Church Planting: When Venture Capital Finds Jesus

I’m going to describe a Type Of Guy starting a business, and you’re going to guess the business:

  1. The founder is very young, often under 25. 
  2. He might work alone or with a founding team, but when he tells the story of the founding it will always have him at the center.
  3. He has no credentials for this business. 
  4. This business has a grand vision, which he thinks is the most important thing in the world.
  5. This business lives and dies by its growth metrics. 
  6. 90% of attempts in this business fail, but he would never consider that those odds apply to him 
  7. He funds this business via a mix of small contributors, large networks pooling their funds, and major investors.
  8. Disagreements between founders are one of the largest contributors to failure. 
  9. Funders invest for a mix of truly caring about the business’s goal, and wanting to receive the glamor of the work without the risk.
  10. Starts a podcast advising others even as he’s failing himself.
  11. Would rather start from scratch than reform an existing institution.
  12. Oversight is minimal and exerted mostly through funding.
  13. Generally unconcerned with negative externalities
  14. Always uses the latest technology to get ahead
  15. Both funding and the job itself heavily reward charisma and narcissism.

Hint for those outside the Bay Area and Twitter: at this point you’re supposed to guess “tech start-up”

  1. Marries before he starts his business, and often has young children. 
  2. Growth metrics are the end in and of themselves, not a proxy for money.

Hint for those outside the Bay Area and twitter: this is obviously not a tech start-up.

This guy is founding an evangelical church, and I find his ecosystem fascinating. First for its stunning similarities to venture-capital-funded tech start-ups, and then for its simplicity and open-heartedness. None of the dynamics in church planting are unique or even particularly rare, but they are unobfuscated, and that makes church planting the equivalent of a large print book for the social dynamics that favor charismatic narcissists. 

My qualifications to speak on church planting are having spent six weeks listening to podcasts by and for church planters, plus a smattering of reading. I expect this is about as informative as listening to venture podcasts is to actual venture capital, which is to say it’s a great way to get a sense of how small players want to be perceived, but so-so at communicating all of what is actually happening. Religion-wise, I also raised in a mainline Protestant denomination, although I left as a teenager. My qualifications to speak on tech start-ups are living in the Bay Area and being on Twitter.*

[*I’ve also been an employee at two start-ups, have angel investor friends, and some of my favorite clients are founders looking for their next thing. But I assure you, going to parties in the bay is sufficient.]

What is Church Planting?

Evangelical Christians are in a bind: they believe that introducing heathens to Jesus is the most important thing they can possibly do, but are fundamentally opposed to the kind of structure that Catholics and mainline Protestant denominations use to support missionaries. Missionaries have a hierarchy they answer to, and one of the things I’ve come to respect about evangelicals is how little use they have for hierarchies and credentials. 

How do you spread the Word when you can’t order someone to do it? You decentralize. Church planting is a do-acracy, where young men decide that God has called them to lead a church, and a decentralized network of financiers fund whoever they choose. This man, and perhaps an assisting team, builds a church from the ground up, answering to no one but his funders. 

The Planters

We’ve already covered many traits of a planter, but let me give a few more:

  • If under 30, he spontaneously came to the belief that God called him to plant a church.
    • A much smaller number of 30- and 40-somethings are pushed into church planting by their pastor
  • He does not have a seminary degree but if he was Saved by high school he probably went to a bible college (which may or may not be accredited by a secular assessor). Evangelicals do not have much use for credentials. 
  • He has probably trained as a youth pastor at an existing church, but it’s also possible he was an assistant pastor or is starting cold. 
  • He does not consider himself affiliated with any denomination, although in practice there are common theological strains among the “non-denominationals.” If you ask a church planter for his beliefs he will say “I teach the bible.” 
  • He may hold a traditional job as well as pastoring, especially early in the process.

Why do I say that church planters tend towards charismatic narcissism? 

First, charisma is a bona fide requirement for being a pastor, especially an evangelical pastor who needs to recruit a new flock. This is doubly true for “parachute plants,” in which a planter moves to a new-to-them area and starts a church, knowing no one beyond their support team. Funders would be stupid not to select for the ability to make people like you and support your goals, and if they somehow were that stupid, the uncharismatic ones would lose in the marketplace (another way in which planting culture embodies American virtues: their embrace of creative destruction). Similarly, VCs like founders who are the subject of positive pieces in trade journals, not because they think those articles have any factual content, but because the skills to get those articles written about oneself have other uses. 

Second, planters are selected for a lack of self-doubt. It takes a special kind of 24-year-old to think, “Hundreds of people should pay me for my advice on the most important topic in existence every week,” and those who do will trend towards narcissism. 

Third, the job is more rewarding and less taxing for narcissists (and extroverts). Lead pastor is an incredibly social job, requiring numerous 1:1 interactions and performing in front of a hopefully large group. 

When I first started this investigation, I expected this push towards charisma and narcissism to be countered by the demand that church planters have strong moral character. Surely planters were selected by wise elders, who’d known them for years and seen them be noble under difficult circumstances. And many places do at least pay lip service to that ideal. But the very first checklist I found for assessing church planters had a noticeable absence of demand for even self-assessed character, much less an appraiser with deep knowledge of the potential founder. 80% of the questions focused on ability to conceive a grand vision and get people to go along with it.

This deeply violates my sense of what organized religion should be, and my lack of participation in organized religion in no way lessens my feelings of entitlement to see it done the way I want. But the fact that anyone can be a pastor is another facet of evangelicalism that accords with the virtues of America. No one can tell you you can’t found a Bible-teaching church. They can decline to fund you or attend, or if they really hate you perhaps write some mean things in a newsletter. But if one funder declines, you can always try another, and another. You just have to believe in your grand vision hard enough (which will select for narcissists).

The Goals

The goal of a church planter (and their funders) is to introduce more people to Jesus. I use the word “introduce” quite literally here; it’s much more like trying to introduce two friends at a party and get them to shake hands than trying to get a friend to read a life-changing book, or introducing them to the ineffable presence of my childhood church. This is one of the biggest differences between evangelical and mainline Protestants- they both talk about both Jesus and God, but for evangelicals the emphasis is on the former, and for mainlines the latter.

Church planters take their goal of Jesus handshakes very, very seriously, considering it the most important biblical commandment. This makes a ton of sense if you accept their belief that the handshake is the difference between eternity in hell and eternity in heaven. Given the importance of saving souls, merely founding and growing a church isn’t enough; You need to grow large and plant churches that themselves grow large and plant more churches. You need to be disciplemaxxing at all times. Leaderboards track the churches that are the largest and fastest-growing (baptisms is another area of competition, although I didn’t find a leaderboard for it).

This philosophy bugged me a lot because why is a handshake (or as they would put it, knowing Jesus Christ and accepting him as your savior) sufficient? How do you know someone really accepted Christ and isn’t just saying it? What if they do it wrong? Protestants don’t believe in salvation through works, so you can’t even use their behavior as a check. And what if a bad Christian nonetheless recruits more people to the Jesus party? Their recruits will never even have a chance at doing it right.

An ex-evangelical friend explained the reasoning as follows: as long as someone is coming to the party and shaking hands with Jesus, there’s a chance for them to get a handshake firm enough to accept him into their heart. But if they’re not even attempting to live as a Christian, Jesus can’t make inroads. The role of a pastor is to enable Jesus to take as many shots on goal as possible. Which again, makes sense once you accept their premises.

The Funders

Lots of charismatic narcissists and young idiots have grand visions for themselves, but only certain ecosystems systematically support those dreams. If we want to understand church planting and environments like it, we need to look at the people who are actually making it happen, i.e., the funders. 

 We’re talking about nondenominational churches, which leaves four sources of funding:

  1. Existing megachurches that devote a portion of their budget to funding church planting. These are the Saudis of the church planting world. They often require the planted church to tithe back to them. 
  2. Sending networks, which pool money from many churches to support planters. These are equivalent to VC firms or investment syndicates. They also often require planted churches to tithe back (same source)
    1. E.g. Acts29, Send Network, Grace Global Network, Grace Church Network, Grace Network (Canada).
  3. A friends-and-family round, where people you know donate significantly.
  4. The Patreon model, where hundreds of people or churches give small amounts. 

Like venture capital, funding from 1+2 is often pledged and released in stages based on meeting milestones. Milestones might be acquiring a new space, attendance, or finding additional funders. They will often have some ideological requirements, like complementarianism (men and women are spiritually equal but called to different roles) or cessationism (the belief that the Holy Spirit no longer enables humans to do miracles).

Churches and sending networks will often provide other support along with their funding, more like incubators than traditional VC. This can include classes, apprenticeships, support groups, and the same for the wife you definitely already have (being a planter’s wife sounds like all of the downside with none of the upside, more on this later).

Funding can be anything from six months of partial expenses to fully covering four years of expenses- but very rarely go beyond four years. At four years you are expected to be self-sufficient and ideally have started nurturing your daughter church plants (which every planter lists as their goal), because if you don’t do it by year five you never will. 

Much like venture capital, church planting is a hits-based business. Funders expect most of their plants to fail, and of those that succeed, they expect most successes to be modest. You make your investment back on the 1 in 100 founding that becomes a unicorn (or mega church). However success rates vary by funder; one church claimed 14/14 successes for their high-touch spawning process, and people on the patreon model are most likely to fail. 

The Human Cost

The worst case scenario for a church plant is something like Mars Hill Church, where a pastor built a successful megachurch with a tightknit community, only to abuse his authority and destroy the church*. At best, this cost members their spiritual home and a community they had come to count on. At worst, they were so badly traumatized they could no longer have a relationship with God. This doesn’t seem that surprising when you’re led by a 25 year old who (untruthfully) brags that he went from heathen to intended pastor with no stops inbetween. 

[*Mars Hill was funded via a friends and family round but received substantial advice and encouragement from the Acts29 network, so I think it’s fair to use it to assess the judgement of the decentralized leadership]

Similarly, I hate how little Silicon Valley pays attention to externalities. I don’t mean the creative destruction via things like Waymo replacing drivers, I mean advice like “advertise two features and implement the one that more people click on,” or “build your fintech business on sex workers and then kick them out once you’re big enough.” Users’ time and energy are treated as free goods. The benefits to users might sometimes outweigh the costs, but I never get the sense anyone is doing that math.

The Life Cycle

Once a man has decided to plant a church, a common starting point is hosting a bible study in his home, but some plants skip this step and go straight to Sunday services. The first step to holding Sunday Services is to find a location. My sense is that if you get a bunch of early-stage pastors together, this is what they complain about. You want somewhere that’s available at prime church time, has seating and A/C, feels like a church, and costs little. The dream is finding a 7th Day Adventist church (who hold their services on Saturday). Movie theaters are not common but pastors who use them seem happier than those in school gyms and hotel conference centers, because it spares them two hours setting up speakers and folding chairs.

The standard advice is to start with “preview services” to draw some interest locally and work out the bugs. Then you do an official launch service that will draw lots of people, mostly existing Christians and your supportive friends. You’re considered successful if your regular attendance reaches half of your launch attendance.

As your church grows you need additional rooms for nursery and Sunday School. If your existing space doesn’t have convenient small rooms, you’ll need to move. In fact you’ll often have to do this anyway as you gain followers. Churches go through several moves as they grow, hermit-crab style. 

Unless you started with a too-big space, you will probably hermit crab your way through larger and larger gymnasiums until a nearby church fails, at which point you merge with them or buy their building. Buying the building is preferable; mergers saddle you with a bunch of people who aren’t bought into your cult of personality. The most successful churches will go on to build their own giant buildings. 

Two hundred regular attendees is a big milestone for planted churches. I first heard it mentioned merely as a size few churches get past, but it’s also a financial threshold. At 200 people, the variation evens out so you can have a longer planning horizon, and probably afford a backup pastor.

Every church planter at least pays lip service to the goal of planting more churches. That requires rapid buildup. I’ve varyingly heard that if you don’t support a new church plant in the first 5, 3, or 1.5 years, you never will. 

Past 200 attendees I know less, because there aren’t that many megachurch planters going on these podcasts. However, you do eventually achieve the biggest crab shell possible, or just put down enough roots that you can’t transition again. If you attract any more people after that you start streaming your sermons to other rooms on the same property. Eventually (2,000 people?), you begin streaming to off-site locations, which is known as being a multi-site church (more recently, you’ll also start streaming online).

Multisite churches are something of a micro-denomination, where an existing church will create a new physical location that is still considered part of the original church, with the same lead pastor. Generally most of its sermons are piped in from the original church (Evangelicals are on the forefront of using new tech in service of God). It will have at least one site-lead pastor. Initially, I assumed this pastor did the work of local ministering- couples counseling, running food banks, etc. But these things aren’t emphasized much at evangelical churches, so I’m not quite sure what fills their days.

A minority of pastors are too entrepreneurial and will leave their settled church to plant a new one, but it seems far more common for the founders to stay on indefinitely.

The Theology

You’ll notice I didn’t mention theology beyond recruitment, or what people do after shaking Jesus’s hand. That’s because independent pastors and even many denominations rarely discuss this. The dominant attitude (going back to at least the 1850s) is that they don’t want to let petty disagreements about the nature of God and the Church disrupt the vital business of throwing parties where people can meet Jesus. 

The passphrase for this is “I teach the Bible.” That sounds neutral but since everyone has a frame and everyone injects that frame into their teaching, what it actually means is “My interpretation of the Bible is so obvious it hasn’t occurred to me people could draw other conclusions” This annoys everyone (exact episode lost) who both teaches from the Bible and recognizes that neutrality is not a human possibility. But it successfully functions as a passphrase for people who have agreed they’re on the same team.

The Failures

This section is weaker because failed planters rarely go on podcasts. That said…

The goal of church planters is to bring people to Jesus. As a whole, evangelicalism is not growing faster than the population, so seems like the system is failing by their lights. 

Individual planters have a failure rate of somewhere between 30% and 90%, depending on their support levels and how you define “attempt”- right in the range of tech start-ups.

For systemic data on why churches fail I rely heavily on this survey by Dan Steel of struggling (not necessarily failed) church plants. The top issues he found:

  1. “No-one is fully rounded when it comes to gifting” aka “skill issue” (75%)
  2. “Not getting what we want”, which seems to be either skill issues in disguise (insufficient attendance) or external shocks like pastoral illness or suddenly losing a location (65%).
  3. “Disunity when you’re fragile is costly”, which is any conflict between the pastor and other people. This got a boost from covid-19, where fights about meetings and masks were common and costly (63%).
  4. Pastor character issues, which they define as getting the job done at the expense of other people (45%).
  5. “Naiveté and over-optimism regarding the speed of growth”, which is a mix of skill issues and bad expectation setting (23%).

A guest on New Churches Podcast gives the following reasons, in unquantified order of importance:

  1. Pastor isolation, which I think is code for discouragement or running out of money. I don’t get the sense planters are leaving thriving churches because they feel isolated; when successful planters feel bad it’s called burnout.
  2. Conflict between the founding team. This surprised me because it very rarely comes up in interviews. From what I’d heard, founding teams aren’t important enough for conflict with them to matter. So either I’m listening to a subset of people without this problem, or they’re hiding it.
  3. Skill issues and a lack of self-awareness around skill issues.

I didn’t bother looking up numbers for why start-ups fail but from party chatter the list is pretty similar. 

The Alternatives

Starting a church is a lot of work; why not just take over an existing one? The official reason is that God called them to, and that new churches are the best way to introduce more people to Jesus, which is the most important act of worship. But I can’t help but notice that for a certain personality type, planting your own church seems way more fun than stepping into an existing one, for the same reason he’d have more fun founding a start-up than being a middle manager at IBM.

When you found a church (or a company), you’re baked into it. Everyone who attends (works for) your church is there because they like you. That’s a great feeling (especially if you’re a narcissist). It also saves you a whole lot of problems with parishioners who remember how their last pastor organized Sunday School and will fight any change tooth and nail. If you join an existing church and it closes, you broke something that worked. If your church plant closes, well, planting is risky, and at least you were willing to try (a pastor’s second planting attempt is much scarier, because now if you fail it’s a pattern). 

Starting a new church is more work, of course, but lots of people would rather put the work in if they can be their own boss. 

The Attendees

Thus far, I’ve found church planting admirably consistent in its efforts to reach its stated goal (recruit people who are not in contact with Jesus and get them to shake his hand, thus saving them from eternal damnation). We’ve already looked at how the system as a whole is not growing, but there’s a subtler issue in who they aim at. 

The closer someone is to death, the closer they are to eternal damnation. So you’d think that if saving souls was your goal, you’d focus on saving the elderly. As a bonus, the old-but-not-decrepit have more money and more hours to volunteer. However, planters seem almost sneering at the elderly, calling them “white hairs” and “bald heads” who are more trouble than they’re worth. In practice, attendees tend to be within 10 years of the age of the pastor, so if a 25-year-old found your plant, it won’t attract 65-year-olds for 30 years. The sense I get is that churches and funders go after young families because they are sexy, the same way that the start-up ecosystem didn’t discover parents as a market until 10 years ago. 

Speaking of sexy: the sexiest recruits are those new to Jesus, or at least prodigal sons. If you listen to church planters talk, these people make up the majority of attendees. But given the population numbers, we know that attendance is not growing faster than the population and have a higher-than-average fertility rate, they are net losing people. They could be shedding lots of people and then recruiting some back, but based on some survey data, it seems like they’re mostly not.*

I ultimately guess that 10-40% of attendees could in some sense be considered new recruits. My sources:

  • This unsourced slideshow says that the previously unchurched make up only 10-15% of attendees at newly planted churches in Canada. 
  • A survey of white American Evangelicals say that 18% were previously unaffiliated, and 4% came from non-Christian-Evangelical backgrounds. 
  • Pew estimates that 40% of evangelicals were not raised Christian. This group includes members of non-Christian churches, but I think does not include people who were raised Christian, walked away, and returned (who church plants would recognize as a win).

It’s good for pastors that most of their flock is already on board with Jesus, because it means they’re also on board with tithing. Conventional wisdom is that it takes 4 years for the previously unchurched to contribute financially. Given that only the most generous funders supply 4 years of expenses, and some only a few months, it is absolutely imperative for pastors to attract people with an existing tithing habit. 

If a new member was already Christian, your hope is that they’re new to the city as well. “Stolen sheep,” aka people who moved to your church because they were dissatisfied with their last one, are considered a mixed blessing. They will tithe and probably volunteer, but it’s unlikely they will be long term satisfied with your church. If they were the type of person to be satisfied, they’d have been so at their last church. If you let them, they’ll suck up a bunch of your time and emotional energy on their way out, which is why one pastor suggests ignoring them. 

The Supporters

Wives

I’ve yet to hear about a church planter who wasn’t married when he founded his church. They always describe their wives as also experiencing a call from God to be a pastor’s wife, which is extremely convenient. 

By default, wives end up with whatever church work their husband doesn’t want or is bad at. This is especially likely to be work that requires high conscientiousness, involves children, or involves other women. They also need to do all the work at home that their partner isn’t doing because pastoring is sucking up all their time, or perhaps provide income because the church can’t fully support the family. And they’re doing most of the parenting. 

Pastors’ wives are expected to make friends with the women of the church but also keep their problems private, because it would undermine their husband’s job if people knew he was unreliable about taking out the trash. 

Overall church wife-ing seems like at least as much work as pastoring, with fewer rewards. 

Support Teams

Many pastors mention launching with other families from their sending church. They frequently discuss how important support teams are, but almost never what their supporters did that was so valuable. Maybe music? Surely set up and tear down. And it’s useful to have people in the pews right from the beginning so nonbelievers don’t walk into an empty church. But overall this feels like a blank spot in my knowledge because the support team never goes on podcasts and for all that pastors sing their praises, they rarely give specifics. 

I posit that pastors are performing the equivalent of thanking the little people at their Oscar speech because they know they’re supposed to, but don’t believe it in their heart of hearts that other people are very important. In contrast, you do tend to incidentally hear about the work their wives do.  

Mission Teams

You know how churches sometimes send teenagers to Mexico for a week to build houses? Well sometimes they instead send those teens to a recently planted domestic church, to ring doorbells, volunteer at vacation bible school, or do manual labor. These have only come up in one episode, which was spent complaining about how they were worse than useless (under the guise of acknowledging that the pastors didn’t know how to use them productively). The most useful function mentioned was mowing the pastor’s own lawn, to free up his time. 

Conclusion

Biology has a concept called convergent evolution– that if you put two distantly related animals in the same ecological niche, they will evolve to be more similar to each other than their respective recent ancestors. Think dolphins evolving the same fins and tail as sharks, despite having bones and needing to breathe air.  Silicon valley and church planting sure seem to me like they’ve gone through convergent evolution, but what is the ecological niche?

  1. Some people really like attention
  2. If you don’t have the energy to do the difficulty, sexy thing, you can get some reflected glory by funding it
  3. Absence of traditional gatekeeping. 
  4. In the absence of a countervailing force, charismatic people will be more successful on the margin. That’s what charisma means.
  5. If you don’t track the eggs broken in your omelette making, there’s no drive to minimize them. 
  6. Youth-worship

And when you combine those, what you get are hits-based economies and a lot of negative externalities. 

Sources

Podcasts

Inside a CATHOLIC Megachurch (Protestant Perspective) 

The Rise and Fall of Mars Hill Church (all episodes)

Everything I Did Wrong as a Church Planter: A Million Part Series (all episodes, as of 2025-06-22)

The Lutheran Church Planter (all episodes, as of 2025-06-22)

New Churches Podcast (26/236 episodes)

Canadian Church Planting (10/41 episodes)

Terminal: The Dying Church Planter (all episodes, as of 2025-06-22)

CMN Church Planting Podcast (all episodes, as of 2025-06-22

Revitalize and Replace (4/236 episodes)

Ministry Wives (1/201  episodes)

Pastors Wives Tell All (1/332 episodes)

Articles

The Priority & Practice of Evangelism: Canadian Church Leader Perspectives in 2021

Religious Change in America

Do We Really Need Another Church Plant?

Evangelism and “Nones and Dones” in Canada

Books

The Evangelicals, by Frances Fitzgerald.

Thanks

Thanks to Patrick LaVictoire and the Progress Studies Blog Building Initiative for feedback on this post. Thanks to my Patreon supporters and the CoFoundation Fellowship for their financial support of my work. 

Mirroring to Substack

I still love and treasure RSS, to the point that I pay money for inoreader. But newsletters are where it’s at right now, especially if you want to be ~~discoverable~~. To that end, I’m mirroring this blog on substack. The Substack will have a slightly more professional angle and lose the bottom ~10% of posts, but otherwise the content is identical. If you prefer email subscriptions or want to help me out with The Algorithm, that’s now available. If you prefer wordpress/RSS/Patreon, do absolutely nothing, things will continue like they always have.

Podcast: Lincoln Quirk from Wave

For two years I had the good fortune to work at Sendwave/Wave (they were one company at the time), a company that made remittances cheap and workable in certain African countries.  I am prouder of working at Wave than of the rest of my programming career combined, and a good bit of my research career as well. Every day I finished work knowing that I had helped save very poor people time and money, by making it cheaper and easier to send money home from abroad or domestically. So I was deeply excited to talk to my ex-boss and co-founder of the company, Lincoln Quirk, on this final episode of the podcast. We talk about a the details of starting a company and the economics of how remittances and mobile do enormous amounts of good while making a profit. 

This is the sixth episode of my podcast with Timothy Telleen-Lawton, and probably the last. This was a worthy experiment but ultimately not accomplishing what I’d hoped, and honestly I’m just tired of criticizing things. Timothy couldn’t make this recording, but he pops in at the end to stay goodbye. 

Transcript

Thanks to the EA Infrastructure fund, our Manifund donors, and my Patreon patrons for supporting this work.

Ketamine Part 1: Dosing

I’m currently investigating ketamine, with the goal of assessing the risks of chronic use. For reasons I will get into in the real post, this is going to rely mostly on in vitro data, at least for neural damage, which means I need a way to translate real-world dosages into the concentration of ketamine in the brain. This post gets into those details so I can use it as a reference post for the one you actually want to read, and invite correction early from the three of you who read it all the way through.

If you’re excited for the main post (or for some inexplicable reason, this post), you can help me out by tax-deductibly donating to support it, or joining my (not tax deductible) Patreon

Cliff Notes

What I care about for purposes of the next post is the concentration of ketamine in the brain. Unfortunately, ethics committees really hate when you set up a tap in people’s skulls and draw a fresh sample every five minutes. The best you can do is a lumbar puncture, which draws cerebrospinal fluid (CSF) from the spine. Unfortunately, spinal fluid and cranial fluid concentrations are not interchangeable. Tentatively, brain concentrations of most substances in this class tend to be lower, so we can still use CSF concentrations as a rough upper bound. 

Most long-term, medically supervised ketamine users use a  lozenge or nasal spray.. However, the only paper that measures ketamine in the cerebrospinal fluid delivered the ketamine by IV. Therefore, to have any hope of contextualizing the in vitro data, I need to translate from ketamine dose (nasal or lozenge) (measured in either straight milligrams, or milligrams per kilogram of body weight) -> plasma concentration -> CSF concentration (also measured in nano- or micro-grams of ketamine per milliliter of fluid). 

There are two metrics we might consider when comparing doses of drugs. The first is peak concentration, which is the highest dose of ketamine your brain experiences at any point. The second is the total cumulative exposure (AKA area under the curve or AUC). These unfortunately have pretty different translations from IV to sublingual doses, and unfortunately I saw no evidence about which of these was more important. I report both just in case. 

Assuming (incorrectly) a linear response, 1 mg of ketamine taken sublingually (under the tongue) or buccally (in the cheek) leads to a mean peak concentration in plasma (blood) of 0.83 – 2.8 ng/ml and a mean total dose (area under curve, AUC) of 1.8-7.4 ng/ml.

1 mg of ketamine taken via a nasal spray leads to a mean peak in plasma of 1.2 ng/ml and a mean total dose of 3 ng*h/ml (based on a single study).

Peak CSF concentration was 37% of plasma concentration, and came 80 minutes later. Total CSF dose was 92% of total plasma dose, indicating almost total diffusion into CSF, eventually. Both findings are from a single study.  

Combining these two results, 1mg sublingual ketamine leads to a median measured peak brain concentration of < 1.1 ng/ml and a total brain dose of < 6.7ng*h/ml. 

On the other hand, 1mg nasal ketamine leads to a median peak concentration of < 0.45 ng/ml and median measured total brain dose of < 2.7ng*h/ml.

The rest of the post goes more deeply into the findings and methodology of individual papers. 

Context and Caveats

Like most 3D molecules, ketamine exists in two forms that are mirror images of each other (called enantiomers). One version is sold under the name eskatamine; the other is not commercially available on its own). Some papers administered only esketamine, some both separately, and some both together (a racemic mix). The pharmacokinetics of these aren’t different enough to be worth distinguishing for my purposes. 

My list of papers is cribbed from Undermind.AI. I occasionally found papers via references, but when I checked those papers were always on Undermind’s list as well. I also looked on Perplexity, but it found only a subset of the papers on Undermind (Perplexity has tragically enshittified over the last few months). 

I treat the translation of dose to concentration in the body as linear. This is almost certainly false, but more likely to be an overestimate. 

I did not even attempt to combine results in some sort of weighted fashion, which would have incorrectly combined subtly different mechanisms of delivery. The numbers you see above are the range of values I saw. 

“Peak” concentration always means “among times samples were taken”, not actual peak.

I mentioned that I assume a linear dose-concentration curve to ketamine (meaning that if you double the amount of ketamine you take, you get double the plasma or CSF concentration). Linear sounds like a nice safe assumption, but it can go wrong in both directions. Your body may absorb a substance less efficiently as you take more, leading to an asymptotic curve. Or your body may only be able to clear so much of a substance at a time, so an increased dose has an outsized impact on concentration. In the case of ketamine there’s very mild evidence that the curve is sublinear, which makes treating it as linear an overestimate. That’s the direction I want to err on, so I went with linear. 

Translating nasal/sublingual doses to plasma concentration

To find out what dose translates to what plasma concentration, we need to give subjects ketamine through whatever route of administration, take repeated blood samples, and measure the concentration of ketamine in that blood. My ideal paper had the following traits:

  1. Studied adult humans.
  2. Delivered ketamine nasally, sublingually, or buccally.
  3. Sampled plasma at least every 10 minutes for the first hour, ideally more often. Only a handful of papers met this criteria, so I had to give a little on this criteria. 
  4. Tracked concentration and total dose received. 

Combining the results below, and assuming (incorrectly) a linear response I get the following results:

  •  1 mg of ketamine taken sublingually or buccally leads to a mean peak concentration in plasma (blood) of 0.83 – 2.8 ng/ml and a mean total dose (area under curve, AUC) of 1.8-7.4 ng/ml
  • 1 mg of ketamine taken nasally leads to a mean peak in plasma of 1.2 ng/ml and a mean total dose of 3 ng*h/ml (based on a single study).

S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine

This paper was definitely selling something and that thing is an “oral thin film” delivery mechanism. 

This study design is a little complicated. N=15 people were given one and two sublingual films (50mg S-ketamine each) on two separate occasions (so everyone received 150mg total, over two doses), and ordered not to swallow for 10 minutes (I have my doubts). Another 5 were given the same doses, but buccally (in the cheek). Buccal and sublingual had indistinguishable pharmacokinetics (at their tiny sample sizes) so we’ll treat them as interchangable from now on. Subjects had blood samples taken at t = 0 (= oral thin film placement) 5, 10, 20, 40, 60, 90, 120, 180, 240, 300, 360 minutes, after which they were given 20mg IV ketamine over 20 minutes, with new samples taken at 2, 4, 10, 15, 20, 30, 40, 60, 75, 90, and 120 min.

Figure 1. Mean measured plasma concentrations following application of the 50 and 100 mg S-ketamine oral thin film (OTF): (A) S-ketamine, (B) S-norketamine, and (C) S-hydroxynorketamine. Individual concentrations are given in panels (D–F) for the 50 mg oral thin film and (G–I) for the 100 mg oral thin film. In black the results of placement below the tongue, in red buccal placement. The OTF was administered at t = 0 min for 10 min (green bars); at t = 360 min, an intravenous dose of 20 mg S-ketamine was administered over 20 min (light orange bars).

There’s a few key points to take from this graph. First, sublingual (under the tongue) and buccal (between cheek and gum) are indistinguishable, at least at this sample size. Second, the 100mg sublingual dose doesn’t have near double peak concentration or AUC of the 50mg dose, although this is not statistically significant. You can see the exact numbers in table 1.

(CMAX = peak concentration, Tmax = time to peak concentration, S-norketamine = a psychoactive metabolite of ketamine, S-hydroxynorketamine=an inactive metabolite of ketamine)

Given that, we have, for peak concentration

 50 mg = 96ng/ml -> 1mg = 1.9ng/ml

100 mg = 144ng/ml -> 1mg = 1.4ng/ml

Which makes a linear dose-concentration relationship look unlikely, although at these sample sizes the difference isn’t significant. 

For AUC:

50mg = 8362 ng*min/ml     -> 1mg = 170 ng*min/ml

100mg = 13,347 ng*min/ml -> 1mg =  130ng*min/ml

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers

This is my favorite paper, looking at no fewer than 5 different methods of delivery. 

This isn’t the primary take-home, but because they injected racemic ketamine but measured the two enantiomers (S- and R- ketamine) we can see that their pharmacokinetics are close enough that I can ignore the difference between them, and use S-ketamine data to inform estimates of racemic ketamine. For the results below I averaged the S- and R- results together

The only routes of administration I care about from this list are sublingual tablet and nasal spray.

For peak concentration, we see:

50 mg sublingual = (42.6+40.4)/2 ng/ml -> 1 mg = 0.83ng/ml

25mg nasal spray = (29.4+29.3)/2 ng/ml  -> 1 mg = 1.2 ng/ml

For area under the curve, we see:

50 mg sublingual = (108.8+110.5)/2 ng*h/ml -> 1 mg = 2.2ng*h/ml = 130 ng*min/ml

25mg nasal spray = (76.8+72.7)/2 ng*h/ml -> 1 mg = 3 ng*h/ml = 180 ng*min/ml

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

You know the drill: 8 subjects were given 25mg sublingual or 10mg IV ketamine

This paper uses geometric mean (the nth root of n numbers multiplied together) rather than arithmetic (sum of numbers divided by their count), so is not directly comparable to the other studies. But roughly, for peak concentration (Cmax) of the sublingual dose: 

25 mg ketamine  = 71.1 ng/ml -> 1mg = 2.8 ng/ml

And for total dose (AUC)

25 mg ketamine = 184.6 ng*h/ml -> 1 mg ketamine = 7.4 ng*h/ml = 443 ng*min/ml

Why I’m ignoring ketamine’s chirality

Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations

10 healthy male subjects aged 24 to 62 yr, weighing 68 to 92 kg, were administered approximately 7 mg of S(+) or R(–) ketamine via a 30-min constant rate IV infusion on two occasions at least 3 days apart. Radial artery and arm vein samples were drawn at 0, 5, 10, 15, 20, 25, 30, 40, 50, 60, 120, 180, and 300 min after the start of the S(+) ketamine infusion and at 0, 5, 10, 15, 20, 25, 30, 36, 43, 50, 180, 300, and 420 min after the start of the R(–) ketamine infusion.

Red = arterial blood, Blue = venous blood

As you can see, arterial and venous blood are quite different, but S- and R- ketamine are close enough for government work. 

Translating plasma concentrations to cerebrospinal fluid concentrations

Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion

These heroes gave a dose of ketamine via IV, then monitored both plasma concentration and cerebrospinal fluid. 

Peak CSF concentration was 37% of plasma concentration, and came 80 minutes later.

Total CSF dose was 92% of total plasma dose, indicating almost total diffusion into CSF, eventually. 

Papers I Want to Complain About

Bioavailability, Pharmacokinetics, and Analgesic Activity of Ketamine in Humans

I mention this paper only to explain why I am mad at it. This 1981 study took beautiful measurements of pain sensitivity as well as plasma concentration of ketamine, and then didn’t publish any of them. They used only intramuscular injection and oral solution, which doesn’t allow me to translate to the more standard IV concentration. Also oral is a terrible route for ketamine, your body processes most of it before it hits your system. 

Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing

For reasons I don’t understand, this paper studies IV alone versus IV + oral ketamine together. Also not useful for our purposes, except for establishing that ketamine taken orally (as in, a pill you swallow and absorb through the digestive track) isn’t very good.

Development of a sublingual/oral formulation of ketamine for use in neuropathic pain

This paper measured concentration in arterial blood, where every other paper used venous blood. One paper that measured both showed that they were shockingly different. I could attempt to translate from arterial to venous concentrations, but the paper also uses an unpopular delivery mechanism so I haven’t bothered. 

Acknowledgements

Thanks to R. Craig Van Nostrand for statistical and paper-reading help, Anonymous Weirdo for many discussions on pharmacokinetics, Ozy Brennan and Justis Mills for editing, and my Patreon patrons and Timothy Telleen-Lawton for financial support. 

What do you Want out of Literature Reviews?

Tl;dr how can I improve my literature-review based posts?

I write a fair number of blog posts that present the data from scientific papers. There’s a balancing act to this- too much detail and people bounce off, too little and I’m misleading people. I don’t even think I’m on the pareto frontier of this- probably I could get better at which details I share and how I share them, to improve readability and rigor at the same time. This post is a little bit my thoughts on the matter and a lot of requests for input from readers- what do you actually want to see? What are examples of doing this well? Any requests for me personally?

I ask for audience feedback explicitly at a few points, but please don’t limit yourself to those. I’m interested in all suggestions and examples .

Context

If you’re just tuning in, here’s a few examples of posts I mean:

These are all posts where the bulk of the text is describing individual papers, but I have some conclusion I would like the reader to consider.

My motivating example is my project on the risks of long term ketamine use. Right now I’m working on a technical post on how to translate doses consumed by humans into concentrations in the cerebro spinal fluid (draft ), which is reference material for a post people might actually read.

Principles

Epistemic Legibility

My goal is always to present information to people they can interpret for themselves, rather than rely on my summaries. My proudest moment as a researcher was when I was hired by a couple to investigate a particular risk during pregnancy, and due to different risk tolerances they came to opposite conclusions from the same model. To accomplish this, I need to give people the relevant details, in as digestible a format as possible. 

What helps you connect with scientific posts? Some ideas:

  1. My search process
  2. My selection criteria
  3. My conclusions
  4. Motivation
  5. Your ideas here

Then there’s the papers themselves. For the ketamine dosing post, there’s  <20, maybe <10 papers in the world that meet my criteria for inclusion, so it’s feasible to include details on each of them. But which details help people understand, and which aren’t worth the attention they cost? 

Some paper details I could include:

  1. Sample size. 
  2. Experimental set up
  3. Key graphs
  4. Description of results
    1. Averages, or with confidence intervals?
  5. My criticisms
  6. Your ideas here

Readability

All else equal, it’s better for a post to take less energy to read than more. Actually that’s not quite true- for posts that would be especially costly if I’m wrong or I expect to be misinterpreted, I will often bury the conclusion, like I did in this post on binge drinking. But we’ll ignore that for now and focus on the much more common case of wanting posts to be as accessible as possible. 

Detail and readability often trade off against each other, but what I’m looking for here is ways to improve readability while holding detail constant. Some ideas I have:

  1. Formatting, probably? Seems like it should help but I don’t know what specifically.
  2. Humor
    1. Unfortunately the easiest way to do this is to make fun of bad studies, which gets repetitive. 
  3. Explaining relevance to the main question
  4. Make the goal/main question clear
  5. Pictures? I’m unconvinced of this
  6. Your ideas here

Audience

Everyone says to have an audience in mind. There are two major audiences and two minor.

People who are Interested in the Opinions of Uncredentialed Internet Weirdos

This is a tautology, but refers to something much more specific than it looks at first. People who are interested in hearing uncredentialed randos describe and interpret academic papers have a lot more in common than just their willingness to do that. 

Some other traits they share: 

  1. Statistical literacy
  2. Desire for interpretations to be quantified
  3. Higher risk tolerance
  4. Your ideas here
  5. Interested in the specific topic- such as ketamine use, or long covid risk.
    1. It’s rare I want to convince people that they should be in a topic when they weren’t before. 
  6. Your ideas here

Fishing for Corrections

Some posts aren’t meant to be read widely. They’re meant to be a reference in other, more readable post, and to invite corrections from the three people who will read them. This is my intention for the ketamine dosage translation post– it’ll be lucky if it’s read by 10 people when it’s first published, but one of those might be quite useful. 

The primary benefit to me is catching mistakes before I write an entire 10,000 word post with information that could hurt people I’m wrong that depends on the false conclusion. It also feels virtuous to explain my reasoning in detail, even if nothing specifically good comes from it.  

Myself

Writing lets me think through things. I always budget at least as much time for the “writing” phase of a project as research, because there are gaps I don’t notice until I start writing them down. 

I’m interested in how this works for other people- have you found ways to improve your writing for yourself?

Potential clients

I make my living as a freelance researcher, with my blog being the major evidence I am good at this. I’d like clients who read my posts to be able to assess my skill level, even if they’re not interested in the topic and have no context. 

Conclusion, such as it is

I would like to get better at writing the kind of posts I write. In particular, I’d like to get better at conveying relevant information, in ways that take as little work from the reader as possible, but no less than that. I will be very grateful for feedback that helps me improve or that helps me create a framework by which I can improve. I expect that to mostly be critical, but compliments are helpful too- I’d hate to throw out the baby with the bathwater.

Ivan Gayton: A Right and a Duty

In this episode of the podcast I talk with Ivan Gayton, former mission head at Doctors Without Borders and currently obsessed with placing mapping technology in the hands of the developing world.

If you prefer the written word, you can see the transcript here.

Some highlights:

  • How Ivan thinks about being fractionally responsible for saving the lives of hundreds of thousands of people, but pretty directly responsible for the killing of 12 (utilitarian deontologicalism, I think?).
  • Why humanitarianism is a right and a duty, but development is merely nice (humanitarianism is countering the intervention of another human being).
  • Casually devastating criticism of various international aid agencies (Tanzania is where aid workers go to retire while still drawing a check).
  • Why accurate open maps are instrumental to humanitarian and development goals in developing countries (contact tracing during epidemics, aid distribution, municipal services, utilities)
  • How you can contribute to mapping with money or programming talent (especially mobile, Unity or other 3D mapping engines, FPGA, AI, especially for vision, and blockchain). Programming positions are potentially paid, although not at competitive rates.

Links and other references:

  • Ivan mentions starting his mapping project with Ping. This refers to Ka-Ping Yee, another former co-worker of mine.
  • The organization Ivan works with most directly is Humanitarian Open Street Maps team.
  • If you’re interested in working with him you can reach him at [firstname].[lastname]@hotosm.org.
  • Missing Maps Project
  • Ivan mentions a blog post with the title “Free Software is Racial Justice”. That can be found here.

Bandwidth Rules Everything Around Me: Oliver Habryka on OpenPhil and GoodVentures

In this episode of our podcast, Timothy Telleen-Lawton and I talk to Oliver Habryka of Lightcone Infrastructure about his thoughts on the Open Philanthropy Project, which he believes has become stifled by the PR demands of its primary funder, Good Ventures.

Oliver’s main claim is that around mid 2023 or early 2024, Good Ventures founder Dustin Moskovitz became more concerned about his reputation, and this put a straight jacket over what Open Phil could fund. Moreover it was not enough for a project to be good and pose low reputational risk; it had to be obviously low reputational risk, because OP employees didn’t have enough communication with Good Ventures to pitch exceptions.  According to Habryka.

That’s a big caveat. This podcast is pretty one sided, which none of us are happy about (Habryka included). We of course invited OpenPhil to send a representative to record their own episode, but they declined (they did send a written response to this episode, which is linked below and read at end of the episode). If anyone out there wants to asynchronously argue with Habryka on a separate episode, we’d love to hear from you. 

Transcript available here.

Links from the episode:

An Update From Good Ventures (note: Dustin has deleted his account and his comments are listed as anonymous, but are not the only anonymous)

CEA announcing the sale of Wytham Abbey

OpenPhli career page

Job reporting to Amy WL

Zach’s “this is false”

Luke Muelhauser on GV not funding right of center work

Will MacAskill on decentralization and EA

Alexander Berger regrets the Wytham Abbey grant

Single Chan-Zuckerberg employee demanding resignation over failure to moderate Trump posts on Facebook

Letter from 70+ CZ employees asking for more DEI within Chan Zuckerberg Initiative.

OpenPhil’s response

Journal of Null Results: EZMelt sublingual vitamins

4 months ago I described my success curing my hypothyroidism by gargling liquid iodine, when iodine pills had failed. The good news is that the cure has held– my thyroid numbers continue to be in the desirable range. 

The bad news is I’ve failed to replicate this success with a multivitamin. Shortly after the thyroid post I was handed a perfect opportunity to put sublingual vitamins to the test when my doctor took me off all my oral vitamins to give my gut a rest. I had already started on EZMelt Multivitamin + Iron (2x standard dosing every other day, because I absorb iron better that way), but now we’d removed all potential assistance (“except food, right?” no. My gut has never been good at extracting vitamins from food except right after I discovered Boswelia. Mold Winter rolled back those gains).

I recently got my nutrition test results back and they suck. I can’t prove I wouldn’t have been even worse off without these vitamins, but there’s a profound absence of positive evidence. However the issue could just be these particular vitamins; after a break I’m now trying Feroglobin, which is a thick liquid iron supplement with a smattering of other vitamins. It’s not intended to be taken sublingually but I don’t live by their rules, man.

Between getting the results and publishing this post I made a market on Manifold, asking whether the EZMelts would work. The market was trading just under 50% “no, not helpful” for most of the week, but in the final hours fluctuated between 30-40% “no”. Seems like a very mild victory for prediction markets. 

I’ve created a similar market for Feroglobin here. This run is not going to be quite as clean- my doctor put me back on oral vitamins, plus I finally found a place that does IV nutrition. So this will be more of a best guess, probably resolved as a probability rather than flat Yes/No. 

Predict the impact of sublingual vitamins

4 months ago I shared that I was taking sublingual vitamins and would test their effect on my nutrition in 2025. This ended up being an unusually good time to test because my stomach was struggling and my doctor took me off almost all vitamins, so the sublinguals were my major non-food source (and I’ve been never good at extracting vitamins from food). I now have the “after” test results. I will announce results in 8 days- but before then, you can bet on Manifold. Will I judge my nutrition results to have been noticeably improved over the previous results?

Austin Chen on Winning, Risk-Taking, and FTX

Timothy and I have recorded a new episode of our podcast with Austin Chen of Manifund (formerly of Manifold, behind the scenes at Manifest).

The start of the conversation was contrasting each of our North Stars- Winning (Austin), Truthseeking (me), and Flow (Timothy), but I think the actual theme might be “what is an acceptable amount of risk taking?” We eventually got into a discussion of Sam Bankman-Fried, where Austin very bravely shared his position that SBF has been unwisely demonized and should be “freed and put back to work”. He by no means convinced me or Timothy of this, but I deeply appreciate the chance for a public debate.

Episode:

Transcript (this time with filler words removed by AI)

Editing policy: we allow guests (and hosts) to redact things they said, on the theory that this is no worse than not saying them in the first place. We aspire but don’t guarantee to note serious redactions in the recording. I also edit for interest and time.