Heather J., et al. “Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: A randomized controlled trial.” BJU international 90.4 (2002): 427-432.

[16]Colizzi, Marco, Rosalia Costa, and Orlando Todarello. “Transsexual patients’ psychiatric comorbidity and positive effect of cross-sex hormonal treatment on mental health: results from a longitudinal study.”Psychoneuroendocrinology 39 (2014): 65-73.

[17]Newhouse, Paul A., et al. “Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women.” Neuropsychopharmacology 33.7 (2008): 1514-1527.

[18]Epperson, C. Neill, Katherine L. Wisner, and Bryan Yamamoto. “Gonadal steroids in the treatment of mood disorders.” Psychosomatic Medicine 61.5 (1999): 676-697.

[19]Björn, Inger, et al. “Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy.” The Journal of Clinical Endocrinology & Metabolism 88.5 (2003): 2026-2030.

[20]Newhouse, Paul A., et al. “Estrogen administration negatively alters mood following monoaminergic depletion and psychosocial stress in postmenopausal women.” Neuropsychopharmacology 33.7 (2008): 1514-1527.

[21]Wharton, Whitney, et al. “Neurobiological underpinnings of the estrogen-mood relationship.” Current psychiatry reviews 8.3 (2012): 247-256.

[22]Wang, Mingde, et al. “Treatment of premenstrual syndrome by spironolactone: A double‐blind, placebo‐controlled study.” Acta obstetricia et gynecologica Scandinavica 74.10 (1995): 803-808.

[23]Fisher, Alessandra D., et al. “Cross‐sex hormonal treatment and body uneasiness in individuals with gender dysphoria.” The journal of sexual medicine 11.3 (2014): 709-719.

[24]Smith, Yolanda LS, Stephanie HM van Goozen, and Peggy T. Cohen-Kettenis. “Adolescents with gender identity disorder who were accepted or rejected for sex reassignment surgery: a prospective follow-up study.” Journal of the American Academy of Child & Adolescent Psychiatry 40.4 (2001): 472-481.

[25]Treleaven, Michelle MM, et al. “Castration and personality: Correlation of androgen deprivation and estrogen supplementation with the Big Five factor personality traits of adult males.” Journal of Research in Personality 47.4 (2013): 376-379.

[26]Asscheman, Henk, and Louis JG Gooren. “Hormone treatment in transsexuals.” Journal of Psychology & Human Sexuality 5.4 (1993): 39-54.

[27]Smith, Yolanda LS, et al. “Sex reassignment: Outcomes and predictors of treatment for adolescent and adult transsexuals.” Psychological medicine35.01 (2005): 89-99.

[28]Hembree, Wylie C., et al. “Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 94.9 (2009): 3132-3154.

[29]Lapauw, Bruno, et al. “Body composition, volumetric and areal bone parameters in male-to-female transsexual persons.” Bone 43.6 (2008): 1016-1021.

[30]Wierckx, Katrien, Louis Gooren, and Guy T’Sjoen. “Clinical review: Breast development in trans women receiving cross‐sex hormones.” The journal of sexual medicine 11.5 (2014): 1240-1247.

[31]Van Goozen, Stephanie HM, et al. “Gender differences in behaviour: Activating effects of cross-sex hormones.” Psychoneuroendocrinology 20.4 (1995): 343-363.

[32]Haraldsen, Ira R., et al. “Cross-sex hormone treatment does not change sex-sensitive cognitive performance in gender identity disorder patients.”Psychiatry research 137.3 (2005): 161-174.

[33]Green, Heather J., et al. “Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: A randomized controlled trial.” BJU international 90.4 (2002): 427-432.

[34]Miles, Clare, Richard Green, and Melissa Hines. “Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals.” Hormones and Behavior 50.5 (2006): 708-717.

[35]Pol, Hilleke E. Hulshoff, et al. “Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure.”European Journal of Endocrinology 155.suppl 1 (2006): S107-S114.

[36]Zubiaurre‐Elorza, Leire, et al. “Effects of Cross‐Sex Hormone Treatment on Cortical Thickness in Transsexual Individuals.” The journal of sexual medicine 11.5 (2014): 1248-1261.

[37]Posthuma, Daniëlle, et al. “The association between brain volume and intelligence is of genetic origin.” Nature neuroscience 5.2 (2002): 83-84.

[38]Jackson, Douglas N., and J. Philippe Rushton. “Males have greater g: Sex differences in general mental ability from 100,000 17-to 18-year-olds on the Scholastic Assessment Test.” Intelligence 34.5 (2006): 479-486.

[39]Halpern, Diane F., and Mary L. LaMay. “The smarter sex: A critical review of sex differences in intelligence.” Educational Psychology Review 12.2 (2000): 229-246.

[40]Parker, Lawrence N., et al. “Treatment of gynecomastia with tamoxifen: a double-blind crossover study.” Metabolism 35.8 (1986): 705-708.

[41]Vermeulen, Alex, and Frank Comhaire. “Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men.” Fertility and sterility 29.3 (1978): 320-327.

[42]Docter, Richard F., and Virginia Prince. “Transvestism: A survey of 1032 cross-dressers.” Archives of Sexual Behavior 26.6 (1997): 589-605.

[43]Valentine, David. Imagining transgender: An ethnography of a category. Duke University Press, 2007.

[44]Robinson, Roger W., Norio Higano, and William D. Cohen. “Long-term effects of high-dosage estrogen therapy in men with coronary heart disease.”Journal of chronic diseases 16.2 (1963): 155-161.

[45]Kaplan, Benjamin M., and Jerome Grunes. “Emotional aspects of estrogen therapy in men with coronary atherosclerosis.” JAMA 183.9 (1963): 734-736.

[46]Klein, Carolin, and Boris B. Gorzalka. “Continuing Medical Education: Sexual Functioning in Transsexuals Following Hormone Therapy and Genital Surgery: A Review (CME).” The Journal of Sexual Medicine 6.11 (2009): 2922-2939.

[47]Van Kesteren, Paul JM, et al. “Mortality and morbidity in transsexual subjects treated with cross‐sex hormones.” Clinical endocrinology 47.3 (1997): 337-343.

[48]Asscheman, Henk, et al. “A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones.” European Journal of Endocrinology 164.4 (2011): 635-642.

[49]Gooren, Louis J., Erik J. Giltay, and Mathijs C. Bunck. “Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience.”The Journal of Clinical Endocrinology & Metabolism 93.1 (2008): 19-25.

[50]Beer, Tomasz M., et al. “Testosterone loss and estradiol administration modify memory in men.” The Journal of urology 175.1 (2006): 130-135.

[51]Basaria, Shehzad, et al. “Long‐term effects of androgen deprivation therapy in prostate cancer patients.” Clinical endocrinology 56.6 (2002): 779-786.

[52]Hembree, Wylie C., et al. “Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 94.9 (2009): 3132-3154.

[53]Thiagaraj, D., et al. “Histopathology of the testes from male transsexuals on oestrogen therapy.” Annals of the Academy of Medicine, Singapore 16.2 (1987): 347-348.

[54]Lübbert, Horst, Inka Leo-Roßberg, and Jürgen Hammerstein. “Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male.” Fertility and sterility 58.3 (1992): 603-608.

Do the Best Thing

A Googler friend of mine once asked me, “If you had a program that was running slow, what would you do to fix it?”

I said, “Run it through a profiler, see which step was slowest, and optimize that step.”

He said “Yeah, that’s the kind of thinking style Google optimizes for in hiring. I’m the odd one out because I don’t think that way.”

“That way” of thinking is a straightforward, naive, and surprisingly powerful mindset. Make a list of all your problems, and try to fix the biggest tractable one.  Sure, there are going to be cases when that’s not the best possible solution — maybe the slowest step can’t be optimized very much as is, but if you rearrange the entire program, or obviate the need for it in the first place, your problem would be solved. But if you imagine a company of people who are all drilled in fix the biggest problem first, that company would have a systematic advantage over a company full of people who poke at the code at random, or according to their varied personal philosophies, or not at all.  Just doing the naively best thing is a powerful tool; enough that it’s standard operating procedure in a company reputed to have the best software engineers in the world.

There are other heuristics that have a similar spirit.

Making a list of pros and cons, a decision procedure started by Ben Franklin and validated by Gerd Gigenzehrer’s experiments, is an example of “do the best thing” thinking. You make your considerations explicit, and then you score them, and then you decide.

Double-entry bookkeeping, which was arguably responsible for the birth of modern capitalism, is a similar innovation; you simply keep track of expenses and revenues, and aim to reduce the former and increase the latter.  It sounds like an obvious thing to do; but reliably tracking profits and losses means that you can allocate resources to the activities that produce the highest profits.  For the first time you have the technology to become a profit-maximizer.

The modern craze of fitness-tracking is a “do the best thing” heuristic; you pick a naive metric, like “calories eaten – calories burned”, and keep track of it, and try to push it in the desired direction.  It’s crude, but it’s often a lot more effective than people’s default behavior for achieving goals — people who self-monitor diet and weight are more likely to achieve long-term deliberate weight loss.

Deciding to give to the charity that saves the most lives per dollar is another example of “do the best thing” — you pick a reasonable-sounding ranking criterion, like cost-effectiveness, and pick things at the top of the list.

Notice that I’m not calling this optimization, even though that’s what it’s often called in casual language.  Optimization, in the mathematical sense, is about algorithms for maximizing some quantity.  DTBT isn’t an algorithm, it’s what comes before implementing an algorithm. It’s just “pick an obvious-seeming measure of importance, and then prioritize by that.”  The “algorithm” may be trivial — just “sort by this metric”.  The characteristic quality is picking a metric and tracking it; and, in particular, picking an obviousstraightforward, reasonable-sounding metric.

Now, there are critics of the DTBT heuristic. “Optimize Everything” can evoke, to some people, a dystopian future of robotic thinking and cold indifference to human values.  “Minimize calories”, taken in isolation, is obviously a flawed approach to health.  “Maximize GDP growth” is obviously an imperfect approach to economic policy.  One can be very skeptical of DTBT because of the complicated values that are being erased by a simple, natural-seeming policy.  This skepticism is present in debates over legibility.  I suspect that some Marxist critiques of “neoliberalism” are partly pointing at the fact that a measure of goodness (like “GDP growth” or even “number of people no longer living in poverty”) is not identical with goodness as judged by humans, even though it’s often treated as though it obviously is.

The DTBT response is “Yeah, sure, simplifications simplify.  Some simplifications oversimplify to the point of being counterproductive, but a lot of them are clearly productive. What people were doing before we systematized and improved processes was a lot of random and counterproductive cruft, not deep ancestral wisdom. Ok, Westerners undervalued traditional societies’ agriculture techniques because they were racist; that’s an admitted failure. Communists didn’t understand economics; that’s another failure. Nobody said that it’s impossible to be wrong about the world. But use your common sense — people shoot themselves in the foot through procrastination and weakness of will and cognitive bias and subconscious self-sabotage all the time.  Organizations are frequently disorganized and incompetent and just need some serious housecleaning. Do you seriously believe it’s never possible to just straighten things up?”

Here’s another way of looking at things. Behaviors are explained by a multitude of causes. Some of those causes are unendorsed. You don’t, for example, usually consider “I got a bribe” as a good reason to fund a government program.  DTBT is about picking a straightforwardly endorsable cause and making it master. This applies both intrapersonally and interpersonally. “Optimizing for a personal goal” means taking one of the drivers of your behavior (the goal) and setting it over your other internal motivations.  “Optimizing for a social outcome” means setting the outcome above all the motivations of the individual people who make up your plan.

In some cases, you can reduce the conflict between the “master goal” and the sub-agents’ goals. Popular vote is one way of doing this: the “master goal” (the choice that gets the most votes) minimizes the sum of differences between the chosen outcome and the preferences of each voter.  Free trade is another example: in a model where all the agents have conventional utility functions, permitting all mutually-beneficial trades between individuals maximizes the sum of individual utilities.  If your “master goal” is arbitrary, you can cause a lot of pain for sub-agents.  (E.g.: governments that tried to ‘settle’ nomadic peoples did not treat the nomadic peoples very well.) If your “master goal” is universal, in some sense, if it includes everybody or lets everybody choose, then you can minimize total frustration.

Of course, this isn’t an objectively universal solution to the problem — some people might say “my frustration inherently matters more than his frustration” or  “you aren’t properly measuring the whole of my frustration.”

Another way to reduce conflict is to see if there are any illusory conflicts that disappear upon greater communication.  This is what “dialogue” and “the public sphere” and “town halls” are all about. It’s what circling is about.  It’s what IFS is about. (And, more generally, conflict resolution and psychotherapy.)

And, of course, once again, this isn’t an objectively universal solution to the problem — there might actually be irreconcilable differences.

The pure antithesis of DTBT would be wu-wei — don’t try to do anything, everything is already fine as it is, because it is caused by human motivations, and all human motivations are legitimate. It would be “conservative” in a way that political conservatives would hate: if the world is going to hell in a handbasket, let it, because that’s clearly what people want and it would be arrogant to suppose that you know better.

This extreme is obviously at least as absurd as the DTBT extreme of “All the world’s problems would be solved if people would just stop being idiots and just do the best thing.

It seems more productive to resolve conflicts by the kinds of “universalizing” or “discourse” moves described above.  In particular, to try to discuss which kinds of motivations are endorsable, and argue for them.

One example of this kind of argument is “No, we can’t use the CEO’s new “optimized” procedure, because it wouldn’t work in our department; here’s where it would break.”  Sheer impracticality is pretty much always considered a licit reason not to do something among reasonable people, so a reasonable CEO should listen to this criticism.

Another, more meta example is discussing the merits of a particular kind of motivation. Some people think status anxiety is a legitimate reason to push for egalitarian policies; some don’t. You can argue about the legitimacy of this reason by citing some other shared value — “people with lower relative status are less healthy” appeals to concerns about harm, while “envy is an ugly motivation that prompts destructive behavior” appeals to concerns about harm and virtue.

Geeks are often accused of oversimplifying human behavior along DTBT lines.  “Why can’t we just use ‘ask culture’ instead of ‘guess culture’?” “Why can’t we just get rid of small talk?” “Why do people do so much tribal signaling?”  Well, because what most people want out of their social interactions is more complicated than a naive view of optimality and involves a lot of subconscious drives and hard-to-articulate desires. What it comes down to is actually a debate about what motivations are endorsable.  Maybe some drives, like the desire to feel superior to others, are ugly and illegitimate and should be bulldozed by a simple policy that doesn’t allow people to satisfy them.  Or maybe those drives are normal and healthy and a person wouldn’t be quite human without them.  Which drives are shallow, petty nonsense and which are valuable parts of our common humanity?  That’s the real issue that gets hidden under debates about optimality.

I happen to lean more DTBT than most people, and it’s because I’m fairly Blue in a spiral dynamics sense.  While the stereotypical Blue is a rigid, conformist religious extremist, the fundamental viewpoint underlying it is the more general notion of “loyalty to Truth” — there are good things and bad things, and one should prefer the good to the bad and not swerve from it.  “I have set before you life and death, blessing and cursing: therefore choose life.”  From a Blue perspective, some motivations are much, much more legitimate than others, and one should sanction only the legitimate ones.  A Blue who values intellectual inquiry doesn’t sanction “saving mental effort” as a valid reason to believe false things; a Blue who values justice doesn’t sanction “desire for approval” as a valid motivation to plagiarize.  Some things are just bad and should feel bad.  From a Blue perspective, people do “counterproductive” things all the time — choices that bring no benefit, if the only benefits we count are the licit ones.  (If you counted all motivations as legitimate, then no human behavior would be truly counterproductive, because it’s always motivated by something.)  And, so, from a Blue perspective, there are lots of opportunities to make the world “more optimal”, by subordinating illegitimate motivations to legitimate ones.

The best way to argue to me against some DTBT policy is to show it fails at some legitimate goal (is impractical, harms people, etc).  A more challenging way is to argue that I ought to consider some motivation more legitimate than I do.  For instance, sex-positive philosophy and evolutionary psychology can attempt to convey to a puritanical person that sexual motivations are legitimate and valid rather than despicable.  A flat assertion that I ought to value something I don’t is not going to work, but an attempt to communicate the value might.

I think it would be better if we all moved beyond naive DTBT or simple critique of DTBT, and started trying to put into practice the kinds of dialogue that have a chance of resolving conflicts.

Haidt-Love Relationship

Epistemic status: personal, exhortatory, expressive

Jonathan Haidt has an ideology.  In his academic life, he poses positive questions, but he definitely has a normative position as well. And you can see this most clearly in his speeches to young people, which are sermons on Haidtism.

Here is an example.

In it, he contrasts “Coddle U” with “Strengthen U,” two archetypal colleges. He’s clearly arguing in favor of psychological resilience, and against fragility. Let’s leave aside the question of whether feminists and other activists are actually oversensitive weenies, and whether trigger warnings are actually coddling, and engage with his main point, that it is better not to be an oversensitive weenie.

Haidt seems to see this as self-evident. The emotionally weak are to be mocked; the emotionally strong are to be respected.

I don’t find it as obvious.

Fragility can have a certain charm. Sensitive, romantic, tender spirits can be quite attractive.  The soft-hearted can be quick to show kindness. The easily-bruised can be alert to problems that more thick-skinned folks ignore.  We usually trust people’s sincerity more when they are moved to strong emotion.  A frail, innocent person is often a lovable person.  And who wouldn’t want to be lovable?

“Do you want to be strong or do you want to be fragile?” takes us back to Nietzsche’s old conflict of Herrenmoral and Sklavmoral.  Is it good to be successful, skilled, strong, powerful (as opposed to weak, cowardly, unhealthy, contemptible)?   Or is it good to be innocent, pure, gentle, kind (as opposed to oppressive, selfish, cruel)?

Of course it’s possible to be both kind and strong.  Herrenmoral and Sklavmoral are both pre-rational viewpoints, more like aesthetics than actual ethics.  It’s a question of whether you want to be this:

or this:

Ultimately, the consideration in favor of strength is simply that the world contains threats.  Fragility may make you lovable, but it can also make you dead.  You don’t get to appreciate the benefits of sensitivity and tenderness if you’re dead.

Being strong enough to do well at the practicalities of the world — physical safety and health, economic security, enough emotional stability not to put yourself or others at risk — is, up to a point, an unalloyed good.

Think of it as a gambler’s ruin situation. You have to win or save enough to stay in the game.  Strength helps you stay in the game.

And because strength is necessary for survival, there’s something to respect in the pro-strength aesthetic.

From the outside, it can seem kind of mean and elitist. You’re scorning people for failure and pain? You think you’re better than the rest of us, just because you’re pretty or smart or tough or happy?

But another way of looking at it is having respect for the necessities of life.  If you consider that starvation is a thing, you’ll remember that food is valuable, and you’ll feel gratitude to the farmers who grow it. In the same way, you can have respect for intelligence, respect for competence, respect for toughness, respect for all skills.  You can be glad for them, because human skill drives out the darkness of death, the hard vacuum of space that surrounds us, and excellent humans are pinpricks of flame in the dark.  You can love that hard brilliance.

And if respect can tinge into love, love can shade into enjoyment. You can enjoy being awesome, or knowing people who are awesome.  It can be exhilarating.  It can be a high and heady pleasure.

And from that vantage point, it’s possible to empathize with someone who, like Haidt, scorns weakness. Maybe, once you’ve been paying attention to the high points of human ability, anything else seems rather dingy.  Maybe you think “It’s so much nicer here upon the heights, why would you want to be down in the valley?”  Maybe some of the people who seem “elitist” actually just want to be around the people who light them up, and have developed high standards for that.

Not to say that there doesn’t exist shallow, vindictive status-grabbing.  But there are also people who aren’t like that, who just prefer the excellent to the mediocre.

Or, on a smaller scale, there are those who seek out “positive people” and avoid “toxic people” — they’re orienting towards success and away from failure, towards strength and away from weakness, and this is an understandable thing to do.

An addict trying to get her life together would try hard to avoid weakness, temptation, backsliding — and this would be a good thing, and any decent person would cheer for her.  That kind of motivation is the healthy thing that drives people to choose strength over fragility.

So Haidt’s basic premise — that you want to be more strong than fragile — is believable.

His prescriptions for achieving that are risk tolerance and minimizing the negative.

I’m going to reframe his ideas somewhat so they refer to individuals.  He’s talking about a top-down perspective — how schools can make students stronger. I have an issue with that, because I think that “improving” people against their will is ethically questionable, and especially trying to “make people tough” by exposing them to adversity, if they have no intrinsic desire to toughen and no input into the type of “adversity” involved, is probably counterproductive.  However, people self-improve all the time, they make themselves tougher, and that’s a more fruitful perspective, in my opinion.

Risk tolerance is the self-motivated version of “we’re not going to coddle you.” It would mean seeking out challenges, looking for criticism, engaging with “hard truths”, going on adventures.  Trying things to test your mettle.

It’s pretty obvious why this works: small amounts of damage cause you to develop stronger defenses. Exercise produces micro-tears in muscle, so it grows back stronger.  Vaccines made of weakened virus stimulate immunity to that virus.  Intermittent, all-out efforts against fear or failure are good for you.

(You’re still playing to stay in the game, so an adversity that takes you out of the game altogether is not good for you. This is why I think it works much better if the individual’s judgment and motivation is engaged.  Voluntary choice is important. Authorities trying to “toughen kids up” against their will can kill them. )

Minimizing the negative means mentally shrinking the sources of your distress. Haidt cites Marcus Aurelius, Boethius, the Buddha, and the tenets of cognitive behavioral therapy as pointing at the same universal truths.

Now, of course, Stoicism, Buddhism, and modern psychology have very different visions of the good life. The ideal Stoic is a good citizen; the ideal Buddhist is an ascetic; the ideal psychological subject is “well.”  The ideal Stoic is protective of his soul; the ideal Buddhist is aware that his “self” does not exist.  Trying to be a serious Stoic is quite different from trying to be a serious Buddhist, and it’s not clear what it would even mean to try to be the “ideal person” by the standards of cognitive behavioral therapy.

What these philosophies have in common is a lot simpler than that: it’s just “Don’t sweat the small stuff.”

Don’t freak out over trivial shit. Remember that it’s trivial.

Stoicism and Buddhism both use meditation as a tactic; both suggest focusing on impermanence and even death, to remind oneself that trivial shit will pass.  CBT’s tactic is disputation — arguing with your fears and frustrations, telling yourself that the problem is not that big a deal.

Marcus Aurelius in particular uses pride a lot as a tactic, encouraging you to view getting upset as beneath the dignity of your soul.

Of course, “Don’t sweat the small stuff” imposed from without is a bit insulting.  Who are you, authority figure, to say what is and isn’t important?  Aren’t you telling me to ignore real problems and injustices?

But seen from within, “don’t sweat the small stuff” is just another perspective on “focus on your goals and values.”

You want to stay in the game, remember? So you can win, whatever that means to you.  So survival matters, robustness matters, because that keeps you in the game.  Freaking out takes you hors de combat.

Haidt tends not to push too hard on Christianity, perhaps because his audience is secular, but it is a very common source of comfort that does, empirically, make people happier.  My impression of Christian positivity, from a non-theological perspective, is that it says the good outweighs the bad. The bad exists; but the good is stronger and bigger and wins in the end.  And this is another way of not freaking out over trivial shit, which is quite different in aesthetic from the others, and maybe underappreciated by secular people.  Instead of trying to shrink your troubles by minimizing or disputing them, you can make them seem less important by contrast to something vast and Good. In a similar, albeit secular, spirit, there’s Camus’ famous line, “In the midst of winter, I found there was, within me, an invincible summer.”

Stripped of the sneering and the political angle and the paternalism, what we have here is a pretty solid message.

It’s a good idea to become stronger; in order to do that, try hard things, and don’t freak out about trivial shit.

Now, I immediately imagine a dialogue with my Weenie Self resisting this idea.

But…that sounds AWFUL!  I don’t want to!

Well, the thing is, “I’m not currently doing X” is not a valid argument against doing X. If it were, nobody would ever have a reason to change their behavior.  We’d all just follow the gradients of our current stimuli wherever they led.  There’s no choice in that world, no deliberate behavior. “But I’m currently freaking out about trivial shit!” doesn’t actually mean that you shouldn’t want to freak out less in future.

I know. It’s weird.  This is a way of thinking about things consciously and explicitly, even when they feel kind of awkward and wrong.

How can it be right when it doesn’t feel right?!  I am currently experiencing a sense of certainty that this is a bad idea! You want me to trust a verbal argument over this overwhelming feeling of certainty?

This, believe it or not, is what people mean when they talk about reason!

Trusting an argument that is correct as far as you can tell, over your feelings, even very strong feelings.  Being consciously aware that a thing is a good idea, and doing it, even when it’s awkward and unnatural and feels wrong.  You’re not used to doing things this way, because you usually discipline yourself with more feelings — guilt or fear, usually.  But there’s a way of making yourself do hard things that starts, simply, with recognizing intellectually that the hard thing is a good idea.

You can make yourself like things that you don’t currently like!  You can make yourself feel things that you aren’t currently feeling!

This bizarre, robotic, abstract business of making decisions on the basis of thoughts rather than feelings is a lot less crazy than it, um, feels.  It’s a tremendous power.

Some people luck into it by being naturally phlegmatic. The rest of us look at them and think “Man, that would suck, having practically no feelings.  Feelings are the spice of life!”  But we can steal a bit of their power, with time and effort, without necessarily becoming prosaic ourselves.

My overall instinctive response to Haidtism is negative.  The ideology initially comes across as smug and superficial.  But upon reflection, I have come to believe that it is right to aim towards self-transcendence, to do hard things and not sweat the small stuff. And I’m resolving to be more charitable towards people who support that creed even when they rub me the wrong way stylistically.  Ultimately, I want to do the things that are good ideas, even when that means awkward, deliberate change.


Epistemic status: medium

There are a lot of drugs and supplements reputed to improve cognitive function.  I was sick of relying on hearsay and anecdote, so I did my best attempt at a systematic overview of what works and what doesn’t.


Caffeine, modafinil, amphetamine, methylphenidate, and maybe a discontinued nicotinic-receptor agonist drug called ispronicline, have really big effects on cognitive function in healthy people.

Caffeine and modafinil work significantly better in sleep-deprived than non-sleep-deprived people.

Caffeine, nicotine, and amphetamine, in contrast to methylphenidate and modafinil, do not improve memory performance or accuracy on cognitive tasks in healthy people, but only reaction time.  In other words: caffeine, nicotine, and amphetamine make you more alert but not smarter; methylphenidate and modafinil also seem to improve memory.

Amphetamine and modafinil work better on people with the COMT val/val phenotype (who tend to be less intelligent) and may be ineffective or counterproductive on COMT met/met phenotype people.

All of the above (caffeine, nicotine, modafinil, amphetamine, and methylphenidate) cause some tolerance.

Cerebrolysin, a mixture of neural growth factors, apparently works really well on Alzheimer’s patients, though there’s fewer studies of it than more common Alzheimer’s drugs.  It might extrapolate to people with other kinds of neurodegenerative problems, or to slow the effects of aging.

Cognitive training (memorization practice including spaced repetition) works moderately well on Alzheimer’s patients and schizophrenics.  It’s quite plausible that it’s also good for healthy people.

Healthy people can get small positive effects from nicotine, possibly the herb Bacopa monniera, and from transcranial magnetic stimulation.

Alzheimer’s patients can get small effects from cholinesterase inhibitors (which are standard Alzheimer’s drugs); from a mixture of vitamins, fatty acids, choline, and uridine; from melatonin, the hormone which regulates sleep; and from the amino acid derivative acetyl-l-carnitine. Apart from the cholinesterase inhibitors (which have GI side effects) these are safe for healthy people to take, but it’s not known whether they affect cognitive function in healthy people.


only looked at published studies on cognitive outcomes in humans: tests of memory, reaction time, and the like.  No animal studies. No measurements of neural correlates or biomarkers. To show up in my list, it has to make humans perform better.  I didn’t restrict attention to healthy humans, however; a lot of the studies on cognitive enhancement are performed on subjects with diseases like Alzheimer’s or schizophrenia, so I included some of those, under the suspicion that they might generalize to healthy people.

I ranked nootropics by effect size. That is, Cohen’s d, the difference in mean outcome between treatment and control groups divided by the pooled standard error.

Assume that a trait, like your score on an exam, has a Gaussian distribution. Suppose you have some treatment that increases the mean score in the treatment vs. the control group. Then you can divide by the (pooled) standard deviation of the score to get an estimate of how big a difference the treatment makes, compared to the population variation in the trait. Does it increase your score by one standard deviation? That’s an effect size of one.  Does it increase your score by half a standard deviation? That’s an effect size of 0.5.

This allows us to compare “how big an effect” different interventions have, along one scale, even if they’re acting on different traits. If drug A improves your reaction times by two standard deviations, and drug B improves your memory by half a standard deviation, you can still say that drug A has a larger effect than drug B, even though the effect isn’t on the same thing.

Conventionally, an effect size of 0.2-0.3 is a “small” effect, around 0.5 is a “medium” effect, and anything greater than 0.8 is a “large” effect. Most drugs used in psychiatry have effect sizes around 0.5.  Intuitively, effect sizes of about 0.5 look like “sorta works” to the naked eye. Effect sizes greater than 1 look like “holy shit, that’s an unmistakable effect” to the naked eye.

Anything with a p-value of <0.05 (but not <0.01) I didn’t include in the table of best nootropics, because the vast majority of studies with such high p-values don’t replicate.  I also didn’t include things in the table if they were shown to not work on healthy subjects (even if they did work on ill subjects).  When there was conflict between studies, I erred on the conservative side and chose smaller effect sizes.


Drug Effect Size Trait
Modafinil, Caffeine 2-3 Executive function in sleep deprived people
Modafinil, Caffeine 2-3 Wakefulness in sleep deprived people
Ispronicline 2.5 Attention and episodic memory in healthy people
Amphetamine 2.3 Reaction time in healthy people
Cerebrolysin 1.8-2.2 ADAS-cognitive test in Alzheimer’s patients
Methylphenidate 1.4 Memory in healthy non-sleep-deprived people
Modafinil 1.22 Working memory in sleep deprived people
Caffeine 0.7 Reaction time in non-sleep-deprived healthy people
Nicotine 0.7 Attention in schizophrenics
Modafinil 0.56 Attention in non-sleep-deprived healthy people
Melatonin 0.56 ADL’s for Alzheimer’s patients
Cognitive training (including spaced repetition) 0.43-0.47 Various cognitive tests and ADL’s for Alzheimer’s patients and schizophrenic patients
Bacopa monniera 0.32 Learning rate in healthy people
Nicotine 0.3 Reaction times in smokers and nonsmokers
Cholinesterase inhibitors 0.2-0.5 ADAS-cognitive test in Alzheimer’s patients
rTMS 0.2-0.3 Working memory and reaction time in healthy subjects
Souvenaid 0.23 Memory in Alzheimer’s patients
Acetyl-L-carnitine 0.2 Various cognitive tests in Alzheimer’s patients



ALCAR, or acetylcarnitine, is an amino acid derivative used in the metabolism of fatty acids.

A meta-study of 21 studies of Alzheimer’s patients found a median effect size of 0.2, with a total of 499 patients, across various cognitive tests.


Amphetamine is a dopaminergic stimulant drug.

Amphetamine improved working-memory performance in healthy subjects only if they had low performance at baseline, and worsened it in those who had high performance at baseline.[4]

Improves working memory on healthy val/val COMT subjects, doesn’t, or deteriorates it, on met/met subjects. (“Warriors” benefit, “worriers” do not.)[38]

Improves reaction time on a movement estimation task (effect size: 2.3) but not digit span.[39]

Bacopa monniera

Bacopa monniera is a plant traditionally supposed to improve memory. The active ingredient is bacoside, a triterpenoid saponin.

Randomized study of 46 healthy adults, AVLT learning rate after 12 weeks is better, effect size 0.32, a significant effect at p < 0.01.  State anxiety also lower, p < 0.001. No effect on digit span.[33] No effects on memory.[34]


Caffeine is the most commonly used psychoactive chemical worldwide, and is a stimulant that works by adenosine receptor antagonism.

Cross-sectional study of 9003 adults finds that higher habitual coffee and tea consumption has a significant dose-response relationship (p < 0.001) with performance tests of memory, visuospatial reasoning, and reaction time, suggesting that tolerance to caffeine is incomplete and caffeine does cause higher absolute levels of cognitive performance.[1]

Metastudy found that caffeine had no effect on free recall in most short-term memory studies. It does reliably improve reaction time.  Reduces the risk of sleep-deprivation-related work accidents by about two-fold.  Generally improves cognitive performance more in sleep-deprived than in non-sleep-deprived subjects. Caffeine improves cognitive function in elderly subjects more than in young (20-60) subjects, and regular caffeine consumers have less (half as much) age-related cognitive decline.[20]

Caffeine improves reaction time over placebo with an effect size of 0.7[21]


Cerebrolysin is a mixture of neurotrophic peptides derived from pig brains, including BDNF, GDNF, NGF, and CNTF. It may have a neuroprotective or neurorestorative effect.

Randomized study of 279 Alzheimer patients found scores on the cognitive subscale of the ADAS improved by 4 points on Cere vs. placebo, effect size of 1.86, p = 0.03.  Global clinical outcome significantly better than placebo (p < 0.001).[27]  A randomized trial of 149 Alzheimer patients found an effect size of 2.22, improvement of 3.2 on the ADAS-cog on Cerebrolysin vs. placebo, p < 0.001.[28]  Effect size of 2 on elderly controls on the ADAS-cog.[67]

Cholinesterase inhibitors

This is a class of drugs used for Alzheimer’s disease, including donepezil and galantamine.  A meta-study found they had median effect size 0.28 on the ADAS-Cog for high-dose studies, 0.15 for low dose.[48]  Another meta-study found they had mean effect size 0.1 for ADLs in Alzheimer’s and there’s no difference between cholinesterase inhibitors.

Cognitive Training

For Alzheimer’s disease. Mostly these are memory practice games or drills, many of which are spaced repetition. Across various measurements of outcome (CPT, memory tests, IADLs, etc) median effect size was 0.47.[50] A metastudy of cognitive remediation for schizophrenia found a median effect size of 0.43 across various cognitive tests.[56]


Donepezil is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 1.25 on ADAS-Cog in Alzheimer’s patients (p < 0.001).[51]  Odd that it is so much better than “cholinesterase inhibitors” as a class.  Doesn’t affect progression to Alzheimer’s in mild cognitive impairment.[53] Effect size of 0.6 on the MMSE in Parkinson’s patients, p = 0.0013.[54]  One study showed that donepezil did not have an effect in mild cognitive impairment.[55] Doesn’t work on schizophrenics either. [58]  Did not have an effect on healthy elderly volunteers on cognitive tasks.[66]  I’m going to take the conservative, lower estimates that effect sizes are around 0.2 or 0.5.


Erythropoietin is a hormone that increases red blood cell production.

It improves working memory, verbal processing, and Wisconsin Card Sorting scores significantly over placebo in schizophrenic patients.[8]  Significantly improves (p < 0.01) sustained attention and information processing speed in bipolar patients.[72] “EPO acts in an antiapoptotic, anti-inflammatory, antioxidant, neurotrophic, angiogenetic, stem cell–modulatory fashion” so it’s investigated as a neuroprotective for stroke and neurodegenerative diseases, but so far mostly in animals.[42]


Galantamine is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 8.18 (?!) in Alzheimer’s patients after 6 months; slows cognitive decline.[59] After 3 months, effect size of 2.4 in Alzheimer’s patients, p = 0.002.[63] Galantamine is better than donepezil for Alzheimer’s ADAS-Cog and MMSE.[64] On schizophrenics, effect size of 0.89 in schizophrenic patients on RBANS test, one standard deviation up on the memory subscale, effectively normalizing performance.[60] A much larger randomized study on schizophrenics, however, found no overall effect. [61]  Metastudy on galantamine vs. donezepil for Alzheimers found much weaker effects: 0.48 effect size for donepezil and 0.52 for galantamine.[65]


Panax ginseng is a plant traditionally used as an “adaptogen” to increase alertness and endurance; the active ingredients are triterpinoid saponins called ginenosides.

In a controlled trial of Alzheimer’s, ginseng improves performance on MMSE and ADAS scales after 12 weeks (p = 0.009 and 0.029 respectively) and declined to baseline after discontinuation.[6] Reduces blood glucose acutely (p < 0.001) in 30 healthy volunteers [40] and improves performance at p < 0.05 at “repeated sevens” task. Effect size of 1-2, but since effects were only slightly significant here and were not in other tasks, there’s some reason for skepticism.  This study found that it didn’t improve working memory or reaction time but did improve the “quality of memory” subscore.[41]


Ispronicline is a nicotinic receptor agonist.  The company that produced it, Targacept, appears to have gone out of business, and the drug was discontinued after it failed to make progress on Alzheimer’s.

It significantly improves measures of attention & episodic memory on healthy male volunteers vs. placebo. Also increases upper alpha peak on EEGs.[44]  2.5 effect size, p < 0.01 for 50 mg AZD vs. placebo for elderly patients on attention, episodic memory, and SDI-cog.[46]   Not statistically significantly effective on Alzheimer’s.[45] 


This is a precursor to dopamine, used as a treatment for Parkinson’s disease.

Slightly reduces reaction time in healthy subjects, p < 0.05.[74]  Some healthy subjects develop side effects of nausea and excitation under L-Dopa, and these have slower reaction time than placebo; those who don’t have adverse effects have faster reaction times, p = 0.02.[75]


Melatonin is the hormone that regulates sleep cycles, often taken as a sleep aid.

Significant (p = 0.004) improvement in IADL score (activities of daily living, effect size 0.56) on 80 Alzheimer’s patients.[25]


Methylphenidate is a stimulant that works by dopamine reuptake inhibition and is used as a treatment for ADD.

Meta-analysis finds a large effect size (1.4) in memory on healthy non-sleep-deprived subjects, but no other improvements on executive function, attention, or mood.  Does not reduce sleepiness after sleep deprivation.[17]


Modafinil is a stimulant that works primarily by histamine agonism.

Significantly improves digit span (by 1-2 digits) and improved pattern recognition (by 8 percentage points), fewer stop errors & lower stop signal reaction time, better spatial planning.[11]

Significant effects (in a meta-study) on working memory, digit span, reaction time, in most studies; no effect on Stroop, spatial planning, verbal fluency; no effect at all on high-IQ population.[14]

Does not cause overconfidence vs. placebo.[15]

Improves performance in a mean 100 IQ group, but not a mean 115 IQ group.[16]

Meta-study founds a moderate improvement on attention (0.56) in healthy non-sleep-deprived individuals. No changes in mood, memory, or motivation.  In sleep-deprived individuals, has a large (2-3) effect size on executive function, a large effect size (1.22) on memory, and a large effect size on wakefulness (2-3).[17]

Comparable alertness and performance effects for 200 or 400 mg modafinil vs. 600 mg caffeine (6 cups of coffee) in sleep-deprived patients.[18]  Caffeine, amphetamine, and modafinil are comparably effective in increasing alertness & reaction time in sleep-deprived patients.[9]


Nicotine is a stimulant and nicotinic acetylcholine receptor agonist.

4-week nicotine skin patch improves performance on continuous performance test vs. placebo in 8-person trials of Alzheimer’s.[3]

In abstinent smokers, nicotine improves performance on all tests; in never-smokers, produces faster reaction times but more errors.

6-month trial on schizophrenics improves performance on the CPT with an effect size of 0.7.[22]

A meta-analysis found that nicotine improved working memory reaction time in both smokers and nonsmokers, effect size 0.34, but did not improve accuracy; also improved reaction time in orienting attention, effect size 0.34, and alerting attention, 0.3


Breathing high-oxygen air increases blood oxygen concentration.

It improves word recall vs. placebo in healthy subjects, but only at a p < 0.05 level.  Reaction time lowered, p < 0.0005.  No effect on working memory.[10]  Effect size on word recall and reaction time in another study on healthy subjects was ~2.5, p < 0.05.[43]


Piracetam has an unknown mechanism of action but is sometimes used as a nootropic.

In a metastudy of piracetam for cognitive impairment (mostly age-related), 63.9% were improved on piracetam vs. 34.1% on placebo. Fixed-effects model OR is 3.35.[29]  Doesn’t work on Alzheimer’s.[69]


PRL-8-53 is an experimental compound with some cholinergic properties.

Significant (p < 0.01) improvement in word retention over placebo; 30-45% improvements in # of words retained.[26]


Repetitive transcranial magnetic stimulation involves placing a magnetic coil near the head of the subject and produces small electric currents in the brain.

A meta-study found improvements with effect size of 0.2-0.3 in working memory and response times on healthy subjects on n-back tasks.[12]


Semax is a Russian nootropic that seems to work by stimulate nerve growth factors.

Significant 74% improvement over placebo on memorization exam in power plant operators.[24]  Most of the other evidence about Semax is from Russian rat studies.


Souvenaid is a cocktail containing essential fatty acids, vitamins, uridine, and choline, used to treat Alzheimer’s.  

A randomized 24-week trial on Alzheimer’s patients found that it improved the memory subscore on the NTB with an effect size of 0.23.[68]


Tandospirone is a serotonin partial agonist, similar to buspirone, used for anxiety and depression.

In schizophrenic patients, improves performance on Wechsler Memory Scale and Wisconsin Card Sorting, p < 0.001 and 0.0001 respectively, effect sizes of 0.63 and 0.7.[4]  However, tandospirone impaired memory in healthy subjects.[71]


Tianeptine is an antidepressant that seems to work by enhancing dopamine release, enhancing BDNF, and/or targeting opioid receptors.

In an uncontrolled trial of depressed patients, tianeptine improved working memory and reaction time.[23]  Did not affect memory, attention, or psychomotor performance on young healthy volunteers.


Tolcapone is a COMT inhibitor used in the treatment of Parkinson’s.

Tolcapone improves memory for val/val COMT healthy subjects, but worsens it for met/met. (“Warriors” benefit, “worriers” don’t.)  Effect size of about 0.8, p < 0.05 on the val/val’s.[73]

B vitamins

No effect on elderly subjects. [7]


Creatine is a compound that occurs naturally in vertebrates and supplies ATP to muscles.

No effect on cognitive function on healthy young adults.[35]  Does have effects on memory in the elderly [36] (d = 1.5, p < 0.001 for backward digit span) and vegetarians [37]


D-cycloserine is an amino acid derivative and antibiotic.

Doesn’t improve cognitive function/digit span in schizophrenics.[57]


DHEA is a steroid hormone and precursor to estrogen and testosterone.

No effect on elderly subjects.[5]

Dual N-Back

Dual N-back is a memory practice game.

Metastudy shows that, while performance on the N-back task improves, no crossover improvement on IQ tests occurs.[13]

Gingko Biloba

Fails to find effect on cognitive performance on Stroop test in MS patients.[2]  Also fails to prevent cognitive decline in older adults.[76]g


Oxiracetam is in the racetam class of drugs, unknown mechanism of action.

Doesn’t work on Alzheimer’s. [32]


Selegiline is an MAOB inhibitor used in Parkinson’s and depression.

Not effective on cognitive performance in Alzheimer’s.[30]  Doesn’t help in Parkinson’s either.[31]


Tarenflurbil is a discontinued putative Alzheimer’s drug that destroys amyloid plaques.

Doesn’t slow cognitive decline in Alzheimer’s.[49]


Unsurprisingly, the classic stimulants do quite well. (Caffeine, nicotine, amphetamine, methylphenidate, modafinil.)  Ispronicline is less well known and its evidence base is much smaller, but since it’s also a nicotinic receptor agonist, it’s possible that it also belongs in this category.

Cerebrolysin is interesting. It’s a legal anti-Alzheimer’s drug in Europe, and one of the few drugs that directly focuses on neural growth factors. These are known (mostly in animal studies) to be protective against brain damage, as from stroke or Parkinson’s.  Deficiency in BDNF is also one of the current hypotheses for what’s going wrong in depression.  “Just give people some growth factors” might be one of these simple obvious-in-retrospect things that could pan out to be widely effective.  In animal studies, growth factor gene therapy often has neuroprotective effects, and Nobel Prize-winning neuroscientist Rita Levi-Montalcini took daily NGF eyedrops.

There’s a common pattern in anything dopaminergic (such as: amphetamines, tolcapone, L-dopa, etc) that they improve cognitive performance in people who have “too little dopamine” (Parkinson’s patients, ADHD patients, val/val COMT genotypes) but are useless or worse in those who have “too much dopamine” (met/met COMT genotypes.)  This seems like a fairly robust finding, across many drugs as well as a lot of fMRI studies about dorsolateral prefrontal cortex activation.  How good dopaminergics are for your mental performance may depend a lot on who you are.



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Measures of Awesomeness

Epistemic status: exploratory. I’m building out a model.  I know zero anthropology, so my speculations may very well be reinventing some wheel.

A visit to the anthropological wings of the Museum of Natural History can cure you of cultural relativism in a hurry. Some cultures, in some times and places, made cooler stuff than others.  In other words, the concept of “technology level” refers to a real thing.

In the context of looking at ancient pottery or metalwork, a casual museumgoer won’t see anything too strange about that assumption.  But there are a lot of uncertainties smuggled in.  How do we know that this pot is superior to that pot?  Doesn’t that depend on who you are and what you value?  When we look at an object and consider it “primitive”, does that mean anything besides mere cultural chauvinism?

Tech trees

One potential way to make the idea of “more advanced/less advanced” technology objective is to talk about a dependency graph.  If one technology is a prerequisite for another, then the “child” technology can be identified as “more advanced” than the “parent” technology. This concept has been referred to as fabricatory depth.  You need kiln-firing technology before you can produce glazed pottery; therefore kilns are a prerequisite for glazing, and glazing is more technologically advanced than kilns.  If you see people who can only make unglazed pottery and not glazed pottery, then, in that particular respect, those people are lower-tech than their glazing neighbors.

The computer game concept of a tech tree (really, it’s a tech DAG) is a simplified version of this concept. The “roots” of the tree are primitive technologies; applications and advancements on these technologies take you to higher levels of the “tech tree”, which in turn can lead to even higher levels.

This puts a partial ordering but not a total ordering on technologies. Not every pair of technologies is directly comparable.  Which means that it’s more nuanced than categories like “Stone Age” — it’s possible for Culture A to be more advanced than Culture B in one sector, but less advanced in some other sector. We’re not assuming that technologies line up in one single March of Progress; but we are noticing that some technologies are structurally, by necessity, more “foundational” or “basic” or “primitive” than others.

Thinking in terms of dependencies/prerequisites means we can talk about technology level while keeping some distance away from value judgments. Forget what’s more “useful” or “higher quality.”  A high-tech object is just an object that depends on a lot of accumulated technologies.  It’s an object that requires a long chain of skills to produce.

Note that this isn’t quite equivalent to a high degree of skill. It takes very high skill to hunt with a throwing stick. But probably not a long sequence of techniques, each of which produces many applications.  We don’t have to assume that a low degree of technological advancement implies a low degree of effort or intelligence; it just means that, for whatever reason, you don’t have a big stack of technologies that build on each other.

Prowess Metrics

If you stroll through the museum and ask yourself what makes “higher-quality” objects, you’ll notice some commonalities.

Usually, finer, more precise work is intuitively higher quality. Finer brushwork or filigree or carving, smoother carvings, finer textiles with tighter weave, straighter or more symmetrical shapes, etc.

Stronger and more durable objects tend to be higher quality.  Steel is harder than iron.  Glazing makes pottery water- and stain-resistant.

Highly replicable objects tend to be higher quality. Molds and casts and potter’s wheels allow identical objects to be produced with little effort.

More efficient objects tend to be higher quality. Structures that are lighter relative to their strength. Machines that consume less fuel or physical effort.

Bigger objects can be higher quality.  Buildings or sculptures or cities on a colossal scale.

These kinds of criteria are still relevant even in the modern day. The semiconductor industry runs on making finer, more precise circuits. Materials science continues to make glass, ceramics, and other substances stronger, more durable, and lighter.  The software and manufacturing industries run on making objects more replicable.  “Big data” refers to the technologies necessary for handling information at scale.

There seem to be some simple qualities like these which continue to be valued in technologies, over time and across industries.  I’ll call them prowess metrics, inspired by Venkat Rao’s discussion, because they’re usually related to excelling at a single property rather than being very well suited to a market niche.

Human wants are enormously varied; but certain inputs tend to be common among them. At the most elemental level, almost anything anyone could want will require things like mass and energy; therefore mass and energy are close to universally valuable.  Prowess metrics are capacities which permit a wide variety of applications.

As you go up a tech tree, producing technologies that are necessary for technologies that are necessary for technologies, the technologies that have a lot of descendants will tend to be high on prowess metrics.  If you develop a technique for very reliable duplication, or a stronger construction material, there are a lot of technologies that can be derived from it.  In fact, we can even define prowess metrics as the qualities that predict having a lot of descendants on the tech tree.  They are what make a technology “generative”, productive of new technology.  Prowess metrics might also be expected to correlate with being high on the tech tree, which makes sense if you picture a long-tailed distribution of technology — most “chains” peter out early, but if you’ve reached a certain level of technology, that means you’re more likely to continue going to yet more advanced technologies.

Being high on a prowess metric is no guarantee that an object will be useful.  Usefulness is defined by humans and the context in which the object would be used.  The fastest cars in the world are novelty items, because most people don’t actually need or want the fastest cars in the world.  Identifying the usefulness of an object to actual humans is the basic function of marketing, and prowess metrics can’t substitute for that.  Usefulness is about utility and value judgments and all that squishy stuff.

However, I hypothesize, prowess metrics are decent predictors of the utility of objects. If you have a way to make your widget faster, bigger, finer, stronger, lighter, cheaper, etc, it’s at least worth privileging the hypothesis that there’s going to be demand for it.

The Innovator’s Dilemma defines a disruptive innovation as one which satisfices on a bunch of the standard metrics, optimizes hard on a different metric, and finds a new market that really values this new metric. Usually, the examples given in the book of all the above metrics fit the pattern of prowess metrics; things like size, speed, cost, etc.  Which prowess metrics matter depends on the market and the use case. But that prowess metrics matter is not really disputed.

In engineering-focused domains like the excavator industry or the semiconductor industry, the technical performance of the machinery matters a lot to purchasers. As you move “up the tech tree” to higher-level applications and consumer-facing products, technical prowess becomes less obviously relevant, but still in some sense underlies what’s possible.  Computing power still ultimately determines limits on what software applications are available.

Prowess metrics seem to be behind intuitions that look like the labor theory of value.  A worthy or excellent object, you feel, gives you a lot of something you can measure: many tons of wheat, high tensile strength, etc.  Objects that are “merely” well adapted to their context and highly desirable to their users may be perceived as having “fake” or “superficial” value, as opposed to the “real” value captured by prowess metrics.  “I care about the fuel economy of my tractor, not what color it’s painted!”

From a conventional economic perspective, this is exactly backwards: the prowess metric is only a correlate, a proxy,  of the things that really matter, the supply and demand.  And it’s not even always a good proxy!  But it’s an understandable fallacy once you accept that prowess metrics are frequently good predictors of value.  Moreover, prowess metrics tend to indicate something like “downstream” value — they mean that future applications of the technology can go farther and likely be worth more.

This is the intuition behind “We wanted flying cars, instead we got 140 characters.” Getting better prowess metrics on basic technologies (as you’d need to, to build flying cars), is substantial because it tends to open the doors to a lot of future technology and future value. Getting good product-market fit on an app built from off-the-shelf parts is less valuable in the long term because it isn’t causally necessary for as much future innovation.  (Twitter’s not a great example of a non-technological “tech” company, but it’s easy to think of better ones.)

Obviously, a lot of this is influenced by glamour — modern logistics is arguably as big a technological advance as flying cars would have been — but there still may be a meaningful, semi-rigorous notion of a foundational rather than a trivial technological improvement, and it seems to have to do with prowess metrics and going to nodes that have a lot of descendants on the tech tree.


There’s an intuition that a civilization can have a certain amount of motive power or mana or ability to do stuff.  Thriving cultures are increasing it; declining cultures are stagnating or losing it. And of course trying to make this intuition rigorous is hard, and potentially impracticable. You can’t directly rank cultures on how awesome they are.

But an armchair-observer, outside-view perspective might point to a handful of prowess metrics (literacy rates, cost of a loaf of bread, etc) and try to use them to get a rough, multidimensional picture of “ok, how rich and powerful is this society really? How much mana is there here?”

Studying material culture in this way is how, for instance, Kenneth Pomeranz argued that China was richer than Europe until the 19th century.  The Chinese consistently consumed more calories and more meat, had more furniture in their homes, and even read more books, than the Europeans. Comparing the historical “GDP’s” of China and Europe is uncertain and subject to statistical shenanigans; but if the Chinese consistently seem to have more of all the necessities and luxuries of life, then it starts to seem undeniable that, for most definitions of “rich”, they were richer.

The “material culture” approach is pretty similar to the “look at a bunch of prowess metrics” approach.  You make no attempt to have a single metric of “intrinsic value”. You can only make pretty modest claims. You merely observe that if a culture seems to be booming along a lot of highly general and “upstream” metrics, then there’s probably something vaguely positive going on.  This is the heuristic behind the kinds of claims in The Great Stagnation — things like ‘maximum vehicular speed isn’t increasing’ or ‘life expectancy isn’t increasing.’  Taken together, a lot of stagnant metrics paint a dispiriting portrait.

With a tech-tree model, most of the dependencies are unobserved, including (of course) all the future ones.  It’s hard to work with empirically, and even if you did know the structure, it would be impossible to put a single number on “the tech level.” If we can talk about that kind of structure at all, it’ll be with simplifying models — things like prowess metrics that are shared across many technologies and correlate with technological advancement.  You still can’t say much objectively about “how much mana do we have?” — as always, there’s an irreducible element of selection and storytelling.  But this at least, I think, gives us a starting point to concretize the questions and hypotheses.

The Peril of the Sublime

The “sublime”, as defined by writers such as Burke, Kant, and Keats, is an experience of immensity and awe.  “THE PASSION caused by the great and sublime in nature, when those causes operate most powerfully, is astonishment; and astonishment is that state of the soul, in which all its motions are suspended, with some degree of horror.”  We experience the sublime when we see vast mountains, violent storms, towering pyramids, dazzling details of pattern,the infinity of space.

The standard psychedelic or religious experiences are classic examples of the sublime.  The impression of infinite hugeness or infinite smallness, the impression of endless fractal intricacy, the impression of infinite recursion, the impression of vast significance  — these are intimations of infinity.

Indeed, it may be appropriate to simply define the sublime as the subjective experience of infinity.

But what, concretely, is the experience of infinity?

I suspect that it is merely the experience of being unable to measure or count. A person can innately see one or two objects and recognize them as one or two, without counting; if you show her more than seven or so, her first perception is of “many”.  The experience of uncountable multiplicity is the experience of losing count. “And he brought him forth abroad, and said, Look now toward heaven, and tell the stars, if thou be able to number them: and he said unto him, So shall thy seed be.”  Our metaphor for impossibly many is the innumerable stars. We measure the size of infinities by trying (and failing) to put them into one-to-one correspondence with each other.  Countlessness provokes awe.

So, too, does scalelessness: when we cannot estimate size, we become dizzy with vastness, with smallness, with the scale-free multiplicity of fractals. Timelessness provokes awe, with thoughts of “eternity in a grain of sand.”  When something breaks our units of measure, when it appears to go beyond them, we experience that as infinity.

If you think of perception as working through convolutional neural nets, you notice that higher level nodes are averages or invariants over measurements — the same object, independent of position or rotation or color shift.  Allow the neural net to run its outputs into its inputs long enough, and you begin to see the kinds of images that show up in DeepDream — highly multiscale, intricately patterned.  Some of these higher-level invariants are, clearly, being activated very intensely if the network is allowed to “ruminate” on its own contents.

I might speculate that ordinary perception puts something like frames or limits on this kind of recursive rumination.  As an artist drawing a picture first sketches the proportions of the main objects, before filling in details, to make sure nothing is out of balance, in ordinary perception we put objects or ideas in proportion or in context with the rest of our world. They have a finite size, a particular place in time, a finite importance, and so on.  If this ability to gauge proportion is baffled or broken, we get the impression of infinity and sublimity.

The sublime naturally inspires worship. When something appears to be infinitely important, infinitely vast or complex, eternal or beyond time, how can we not ascribe it with huge significance?  We can easily claim that some particular sacred cow is not, in fact, sacred; but to deny the importance of the sublime is tantamount to saying sacredness itself is not sacred.  From the perspective of someone who has experienced raw barefaced wonder, an enemy of the sublime is a desecrator, a dirty vandal, trying to reduce us all to his level of prosaic blindness.

I am not a vandal. But I am a scientist by training. And so, I find myself in a complicated relationship with the sublime.

The danger of worshiping the sublime is that it can all too easily reduce to worshiping one’s own incapacity.  The sublime’s favorite phrase is “I can’t even.”  It is the inability to put things into context and perspective.  To be overwhelmed by a wildflower is a kind of elevated sensitivity and acuteness of observation; but if you can be overwhelmed by anything, then you have a failure to prioritize.  If you perceive “infinity” as simply beyond what you can measure or comprehend, then seeking a sense of infinity is seeking your own ignorance.  You find yourself looking backwards and inwards, towards childhood, towards faith, towards “unmediated” perception, trying to peel back the layers of ordinary reason towards something “beyond” the workaday world.

I suspect that this kind of a backwards mental move is a fundamental kind of error. I’ve done it myself, enough times to recognize the pattern. You remember experiencing something as awe-inspiring and mysterious; you want to recreate that experience; you try to come up with a rational structure that preserves that intuition of mystery, that delicious sublimity; and look! you find you have come to a dead end, and the facts force you to acknowledge failure.

The first and most canonical example of this pattern is trying to prove the existence of God.  I recognize a similar kind of flavor in trying to defend superrationality, trying to refuse the No-Free-Lunch theorem, and trying to argue against digital physics.  There’s a deep appeal in ideas that seem to cut through our finite, parochial, incremental limitations to something “beyond,” but I’ve frequently found those intuitions impossible to justify.

Beyondness is sublime; locality is mundane.  But “beyond” is not a place you can get to.  We always represent infinity in terms of the failure of the finite. “For every N, there exists an n such that a_n > N.”  In other words: every bound will break. This is a temptation towards falling in love with brokenness.

The danger is that in reaching for infinity, reaching for the sublime, you wind up committing a kind of self-harm. Stunting your actual, real-world powers; admitting frank impossibilities into your belief system; seeking not the universe’s bigness but your own smallness.

The universe really is vast and awe-inspiring — it is not an accident that Carl Sagan, our contemporary poet of transcendence, was an astronomer — but to experience awe at the genuinely vast, you have to actually be moving outward along with the scientists, claiming old territory as comprehensible and well-mapped even as you look toward uncharted skies.  There’s a robust, outward-facing experience of the sublime that is dual to the “stolid, prosaic” approach that treats the world as finite and moderate in importance; if you can be cool-headed and proportionate and realistic, you can take on grand adventures and explorations.


There Is No Secret Notebook

Once, a friend of mine asked me to help out on his organization’s project. I didn’t feel qualified; I had read everything they’d published, but I assumed that all the things I was uncertain about were solved and written up somewhere in a “secret notebook” by people much smarter than I. My friend laughed and said “that’s what used to think!  I assumed everything had already been written up in a secret notebook! and then I joined the project and found out that there is no secret notebook.  We’re all just figuring it out as we go.”

There seems to be a phenomenon here of a sense that a thing is known.

Known by whom? Unclear. Known by smarter people than you.

But because it is known, it is not your job to deal with, and probably a waste of time for you to try to personally find out the answer.

This is a failure mode when, for instance, everybody in a group thinks somebody else is responsible for a task (surely it is known, surely it is being taken care of) and then nobody does it.

It’s also a failure mode that leads people to underestimate their capacity to contribute.

“Surely this simple question must already have been answered, right?”  Yeah, probably, you should check and see.  Your first move should be to consult StackExchange, Wikipedia, Google Scholar, a textbook, the smart guy at your office, etc.

But if you try a bunch of avenues and don’t find the answer, and you still care, the mistake is to conclude (even subconsciously) that the answer is intrinsically inaccessible to you.  “This is something that insiders know, and since I’m not an insider, nobody will ever tell me.”  “Normal people get this intuitively, but I’m a weirdo and I just can’t understand.”

The feeling is that the answer to your question belongs to people who have some essential quality that you forever lack. You look at yourself, with your slow and fragile reasoning power, and you feel like you’re counting on your fingers, and imagine that someone out there has a supercomputer.  (Or maybe that everybody on Earth but you has a supercomputer.)

This is an illusion. Everybody’s brain is made out of the same stuff, more or less. Sure, different people have different talents and levels of experience. But humans have general intelligence. Counting on your fingers, checking things to see if they match up to facts, going through arguments to see if they’re valid, trying things to see how they work — that’s how everyone figures out what’s true. There aren’t people out there who have found a shortcut.

If something is important to you, you can’t just defer it to “it is known.” You, personally, should try to find out. If it does happen to be known, out there somewhere, by someone whom you have no way of contacting, then it still doesn’t help you.

This isn’t to say that one person is capable of understanding everything on earth. It’s inevitable that the answer to some questions is going to be “I have no idea, and I’ll leave it at that.”  The failure mode is taking on faith that someone else has it covered. If there is no evidence of a “secret notebook”, then there probably isn’t one.

There is probably nobody, for instance, with a secret plan to end global warming.  If I were really motivated to do so,  which I’m not, I’d look much more carefully to see who the players are, and what the most promising proposals are, and so on. But if, after a long and careful search, I could find nobody steering effectively, I wouldn’t imagine that there were, somewhere out of sight, never mentioned in the news, a cabal of wise men guiding Earth’s climate.  That would be a kind of “god of the gaps” fallacy.

The assumption of “I don’t know, but someone must“, might be a habit learned in childhood. When you are a small child, you really are a lot less experienced than everyone else, and it really does make sense to assume that the grownups know things that you don’t.

But if you continue on into adulthood, and in particular if you continue to grow in expertise and achievement, and you keep running into situations where you feel like someone should know this and you can’t find anybody who does —

Maybe that’s because nobody actually knows.

Maybe that’s because you’re more capable than you think.

Maybe that’s because it’s your job to figure out.


Contra Science-Based Medicine

Epistemic status: hand-wavy, but making a serious point

TW: diets.

I recently did some reading about ketogenic diets for cancer, and I’d like to compare and contrast my approach with the explanation on the blog Science-Based Medicine, which consistently presents the “skeptical” perspective on alt-med questions.

David Gorski is a cancer biologist himself, as I am not; his posts are always informative, and I have no quarrel with his facts. I read the studies mentioned in the post, so we’re using pretty much the same set of data points. And I agree with the broad outlines of his claims: ketogenic diets have some promising but by no means conclusive preclinical evidence for brain cancers; they’re definitely not a substitute for chemotherapy in general; and Dr. Seyfried has been overselling his research as a cure for cancer in disreputable alt-med venues.

But I want to pick apart some points of perspective and interpretation.

The first part of the post is all about painting Seyfried as disreputable because of his associations with alt-med institutions. Gorski says of the American College for Advancement in Medicine, “this is not an organization with which a scientist who wishes to be taken seriously by oncologists associates himself.”

Now, I’m not defending the cancer quacks mentioned; these are people who pitch chelation and coffee enemas, things that are pretty clearly scientifically disproven.  However, I’m suspicious of the rhetorical trick of guilt by association and argument from consensus.  Surely we care about whether Seyfried is correct, not whether he is “taken seriously”, “reputable”, or “legitimate.”  These are all social words, not scientific ones, and constitute an emotional appeal to social conformity and authority.

To his credit,  Gorski doesn’t stop there; he does make substantive criticisms of Seyfried’s work.  But I think it’s worth pointing out when, as happens so often in the biomedical world, a social argument is conflated with a scientific one.

Gorski goes on to criticize Seyfried for “exaggerating how hostile the cancer research community is towards metabolism as an important, possibly critical, driver of cancer” when cancer metabolism is, in fact, an active area of current cancer research.  He goes on to say, “Dr. Seyfried, in my readings, appears all too often to speak of “cancer” as if it were a monolithic single disease. As I’ve pointed out many times before, it’s not. Indeed, only approximately 60-90% of cancers demonstrate the Warburg effect.”

None of these facts are wrong, but the interpretation is misleading. Cancer metabolism and metabolic mechanisms for cancer treatments are, in fact, common topics of cancer research; but this ought to be evidence in favor of Seyfried’s hypothesis, that it’s within the range of mainstream science and is supported by many cancer biologists, rather than being pure invention like most alt-med “cancer cures.”

I’d also argue with the statement that “cancer isn’t one disease.”  It’s true that not all cancers demonstrate the Warburg effect, but 60-90% is a lot of cancers; a drug that was effective in 60-90% of cancers would be as revolutionary an advance as chemotherapy.  An antibiotic that killed 60-90% of bacteria could fairly be said to “kill bacteria.” When most (if not all) cancers have structural features in common, that indicates that talking generally about “cancer” is meaningful, and that it doesn’t make sense to treat every sub-sub-type as though it is a completely different disease.  Cancer has both unity and diversity.  Saying “cancer isn’t one disease” is a rhetorically loaded move that means “don’t generalize from one type of cancer to another.”  But it’s not correct to never generalize; that would utterly paralyze research.  How much it’s safe to generalize depends on how common the relevant feature is across cancers; in the case of the Warburg effect, that’s a matter of current debate, but it’s fair to call it pervasive.

I don’t have much criticism of the way Gorski handles the ketogenic diet studies. He’s on the skeptical side, but skepticism is warranted. Mouse studies very frequently don’t generalize to humans; they’re suggestive, but only weak evidence. And while there were two case studies of patients who did notably better than typical glioblastoma patients on ketogenic diets, we don’t have enough patients to be confident that the improvements were a result of the diet.

But then Gorski says, “Clearly, ketogenic diets are not ready for prime time as a treatment for cancer.”

Now, wait a minute. What does that even mean?

As a cancer patient, does it make sense for you to try a ketogenic diet?  Well, there’s a plausible mechanism for it to work (particularly in brain cancer), there’s some suggestive evidence in mice and a few humans with brain cancers, and — crucially — it’s just a diet.  People go on ketogenic diets all the time, for no other reason than wanting to lose weight. It’s even been shown medically safe (though apparently hard to comply with) in cancer patients. Trying a special diet is pretty low risk, and a reasonable person aware of the evidence might very well choose to try it.

It doesn’t make sense to use a ketogenic diet as a replacement for chemotherapy or radiotherapy in cancers where those treatments work. That would be very unsafe.  But for certain advanced brain cancers, chemo barely extends life if at all, and is very unpleasant. If there’s anyone who has a good reason to refuse chemotherapy, it’s someone who’s almost certain to die soon and doesn’t want their last few months to be agonizing.

Is a ketogenic diet for cancer something that every oncologist in the world should be prescribing for his patients? No way. Should it be the “standard of care”? No; there isn’t enough evidence that it helps.  But is it worth trying for an individual who wants to? Quite possibly.

The distinction here is about where you put the reader’s locus of identity. Is a reader supposed to imagine herself as a potential cancer patient, considering whether or not to try the diet? Or as a potential administrator, considering whether or not to make the diet a policy for everyone?  The rhetorical trick Gorski’s using here is in identifying the reader with a nebulous “we”, as in “should we put cancer patients on ketogenic diets?”  You are meant to imagine a consensus, or an authoritative body.  The medical profession, the government, something like that.  This imagined “we” is the mirror image of the nebulous “they” that conspiracy theorists believe in, the “they” who doesn’t want you to know about cancer cures.

The overall effect of believing in an imagined “we” or an imagined “they” is to make social reality the primary reality.  “We” or “they” represents a vague model of “society” — the “respectable” people, the “legitimate” and “reputable” people, the “consensus”. In other words, the tribal elders. If you have a positive association with “the consensus”, as Gorski clearly does, then you want to expel the “disreputable” from the consensus.  If you have a negative association with “the consensus”, then you mistrust anything that sounds official and look for fellow mavericks and outsiders.  In neither case are you primarily evaluating claims of fact; you are evaluating people.

For instance, the existence of Phase I/II trials of the ketogenic diet on glioblastoma ought to be good news for ketogenic diets.  More evidence will soon come in; and the fact that the studies exist at all is further evidence that ketogenic diets are taken seriously by mainstream cancer researchers.  However, Gorski treats this as an indictment of Seyfried, because he wanted to do an (uncontrolled) case series of ketogenic diets rather than the more thorough controlled studies.  The overall intent of the blog post is to communicate Seyfried is disreputable, cancer is complicated, people who believe in cancer cures are beyond the pale, when one could have used exactly the same facts to make the point ketogenic diets are an exciting possibility for glioblastoma and the preliminary evidence is encouraging.

My own perspective can perhaps be summarized as “a contrarian worldview from mainstream sources.”  Looking at ordinary sources like journal articles and historical primary sources, looking at uncontroversial claims of fact, often gives me a view of the world that is quite different from the “we”-based view where “society” is more or less getting things right.  My object-level beliefs are rarely that unusual; the connotation of those beliefs is where I differ from most people.  I don’t feel myself to be safely nestled in the lamplit circle of “we”; I feel like I’m outside, tumbling in the abyss, with only the frail spark of my mind to illuminate a small patch around me.  And I think that, ultimately, the abyss is real, and the lamplit circle is imaginary.

What Is To Be Done?

Epistemic status: loose and speculative

This is the last post in my cancer series. On reflection, there’s a lot I want to edit and expand here, and I think the right format for this  is a book rather than a blog. So, over the next several months I’ll be working on that.

In the meantime, I want to draw some conclusions given what I’ve found out about cancer so far. What are the next steps? Where do we go from here? The world I see is one where the “efficient market hypothesis” doesn’t hold in cancer research. Just because an idea is promising doesn’t mean it’ll be tried, particularly in human clinical trials.

So what can you, a reader, do to cure cancer?

1. Do cancer research

This one’s kind of a no-brainer, but I put it here because I see a lot of young EA’s wondering what to do with their lives, and the most frequent ideas are things like “make a lot of money to give to charity” or “work at an EA organization”, but I really believe a broader range of object-level skills could be useful for bettering the world. Doctors and biologists are important. Ultimately, the things that kill the most human beings today are the noninfectious diseases of aging.  If your heroes are the people who eradicated smallpox, maybe you should take up the cause of ending another disease.

2. Invest in or donate to organizations doing undervalued cancer work

In my blog series, I pointed out some researchers that I thought were doing unusually promising early-stage research.  Getting preclinical studies to clinical trials takes funding.

I haven’t investigated any of these organizations as organizations — I don’t claim to know that they’re likely to be profitable investments or efficient charities. I’m just looking at the drug candidates that I’ve found promising and seeing which existing organizations are involved in researching them.

3-bromopyruvate, the glycolysis inhibitor I’m bullish on, is being developed by PreScience Labs.

The Cancer Research Institute, a nonprofit that accepts donations, has funded a great deal of important immunotherapy research, including most of the recent work on mixed bacterial vaccine by the late renowned immunologist Lloyd J. Old.

The Fibrolamellar Cancer Foundation, which focuses on the rare liver cancer fibrolamellar hepatocellular carcinoma, has Sanford Simon on its advisory board and funded his research on anti-IgG antibodies to precisely detect and potentially destroy cancer cells.

I expect that there are other avenues to funding particular lines of scientific research, from creating novel grant-giving foundations to crowdfunding experiments.

I’m also interested in institutions like IndieBio, which try to bring a radical, Silicon Valley spirit to the biotech industry, and get funding for biomedical startups working on hard problems.

3. Political reform

It would be easier to innovate in cancer research if the regulatory challenges were less onerous.  Lobbying and activism, in the US or elsewhere, could probably be helpful.

This is an area where think tanks and patient advocacy groups are relevant.  I don’t have a clear idea of which precise policy goals are the most useful and attainable, but people with more of a policy bent can probably answer that question.

A different kind of “political” approach is regulatory arbitrage — trying to find or negotiate a favorable political climate to research somewhere outside the US.

4. Further meta-research

We clearly need more evaluative work done on the questions “What types of cancer research are most promising? Where is the low-hanging fruit, if any?”  I’ve been doing that, but I’m only one perspective.  This seems valuable in the context of something like the Open Philanthropy Project, which tries to evaluate the tractability of entire goals.