Thanks to everyone who commented on Zounds! It’s Zulresso and Zuranolone and on the followup Progesterone Megadoses Might Be A Cheap Zulresso Substitute. I’m constantly impressed by the expertise of commenters here and on how much better the biomedical comment threads are compared to some of the others. Among the things I learned:

— Metacelsus (who writes the blog De Novo) doubts the price estimates I posted:

There’s no way it costs $10,000 to $20,000 a gram at scale. Those 3 chemical supply companies specialize in having a very large catalog of small quantities of chemicals for biologists to test in their experiments. (I have personally ordered from 2 out of those 3 for my research.) The price they charge per gram is not competitive at all.

He also wrote a longer blog post about the science of progesterone here.

— Douglas (who writes the blog A Mindful Monkey) clears up some mechanism details I missed:

From Stahl’s: ‘the precipitous decline in circulating and presumably brain levels of allopregnanolone hypothetically trigger the onset of a major depressive episode in vulnerable women. Rapidly restoring neurosteroid levels over a 60-hour period rapidly reverses the depression, and the 60 hour period seems to provide the time necessary for postpartum patients to accommodate their lower levels’. So the idea is the taper of the steroid is a helpful part.

Also, (also Stahl’s), there are two GABA-A receptors with comprosied of different sub-units as you mentioned. Benzodiazepines bind to, cleverly named, benzodiazepine-sensitive GABA-A receptors while allopregnalone bind to their cousins- the benzodiazepine-insensitive GABA-A receptor. The former is found post-synaptically and involved with phasic, quick bursts of GABA (i.e. useful information processing) while the latter is found extrasynaptically and involved with tonic (i.e. chronic) ‘tone’ setting of the neuron. So they seem to have very different functions despite both involving GABA.

Stahl’s goes onto say that allopregnanlone ‘hypothetically could cause more efficient information processing in over excited brain circuits causing symptoms of depression’, but that just seems hand-wavy to me.

— Zutano (whose name makes them sound like another novel drug in this class!) debunks my urban legend that the -pam at the end of benzo names (eg “diazepam”) stands for positive allosteric modulator:

I’m gonna go with urban legend for this one. The early benzos look to me to be chemically named; “azepine” is the word for a 7-membered ring made up of 6 carbon atoms and 1 nitrogen, then “diazepine” is the same but with two nitrogens. The first benzo was chlordiazepoxide (Librium), which if you look at the chemical structure on wikipedia, contains chlorine, diazepine and oxide (the oxygen atom). Then next is diazepam, which to me looks like “diazepine” plus “amide” (which is the word for “double-bonded oxygen atom with a nitrogen next door”). 10 years later we get alprazolam, which looks like it was named after the triazole ring (that’s the 5-membered ring with 3 nitrogens), but now the “am” suffix is starting to become generic, to emphasise that its still in the same chemical class as the previous -azepams.

I doubt that the concept of “positive allosteric modulator” existed in 1955 when chlordiazepoxide was invented; in those days drugs were discovered by making random chemicals and feeding them to animals to see what happened. The receptor theory of medchem (i.e. that drugs have a specific biochemical target in the body) is generally credited to James Black and his fellow Nobel laureates, and propranolol (the first drug discovered in the target-based way) wasn’t patented until 1962.

—Jimmy Steier on Twitter gives more information on tolerance development:

Key point missing in this post is that ALLO/zulresso mediates tonic GABA inhibitory tone (as opposed to phasic for benzos). I wouldn’t touch an exogenous analog of ALLO w/ a ten foot pole. Context on severe issues w/ tolerance and withdrawal: Tolerance to allopregnanolone with focus on the GABA-A receptor.

This paper confirms that women with PMDD or PPD (but not other women) get tolerance to allopregnanolone within the normal course of the menstrual cycle or pregnancy. There’s actually a study showing that these women get less effect from benzos during this time, since the allopregnanolone and benzos have cross-tolerance!

— Thomas Reilly has a new blog Rational Psychiatry where he’s written up some more info on premenstrual dysphoria and progesterone. For example:

In an elegant series of experiments, Peter Schmidt and David Rubinow gave participants a medication (leuprolide) that suppresses oestrogen and progesterone. This eliminated PMDD symptoms. Whats more, when they reintroduced either oestrogen or progesterone, symptoms returned.

And:

An RCT (n=206) of isoallopregnanolone (sepranolone) in PMDD did not beat placebo for the primary outcome. However, blocking allopregnanolone production with the 5α-reductase inhibitor dutasteride does seem to work, in a small RCT at least.

See here for further discussion of the failed trial.

— Benjamin Jolley (who writes the blog Ramblings Of A Pharmacist), has a couple interesting comments:

We’ve been giving progesterone for like 4 decades at the compounding pharmacy where I work, and we’ve been talking about its metabolism to allopregnanolone for about 20 years.

Notably, the route of administration MATTERS. A fraction of oral progesterone certainly seems to get metabolized to allopregnanolone and have -pam like effects, so a lot of HRT docs will write oral progesterone for bedtime administration as it seems to help with calming prior to sleep (it’s -pam like, as you lay out, so it’s not dissimilar from giving a z-drug for sleep pharmacologically).

topically administered and injected progesterone doesn’t really seem to have comparable effects, likely due to bypassing the portal circulation and thereby the first-pass effect. At least that’s how this works in my head. The standard of evidence in compounding land is a little lower than in big PhRMA manufacturing land.

Progesterone is also really cheap (at least in comparison to the insanity of brexanolone IV).

the chemical difference between zuranolone and brexanolone is more substantial than the chemical difference between testosterone and estradiol. So… maybe it has the same effects, but maybe it’s too far removed.

— Many commenters took progesterone for one reason or another and said it made them feel either more or less anxious; the thread starts here and keeps going for a bit. For example, Reader:

I take progesterone supplements and find it’s an extremely delicate balance. My natural levels (almost 0, my body struggles to make it for some reason) make me incredibly anxious. 100mg oral supplement makes me feel great and completely erases my anxiety. 200mg or more makes me anxious and slightly depressed. Bodies are delightfully strange and complicated things. :)

And Angela:

I have taken progesterone after several pregnancies to help with post partum depression. If I recall correctly, 100 mg/day does the trick for me. The effect is immediate and astonishing: you go from terrified the baby will die any second, to feeling totally normal. Most women who do this wean themselves off it by 4-6 weeks postpartum in some way. The biggest two side effects are that it can make you very pleasantly sleepy - I can’t imagine waking up to take it every two hours - and that it might keep you from losing weight/cause weight gain. In my own case, I basically just stop taking it once life is returning to normal in other ways (again, after 4-6 weeks).

Leah Libresco Sargent (who writes the blog Other Feminisms):

I took 200-400mg progesterone for fertility reasons without noticeable side effects (other friends found lower doses intolerable). Catholic fertility doctors are more interested in progesterone than the mainstream, and I know friends who were prescribed oral progesterone for PPD/PPA at lower doses that Scott considers here who felt it made a huge, immediate difference. Here’s the major institute behind this: https://popepaulvi.com/

— Slimepriestess on side effects:

I take 200mg of oral progesterone as transfemme hormone therapy, I’ve been on it for a while and I and a good number of other transfemmes I know have experimented with taking high doses of it recreationally.

The claim that progesterone doesn’t have any side effects at the doses you’re talking about is very contrary to a lot of testimonials as well as pharmacological effects that should be kind of obvious. The metabolite you’re trying to maximize here is a a GABA-A receptor agonist, which is going to give it somewhat intoxicating, sedative effects heading towards nauseating and disorienting as dosage trends upwards. It can also significantly spike your libido. These aren’t totally bad effects and they might even be a part of what you want for treating PPD, but saying “there’s no side effects” is just not true.

There’s also multiple kinds of progresterone on the market and non-bioidentical progesterone is much worse than bioidentical, when I was on it for a month it made me suicidally depressed, taking a high dose of that might be legitimately dangerous to someone’s mental health.

Yeah, this has me confused about why pregnancy isn’t more sedating than it is.

In general, I appreciated everyone’s progesterone-related thoughts. I spent most of my career in a clinic with ten psychiatrists. Nine of them were women, the tenth one was me. You can imagine who all the women with female-hormone-related problems didn’t want to see, so my hands-on experience here is more limited than usual. Thanks for filling this gap in my education!