Sorry, this seems like an exceptionally silly study. I don't think it proves anything other than asking people questions about how many times they've had disturbed sleep, appetite or various kinds of thoughts immediately after major surgery is really silly (as you say but I'd go further and say it doesn't even conflict with claims about placebo).

Why didn't they administer a follow up 2 weeks later? That's an awful lot of trouble and expense to go to not to bother.

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The sample size was only 20 per group, I think this is too small to say anything for sure - have written my own post here: https://open.substack.com/pub/rationalpsychiatry/p/the-powerful-and-the-damned?r=g83wq&utm_campaign=post&utm_medium=web

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> Sometimes researchers try to use an “active placebo” like midazolam - a drug that makes you feel weird and floaty

How do the ethics of "active placebos" work?

In a normal trial you either give a trial drug (which we have a fairly good reason to suspect might be helpful) or a placebo (which we are confident will have no effect at all). But giving an active drug with potential harms and side effects, without any kind of belief that it will cure what ails the patient, just for the purposes of a more realistic placebo, seems ethically fraught.

Also, if the trial group does better than the placebo group, can you be confident that it's not just due to undocumented deleterious side effects of the active placebo?

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Also, did they give patients opioids after surgery?

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Typo thread: "Third" appears twice, should be "Fourth" the second time.

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Tangential: Is anyone else a bit sceptical of the current focus on measures of "effect size" as currently defined? Lots of review articles just quote those, and I suspect that a lot of nonmathematical readers assume from the name that it means something like "how effective the treatment is" , which ought to be scaled such that some number eg 1.0 meant "completely cured". But actually it really seems to mean something more approaching "signal to noise ratio", so it's telling you how reliable the study is. Which is vital to know, but actually I'd like to know how effective the treatment is too. In theory it's useful as a comparator of treatment effectiveness, but I'm not convinced that people are paying sufficient attention to the conditions for that to be the case.

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I think you have a typo: You list "Third" twice, instead of "Third" and "Fourth."

In any case case, I agree with your (first) "Third" reason for doubting this study. The conscious, subjective effects of the drug are likely causal for its antidepressant effects. There is no reason to expect that the drug would or ought to have the same effects if the patient is unconscious when the drug is administer. (I would suggest that the same is true for MDMA, which has achieved good results in the MAPS trials, and psilocybin as well.)

The fact that this simple point seems lost on many suggest a serious misunderstanding as to how these drugs work. There's a bad mental model in play, as if depression were like a bacteria and the drug were an antibiotic that kills it, or some other such simplistic mechanistic model.

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Nov 14·edited Nov 14

This is absurd! Hallucinogens don't counteract depression while you're asleep. They work (or don't) because you experience something profound that you take with you after it wears off.

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Placebo controls for drugs people can feel are always fun.

The classic for psychedelics is niacin, which gives you a flushed face at high doses but people nearly always know they haven’t been given magic mushrooms or whatever which makes it less useful as a placebo (from Aday et al. “divinity school students were assigned to receive psilocybin or niacin, a B vitamin with mild physiological effects, in a group setting at a chapel (Pahnke 1963). Despite some initial confusion because of niacin’s fast-acting effects on vasodilation and general relaxation, before long, it became clear which participants had been assigned to which condition, as those in the psilocybin group had intense subjective reactions and often spiritual experiences, whereas the niacin group “twiddled their thumbs” while watching on”.

On the other hand lower doses of alcohol can be very convincingly placebo-ed by giving orange juice but stuffing vodka soaked cotton buds up everyone’s nose, or secretly dipping the rim of a glass of cranberry juice in vodka (Bowdring 2018).

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It is not just propofol and midazz, benzos in general are fairly effective against depression, but are off-patent and so nobody cares. Since benzos are generally administered before anaesthesia/surgery to calm down the patient and to reduce anaesthetic consumption, I would highly suspect this contributes to the large effect in the control group. This likely also renders the midazz controlled studies useless.

I have no personal stock or interest in this debate (not even professional interest, tbh), but it would seem to me that the common link between a lot of mental disorders (i.e. anxiety, depression, OCD) is a sort of runaway of the sympathetic nervous system. This simultaneously explains the overlaps in these syndromes, the overlaps in therapeutic responses to SSRIs observed for a variety of similar disorders and their kinda mid efficacy against any of them (they simply aren't a very good smypatholytic). It also ties in nicely the original reason SSRIs were developed (hypertension, also partially thought to be due to increased sympathetic drive). Begs the question what is causing this?

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This is so dumb. It’s the experience of the ketamine that’s therapeutic. The experience is nil if you’re under anasthesia. Case closed. Waste of time.

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Sorry, people report feeling no effects from 70mg intranasal? That's... surprising. Is there some kind of genetic variant that makes you immune to dissociatives?

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I think there's another confounding factor here: people are likely to have higher levels of stress due to an upcoming surgery. The authors refer to these as 'minor' surgeries, but a surgical procedure is only routine to the surgeon. The paper says the length of the surgeries was 4 hours (+/- 2 hr SD). That's basically an all-day procedure for a patient. Not an in-and-out kind of thing, even some of these were outpatient (though I didn't see an inpatient/outpatient breakdown in the paper).

They measured these patients up to 5 days pre-op, meaning the patients knew of their upcoming surgery at least a week in advance (otherwise they'd never have screened into the study) and had all that time to fret about complications and the like. Meanwhile, post-op they were told whether there were complications (looks like only 1 patient had complications) so the uncertainty about long-term bad outcomes would have resolved at that point.

TL;DR: Because of the stress of upcoming surgery, there's clearly still lots of room for regression to the mean in this study design.

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I look forward to reading this researchers follow up paper "Randomized trial of Cognitive Behavioral Therapy masked by surgical anesthesia in patients with depression"

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As an anaesthetist, my first impression was that there would be simply too much interference from the anaesthetic itself. Not just from the lack of consciousness that will clearly interfere with any of the putative benefits around changed appreciation of conscious perception. Rather, that the brain state is so different under anaesthesia that it is surely challenging to infer anything relating to non-anaesthetised life based on this. That seems especially true when the feature in question is something as complex and organised as this.

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Sort of an aside:

Do doctors prescribe antidepressants at sub-therapeutic doses to see if the placebo effect is enough to help the patient before increasing the dose (to levels where side effects become more of an issue)?

This seems like a good idea. What am I missing?

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I've wondered about this question myself, and even asked an anesthesiologist about it before he was about to put me under (ketamine/fentanyl/midazolam). I got this mix twice actually, the first time the ketamine was clearly withdrawn later than the other two drugs, and that was a crazy experience when coming back to consciousness - the second time was just waking normally but drowsy. In both cases though my immediate post-surgical state was dominated by pain and dealing with the surgery and opiate haze and I detected no discernible effect on mood.

One theory is that the effect requires neural annealing-type processes, and the presence of a heavy benzo dose basically disrupts any beneficial memory reconsolidation. I could believe this given my experience.

The S-ketamine vs R-ketamine debate is also relevant here. Some folks think R-ketamine helps just as much or more despite not having the psychoactive effects, due to non-NMDA mediated effects. That shouldn't be too disrupted by anesthesia though? Or the most potent mixture is actually racemic ketamine which gives you *both* a positive mood push *and* the psychoactive effects and everything resulting from those.

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> Since this happened in both the ketamine and placebo groups, the obvious guess is “placebo effect”.

Unless I'm misunderstanding the experimental design, I'm confused why your obvious guess is "placebo effect" instead of the effect of surgery plus anaesthetic plus post-surgical painkillers.

Was there a third experimental arm where they administered the MADRS with neither ketamine nor a placebo to check whether surgery itself makes you more depressed?

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In an interview, Dr. John Krystal, the Yale professor who pioneered ketamine as a treatment for depression, is very specific that dosage is important for getting antidepressant effects from ketamine.

He specifically says that if the dose is too high or too low, you don't get the antidepressant effects.

I'll spare you the long quote about it, but if you go to the transcript here https://tim.blog/2022/10/03/dr-john-krystal-ketamine-transcript/ it starts at about here "And in 1997, she published a paper that showed that ketamine released glutamate in the brain..."

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Is there any evidence that depression is something other than persistent defense cascade activation combined with various maladaptive schemas?

Ketamine never worked for me. Then MDMA-therapy was the magic solution (though it took quite a few sessions). My research on the topic leads me to see most mental illness as persistent autonomic nervous system defense cascade (fight or flight, dissociation, etc) activation mixed with various maladaptive schemas (integrated memory structures containing emotional reactions, episodic memory, and semantic memory). The ANS activation seems to be primary a response to fear or bodily damage. So I think the primary treatment is healing the underlying fear. And it seems somewhat well established that the primary mechanism of durable treatment of maladaptive schemas (and the fear underlaying ANS activation) is memory reconsolidation.



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A lot of depression patients I've met seem to suffer from cognitive spirals, where they spiral in on themselves, but the spiral being significantly disrupted can result in them being better for a while before whatever defect causes depression causes another spiral.

I have a friend who gets depressed if they're awake for too long, but sleep cures the depression.

Something that causes an altered conscious state or which terminates it entirely might plausibly "reset" them, which would explain why a lot of such things (ketamine, hallucinogens, and anesthesia) seem to "work" on depression.

Turning a computer off, and then back on again, fixes a lot of weird problems with computers as it flushes out their memory. It seems entirely plausible that doing the same with a biological computer might accomplish the same thing.

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I commented on this study back when it was still a preprint, juxtaposing it with the other study comparing ketamine vs ECT. The ketamine-ECT study is far more persuasive to me. Ketamine might even be superior to ECT for outpatient depression, with benefits that seem to hold up over months.


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why aren't we trying propofol for depression more often if it seems to be so effective?

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Nov 14·edited Nov 14

Here's another way possibly to run an experiment like this, only I think it's also silly, but perhaps not as silly.

A lot of cancer patients going through chemo experience depression. While you're getting chemo they often administer a big fat dose of benadryl as well as a steroid. The combo benadryl and steroid is actually pretty trippy feeling.

They could add a low dose of ketamine to the same infusion (you're sitting there for hours and they put all kinds of things into you). And then see if the ketamine group has more improvement on depression scores than the people not being treated for depression (but still experiencing it). Also in chemo rooms they already screen people every time with depression questions and so the protocol would hardly have to change. Also people already have to go in multiple times over weeks so the routine wouldn't change at all.

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1. Patient has problem I can fix with surgery.

2. I do surgery and fix the problem.

3. Patient feels better.

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Recently I've been thinking about fundamental limits to the scientific method.

Can you *scientifically* prove that bright lights cause / worsen headaches in hungover people?

To fully "blind" the experiment (hah!) you'd have to stop them from actually seeing the light. Blindfold them? Shine the light on the back of their head instead of the front?

Intuitively we could guess that something about the *sensation* of bright light is what causes headache. Maybe the neural stimulation itself is overloading the brain. But a blind study would by its nature prevent that from being tested.

I feel like there's a similar problem with MSG-headache studies. "Blinded" studies show that ingesting MSG without tasting it doesn't seem to cause headache. But what if it's the *sensation* of tasting MSG that somehow overloads the brain and causes headache?

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Also worth noting that it seems GABA-ergic medications (through which general anesthesia probably produces hypnosis and amnesia) appear to block the ketamine antidepressant effect. I agree that this study does not change my practice whatsoever.


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Nov 14·edited Nov 14

Great article, and I don't think the following point of disagreement affects the appropriate uncertainty of your conclusion. But:

"But it’s hard to run a placebo controlled trial of a dissociative. Either you feel bodylessness and ego death (in which case you know you’re getting the real drug) or you don’t (in which case you know you’re in the placebo group)."

Uh. Dissociation can be a depression symptom. And if you tell me when I'm depressed that what you're doing is likely to make me dissociate, with a detailed reminder of what that feels like, *I probably will.* Even if I'm in the control group.

Non-anesthesia trials of dissociative drugs should control for amount of dissociation that patients experience.

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>"three days in the mental hospital will cure all suicidal patients, whether or not they get any treatment - the sheer boredom of hospital life is incompatible with the level of worked-up-ness you need to consider drastic action."

Is this even close enough to the truth to be a good joke? It just strikes me as weird, to the extent that I feel I must be missing something fundamental. Whenever I read descriptions of mental hospitals, I think that if I ever found myself committeed to one "for my own safety" I would do everything possible to get myself discharged and then take immediate irreversible measures to guarantee that I never landed in that situation again. Do actual suicidal patients not think like this?

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After I read Scott's piece I poked around online a bit, trying to find out more about ketamine, and ran across a well-done meta-analysis of studies with a similar design. It's here:


They winnowed a total of 700+ studies down to 15 which were conducted in the way most likely to give valid results -- both patients and raters blinded to whether the patient received ketamine or placebo (they used dexmethasone) during their surgery, as well as various other features. Some of the studies used depressed people and some not, but according to these researchers depression and anxiety after surgery is pretty common (they cite a number of studies, which I did not read). Researchers of the meta-analysis article were most interested in ketamine administration during surgery as a protector agains post-surgical depression. They cited quite a number of studies that found an upsurge in depression and anxiety states following surgery. (I had actually thought what Scott had said about the mood benefits of hospitalization for surgery was quite plausible.)

So their findings were:

-Patients who received ketamine had considerably higher mood scores after surgery than those who did not. The difference was about one standard deviation, which is quite large, and was statistically significant.

-Both patients who had been depressed before surgery and those who had not benefitted from ketamine (i.e., their mood scores were better than placebo group's), and to about the same degree.

-Both patients whose surgeries were done under spinal anesthesia and patients who had been knocked out benefitted from ketamine, and to about the same degree. (And note that the patients who had had a spinal would have felt the effects of the ketamine, and likely guessed what they had gotten, whereas those who had received it while under general anesthesia would not know. It seems that whatever placebo boost there is to being pretty sure you got ketamine made no difference in the studies looked at here.)

So this meta-analysis supports Scott's belief that ketamine the drug has antidepressant effects. It also does not support the idea that the effect is dependent on the person having a ketamine "trip," since those who received the drug when unconscious benefitted as much as those who had received a spinal and were awake . I hope this result, if it continues to be supported, slows down the ketamine gold rush that is going in psychiatric treatment. Where I am, there is a whole industry based on doing psychedelic-assisted therapy on people taking ketamine. I took a whole course on psychedelic-assisted therapy, read quite a number of studies about its effects, and believe it's a valid treatment modality. Ketamine, however, is not a much of psychedelic, even when you take high enough doses to get strong subjective effects.

At least it sure isn't for me. A psychiatrist acquaintance helped me try it a few times, and though I took quite a high dose, I thought the state it induced was much less rich that what you get even from good old cannabis. Its chief effect -- on me anyway -- what to shut down about 80% of whatever it is that supports the sense that I am I, and I am presently engaging in some identifiable activity. I felt extremely disoriented and knew I was not in my usual state, but some of the time could not even get it together enough to remember I had just taken a drug, or to ask the person with me questions. I couldn't really distinguish between what was actually happening and what I thought was happening -- like, was I sitting on a couch with my face in my hands, or was I thinking that I felt like doing that? And nothing *else* came in to fill the void left when my ability to stay oriented disappeared. I didn't have wild dreams or hallucinations, didn't remember anything special, and did not feel much emotion except about one thing: being so fucking disoriented, which scared me. I also tried ketamine lozenges a couple of times. That was much less overwhelming, but not a richer experience. I try to stay open to the possibility that ketamine affects other people differently, but it's hard for me to believe it. It really *felt* like a knock-out drug -- except the dose I took only knocked me out 80% of the way. Nothing very psychedelic about that.

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When was the baseline taken? If it was taken directly before surgery, it seems like the uncertainty of an invasive medical procedure could cause anxiety, which I could see increasing your MADRS score.

Presumably everyone in the study survived their surgeries, since they filled out the questionnaires after, so they were no longer anxious about dying on the operating table.

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And as always, if a patient is suffering from a mental disorder, you give them a sugar pill, and they are cured, that sounds like a successful treatment, not a placebo.

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> "I think this rules ketamine out as a miracle drug that cures everybody of everything."

This isn't exactly a groundbreaking statement, is it? You could replace Ketamine in this sentence with literally anything and it would still be true. There isn't a miracle drug, treatment, etc. that cures everybody of everything, full stop. Anyone saying there is doesn't deserve time investment to 'disprove' it.

I'm enduringly curious about the idea (which seems particularly alluring in the US culture) that there is a light switch for healing. There's an ongoing, fruitless callout for the 'miracle drug' that will heal everyone from their ailments - mental health, physical health, etc.

I just spent three weeks in Ketamine treatment and found myself assuring the staff that I don't need the disclaimers about how the number of treatments is based on their extensive (more than 27,000) infusion experience and doesn't guarantee an outcome. Everyone wants to feel the best while doing the least and it's really troubling.

Questionnaires have their value but they're not a complete picture with Ketamine IMO. What about brain scans showing the effects on neuroplasticity and synaptic connections? Some of us are lucky enough to have fantastic therapists and to make great strides with talk therapy, and Ketamine can be supplementary to that. Rewiring your brain doesn't shed learned behaviour and patterns, purge first hand or epigenetic trauma, or erase life experience.

I have a family member who wants to try Ketamine but refuses to see a therapist, change her diet, do any self reflection, etc. She's on a long list of pharmaceuticals that she believes she needs (including some that counter the effects of others) but can't account for the fact that she's still depressed, still anxious, still can't sleep, still overweight, still has high blood pressure, and so on. She refuses lifestyle changes and is sure that healing is right on the other side of a hill shaped like an elusive treatment. After many years outside of the US and recently returning, I see this mentality as more the rule than the exception, culturally speaking.

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Nov 15·edited Nov 15

Imagine you want to find out if adding some sugar to a pasta sauce recipe improves people's rating of the pasta sauce compared to without added sugar. You want to know whether it's worth paying for the extra sugar to put into the bottled recipe that you're going to sell to Americans.

To run the study, you fly all forty Americans in both arms of the study to Italy and you serve them the pasta sauce (with and without sugar, appropriately blinded) at little tables overlooking the ocean in Cinque Terre. You give them free wine to help wash the pasta down, you play them some opera music quietly in the background, and you finish the meal with tiramisu. Over the next two weeks you pay for them to roam all around Italy, drinking espresso and looking at art.

You administer the pasta sauce taste assessments to them at days 1, 4, 7, 10, and 14 and you discover that there is no significant difference between the groups in how they rate the sauces, with or without sugar. Everyone in both arms of the study quite likes the pasta sauce either way. You take everyone home and decide it's not worth putting sugar into your new bottled pasta sauce to put into American grocery stores.

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I really have to ask how you could possibly think "Randomized trial of ketamine masked by surgical anesthesia in patients with depression" is the study "everyone's" talking about this month. I'm sorry maybe I'm just a turbonormie but I just can't imagine ANYONE caring the least bit about this except a few people who happen to feel extremely vested in the conclusions of the study.

I'm assuming this was meant as a defense of ketamine therapy (which I myself have seen work wonders for friends), but I'm not sure if you've done more harm or good here.

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Hm. I was under anesthesia a lot, a few years ago, for ECT treatment for severe depression. I literally always came out of it happy and dopey and fuzzy, and I was never quite sure how much was the ECT, and how much was waking up in a place with smiling nurses who knew me, who gave me apple juice and granola bars, and then getting picked up by a friend whom I'd rarely if ever see except for this. But perhaps the anesthesia itself was also contributing.

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"Since this happened in both the ketamine and placebo groups, the obvious guess is “placebo effect”. I think that guess is right."

The obvious guess for me is that the patients are no longer worried about people cutting them open with knives, or about whatever medical problem they had that required being cut open with knives. Instead, the cutting already happened and the problem is gone. Why would any reasonable person not be happier?

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Just a point of clarification: Regression to the mean has nothing to do with time elapsed. It is a purely statistical phenomenon having to do with measurement error and selecting an extreme group. I think you mean homeostasis or perhaps opponent processes.

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Nov 15·edited Nov 15

". . . but there’s a difference between “very minor” and “literally zero”, and this study seems to show literally zero."

The error bars on the plot literally range from 0 to -25 (almost half the full range of the scale). There's no point in discussing anything related to this study which relies on even vaguely precise estimates.

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Asterisk Magazine actually had an article about psychedelics and how one of the debates in the field is whether or not the subjective experience of the individual is important for the effects of the substance. Their proposed experiment is exactly to render people unconscious - https://asteriskmag.com/issues/04/mysticism-empiricism

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Can you go into more detail on why an active placebo doesn't work? If both control and actual patients feel a noticeable effect, then it seems like both sets would equally believe they are in the therapy arm, not the control arm, and thus the placebo effect would be the same in both cases.

Of course, you need to pick an active placebo that you are confident doesn't provide any non-placebo therapeutic value, but this seems like a far better approach than trying to test a psychological therapeutic while people are unconscious (not even dreaming, just brain-off).

I would be *incredibly* surprised to hear that ketamine worked while the user was unconscious.

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My completely uninformed thought about how ketamine works was related to trapped priors : a significant cause of depression is installed though processes that are connected to each other an reinforce each other everytime you go through a thought cycle. When using ketamine, you change the local neuron chemistry, giving them a chance to learn different connection modes.

Thus I would expect a normal therapeutic use to actively try to stimulate the depression-connected neurons while the patient is high.

Am I completely off ? Is that a therapeutic mode that is used for some drugs other than ketamine ?

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Looks like the possibilities are:

1. Ketamine doesn't work.

2. Ketamine might work, but requires the twilight state and a GA prevents this.

3. A GA (particularly a propofol GA?) works as well as ketamine.

My wife the psychiatrist says she understands ketamine works best if you have some kind of spirit guide to lead the patient through the awakening. I had thought it was just to prevent craziness on waking (as I used to see when giving kids ketamine for bone marrow biopsies). "Sound like abreaction" said I. All that is old has become new again.

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I suppose it would be useful in the interest of finding things out if we could distinguish whether ketamine's effect on depression is achieved through dissociation vs. through chemistry, i.e. a psychological effect.

But I think this study was paid for because God forbid someone should get stoned via medicine. Medicine should be unpleasant; that's what makes it medicine as opposed to recreation.

This attitude has ruled out a lot of studies for drugs that might be useful. It has also contributed to lowering trust in medicine. I have...exchanged words... with a few people who trust pot to basically do anything and everything. Why? Because it *hasn't* been studied, so people can make wild claims about it.

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My very simple theory is that general anesthesia and ketamine have antidepressant properties because they release smooth muscle clenches and latches.

Earlier this summer I wrote a piece suggesting that muscle tension, and in particular VSMC tension, is where the body stores its Active Inference predictions / to-do list. In mechanistic terms, I believe tension ‘freezes’ the local neural patterns by cutting off bloodflow. In Bayesian terms, holding tension is equivalent to holding a prior as to what parts of your natural cognitive/emotional/behavioral range are safe.

A simple example of this system in use: when we turn on the stove to cook something, we hold some muscle tension. This tension functions as a memory/prior/prediction/reduction in dynamic range, and when we turn the stove off we release it.

Smooth muscles also have a special feature, the “latch bridge mechanism”, which effectively ‘glues’ it into a contracted state, such that it requires very little metabolic cost to stay contracted. Depending on where they are, these “smooth muscle latches” can function as something like strongly held priors (and can stay contracted indefinitely). This could be understood as something very similar to Scott’s notion of a “trapped prior”, and are certainly interesting in the context of trauma.

We slowly accumulate predictions/tension in daily life, and very quickly in trauma. Some of this tension we release naturally. Our body also has generalized ‘garbage collection’ mechanisms that release tension once it’s no longer needed, but these mechanisms are imperfect. The body tends to hold onto things unless it’s sure it doesn’t need to do so.

There’s a class of drugs we call “anesthetics”; ketamine is one of them. They’re known to have particular effects on muscle tone. I think the antidepressant effects of these drugs come specifically from their effects on muscle and tension; in particular I expect Ketamine to drive generalized muscle tension release (and in particular, I expect it to release latches). This functions as a partial reset / garbage collection pass — like turning your Active Inference to-do list off and on again. Some of the tension will regenerate (from the conditions which generated it in the first place), but some will not. Furthermore, I would expect tension to play a huge causal role in depression — reducing tension will help depression.

Much of this should be highly falsifiable, and could lead to novel and safe interventions. Sample predictions (which I would stand behind): ketamine’s effects on smooth muscle tone & smooth muscle latches are causal for its antidepressant effects, and other anesthetics which have similar effects on these will have similar antidepressant effects. Anesthetics which lack effects on muscles (if there are any!) will lack antidepressant effects (similarly, if we block ketamine’s effects on muscles we would block its antidepressant effects).


Principles of Vasocomputation: A Unification of Buddhist Phenomenology, Active Inference, and Physical Reflex (Part I)


The Hemo-Neural Hypothesis: On The Role of Blood Flow in Information Processing


Trapped Priors As A Basic Problem Of Rationality


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My first thought was, I can't believe they got the surgeons to go along with it.

My second thought, I absolutely can't believe they got the anaesthesiologist to go along with it.

And yet...

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> I would update hardest on a trial of 70 mg intranasal ketamine on one side vs. midazolam on the other

Hang on, you can control by giving the two medications on different nostrils?

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Why do we need to have a placebo with similar effects as the studied drug? The study could recruit patients for testing an antidepressant (without stating which one), and give the study group ketamine, and give a sugar pill to the control group.

*Double* blinding would be hard (if not impossible), but mere blinding *is* possible: the patient need not know which group they were in, most antidepressants won't bring you on a trip anyhow.

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I suspect ketamine works best in patients suffering primarily from excitotoxicity at the NMDA receptor, e.g. the kind you'd expect from an excess of quinolinic acid.

This is an endogenous NMDA receptor-specific excitotoxin that's elevated 2-3x in the CSF of suicide attempters. It's an alternative byproduct of tryptophan—i.e. it's one of the things that can result when tryptophan doesn't turn into serotonin.

There's clearly something up with tryptophan metabolism in depression, and I expect quinolinic acid is one arm of it. You can imagine a "shunt" model, where there's a problem with tryptophan hydroxylase—the enzyme that produces 5-HTP—and that means less serotonin, but also more of these alternative products in the brain. In that model, an NMDA antagonist would clear off the excitotoxin, alleviating the most serious effects (the "worked-up"ness, as Scott put it) but wouldn't necessarily help a case of mild depression.

Wrote about the phthalates<>suicidality connection here: https://stephenskolnick.substack.com/p/the-thousand-secret-ways-the-food-f96

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GABA-ergics strongly attenuate the antidepressive effect of ketamine. This is well known. Ketamine works (at least for me) even when i fall asleep immediately after the effects set in. And propofol causes a very notable, probably dopaminergic rebound effect which some patients notice so strongly that when they get propofol for a procedure they actually look forward to the afterglow on the following day. Again, this stuff is well known, in the scientific literature, and the study was idiotic and a waste of time for all participants.

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All these substances work through the same pathway -- upregulation of mTOR and subsequent synaptogenesis. The mTOR system is a nutrient-sensing mechanism that stimulates protein growth; it's literally responsible for your gains and your brains. Chronic inflammation and oxidative stress cause it to downregulate.

Psychedelics upregulate mTOR: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/

NMDA antagonists (ketamine) upregulate mTOR: https://pubmed.ncbi.nlm.nih.gov/20724638/ [in particular, this is a very "fundamental" effect of a direct cascade. Consciousness of a "trip" should not be required, but strong enough GABAergics can block this]

(a) Blockade of the serotonin-2C receptor upregulates mTOR (b) chronic downregulation of this receptor (analogous to blockade) seems to underpin the successful activity of SSRIs (c) Some SSRIs more directly increase mTOR, but my hunch is that the chronic effect would be the same either way through the 5HT2C receptor.

(a) https://pubmed.ncbi.nlm.nih.gov/24166413/

(b) https://pubmed.ncbi.nlm.nih.gov/16433010/

(c) https://pubmed.ncbi.nlm.nih.gov/24901414/

Interestingly, anesthetics *block* mTOR activation, perhaps through the GABA pathway. However, it is known that some other mTOR blockers can also work as antidepressants, i.e., rapamycin itself (the R in mTOR). They can even *enhance* NMDA antagonists' antidepressant effects. My guess is that there's a rebound upregulation, but I haven't seen direct evidence of that in the literature.




As a scientist in another field who has followed depression literature for some time, these mechanisms don't seem to be known outside of academia, even though they've been consistently replicated for at least a decade. Is the explanation *bad* for reasons I didn't have the expertise to detect on my own, or is it just an unfamiliar one? I know pharma companies have had little success using direct mTOR activators as anti-depressants -- and yeah they also seem to me to be terribly risky for tumor growth -- so perhaps there are not pharma reps spreading this story around the same way the serotonin narrative got spread.

I do like the self-consistency of the description of this mechanism: you change your mind when your mind physically changes.

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This is not a convincing study for several reasons, but the biggest one is the construct validity itself. Ie, the study conditions do not match the patient experience. This is usually inevitable to a degree, but toggling consciousness and memory formation itself really means everything has to be appended with "in unconscious people."

1) Ingesting alcohol does not increase sociability (in unconscious people)

2) Exposure to pornographic images does not create physical arousal in (unconscious people)

3) Being rejected by peers does not light up pain receptors (in unconscious people)

4) Winning the lottery does not raise or lower baseline cortisol levels a month or year later (for people in a persistent vegetative coma)

All of these make for great clickbait titles when you exclude the most important information that makes these results hard to generalize to the waking life of the senses. I think it's valuable to distinguish between the purely involuntary response and the subjective experience, but a better baseline would be between the conscious and the unconscious, not between "mostly unconscious mingled with some people semi-conscious but also on other anesthetics."

Psychedelics are difficult if not impossible to study through the standard methodology of control groups, but trying to negate the primary effects of the drug by adding other drugs in order to have a control group seems self-defeating as the control group no longer corresponds to the 99.9% usecases.

It's mildly interesting to know that adding ketamine for people already under another general anesthetic doesn't seem to have anti-depressant effects, but that's not how it's being presented. It's about like telling me a study proved caffeine doesn't create a feeling of jittery wakefulness after they administered it to people under general anesthesia and everybody stayed asleep, just like in the control group.

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Anecdotage: chronic MDD sufferer, major surgery n=3 colon cancer, hip, other hip. Have always come round from anaesthetic markedly euphoric in a way which feels chemically induced (and I have a fair amount of experience of euphoriant chemicals). Secondly being a (serious but excellent recovery prospects) cancer patient is a massive antidepressant in its own right, giving you a clear and serious purpose in life, an interesting new area of science to get stuck in to, and teams of professionals all dedicated to your wellbeing (and all for free in the uk). Same applies but less so to shiny new titanium body parts.

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Nov 16·edited Nov 16

Could the "feelings of bodylessness" and "ego death" just be made-up woo-woo nonsense? Is there any way other than self-reports to verify this? If I heard a transcendental meditation bro make claims like that, I would assume he's either fabricating the claim to resemble something he's heard about or that he has deluded himself into thinking that's going on (in which case it would fit his pre-existing expectations and he'd use those phrases to describe it, just as Christians with "out of body" experiences do.) If I assume that from the mystic's reports, I ought to assume the same from some hippie hopping out of Ken Kesey's bus.

In order to know if ANY of this is real, you'd have to dose somebody with ketamine without their knowledge, and with no cultural foundation for how to describe such an experience. If you did that (presumably that's horribly illegal of course), you could see whether they reported any experience at all, and if so how they described it. I'm confident you'd get a result if you spiked the punch with vodka at a Baptist college mixer, and it would fall into one of a few familiar categories of experience even though the phenomenology of being drunk isn't similar across all individuals and cultures. If you spiked my soda with ketamine yesterday before I'd read any description of what ketamine is supposed to do, would I have reported experiencing "bodylessness" and "ego death" of some unknown origin?

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Interesting article but my eyebrows entered the stratosphere on your casual line:

"I usually prescribe it at about 70 mg intranasal. Some of my patients report feeling a little drunk or giddy on this amount, but nothing like the k-hole that people report at the really high levels. Other patients report nothing at all, but still feel better."

Am I interpreting this correctly that the large majority of your patients report nothing or "a little drunk" on 70mg of intranasal ketamine with zero tolerance? As someone who has seen many people first try (pharma vial) ketamine in doses around 25-50mg, they should be EXTREMELY inebriated at 70mg. Nothing at all? The fuck? I wouldn't expect a K-hole or much hallucinatory/psychedelic effect, but I would expect a very strong effect.

While there may be some very small portion of the population which is very very resistant to this type of dissociative, I would be shocked if it was more than a percent or two. I'd also naively expect a similar proportion to be very sensitives and have wild trips. Something super super weird is going on here.

1. Are they really bad at snorting things? There is some technique here and I'm guessing they don't get great instructions. It's possible to do it completely wrong and waste all your drugs

2. Are they lying? Perhaps they feel that telling their doctor about a distinctly intense or recreational drug experience indicates that they are abusing the substance or aren't a "legitimate" medical patient using therapeutically? The ADHD stimulant lobby has spent years trying to convince the public that people with "legitimate" ADHD don't get high on stimulants.

3. Are they so totally inexperienced with psychoactives that they legitimately don't have the self awareness to realize the shift in their consciousness? Are they primed and ready for a medical experience so hard that they don't even notice a drug experience? I don't buy this one at all TBH but there are some truly baffling study results out there which seem to support the idea that many people have no idea what they are feeling/taking. This just seems wildly improbable due to the magnitude and obviousness of the expected effects at 70mg, for example extreme motor impairment.

I don't know, but this seems another really stark example of the medical community's impression of a drug and the recreational community's being shockingly and bizarrely incompatible. Seriously something is up here and I'm very curious what it could be.

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Nov 23·edited Nov 23

> But it’s hard to run a placebo controlled trial of a dissociative.

I don’t understand this part. How hard it is to just administer orally before sleep, using a delayed-release capsule calculated to dissolve in the middle of the night? You could even have some kind of injected or nasal delivery system that is actively triggered when the patients are detected to be sleeping based on anything from breathing patterns to an IR camera watching them, and even filter out of the analysis everyone who wakes up less than an hour after administration. Sure it’s not super easy to do all that, but it should still be *much* easier than trying to do it during anesthesia for surgery.

Heck, you could even just put them under (lighter?) anesthesia *just* for the administration of ketamine (or placebo) to mask it, and it would still avoid three quarters of the complications of this study.

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