Direct Primary Care

Epistemic Status: PSA and raising questions

Medical care in the US is expensive. There aren’t that many demonstrated ways to make it drastically cheaper.

Direct primary care seems to be an exception.  It makes routine medical expenses 95% cheaper.

Yes, really.

If you have a cash-only, or “direct”, primary care practice — i.e. you don’t accept insurance — you can negotiate much lower wholesale rates from providers of tests (like EKGs, MRIs, blood tests) or prescription drugs. Why? Because you can guarantee the providers immediate payment, rather than the uncertainty and inconvenience of insurance reimbursement.  They’re willing to give you a discount for that.

Direct primary care also cuts down on paperwork for doctors, because they don’t have to document everything with the ICD codes that insurance companies require.

Atlas MD is an EMR designed for direct primary care practices that use a subscription model, founded by Dr. Josh Umbehr, who also uses it in his own direct primary care practice in Wichita.  I’ve spoken to him via phone and tried to poke holes in his model, and came away even more impressed.

My question is, could this model scale up nationwide — and would it still be as effective at cutting costs if it did?

Right now, as I understand, direct primary care practices negotiate individually with suppliers to get discounts. I imagine that it would be much more efficient if done by a nationwide chain of direct primary care practices.  Bulk wholesale purchases, after all, could be even cheaper than what a single practice might hope to get.

With Amazon moving into healthcare, direct primary care might get a chance to shine. Amazon has a lot of experience cutting prices through economies of scale & supply chain optimization. Jeff Bezos even funded direct primary care startup Qliance, which went bankrupt last year.

Direct primary care only works as a complement to insurance that pays for more catastrophic care like emergency room visits and specialists.  And if you can get a “minimalist” insurance plan that’s not redundant with the direct primary care membership, your total healthcare costs (membership + premiums) can be much lower.  The potential problem arises if it’s difficult (or illegal) to sell sufficiently “bare-bones” insurance plans — in that case patients wouldn’t be willing to pay out of pocket for a direct-care membership in addition to their already pricey insurance.

Umbehr has managed to negotiate deals with insurers to offer lower premiums when patients bought insurance along with direct care subscriptions, but maybe Qliance, which apparently struggled to keep customers, didn’t successfully pull it off.

At any rate, if I’m not missing something, this seems like an ideal opportunity for Amazon to make healthcare a lot more affordable. Are there barriers I haven’t thought of?

Oops on Commodity Prices

Epistemic status: Casual

Some patient and thoughtful folks on LessWrong, and, apparently, some rather less patient folks on r/SneerClub, have pointed out that GDP-to-gold, or GDP-to-oil, are bad proxy measures for economic growth.

Ok, this is a counterargument I want to make sure I understand.

Is the following a good representation of what you believe?

When you divide GDP by a commodity price, when the commodity has a nearly-fixed supply (like gold or land) we’d expect the price of the commodity to go up over time in a society that’s getting richer — in other words, if you have better tech and better and more abundant goods, but not more gold or land, you’d expect that other goods would become cheaper relative to gold or land. Thus, a GDP/gold or GDP/land value that doesn’t increase over time is totally consistent with a society with increasing “true” wealth, and thus doesn’t indicate stagnation.

Yes. The detailed dynamics depend a lot on the particular commodity, and how elastic we expect demand to be; for example, over the long run I expect GDP/oil to go way up as we move to better substitutes, but over a short period where there aren’t good substitutes it could stay flat.

Commenters on this blog have also pointed out that the Dow is a poor measure of the value of the stock market, since it’s small and unnormalized.

These criticisms weaken my previous claim about economic growth being stagnant.

Now, a little personal story time:

Nearly ten years ago (yikes!) in college, I had an econ blog. My big brush with fame was having a joke of mine hat-tipped by Megan McArdle once. I did most of the required courses for an econ major, before eventually settling on math. My blog, I realized with dismay when I pulled it up many years later, consisted almost entirely of me agreeing with other econ bloggers I encountered, and imitating buzzwords. I certainly sounded a lot more mainstream in those days, but I understood — if possible — less economics than I do now.  I couldn’t use what I’d learned in school to reason about real-world questions.

I think I learn a heck of a lot more by throwing an idea out there and being corrected than I did back when I was not even asking questions.  A shy person cannot learn, an impatient person cannot teach” and all that.

Admittedly, my last post may have sounded more know-it-all-ish than it actually deserved, and that’s a problem to the extent that I accidentally misled people (despite my disclaimers.)  I actually tried, for several years, to be less outspoken and convey less confidence in my written voice.  My impression is that the attempt didn’t work for me, and caused me some emotional and intellectual damage in the meanwhile.  I think verbally; if I try to verbalize less, I think less.

I think the M.O. that works better for me is strong opinions, weakly held.  I do try to learn from knowledgeable people and quickly walk back my errors.  But realistically, I’m going to make errors, and dumber ones when I’m newer to learning about a topic.

To those who correct me and explain why — thank you.

Monopoly: A Manifesto and Fact Post

Epistemic Status: exploratory. I am REALLY not an economist, I don’t even play one on TV.

You can call it by a lot of names.  You can call it crony capitalism, the mixed economy,  or corporatism.  Cost disease is an aspect of the problem, as are rent-seeking, regulatory capture, and oligopoly.

If Scrooge McDuck’s downtown Duckburg apartment rises in price, and Scrooge’s net worth rises equally, but nothing else changes, the distribution of purchasing power is now more unequal — fewer people can afford that apartment.  But nobody is richer in terms of actual material wealth, not even Scrooge.  Scrooge is only “richer” on paper.  The total material wealth of Duckburg hasn’t gone up at all.

I’m concerned that something very like this is happening to developed countries in real life.  When many goods become more expensive without materially improving, the result is increased wealth inequality without increased material abundance.

The original robber barons  (Raubritter) were medieval German landowners who charged illegal private tolls to anyone who crossed their stretch of the Rhine.  Essentially, they profited by restricting access to goods, holding trade hostage, rather than producing anything.  The claim is that people in developed countries today are getting sucked dry by this kind of artificial access-restriction behavior.  A clear-cut example is closed-access academic journals, which many scientists have begun to boycott; the value in a journal is produced by the scholars who author, edit, and referee papers, while the online journal’s only contribution is its ability to restrict access to those papers.

Scott Alexander said it right:



Except that it’s pretty easy to see why. We have a lot of trolls sitting under bridges charging tolls to people who want to cross. Modern Raubritter can easily maintain a hard-to-refute image that they’re providing value, and so make it hard for anyone to coordinate to avoid them.  It’s genuinely risky to unilaterally skip college, refuse to publish in closed-access journals, or leave an expensive city with a booming economy.  You know you’re being charged a ton for some stuff you don’t want or need, but it’s hard to tell where exactly the waste is; it’s dissipated and concealed and difficult to disentangle.  As 19th century businessman John Wanamaker said, “Half the money I spend on advertising is wasted; the problem is, I don’t know which half.”

But, for now, let’s try to get a factual picture of what’s actually going on.

Stagnant Commodity-Denominated Growth

GDP is supposed to be adjusted for inflation, but the calculation of the inflation rate is pretty political and might be misleading. What happens if you instead denominate in commodities?


This is the Dow-to-gold ratio for the past 100 years; as you can see, there are three major contractions in the places you’d expect: one in the Great Depression, an even deeper one that began around 1972, and the most recent in the Great Recession that began in 2008.

You get a similar picture looking at the US GDP-to-gold ratio:

and the global GDP-to-gold ratio:

In 100 years we’re looking at something like an average of 1.4% growth in gold-denominated stocks or GDP; and gold-denominated GDP is comparable to where it was in the 1980’s.

But maybe that’s just gold. What about GDP denominated in other commodity prices? Here’s US GDP in terms of crude oil prices:


Once again, this shows US GDP never really recovering from the 2001 tech bust, and not being much higher than where it was in the 80’s.

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Compared to the global price of corn, again, US GDP barely seems to have an upward trend since 1980; something like 1.5% growth.

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Compared to a global commodities index, once again, GDP seems no higher than it was in the 90’s.

This should make us somewhat suspicious that “real” GDP growth is overestimating growth in material wealth.

Of course, since median income has grown slower than GDP, this means that median income relative to commodities has actually dropped in recent decades.

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Stagnant Productivity

Labor productivity, in dollars per hour, has risen pretty steadily in advanced economies over the past half-century.


On the other hand, total factor productivity, the return on dollars of labor and capital, seems to have stagnated:

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Total factor productivity is thought to include phenomena such as technological improvement, good institutions and governance, and culture. It’s been stagnating in other developed countries, not just the US:
Image result for total factor productivity

A Brookings Institute report broke down US total factor productivity by sector, and concluded that the declining growth from 1987 to today was in services and construction, while manufacturing and other sectors continued to improve:

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Services and construction, please note, pretty much match the “cost disease” sectors whose prices are rising faster than the rest of the economy can grow: education, housing, transportation, and especially healthcare.  As services become more expensive, they’re also becoming less efficient.

Declining productivity means that we’re doing less with more.  This is particularly true for innovation, where, for instance, we’re not getting much increase in crop yields despite huge increases in the number of agricultural researchers, and not getting much increase in lives saved despite increasing volume of medical research.



Monopoly and Declining Dynamism

The Herfindahl Index is a measure of market concentration, defined by the sum of the squares of the market shares of firms in an industry. (If a single firm held a monopoly it would be 1; if N firms each had equal shares, it would be 1/N.)

US industries have become more concentrated since the mid-1990s, with the number of firms dropping and the Herfindahl index rising:

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Firms have also gotten larger:

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You can also look at concentration in terms of employment.  Education and healthcare are the most concentrated industries by occupation, while computers are the least:

Occupational groups by industry concentration, May 2012

There has been a steady increase in market power since 1980, with markups rising from 18% above cost in 1980 to 67% above cost in 2014.


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More concentrated industries can charge higher prices relative to costs.

As industries are becoming more concentrated, they’re also becoming more static. Fewer new firms are being created:

Fig. 2: Firm Entry and Exit Rates (1978-2011)

Americans are moving less between states:

Image result for falling labor mobility

And self-employment is dropping:

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As market power increases (i.e. as industries become more monopolistic), you can get a scenario where the financial value of firms outpaces their investment in capital or their spending on labor.

With an increase in market power, the share of income consisting of pure rents increases, while the labor and capital shares both decrease. Finally, the greater monopoly power of firms leads them to restrict output. In restricting their output, firms decrease their investment in productive capital, even in spite of low interest rates.

If you divide the economy into “capital” and “labor”, you find a long-term decline in the share of labor and increase in the share of capital. But if you decompose the capital share, you find that the returns on structures, land, and equipment are static or declining, while pure profits are on an upward trajectory:

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This story is consistent with other long-term trends, like the increasing share of the value of firms that consists of intangibles — that is, “the value of things you couldn’t easily copy, like patents, customer goodwill, employee goodwill, regulator favoritism, and hard to see features of company methods and culture.

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Those intangibles constitute barriers to entry, precisely because they can’t be easily copied by new firms.  The rise of intangibles is also a sign of a more monopolistic economy.

It’s Not (Just) Regulation

Alex Tabarrok, a libertarian economist, argues that the decline in dynamism is not due to regulation.

Since the 1970’s, the most stringently regulated industry by far has been manufacturing:

Regulatory stringency by major sector

(“FIRE” here refers to finance, insurance, and real estate.)

However, more stringently regulated industries are not less dynamic:

Startup rates vs. regulatory stringency

Some of these results are weird, since #622, marked as a lightly regulated industry, is “Hospitals”, which I don’t really think of as freewheeling.  Maybe these numbers don’t include indirect effects like occupational licensing for medical professionals restricting the supply of people to work in hospitals.

But at any rate, regulations are not the only way to enforce monopoly power, and it seems that they’re not the decisive factor.  Governments have means other than regulation to promote monopoly (for instance, grants, contracts, or subsidies to insider firms, or increases in the scope of what can be patented and for how long).  And there are purely private mechanisms (like prestige/signaling in the scientific publishing industry) that can preserve monopolies as well.

Problems for the Middle and Lower Classes

US income inequality is rising; in real dollar terms, this looks like the rich getting richer while everyone else stays the same:


On the other hand, it’s worth moderating this picture by awareness of cost disease. High-income people as well as lower-income people are spending a larger fraction of their budget on housing and healthcare, which aren’t really improving much in quality.

Image result for household consumption in high income

Income mobility is also dropping:

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Some Slogans

Why is monopoly bad?

Monopoly drives up prices while depressing production.  That means we have fewer nice things. Yes, even for the “winners” of this negative-sum game, though of course the problem is worse for everyone else.

Monopoly and lack of innovation go together, since monopolists have less incentive to produce or compete.

Monopoly and intangibles go together.  Branding is a form of market power. As are patents.

Monopoly causes inequality; it also causes absolute economic insecurity (if necessities cost more, the poor are most harmed).

Monopoly is anti-meritocratic. It’s a troll guarding a bridge, not a hardworking genius inventor.


None of this tells us what to do about monopoly. I’m not at all confident that antitrust law works or is a fair solution to the problem.  There’s also reason to doubt that deregulation would fix everything, though fixing zoning and occupational licensing laws seems like it would at least help.

Introducing the Longevity Research Institute

I’ve just founded a nonprofit, the Longevity Research Institute — you can check it out here.

The basic premise is: we know there are more than 50 compounds that have been reported to extend healthy lifespan in mammals, but most of these have never been tested independently, and in many cases the experimental methodology is poor.
In other words, there seems to be a lot of low-hanging fruit in aging.  There are many long-lived mutant strains of mice (and invertebrates), there are many candidate anti-aging drugs, but very few of these drugs have actually been tested rigorously.
Why?  It’s an incentives problem.  Lifespan studies for mice take 2-4 years, which don’t play well with the fast pace of publication that academics want; and the FDA doesn’t consider aging a disease, so testing lifespan isn’t on biotech companies’ critical path to getting a drug approved.  Mammalian lifespan studies are an underfunded area — which is where we come in.
We write grants to academic researchers and commission studies from contract research organizations.  Our first planned studies are on epitalon (a peptide derived from the pineal gland, which has been reported to extend life in mice, rats, and humans, but only in Russian studies) and C3 carboxyfullerene (yes, a modified buckyball, which prevents Parkinsonism in primate models and has been reported to extend life in mice).  I’m also working on a paper with Vium about some of their long-lived mice, and a quantitative network analysis of aging regulatory pathways that might turn up some drug targets.
We’re currently fundraising, so if this sounds interesting, please consider donating. The more studies that can be launched in parallel, the sooner we can get results.

Wrongology 101

Epistemic Status: Speculative.

Jean-Paul Sartre’s Anti-Semite and Jew, available online here, is a really interesting study of the psychology of anti-Semitism, written in a time (1940’s France) when it was common for people to talk overtly about how much they hated Jews.  Sartre, being Gentile and from a culture where anti-Semitism was much more common than it is in 21st century America, had an opportunity to observe these people that I do not.  So while he paints an extremely unflattering picture of anti-Semites, one that’s almost hard to believe, I take it seriously.

What are anti-Semites like, according to Sartre?

They are lazy. Sartre gives the example of a man who believes Jews are given unfair advantages in passing an exam he failed, but readily admits that he didn’t study for it.

They are people-oriented rather than thing-oriented.  “They behave toward social  facts like primitives who endow the wind and the sun with little  souls.  Intrigues, cabals, the  perfidy of one man, the courage and virtue of another —  that is what determines  the  course of their business, that is what determines the course of the world.”

They are impulsive.  “the anti‐Semite understands nothing about modern society.  He  would be incapable of conceiving of a constructive plan; his action cannot reach the level of the methodical; it remains on the ground of passion.  To a long‐term enterprise he prefers an explosion of rage analogous to the running amuck of the Malays.”

They are bullies.  “He has chosen also to be terrifying.   People are afraid of irritating  him.   No one knows to what lengths the aberrations of his passion will carry him  —  but he knows, for this passion is not provoked by something external.  He has it well in hand; it is obedient to his will: now he lets go of  the reins and now he pulls back on them.”

They are conformists.  “This man fears every kind of solitariness, that of the genius as  much as that of the murderer; he is the man of the crowd.   However small his stature,  he takes every precaution to make it smaller, lest he stand out from the herd and find  himself face to face with himself.  He has made himself an anti-Semite because that is something one cannot be alone.  The phrase, “I hate the  Jews,” is one that  is  uttered  in  chorus;  in  pronouncing  it,  one  attaches himself to a tradition and to a community  —  the tradition and community of the mediocre.”

They are irrational.  “The anti-Semite has chosen to live on the plane of passion.” They like being angry (at the Jews), and seek out opportunities to work themselves up into a rage.  They deliberately say trollish things that make no sense: “Never believe that anti‐ Semites are completely unaware of the absurdity of their replies.  They know  that  their remarks are  frivolous, open to challenge.   But they are amusing themselves, for it is their adversary who is obliged to use words responsibly, since he believes in words. The anti‐Semites have the right  to play.”

They are mystical and anti-intellectual.  “The anti‐Semite has a fundamental  incomprehension of the various forms of modern property:  money,  securities,  etc.   These are abstractions, entities of reason related to the abstract intelligence of the Semite…What his subtle sense seizes upon is precisely that which the intelligence cannot perceive.” In other words: he cannot understand complicated abstract ideas which in principle anybody could grasp, with enough time and effort and ordinary thinking; but he believes he has magical powers of intuition that reach beyond the intellect and which the Jews innately will forever lack.

They are a mob. “He  wants  his  personality  to  melt  suddenly  into  the  group  and  be  carried  away  by  the  collective  torrent.   He  has  this  atmosphere  of  the  pogrom  in  mind  when  he  asserts  “the  union of all Frenchmen.”

Why would a person want to be wrong on purpose?

Sartre explains:

How  can  one  choose  to  reason  falsely?  It  is  because  of  a longing for impenetrability. The rational man groans as he  gropes for the truth;  he  knows  that his  reasoning is no more than tentative, that other considerations may supervene  to  cast doubt on it.  He never sees very clearly  where he is going; he is “open”; he may even appear to be hesitant.   But there are people who are attracted  by the durability of a stone.   They wish to be massive and impenetrable;  they wish  not to change.   Where, indeed, would change take them?   We have here a basic fear of oneself and of truth.  What frightens them is not the content of truth, of which they have no conception, but the form itself of truth, that thing of indefinite approximation. It is as if their own existence were in continual suspension.

In other words: the person who is wrong on purpose is afraid of the vulnerability of trying at a task that may fail.  In particular, he is afraid of the process of learning.  The “indefinite approximation” Sartre mentions is the process of double-checking, doubting, asking questions, second-guessing, saying “oops”, moderating or complicating one’s views, all the millions of mental motions involved in trying to understand things accurately. The person who is wrong on purpose wants to just stop all of that motion, forever.

Only  a  strong  emotional  bias  can give a lightning‐like  certainty; it alone  can hold reason in leash; it alone can remain impervious to  experience and last for a whole lifetime.

People choose to be wrong so that they can play a game that is by definition impossible to lose.  They don’t like trying or working hard. They don’t like expectations being placed on them.

The  anti‐Semite  is  not  too  anxious  to  possess  individual  merit.   Merit  has  to be sought, just like truth; it is discovered with difficulty; one must deserve it.  Once acquired, it is perpetually in question: a false step, an error, and it flies away.  Without respite, from the beginning of our lives to the end, we are responsible for what merit we enjoy.

But the anti-Semite wants a respite from responsibility, very badly.  He wants to be done.  He wants an end to trying altogether.

 Anti‐Semitism, in short, is fear of the human condition.  The anti‐Semite is a  man  who wishes to be pitiless stone, a furious torrent, a devastating thunderbolt‐anything except a man.

Sartre’s “Anti-Semitism” Isn’t Just About Jews

Sartre says explicitly that the character that made a Frenchman of his time into an anti-Semite could in other contexts apply to other races: “The Jew only serves him as a pretext; elsewhere his  counterpart  will  make  use  of  the  Negro  or  the  man  of  yellow skin.”

Sartre’s version of anti-Semitism is a lot like the American institution of herrenvolk democracy, established around the time of Andrew Jackson, in which white people, no matter how poor, formed a coalition that allowed them to be socially superior to black people, given arbitrary privileges over them and free to enact unpunished mob violence against them.

Anti-Asian prejudice (“sure, they’re smart, but they’re not really a good culture fit“) is also structurally very similar to the defiant mediocrity that Sartre describes in anti-Semites.

More controversially, there is something about the concept of Asperger’s Syndrome, which is no longer officially a medical designation and was arguably never a natural category, that matches this pattern.  Smart, logical people who just aren’t one of us, who may technically fulfill the requirements of a job but don’t have the right intangibles, who aren’t good at politicking, who naively believe in the literal rules, and who inevitably get bullied.

Structurally, we’re talking about a cartel, or a mob.  Mob in both the “mafia” and the “riot” sense.  Collusion to keep unmerited privilege, enforced by acts of random violence.

If you are trying to enforce an eternal privilege, something that cannot be lost no matter what you do, then being wrong, or being bad at things, or treating others badly, is the fundamental test of the security of your status.  Being wrong is both a badge and one of the perks of class membership.

Fascism and Mysticism

This article on Jordan Petersen is infuriating in some ways — there are gratuitous digs at masculinity and self-help that I don’t endorse — but it’s worth reading because it outlines his historical influences.

A range of intellectual entrepreneurs, from Theosophists and vendors of Asian spirituality like Vivekananda and D.T. Suzuki to scholars of Asia like Arthur Waley and fascist ideologues like Julius Evola (Steve Bannon’s guru) set up stalls in the new marketplace of ideas. W.B. Yeats, adjusting Indian philosophy to the needs of the Celtic Revival, pontificated on the “Ancient Self”; Jung spun his own variations on this evidently ancestral unconscious. Such conceptually foggy categories as “spirit” and “intuition” acquired broad currency; Peterson’s favorite words, being and chaos, started to appear in capital letters. Peterson’s own lineage among these healers of modern man’s soul can be traced through his repeatedly invoked influences: not only Carl Jung, but also Mircea Eliade, the Romanian scholar of religion, and Joseph Campbell, a professor at Sarah Lawrence College, who, like Peterson, combined a conventional academic career with mass-market musings on heroic individuals.

There is, historically, a connection between occultism and the study of mythology, on the one hand, and fascism, on the other. (I would add D.H. Lawrence to the list of fascist-sympathizing mystics.)  The literal Nazis were very fond of myth and magic — see the Thule Society.  Start exploring contemporary neopaganism and occultism and you’ll quickly run into people with some very disturbing politics.

There’s a historical explanation — both the Theosophists and the fascists drew intellectually from German Idealism — but Sartre gives a more psychological explanation.  Both the desire to enjoy unearned (racial) privilege and the desire to believe in occult forces essentially boil down to the desire not to be tested.  One can fail tests.

If you have an invisible, magical essence that makes you special, however — that can’t be taken away by any inconvenient facts.

Cartel Thinking

The Western Elite from a Chinese Perspective “, an account of a Chinese immigrant’s experiences at Cambridge, Goldman Sacks, and Stanford Business School, talks a fair bit about the mentality of seeking to live insulated from fair tests.

“In Communist China, I was taught that hard work would bring success. In the land of the American dream, I learned that success comes through good luck, the right slogans, and monitoring your own—and others’—emotions.”

When Puzhong makes a successful trade by accident at Goldman Sacks, he expects to be reprimanded for his mistake, but is instead rewarded. But “it was not enough to just be a good trader. It was also essential to be able to manage one’s boss, other colleagues, and those who report to them.”

In business school, he learns (amusingly enough) that the way one is supposed to express feelings in American elite culture seems a lot like falsifying them:

We talked about microaggressions and feelings and empathy and listening. Sometimes in class the professor would say things to me like “Puzhong, when Mary said that, I could see you were really feeling something,” or “Puzhong, I could see in your eyes that Peter’s story affected you.” And I would tell them I didn’t feel anything. I was quite confused.

One of the papers we studied mentioned that subjects are often not conscious of their own feelings when fully immersed in a situation. But body indicators such as heart rate would show whether the person is experiencing strong emotions. I thought that I generally didn’t have a lot of emotions and decided that this might be a good way for me to discover my hidden emotions that the professor kept asking about.

So I bought a heart rate monitor and checked my resting heart rate. Right around 78. And when the professor said to me in class “Puzhong, I can see that story brought up some emotions in you,” I rolled up my sleeve and checked my heart rate. It was about 77.  And so I said, “nope, no emotion.” The experiment seemed to confirm my prior belief: my heart rate hardly moved, even when I was criticized, though it did jump when I became excited or laughed.

This didn’t land well on some of my classmates. They felt I was not treating these matters with the seriousness that they deserved. The professor was very angry. My takeaway was that my interpersonal skills were so bad that I could easily offend people unintentionally, so I concluded that after graduation I should do something that involved as little human interaction as possible.

Puzhong is noticing that American elite businesspeople appear to be colluding rather than competing.  They’re not racing each other for profits, they’re signaling that they’re cozy insiders who will play nice and share the spoils with others who know the right buzzwords.  Cartel behavior, in other words.

I had always thought that things happen for reasons. My parents taught me that good people get rewarded while evil gets punished. My teachers at school taught me that if you work hard, you will succeed, and if you never try, you will surely fail.

If people are rewarded for reasons, then anyone who meets these publicly known criteria can gain rewards.  If rewards are given opaquely, then they can be safely restricted to existing insiders. Therefore, people who want to preserve cartel privilege have an interest in being mysterious and not making sense.

Applied Wrongology

I have never been an anti-Semite, for obvious reasons; I have never been a banker or MBA, either, and I like to think that racism is not particularly my vice.  But I do understand the longing for security.

It gets tiring to be tested all the time, to be subject to skepticism, to be second-guessed, to have expectations placed upon you.  It’s nerve-wracking to have to perform and worry that you’ll fail.  Merit is intimidating. Objectivity is daunting.

And, on the other hand, to float completely free, to have a space where you can just be, to feel the world is faintly gold-dusted and magical, to build castles in the air without any annoying people coming around to check on whether you’re being “productive” or whether the castles are, in fact, real…that would be lovely, wouldn’t it?  Doesn’t that seem more like the way life should naturally be?

And wouldn’t it be nice to be sure that nobody will ever come round to weigh and measure and count and judge?  Forever, no matter what?

I can’t, in sincerity, say people shouldn’t want that. It’s a very understandable thing to want, to be cut slack, to not be judged. At times I want it myself.

But Sartre’s anti-Semite only wants to be secure — he isn’t said to succeed.  Just because he wants to stop being human doesn’t mean he can get what he wants. Total security, and total absence of thought, is probably unattainable.


Good News for Immunostimulants

Epistemic Status: Moderate

Way back in 2015 I was writing about the connection between cancer remissions and the immune response to infection.  To recap the facts:

  • A plurality of recorded spontaneous cancer remissions happened when the patient had a strong immune response (often with fever) to a bacterial infection at the tumor site.
  • William Coley’s bacterial therapies for cancer at the turn of the 20th century, while not tested to the standards of modern experimental methods, did seem to produce recovery rates comparable or superior to chemotherapy.
  • Endotoxin, a poisonous substance found in the outer membrane of Gram-negative bacteria, can cause tumor regressions.
  • TNF-alpha, an inflammatory cytokine involved in the body’s response to endotoxin, is equally effective at causing tumor regressions; it is too dangerous to give to patients systemically, but is an effective cancer treatment for advanced melanoma when used in isolated limb perfusion.
  • There are quite a few cases, both in animals and humans, of inflammatory cytokines causing complete tumor regressions in metastatic cancers, particularly when injected directly into the tumor.

At the time, I predicted that if only there were a delivery mechanism that could more effectively isolate inflammatory cytokines to the tumor site, it might work safely for more than just special cases like isolated limb perfusion; and that there might be some delivery mechanism that made a bacterial therapy like Coley’s toxins work.

The heuristic here was that when I went looking for the biggest responses (remissions, complete tumor regressions) in the toughest cases (metastatic cancers, sarcomas which don’t respond to chemotherapy), many of them seemed to involve this picture of acute, intense activation of the innate immune response.

It turns out that two new therapies with very good results pretty much support this perspective.

CpG oligodeoxynucleotides,  a motif found in bacterial DNA, are the active ingredient in Coley’s toxins; they are the part of bacterial lysate that triggers the immunostimulatory effects.

Today, SD-101, a CpG oligodeoxynucleotide drug produced by the biotech company Dynavax, is about to present its results from two trials.

This January, Stanford scientists reported that SD-101 combined with another immunotherapy — but no traditional chemotherapy — eradicated both implanted and spontaneous tumors when injected into mice, both at the injection site and elsewhere.

We’ll have to see the results of the human trials, but this looks promising.

Another drug, NKTR-214, is an engineered version of the inflammatory cytokine IL-2, designed to localize more effectively to tumors.  The IL-2 core is attached to a chain of polyethylene glycols, which release slowly in the body, preferentially activating the tumor-killing receptors for IL-2 and resulting in 500x higher concentrations in tumors than a similar quantity of IL-2 alone.  This is the tumor-localizing property that could make inflammatory cytokines safe.

In patients with advanced or metastatic solid tumors, previously treated with PD-1 inhibitors, NKTR-214 resulted in 23% of patients experiencing partial tumor regression.

While this still doesn’t mean much chance of recovery, it’s still notable — any treatment for advanced cancers with more than a 20% response rate is remarkable. (Chemotherapy usually produces partial response rates in the 2-20% range for metastatic cancers, depending on cancer type and drug regimen.)

It’s early days yet, but I continue to think that immunostimulants have a lot of potential in cancer treatment.

Moreover, I think this is a little bit of evidence against the frequently heard claim that it’s impossible to “pick winners” in biotech.

The conventional wisdom is that you can’t know ahead of time which drugs that seem to work in preclinical studies (in vitro or in mice) will succeed in humans.

Most preclinical drug candidates do fail, it’s true. And there are a lot of reasons to expect this: mouse models are not perfect proxies for human diseases, experimental error and outright fraud often make early results unreplicable, and we don’t understand all the complexities of biochemistry that might make a proposed mechanism fail.

But the probability distribution over drug candidates can’t be uniform, or it would have been impossible to ever develop effective drugs!  The search space of possibly bioactive molecules is too large, and the cost of experiments too high, to get successes if drugs were tested truly at random.  We would never have gotten chemotherapy that way.

I think it’s likely that using the simple heuristic of “big effects in tough cases point to a real mechanism somewhere nearby” gets you better-than-chance predictions of what will work in human trials.


Naming the Nameless

Epistemic status: political, opinionated, personal, all the typical caveats for controversial posts.

I was talking with a libertarian friend of mine the other day about my growing discomfort with the political culture in the Bay Area, and he asked why I didn’t just move.

It’s a good question.  Peter Thiel just moved to L.A., citing the left-wing San Francisco culture as his reason.

But I like living in the Bay, and I don’t plan to go anywhere in the near future. I could have said that I’m here for the tech industry, or here because my friends are, or any number of superficially “practical” reasons, but they didn’t feel like my real motivation.

What I actually gave as the reason I stay was… aesthetics.

Wait, what?

Let’s Talk About Design

I’m not a designer, so I probably don’t have the correct vocabulary to express what I see.  Please bear with me, while I use simple and ignorant language; if any of my readers have a more sophisticated understanding, I’d love to hear about it in the comments.

Stuff that’s marketed to Bay Area bourgeois bohemians has a coherent appearance.  You see it in websites that are all smooth scrolling and gradients and minimalism — see the sample websites on Squarespace, for instance.  You see it in the product design on the labels and menus of cafes and juice bars and coffee shops — The Plant Cafe is a good example.  You see it in the almost-identical, smoothly minimalist layouts of every tech-startup office.

Professional designers may be getting bored of this “light-contrast, minimalist elegance” or “objectively beautiful, but mostly unremarkable, templates”, and are trying out more deliberately jarring styles like Brutalism.

But for your typical consumer, the generic California/BoBo style works fine.  It signals elegance, which means, more or less, that it’s designed for educated, high-Openness, upper-middle-class, urban people.  When I enter a space or a website with this aesthetic, or buy a product with this branding, it’s shorthand for “Ahhhh, this place is run by competent professionals who know how to give me a pleasant experience. I will not feel harried or inconvenienced or confused here; I will be well taken care of.  I will easily be able to slot my existing behavior patterns into the implicit “rules” of how to use and navigate this place or device or website.”

Apple products are, of course, the archetype of this kind of “good” design.  Smooth, urbane, almost childishly easy to use.  Most computers are still PCs; office workers, older people, hardcore programmers and gamers, and the price-conscious still go for PCs.  It’s among the style-conscious (who skew affluent, educated, aesthetically/socially sensitive, and slightly more female than male) that Macs are universal.  When I asked a Marine from Texas what kind of computer he used, he scoffed, Do I look like a Mac guy?

Let’s look at one of my favorite things to buy, GT’s Kombucha.

This is pretty much the most BoBo thing in the world. It makes a nod to Buddhism (“Enlightened”, the mandala-like radially symmetric logo), psychedelia (the rainbow label), Human Potential Movement-ish self-improvement (“SYNERGY” and “renew, rebalance, rebuild, reclaim, rekindle, recharge”) and environmentalism (“organic”).  But the design is simple and clean enough to seem like a modern company run by professionals.

In this case, it’s not just a pretty label: the probiotics in fermented foods like kombucha are probably good for you, kombucha is lower in sugar than juice but pleasantly tangy and fizzy, and in my experience it’s uncannily good at settling an upset stomach.  But the branding is a big part of what makes it delightful.  And, I’m almost embarrassed to say, being able to buy kombucha at the nearest drugstore is a non-negligible part of why I like living in this neighborhood.


I have a friend who’s very good at digging up evidence of crime and scam artistry.  It’s part hobby, part crusade; give her a public figure and she can investigate with great speed and accuracy what kinds of shady dealings he’s been involved with.

Once, she showed me some companies she had proved were fraudulent, and my first reaction was “I could have told you that in seconds; their web design looks scammy.”

Of course, it’s not really the same thing. She had hard evidence; I only had an intuition, and intuition can be wrong.

But, for instance, this penis enlargement website just looks noisy. It’s jam-packed with content, it’s screaming about sales and deals, there’s a bright red “Buy Now” button with a ticking countdown clock.  It’s not classy.  Even if you didn’t know anything about the product, you could see that it’s being packaged (pun intended) much differently than this website selling relationship workshops.

But my friend, like a lot of nerds, couldn’t see that difference in branding at a glance. She couldn’t see the difference in connotations that different aesthetic choices evoke.  She was almost completely style-blind.

Some people claim that aesthetics don’t mean anything, and are very resistant to the idea that they could.  After all, aesthetic preferences are very individual. Chinese opera sounds beautiful to people raised with it, and discordant to the untrained Western ear.

So, claim the skeptics, all descriptions of what aesthetic choices “mean” are basically pseudoscience. When design experts tell us that red evokes passion and blue evokes calm, they’re using associative thinking, which is no more fact-based than the Four Elements or the five colors in Magic: The Gathering.

Clustering things based on associations and connotations is risky.  It’s going to differ from individual to individual, and even more from culture to culture.  It’s easy to take intuitive leaps for granted and quickly get to the point where people are talking past each other.  So it’s safer just not to talk about what aesthetics connote, right?

To my view, the skeptics have a good point, but they’re too epistemically conservative. There’s obviously signal being carried through aesthetics.  Colors don’t have intrinsic meanings, of course, but they do have shared connotations within a culture.

Note that the M:TG color “meanings” and the design/marketing color “meanings” are very similar — not because everyone is tapping into some magical collective unconscious, but because Magic is a game designed in contemporary America, by designers who probably share the same color associations as the designers of websites and product labels.

When Pantone says their 2018 color of the year, Ultra Violet, “communicates originality, ingenuity, and visionary thinking”, they’re not just making up random nonsense.  Pretty much any present-day English-language “color meaning” summary for designers or marketers will associate purple with something like creativity or imagination or spirituality. I don’t know where this meme comes from originally, but it’s certainly not unique to Pantone or chosen at random.

Our physical environment is built primarily by corporations which employ designers.  Those designers draw inspiration from artistic or creative subcultures. Design has a life cycle in which it starts as an original aesthetic trope being used by some individual artist, to being imitated by other artists, to becoming trendy, to becoming ubiquitous.  Tastemakers may be a tiny minority of the population, aesthetics may not be a big deal for everyone, but everything manmade you see around you has its origins in someone obsessed with aesthetics.  Designers “rule” our visual world in the same way writers “rule” our verbal world, in the same way that “practical men who believe themselves to be quite exempt from any intellectual influence, are usually the slaves of some defunct economist.”  In this sense, aesthetics very much mean things, and you have to look to their origins and contexts to understand what they mean.

This essay, worth reading in full, calls the process “subcultural sublimation” and tracks how Pantone’s 2016 colors, Rose Quartz and Serenity, drew inspiration from seapunk (a musical subgenre with an online visual aesthetic). Seapunk aesthetics propagated through fashion blogs, the NYT style section, and pop stars’ music videos, all the way to the Pantone Institute, which sets the tone for fashions in mainstream commercial design. The popularity of pastels began with feminist artists interrogating softness and femininity, propagated through Tumblr “aesthetic” blogs, and likewise eventually reached Pantone. Aesthetic tropes are “commodified” over time; they drift from artistic or countercultural milieux towards corporate branding.

Mostly implicit in the article, but worth mentioning, is that commercial design ultimately borrows from creatives who are politically opposed to business and resent this commercial appropriation.  More on that later.

If you’re style-blind, you’ll look at Rose Quartz and Serenity and say “they’re just colors! they don’t mean anything! all this cultural criticism is just pretentious noise!”  If you’re mildly style-sensitive, like myself, you’ll notice that the colors seem Tumblresque, and you’ll note that Pantone’s description makes a nod to “gender blur” and “societal movements toward gender equality and fluidity”.  If you’re actually an expert, like the author of the article, you can concretely trace where the popularity of that color scheme came from.

“Subcultural sublimation” runs on ordinary, non-magical cause and effect, the propagation of memes from their originators towards mass popularity.  It can be understood and analyzed.  You can isolate where aesthetic tropes come from, why they’re used, what their creators believe, and what channels govern their imitation and spread — and that tells you something about their “meaning” that’s not purely subjective.

Politics and Aesthetics

Artists tend to be on the political left; arts and media occupations are among the most heavily weighted towards Democrats over Republicans.

It’s not clear to me why. Maybe it’s a temperamental thing — high openness to experience drives both an interest in aesthetics and a preference for left or liberal politics.  Maybe it’s explained by education, which both inculcates interest in the arts and left politics.  Regardless of cause, it’s a real and important phenomenon.  And it’s a problem for anyone who’s not on the left, as Rod Dreher, the original CrunchyCon, pointed out years ago.

Beauty matters to people. So does health and emotional wellbeing. So does everyday kindness.  Living well, in other words. Quality of life.  You can’t cede all of that to the opposing political team without losing something valuable.

Rod Dreher points out that, while, say, organic vegetables are coded liberal, they also taste better and are healthier than processed food.  Yet conservatives often have a knee-jerk condemnation of anything “green” or “pretentious”, which means they’re boxed into being cultural philistines who miss out on flavor and beauty and health.

“It’s a PR disaster for the Right to allow discussions of fun and beauty and poetry and nature to be owned by the Left,” says a New York publishing executive and closet conservative. “The right wing just looks unappealing. Do they not understand this?” 

If you like the arts, if you’re temperamentally high-Openness and aesthetically sensitive, you’re going to be drawn to coastal cities and educated social groups, and those environments tend to skew left-wing. It’s hard to leave without giving up something intangible that’s hard to convey to people who don’t share your sensibility.

Dreher, a conservative Catholic who values tradition, can with some justice argue that beauty and art properly belong to his culture; after all, it was Catholics who built the cathedral of Chartres.

Libertarians are, if anything, in a tougher position, because we’re not traditionalists, and because strong individualism runs counter to even being able to talk about shared cultural sensibilities.  Ask a libertarian “Why don’t we have any good songs about our values?” and there’s a good chance that you’ll get the response “Ew, who’d want one?  That’s too collectivist for me.”

But the result is that you’re living in an aesthetic environment that’s largely created by your ideological opponents, and subjected to constant subliminal messaging that your values are uncool. This causes an evaporative cooling effect where the only people willing to express libertarian views are “style-blind” and sometimes even socially blind, people who do not perceive that they are being mocked or that their aesthetic signaling is clumsy.

It’s hard to argue to a skeptic why this even matters. Why care about aesthetics and culture? What do you care what other people think?  Surely an independent-minded person would simply refuse to succumb to social pressure — and the cultural connotations of aesthetics are inherently relative to social context, so maybe the best way to keep your independence is to choose style-blindness as a cognitive strategy.  What you can’t see, you can’t be manipulated by!

But I think it’s unvirtuous to choose blindness or ignorance. And it’s also ineffective. What you can’t see can sneak up behind you.  People who think they’re immune to social pressure get manipulated all the time.

Scott Alexander is honest enough to admit that it happens to him:

Sometimes I can almost feel this happening. First I believe something is true, and say so. Then I realize it’s considered low-status and cringeworthy. Then I make a principled decision to avoid saying it – or say it only in a very careful way – in order to protect my reputation and ability to participate in society. Then when other people say it, I start looking down on them for being bad at public relations. Then I start looking down on them just for being low-status or cringeworthy. Finally the idea of “low-status” and “bad and wrong” have merged so fully in my mind that the idea seems terrible and ridiculous to me, and I only remember it’s true if I force myself to explicitly consider the question. And even then, it’s in a condescending way, where I feel like the people who say it’s true deserve low status for not being smart enough to remember not to say it. This is endemic, and I try to quash it when I notice it, but I don’t know how many times it’s slipped my notice all the way to the point where I can no longer remember the truth of the original statement.

Now, I could say “just don’t do that, then” — but Scott of 2009 would have also said he believed in being independent and rational and not succumbing to social pressure.  Good intentions aren’t enough.

And I’m seeing people in roughly my demographic going silent or submitting to pressure to conform, and it’s worrisome.

I think it’s much better to try to make the implicit explicit, to bring cultural dynamics into the light and understand how they work, rather than to hide from them.

Defensive Postures

There are a number of defensive strategies people (of varying political views) adopt against the cultural dominance of the left.

Reaction is what, say, Ann Coulter does, or, or the Donald Trump campaign.  It’s defiantly anti- progressive, rejecting the “mainstream media” and “coastal elite” tastemakers.  It’s happy to be perceived as tacky and rude.

The problem with reaction is that it has no positive vision.  It’s just “the opposite of what my opponents want.”  It’s uncreative and it can easily descend into spitefulness.

Respectability politics is a different tactic, and, in this context, usually takes the form of (not very credible) claims to be apolitical.  Early forms of this include “Keep Your Identity Small” or “Politics is the Mind-Killer.”  By declaring the importance of not taking sides, you’re already asserting that you’re not wholly on one side; a progressive can reasonably infer that any avowedly “apolitical” person disagrees with them at least somewhere.

Claims of aloofness from politics have always, correctly, been identified as evidence of covert dissent from “good” politics: “formalism” was a political offense in Soviet Russia.  There are many thinkpieces like this one observing (rightly) that Silicon Valley culture is nominally apolitical but implicitly capitalist.

And then you see obviously defensive moves by the tech industry to distance itself from that allegation, like YCombinator’s announcement of its New Cities  project:

Just to get ahead of the inevitable associations: We want to build cities for all humans – for tech and non-tech people. We’re not interested in building “crazy libertarian utopias for techies.”

Once you have to defend against a stereotype, you’re already losing the messaging war.  As with reaction, there’s no positive vision, only the frantic assurance that you’re not really the bad guy.

Cooptation doesn’t seem to be that popular, and might be underrated.

It’s a kind of judo where you claim to be the true exemplar of the goal your opponents want.  They hate capitalism?  Well, you note that what most people think of when they hear that word is crony capitalism, which is indeed terrible, and that you are bitterly opposed to the system in which unfair legal privileges give vast wealth to a few and deprive everyone else.  C4SS does this, quite well in my opinion, but hardly anyone outside of libertarian-world has heard of them.

It’s still not fundamentally creative, though. You’re borrowing your opponents’ tropes and aesthetics, not building your own.  And if you get too good at it, you end up being easily confused for believing things that you don’t actually believe.

The Opposite of Defensiveness

One of the things I like best about Ayn Rand is that she staked out aesthetic and cultural territory without resorting to any of these defense mechanisms.  She actually made art that was fundamentally in a different style than that of the cultural establishment.  Of course, this left her vulnerable to the allegation that it was bad art — there are 52 million Google results for “ayn rand bad art.”

But most of the common criticisms — of black-and-white thinking, didacticism, utopian optimism, overly heroic characters, and so on — are based on implicit presumptions about the nature of life and the role of art which she explained (or, at least, began to explain) why she did not share.  She brought the dissent into the light, into explicit discourse.

If you take something about yourself that’s “cringeworthy” and, instead of cringing yourself, try to look at why it’s cringeworthy, what that’s made of, and dialogue honestly with the perspective that disagrees with you — then there is, in a sense, nothing to fear.

There’s an “elucidating” move that I’m trying to point out here, where instead of defending against an allegation, you say “let’s back up a second” and bring the entire situation into view.  It’s what double crux is about — “hey, let’s find out what even is the disagreement between us.”  Double crux is hard enough with arguments, and here I’m trying to advocate something like double-cruxing aesthetic preferences, which sounds absurdly ambitious.  But: imagine if we could talk about why things seem beautiful and appealing, or ugly and unappealing.  Where do these preferences come from, in a causal sense? Do we still endorse them when we know their origins?  What happens when we bring tacit things into consciousness, when we talk carefully about what aesthetics evoke in us, and how that might be the same or different from person to person?

Unless you can think about how cultural messaging works, you’re going to be a mere consumer of culture, drifting in whatever direction the current takes you.

The Arts and Imitation

Let’s go back for a moment to subcultural sublimation.

Artistic trends have a life cycle, of creation, expansion, and destruction, or more specifically, the artist, the marketer, and the critic.  First, the artist creates a new thing. Then, a succession of tastemakers and creatives imitate that thing and scale it up, from a subcultural scene to mass-market production.  Finally, the critic notices that it’s become commoditized (in the literal economic sense: if it’s exactly the same everywhere and anyone can copy it, its price goes to zero) and deflates the hype.

This isn’t specific to the arts, of course.  Companies are created, expand, and eventually succumb to competition.  Empires are founded, expand, and succumb to invaders. It’s a human-organization pattern.

But expansion in particular is enabled by mechanical reproduction processes dating to the Industrial Revolution.  We can systematize “scaling up” much easier and faster than pre-industrial peoples could.

Commerce is ancient — in different times and places, trade has been more free or less so, and it became somewhat more free in the West with the introduction of classical liberalism and economic theory at the end of the 18th century, but trade itself is as old as the first anatomically modern humans, living 300,000 years ago.

Invention is ancient — the Greeks had it, including more advanced science than modern stereotypes would assume. Archimedes probably knew calculus.

What’s modern is scaling-up, the ability to make many copies of things, from physical objects to social systems.  That’s what allows for mass culture.  That’s what allows startups to grow exponentially.  For the past two hundred years or so, we’ve been living in an era where the expander of the reach of a creation is more powerful than ever.

Expanders sometimes like to present themselves as creators, but they’re not.  The creator makes the first prototype, the original. No scale at all. “Zero to one.”  In fact, creators often resent expanders for taking credit for their work or diluting it for the mass audience.  This is why seapunk artists were frustrated at being imitated in music videos:

also, why aren’t y’all frustrated AT ALL at the rihanna thing? that performance marked the commodification of an aesthetic movement…— Bebe Zeva (@BebeZeva)

…which means all taste-makers have to start all over. it’s a lot of work. clearly ur not doing shit but consuming if ur not peeved by this— Bebe Zeva (@BebeZeva)

“wow amazing rihanna performance i love seeing my tumblr on SNL” why? that Aesthetic served as an exclusive binder for URL counterculture…— Bebe Zeva (@BebeZeva)

…tomorrow, when it enters Phase Three and Forever 21 puts a price tag on it, it will no longer be exclusive. its purpose is gone.— Bebe Zeva (@BebeZeva)

My own addition to the pile of theories on “why don’t creative professionals like capitalism?” is that creators feel defrauded by expanders, and the core of modern capitalism is superpowered expanders.  Expanders capture most of the economic value and social credit from scaling up things originated by creators.  Expanders are sociopaths, in the “geeks, mops, and sociopaths” trichotomy.

And we don’t really have good tools for fairly compensating people for intellectual originality.  Intellectual property law is a kludge, with a lot of problems.  Creators don’t really know how to extract “fair market value” for ideas, possibly because they’re intrinsically motivated to create them and the kind of “payment” they want is more like appreciation or kindred-spirit-ness than money.  Standard startup ideology says that ideas are of low value: “If you go to VC firms with a brilliant idea that you’ll tell them about if they sign a nondisclosure agreement, most will tell you to get lost.  That shows how much a mere idea is worth. The market price is less than the inconvenience of signing an NDA.” That may be true, but you could also interpret it as markets not knowing how to price ideas, in the same way that markets can’t price natural resources until you figure out a way to define property rights over them.

So, whenever you encounter a piece of media — words or images or music or anything representational — no matter how many levels of imitation or expansion it’s been through, you’re still hearing some distant signal from its originator.  And its originator probably feels ripped off and undervalued.  When you go looking for good art, you’re looking for art that’s closer to its creative source, and that means you’ll hear in it the voice of the frustrated creator.

In a sense it’s inherently paradoxical to enjoy something like GT’s Kombucha — it’s a product produced by a process (scaling-up) which the hippies who inspired its aesthetic would have vehemently opposed.  To like it knowledgeably is to partly dislike it.

I think there may be some kind of necessary project in the vicinity of “making amends between creators and expanders” that would be required for creative work not to have the dynamic where scaling up is seen as selling out.  I think scaling-up is probably net good — it allows more people to have nicer things.  But there may well be legitimate grievances with it that deserve to be addressed.  That’s another one of those cases where dialogue and making the implicit explicit would be really helpful.

Atypical & Treatment-Resistant Depression

This report was commissioned by one of my freelancing clients and published with permission.


Roughly 20-30% of people with depression don’t respond to the first antidepressant or two they try. One of the harder-to-treat subtypes of depression is atypical depression, which comes with sleeping and eating more than usual (rather than less), and high emotional sensitivity.  This report is an overview of options for treatment-resistant or atypical depression.

For context, “response rates” with respect to a particular depression rating scale are the probability that a patient will see at least 50% improvement from baseline after the treatment.

HAM-D Response Rates in Treatment-Resistant or Atypical Depression

Treatment Response Rate Placebo-Controlled Possible Side Effects
Selegiline 67% Yes Minor
Deep brain stimulation 62% No Complications of brain surgery
Traxoprodil 60% Yes QT prolongation (risk of sudden death)
T4 58% No Hyperthyroidism
D-cycloserine 54% Yes Minor
Atypical antipsychotics 47% Yes Weight gain, motor disorders, sedation
Lithium 45% Yes Dehydration, hypothyroidism, kidney damage
T3 42% No Hyperthyroidism
SAM-E 36% Yes Minor
Ketamine 35% Yes Minor
Methylfolate 33% Yes Minor
Vagus nerve stimulation 27% Yes Surgery complications
Nitrous oxide 20% Yes Minor


Bottom lines: SSRIs and MAOIs work better than tricyclics in atypical depression; there’s no clear indication that any particular drug is best; SSRIs and MAOIs work similarly well.

Phenelzine (Nardil, an MAOI) has a 58% response rate on the HAM-D in atypical depression, same as therapy, and significantly better than placebo. N=108.[1]

Fluoxetine (an SSRI) and imipramine (a tricyclic) had equivalent response rates in atypical depression in clinical global impression, 51% and 53% respectively, both superior to placebo.  No significant differences on the HAM-D either.[2]

Sertraline (an SSRI) caused a 77.5% response rate on the CGI in 197 patients with atypical depression, compared to 67.5% in the moclobemide group (moclobemide is an MAOI).  This difference was not statistically significant (p = 0.052).[3]

No significant difference in response rate between fluoxetine and phenelzine in atypical depression, N=42.[4]

Isocarboxazid (an MAOI) significantly more effective than placebo in atypical depression.[6]

Imipramine (a tricyclic) significantly better than placebo in 76 patients with atypical depression; 45% response rate in treatment group vs. 12% in placebo.[7]

Moclobemide had a positive response in 67% of atypical depressive patients, while the response rate was 55% with fluoxetine. This was a significant difference. N=53.[8]

67% of atypical patients responded to fluoxetine while 0% responded to nortriptyline (a tricyclic), n=16.[10]

119 patients with atypical depression randomized to phenelzine, imipramine, or placebo; response rate was 71% with phenelzine, 50% with imipramine, 28% with placebo. Phenelzine vs. imipramine difference was significant.[12]

Meta-analysis: MAOIs are more effective than placebo in atypical depression (effect size = 0.42), not significantly more effective than SSRIs, and more effective than tricyclics (effect size = 0.27).[13]


Bottom line: agomelatine is an antidepressant with a different mechanism of action than most: it’s a melatonin receptor agonist. It works comparably well to SSRIs, with less risk of sexual dysfunction.

In a placebo-controlled trial of 212 depressive patients, agomelatine had a 49% response rate on the HAM-D rating scale, significantly (p = 0.03) better than placebo.[19]

In a placebo-controlled trial of patients randomized to agomelatine or placebo, agomelatine resulted in statistically greater improvement on HAM-D than placebo.[62]

In a placebo-controlled trial of 238 depressive patients, agomelatine was significantly more effective than placebo, and had a HAM-D response rate of 53%.[63]

In a randomized controlled trial of agomelatine and venlafaxine on 276 depressed patients, both treatments had comparably high remission rates, but venlafaxine was more likely to cause sexual dysfunction (8.6% vs. 2.2%.)[64]

In a meta-study of agomelatine in depression, comprising 7460 patients, agomelatine was significantly more effective than placebo and equally effective to other antidepressants.[65]


Bottom line: aripiprazole is an atypical antipsychotic which works comparably to other atypical antipsychotics in atypical or treatment-resistant depression.  It may work when SSRIs fail.

Adjunctive aripiprazole was significantly more effective than placebo in anxious or atypical depressive patients who were already on antidepressants, as measured by MADRS score.[14]

In an open-label study of 30 patients with treatment-resistant depression, 46.7% were rated “much improved” or “very much improved” after adjunctive treatment with aripiprazole.[30]

Atypical Antipsychotics

Bottom line: atypical antipsychotics improve symptoms in treatment-resistant depression.

In a meta-study comprising 1500 patients with treatment-resistant depression randomized to adjunctive treatment with an atypical antipsychotic, the typical response rate was 47.4% with treatment vs 22% for placebo, with an odds ratio of 1.75.[27]

In a meta-study comprising 3480 patients with treatment-resistant depression randomized to adjunctive atypical antipsychotics, response rates had an odds ratio of 1.69 compared to placebo.  The overall response rate was 45%.  Roughly similar response rates for olanzapine, risperidone, quetiapine, and aripiprazole.[33]


Bottom line: bromantane is a Russian drug with unknown mechanism of action. It has never been tested on humans for depression.  It has been reported to improve “asthenia” (a catch-all term for mood disorders) in one uncontrolled study.

In an uncontrolled Russian study of 728 patients with asthenic disorders, 90% of patients responded according to the CGI-I scale.[61]


Bottom line: buprenorphine is an opioid used to treat opioid addiction; it has been reported to improve symptoms in treatment-resistant depression.

In an open-label study of 13 elderly patients with treatment-resistant major depression, buprenorphine resulted in a 61% response rate according to the MADRS scale after 8 weeks.[40]

In an uncontrolled study of 7 patients with treatment-resistant major depression, 4 (57%) had a full remission after treatment with buprenorphine.[66]


Bottom line: one study found that chromium supplementation helped with atypical depression, but it didn’t replicate.

Chromium picolinate caused response in 70% of patients with atypical depression; 0% of placebo responded. N=15.[5]

Replication study, N=113, failed to find more response than placebo in atypical depression patients treated with chromium, but chromium did reduce carbohydrate cravings.[9]


Bottom line: cycloserine is an antibiotic which also seems to be effective in psychiatric disorders; it has been reported to improve symptoms in treatment-resistant depression.

In a randomized study of 26 patients with treatment-resistant depression given high-dose D-cycloserine or placebo, 54% in the treatment group responded according to the HAM-D score, compared to 15% of placebo.[36]

Deep Brain Stimulation

Bottom line: deep brain stimulation involves surgically implanting an electrode in the brain. DBS to the subcallosal cingulate gyrus is highly effective against treatment-resistant depression in uncontrolled studies, but hasn’t been confirmed in controlled studies.

In 20 patients with treatment-resistant depression who received deep brain stimulation to the subcallosal cingulate gyrus, the HAM-D response rate after 1 year was 62.5%, after 2 years, 46.2%, and after 3 years, 75%.[21]

In an uncontrolled study of 6 patients with treatment-resistant depression receiving deep brain stimulation to the subgenual cingulate region (Brodmann 25), at 6 months 4 patients (67%) were responders according to the HDRS-17 rating score.[24]

In an uncontrolled study of 10 patients with treatment-resistant depression receiving deep brain stimulation to the nucleus accumbens, there was a 50% response rate according to the HAM-D scale at 12 months.[67]

In an uncontrolled study of 7 patients with treatment-resistant depression receiving deep brain stimulation to the supero-lateral branch of the medial forebrain bundle, all of them responded according to the HAM-D scale after a week; at 33 weeks follow-up, 67% were responders.[68]

In an uncontrolled study of 8 patients with treatment-resistant depression treated with deep brain stimulation to the subgenual cingulate gyrus (Brodmann 24-25), at 6 months the response rate was 87%.[69]

In a sham-controlled trial of 30 patients with treatment-resistant depression treated with ventral capsule/ventral striatum deep brain stimulation or control, there was no difference in response rates according to MADRS criteria.[50]

In a systematic review of 22 studies of deep brain stimulation for depression, reported response rates are 40-70%, but most of these are from open-label trials.[70]


Bottom line: methylfolate, a dietary supplement, may work on treatment-resistant depression.  It may be relevant that depressives are more likely to be folic acid deficient than healthy people.

Folinic acid, in an uncontrolled study of 22 patients with depression unresponsive to SSRIs, had a 33% response rate according to the HAM-D rating scale.[17]

Methylfolate at 15 mg/day in a controlled study of 75 patients with depression unresponsive to SSRIs had a response rate on the HAM-D rating scale of 32.3% compared to a placebo response rate of 14.6%, a significant difference.[20]

In a retrospective study of 242 patients either given methylfolate + SSRI or SSRI alone, the patients given methylfolate were significantly more likely to experience major improvement (according to CGI rating) compared to the SSRI-only group.[71]


Bottom line: ketamine is an NMDA antagonist and anaesthetic drug, used intravenously as an experimental treatment for depression. Ketamine very rapidly produces high response rates in treatment-resistant depression, but these seem to be short-lived.

In a placebo-controlled trial of 18 subjects with treatment-resistant major depression, receiving an intravenous infusion of ketamine or placebo, 71% responded the day after treatment, according to the HAM-D score, and 35% remained responders after a week.[25]

In a placebo-controlled trial of 73 patients with treatment-resistant depression, receiving an intravenous infusion of ketamine or active control, 64% responded the day after treatment, significantly more than controls.[29]

In a review of 20 studies of ketamine for depression, response rates at 4 hours averaged 77% and 43% at 72 hours; no studies had follow-up times of more than two weeks.[72]


Bottom line: lithium improves symptoms of treatment-resistant depression.

In a meta-analysis of 9 trials comprising 234 patients with treatment-resistant depression, randomized to adjunctive lithium or placebo, 45% of treated patients responded according to the HAM-D scale, compared to 18% of controls, p < 0.0001.[37]


Bottom Line: Modafinil improves symptoms in depression when added to other treatment.

Modafinil had significant effects in atypical depression: mean HAM-D changed from 34 to 9.7, n = 89.[11]

In a systematic review of studies of modafinil in unipolar and bipolar depression,  from 6 RCTs, modafinil significantly improved depression scores and remission rates relative to placebo.[73]

Nitrous Oxide

Bottom line: a single use of nitrous oxide has been reported to have a short-term effect on depression.

In a placebo-controlled, blinded trial of nitrous oxide inhalation in 20 patients with treatment-resistant depression, 20% of treated patients had a response on the HAM-D after 24 hours, compared to 5% placebo responders.[44]


Bottom line: pramipexole is a dopamine agonist used for Parkinson’s disease; some uncontrolled studies report that it improves symptoms in treatment-resistant depression.

In an uncontrolled study of 37 patients with treatment-resistant depression given adjunctive pramipexole, 67.7% of patients were responders according to the MADRS score and 74% on the Clinical Global Impression score.[31]

In an uncontrolled study of 10 patients with treatment-resistant depression given adjunctive pramipexole, 60% responded on the MADRS score.[41]


Bottom line: psilocybin may improve depressive symptoms but the evidence is very preliminary.

In an uncontrolled study of 12 patients with treatment-resistant depression given two doses of psilocybin, depressive symptoms according to the QIDS score were significantly reduced one week and three months after treatment.[24]


Bottom line: SAM-E is a dietary supplement which improves symptoms in treatment-resistant depression.

In an open-label study of thirty patients with treatment-resistant depression, SAM-E supplementation caused a 50% response rate and 43% remission rate, as measured by the HAM-D rating score.[22]

In a randomized trial of 75 patients with treatment-resistant depression, 36% of patients given 800 mg/day SAM-E had a response according to the HAM-D score, while only 17.6% of placebo patients did.[23]

In an open-label study of 9 patients with treatment-resistant depression, 22% responded to SAM-E according to the HAM-D score.[45]


Bottom line: selegiline has a high response rate in atypical and treatment-resistant depression, as well as depression in general.  It is an MAOI but doesn’t cause the dangerous “cheese reaction” of other MAOIs.

In an open trial of 17 patients with atypical depression, 59% responded to selegiline.  Selegiline was superior to placebo in a separate double-blind study.[15]

In a randomized study of 44 patients with depression, 50% responded according to the HAM-D score, compared to 13.6% of placebo.  67% of atypical patients responded to selegiline, compared to 28.6% in placebo, n = 13.[16]

In a randomized study of 177 patients with depression randomized to transdermal selegiline or placebo, HAM-D scores were significantly lower in the treatment group.  37% of patients responded according to the CGI score.[46]

In a randomized study of 16 treatment-resistant older depressive patients, high-dose selegiline significantly improved scores on the HAM-D compared to placebo.[47]

In a randomized study of 365 patients with depression treated with a selegiline patch or placebo, selegiline caused significantly (p = 0.03) more improvement in HAM-D scores; the selegiline group had a 48% response rate according to the MADRS score, compared to a 30% response rate for placebo, a statistically significant difference.[48]

In a randomized study of 27 patients randomized to selegiline or placebo, 71% of selegiline patients responded on the HAM-D rating scale, compared to only 15% of placebo, a significant difference.[49]


Bottom line: T3 is a thyroid hormone. It has been reported to improve symptoms in treatment-resistant depression, even in patients who are not hypothyroid.

In an uncontrolled study of 12 subjects with treatment-resistant depression, T3 (triiodothyronine) resulted in 42% of patients responding according to HAM-D criteria, and 25% experiencing remission.[32]

In an uncontrolled study of 20 patients with treatment-resistant depression, T3 augmentation resulted in 35% of patients responding according to HAM-D criteria.  All 5 subjects with atypical depression responded.[42]


Bottom line: T4 is a thyroid hormone.  It may improve symptoms in treatment-resistant depression even in people who are not hypothyroid.

In an uncontrolled study of 17 patients with treatment-resistant depression, high-dose T4 resulted in 58% of patients having a full remission.[38]

In an uncontrolled study of nine patients with treatment-resistant depression, high-dose T4 resulted in 56% of patients responding according to the HAM-D scale.[43]

In a meta-analysis of eight controlled studies comprising 232 euthyroid patients with refractory depression, T3 augmentation was significantly more likely to result in a response (RR = 2.09).[54]


Bottom line: tianeptine is an antidepressant with an unusual mechanism of action: probably stimulating BDNF release. It works about as well as other antidepressants.

In a placebo-controlled study of 123 depressed patients, tianeptine did not cause a significantly higher response rate than placebo according to the MADRS score, but did cause a significant drop in mean MADRS score.[53]

Tianeptine, in a randomized trial of 265 patients with anxious depression, caused a 78% response rate on the MADRS score, while amitriptyline caused an 83% response rate, a non-statistically-significant difference. Both treatments were safe, and tianeptine caused less sedation.[52]

In a randomized study of 387 patients given tianeptine or fluoxetine, MADRS response rates were 58% and 56%, respectively; there was no statistically significant difference in efficacy or safety.[54]

In a randomized study of 277 patients randomized to tianeptine or paroxetine, there was no significant difference in MADRS score, other efficacy parameters, or safety parameters.[55]

In a retrospective study of 1858 depressed patients treated with tianeptine, 61% were responders according to the MADRS score.[56]


Bottom line: traxoprodil is an experimental NMDA-antagonist compound which was reported to have a high response rate in treatment-resistant depression, but testing was discontinued due to cardiac adverse events.

In a study of 30 patients with treatment-resistant major depression randomized to the NMDA antagonist traxoprodil or placebo, 60% of treated patients responded according to the HAM-D scale, compared to 20% placebo.  Treatment also produced better response in MADRS scores than placebo.[34] Testing of traxoprodil was discontinued because of an increase in QT interval.[35]

Vagus Nerve Stimulation

Vagus nerve stimulation involves surgically implanting an electrical device under the skin of the chest; it has positive effects on treatment-resistant depression, but takes a while to work.

In an open-label study of 59 patients with treatment-resistant major depression, vagus nerve stimulation caused a 31% response rate within 3 months and 44% within a year, measured on the HAM-D rating scale.[18]

In a controlled trial of 235 patients with treatment-resistant depression or bipolar, randomized to vagus nerve stimulation or sham treatment, there was no significant difference in response rates after 10 weeks.[26]

In a one-year trial of 329 patients with treatment-resistant depression, vagus nerve stimulation resulted in a 27% response rate for vagus nerve treatment, compared to 13% for control, significant at p< 0.011.[28]

In a meta-analysis of six randomized controlled trials comprising 1225 patients with treatment-resistant depression, the MADRS response rate at 96 weeks was 32% for vagus nerve stimulation compared to 14% for treatment as usual, a statistically significant odds ratio at 3.19.[39]


Bottom line: Viloxazine is a norepinephrine reuptake inhibitor which has stimulant effects.  It’s unclear whether it’s an effective antidepressant.

In a randomized study of 129 depressed patients, viloxazine and imipramine caused a statistically significant improvement from baseline; there was no significant difference between drugs.[57]

In a study of 62 severely depressed patients randomized to viloxazine or citalopram, both had a significant improvement in mean MADRS score; there was no significant difference between drugs.[58]

In a study of 21 depressed elderly patients randomized to viloxazine or placebo, viloxazine caused a larger response on the Cronholm-Ottosson Depression Rating Scale than placebo after three weeks.[59]

In a study of 43 depressed patients randomized to viloxazine or placebo over 7 weeks, there was no significant difference in HAM-D scores between treatment and placebo.[60]


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Preventing Respiratory Tract Infections

Epistemic Status: pretty confident, typical lit review.  

This report was commissioned by one of my freelancing clients and published by permission.

Bottom Lines

Bacterial immunostimulants are safe and effective in preventing respiratory infections, cutting the risk of infection by 40-50%.

Antiseptic mouthwash and oral care cut the risk of respiratory infection in elderly or ventilator-bound patients by 50-60%, and may also have effects on healthy adults.

Probiotics probably reduce the duration, but not the incidence, of respiratory infections and improve immune function.

Alfa-interferon may reduce the risk or duration of colds, but causes nasal irritation and bleeding that may be more severe than the colds themselves.

Meditation, moderate exercise, and writing personal narratives may reduce the incidence or severity of respiratory tract infections and improve immune function. Spending time in forests and getting massages may improve immune function.

Echinacea and ginseng extracts have mixed and equivocal evidence of effectiveness at preventing respiratory tract infections.

Bacterial Immunostimulants

Bacterial immunostimulants are used in Europe to prevent recurrent respiratory infections. These are made of lysed bacterial cells, and cause both a cellular and humoral immune response, making people more resilient to infections.  A common bacterial immunostimulant, Broncho-Vaxom, can be ordered online, though I can’t vouch for the sites. There are a large number of studies, of which the following are only a selection, confirming that immunostimulants significantly reduce the incidence of recurrent respiratory infections. 

Broncho-Vaxom taken 10 consecutive days per month for three months, tested in a double-blind, placebo-controlled trial of 200 children in a Mexican girls’ orphanage, reduced the incidence of respiratory tract infections by 50%.[1]

In a randomized controlled study of 357 elderly patients with chronic bronchitis, Broncho-Vaxom taken 10 consecutive days per month for three months decreased respiratory infections by 28%.[2]

In a systematic review comprising 851 children, 32% of children treated with Broncho-Vaxom had at least 3 respiratory infections in a six-month period, compared to 58.2% of controls, p<0.001.[3]

In a meta-analysis of 15 randomized trials comprising 2557 patients, polyvalent mechanical bacterial lysate (an extract of multiple bacteria) reduced the incidence of respiratory tract infections by 51%.  These include studies on adults as well as children.[4]

Cochrane’s review, comprising 36 placebo-controlled studies totaling 4060 children, finds that immunostimulants reduce the incidence of respiratory infections by 40% in susceptible children (those who have 3 or more respiratory infections a year.)  Most trials indicated no adverse effects or low rates of adverse effects.[5]

While most of the evidence on bacterial immunostimulants is in children or the elderly, the mechanism of action should be applicable to healthy adults as well, except that it may not have as large an effect if your immune system is stronger.  They are safe and well-tolerated, and the evidence that they prevent respiratory infections in the populations studied is quite robust and consistent.

Oral Hygiene

Using antiseptic mouthwash or even just gargling with water may prevent respiratory infections. There is a lot of evidence for this in the context of patients in the ICU or elderly people in nursing homes, whose oral hygiene is probably worse than the typical healthy adult, but mouthwash makes a large difference there.  There are a few studies on healthy adults suggesting that oral care helps them as well.  Chlorhexidine mouthwash is prescription-only; you can get it from your dentist if you have gingivitis.  

Chlorhexidine gluconate mouthwash reduced respiratory tract infections in patients undergoing heart surgery by 69%.[6]

The rate of nosocomial pneumonia in patients undergoing heart surgery was reduced by 52% in patients given chlorhexidine mouthwash.[7]

A meta-analysis of randomized controlled trials of chlorhexidine gluconate mouthwash in patients on ventilators found that it reduced the risk of pneumonia by 47%.[8]

Oral hygiene (help brushing after meals and regular visits to a dentist) reduced the incidence of pneumonia in nursing homes by 59%.[9]

Gargling with water, in a study on 387 healthy adults, reduced the incidence of upper respiratory tract infections in a 1-month period by 36% compared to controls.[10]


Alpha-interferon is a protein involved in the innate immune response against viral infection.  Taken as a nasal spray, it can stimulate the immune system against respiratory infections. However, it also has side effects, such as nasal irritation and bleeding.  Interferon is not prescribed as a preventative because of its side effects; however, it is sold online, e.g. here.

In a placebo-controlled study of 448 adults, intranasal alpha-interferon spray given at the onset of a cold in a family member significantly reduced the risk of colds. (1.3% of treated vs. 15.1% of placebo got colds within 2 weeks after spraying, p=0.003).  Overall, this led to a 39% reduction in number of respiratory infections in the treatment group.[27]

In a placebo-controlled study of 229 adults given intranasal alpha-interferon spray over six months, the treatment group got 41% fewer colds.[28]

In a study of 304 adults given intranasal alpha-interferon or placebo, 8.5% of placebo-treated patients got a cold over a 22-day period compared to no interferon-treated. (p = 0.0002).  However, the treatment group didn’t get fewer respiratory infections overall.[29]

Low-dose interferon-alpha spray didn’t significantly reduce the incidence of respiratory infections in a randomized trial of 200 healthy adults.  It did significantly reduce the incidence of moderate-to-severe symptoms in those who had serologically confirmed viral illnesses.[30]

In a randomized trial of 220 subjects with confirmed colds, mucus was 66% less likely to contain cold viruses at day 5-7 in treated patients than controls, and the median duration of colds was significantly longer (9 days) in the placebo group than the treated group (6 days).  Treated patients were significantly more likely to have blood in their mucus than placebo.[31]


Probiotics, especially Lactobacillus and Bifidobacterium species (the kind found in yogurt) have been found to reduce the duration of respiratory tract infections, though not their incidence. Probiotics sometimes enhance immune parameters such as lymphocyte count and NK activity.

In a meta-study of 14 randomized controlled studies comprising 3451 participants, the pooled risk of having an upper respiratory tract infection when given a probiotic was 47% lower compared to placebo.[56]

In a meta-study of 14 RCTs, ten out of the fourteen found no significant difference in incidence of respiratory tract infections between probiotic and placebo, but five out of six found significant reductions in symptom severity.[57]

In a systematic review of 20 RCTs, probiotics significantly decreased the duration of respiratory tract infections (by about a day) and resulted in significantly fewer days absent from school/work due to respiratory tract infections.[58]

In a Cochrane review of 12 RCTs, probiotics significantly reduced the duration and incidence of upper respiratory tract infections, in both children and adults; however, the quality of evidence was low.[59]

In a study of 1072 elderly volunteers randomized to a fermented dairy product containing Lactobacillus casei or a control dairy product, treated patients had significantly shorter duration (by 4 days) of upper respiratory tract infection. [60]

In a study of 47 military recruits randomized either to a fermented dairy product containing Lactobacillus casei or a placebo dairy product, there was no difference in the incidence of respiratory infections.[61]

In 30 healthy elderly subjects, Bifidobacterium lactis but not control significantly increased the number of lymphocytes and NK activity.[62]

In a controlled study of 50 healthy Taiwanese subjects aged 40-81, Bifidobacterium lactis HN019 significantly increased NK and CD4+ activity over a period of 6 weeks, while milk alone did not.[63]

In one study on 20 healthy subjects aged 40-65, Lactobacillus casei strain Shirota had no effect on immune parameters.[64]

However, in a study of 30 elderly subjects, Lactobacillus casei strain Shirota caused significantly higher NK activity compared to placebo. [65]

And in a study of 20 subjects, both elderly and young, Lactobacillus casei strain Shirota caused significantly higher NK activity compared to baseline or placebo.[66]

Fermented dairy products containing probiotics are safe and probably somewhat helpful for promoting recovery from respiratory infections.

Psychological Interventions

It’s well known that psychological stress can weaken the immune system; stressful events like bereavement or studying for exams, as well as depression and anxiety disorders, increase susceptibility to infection. Some psychological interventions also reduce the risk of respiratory infections or have more indirect immune-stimulating effects.  These include meditation, written emotional expression (writing about traumatic and emotional experiences in your own life), massage, and forest bathing (spending several hours walking mindfully in a forest.)


An 8-week mindfulness meditation course significantly increased (p < 0.05) antibody titers in response to a flu vaccine.[38]

An 8-week meditation course reduced days of work lost to respiratory infections by 76% (p < 0.001) and global severity was significantly lower for meditation than control (p =0.004).[39]

A guided relaxation exercise with imagery increased NK activity (p < 0.05) in an uncontrolled study on 10 healthy subjects.[40]

In a randomized trial of 48 patients with HIV, those enrolled an 8-week mindfulness meditation course had significantly (p = 0.02) higher CD4+ T lymphocyte counts than patients in the placebo 1-day course.[41]

In a trial of 28 patients with breast cancer randomized to either a 10-week mindfulness-based stress reduction class or no intervention, the treatment group had significantly more lymphocyte proliferation than the controls.[42]

Written Emotional Expression

Written emotional expression — being prompted to write about “the most traumatic and emotional experiences of their lives” — for thirty minutes at a time for four consecutive days — in HIV patients raised their CD4 count gradually over a period of 6 months and instantly dropped their viral load, p=0.024 and p=0.035 respectively.[43]

40 medical students randomly assigned to write about traumatic personal experiences or control topics for 4 consecutive daily sessions had significantly higher antibody titers in response to a hepatitis C vaccine.[44]

In a study of 50 healthy undergraduates randomized to either writing about personal trauma or control topics for 4 consecutive daily sessions, those who wrote about trauma were significantly less likely to visit the health center for illness, and had stronger lymphocyte increases in response to mitogens.[45]

Forest Bathing

Shinrinyoku, or “forest bathing” — a three-day trip to a forest, spending a total of 3 hours walking outside — increased NK counts significantly (p < 0.01) while a three-day city tourist visit did not.[46]

Out of 12 male subjects taken on a 3-day “forest bathing” trip, 11 had significantly increased NK activity (by about 50%)[47]


Back massages, but not progressive muscle relaxation therapy, significantly increased (p<0.05) CD4 count in adolescent girls with HIV.[48]

Full-body massage in women undergoing radiation therapy for breast cancer significantly attenuated the drop in NK activity compared to controls.[49]

Compared to light touch, Swedish massage significantly increased the number of lymphocytes in 53 healthy adults.[50]

Compared to no massage, a month of daily massage significantly increased NK count, NK activity, and CD8 lymphocyte count in 29 gay men.[51]


Moderate exercise can prevent respiratory tract infections and improve other measures of immune function.  However, very intense exercise (as in marathon training) increases susceptibility to infection.

Cardiovascular exercise, but not flexibility exercise, prolonged seroprotection from the flu vaccine (increasing the percentage of subjects who were still protected at 24 weeks by 30-100%.)  People in the flexibility group reported no more respiratory tract infections, but reported them as being less severe (p = 0.03).[52]

An 8-week exercise course reduced sick days from respiratory infections by 52% (p = 0.042).[39]

A program of treadmill exercise in elderly women significantly (p < 0.05) increased NK activity relative to sedentary controls.[53]

An exercise program (brisk walking 5 times a week) significantly (p < 0.001) increased NK activity and cut the duration of respiratory infections in half compared to control in a study of 36 sedentary women.[54]

Endurance athletes, compared to the rest of the population, experience more upper respiratory tract infections around training and competition. In non-athletes, higher rates of physical activity are associated with lower risk of upper respiratory tract infections.[55]


Extract from Echinacea purpurea or Echinacea angustifolia (purple coneflower) reduces the incidence of respiratory infections in some but not all studies.  The largest and most stringent meta-analyses have concluded that echinacea extracts don’t prevent respiratory infections, but it’s possible that some preparations are effective, more likely alcoholic extracts than pressed juice.

A meta-analysis comprising 1630 patients found that echinacea reduced the probability of a patient contracting a cold by 58%, p <0.001, and reduced the duration of colds by 1.4 days, p < 0.01.[11]

A subsequent meta-analysis of 6 clinical studies comprising 2458 participants found that echinacea caused a 35.1% lower risk of recurrent respiratory tract infection than placebo.  Alcoholic extracts reduced the risk of recurrent infections by 45%, while pressed juices did not have a significant effect.[21]

A meta-analysis of 14 studies  where subjects were experimentally infected with rhinovirus, comprising a total of 2040 patients, found that the likelihood of experiencing a clinical cold was 55% lower in patients treated with echinacea than controls, and the duration of a cold was 1.4 days lower with echinacea vs. placebo.[12]

In a structured meta-analysis of 9 studies of echinacea on the common cold, the only two studies that met all criteria for high-quality experimental design was negative, while the other studies, which tended to have positive results, usually lacked proof of blinding.[24]

In a Cochrane review of 24 double-blind trials comprising 4631 subjects found that echinacea extracts had no significant effect on preventing colds, though there were non-significant trends towards an effect.[26]

A study of 430 young children randomized to echinacea, propolis and vitamin C extract or placebo for 12 weeks found a 50% reduction in the number of respiratory tract infections per child in the treatment group.[13]

A randomized controlled study of 302 adults at military institutions or an industrial plant found no difference between echinacea ethanolic extract and placebo in the incidence of respiratory tract infections over a 12 week period.[14]

In a randomized controlled study of 432 volunteers experimentally given rhinovirus, echinacea alcohol tincture had no effect on the incidence or severity of colds.[15]

A randomized controlled trial of 128 adults given echinacea pressed juice or placebo at the onset of a cold found no significant difference in symptom severity or duration.[16]

In a randomized controlled trial of 282 adults given echinacea tincture or placebo, symptom scores were 23% lower for echinacea than placebo.[17]

In a randomized study of 524 children randomized to echinacea juice or placebo after getting a single respiratory infection, the treatment group was 24% less likely to get another respiratory infection over a 4-month observation period.[18]

In a randomized controlled trial of 90 hospital staff members, those treated with echinacea did not significantly alter the risk of upper respiratory tract infections.[19]

In a randomized study of 48 adults infected with the common cold and given echinacea pressed juice or placebo, echinacea did not significantly reduce incidence of colds.[22]

In a randomized study of 719 adults with new-onset common colds, echinacea extract didn’t significantly reduce severity or duration.[23]

In a randomized study of 755 subjects given either an alcohol extract of echinacea or placebo, the echinacea-treated patients had 21% fewer respiratory infections over a period of 4 months.[25]

Echinacea extract is safe, and may have some effect on preventing respiratory infections, but the evidence is inconsistent and equivocal.


There are some studies providing positive evidence that ginseng reduces the incidense of respiratory infections, but the meta-studies show that overall its effects are non-significant.

A systematic review comprising 747 patients found that there was “insufficient evidence to conclude that ginseng reduces the incidence or severity of common colds” — there was a trend towards reduced incidence of colds, but this wasn’t statistically significant.[32]

In a randomized study of 323 adults with a history of at least two colds in the past season given American ginseng (Panax quinquefolium) extract or placebo reduced the average number of colds per person in a four-month period by 27%, from 0.93 in the placebo group to 0.68 in the treated group.[33]

In a randomized study of institutionalized elderly subjects treated with American ginseng extract or placebo, treated patients had 85% less chance of getting influenza (p < 0.033) and 89% less chance of getting any acute respiratory infection (p = 0.009).[34]

In a study of 323 healthy volunteers randomized to COLD-FX (a ginseng extract) or placebo, there was no effect from the treatment on the number or duration of colds.[35]

In a study of 783 adults treated with American ginseng extract or placebo, ginseng did not significantly affect the number of laboratory-confirmed respiratory infections.[36]

Panax ginseng extract significantly (p < 0.001) increased NK cytotoxicity (a measure of immune function) over placebo.[37]

Ginseng extract is safe and may have some immunostimulant activity, but there’s only weak evidence that it prevents respiratory infections.



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[21]Schapowal, Andreas, Peter Klein, and Sebastian L. Johnston. “Echinacea reduces the risk of recurrent respiratory tract infections and complications: a meta-analysis of randomized controlled trials.” Advances in therapy 32.3 (2015): 187-200.

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[28]Douglas, Robert M., et al. “Prophylactic efficacy of intranasal alpha2-interferon against rhinovirus infections in the family setting.” New England Journal of Medicine 314.2 (1986): 65-70.

[29]Farr, B. M., et al. “Intranasal interferon-alpha 2 for prevention of natural rhinovirus colds.” Antimicrobial agents and chemotherapy 26.1 (1984): 31-34.

[30]Bennett, Alayne L., et al. “Low‐dose oral interferon alpha as prophylaxis against viral respiratory illness: a double‐blind, parallel controlled trial during an influenza pandemic year.” Influenza and other respiratory viruses 7.5 (2013): 854-862.

[31]Hayden, FREDERICK G., D. L. Kaiser, and J. K. Albrecht. “Intranasal recombinant alfa-2b interferon treatment of naturally occurring common colds.” Antimicrobial agents and chemotherapy 32.2 (1988): 224-230.

[32]Seida, Jennifer Krebs, Tamara Durec, and Stefan Kuhle. “North American (Panax quinquefolius) and Asian Ginseng (Panax ginseng) preparations for prevention of the common cold in healthy adults: a systematic review.” Evidence-Based Complementary and Alternative Medicine 2011 (2011).

[33]Predy, Gerald N., et al. “Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized controlled trial.” Canadian Medical Association Journal 173.9 (2005): 1043-1048.

[34]Mcelhaney, Janet E., et al. “A Placebo‐Controlled Trial of a Proprietary Extract of North American Ginseng (CVT‐E002) to Prevent Acute Respiratory Illness in Institutionalized Older Adults.” Journal of the American Geriatrics Society 52.1 (2004): 13-19.

[35]Predy, Gerry N., et al. “Immune modulating effects of daily supplementation of COLD-fX (a proprietary extract of North American ginseng) in healthy adults.” Journal of Clinical Biochemistry and Nutrition 39.3 (2006): 162-167.

[36]McElhaney, Janet E., et al. “Efficacy and Safety of CVT-E002, a proprietary extract of Panax quinquefolius in the prevention of respiratory infections in influenza-vaccinated community-dwelling adults: a multicenter, randomized, double-blind, and placebo-controlled trial.” Influenza research and treatment2011 (2011).

[37]Scaglione, F., et al. “Immunomodulatory effects of two extracts of Panax ginseng CA Meyer.” Drugs under experimental and clinical research 16.10 (1990): 537-542.

[38]Davidson, Richard J., et al. “Alterations in brain and immune function produced by mindfulness meditation.” Psychosomatic medicine 65.4 (2003): 564-570.

[39]Barrett, Bruce, et al. “Meditation or exercise for preventing acute respiratory infection: a randomized controlled trial.” The Annals of Family Medicine 10.4 (2012): 337-346.

[40]Zachariae, R., et al. “Effect of psychological intervention in the form of relaxation and guided imagery on cellular immune function in normal healthy subjects.” Psychotherapy and Psychosomatics 54.1 (1990): 32-39.

[41]Creswell, J. David, et al. “Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: A small randomized controlled trial.” Brain, behavior, and immunity 23.2 (2009): 184-188.

[42]McGregor, Bonnie A., et al. “Cognitive–behavioral stress management increases benefit finding and immune function among women with early-stage breast cancer.” Journal of psychosomatic research 56.1 (2004): 1-8.

[43]Petrie, Keith J., et al. “Effect of written emotional expression on immune function in patients with human immunodeficiency virus infection: a randomized trial.” Psychosomatic Medicine66.2 (2004): 272-275.

[44]Petrie, Keith J., et al. “Disclosure of trauma and immune response to a hepatitis B vaccination program.” Journal of consulting and clinical psychology 63.5 (1995): 787.

[45]Pennebaker, James W., Janice K. Kiecolt-Glaser, and Ronald Glaser. “Disclosure of traumas and immune function: health implications for psychotherapy.” Journal of consulting and clinical psychology 56.2 (1988): 239.

[46]Li, Qing. “Effect of forest bathing trips on human immune function.” Environmental health and preventive medicine 15.1 (2010): 9-17.

[47]Li, Q., et al. “Forest bathing enhances human natural killer activity and expression of anti-cancer proteins.” International journal of immunopathology and pharmacology 20.2_suppl (2007): 3-8.

[48]Diego, Miguel A., et al. “HIV adolescents show improved immune function following massage therapy.” International Journal of Neuroscience 106.1-2 (2001): 35-45.

[49]Billhult, A., et al. “The effect of massage on immune function and stress in women with breast cancer—a randomized controlled trial.” Autonomic Neuroscience 150.1 (2009): 111-115.

[50]Rapaport, Mark Hyman, Pamela Schettler, and Catherine Bresee. “A preliminary study of the effects of a single session of Swedish massage on hypothalamic–pituitary–adrenal and immune function in normal individuals.” The Journal of Alternative and Complementary Medicine 16.10 (2010): 1079-1088.

[51]Ironson, Gail, et al. “Massage therapy is associated with enhancement of the immune system’s cytotoxic capacity.” International Journal of Neuroscience 84.1-4 (1996): 205-217.

[52]Woods, Jeffrey A., et al. “Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial.” Journal of the American Geriatrics Society 57.12 (2009): 2183-2191.

[53]Crist, Douglas M., et al. “Physical exercise increases natural cellular-mediated tumor cytotoxicity in elderly women.” Gerontology 35.2-3 (1989): 66-71.

[54]Nieman, D. C., et al. “The effects of moderate exercise training on natural killer cells and acute upper respiratory tract infections.” International journal of sports medicine 11.06 (1990): 467-473.

[55]Moreira, André, et al. “Does exercise increase the risk of upper respiratory tract infections?.” British medical bulletin90.1 (2009): 111-131.

[56]Hao, Qiukui, et al. “Probiotics for preventing acute upper respiratory tract infections.” Cochrane Database Syst Rev 9.9 (2011).

[57]Vouloumanou, Evridiki K., et al. “Probiotics for the prevention of respiratory tract infections: a systematic review.” International journal of antimicrobial agents 34.3 (2009): 197-e1.

[58]King, Sarah, et al. “Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis.” British Journal of Nutrition 112.1 (2014): 41-54.

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[60]Guillemard, E., et al. “Consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 reduces the duration of respiratory infections in the elderly in a randomised controlled trial.” British journal of nutrition103.1 (2010): 58-68.

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The Right to Be Wrong

Epistemic Status: pretty confident

Zvi recently came out with a post “You Have the Right to Think”, in response to Robin Hanson’s “Why be Contrarian?”, itself a response to Eliezer Yudkowsky’s new book Inadequate Equilibria.  All of these revolve around the question of when you should think you “know better” or can “do better” than the status quo of human knowledge or accomplishment.  But I think there’s a lot of conflation of different kinds of “should” going on.

Yudkowsky’s book, and Hanson’s post, are mostly about epistemic questions — when are you likely to get the right answer by examining an issue yourself vs. trusting experts?

Inadequate Equilibria starts with the canonical example of when you can’t outperform the experts — betting on the stock market — and explains about efficient markets, and then goes on to look into what kinds of situations deviate from efficient markets such that an individual could outperform the collective intelligence of everyone who’s tried so far.  For instance, you might well be able to find a DIY treatment for your health problem that works better than anything your doctor would prescribe you, in certain situations — but due to the same incentive problems that prevented medical consensus from finding that treatment, you probably wouldn’t be able to get it to become the standard of care in the mass market.

Hanson mostly agrees with Yudkowsky’s analysis, except on some points where he thinks the argument for individual judgment being reliable is weaker.

Zvi seems to be talking about a different thing altogether when he talks about the “rights” that people have.

When he says “You have the right to disagree even when others would not, given your facts and reasoning, update their beliefs in your direction” or “You have the right to believe that someone else has superior meta-rationality and all your facts and reasoning, and still disagree with them”, I assume he’s not saying that you’d be more likely to get the right answer to a question in such cases — I think that would be false.  If we posit someone who knows better than me in every relevant way, I’d definitionally be more likely to get the right answer by listening to her than disagreeing with her!

So, what does it mean to have a right to disagree even when it makes you more likely to be wrong?  How can you have a right to be wrong?

I can think of two simple meanings and one subtle meaning.

The Right To Your Opinion

The first sense in which you “have a right to be wrong” is social and psychological.

It’s a basic tenet of free and pluralistic societies that you have the legal right to believe a false thing, and express your belief.  It is not a crime to write a horoscope column.  You can’t be punished by force just for being wrong.  “Bad argument gets counterargument.  Does not get bullet.  Never.  Never ever never for ever.”

And tolerant, pluralist cultures generally don’t believe in doing too much social punishment of people for being wrong, either.  It’s human to make mistakes; it’s normal for people to disagree and not be able to resolve the disagreement; if you shame people as though being wrong is horribly taboo, your community is going to be a more disagreeable and stressful place. (Though some communities are willing to make that tradeoff in exchange for higher standards of common knowledge.)

If you are regularly stressed out and scared that you’ll be punished by other people if they find out you believe a wrong thing, then either you’re overly timid or you’re living in an oppressive environment.  If fear of punishment or ostracism comes up regularly when you’re in the process of forming an opinion, I think that’s too much fear for critical thinking to work properly at all; and the mantra “I have the right to my opinion” is a good counterweight to that.

Discovery Requires Risking Mistakes

The second sense in which you have a “right to be wrong” is prudential.

You could ensure that you’d never be wrong by never venturing an opinion on anything.  But going all the way to this extreme is, of course, absurd — you’d never be able to make a decision in your life!  The most effective way to accomplish any goal always involves some decision-making under uncertainty.

And attempting more difficult goals involves more risk of failure. Scientists make a lot of hypotheses that get falsified; entrepreneurs and engineers try a lot of ideas that don’t work; artists make a lot of sketches that wind up in the wastebasket.  Comfort with repeated (hopefully low-stakes) failure is essential for succeeding at original work.

Even from a purely epistemic perspective, if you want to have the most accurate possible model of some part of the world, the best strategy is going to involve probabilistically believing some wrong things; you get information by testing guesses and seeing where you’re mistaken.  Minimizing error requires finding out where your errors are.

Note, though, that from this prudential perspective, it’s not a good idea to have habits or strategies that systematically bias you towards being wrong.  In the “right to your opinion” sense, you have a “right” to epistemic vices, in that nobody should be attacking you for them; but in this goal-oriented sense, they’re not going to help you succeed.

Space Mom Accepts All Her Children

The third sense in which you have a “right to be wrong” is a little weirder, so please bear with me.

There’s a mental motion you can do, when you’re trying to get the right answer or do the right thing, where you’re trying very hard to stay on the straight path, and any time you slip off, you violently jerk yourself back on track.  You have an aversion to wrongness.

I have an intuition that this is…inefficient, or mistaken, somehow.

Instead, there’s a mental motion where you have peripheral vision, and you see all the branching paths, and consider where they might go — all of them are possible, all of them are in some cosmic sense “okay” — and you perform some kind of optimization procedure among the paths and then go along the right path smoothly and without any jerks.

Or, consider the space of all mental objects, all possible thoughts or propositions or emotions or phenomena or concepts.  Some of these are true statements; some of them are false statements. Most of them are unknown, or not truth-apt in the first place.  Now, you don’t really want to label the false ones as true — that would just be error.  But all of them, true or false or neither or unknown, are here, hanging like constellations in this hypothetical heaven. You can look at them, consider them, call some of them pretty.  You don’t need to have an aversion response to them. They are “valid”, as the kids say; even if they don’t have the label “true” on them, they’re still here in possibility-space and that’s “okay”.

In a lot of traditions, the physical metaphor for “good” is high and bright.  Like the sun, or a mountaintop. The Biblical God is described as high and bright, as are the Greek Olympians or the Norse gods; in Indian and Chinese traditions a lot of divine or idealized entities are represented as high and bright; in ordinary English we talk about an idealistic person as “high-minded” and everybody knows that the “light side of the Force” is the side of the good guys.

To me, the “high and bright” ideal feels connected to the pattern of seeking a goal, seeking truth, trying not to err.

But there are also traditions in which “high and bright” needs to be balanced with another principle whose physical metaphor is dark and vast.  Like the void of space, or the deeps of the sea.  Like yin as a complement to yang, or prakrti as a complement to purusa, or emptiness as a complement to form.  

The “high and bright” stuff is value — knowledge, happiness, righteousness, the things that people seek and benefit from.  The “dark and vast” stuff is possibility.  Room to breathe. Freedom. Potential. Mystery. Space.

You can feel trapped by only seeking value — you can feel like you lack the “space to be wrong”.  But it’s not really that you want to be wrong, or that you want the opposite of value; what you want is this sense of “enough room to move”.

It’s something like Keats’ “negative capability“:

…at once it struck me, what quality went to form a Man of Achievement especially in Literature & which Shakespeare possessed so enormously—I mean Negative Capability, that is when man is capable of being in uncertainties, Mysteries, doubts, without any irritable reaching after fact & reason—Coleridge, for instance, would let go by a fine isolated verisimilitude caught from the Penetralium of mystery, from being incapable of remaining content with half knowledge.

or something like the “mother” Ahab perceives behind God:

But thou art but my fiery father; my sweet mother, I know not. Oh, cruel! what hast thou done with her? There lies my puzzle; but thine is greater. Thou knowest not how came ye, hence callest thyself unbegotten; certainly knowest not thy beginning, hence callest thyself unbegun. I know that of me, which thou knowest not of thyself, oh, thou omnipotent. There is some unsuffusing thing beyond thee, thou clear spirit, to whom all thy eternity is but time, all thy creativeness mechanical. Through thee, thy flaming self, my scorched eyes do dimly see it. Oh, thou foundling fire, thou hermit immemorial, thou too hast thy incommunicable riddle, thy unparticipated grief.

The womb of nature, the dark vastness of possibility — Space Mom, so to speak — is not the opposite of reason and righteousness so much as the dual to these things, the space in which they operate.  The opposite of being right is being wrong, and nobody really wants that per se.  The complement to being right is something like “letting possibilities arise” or “being curious.” Generation, as opposed to selection.  Opening up, as opposed to narrowing down.

The third sense in which you have the “right to be wrong” is a lived experience, a way of thinking, something whose slogan would be something like “Possibility Is.”

If you have a problem with “gripping too tight” on goals or getting the right answer, if it’s starting to get oppressive and rigid, if you can’t be creative or even perceive that much of the world around you, you need Space Mom.  The impulse to assert “I have the right to disagree even with people who know better than me” seems like it might be a sign that you’re suffocating from a lack of Space Mom.  You need openness and optionality and the awareness that you could do anything within your powers, even the imprudent or taboo things.  You need to be free as well as to be right.