SSRIs
Article
SSRIs is a recurring concept in the Astral Codex Ten archive, appearing 16 times across 16 issues between February 22, 2021 and February 18, 2026. The archive places it in contexts such as ""we give people SSRIs, their serotonin levels go up, and this makes them feel better""; “usual SSRIs → serotonin → BDNF → TrkB → nerve growth theory”; “other SSRIs only bind to the main site of the serotonin transporter and block it”. It most often appears alongside FDA, US, Adderall.
Metadata
- Category: Concepts
- Mention count: 16
- Issue count: 16
- First seen: February 22, 2021
- Last seen: February 18, 2026
Appears In
- A Look Down Track B
- Oh, The Places You’ll Go When Trying To Figure Out The Right Dose Of Escitalopram
- Peer Review Request: Depression
- Book Review: Crazy Like Us
- Zounds! It’s Zulresso and Zuranolone!
- Lavender’s Game: Silexan For Anxiety
- Unpredictable Reward, Predictable Happiness
- Contra Resident Contrarian On Unfalsifiable Internal States
- Semaglutidonomics
- Highlights From The Comments On Telemedicine Regulations
- Attempts To Put Statistics In Context, Put Into Context
- Does Anaesthesia Prove Ketamine Placebo?
- Links For February 2024
- Your Book Review: The Pale King
- On Priesthoods
- Record Low Crime Rates Are Real, Not Just Reporting Bias Or Improved Medical Care
Related Pages
-
- FDA (6 shared issues)
-
- US (5 shared issues)
-
- Adderall (4 shared issues)
-
- Canada (3 shared issues)
-
- fluoxetine (3 shared issues)
-
- Jesus (3 shared issues)
-
- ketamine (3 shared issues)
-
- ketamine (3 shared issues)
-
- paroxetine (3 shared issues)
-
- serotonin (3 shared issues)
-
- Wikipedia (3 shared issues)
-
- ADHD (2 shared issues)
External Links
Source Context
Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.
This part sort of makes sense. But it coexists uneasily with other puzzle pieces in our knowledge of depression. For example, we give people SSRIs, their serotonin levels go up, and this makes them feel better. Why? Because of BDNF something TrkB something mTORC something? Probably; mice with dysregulated BDNF/TrkB systems don't benefit from antidepressants. But why does more serotonin cause BDNF something TrkB something? I've looked for years for a paper that says something like "by the way, serotonin makes cells release more BDNF". But despite a few suggestive links I don't see anyone strongly asserting that they understand this.
First off: if antidepressants' effects are unrelated to monoamines, why are so many antidepressants monoaminergic? Actually, that's the wrong question, if pharma companies only looked for monoamine antidepressants, that's all they'd find. But why are so many monoaminergic substances antidepressants? Where are all the papers saying "we tested this new SSRI, it did a great job inhibiting serotonin reuptake, but there was no antidepressant effect whatsoever"? Surely some substances that are SSRIs don't also interact with this new TrkB receptor domain? Are pharma companies hiding their failures? But if they kept failing, surely they themselves would realize something was up and stop throwing money at serotonergic antidepressants? So many people for so many years have been trying to poke holes in the serotonergic model of antidepressants, and they've made some good points, but I've never seen any of them say "and here are these fifty chemicals which are great SSRIs but totally useless for depression". Why not?
The TrkB paper cites two papers saying antidepressants still work on mice genetically engineered so they can't reuptake serotonin, which would mean serotonin isn't involved in their effects and it's probably this new TrkB thing. They also cite one paper saying the antidepressants don't work on the mice, just as the standard theory would predict. They imply this means it's two to one, but reviews of this literature make it sound like the antidepressants not working is the more common finding, and when I Google around on this subject most papers seem to agree. @zenbrainest @Dereklowe (excuse my self-promotion) We did show that SERT M172 mice lost acute and chronic SSRI behavioral and neurogenic efficacy, which should retain all TrkB effects. Thus TrkB effects are insufficient alone to produce AD effects. ","username":"anackenoff","name":"Alex Nackenoff, Ph.D.","profile_image_url":"","date":"Fri Feb 19 17:18:54 +0000 2021","photos":[],"quoted_tweet":{},"reply_count":0,"retweet_count":3,"like_count":15,"impression_count":0,"expanded_url":{"url":"https://pubmed.ncbi.nlm.nih.gov/26514584/","image":"https://bucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com/public/images/39b37056-9b5e-4056-9952-3d45751866ec_1200x1200.png","title":"Essential Contributions of Serotonin Transporter Inhibition to the Acute and Chronic Actions of Fluoxetine and Citalopram in the SERT Met172 Mouse - PubMed","description":"Depression is a common mental illness and a leading cause of disability. The most widely prescribed antidepressant medications are serotonin (5-HT) selective reuptake inhibitors (SSRIs). Although there is much support for 5-HT transporter (SERT) antagonism as a basis of antidepressant efficacy, this…","domain":"pubmed.ncbi.nlm.nih.gov"},"video_url":null,"belowTheFold":true}" data-component-name="Twitter2ToDOM"> Likewise, there are a lot of papers showing that antidepressant treatment increases levels of BDNF and that this seems to be necessary for its effects. If antidepressants just positive-allosteric-modulated TrkB, we'd expect to see the same amount of (maybe less) BDNF.
But Jakubovski et al's Dose-Response Relationship Of Selective Serotonin Reuptake Inhibitors discusses which doses of which antidepressants are equivalent to each other, and comes up with the following suggestion (ignore the graph, read the caption):
Now that we know the heart risk was overblown, should we increase the maximum dose to something closer to other SSRIs? Maybe not. Right now, escitalopram keeps showing up in studies and head-to-head comparisons as the most effective SSRI.
Inline links: the most effective SSRI
They note that other SSRIs only bind to the main site of the serotonin transporter and block it. Lexapro does this too, but it also binds to what's called an allosteric site - a separate site which doesn't block it, exactly, but changes its shape a bit. This means that although all SSRIs make the serotonin transporter work less well in one way, Lexapro makes it work less well in two ways. Because of this, Lexapro increases serotonin to a higher level than other antidepressants:
Advantages of escitalopram: it’s slightly better at dealing with anxiety, rumination, and obsessive thoughts, although some studies have challenged this. Disadvantages of escitalopram: it frequently decreases sex drive/ability/performance, and occasionally causes tiredness, weight gain, or emotional flatness. Read more at my page on SSRIs.
Inline links: SSRIs
Duloxetine is an SNRI, which supposedly means it might have some advantages over SSRIs, although studies are not completely clear. It might be better for patients with chronic pain, since it sometimes helps this also. I tend to avoid the other popular SNRI, venlafaxine, because it has very difficult withdrawal and no obvious advantages over duloxetine.
(I don’t remember if Watters mentions it, but this is also the pre-mid-20th-century American/European conception of depression - there’s nothing particularly Japanese about it. The usual term for this idea is melancholia, sometimes used to mean an especially severe endogenous depression, although other people use the word in different and confusing ways. Better historians than I can debate whether the West saw the concept of melancholia fade gradually into modern depression, or whether it had to do with SSRI-induced marketing campaigns here too; I suspect there was a gradual halfway transition from 1900 - 1990, followed by an extremely sudden transition after the invention of SSRIs and the publication of Listening To Prozac. But let’s go back to pretending this is an exotic Japanese phenomenon.)
As part of GlaxoSmithKline’s marketing work, they replaced utsubyo with a new idea, kokoro no kaze, “cold of the soul”. This was supposed to mean that depression was a minor illness (like a cold), something everyone got occasionally (like a cold), and something that was purely biological and could/should be controlled with medication (like a cold). Japanese people were extremely excited about this and bought Paxil by the bushel, and now they use SSRIs at a rate close to Americans.
(source) GABA is the main inhibitory neurotransmitter; it’s usually associated with relaxation and sedation. A positive allosteric modulator is a chemical that makes receptors respond more strongly to their targets. So “a positive allosteric modulator of GABA” means a chemical that makes the brain respond stronger to relaxation/sedation signals. Sounds pretty useful! You may do some positive allosteric modulation of GABA yourself sometimes; this is one of the major actions of alcohol. Also of the benzodiazepines, a popular class of psychiatric medication including Ativan (lorazepam), Valium (diazepam), and Klonopin (clonazepam). The “-pam” at the end stands for positive allosteric modulator! (or maybe that’s just an urban legend, I’ve never found proof either way) The discovery of endorphins (ie endogenous opiates) helped shed light on the brain’s reward system. So the discovery of a sort of endogenous benzodiazepine was pretty exciting. Maybe it’s some kind of master control switch for anxiety or something? Psychiatrists only know two ways to respond to an exciting new thing: publishing breathless studies claiming that it’s the true mechanism of action for SSRIs, and publishing breathless studies claiming that it’s the true biological basis of depression. This time, they did both: see eg Fluoxetine elevates allopregnanolone levels in female rat brain and The role of allopregnanolone in depressive-like behaviors. The basic theory was that stress / social isolation / etc → decreased allopregnanolone → something something BDNF and synaptogenesis → depression. And SSRIs → increased allopregnanolone → something something BDNF and synpatogenesis → recovery! Change the word “allopregnanolone”, and that’s every theory in psychiatry. But this particular theory had two extra pieces of evidence: premenstrual dysphoric disorder and postpartum depression. Remember, allopregananolone is a natural metabolite of the female hormone progesterone. Progesterone levels go up during pregnancy and the ~18th day of the menstrual cycle, then crash back down after delivery and the ~24th day of the menstrual cycle. Meanwhile, some women get depressed after delivering a baby, or on the ~24th day of their menstrual cycle. Suspicious! Maybe it’s because their progesterone was getting converted into allopregnanolone, an antidepressant hormone that affects mood! (why doesn’t every woman get PPD and PMDD? This study suggests that women with PMDD have altered sensitivity to allopregnanolone; plausibly people with PPD have some other form of altered sensitivity. In case you have the same question I do: the correlation between PMDD and PPD is not 100% but still pretty significant) History of allopregnanolone research (source) The next step was to see if making patients take allopregnanolone can treat these conditions. This is kind of hard, because allopregnanolone is a tough chemical to get into people’s bodies; the traditional method involves sticking an IV into someone and infusing it slowly over several days, and it has to be done in a hospital. Still, Kanes et al tried this in 2017. The study was open-label (ie no placebo) and very small (only four women) but appeared to work extraordinarily well. Four post-partum women who qualified as “severely depressed” when they started the infusion progressed to “completely recovered” within twelve hours. Nothing else except maybe ketamine had produced results like this before. 3: What studies were done on Zulresso? This followup study by Kanes was the first real RCT, although it only had 21 patients. In accordance with the venerable First Study Ever tradition, it found really large positive effects on post-partum depression. That encouraged Sage Therapeutics to fund a bigger Phase 3 trial, Meltzer-Brody (2018). In accordance with venerable Bigger Phase 3 Trial tradition, its results weren’t quite as good as the First Study Ever. But they were still pretty good: Notice that lower doses worked better than higher doses. This is sometimes a red flag on a study. But this time it seems legit; see “Biphasic Actions At The GABA-A Receptor” here for an explanation. Both studies also evaluated side effects. These were generally mild, but two people (about 2% of the study population) lost consciousness. Nothing seemed wrong with them, and researchers mostly attributed this to allopregnanolone being a sedating drug. If you sedate people too hard, they pass out. Faced with these results, the FDA approved allopregnanolone for post-partum depression, but subjected it to a REMS (Risk Evaluation And Mitigation Strategy) - basically, doctors who want to prescribe it will need to take special courses and do extra paperwork. This kind of surprised me - there are plenty of sedating drugs that make you pass out in overdose. Also, since patients will be getting it IV, there will probably be a nurse around to check if they passed out and take appropriate actions if so. But the FDA really likes putting restrictions on things, and I guess this was a free chance for them to do that. 4: Is Zulresso freely available at a doctor’s office near me? It’s possible to get Zulresso, but really hard. Because Zulresso is an IV infusion lasting four days, you need to spend four days somewhere that people can put an IV into you and monitor it. Realistically that means a hospital or some other big medical institution. So this is only available for inpatients. Because of the REMS (extra certification and paperwork), most hospitals aren’t interested. You can find a list of ones that are here - it looks like there are about 89 locations in the US with the right certification. Last but not least, a four-day course of Zulresso costs $35,000 for the medication itself, plus much more for the four-day hospitalization it takes to receive it. As usual, insurances will cover it iff you can document you’ve tried lots of other stuff first. 5: Hold on, does it really cost $35,000? Oho, I see you’ve played the “pharma price analysis” game before. But this time I think the price might actually be defensible. Chemical supply companies (1, 2, 3) generally sell allopregnanolone for $10,000 to $20,000 a gram. (I found one company with a much lower price, but I’m suspicious and am going to dismiss them as an outlier). The usual dose of allopregnanolone is 60 ug/kg/hour x 60 hours, which for a 60 kg person comes out to a total of 0.25g total. Getting that amount from the chemistry supply store would cost about $2,500 - 5,000. I assume pharma-grade allopregnanolone is more expensive than chemistry-store-grade, so it wouldn’t surprise me if a price in the low five-figures was justified by manufacturing alone. Isn’t it still a pretty good deal to find an endogenous neurosteroid, do one or two studies confirming it’s great, produce it for the low five figures, then sell it for the mid five figures? I think maybe not. This drug has a terrible value proposition. Post-partum depression is one of the rarer psych conditions. Most people with PPD won’t check into a hospital and pay $35,000 for a drug infusion. And the people who do will get the drug infusion, feel better, and never need it again (at least until they have another kid) - unlike SSRIs where you can keep charging for monthly prescriptions forever. Sage Therapeutics, the pharma company that owns the patent on Zulresso (and nothing else - this is their only drug!) has done terribly. Their stock is in the doldrums, they almost went bankrupt, and they survived only with the help of a cash infusion by a bigger pharma company. I think this confirms a general trend where at least some expensive medications are pricey because of fundamentals (including regulatory fundamentals) and not just pharma companies making obscene profits. 6: Hold on, how is allopregnanolone different from benzodiazepines? Remember, allopregnanolone is a positive allosteric modulator of GABA, much like benzodiazepines such as Xanax. But Xanax is cheap ($10 for 30 pills). And you can get it at any local pharmacy (plus sometimes on street corners). What’s so special about allopregnanolone that you should pay $35,000 and go into the hospital to get it? The official answer is “allopregnanolone modulates GABA differently from benzodiazepines”. For example, this paper says that: Allopregnanolone allosteric modulation of the action of GABA at GABA-A receptors is much less selective than that of benzodiazepines, which are relatively inactive at α4- or α6-containing GABA-A receptors. If you really like details about receptor subunits, this paper presents the full case. The skeptic’s answer is “who knows?” Psych drugs often work for reasons totally different than we thought. People thought tianeptine was an SSRE for years, until it turned out to be a mild opioid. People thought ketamine was NMDA-ergic for years, until it turned out to be [fill this part in 10 years from now]. Last year a bunch of very smart people tried to claim that SSRI effects had nothing to do with serotonin (I think they were wrong). Just because some guy found that Zulresso acts as a GABA-PAM in some test tube doesn’t mean that’s what’s having any of the relevant antidepressant effects. The troll’s answer is “who says it’s different?” Do benzodiazepines treat depression? Depends who you ask. If you ask benzodiazepine users, their answer is “yes, definitely”. If you ask drug warriors, their answer is “Addictive Substances May Make You Temporarily Feel Good, But They Are Not A Responsible Treatment Option”. If you ask the research literature, it gives vague indeterminate answers, as always. But nobody has ever said benzodiazepines instantly and miraculously cure depression, so how come allopregnanolone seems to do that? A true troll would point out that we probably give allopregnanolone at much higher doses - 2% of allopregnanolone patients were sedated so hard they lost consciousness, whereas this is exactly the sort of side effect I try to avoid when calculating benzodiazepine doses. Maybe if you gave postpartum women an infusion of 300 mg Valium, and maximized your placebo effect by calling it the hot new thing, they’d do pretty well too (several days later, after recovering consciousness). I think the troll answer would be hilarious but I don’t really want to defend it as correct; if I had to bet I’d say the official explanation is the right one. 7: Hold on, why can’t we just give people progesterone and let them metabolize it into allopregnanolone? This turned out to be an interesting enough rabbit hole that I’m going to spin it off into another post later this week. 8: Hold on, people have lots of allopregnanolone when they’re pregnant, right? And then post-partum depression happens when they give birth, and their allopregnanolone level drops. So if you give someone an infusion of allopregnanolone, and then take them off it, that’s a hormonal simulation of giving birth, ie the same thing that caused the problem in the first place? How is that good? Oh, you think you’re clever, do you? What you failed to consider is . . . I didn’t end that sentence because I can’t find anything in the literature addressing this question. But the difference might be that the infusion schedule ramps up gradually, peaks, and then ramps down gradually, which is more of a soft taper than the sudden crash of birth. If anyone knows more about this, please let me know. [EDIT: see this comment] 9: Is allopregnanolone addictive? No, because good luck getting addicted to a $35,000-per-dose chemical. We should probably expect allopregnanolone to be addictive, by analogy to other GABA-PAMs like benzodiazepines and alcohol. But nobody has ever received more than a single dose. You don’t get addicted to benzos after a single pill, or alcohol after a single beer, so in practice AFAIK nobody has ever gotten addicted to this. Or who knows, maybe it’s not addictive. Remember, allopregnanolone is naturally elevated during pregnancy; pregnancy isn’t addictive. And some scientists claim the brain endogenously uses allopregnanolone as a master regulator of depression and anxiety. In theory, if you could give yourself the same amount a non-anxious person’s brain gives them all the time, shouldn’t you be no worse off than that non-anxious person? I don’t know, and remember that your brain also has a lot of endogenous opioids; doesn’t make the exogenous kind any safer. The Drug Enforcement Administration has made Zulresso a Schedule IV controlled substance, which means they’re putting a few very weak restrictions on it but not worrying too much. 10: Does allopregnanolone work for depression that isn’t post-partum? If all psychiatric disorders are secretly allopregnanolone imbalances, then you might expect it to work on all depressions, not just post-partum. I’m sure pharmaceutical executives with dollar signs instead of pupils in their eyes have had this same thought, but I can’t find studies about it. Some of the same people behind the postpartum studies did a very small, very weak study on ganaloxone (a close allopregnanolone relative) for persistent depression; it seemed to work, but also caused a lot of sedation (more than in the postpartum trials? Hard to tell). Nobody’s looked into this further since then, maybe because that was around when the pharma companies realized that the 4-day hospital stay and $35,000 price tag made allopregnanolone a financial loser. The evidence from zuranolone (see below) suggests that allopregnanolone might not work very well against regular depression. 11: What is zuranolone? Wikipedia describes zuranolone as “a swirling, black vortex revered by the Mutsune Native Americans as a dire death god . . . also worshiped by mysterious servitors known as the Hidden Ones.” No! Sorry again! That’s Zushakon, another Great Old One. Zuranolone is Sage Therapeutics’ attempt to turn allopregnanolone into an accessible medication that might actually make them real money. Zuranolone is mostly just allopregnanolone with some extra stuff attached that changes the absorption. Zuranolone can be taken orally, so you don’t have to go to a hospital for four days to receive it IV. It’s potentially less likely to cause loss of consciousness and other undesirable side effects. And it’s under investigation as a potential treatment for postpartum depression, bipolar depression, regular depression, insomnia, and various movement disorders. (that might seem excessive, but benzodiazepines treat a lot of stuff, and if these neurosteroids are kind of like super-benzodiazepines, then this level of optimism might be warranted.) 12: Does zuranolone work? Sage Therapeutics answered this question the same way pharma companies answer every question: with a bunch of studies whose names form overly-cute acronyms. We’ll talk here about ROBIN, WATERFALL, MOUNTAIN, and CORAL - though I assure you there are others. ROBIN tested efficacy in postpartum depression. Results were positive and relatively impressive, about the same as the weaker allopregnanolone studies. WATERFALL, MOUNTAIN, and CORAL tested results in regular depression. WATERFALL was positive but weak. MOUNTAIN was negative. That scared the pharma company and they hacked CORAL to be more likely to give positive results. It did give positive results, but the FDA reads the same biotech magazines I do and knows perfectly well what they did, so I don’t know what Sage expects to gain from this. Overall these trials were disappointing. I think the most likely story is that allopregnanolone = zuranolone, both are moderately effective in postpartum depression, and both have much less efficacy in regular depression, probably not literally zero but also not enough to be worthwhile antidepressants (especially considering cost). Might zuranolone be an excellent anti-anxiety medication? You’d think so - it should be at least as good as benzodiazepines, which are excellent anti-anxiety medications. And researchers seem excited about allopregnanolone as a master regulator of brain anxiety. But the studies aren’t promising. ROBIN and WATERFALL incidentally assessed anxiety; ROBIN found good results in its postpartum population, but WATERFALL found poor-to-mediocre results in its regular population. Studies are hard, and sometimes even really effective drugs can have trouble showing strong results. But these aren’t encouraging. 13: So where do we go from here? Getting FDA approval for zuranolone for postpartum depression seems reasonable; it’ll probably be cheaper and easier than making people go to the hospital to get allopregnanolone. I’m uncertain about the financials of this for Sage, but since they did the study they hopefully think it’s worth it. Otherwise, I’m not sure. It would have been great if zuranolone had shown robust efficacy against regular depression and anxiety, but this is exactly the kind of great thing that never happens in psychopharmacology (motto: “Disappointing Doctors And Patients Since 1982”). It might be worth throwing it against anxiety disorders and PTSD to see if anything sticks, but I wouldn’t bet on it. The research into allopregnanolone as master regulator of brain anxiety states is fascinating, but as far as I know it hasn’t reckoned with the failure of zuranolone to really treat much anxiety. The cynical part of me predicts that once pharma’s done making money off neurosteroids then all of this will die down, and something else that pharma can make more money from will become the master regulator of everything. I expect that the main thing we get out of all this is somewhat better post-partum depression treatment, which might or might not ever become accessible for ordinary people. 14: Predictions In the next five years… Zuranolone gets FDA approval for major depression: 15%
Inline links: source, Fluoxetine elevates allopregnanolone levels in female rat brain, The role of allopregnanolone in depressive-like behaviors, This study, is not 100% but still pretty significant, https://substackcdn.com/image/fetch/$s_!WAyF!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F3c4db9d4-d5f8-45cf-8cde-17e2bbd216b6_904x334.png, source, Kanes et al, This followup study by Kanes, https://substackcdn.com/image/fetch/$s_!3b3x!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F63f81091-7084-4ad3-b0a3-28394059b2c3_369x282.png, Meltzer-Brody (2018), https://substackcdn.com/image/fetch/$s_!l7Uh!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F2b579fea-c6c8-4d46-8de7-c4a3e6852766_797x335.png, here, here, 1, 2, one company, has done terribly, this paper, this paper, tried to claim, their answer is, their answer is, it gives vague indeterminate answers, this comment, a very small, very weak study, describes, https://substackcdn.com/image/fetch/$s_!hqfF!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5b386f78-93b3-4d16-98c4-6d2eedef5a1f_548x256.png, ROBIN, WATERFALL, MOUNTAIN, CORAL, to be more likely to give positive results
Notice that lower doses worked better than higher doses. This is sometimes a red flag on a study. But this time it seems legit; see “Biphasic Actions At The GABA-A Receptor” here for an explanation. Both studies also evaluated side effects. These were generally mild, but two people (about 2% of the study population) lost consciousness. Nothing seemed wrong with them, and researchers mostly attributed this to allopregnanolone being a sedating drug. If you sedate people too hard, they pass out. Faced with these results, the FDA approved allopregnanolone for post-partum depression, but subjected it to a REMS (Risk Evaluation And Mitigation Strategy) - basically, doctors who want to prescribe it will need to take special courses and do extra paperwork. This kind of surprised me - there are plenty of sedating drugs that make you pass out in overdose. Also, since patients will be getting it IV, there will probably be a nurse around to check if they passed out and take appropriate actions if so. But the FDA really likes putting restrictions on things, and I guess this was a free chance for them to do that. 4: Is Zulresso freely available at a doctor’s office near me? It’s possible to get Zulresso, but really hard. Because Zulresso is an IV infusion lasting four days, you need to spend four days somewhere that people can put an IV into you and monitor it. Realistically that means a hospital or some other big medical institution. So this is only available for inpatients. Because of the REMS (extra certification and paperwork), most hospitals aren’t interested. You can find a list of ones that are here - it looks like there are about 89 locations in the US with the right certification. Last but not least, a four-day course of Zulresso costs $35,000 for the medication itself, plus much more for the four-day hospitalization it takes to receive it. As usual, insurances will cover it iff you can document you’ve tried lots of other stuff first. 5: Hold on, does it really cost $35,000? Oho, I see you’ve played the “pharma price analysis” game before. But this time I think the price might actually be defensible. Chemical supply companies (1, 2, 3) generally sell allopregnanolone for $10,000 to $20,000 a gram. (I found one company with a much lower price, but I’m suspicious and am going to dismiss them as an outlier). The usual dose of allopregnanolone is 60 ug/kg/hour x 60 hours, which for a 60 kg person comes out to a total of 0.25g total. Getting that amount from the chemistry supply store would cost about $2,500 - 5,000. I assume pharma-grade allopregnanolone is more expensive than chemistry-store-grade, so it wouldn’t surprise me if a price in the low five-figures was justified by manufacturing alone. Isn’t it still a pretty good deal to find an endogenous neurosteroid, do one or two studies confirming it’s great, produce it for the low five figures, then sell it for the mid five figures? I think maybe not. This drug has a terrible value proposition. Post-partum depression is one of the rarer psych conditions. Most people with PPD won’t check into a hospital and pay $35,000 for a drug infusion. And the people who do will get the drug infusion, feel better, and never need it again (at least until they have another kid) - unlike SSRIs where you can keep charging for monthly prescriptions forever. Sage Therapeutics, the pharma company that owns the patent on Zulresso (and nothing else - this is their only drug!) has done terribly. Their stock is in the doldrums, they almost went bankrupt, and they survived only with the help of a cash infusion by a bigger pharma company. I think this confirms a general trend where at least some expensive medications are pricey because of fundamentals (including regulatory fundamentals) and not just pharma companies making obscene profits. 6: Hold on, how is allopregnanolone different from benzodiazepines? Remember, allopregnanolone is a positive allosteric modulator of GABA, much like benzodiazepines such as Xanax. But Xanax is cheap ($10 for 30 pills). And you can get it at any local pharmacy (plus sometimes on street corners). What’s so special about allopregnanolone that you should pay $35,000 and go into the hospital to get it? The official answer is “allopregnanolone modulates GABA differently from benzodiazepines”. For example, this paper says that: Allopregnanolone allosteric modulation of the action of GABA at GABA-A receptors is much less selective than that of benzodiazepines, which are relatively inactive at α4- or α6-containing GABA-A receptors. If you really like details about receptor subunits, this paper presents the full case. The skeptic’s answer is “who knows?” Psych drugs often work for reasons totally different than we thought. People thought tianeptine was an SSRE for years, until it turned out to be a mild opioid. People thought ketamine was NMDA-ergic for years, until it turned out to be [fill this part in 10 years from now]. Last year a bunch of very smart people tried to claim that SSRI effects had nothing to do with serotonin (I think they were wrong). Just because some guy found that Zulresso acts as a GABA-PAM in some test tube doesn’t mean that’s what’s having any of the relevant antidepressant effects. The troll’s answer is “who says it’s different?” Do benzodiazepines treat depression? Depends who you ask. If you ask benzodiazepine users, their answer is “yes, definitely”. If you ask drug warriors, their answer is “Addictive Substances May Make You Temporarily Feel Good, But They Are Not A Responsible Treatment Option”. If you ask the research literature, it gives vague indeterminate answers, as always. But nobody has ever said benzodiazepines instantly and miraculously cure depression, so how come allopregnanolone seems to do that? A true troll would point out that we probably give allopregnanolone at much higher doses - 2% of allopregnanolone patients were sedated so hard they lost consciousness, whereas this is exactly the sort of side effect I try to avoid when calculating benzodiazepine doses. Maybe if you gave postpartum women an infusion of 300 mg Valium, and maximized your placebo effect by calling it the hot new thing, they’d do pretty well too (several days later, after recovering consciousness). I think the troll answer would be hilarious but I don’t really want to defend it as correct; if I had to bet I’d say the official explanation is the right one. 7: Hold on, why can’t we just give people progesterone and let them metabolize it into allopregnanolone? This turned out to be an interesting enough rabbit hole that I’m going to spin it off into another post later this week. 8: Hold on, people have lots of allopregnanolone when they’re pregnant, right? And then post-partum depression happens when they give birth, and their allopregnanolone level drops. So if you give someone an infusion of allopregnanolone, and then take them off it, that’s a hormonal simulation of giving birth, ie the same thing that caused the problem in the first place? How is that good? Oh, you think you’re clever, do you? What you failed to consider is . . . I didn’t end that sentence because I can’t find anything in the literature addressing this question. But the difference might be that the infusion schedule ramps up gradually, peaks, and then ramps down gradually, which is more of a soft taper than the sudden crash of birth. If anyone knows more about this, please let me know. [EDIT: see this comment] 9: Is allopregnanolone addictive? No, because good luck getting addicted to a $35,000-per-dose chemical. We should probably expect allopregnanolone to be addictive, by analogy to other GABA-PAMs like benzodiazepines and alcohol. But nobody has ever received more than a single dose. You don’t get addicted to benzos after a single pill, or alcohol after a single beer, so in practice AFAIK nobody has ever gotten addicted to this. Or who knows, maybe it’s not addictive. Remember, allopregnanolone is naturally elevated during pregnancy; pregnancy isn’t addictive. And some scientists claim the brain endogenously uses allopregnanolone as a master regulator of depression and anxiety. In theory, if you could give yourself the same amount a non-anxious person’s brain gives them all the time, shouldn’t you be no worse off than that non-anxious person? I don’t know, and remember that your brain also has a lot of endogenous opioids; doesn’t make the exogenous kind any safer. The Drug Enforcement Administration has made Zulresso a Schedule IV controlled substance, which means they’re putting a few very weak restrictions on it but not worrying too much. 10: Does allopregnanolone work for depression that isn’t post-partum? If all psychiatric disorders are secretly allopregnanolone imbalances, then you might expect it to work on all depressions, not just post-partum. I’m sure pharmaceutical executives with dollar signs instead of pupils in their eyes have had this same thought, but I can’t find studies about it. Some of the same people behind the postpartum studies did a very small, very weak study on ganaloxone (a close allopregnanolone relative) for persistent depression; it seemed to work, but also caused a lot of sedation (more than in the postpartum trials? Hard to tell). Nobody’s looked into this further since then, maybe because that was around when the pharma companies realized that the 4-day hospital stay and $35,000 price tag made allopregnanolone a financial loser. The evidence from zuranolone (see below) suggests that allopregnanolone might not work very well against regular depression. 11: What is zuranolone? Wikipedia describes zuranolone as “a swirling, black vortex revered by the Mutsune Native Americans as a dire death god . . . also worshiped by mysterious servitors known as the Hidden Ones.” No! Sorry again! That’s Zushakon, another Great Old One. Zuranolone is Sage Therapeutics’ attempt to turn allopregnanolone into an accessible medication that might actually make them real money. Zuranolone is mostly just allopregnanolone with some extra stuff attached that changes the absorption. Zuranolone can be taken orally, so you don’t have to go to a hospital for four days to receive it IV. It’s potentially less likely to cause loss of consciousness and other undesirable side effects. And it’s under investigation as a potential treatment for postpartum depression, bipolar depression, regular depression, insomnia, and various movement disorders. (that might seem excessive, but benzodiazepines treat a lot of stuff, and if these neurosteroids are kind of like super-benzodiazepines, then this level of optimism might be warranted.) 12: Does zuranolone work? Sage Therapeutics answered this question the same way pharma companies answer every question: with a bunch of studies whose names form overly-cute acronyms. We’ll talk here about ROBIN, WATERFALL, MOUNTAIN, and CORAL - though I assure you there are others. ROBIN tested efficacy in postpartum depression. Results were positive and relatively impressive, about the same as the weaker allopregnanolone studies. WATERFALL, MOUNTAIN, and CORAL tested results in regular depression. WATERFALL was positive but weak. MOUNTAIN was negative. That scared the pharma company and they hacked CORAL to be more likely to give positive results. It did give positive results, but the FDA reads the same biotech magazines I do and knows perfectly well what they did, so I don’t know what Sage expects to gain from this. Overall these trials were disappointing. I think the most likely story is that allopregnanolone = zuranolone, both are moderately effective in postpartum depression, and both have much less efficacy in regular depression, probably not literally zero but also not enough to be worthwhile antidepressants (especially considering cost). Might zuranolone be an excellent anti-anxiety medication? You’d think so - it should be at least as good as benzodiazepines, which are excellent anti-anxiety medications. And researchers seem excited about allopregnanolone as a master regulator of brain anxiety. But the studies aren’t promising. ROBIN and WATERFALL incidentally assessed anxiety; ROBIN found good results in its postpartum population, but WATERFALL found poor-to-mediocre results in its regular population. Studies are hard, and sometimes even really effective drugs can have trouble showing strong results. But these aren’t encouraging. 13: So where do we go from here? Getting FDA approval for zuranolone for postpartum depression seems reasonable; it’ll probably be cheaper and easier than making people go to the hospital to get allopregnanolone. I’m uncertain about the financials of this for Sage, but since they did the study they hopefully think it’s worth it. Otherwise, I’m not sure. It would have been great if zuranolone had shown robust efficacy against regular depression and anxiety, but this is exactly the kind of great thing that never happens in psychopharmacology (motto: “Disappointing Doctors And Patients Since 1982”). It might be worth throwing it against anxiety disorders and PTSD to see if anything sticks, but I wouldn’t bet on it. The research into allopregnanolone as master regulator of brain anxiety states is fascinating, but as far as I know it hasn’t reckoned with the failure of zuranolone to really treat much anxiety. The cynical part of me predicts that once pharma’s done making money off neurosteroids then all of this will die down, and something else that pharma can make more money from will become the master regulator of everything. I expect that the main thing we get out of all this is somewhat better post-partum depression treatment, which might or might not ever become accessible for ordinary people. 14: Predictions In the next five years… Zuranolone gets FDA approval for major depression: 15%
Inline links: here, here, 1, 2, one company, has done terribly, this paper, this paper, tried to claim, their answer is, their answer is, it gives vague indeterminate answers, this comment, a very small, very weak study, describes, https://substackcdn.com/image/fetch/$s_!hqfF!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5b386f78-93b3-4d16-98c4-6d2eedef5a1f_548x256.png, ROBIN, WATERFALL, MOUNTAIN, CORAL, to be more likely to give positive results
But recently silexan (derived from lavender) has started to stand out of the crowd. Daily Mail had an interview with psychiatry professor Hans-Peter Volz, who said that silexan should be first-line for anxiety, replacing things like SSRIs and Xanax. And a very reputable professional publication within psychiatry, The Carlat Report, published an article and a podcast touting silexan:
SSRIs, which work fine, but only about half of people respond to them and some people have intolerable side effects.
Now people are saying that silexan works even better than benzodiazepines, doesn’t cause addiction, and has no major side effects! If true, this would change the world. SSRIs changed the world, and they’re nowhere near as impressive as silexan claims to be.
Seen on the subreddit: You Seek Serotonin, But Dopamine Can’t Deliver. Commenters correctly ripped apart its neuroscience; for one thing, there’s no evidence people actually “seek serotonin”, or that serotonin is involved in good mood at all. Sure, it seems to have some antidepressant effects, but these are weak and probably far downstream; even though SSRIs increase serotonin within hours, they take weeks to improve mood. Maxing out serotonin levels mostly seems to cause a blunted state where patients can’t feel anything at all.
Inline links: You Seek Serotonin, But Dopamine Can’t Deliver
I have really low sex drive in certain areas (I sometimes round this off to “asexual”, even though that’s not quite right). This might be because I was on SSRIs for ten years as a kid. Until I was in my mid-20s, I didn’t really realize this. I thought that people talking about teenage boys desperate to see their neighbor naked or something were making humorous exaggerations. Or that I (or my partners) were just unusually bad at sex and eventually I would figure it out (and teenage boys talking about how much they loved sex even though they were sexually inexperienced were just boasting or exaggerating). Eventually I realized that no, I was just missing a very important and very blissful mental experience that a lot of other people had naturally. This has made me more sensitive to believing other people could be having strange mental experiences I’m missing.
You might ask: why was I on SSRIs for several years? Answer - I have a weird subtype of OCD where I feel a strong compulsion to perform certain meaningless actions. For example, it might feel self-evident to me that it’s wrong that my left hand hasn’t touched a certain glass, so I reach out and touch it. I’ve since gotten this mostly under control and I feel fine. But a big part of my inner life seems completely insane to other people and I try not to talk about it very much. This has left me with some sympathy for other people whose inner lives might seem insane to spectators.
Semaglutide is now as searched-for on Google as Prozac or Viagra. Even if this is a temporary Musk-related spike, even pre-Musk it was getting a little above half their level. But Google Trends doesn’t exactly track awareness; few people search for Prozac these days precisely because everyone already knows what it is. So all this tells us is that there’s a lot of buzz around semaglutide. Suppose for the sake of argument that 5% of obese people have heard of this drug. Step 2: Prescription Accessibility The FDA says Wegovy is indicated for obesity, defined as BMI ≥ 30, or for people with BMI ≥ 27 and certain medical conditions. Does that mean that if you have that BMI, your doctor will give you a prescription? I think most doctors will want patients to try diet and exercise first. My experience as a doctor is that most obese people have already considered diet and exercise. Sometimes if you have a very compelling reason and a very well-thought out plan you can get them to try again. But usually they are obese because diet and exercise are hard for them, or don’t work for them, or some other reason besides “they never thought of it”. Still, I hear lots of stories about patient-doctor fights here. I assume this will happen with Wegovy too. Every doctor will have their own threshold for what amount of “already tried diet and exercise” is enough to justify a Wegovy prescription, and sometimes patients won’t meet that threshold. The history of medicine includes the following story many times: there’s some condition that doctors recommend lifestyle changes for. Then an exciting new medication comes out that treats the condition effectively. Over a generation or so, doctors go from demanding the lifestyle change, to gesturing at the lifestyle change before prescribing the medication, to mostly just prescribing the medication. We saw this with cholesterol and statins, with hypertension and ACE inhibitors, with depression and SSRIs. You can form your own opinion on whether this is good or bad, but we’re probably in the very beginning of this process with obesity. Opinions will be all over the map for a while before the inevitable pharma company victory makes everyone agree that semaglutide is first-line therapy. …except that this time, Silicon Valley is short-circuiting the process with fly-by-night telemedicine companies that guarantee you’ll get the drugs you want. For example, NextMed charges $138/month ($99 first month only!) for a guaranteed GLP-1 agonist prescription, plus “support and messaging with expert doctors”. The DEA sometimes shuts these groups down when they start playing around with controlled substances (eg addictive drugs like Adderall), but Wegovy isn’t controlled, and the government probably doesn’t care that much here. These services guarantee that people with money will be able to circumvent conservative doctors and access a prescription. Only 75% of Americans have PCPs at all. If we assume half of them will eventually be able to get a Wegovy prescription from their doctor, that’s 37.5%. Step 3: Affordability Semaglutide costs $15,000/year. Well-off people like Elon Musk might be able to pay that out-of-pocket, but most people will probably need insurance coverage. Right now this is spotty. Medicare doesn’t cover obesity drugs. This isn’t a reaction to the threat of semaglutide-related cost explosions - they’re not that smart. I think Medicare laws were just written in the old days when people were less likely to think of obesity as a disease. Is it time for change? Some Congressmen have proposed a very noble-sounding law telling Medicare and Medicaid to start covering weight loss drugs. I‘m sure this is out of deep compassion for America’s obese population and not because it would make pharma companies one billion zillion dollars. One of the Congressmen even has the last name “Kind!” Some pharma lobbyist probably got a bonus for that one. Private insurers mostly have to cover whatever Medicare does, but they can choose whether or not to include extra non-Medicare-covered drugs. Some have chosen to cover semaglutide under some conditions. Others would prefer not to cover it, but can be scared into covering it by the magic words “medical necessity”. Overall I don’t understand the laws here beyond that maybe they’ll cover it and maybe they won’t. Here, too, it might be time for change. The New York Times is publishing articles trying to convince us that private insurances not covering semaglutide is an outrage. Here in the tiny gray text, I want to take a second to complain about this article. It notes that Wegovy (semaglutide for obesity) costs more per prescription than Ozempic (semaglutide for diabetes), and calls this “a gross inequity”, accusing Novo Nordisk of “charg[ing] people more for the same drug because of their obesity”. But the obesity prescription is higher dose than the diabetes prescription! Milligram per milligram, Wegovy costs *less* than Ozempic! A steelmanned version of the NYT might object - don’t most of the costs come from the intellectual property and not the manufacturing, so that dose shouldn’t matter? Yes, but if you made the obesity version cost too much less per milligram than the diabetes version, then diabetics would cheat the system by buying the obesity version and splitting it into smaller doses! Insurances that do cover it may require extra documentation that the patient has tried lots of diet and exercise, maybe including some official diet-and-exercise program like WeightWatchers. They might also want documentation that patients have tried cheaper earlier-generation weight loss drugs without success. Even when insurances do cover semaglutide, copays may be very high. I have a pretty minimal insurance and it looks like if I got semaglutide my copay would be about $500/month until I reach my out of pocket limit. Harsh. People with better insurances might get hit less hard, but I don’t think anyone will be picking this up for cheap. Let’s say only 5% of people who clear all previous hurdles can afford the drug. How Many People Get Semaglutide? 140 million obese Americans * 25% interested * 5% know of semaglutide’s existence * 37.5% can get prescriptions * 5% can afford it = 33,000, which is a pretty good match for the 50,000 estimated prescriptions. I didn’t even fudge the numbers to come out right, it just happened. The Coming Decade As a service to pharma investors, Morgan Stanley modeled the economic future of obesity medications over the next decade. Their headline result: semaglutide and various semaglutide-copycat-drugs will be a $30 billion market by 2030. That’s less than the $500 billion disaster I was afraid of! But still almost 10% of all US drug spending! Here are two core analyses from the report: The first analysis asks “what if doctors medicalized obesity as comprehensively as they’ve medicalized hypertension and high cholesterol?” That is: what if we put in a society-wide effort to get every obese person to a doctor, and after only a little diet and exercise, the doctor puts them on a medication? They find that the US obesity market would multiply by a factor of 25, to about $87 billion/year. The second analysis is a more realistic projection for the next decade. Two things stand out. First, the number of patients on Wegovy or related medications goes from an estimated 46,910 now (pretty close to my 50,000 estimate!) to 11.3 million in 2030. Second, the cost per prescription goes from $15,000/year to about $4,000 year. Let’s look at this second change in more detail. Right now semaglutide is literally in a class of its own for weight loss. But remember, it started as a GLP-1 agonist diabetes drug. And there are other GLP-1 agonists already in use for diabetes. Novo Nordisk’s competitor Eli Lilly owns a closely related molecule, tirzepatide (Mounjaro®). They’ve already done studies showing it also works very well for weight loss - if anything even better than semaglutide - and they’re expected to get FDA approval to market it as a weight loss medication next year. Although capitalism fans might expect the presence of two competing drugs to immediately drive down prices, this is mysteriously not how things work in health care and prices will probably stay the same in the short term. But several other companies are working on semaglutide-like drugs, some will be cheaper to produce than semaglutide, and Morgan Stanley expects that this stronger level of competition will eventually drive costs down to $350/month ($4,000/year) by 2030. “Mounjaro” sounds like the playful animal sidekick in a Disney movie. From a purely economic perspective, semaglutide costs the health system money (because it’s expensive) but also saves the health system money (because we don’t have to pay for obesity consequences like diabetes and heart attacks). Which effect wins out? According to the Institute for Clinical and Economic Review, benefits would outweigh costs if semaglutide cost less than about $8,000/year. Since it costs $15,000 year now, it’s not cost effective. But if Morgan Stanley’s model comes true and it costs $4,000/year in 2030, then it will be cost effective. So at some point, Medicare (and so insurance companies) may start covering it more out of self-interest. I can’t tell whether the model takes this into account or not. (there’s also a third-level effect where it costs the health system money again, because it prevents people from dying of obesity-related complications, and dead people stop needing expensive health care. I think health economists are supposed to ignore this level.) 11.3 million prescriptions at $4,000/year comes to $45 billion, but Morgan Stanley expects that not everyone will fill their prescriptions consistently or stay on the medication the same amount of time, leading to their $31 billion figure. Towards The Glorious Post-Obesity Transhuman Future The Morgan Stanley report shows that even the greediest pharma investors, openly plotting to medicalize obesity, can’t bring themselves to believe in more than 11 million US semaglutide patients by 2030. That’s less than 10% of the US obese population. Isn’t that kind of disappointing? We’ve got > 100 million people dealing with a condition that not only makes them unhealthy, but also causes them psychological distress, and makes lots of people low-grade disappointed in and repulsed by our society. And we’ve got an effective drug that treats the condition. And we’re going to use it on less than 10% of the people involved? In 2032, semaglutide goes off-patent. It will probably take a few years to sort out legal issues and ramp up generic production, but by the mid-2030s, its price will go way down. I don’t think there are technical barriers to getting it down as low as $10 - $100 per month. By then, maybe there will be even more exciting branded weight loss drugs for wealthy people to choose from. But at the very least, semaglutide itself should become much more widely available even to poor or uninsured patients. I’m not sure what will happen. Will there be an inflection point, where so many people use semaglutide that obesity becomes unusual again, and then the remaining obese people start using it just to fit in? Will obesity become an optional fashion statement, like shaving your head or getting a tattoo? Or will semaglutide end up disappointing us in some way, like so many promising drugs have before? I come at semaglutide from a transhumanist perspective. I want to hack genetics and biology until everyone is as tall as they want, as strong as they want, as smart as they want, and whatever gender they want. If you want wings, you should be able to have wings. And yes, part of this vision is everyone having the weight they want. I’m not sure this will happen, but for the first time I can see a clear path to how it might. Postscript 1: Should You Take Semaglutide? I can’t answer this, please ask your doctor. But I do want to add that there are potential side effects I haven’t mentioned in this post, including nausea, gastrointestinal problems, pancreatitis, and kidney problems. Semaglutide has been accused of slightly increasing risk of pancreatic and thyroid cancers. Studies have found trends in this direction, but these conditions are so rare that even over thousands of patients over many years, the increase hasn’t yet reached clear statistical significance. The current consensus position is that it may increase thyroid cancer by a tiny amount not relevant to most patients, and that it probably doesn’t increase pancreatic cancer. I think my father has looked over these data more and is less sure than other people about the lack of pancreatic cancer risk, but he can’t get the resources he needs to prove anything, and I can’t remember his exact argument. More broadly: like all medications, semaglutide has benefits and risks, and you shouldn’t blindly take it after reading one blog article. Postscript 2: Is There A Way To Cheat The System To Get Semaglutide For Lower Cost? Health care is much like airline tickets: everyone pays a different price for everything and there’s usually a secret way to get what you want for much less money. Is this true of semaglutide? Pharma company Novo Nordisk offers a Savings Card that they say brings the price down to as low as $25 per month. I’m a little suspicious of this - pharma company offers are rarely as good as they sound - but I don’t notice any obvious tricks in this one and it should probably be your first bet. This startup claims that they can get insured people semaglutide for a $25/month copay “after their deductible is met” by negotiating with the insurance company very effectively. I can’t imagine how that works or what they have to negotiate with, but they seem pretty convinced, so I would welcome more information. Otherwise, you don’t have many great options. Although there are two older forms of semaglutide not FDA-approved for weight loss - Ozempic and Rybelsus - these are both more expensive, milligram per milligram, than Wegovy itself. Canada is also of no help. The usual Canadian pharmacies don’t seem to carry Wegovy, and charge about the same amount for Ozempic as American pharmacies do. This article in Drug Discovery Trends says that compounding pharmacies have been selling semaglutide for $300/month, less than a quarter of the sticker price. This is a bit confusing: compounding pharmacies are small local operations permitted to dispense unusual medications by mixing existing ones together in nonstandard ways. They’re arguing that they can legally dispense the semaglutide because they’re mixing it with vitamins, which, fine, but how are they getting it in the first place? Everyone else seems as confused as I am: "Nobody knows how [compounding pharmacies are] getting it," said Karl Nadolsky, an endocrinologist at Spectrum Health. "Who's making it? [The pharma company that makes it] Novo [Nordisk]'s not giving it to them. They're the ones with the rights to the molecule, so how is anybody getting semaglutide?" Has nobody asked compounding pharmacists about this? Do they have a conspiracy of silence? Does the FDA sometimes send their goons in to extract the information, but the compounding pharmacists compound sleeping gas / smoke grenades and vanish into the night? Anyway, the usual authorities warn you not to take compounded semaglutide under any circumstances, but they’re the same people who tell you never to buy drugs from a Canadian pharmacy because they might be adulterated. You can decide how much you want to trust them. Postscript 3: What About Europe And The Rest Of The World? Countries that are not the US usually negotiate with pharmaceutical companies over price. Because of some combination of “negotiation works” and “they are free-riding off Americans’ hard work”, they usually get much lower prices. What does semaglutide cost elsewhere? This is hard to find out because government health agencies sometimes keep their prices secret, plus Wegovy mostly isn’t available in other countries yet. The only information I could find was from Britain, which is in the process of making Wegovy available to patients. It looks like NHS will “restrict the expensive drug’s availability to very obese people attending specialist weight-loss clinics”, but that it might be possible to get it from private clinics for £199/month = £2400/year. Wegovy has been approved in the EU but doesn’t seem to have made it there yet. I can’t find any information about any other country. Non-weight-loss-indicated versions of semaglutide are available in many countries, but I wouldn’t expect their health care systems to be flexible about redirecting it for weight. Canadian regulators have approved Wegovy, but it doesn’t seem to be available there yet. I haven’t seen any evidence that Ozempic costs less in Canada than it does in the US, and I’m not sure why. Maybe the pharma companies have figured out that anything that happens in Canada gets imported into the US, and they’re playing hardball this time. I don’t know whether Canadians will be able to get it for cheaper than Americans or not. Postscript 4: Predictions (all predictions are conditional on no singularity or global catastrophe) 10 million Americans on semaglutide (or yet-to-be-approved equally good or superior alternatives) by 2030: 75%
Inline links: NextMed, a very noble-sounding law, https://substackcdn.com/image/fetch/$s_!l_X7!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F1dbb9e98-6e07-4237-988e-3b7a61af3e5a_1381x834.png, is publishing articles, https://substackcdn.com/image/fetch/$s_!R-zS!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F0f24b293-27de-462a-84fd-bed2ba7cf07f_1723x831.png, modeled the economic future of obesity medications over the next decade, https://substackcdn.com/image/fetch/$s_!zSOS!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F0906b28a-1ad4-421d-a055-87ed95db59ce_918x261.png, https://substackcdn.com/image/fetch/$s_!QJj9!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fb966f730-6b24-48e1-98b1-e710cda9264c_903x656.png, this is mysteriously not how things work in health care, https://substackcdn.com/image/fetch/$s_!5poy!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fc201f05a-7d1f-4738-911f-11d0d051adf9_2880x1562.png, Institute for Clinical and Economic Review, don’t think there are technical barriers, offers a Savings Card, This startup, about the same amount for Ozempic, This article in Drug Discovery Trends, Everyone else seems as confused as I am, NHS will, private clinics
There were some very dubious telemedicine psychiatry startups that would prescribe Adderall or Ritalin, seemed to have very low prescribing standards, and advertised very aggressively on social media. They were previously only doing SSRIs and the like, but moved to ADHD drugs when this became temporarily possible after COVID.
SSRIs help depression: 0.4
Inline links: 0.4
Second, anaesthetics themselves are antidepressants! (thanks to St_Rev for mentioning this). The anaesthetic propofol, used in about 88% of these patients, “may trigger rapid, durable antidepressant effects”, with a purported effect size well above that of SSRIs (these trials are very small, but so was the ketamine trial).
I’m defending ketamine because I’ve seen it work pretty well for a lot of patients. It’s no miracle, and I get exasperated when people want to skip all the normal medications and go straight to ketamine because “I heard SSRIs don’t work but ketamine treats depression at its root”. It just seems to work sometimes, for some people.
And my patients’ experience is that it works even at low doses that produce no dissociative or ego death effect. I usually prescribe it at about 70 mg intranasal. Some of my patients report feeling a little drunk or giddy on this amount, but nothing like the k-hole that people report at the really high levels. Other patients report nothing at all, but still feel better. This makes me doubt that you necessarily need an study under anaesthesia to control for dissociative effects. A simple midazolam active placebo would work fine. But also, SSRI studies have shown that active placebos don’t really work any better than inactive placebos. This might be more true for SSRIs (which have boring side effects) than ketamine (which at least sometimes has exciting ones). But it means that when evaluating normal ketamine studies (which risk confounding through inactive placebos) vs. this study (which risks confounding through anaesthesia and surgery), I’m more likely to just go with the normal ones.
42: A while ago I discussed the “scientific search engine” Consensus; I expressed skepticism that you could make it work without AIs that were good at natural language. Now it’s a few years later, we have AIs that are good at natural language, and Consensus has incorporated them. So how’s it going? I asked it whether SSRIs are safe during pregnancy. It said:
Inline links: Consensus
SSRIs usually are an option during pregnancy . . . risks include high blood pressure for the pregnant person and premature birth. These risks are small. Your health care team watches for them during your prenatal care. Most studies show that SSRIs aren't linked with birth defects. But an SSRI called paroxetine (Paxil) might slightly raise the risk of heart defects in babies when used during the first trimester.
43: New meta-analysis claims that exercise is at least as effective as SSRIs against depression (study, popular article). But Cremieux digs deeper and finds some of the included studies have effect sizes between 5 and 12, too large to possibly be real (he describes this as “like the effect size of taking a punch to the face on having a hurt jaw”). He thinks he’s identified some major coding errors that might be influencing the result.
By then MAOIs were on the way out, and SSRIs were ascendant (and to a lesser extent tricyclics). If we’re really going to get into the weeds, and this is a DFW essay so why not, we might focus in on the fact that MAOIs got ditched not because of their efficacy, but because of side effects: MAOIs work better for many forms of depression than SSRIs. I haven’t found any studies comparing the effects of MAOIs and SSRIs on creativity, but one might speculate that SSRIs, which leave many users complain of creative dysfunction, and which reduce serotonin reuptake in particular parts of the brain, might in a sense bind the brain more tightly than the looser MAOIs, which produce a more global increase across a richer buffet of monoamines. But that’s just speculation.
Society-wide: The marketplace of ideas! This is where everyone gets to have their say. New hypotheses get stress-tested, bounced off against each other, and only the strongest survive. This level also produces true learning - if only one idea survives the marketplace, then average spectators can easily pick it out (although of course it can still be wrong). Its disadvantage is that it’s impossible for several billion people to hold a true “discussion” among themselves. Also, many of these people are extremely stupid, their ideas are bad, and they fill the conversation with noise. Is there a useful group size in between these two? What about discussing ideas in a group made of only the most intelligent and knowledgeable people? This gives you the debate and collaboration functions that you only get in group conversation. But it’ll have a better signal-to-noise ratio than all of society, and it might be small enough to manage. Also, you can make people sign on to good discussion norms before they enter, and you can expel them if they screw up. The Boundary Against The Public From this formulation, it becomes clear that such a priesthood is only useful insofar as it has some kind of barrier between itself and the general public. The priesthoods don’t exactly hate the public. But they hate the idea of letting the public’s ideas mix with their own. It’s not just that they discount the public’s ideas insofar as the public is less sophisticated than themselves. Their whole identity comes from their separation from the public. Ideas that seem too similar to the public’s get actively penalized, the same way it would be hard to convince Democrats to accept a plan that Donald Trump proposed first, even if it otherwise fit with Democratic ideals. I recently reviewed Tom Wolfe’s From Bauhaus To Our House, on the architectural priesthood. It discusses the response when renegade architects would build things in styles favored by the public - for example, Edward Stone and the Kennedy Center: Stone and Saarinen, like Frank Lloyd Wright and Goff and Greene, were too American, which meant both too parochial (not part of the International Style) and too bourgeois. Somehow they actually catered to the hog-stomping Baroque exuberance of American civilization. When Stone designed the Kennedy Center in Washington with a lobby six stories high and six hundred and thirty feet long – so big, as one journalist pointed out, that Mickey Mantle’s mightiest home run would have been just another long fly ball – it was regarded as an obscenity. Stone was actually playing upto American megolomania. He was encouraging the barbaric yawps. He was glorifying The Client’s own grandiose sentiments. More generally: In a way, the very productivity of a man like Wright, Portman, or Stone counted against him, given the new mental atmosphere at the universities. Oh, it was easy enough, one supposed, to go out into the marketplace and wheedle and vamp and dance for clients and get buildings to do. But the brave soul was he who remained within the compound, stayed within the university orbit. Or, from the comments, this quote by architect Peter Eisenman: What I’m suggesting is that if we make people so comfortable in these nice little structures of yours, that we might lull them into thinking that everything’s all right, Jack, which it isn’t. And so the role of art or architecture might be just to remind people that everything wasn’t all right. I used to wonder why so many econ-bloggers I liked were at GMU. GMU only is only the 74th best economics department in the country, but more than half of the econbloggers I like are affiliated with it in some way (Tyler Cowen, Alex Tabarrok, Garett Jones, Robin Hanson, Bryan Caplan, Arnold Kling, Scott Sumner, Mark Koyama, sorry if I’m forgetting anyone!). Granted that some of this is because I lean libertarian and so do they - but I don’t think there’s a mountain of amazing and popular left-wing econbloggers who I’m ignoring. Part of this must be that Mercatus head Tyler Cowen is better at spotting and cultivating talent than others - but you’d still think the #73 ranked department would try to poach some of his hard work. When I asked academics about this, they didn’t find it mysterious at all. The average high-ranked economics department doesn’t care that you have a popular blog. They might even count it against you. Only your reputation within the priesthood matters. This is my experience too. I once got rejected from a psychiatry residency I wanted, partly because they saw I had a blog and thought it might cause trouble (though the less prestigious hospital that eventually accepted me did consider it a plus, for which I remain grateful). I wish I could say that the program which rejected me is kicking themselves right now - I’m probably one of the most-read psychiatrists in the world, and most of what I write is relatively orthodox and (I hope) reflects well on the field. But outside of my fantasies, they are doing nothing of the sort. At best, my blog has gone from a liability to being neutral or a very slight positive. Certainly it doesn’t make me as impressive as someone who went to a medical school one tier above mine. Consider how impressive a boundary this is - someone can have literally tens of thousands of fans for doing popular writing in a field, and the amount of extra status it gives them in the field is within a rounding error of zero. Only your reputation within the priesthood matters. Still, at least I’m a member in good standing. At least I’m higher than pond scum. The lowest-status doctor in the world - the guy who, if doctors were Maoist revolutionaries, would get his face on the “Criticize X, Criticize Y” posters - is Dr. Oz. This isn’t because Dr. Oz lacks medical skill. Back in the day, he was a professor of surgery at Columbia, and by all accounts quite good at it. But then he went on TV and started catering to the public. He told them their stupid miracle cures and $19.99 supplements were Real Medicine. Imagine a Catholic bishop declaring ex cathedra that The Da Vinci Code is 100% real. Authority bestowed to fight the heresies of a fallen world, instead used to prop up those heresies. Columbia recently “cut ties” with Oz in some vague way, but as far as the medical profession is concerned, it’s too little, too late. I think the profession’s hatred for Oz is justified - his claims are false and probably cause a lot of harm. But other doctors who say false harmful things get only a fraction of the hatred that Dr. Oz does. He’s not just defrauding and maybe killing the people who take his supplements. He’s sullying Medicine itself. This hard boundary - this contempt for two-way traffic with the public - might seem harsh to outsiders. But it’s an adaptive artifact produced by cultural evolution as it tries to breed priesthoods that can perform their epistemic function. The outside world is so much bigger than the priesthoods, so much richer, so full of delicious deposits of status waiting to be consumed - that any weaker border would soon be overrun, with all priesthood members trying to garner status with the public directly. Only the priesthoods that inculcated the most powerful contempt for the public survived to have good discussions and output trustworthy recommendations. The Boundary Against Capitalism Dr. Oz illustrates another point: power corrupts, and the priests (as people known to be more knowledgeable than the public) have the power to bless or damn interventions in their field. Without some boundary against capitalism, they would abuse that power to make money. Again, cultural evolution has produced such a boundary. A doctor who seems too mercenary loses status in the priesthood. My father - a much more orthodox (and hence higher-status) member of the medical priesthood than I will ever be - used to even get suspicious of concierge doctors. Was it really in keeping with the principles of medicine to care about the amount of money you got for your service? Shouldn’t the usual insurance payments (calculated behind the scenes, without you ever having to think about it) be enough for anybody? If you let doctors charge extra for their services, they might do bad medicine in order to increase profits. In the worst case scenario, they might flatter members of the public who wanted all-natural $19.99 supplements. This taboo has faded as insurance squeezes doctors harder; even my father eventually relented. But there’s still the sense that doctor is a calling in a way that used-car salesman isn’t. If you pursue money too aggressively, can we really be sure you’ve heard the call? Why doesn’t every doctor pursue their own $19.99 supplement business? Some of this is professional regulation - there’s a sense that probably the Medical Board will come down on you if you do something wrong (though most doctors are proudly ignorant of the exact limits of the Medical Board’s power - why should the pious worry about the exact boundaries of excommunicable offenses?) But most of the barrier comes from self-regulation based on social status. By the time you’re done with medical school and residency, all of your non-doctor friends have long since abandoned you, and all the old sources of status and approval that you used to crave have been excised and replaced with the all-seeing eye of the medical priesthood. If you sell out and start the supplement line, you might get a new Ferrari, but everyone whose opinion you respect will hold you in contempt. The public might think it’s cool that you have a Ferrari, but doctors know better: nobody with a supplement line has ever been cool. This doesn’t mean doctors are incorruptible. Plenty of them become pharma company shills. But that’s because being a pharma company shill doesn’t burn intra-priesthood respect the same way. For better or worse, pharma companies straddle the priesthood boundary. They may not be fellow priests, but they’re at least nuns or deacons or something. They won this by sacrificing certain capitalist parts of themselves (for example, becoming heavily regulated) and by agreeing to follow the norms of the medical priesthood (for example, communicating through papers published in medical journals with high-status doctors as lead authors). Through their sacrifice, they achieve ritual purity; now priests can interact with them guilt-free. Is ritual purity really the same as moral acceptability? Sounds like the kind of question a member of the public might ask! Communication Norms Within The Priesthoods Although priests talk normally when when they meet one another at the water cooler, ex cathedra communication must be performed in a ritually pure way. For the medical priesthood, that means papers published in a medical journal. Consider ritually impure communication - for example, Twitter. Someone may try to make a medical claim (“SSRIs are a great depression treatment!”). But one can’t even predict the genre the reply will take. It could be any of: Insult (“You’re just another a big pharma shill trying to poison us!”)
Inline links: recently reviewed, is only the 74th best, recently “cut ties” with Oz, too little, too late
Extremely erroneous attempt at a statistical claim (“Here’s a survey showing that people who take SSRIs are MORE DEPRESSED than people who don’t, that obviously means that SSRIs cause depression!”)
Hence ritually-pure communication. Only the most expert members of the priesthood are allowed to participate. They must submit their opinions to a medical journal, which will carefully remove all the human element, force them to add whatever hobbyhorse Reviewer #2 is on about that day, and publish a bloodless collection of sentences and figures with a title like “Shmenger And Wong Respond To MacOMillicuddy Et Al On The Possible Benefits Of SSRIs: Did Figure 2 Fail To Control For Age-Related Effects?”. Conversations will be naturally sorted by importance - the most crucial ones in the best journals that everyone reads, less important ones in the smaller journals read only by a specific field. Everyone in the priesthood reads the same few journals and ends up on the same page about the big issues of the day - you can even talk about them in natural language with your friends around the water cooler if you want.
Increased psychiatric care: all of the would-be criminals are on SSRIs, antipsychotics, and Adderall.
Backlinks
- A Look Down Track B
- Adderall
- Attempts To Put Statistics In Context, Put Into Context
- benzodiazepines
- Book Review: Crazy Like Us
- Brands
- Carlat Report
- Concepts: B
- Concepts: P
- Concepts: S
- Contra Resident Contrarian On Unfalsifiable Internal States
- depression
- Does Anaesthesia Prove Ketamine Placebo?
- Eli Lilly
- escitalopram
- fluoxetine
- Highlights From The Comments On Telemedicine Regulations
- imipramine
- ketamine
- ketamine
- Lavender’s Game: Silexan For Anxiety
- Links For February 2024
- Oh, The Places You’ll Go When Trying To Figure Out The Right Dose Of Escitalopram
- On Priesthoods
- paroxetine
- Paxil
- PCPs
- Peer Review Request: Depression
- Platform
- Prozac
- Publications: C
- quetiapine
- Record Low Crime Rates Are Real, Not Just Reporting Bias Or Improved Medical Care
- Semaglutidonomics
- serotonin
- tianeptine
- Unpredictable Reward, Predictable Happiness
- Xanax
- Your Book Review: The Pale King
- Zounds! It’s Zulresso and Zuranolone!