Time heals better than medicine though. After a few days, the improvement in placebo score was far more than any additional benefit generated by BRX60 or 90.
That's true for every medication - regression to the mean. People are usually at their worst right when they sign up to study an experimental new drug, so every drug study shows both groups getting better quickly, and you judge it on how much better the drug group does than placebo.
You're making the mistake of thinking that the Hamilton depression scale is a nice linear thing so that going from baseline to -20% is the same as going from -20% to -40%. This would be an extremely poor assumption. You can see what the scale looks like here: https://dcf.psychiatry.ufl.edu/files/2011/05/HAMILTON-DEPRESSION.pdf
Notice also the questions relating to insomnia, genital symptoms, gastrointestinal symptoms and weight loss, which are all going to naturally be somewhat volatile in pregnant women after giving birth.
That nonlinearity actually supports my statement that time is the most powerful healer. Changes near 0% (closer to self-harm) will be more important than changes near -50% (closer to feeling blue). The initial reduction from 0% to -45% for the placebo vastly outweighs the change from -45% to -60% for BRX60.
This really isn't how it works. If you look at the first three questions on the inventory, they are typically reflective of what most people think of as depression symptoms. They contribute a maximum of 12 points to the score, and to get to that maximum, you have to be in a state where:
* You only talk about how depressed you feel,
* You have lost touch with reality and are experiencing threatening hallucinations,
* You have actively attempted suicide.
You can also get 12 points on the inventory if
* You have severe insomnia,
* Your appetite has gone and you're struggling to eat,
* You feel achy and fatigued,
* Your sex drive has disappeared
So, dropping 12 points on the scale might mean that you're feeling much happier, you're not hearing voices any more, and you're no longer actively trying to kill yourself. It might also mean that your fairly common symptoms of pregnancy have gone away now your baby was born. The scale does not tell you which. The big drop that you see in the first few days in the placebo group is likely just an artifact that the depression inventory was not really designed for pregnant women.
"likely just an artifact that the depression inventory was not really designed for pregnant women"
Wow, that is some serious rhetorical sand being tossed about. What caused the placebo group's HAM-D score to drop from 28.6 (severe depression) to 15 (mild) after 2 days? The BRX60 group's further reduction to 11.1 (mild) is nice, but far less significant. https://pubmed.ncbi.nlm.nih.gov/23759278/
No, it's really not "serious rhetorical sand" and I'm not trying to throw mud at either psychiatric diagnosis in general or this paper. I'm say that when you have a depression inventory where literally half the questionnaire is asking about common side effects of pregnancy you're going to get weird results trying to apply it to women who've just given birth.
So yes, I'm sure you can find a study that correlates HAM-D score with depression severity as measured by subjective judgment of clinicians. How many of the study cohort were pregnant? How many gave birth during the study?
Day 0 in these graphs is not when the women gave birth, so the huge decline in HAM-D scores needs explanation. Women in the study were 6 months post partum or less. "Patients were recruited to clinical research centres and specialised psychiatric units through self-referrals, physician referrals, and radio-based, television-based, and web-based methods." The graphs show that the unspecified non-pharmaceutical interventions (NPI) and time helped more than the pharmaceuticals.
Edit: It seems likely that doubling the NPI would have led to even lower HAM-D scores than the NPI + drugs that were tried.
1. 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.
Of course, if you want to buy 100g of allopregnanolone at $10,000/g, I'd be happy to make it for you.
2. For point 7 ( why not just give people progesterone?) In my opinion it seems like it should work, since it's the relevant precursor (and the fact that progesterone levels decline after birth is what's driving the decline of allopregnanolone). I'm interested in seeing your follow-up.
I was going to ask this about progesterone as well. I know some functional medicine doctors who prescribe oral progesterone to their still-menstruating patients for: insomnia, anxiety, depression, and PMDD. I had it prescribed to me by one to help with insomnia. It didn't help my insomnia, and made me very nauseous (like morning sickness) and depressed, which is what birth control pills did to me in the old days.
Also healthfood stores sell pregnenolone as an OTC supplement for depression, arthritis, etc etc. I don't know that it's absorbed anywhere that it needs to be when taken in that form, but I was curious about whether it's much different from allopregnanolone and whether anyone has studied the efficacy of it as a supplement.
I don't know if this is hocus pocus, but I remember reading that pregnenolone is "the mother of all hormones" in that it's a precursor to DHEA, progesterone, estrogen, etc and that the body kind of knows (?) what downstream hormone to convert it into if given enough supply of it. I've read similar things about Vitamin D. Is all of that nonsense?
From a quick Wiki look at pregnenolone, it looks like its metabolite is a *negative* allosteric modulator of GABA - I don't know if that means it would be prodepressant, but it doesn't seem good for it being antidepressant for the same reasons as Zulresso.
This is curious as elevated progesterone levels (luteal phase of menstrual cycle) have often been linked as cause of mood symptoms such as in PMDD. Also, depression is a common side effect of progestin-containing contraceptives eg. Mirena IUD, depo-Provera, etc.
Another thing about production costs is that the acetate seems like 500x cheaper than the original (270$ for 5G in sigma). I feel like the cost of the acetate is the real production cost (maybe up to 2-4x to get it to pharma grade purity) and the allopregnanolone itself is really inflated.
Created some prediction markets on Manifold Markets for your predictions here (with the starting prediction at your guesses and with the resolve date being March 8, 2027):
Beat me to it. I would have expanded on the description a bit "Another neurosteroid gets FDA approval..." doesn't tell the reader enough without the context of the other predictions.
I wanted the titles to match the predictions given on this post to make them easy to search. I could definitely add something more to the description though
Thanks for doing this, Gabrielle! I've contributed my M$ 20 loan in each market as liquidity for each (we should maybe make this easier to do, instead of having to buy opposite YES and NO shares and guesstimate at the values).
Fellow chemists, help me with something weird about the chemicals I can't figure out: Allopregnanolone on Sigma costs 225$ for 10milligrams, but its acetate, which is essentially just adding a bit on the -OH group in the corner, costs nearly 500 times less! (270$ for 5 grams).
The chemical has only one hydroxyl group. No funky site-specific games are needed. Adding or removing the acetate on it should be extremely easy - acetic anhydride-alcohol condensation reactions (and the opposite - ester hydrolysis to alcohol and acid) are taught in 2nd year orgo labs. I find it hard to believe that running this reaction on 5 grams of the acetate costs 498 times more than the starting material.
I also don't think it's just purity - the acetate says 98%, but neither of them are listed as "pharmaceutical standard" (and those tend to be ~2-4x as expensive, not 500x). Purification costs money, but not *that* much.
Could it be a regulatory/tax issue? Or is there actual production chemistry I'm missing?
I don't know anything about chemical production, but could it just be an issue of scale? If there's not much demand for either one, a minor difference in production could dominate.
Yeah it may be that no one ever needs more than 10mg APG in research, although I wonder who buys 5gr of the acetate then...
Like, if I needed 2gr of APG I would buy the acetate and do the hydrolysis myself, but if I only need 10mg I'll just save time and buy the APG directly. So the cost may be inflated by this cliff of tiny amounts (plus always by the fact that it's grant money, not your own), but the acetate is a better reflection of actual production costs.
Well, the obvious issue is that any straightforward hydrolysis of that ester bond is going to have lowish yield (because of the reversibility of hydrolysis in general) and more importantly produce a racemic mixture, and trying to separate the enantiomer you want from the other one might be quite expensive. What will be the difference in column times? Pretty darn small, is my guess.
If I had to guess, though, I'd guess neither of those are coming from any organic synthesis at all, but rather both are purified from natural sources. If nothing else, they're only showing one enantiomer for both. So the price difference may simply reflect the relative expense of the underlying natural source, whatever it is, plus the purification process, whatever it is.
Sigma Aldrich's prices are just really ridiculous. For example they charge $27.4/MG or $27,400/g for MDMA. https://www.sigmaaldrich.com/US/en/product/cerillian/m013 that's 274x its cost when sold as a drug which is already heavily inflated from its production cost
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.
I’m curious… I have PPD and have been greenlit for Zulresso. I previously had a bad experience with Xanax (made my depression worse) it was an Acute reaction…never had a benzo before that. But I’ve also used progesterone supplements in the past with no depression side effects. Any idea if Zulresso May act like the Xanax?
I have PMDD, klonapin made my depression worse. I've tried various BC's with little success. Anyone well versed in psychiatry want to study me ? I'd love to find a drug that works. (This is mostly facetious of course, but if someone is genuinely interested...)
Obligatory I'm-not-trained-in-the-thing warning, but here are my thoughts.
Did klonopin make your depression worse acutely (right after you took it), chronically (over the span of a few weeks), or both? If the answer is acutely or both, one starting point might be negative modulators of the GABA-A receptor. Some accessible ones are the neurosteroid pregnenolone, and the herbs Ginkgo Biloba and Oroxylum Indicum. Start slow though—if you're prone to anxiety, these can cause or exacerbate it.
After that, I would try tianeptine (potentially addictive if you go above recommended dosages, but relatively safe if you stay in the recommended range). For me, this drug does almost nothing if I'm feeling fine, but when I'm experiencing depressive emotions, it takes me back to feeling fine within an hour and a half at most. But this is not typical—it should have an effect even on your "good" days.
Coincidence but I was researching zulresso and zushakon just yesterday.
Is PPD just depression after a specific event? Maybe?
I found some interesting results regarding the difference between plain major depressive episodes and PPD or PND. One study found that between women who were 0–12 months postpartum and women of childbearing age who were outside of the peripartum period rates of PPD and other depressive episodes did not differ in a statistically significant way (10.2% vs. 13.1%, respectively).
Additionally, people with a history of depression are significantly more likely to develop PPD. People who experience traumatic births (emergency C sections, long hard labors) are also more likely to develop PPD.
However, another study found that if women developed PPD in the first 8 weeks after birth the symptoms were more severe, more likely to be passed on, and had some epigenetic markers (not really sure what that means).
One issue is that PPD isn't well defined, some include developing symptoms up to 12 months after birth however others only include 6,8,12 weeks.
I always wonder how much stress accounts for PPD, and what buffering factors a new mom has in the face of these multiple new stressors -- pain, sleep deprivation, relentless new caregiving demands, isolation, social pressures, new fears, etc etc.
I haven't looked at this research recently, but I think women with high ACEs scores (childhood adversity) are at higher risk for PPD as well. Someone with a lot of prior adversity fares less well in the face of more adversity with inadequate social supports. Someone with prior adversity is less likely to have adequate social supports later.
I know those life history and environmental factors aren't the only ones and that genetics plays a part as well, but those factors seem to be under addressed, also probably because can't be solved with any amount of medication.
I also wonder how much the benefit of GABA agonists is because it calms a bunch of the nervous system's reactions to stress, so that it creates the effect of reducing stress without actually reducing the external stressors. So many of the people I see who are depressed use the word "overwhelmed" to describe much of their experience of daily life. They seem to be chronically in fight, flight, or freeze mode and then suffering the relentless self-criticism of feeling that they shouldn't be feeling overwhelmed and that there's something fundamentally broken about them that they do feel that way. If you back off someone's feeling of overwhelm, it seems to back off their self-criticism about it as well, all of which leads to feeling better.
Entertaining, but not informative. Hard to say what medical science will say, if anything. They seem more interested in things that treat symptoms rather than diseases. Long term treatments seem to also be preferred by patients, too. Endless jabbering about their rare medical conditions seems to be the only activity that older people find enjoyable. Even Hugh Hefner seemed to enjoy talking about his (occasional, of course) flaccidity.
I wonder about the nutritional component or the use of oral pregnenalone. Rather to flood the body with additional supplies of hormonal building blocks rather than to attempt to up or down regulate various metabolic processes.
An extra 50mg a day of a 50 cent pill would be more viable for more people than some 4 day IV solution for 35k which almost no one would get until after their symptoms were already very bad. Even if pregnenalone capsules were not quite as good...perfect is the enemy of good.
It is a cheap and easy solution, hence probably one which would not get big pharma research dollars.
And in general a more nutrient oriented approach for post-partum issues when a woman's body is already going through an enormous torrent of metabolic changes seems like a wiser and more precautionary approach.
If there is a hole in a bucket and that hole will likely heal itself over time...then we can simply add more water for a little while until the natural process heals the vast majority of such holes.
This may be better than seeking out other interventions to speed up the rate the body/bucket will notice there is a leak or try to heal the hole faster by forcing the healing process.
I wonder if it'd be helpful to have women at risk for PPD do a blood draw before giving birth and then get their own blood serum injected into them afterwards to even out the hormone shift....
I think that would be really inefficient. Assuming that some hormone goes from 100% to 0% and you want it to be at 50%, wouldn't you have to inject an amount of blood equal to half the person's total blood volume? (which would then dilute the hormones further and I don't want to do the math to figure out where this would stop)
I'm really curious about the progesterone->allopregnanolone thing. I find that I need to take the progesterone part of my feminizing HRT shortly before bed, because it tends to make me a bit drunk and sleepy. That's a known side-effect and I would love to know how and in what form it crosses into the brain to do that, given what you said in this post.
I'll talk about this more Thursday, but I think normal doses of progesterone produce non-trivial amounts of allopregnanolone and it would make sense for this to be the mechanism for your sleepiness.
I take Micronor, a low dose (35 microgram) progesterone to control endometriosis symptoms. I used to take a low dose estrogen, but it might have increased my BP, so the gynac suggested switching.
I didn't know there were psychiatric implications for progesterone! I wish I could get off it. The hope is to reach a cessation of periods due to menopause, at which point the endometriosis will likely resolve itself, but I'm 52 and that has still not occurred. Sometimes I wonder if taking Micronor is delaying that.
Bioidentical progesterone is apparently a lot better in terms of long-term negative effects than synthetic progestins (that's why my doctor prescribes it), but it may not work for your needs and it is more expensive, I believe. As to Micronor possibly delaying menopause, that would be a really interesting question to ask an endocrinologist.
So apparently 13% of US adults are on some form of antidepressant, including 18% of women. This is up significantly in the last ten years.
I can't help but be reminded of the recent and equally American phenomenon of the over-prescription of painkillers, which everyone now seems to think was a Bad Idea. According to the popular narrative, some Big Bad Drug Companies managed to persuade everyone that any level of pain at all was unacceptable and should be treated with painkillers, damn the consequences.
Would it be reasonable to say that the Big Bad Drug Companies are doing similar things in the depression world, trying to pathologise ordinary levels of depression into something that requires drugs?
I don't accept the standard narrative on painkillers; I think the pharma companies were largely correct, the scale of the problem mostly exaggerated, and said problem coming almost entirely from a very small subset of doctors and users — who knew exactly what they were doing.
***
E.g., most doctors prescribed responsibly; the ones flooding areas with oxycodone were prescribing amounts that even the most optimistic drug company literally didn't get within a *tenth* of.
In other words, it wasn't innocent doctors being brainwashed by pharma companies, and innocent users being pushed into huge amounts of opioids: the patients getting inhuman amounts of oxycodone on a first visit knew exactly what they were getting, and the doctors prescribing them were well aware.
Tearful media portrayals of a young man who was "forced" into addiction be damned; very few of these, if looked into further, turn out to actually be cases of "he was just prescribed a few pills and then he got addicted!" E.g., again, one famous short documentary covered a fellow who supposedly was pushed into ridiculous amounts by his doctor... and then you notice, in the interviews with his friends, *he went to that doctor to get more painkillers* — because he was *already* abusing them.
***
The question of "pseudo-addiction" also gets raised, usually derisively. But I have worked with people in real agony, and I have seen firsthand that the exact things a supposed abuser does are the same things someone who really needs some pain relief does; in both cases, it's simply behavior motivated by a very strong desire — of course they'll be similar. Denying someone medication because they really want it removes some chance of abuse, but it also removes some chance of palliating the suffering of someone who is genuinely in torment.
In my mind, the kinder option — the one that provides the most utility to the most people, certainly — is to err the other direction. But people love a witch hunt.
Pain relief, which was already (ask anyone with chronic pain) damned hard to get if you weren't a certain type of person (obviously infirm, elderly, etc), is now even harder. (But at least drug overdoses have completely stopped... wait... they didn't? Shit.)
"Denying someone medication because they really want it removes some chance of abuse, but it also removes some chance of palliating the suffering of someone who is genuinely in torment."
Reminds me of Scott's description of painting words to the effect of "take two aspirin and call me in the morning" on a rock. And, about as effective to someone in need.
This is a good comment. I've been thinking this for a while.
I think for most of the people that do get addicted to pain-killers out of the blue, what's happening is basically this: they have been living most of their life with some form of emotional pain that they may or may not have learned to cope with. They hurt their back on the job and get an oxycontin script, which fixes their back pain, but also fixes their emotional pain, making them feel normal for the first time in at least a very long time.
Most of these people, I think, are not addicted to getting high or even taking the pills to get high. They're just taking them because they suddenly realize it's possible to feel not bad. But tolerance obviously rises over time.
Personally, I'd rather let five people get addicted to oxycontin than let one person remain in moderate to severe pain. I don't think this is an objective moral judgement—it's mostly just based on my feeling that I'd rather be addicted to an opioid than in severe pain.
Alternative hypothesis: doctors wrote prescriptions like "take 1 pill every 6 hours" and then the patients did exactly that until the sudden stop at the end. Whereas the doctor should have emphasized that was the upper limit and that the patient should use them as sparingly as possible, tapering off as quickly as possible.
I work with Heroin addicts. I have experienced severe pain and have on some occasions taken opioids. The addiction and the pain scenarios both suck. For anyone with bad pain, the route is to find out and treat the causative lesion at all means. Best do it before you get addicted.
Naw, problem is just that Prozac Deficiency Disorder is on the rise, and pharma's doing its heroic best to save the public from the tragic deficiency disease of our age.
My thought is that we've already discovered a type of medication that works amazingly well for depression, anxiety, and nearly any other sort of suffering as well: the humble (yet loyal) opioid.
So we have a system in the brain that is directly linked to feeling good and suppressing pain. And we know opioids cause the most direct, intense and unalloyed mood lift available, and essentially erase depressive systems when administered (even and especially in treatment-resistant cases). And we know all kinds of other things in the brain can go a little bit wrong in subtle yet upsetting ways.
This suggests to me that probably a lot of cases of depression are due to some sort of malfunction with the individual's endogenous opioid peptides.
It also suggests to me that it's unsurprising when the search for something that will work just as well is littered with disappointments — anything that worked as immediately and dramatically as morphine would seemingly also have to be hitting some sort of "FEEL BETTER" button pretty hard, and the mOR is about the best one of those we've got.
Any miracle drug for depression would probably be found to just be an opioid in disguise, as indeed has happened more than once before (I predicted this, and was right about it, with kratom, tianeptine, and — possibly — also ketamine, though that one's still up in the air).
Tianeptine apparently doesn't develop tolerance at clinical dosages. I'm not sure how true this is—I can try to find the studies if you're interested.
Also, NMDA antagonists seem to prevent opioid tolerance to some extent, as does agmatine.
I think there also might be some promise to kappa opioid antagonists. Kappa agonists tend to be dysphoric, and I believe activation of the kappa receptor inhibits dopaminergic transmission in the nucleus accumbens. Unfortunately, I don't think there are any viable selective kappa antagonists yet. JDTic seems promising, but comes with some side effects, and I believe it actually destroys the kappa receptors (in the same way irreversible MAOIs destroy the MAO enzyme) which could be a problem.
My father in India has cervical spondilosis. He wakes up from sleep with a head, back or shoulder ache. It gets better with massage, hot pad.
He was told it sounds like muscle tension maybe pinching on a nerve or a few ...
His cardiologist gave him Gabapentin 100 mg twice a day (sounds like what you talk about) for it. Sleepiness and feeling a bit off balance when walking have been 2 side effects of it. It made him so drowsy during the day that he decided to stop it. He tried a 100 mg once a day first.
It has been a week since he stopped that, and the side effects are not fully gone. Here, we don't get to see good doctors easily. There is a long wait.
I wonder if he should play with the dosage to fix the headaches and not have these effects. We found Lyrica to be similar (googlimg, not from a doctor) here at 75 mg, as Gabapentin is a capsule and 100 mg is the lowest. Is there a way to get advice on how to play with the dosage?
It reduced the frequency of waking up with pain, but the drowsiness all day was unbearable. He is an intellectually active, happy person as such. He is 87 by the way.
There are very few specialists who are good. The city has a population of > 11 million.
The few specialists who are good, have so many patients, that appointments with them are hard to get. And then on the appointment day, you're expected to wait for hours, because they don't give anyone a specific appointment time. Very hard for an elderly person.
Once you get in to see the doctor, they'll typically spend almost as much time as you want with you (hence the lack of specific appointment time, I guess...each appointment takes an unpredictable amount of time).
This is typical in India for the top doctors. Unless you're well connected politically or some sort of big shot, and then you can get whatever you like.
Here's something that's worth a try for your father's pan: Look at the Pain Science site, run by Paul Ingraham. He is very smart, sensible and no-bullshit. I have a lot of back pain from well-documented and unfixable problems, and some of his tips have helped me a lot. Best for me is lying on my back with a hard rubber ball under me, scooting around til I feel it's on a "trigger point," then putting my weight on it. Gives very substantial pain reduction for the rest of the day. Pain always comes back, but then I just do the same thing the next day and it works again.
Sounds weird to me. I wouldn't treat such pain with Pregabalin or Gabapentin. It doesn't sound like neuropathic pain. Pregabalin addiction seems to be harder to shake off than benzodiazepine addiction. The risks of falls with injuries must be considered. Aren't there any good bodyworkers he can go to? Maybe the hot pads contribute to chronification, such things have been reported.
Pregnanolone (an isomer of allopregnanolone) is being studied to treat loneliness / perceived social isolation. I have tried it a few times... can't say I noticed much effect but I only tried it 2-3 times.
Given that loneliness is a rampant public health crisis, the fact that it has a fairly unique biological mechanism (neurons in the dorsal raphe nucleus), and the fact that loneliness is said to be worse for your health than smoking cigarettes, an effective medication for it would be amazing.
Only thing I would say is to note that pregnenolone, because it is downstream of a ton of hormones, can have a lot of disparate effects depending how it is used by your body. It's not something most people should take regularly.
>>The “-pam” at the end 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.
That definitely hasn't been proven and I would only give it about 50-50 odds, but my real question is where you're getting ketamine nasal sprays for $5.
I don't, just a say. But this thing is super expensive and I bet they only tested it against a non active placebo. You can get a lot of false positives like that and that is all they need to get FDA approval. Show me a test against generic SSRI and against generic ketamine showing that is more effective and then we talk about $35,000. (The FDA does not ask for this). The moment I read that this drug is for "postpartum depression" I started to be very suspicious. How can the drug know what kind of depression you have? Big pharma can do a lot of good, like the covid vaccines, but also a.lot of BS.
Progesterone cream is already available OTC for $15. It absorbs transdermally into the bloodstream and thence is metabolized into the same thing as that $35,000 IV. A quick google search seems to indicate widespread off-label use of progesterone cream to treat PPD.
You don’t typically get significant serum levels of progesterone with the available OTC progesterone creams. Have not been shown to be efficacious at least for other clinical endpoints such as endometrial protection. Transdermal patch is an alternative, but not available as micronized progesterone just synthetic progestins.
Correct. My comment had more to do with the formulation i.e. compounded vs FDA-approved, rather than the route of administration. Agree that TD or vaginal > oral.
I'm afraid that I'm a massive cynic of anti-depressants per se. Get into the cold sea, get out walking and stay largely away from coffee and alcohol and other stuff. Listen to Mozart, simplify your life, be with good people if you can, get fresh air, talk to strangers with kind faces, smile.
> 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.
It wasn't clear if this is sarcasm that I'm missing, or if you really believe that the FDA cares about studies that game the system? I thought (maybe I'm misremembering) that you have in the past on this very substack lamented about how the FDA is at least mildly broken and it is well known how to game it by pharmaceutical companies?
Or perhaps I was over-reading between the lines to make your statements align with my own internal personal narratives. 🤷
The FDA has many problems, but I don't think they will accept "we couldn't find an effect on day 15, so we changed our endpoint to day 7 instead". Maybe I'm being too optimistic.
Opioids are very effective antidepressants; no one feels depressed while taking heroin for the first time. The problem is tolerance: Take the same dose of heroin every day and by day 7 it will have little to no effect, meaning you have to increase the dose to keep it effective. All drugs that increase happiness exhibit this phenomenon to a greater or lesser extent.
So the problem isn’t that we don’t have an effective treatment for depression. The problem is that effective depression treatments i.e. drugs that directly increase happiness, cause tolerance.
We therefore need to shift our pharmaceutical efforts away from producing endless variants of pharmaceuticals witch already exist (SSRIs, SNRIs, PAMs) and towards understanding and preventing tolerance.
We need to start developing and co-testing various anti-tolerance drugs with opioids to find a drug cocktail that prevents opioid tolerance. We can then administer this cocktail to anyone with depression, anxiety or any other kind of pain without risking addiction.
QRI sometimes thinks about this - see https://qualiacomputing.com/2018/11/07/anti-tolerance-drugs/ . I think it would be hard to sell the establishment on because antitolerance drugs don't necessarily make things less addictive or dangerous.
Definitely harder to sell to the establishment than conventional depression medication, but ketamine and tianeptine are approved for depression treatment despite both having addictive potential.
There are two ways something can be addictive: Addiction because you like a thing a lot, and addiction because you suffer withdrawal symptoms without it. Opioid addiction can cause both types, but the serious problem with opioid addiction is the latter. Withdrawal symptoms don’t occur without tolerance, so eliminating tolerance eliminates the most addictive quality of the drug.
What makes opioids dangerous? It’s my understanding that the physical dangers of opioids (respiratory depression and needle usage) come from dose escalation. In the absence of tolerance, a strong opioid effect can be produced from a safe oral dose, and most opioids don’t cause toxicity with chronic use.
The QRI article you linked puts this better than I can and I’m very happy to learn that you are familiar with their work.
Like someone else mentioned, oral progesterone makes you feel very drunk and sleepy, likely because of conversion to allopregnanolone in the liver. I’m assuming the logic for not using oral progesterone is variance in liver enzymes which would lead to unstable and somewhat unpredictable amounts of allopregnanolone in the brain (waiting for the next post), in the same way SSRIs are prescribed instead of 5-HTP. However, from personal experience, it’s the best antidepressant and anti anxiety medication I have tried (and I have tried everything there is) and the results blew me away. My anxiety and depression vanished for the time I was taking oral progesterone, and it didn’t make me apathetic unlike SSRI/SNRIs, nor did it make me feel like I was drunk during the day like benzodiazepines. I am glad these molecules are being investigated for their antidepressant properties.
Oral progesterone is not absorbed quite as well as intramuscular or vaginal forms (at least for uterine/pregnancy indications). But seems to work well for menopausal symptoms.
If the mechanism of post-partum depression is a sudden decrease in GABA stimulation, how come it looks so different (clinically) from alcohol withdrawal or benzo withdrawal? People with alcohol withdrawal (or benzo withdrawal, which works via the same mechanism) have tremors, sweats, racing heart rates, and can have seizures if it's bad enough.
By the way, this isn't to say that I don't think allopregnalonone works! More so that GABA stimulation doesn't seem like it would be the mechanism?
> 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.
What biotech magazines? I'm curious, and I want to read them!
> 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).
Comedy is bringing someone who ODd by taking a whole bottle of benzos to the ER and watching the physician swear. There's a reversal agent for benzos (flumazenil), but it has enough side-effects and risks that it isn't used unless it's really dire. So instead you need to find the patient an ICU bed for a couple of days to nap. You can't use a regular hospital bed because you need to account for the possible respiratory depression. But the ICU doesn't want to deal with this stuff, either.
re your #7, 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).
re zuranolone - a thought here - 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.
But I'm a pharmacist, not a medicinal chemist, so maybe I've got this wrong.
also, you've now done a small bit on three of the main interesting drugs that I see in the compounding world, and I agree with your take on all of them. ivermectin, ketamine and (progesterone, but a derivative). Do "low-dose" naltrexone next. I'd love to hear your take on that one, because it's definitely doing SOMETHING, but I'm fairly certain that the adage "the more things it purports to treat, the more likely it treats none of them" probably applies here. See, for example, this bit of marketing: https://ldnresearchtrust.org/what-is-low-dose-naltrexone-ldn
But given my anecdotal experience with folks that take the stuff swearing it cures all of the things, I'm hesitant to say it doesn't in the absence of strong evidence to the contrary.
I don't understand LDN either. My guess (very weak) is that you gain some kind of weird backwards tolerance to it which upregulates the endogenous opioid system, and having higher opioid levels makes everything feel better.
I've read LDN acts as an immune suppressant. The dose of naltrexone that hits TLR-4 is lower than the dose that hits opioid receptors, so you can calm down the wayward microglia without involving the opioid system too much. Can't find the exact reference I was thinking of here, but it could have come via this really interesting Nature article that ties together the opioid system, the immune system, and pregnancy hormones: https://www.nature.com/articles/d41586-019-00895-3
Hey Scott, just wanted to thank you for covering this topic. Hormones and their side effects can feel like a plague on the female body, especially since they are so poorly understood. The limited knowledge leaves women to rely on anecdote and trial by error to manage something that affects quality of life at nearly every waking moment (ok and sleeping moments too). Seems like the curiosity on this topic among researchers is not commensurate to percentage of humanity impacted. Looking forward to your post on progesterone.
Evolution would tend to make it addictive. Plus, when you consider how inconvenient and dangerous it is, not to mention how much it f'n hurts to give birth, maybe addiction is playing some role?
Okay, I get it, I get it, evolution has dealt with this problem primarily by making sex addictive and . . . oh, hey, pregnancy, where did that come from? But still, do we really know? What's the evidence that you can't get hooked on pregnancy?
One of the key aspects of chemical products is their ability to be tailored to meet specific needs. Through chemical synthesis and formulation, products can be designed with precise characteristics, such as improved durability, enhanced performance, or reduced environmental impact.
"Crunchy elderly multigravida" has to be the coolest new phrase I have heard in a long time.
> As usual, insurances will cover it iff you can document you’ve tried lots of other stuff first, but I imagine
Lose something? :)
Sorry, thanks.
Oh, ha, I had assumed that was deliberate and the next question was supposed to be interrupting you!
Same! (Although to be fair I would have expected a dash at the end of the sentence to make it unambiguous.)
Time heals better than medicine though. After a few days, the improvement in placebo score was far more than any additional benefit generated by BRX60 or 90.
That's true for every medication - regression to the mean. People are usually at their worst right when they sign up to study an experimental new drug, so every drug study shows both groups getting better quickly, and you judge it on how much better the drug group does than placebo.
https://www.clinicaloptions.com/-/media/oncology/programs/parpi-in-ovarian/module-thumbs/ovarian-cancer_clinicalimpact-tu_2019_thumb-09.png
PFS = progression-free survival
You're making the mistake of thinking that the Hamilton depression scale is a nice linear thing so that going from baseline to -20% is the same as going from -20% to -40%. This would be an extremely poor assumption. You can see what the scale looks like here: https://dcf.psychiatry.ufl.edu/files/2011/05/HAMILTON-DEPRESSION.pdf
Notice also the questions relating to insomnia, genital symptoms, gastrointestinal symptoms and weight loss, which are all going to naturally be somewhat volatile in pregnant women after giving birth.
That nonlinearity actually supports my statement that time is the most powerful healer. Changes near 0% (closer to self-harm) will be more important than changes near -50% (closer to feeling blue). The initial reduction from 0% to -45% for the placebo vastly outweighs the change from -45% to -60% for BRX60.
This really isn't how it works. If you look at the first three questions on the inventory, they are typically reflective of what most people think of as depression symptoms. They contribute a maximum of 12 points to the score, and to get to that maximum, you have to be in a state where:
* You only talk about how depressed you feel,
* You have lost touch with reality and are experiencing threatening hallucinations,
* You have actively attempted suicide.
You can also get 12 points on the inventory if
* You have severe insomnia,
* Your appetite has gone and you're struggling to eat,
* You feel achy and fatigued,
* Your sex drive has disappeared
So, dropping 12 points on the scale might mean that you're feeling much happier, you're not hearing voices any more, and you're no longer actively trying to kill yourself. It might also mean that your fairly common symptoms of pregnancy have gone away now your baby was born. The scale does not tell you which. The big drop that you see in the first few days in the placebo group is likely just an artifact that the depression inventory was not really designed for pregnant women.
"likely just an artifact that the depression inventory was not really designed for pregnant women"
Wow, that is some serious rhetorical sand being tossed about. What caused the placebo group's HAM-D score to drop from 28.6 (severe depression) to 15 (mild) after 2 days? The BRX60 group's further reduction to 11.1 (mild) is nice, but far less significant. https://pubmed.ncbi.nlm.nih.gov/23759278/
No, it's really not "serious rhetorical sand" and I'm not trying to throw mud at either psychiatric diagnosis in general or this paper. I'm say that when you have a depression inventory where literally half the questionnaire is asking about common side effects of pregnancy you're going to get weird results trying to apply it to women who've just given birth.
So yes, I'm sure you can find a study that correlates HAM-D score with depression severity as measured by subjective judgment of clinicians. How many of the study cohort were pregnant? How many gave birth during the study?
Day 0 in these graphs is not when the women gave birth, so the huge decline in HAM-D scores needs explanation. Women in the study were 6 months post partum or less. "Patients were recruited to clinical research centres and specialised psychiatric units through self-referrals, physician referrals, and radio-based, television-based, and web-based methods." The graphs show that the unspecified non-pharmaceutical interventions (NPI) and time helped more than the pharmaceuticals.
Edit: It seems likely that doubling the NPI would have led to even lower HAM-D scores than the NPI + drugs that were tried.
Some quick comments (might post more later):
Edit: the long version about progesterone became long enough to be its own blog post, which is now here: https://denovo.substack.com/p/progesterone-explained
1. 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.
Of course, if you want to buy 100g of allopregnanolone at $10,000/g, I'd be happy to make it for you.
2. For point 7 ( why not just give people progesterone?) In my opinion it seems like it should work, since it's the relevant precursor (and the fact that progesterone levels decline after birth is what's driving the decline of allopregnanolone). I'm interested in seeing your follow-up.
Re 2 - See part 7 of this post - at the risk of spoiling my planned Thursday post, this would totally work and we're being dumb by not trying it.
Ahh sorry I somehow missed that part! I edited my above comment. It would interfere with the menstrual cycle though.
I was going to ask this about progesterone as well. I know some functional medicine doctors who prescribe oral progesterone to their still-menstruating patients for: insomnia, anxiety, depression, and PMDD. I had it prescribed to me by one to help with insomnia. It didn't help my insomnia, and made me very nauseous (like morning sickness) and depressed, which is what birth control pills did to me in the old days.
Also healthfood stores sell pregnenolone as an OTC supplement for depression, arthritis, etc etc. I don't know that it's absorbed anywhere that it needs to be when taken in that form, but I was curious about whether it's much different from allopregnanolone and whether anyone has studied the efficacy of it as a supplement.
I don't know if this is hocus pocus, but I remember reading that pregnenolone is "the mother of all hormones" in that it's a precursor to DHEA, progesterone, estrogen, etc and that the body kind of knows (?) what downstream hormone to convert it into if given enough supply of it. I've read similar things about Vitamin D. Is all of that nonsense?
From a quick Wiki look at pregnenolone, it looks like its metabolite is a *negative* allosteric modulator of GABA - I don't know if that means it would be prodepressant, but it doesn't seem good for it being antidepressant for the same reasons as Zulresso.
This is curious as elevated progesterone levels (luteal phase of menstrual cycle) have often been linked as cause of mood symptoms such as in PMDD. Also, depression is a common side effect of progestin-containing contraceptives eg. Mirena IUD, depo-Provera, etc.
Another thing about production costs is that the acetate seems like 500x cheaper than the original (270$ for 5G in sigma). I feel like the cost of the acetate is the real production cost (maybe up to 2-4x to get it to pharma grade purity) and the allopregnanolone itself is really inflated.
https://www.sigmaaldrich.com/US/en/product/sigma/p8004
https://www.sigmaaldrich.com/US/en/product/sigma/p8887
Created some prediction markets on Manifold Markets for your predictions here (with the starting prediction at your guesses and with the resolve date being March 8, 2027):
Zuranolone gets FDA approval for major depression: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-ma
Zuranolone gets FDA approval for postpartum depression: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-po
Zuranolone gets FDA approval for some other condition: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-so
Another neurosteroid gets FDA approval for a psychiatric indication: https://manifold.markets/Gabrielle/another-neurosteroid-gets-fda-appro
Researchers become more convinced that allopregnanolone is an important regulator of brain anxiety states (at least as important as serotonin): https://manifold.markets/Gabrielle/researchers-become-more-convinced-t
The scientific consensus is still that allopregnanolone works by modulating GABA receptors in a way importantly different from benzodiazepines: https://manifold.markets/Gabrielle/the-scientific-consensus-is-still-t
Beat me to it. I would have expanded on the description a bit "Another neurosteroid gets FDA approval..." doesn't tell the reader enough without the context of the other predictions.
I wanted the titles to match the predictions given on this post to make them easy to search. I could definitely add something more to the description though
Thanks for doing this, Gabrielle! I've contributed my M$ 20 loan in each market as liquidity for each (we should maybe make this easier to do, instead of having to buy opposite YES and NO shares and guesstimate at the values).
Fellow chemists, help me with something weird about the chemicals I can't figure out: Allopregnanolone on Sigma costs 225$ for 10milligrams, but its acetate, which is essentially just adding a bit on the -OH group in the corner, costs nearly 500 times less! (270$ for 5 grams).
https://www.sigmaaldrich.com/US/en/product/sigma/p8887
https://www.sigmaaldrich.com/US/en/product/sigma/p8004
The chemical has only one hydroxyl group. No funky site-specific games are needed. Adding or removing the acetate on it should be extremely easy - acetic anhydride-alcohol condensation reactions (and the opposite - ester hydrolysis to alcohol and acid) are taught in 2nd year orgo labs. I find it hard to believe that running this reaction on 5 grams of the acetate costs 498 times more than the starting material.
I also don't think it's just purity - the acetate says 98%, but neither of them are listed as "pharmaceutical standard" (and those tend to be ~2-4x as expensive, not 500x). Purification costs money, but not *that* much.
Could it be a regulatory/tax issue? Or is there actual production chemistry I'm missing?
I don't know anything about chemical production, but could it just be an issue of scale? If there's not much demand for either one, a minor difference in production could dominate.
Yeah it may be that no one ever needs more than 10mg APG in research, although I wonder who buys 5gr of the acetate then...
Like, if I needed 2gr of APG I would buy the acetate and do the hydrolysis myself, but if I only need 10mg I'll just save time and buy the APG directly. So the cost may be inflated by this cliff of tiny amounts (plus always by the fact that it's grant money, not your own), but the acetate is a better reflection of actual production costs.
Chemical pricing is weird, especially for small quantities. There's no chemical issue why one would cost that much more.
Well, the obvious issue is that any straightforward hydrolysis of that ester bond is going to have lowish yield (because of the reversibility of hydrolysis in general) and more importantly produce a racemic mixture, and trying to separate the enantiomer you want from the other one might be quite expensive. What will be the difference in column times? Pretty darn small, is my guess.
If I had to guess, though, I'd guess neither of those are coming from any organic synthesis at all, but rather both are purified from natural sources. If nothing else, they're only showing one enantiomer for both. So the price difference may simply reflect the relative expense of the underlying natural source, whatever it is, plus the purification process, whatever it is.
Sigma Aldrich's prices are just really ridiculous. For example they charge $27.4/MG or $27,400/g for MDMA. https://www.sigmaaldrich.com/US/en/product/cerillian/m013 that's 274x its cost when sold as a drug which is already heavily inflated from its production cost
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.
Thanks!
I’m curious… I have PPD and have been greenlit for Zulresso. I previously had a bad experience with Xanax (made my depression worse) it was an Acute reaction…never had a benzo before that. But I’ve also used progesterone supplements in the past with no depression side effects. Any idea if Zulresso May act like the Xanax?
I have PMDD, klonapin made my depression worse. I've tried various BC's with little success. Anyone well versed in psychiatry want to study me ? I'd love to find a drug that works. (This is mostly facetious of course, but if someone is genuinely interested...)
Obligatory I'm-not-trained-in-the-thing warning, but here are my thoughts.
Did klonopin make your depression worse acutely (right after you took it), chronically (over the span of a few weeks), or both? If the answer is acutely or both, one starting point might be negative modulators of the GABA-A receptor. Some accessible ones are the neurosteroid pregnenolone, and the herbs Ginkgo Biloba and Oroxylum Indicum. Start slow though—if you're prone to anxiety, these can cause or exacerbate it.
After that, I would try tianeptine (potentially addictive if you go above recommended dosages, but relatively safe if you stay in the recommended range). For me, this drug does almost nothing if I'm feeling fine, but when I'm experiencing depressive emotions, it takes me back to feeling fine within an hour and a half at most. But this is not typical—it should have an effect even on your "good" days.
Coincidence but I was researching zulresso and zushakon just yesterday.
Is PPD just depression after a specific event? Maybe?
I found some interesting results regarding the difference between plain major depressive episodes and PPD or PND. One study found that between women who were 0–12 months postpartum and women of childbearing age who were outside of the peripartum period rates of PPD and other depressive episodes did not differ in a statistically significant way (10.2% vs. 13.1%, respectively).
Additionally, people with a history of depression are significantly more likely to develop PPD. People who experience traumatic births (emergency C sections, long hard labors) are also more likely to develop PPD.
However, another study found that if women developed PPD in the first 8 weeks after birth the symptoms were more severe, more likely to be passed on, and had some epigenetic markers (not really sure what that means).
One issue is that PPD isn't well defined, some include developing symptoms up to 12 months after birth however others only include 6,8,12 weeks.
Links:
https://focus.psychiatryonline.org/doi/10.1176/appi.focus.20190045
https://www.ncbi.nlm.nih.gov/books/NBK519070/
I always wonder how much stress accounts for PPD, and what buffering factors a new mom has in the face of these multiple new stressors -- pain, sleep deprivation, relentless new caregiving demands, isolation, social pressures, new fears, etc etc.
I haven't looked at this research recently, but I think women with high ACEs scores (childhood adversity) are at higher risk for PPD as well. Someone with a lot of prior adversity fares less well in the face of more adversity with inadequate social supports. Someone with prior adversity is less likely to have adequate social supports later.
I know those life history and environmental factors aren't the only ones and that genetics plays a part as well, but those factors seem to be under addressed, also probably because can't be solved with any amount of medication.
I also wonder how much the benefit of GABA agonists is because it calms a bunch of the nervous system's reactions to stress, so that it creates the effect of reducing stress without actually reducing the external stressors. So many of the people I see who are depressed use the word "overwhelmed" to describe much of their experience of daily life. They seem to be chronically in fight, flight, or freeze mode and then suffering the relentless self-criticism of feeling that they shouldn't be feeling overwhelmed and that there's something fundamentally broken about them that they do feel that way. If you back off someone's feeling of overwhelm, it seems to back off their self-criticism about it as well, all of which leads to feeling better.
Entertaining, but not informative. Hard to say what medical science will say, if anything. They seem more interested in things that treat symptoms rather than diseases. Long term treatments seem to also be preferred by patients, too. Endless jabbering about their rare medical conditions seems to be the only activity that older people find enjoyable. Even Hugh Hefner seemed to enjoy talking about his (occasional, of course) flaccidity.
I wonder about the nutritional component or the use of oral pregnenalone. Rather to flood the body with additional supplies of hormonal building blocks rather than to attempt to up or down regulate various metabolic processes.
An extra 50mg a day of a 50 cent pill would be more viable for more people than some 4 day IV solution for 35k which almost no one would get until after their symptoms were already very bad. Even if pregnenalone capsules were not quite as good...perfect is the enemy of good.
It is a cheap and easy solution, hence probably one which would not get big pharma research dollars.
And in general a more nutrient oriented approach for post-partum issues when a woman's body is already going through an enormous torrent of metabolic changes seems like a wiser and more precautionary approach.
If there is a hole in a bucket and that hole will likely heal itself over time...then we can simply add more water for a little while until the natural process heals the vast majority of such holes.
This may be better than seeking out other interventions to speed up the rate the body/bucket will notice there is a leak or try to heal the hole faster by forcing the healing process.
(I think it’s NMDA, not NDMA)
Sorry, fixed.
I wonder if it'd be helpful to have women at risk for PPD do a blood draw before giving birth and then get their own blood serum injected into them afterwards to even out the hormone shift....
I think that would be really inefficient. Assuming that some hormone goes from 100% to 0% and you want it to be at 50%, wouldn't you have to inject an amount of blood equal to half the person's total blood volume? (which would then dilute the hormones further and I don't want to do the math to figure out where this would stop)
I'm really curious about the progesterone->allopregnanolone thing. I find that I need to take the progesterone part of my feminizing HRT shortly before bed, because it tends to make me a bit drunk and sleepy. That's a known side-effect and I would love to know how and in what form it crosses into the brain to do that, given what you said in this post.
I'll talk about this more Thursday, but I think normal doses of progesterone produce non-trivial amounts of allopregnanolone and it would make sense for this to be the mechanism for your sleepiness.
I take Micronor, a low dose (35 microgram) progesterone to control endometriosis symptoms. I used to take a low dose estrogen, but it might have increased my BP, so the gynac suggested switching.
I didn't know there were psychiatric implications for progesterone! I wish I could get off it. The hope is to reach a cessation of periods due to menopause, at which point the endometriosis will likely resolve itself, but I'm 52 and that has still not occurred. Sometimes I wonder if taking Micronor is delaying that.
Bioidentical progesterone is apparently a lot better in terms of long-term negative effects than synthetic progestins (that's why my doctor prescribes it), but it may not work for your needs and it is more expensive, I believe. As to Micronor possibly delaying menopause, that would be a really interesting question to ask an endocrinologist.
We usually recommend taking progesterone at night because it has been shown to help with sleep disruption which is a common menopausal symptom.
So apparently 13% of US adults are on some form of antidepressant, including 18% of women. This is up significantly in the last ten years.
I can't help but be reminded of the recent and equally American phenomenon of the over-prescription of painkillers, which everyone now seems to think was a Bad Idea. According to the popular narrative, some Big Bad Drug Companies managed to persuade everyone that any level of pain at all was unacceptable and should be treated with painkillers, damn the consequences.
Would it be reasonable to say that the Big Bad Drug Companies are doing similar things in the depression world, trying to pathologise ordinary levels of depression into something that requires drugs?
I don't accept the standard narrative on painkillers; I think the pharma companies were largely correct, the scale of the problem mostly exaggerated, and said problem coming almost entirely from a very small subset of doctors and users — who knew exactly what they were doing.
***
E.g., most doctors prescribed responsibly; the ones flooding areas with oxycodone were prescribing amounts that even the most optimistic drug company literally didn't get within a *tenth* of.
In other words, it wasn't innocent doctors being brainwashed by pharma companies, and innocent users being pushed into huge amounts of opioids: the patients getting inhuman amounts of oxycodone on a first visit knew exactly what they were getting, and the doctors prescribing them were well aware.
Tearful media portrayals of a young man who was "forced" into addiction be damned; very few of these, if looked into further, turn out to actually be cases of "he was just prescribed a few pills and then he got addicted!" E.g., again, one famous short documentary covered a fellow who supposedly was pushed into ridiculous amounts by his doctor... and then you notice, in the interviews with his friends, *he went to that doctor to get more painkillers* — because he was *already* abusing them.
***
The question of "pseudo-addiction" also gets raised, usually derisively. But I have worked with people in real agony, and I have seen firsthand that the exact things a supposed abuser does are the same things someone who really needs some pain relief does; in both cases, it's simply behavior motivated by a very strong desire — of course they'll be similar. Denying someone medication because they really want it removes some chance of abuse, but it also removes some chance of palliating the suffering of someone who is genuinely in torment.
In my mind, the kinder option — the one that provides the most utility to the most people, certainly — is to err the other direction. But people love a witch hunt.
Pain relief, which was already (ask anyone with chronic pain) damned hard to get if you weren't a certain type of person (obviously infirm, elderly, etc), is now even harder. (But at least drug overdoses have completely stopped... wait... they didn't? Shit.)
"Denying someone medication because they really want it removes some chance of abuse, but it also removes some chance of palliating the suffering of someone who is genuinely in torment."
Reminds me of Scott's description of painting words to the effect of "take two aspirin and call me in the morning" on a rock. And, about as effective to someone in need.
This is a good comment. I've been thinking this for a while.
I think for most of the people that do get addicted to pain-killers out of the blue, what's happening is basically this: they have been living most of their life with some form of emotional pain that they may or may not have learned to cope with. They hurt their back on the job and get an oxycontin script, which fixes their back pain, but also fixes their emotional pain, making them feel normal for the first time in at least a very long time.
Most of these people, I think, are not addicted to getting high or even taking the pills to get high. They're just taking them because they suddenly realize it's possible to feel not bad. But tolerance obviously rises over time.
Personally, I'd rather let five people get addicted to oxycontin than let one person remain in moderate to severe pain. I don't think this is an objective moral judgement—it's mostly just based on my feeling that I'd rather be addicted to an opioid than in severe pain.
Alternative hypothesis: doctors wrote prescriptions like "take 1 pill every 6 hours" and then the patients did exactly that until the sudden stop at the end. Whereas the doctor should have emphasized that was the upper limit and that the patient should use them as sparingly as possible, tapering off as quickly as possible.
Agreed. We should be treating more temporary medications the way we do steroids and taper them.
I work with Heroin addicts. I have experienced severe pain and have on some occasions taken opioids. The addiction and the pain scenarios both suck. For anyone with bad pain, the route is to find out and treat the causative lesion at all means. Best do it before you get addicted.
Naw, problem is just that Prozac Deficiency Disorder is on the rise, and pharma's doing its heroic best to save the public from the tragic deficiency disease of our age.
My thought is that we've already discovered a type of medication that works amazingly well for depression, anxiety, and nearly any other sort of suffering as well: the humble (yet loyal) opioid.
So we have a system in the brain that is directly linked to feeling good and suppressing pain. And we know opioids cause the most direct, intense and unalloyed mood lift available, and essentially erase depressive systems when administered (even and especially in treatment-resistant cases). And we know all kinds of other things in the brain can go a little bit wrong in subtle yet upsetting ways.
This suggests to me that probably a lot of cases of depression are due to some sort of malfunction with the individual's endogenous opioid peptides.
It also suggests to me that it's unsurprising when the search for something that will work just as well is littered with disappointments — anything that worked as immediately and dramatically as morphine would seemingly also have to be hitting some sort of "FEEL BETTER" button pretty hard, and the mOR is about the best one of those we've got.
Any miracle drug for depression would probably be found to just be an opioid in disguise, as indeed has happened more than once before (I predicted this, and was right about it, with kratom, tianeptine, and — possibly — also ketamine, though that one's still up in the air).
Tianeptine apparently doesn't develop tolerance at clinical dosages. I'm not sure how true this is—I can try to find the studies if you're interested.
Also, NMDA antagonists seem to prevent opioid tolerance to some extent, as does agmatine.
I think there also might be some promise to kappa opioid antagonists. Kappa agonists tend to be dysphoric, and I believe activation of the kappa receptor inhibits dopaminergic transmission in the nucleus accumbens. Unfortunately, I don't think there are any viable selective kappa antagonists yet. JDTic seems promising, but comes with some side effects, and I believe it actually destroys the kappa receptors (in the same way irreversible MAOIs destroy the MAO enzyme) which could be a problem.
My father in India has cervical spondilosis. He wakes up from sleep with a head, back or shoulder ache. It gets better with massage, hot pad.
He was told it sounds like muscle tension maybe pinching on a nerve or a few ...
His cardiologist gave him Gabapentin 100 mg twice a day (sounds like what you talk about) for it. Sleepiness and feeling a bit off balance when walking have been 2 side effects of it. It made him so drowsy during the day that he decided to stop it. He tried a 100 mg once a day first.
It has been a week since he stopped that, and the side effects are not fully gone. Here, we don't get to see good doctors easily. There is a long wait.
I wonder if he should play with the dosage to fix the headaches and not have these effects. We found Lyrica to be similar (googlimg, not from a doctor) here at 75 mg, as Gabapentin is a capsule and 100 mg is the lowest. Is there a way to get advice on how to play with the dosage?
It reduced the frequency of waking up with pain, but the drowsiness all day was unbearable. He is an intellectually active, happy person as such. He is 87 by the way.
'Here, we don't get to see good doctors easily. There is a long wait.'
What do you mean?
There are very few specialists who are good. The city has a population of > 11 million.
The few specialists who are good, have so many patients, that appointments with them are hard to get. And then on the appointment day, you're expected to wait for hours, because they don't give anyone a specific appointment time. Very hard for an elderly person.
Once you get in to see the doctor, they'll typically spend almost as much time as you want with you (hence the lack of specific appointment time, I guess...each appointment takes an unpredictable amount of time).
This is typical in India for the top doctors. Unless you're well connected politically or some sort of big shot, and then you can get whatever you like.
Here's something that's worth a try for your father's pan: Look at the Pain Science site, run by Paul Ingraham. He is very smart, sensible and no-bullshit. I have a lot of back pain from well-documented and unfixable problems, and some of his tips have helped me a lot. Best for me is lying on my back with a hard rubber ball under me, scooting around til I feel it's on a "trigger point," then putting my weight on it. Gives very substantial pain reduction for the rest of the day. Pain always comes back, but then I just do the same thing the next day and it works again.
Sounds weird to me. I wouldn't treat such pain with Pregabalin or Gabapentin. It doesn't sound like neuropathic pain. Pregabalin addiction seems to be harder to shake off than benzodiazepine addiction. The risks of falls with injuries must be considered. Aren't there any good bodyworkers he can go to? Maybe the hot pads contribute to chronification, such things have been reported.
Pregnanolone (an isomer of allopregnanolone) is being studied to treat loneliness / perceived social isolation. I have tried it a few times... can't say I noticed much effect but I only tried it 2-3 times.
https://www.smithsonianmag.com/innovation/can-pill-fight-loneliness-180971435/
https://www.theguardian.com/lifeandstyle/2020/aug/06/loneliness-cure-pill-research-scientists
Given that loneliness is a rampant public health crisis, the fact that it has a fairly unique biological mechanism (neurons in the dorsal raphe nucleus), and the fact that loneliness is said to be worse for your health than smoking cigarettes, an effective medication for it would be amazing.
Wow, that's really interesting. Any tips on how to try this stuff?
Only thing I would say is to note that pregnenolone, because it is downstream of a ton of hormones, can have a lot of disparate effects depending how it is used by your body. It's not something most people should take regularly.
>>The “-pam” at the end 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.
Darn.
Further reading on that last sentence, mostly free of chemistry:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1369014/
I’ve used propranolol and it was great. It made me a much better StarCraft player and much less socially awkward.
So the medication costs $35,000. Is it more effective than a $5 ketamine nasal spray? I kind of don't trust big pharma.
That definitely hasn't been proven and I would only give it about 50-50 odds, but my real question is where you're getting ketamine nasal sprays for $5.
I don't, just a say. But this thing is super expensive and I bet they only tested it against a non active placebo. You can get a lot of false positives like that and that is all they need to get FDA approval. Show me a test against generic SSRI and against generic ketamine showing that is more effective and then we talk about $35,000. (The FDA does not ask for this). The moment I read that this drug is for "postpartum depression" I started to be very suspicious. How can the drug know what kind of depression you have? Big pharma can do a lot of good, like the covid vaccines, but also a.lot of BS.
At the prices charged by compounding pharmacies, I can imagine one squirt would be in that price range.
> psychopharmacology (motto: “Disappointing Doctors And Patients Since 1982”)
What's the significance of the 1982 date?
It's another Z -- Zelmid (zimeldine) was released in Europe in March 1982, the earliest approval for an SSRI.
>>ROBIN, WATERFALL, MOUNTAIN, and CORAL
Now, hold on here.
ROBIN sacrifices herself to allow the Comet King to defeat Hell.
The Comet King fights Thamiel's army of demons using a WATERFALL from a broken dam.
A MOUNTAIN gets blown up when Sohu fights Thamiel and his forces.
Now where does CORAL come from here?
Coral grows under the sea, which is where they must go to find the answer
[epistemic status: kinda speculative]
Progesterone cream is already available OTC for $15. It absorbs transdermally into the bloodstream and thence is metabolized into the same thing as that $35,000 IV. A quick google search seems to indicate widespread off-label use of progesterone cream to treat PPD.
You don’t typically get significant serum levels of progesterone with the available OTC progesterone creams. Have not been shown to be efficacious at least for other clinical endpoints such as endometrial protection. Transdermal patch is an alternative, but not available as micronized progesterone just synthetic progestins.
transdermal bioavailability 10% exceeds oral bioavailability 2.4% though
Correct. My comment had more to do with the formulation i.e. compounded vs FDA-approved, rather than the route of administration. Agree that TD or vaginal > oral.
"pregnancy isn’t addictive" wait what? It definitely is for some. Just like opioids, actually.
I'm afraid that I'm a massive cynic of anti-depressants per se. Get into the cold sea, get out walking and stay largely away from coffee and alcohol and other stuff. Listen to Mozart, simplify your life, be with good people if you can, get fresh air, talk to strangers with kind faces, smile.
> 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.
It wasn't clear if this is sarcasm that I'm missing, or if you really believe that the FDA cares about studies that game the system? I thought (maybe I'm misremembering) that you have in the past on this very substack lamented about how the FDA is at least mildly broken and it is well known how to game it by pharmaceutical companies?
Or perhaps I was over-reading between the lines to make your statements align with my own internal personal narratives. 🤷
The FDA has many problems, but I don't think they will accept "we couldn't find an effect on day 15, so we changed our endpoint to day 7 instead". Maybe I'm being too optimistic.
Following on from what Himaldr said:
Opioids are very effective antidepressants; no one feels depressed while taking heroin for the first time. The problem is tolerance: Take the same dose of heroin every day and by day 7 it will have little to no effect, meaning you have to increase the dose to keep it effective. All drugs that increase happiness exhibit this phenomenon to a greater or lesser extent.
So the problem isn’t that we don’t have an effective treatment for depression. The problem is that effective depression treatments i.e. drugs that directly increase happiness, cause tolerance.
We therefore need to shift our pharmaceutical efforts away from producing endless variants of pharmaceuticals witch already exist (SSRIs, SNRIs, PAMs) and towards understanding and preventing tolerance.
We need to start developing and co-testing various anti-tolerance drugs with opioids to find a drug cocktail that prevents opioid tolerance. We can then administer this cocktail to anyone with depression, anxiety or any other kind of pain without risking addiction.
That's very interesting to learn, thank you.
QRI sometimes thinks about this - see https://qualiacomputing.com/2018/11/07/anti-tolerance-drugs/ . I think it would be hard to sell the establishment on because antitolerance drugs don't necessarily make things less addictive or dangerous.
Definitely harder to sell to the establishment than conventional depression medication, but ketamine and tianeptine are approved for depression treatment despite both having addictive potential.
There are two ways something can be addictive: Addiction because you like a thing a lot, and addiction because you suffer withdrawal symptoms without it. Opioid addiction can cause both types, but the serious problem with opioid addiction is the latter. Withdrawal symptoms don’t occur without tolerance, so eliminating tolerance eliminates the most addictive quality of the drug.
What makes opioids dangerous? It’s my understanding that the physical dangers of opioids (respiratory depression and needle usage) come from dose escalation. In the absence of tolerance, a strong opioid effect can be produced from a safe oral dose, and most opioids don’t cause toxicity with chronic use.
The QRI article you linked puts this better than I can and I’m very happy to learn that you are familiar with their work.
Like someone else mentioned, oral progesterone makes you feel very drunk and sleepy, likely because of conversion to allopregnanolone in the liver. I’m assuming the logic for not using oral progesterone is variance in liver enzymes which would lead to unstable and somewhat unpredictable amounts of allopregnanolone in the brain (waiting for the next post), in the same way SSRIs are prescribed instead of 5-HTP. However, from personal experience, it’s the best antidepressant and anti anxiety medication I have tried (and I have tried everything there is) and the results blew me away. My anxiety and depression vanished for the time I was taking oral progesterone, and it didn’t make me apathetic unlike SSRI/SNRIs, nor did it make me feel like I was drunk during the day like benzodiazepines. I am glad these molecules are being investigated for their antidepressant properties.
Oral progesterone is not absorbed quite as well as intramuscular or vaginal forms (at least for uterine/pregnancy indications). But seems to work well for menopausal symptoms.
That might be a reach, but are you posting about postpartum depression as a roundabout way to celebrate international women's day?
No.
Looking forward to the next post! I'm curious about the possible effects of progesterone on PMDD and I hope you'll discuss them.
If the mechanism of post-partum depression is a sudden decrease in GABA stimulation, how come it looks so different (clinically) from alcohol withdrawal or benzo withdrawal? People with alcohol withdrawal (or benzo withdrawal, which works via the same mechanism) have tremors, sweats, racing heart rates, and can have seizures if it's bad enough.
By the way, this isn't to say that I don't think allopregnalonone works! More so that GABA stimulation doesn't seem like it would be the mechanism?
See Douglas' comment above - https://astralcodexten.substack.com/p/zounds-its-zulresso-and-zuranolone/comment/5447835
Ahh thank you Scott!
> 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.
What biotech magazines? I'm curious, and I want to read them!
the Demon-name is apt for a Sci who forces Swim Tests.
Pretty sure the suffix is "-azepam" and comes from "benzodiAZEPine AMide" since that describes the basic chemical structure.
> 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).
Comedy is bringing someone who ODd by taking a whole bottle of benzos to the ER and watching the physician swear. There's a reversal agent for benzos (flumazenil), but it has enough side-effects and risks that it isn't used unless it's really dire. So instead you need to find the patient an ICU bed for a couple of days to nap. You can't use a regular hospital bed because you need to account for the possible respiratory depression. But the ICU doesn't want to deal with this stuff, either.
Would it be possible to combine this in a depo- form for non-inpatient administration? Or would the sedating effects still be of concern?
re your #7, 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).
re zuranolone - a thought here - 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.
But I'm a pharmacist, not a medicinal chemist, so maybe I've got this wrong.
also, you've now done a small bit on three of the main interesting drugs that I see in the compounding world, and I agree with your take on all of them. ivermectin, ketamine and (progesterone, but a derivative). Do "low-dose" naltrexone next. I'd love to hear your take on that one, because it's definitely doing SOMETHING, but I'm fairly certain that the adage "the more things it purports to treat, the more likely it treats none of them" probably applies here. See, for example, this bit of marketing: https://ldnresearchtrust.org/what-is-low-dose-naltrexone-ldn
But given my anecdotal experience with folks that take the stuff swearing it cures all of the things, I'm hesitant to say it doesn't in the absence of strong evidence to the contrary.
I don't understand LDN either. My guess (very weak) is that you gain some kind of weird backwards tolerance to it which upregulates the endogenous opioid system, and having higher opioid levels makes everything feel better.
I've read LDN acts as an immune suppressant. The dose of naltrexone that hits TLR-4 is lower than the dose that hits opioid receptors, so you can calm down the wayward microglia without involving the opioid system too much. Can't find the exact reference I was thinking of here, but it could have come via this really interesting Nature article that ties together the opioid system, the immune system, and pregnancy hormones: https://www.nature.com/articles/d41586-019-00895-3
What doses do you give it in when you want to metabolize it to allopregnanolone? Does anybody prescribe it for PPD? On what schedule?
Hey Scott, just wanted to thank you for covering this topic. Hormones and their side effects can feel like a plague on the female body, especially since they are so poorly understood. The limited knowledge leaves women to rely on anecdote and trial by error to manage something that affects quality of life at nearly every waking moment (ok and sleeping moments too). Seems like the curiosity on this topic among researchers is not commensurate to percentage of humanity impacted. Looking forward to your post on progesterone.
Do we know that pregnancy is not addictive?
Evolution would tend to make it addictive. Plus, when you consider how inconvenient and dangerous it is, not to mention how much it f'n hurts to give birth, maybe addiction is playing some role?
Okay, I get it, I get it, evolution has dealt with this problem primarily by making sex addictive and . . . oh, hey, pregnancy, where did that come from? But still, do we really know? What's the evidence that you can't get hooked on pregnancy?
The names pharma comes up with for these new drugs are such grotesque, cynical neologisms. Yurolone, stabomab, perkopam. Fuck that shit.
One of the key aspects of chemical products is their ability to be tailored to meet specific needs. Through chemical synthesis and formulation, products can be designed with precise characteristics, such as improved durability, enhanced performance, or reduced environmental impact.
https://www.echemi.com/