168 Comments

I’m replying to let you know, I have begun your peer review.

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9.3: Can I just informally take ketamine and call it ketamine-assisted psychotherapy?

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I am a prior decades-long recreational drug enthusiast, an advocate for total drug decriminalization, a patient who has benefited from psychiatric medication, and a believer in the clinical efficacy of ketamine treatment. But I think it's absolutely essential that people understand that ketamine, like almost all black/grey market drugs, is now routinely adulterated with/substituted with fentanyl by dealers and the supply chain, dramatically increasing the risks of getting some of the black/grey market to treat depression. You can get low-cost drug treatment kits fairly easily to detect if your ketamine is actually fentanyl, I believe, depending on area. Please don't buy Special K from that oily guy at Club Scum so that you can self-treat your depression without testing it first. (Tell him I said hi.)

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I was diagnosed with Interstitial Cystitis in 2002 and experienced total relief from my symptoms after a bladder distention operation. My symptoms have been mild ever since but seem to be getting worse (slowly, thankfully) lately.

I was considering ketamine to help lift me out of a deep depression last fall, but when I brought up my history with IC the psychiatrist advised me to consider the decision carefully. I tried to research thing myself but I'm not trained in reading scientific literature and don't have access to databases.

If anyone can advise on this situation, I would like to know if ketamine is an option for me in the future. Ketamine abuse can lead to cystitis, but what about those of us who are already in the cystitis camp but only plan to use it for one treatment session? (Or a few times over a lifetime, I've been situationally depressed like this 2x in my life and I'm 36 years old. It would be nice to know if I can reach for this if it happens again.)

Thank you for any insight you can offer (and I realize this isn't what is being requested in the comments but if any group of people is going to help me answer this question I think it is this one).

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If you want this for your website, the most important question for potential clients is "Is it for me?" So I would recommend to have at least a sentence about it in the short version. Something like "Ketamine therapy usually works best for people that..." or "Ketamine should be considered if..."

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typo: long0term

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"the threshold dose for long0term cognitive impairment" should be "long-term"

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founding

Don't take this the wrong way — I'm a libertarian and support what you're doing on every level — but:

> If you’re going to do this illegally, you might want to consider using an actually illegal substance, which could be more effective.

Can doctors say things like this without risking their license?

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After the intro, I suggest you adding a disclaimer at the top that ketamine is at best expiremental and is a dangerous substance that should not be self-medicated, similar to your eventual disclaimer on the mitochondria article

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Proofreading first pass, and the only things that stick out to me are:

(1) "eg" and "ie" instead of "e.g." and "i.e.". Depending on how much of stickler you want to be, this may or may not be a change you want to make.

(2) A couple of small errors

"Murrough and colleagues reported that low¬dose ketamine was associated with minimal acute neurocognitive effects in patients with treatment¬resistant depression 40 min after ketamine infusion. They also reported that any changes in cognition appeared to be transient in nature, with no adverse neurocognitive effects 7 days after treatment. In both Koffler’s and Murrough’s studies, however, the follow¬up periods were short, making it difficult to comment on long¬term risks associated with repeated use." - "low-dose, treatment-resistant, follow-up, long-term" (probably happened when copying from a different source and the formatting slightly changed)

"Both groups used much much much more ketamine than any clinical user would" - "much, much, much"

"This suggests that the threshold dose for long0term cognitive impairment" - "long-term"

"This studies are very preliminary" - "These studies are very preliminary"

"and when these neurons are less active, it makes other neurons more activate" - "it makes other neurons more active" or "other neurons are activated more"

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One thing that isn't mentioned here and matters when comparing to recreational doses - Ketamine has one of the most brutal tolerances that barely if at all goes away (even if it does the tolerance comes back in a session or two). This is much more true than for any drug I know, e.g. a lot of psychedelics have quick increases in tolerance but quick decreases on break, while with ketamine it is more cumulative.

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I recently did a course of Spravato and would love to send you my personal experience if that would be helpful. I'm currently not on it solely because of the endless hoops I had to jump through and unfortunately my depression has returned to severe levels despite being on 20mg Trintellix q d.

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I think this article might benefit from a brief explanation of what a dissociative drug is, and what dissociation is - a lot of people are unfamiliar with those concepts. I also think it would be helpful to describe the contraindications for the treatment, so people can see if their doctor is likely to discourage it.

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Typos:

10: "many neurons suppress other neurons, and when these neurons are less active, it makes other neurons more activate" <- should be "makes other neurons more active"?

11: "I prefer not do to do this" <- remove the first 'do'

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My comments as a patient:

- The ketamine clinic I go to in Utah County, Utah costs $325 for IM, $375 for an IV ketamine session, which is far lower than the prices you cite.

- Your estimate of effects in maintenance mode lasting about one month seems about right to me.

- My provider uses about 1mg/kg instead of 0.5mg/kg. At that level I'm completely dissociated and entirely out of touch with reality during the session. (That's probably intensified by the fact that I'm wearing a sleep mask with head phones on too.) It's hard to even remember the experience afterwards because the state of mind is so alien.

- A therapist talked with me before and after each of my initial six sessions (twice a week for three weeks), but for maintenance sessions it has been at most only a very brief conversation before and almost always nothing afterwards.

- On my own, I have found that priming my mind with certain thoughts just as they're injecting me (usually IM) can have a strong effect. I went into one session thinking about some recent experiences that suggested I was stronger than I had supposed, and came out feeling extremely positive, like I could handle anything the world might throw at me.

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To give some gut-level feedback on your ‘formal vs informal spectrum’ question, I found myself a bit put off by some ‘informal’ (blog-post-voice-y) things you do in this article, like exclamation marks, or phrases like ‘no, use whichever’.

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You use the words "hepatic" and "hepatoxicity" a fair ways before you use the word "liver". I was pretty sure I knew what it means, and googled it to be sure, but I think it's not as commonly known as, say, "urinary", so it might be kind to unpack that earlier.

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founding

I would write out "intranasal" and "oral" instead of saying IN/PO. I think people generally have heard "IV" before, "IN" is borderline (can be figured out pretty easily from context), but "PO" is deeply jargony, and doesn't obviously abbreviate anything from the paper title.

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In question 10 “How does ketamine work”, paragraph two ("Ketamine is is a very strong…”), maybe the long main sentence should end “it makes other neurons more active”, rather than “more activate"?

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Section 4: 8 treatments of 35mg would be 280mg, not 3g

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I realize the ontological or philosophical position shared by most here is that SSRI’s, neuropharmacology and other authentic sanctioned and emergent chem interventions are useful, often profound and at least consequential. But, here’s some anecdotal stuff: Ketamine was and is used recreationally and like all mind and mood altering substances (and behaviours that trigger highs or dissociative numbing lows) it is addictive. This is not to say that all, or even most (though many) people suffering long term depression have overlapping issues w addiction. But it should be an indicator of the folly associated with chemical intervention as solution.

Trauma informed treatment, depth therapy of most types offered with proficiency by a truly compassionate, experienced helper whether a roundly adept and ethical shaman or a proper gestalt / integral therapist with a big heart and experiential wisdom etc - will likely always produce the results in spiritual and thusly biochemical neuropathy re-templating in by habitual / behavioural shift and reward centre recalibration.

In contrast, I’ve never seen in my practice, or in my life, working with many depressed humans and addicts in and out of recovery alike - a chemical intervention, besides as short term complimentary appendage do much besides blunt a human into dependency and deeper dislocation from the truth set of feelings and gestures of release needed to breath life into ones moods/cognition/perspective etc.

Ketamine has mostly caused my friends to become dependant and druggy even when they used it for therapeutic reasons. I doubt doubt they find uplifting states with lost cost on the downs, but they are still using.

I wouldn’t prescribe it and I wouldn’t recommend it.

I WOULD recommend people, including the author, explore Kambo, frog venom, that we have down here in the Amazon, for medicines that truly know their roll. There are many.

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I was prescribed 20mg of oral ketamine for chronic musculoskeletal pain. It wasn’t quite a panacea, as the numbness makes it terribly easy to overexert muscles whose whining you can no longer hear.

For depression it (briefly) kicks ass. I had optimistic, self-affirming, hour-long conversations with my reflection in the window. But for me the psychedelic effects and the positive mood were both very short-lived; I’d wake up the next day in a depressed state and read a scheduled email from “keta-me” about the happiness of being.

I didn’t take ketamine on consecutive days for very long owing to caution about the numbness, and Table 4 in the IV / IN / PO meta-analysis weakly suggests taking it consecutively for oral troches is important? It might be worth mentioning that instant, lasting relief is more evident for IV treatment than PO so that those patients don’t get too easily discouraged.

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Nice guide!

In the "short version" section: What does "2-3x more effective" mean? 2-3x higher proportion of responders? 2-3 times as effective for people who respond? Quite relevant for antidepressants, and I'd want to know which you mean if I were looking at using ketamine.

Section 4: It doesn't seem a bit irresponsible to report the *total* amount of lifetime ketamine delivered to recreational vs. clinical users. What I would expect to really matters is the per-use dose and, maybe, frequency/length of use. Do we have any reason to think ketamine has cumulative effects, like a carcinogen?

4.1: "long0term" --> "long-term"

4.2: This reads slightly disingenuously -- you say [that organization] "only know[s] of a single case", but then you go on to mention three others that they sort-of-report. This reads like "there's only one case" --> "there are four cases". Better to lead with some thing like "[that organization] mentions four case studies, of which three were from some self-reporting user group that I can't access and can't confirm".

4.3: Again, I'm not sure total dose matters so much as peak dose + duration... though since this is for a single sitting maybe total does is appropriate.

4.4: The ketamine-tobacco/alcohol comparison is great! But this reeeeally needs a citation.

6: Is esketamine less addictive than ketamine? Does it have fewer side effects? If so, it would go a long way toward explaining why doctors, insurance companies, drug companies, and the government all might suggest taking esketamine over ketamine. I'm not necessarily suggesting esketamine is better (this is triggering pattern-matching to the case of ethidium bromide vs. alternatives in molecular biology: https://blogs.sciencemag.org/pipeline/archives/2016/04/18/the-myth-of-ethidium-bromide), but it's at least another quasi-plausible explanation for the, uh, "establishment" fixation on esketamine.

8: "I can’t stress enough how poor the research is here and how little anyone seems to care about this." <- You're putting thoughts and motivations into other people's heads. LOTS of other peoples' heads. Stressing that the research is poor is good; griping that nobody seems to care is neither charitable, necessary, nor kind. That's fine for a normal blog post (I expect your gripes and personal commentary, please keep giving it!), but I don't recommend it for a medical guide.

9: Careful about *actively recommending* recommending illegal substance use. Where are you posting this again? Are patients going to be referred to this? Personally I'd stick to "when people do this illegally, they prefer to do it with those other drugs" without *actually recommending* the other drugs.

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Right off the bat: "...which probably works by activating AMPA.... This phrase may sound to you and us like a straightforward probabilistic statement. But to many beyond this tribe, it'll more likely come across like you're just riffing.

It could turn a certain population right off, which I don't think is your intent. Suggest rewording to "which is currently believed to work by activating..." or something along those lines.

If belief isn't a word that makes you comfortable, consider replacing with "understood."

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More tone concerns from your friendly neighborhood tone assessor:

I fear the somewhat casual/approachable tone and language (which I, personally, happen to appreciate in your writing style in general) will turn off many-a-psychiatrist who will be referred to this document if they are even considering prescribing Ketamine and haven't done so before.

Just something to think about in terms of what the primary/secondary purposes of this document are.

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"treatment­resistant" --> treatment resistant

"long0term" --> long-term

"racemic ketamine" --> this is the first time you use 'racemic' so laymen may not understand

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I think it would be helpful to have a section on 'Can I take Ketamine in tandem with other anti-depressants'?

Those considering taking this will likely have already or will still be taking various anti-depressants and anti-anxiety medications. Are there any known interactions or safety concerns?

What about other drugs? In a place like the USA there is a very high level of prescription medication with ones for heart disease and diabetes, questions about this may come up.

Also about other drugs such as the big 3 of Tobacco, Alcohol, and Cannabis. I'm thinking as a tranquilliser one should probably avoid any alcohol for a least a couple of days before and after the treatment - in my own view I'd recommend total avoidance of alcohol and tobacco, especially for someone suffering from depression or just anyone in general.

So an extra section in section 4 could address these types of recommendations and any known contraindications. With the lack of studies on ketamine....your 'best guess' as a doctor to intuit the types of potentially bad interactions would be appreciated. i.e. it is known to work along 'this random metabolic pathway of alphabet acronyms you don't understand' and I take that to mean it probably would not pair well with alcohol or benzos or anti-depressant x because they also work along a similar metabolic pathway.

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This one feels more readable and polished than the last one you asked us to review. You seem to be mastering this task of translating huge amounts of unclear information into something useful for patients and colleagues in a way that doesn't sound like WebMD. No small task.

Reading through the comments, I find I agree with almost all of them, which is a new experience for me. I agree some kind of CYA language in italics would be good somewhere as well as underscoring the risks of acquiring ketamine off the street. And that it would be good to give readers at the beginning a short-hand way to figure out whether they might be a good candidate and whether therefore they should keep reading.

My main suggestion is to edit to be more declarative, simple, and straightforward wherever you can. I happen to like your tone a lot, and I appreciate that you're not aiming for something stiff and generic, and as a mental health professional, I'm not put off by any of the more informal-sounding aspects of your tone (that's just me). It's a bit weedy is all.

So the first sentence "Ketamine is a new and exciting depression treatment, which probably works by activating AMPA receptors and strengthening synaptic connections" -- I would put a period after "new and exciting treatment." The second half of the sentence weakens the whole thing by introducing jargon and with the word 'probably'. I recommend more of that kind of editing everywhere.

Short and declarative is particularly helpful at the beginning of paragraphs. So like this one: "Why? First and foremost, because although I’m optimistic about ketamine, it’s new and poorly understood, and anything which is new and poorly understood has higher risk of having some side effect we don’t know about." Maybe better as: "Why? Because while I'm optimistic about ketamine, it's new and poorly understood." If you're concerned about a higher risk of unknown side effects, put that under side effects. "New and poorly understood" conveys all you need to here I think. A better editor than I am could go through and do this for you if you don't have the time.

Like the "first and foremost" above, there are a number of places where you start sentences with modifying phrases that don't really add anything: "Over the past few years, increasing evidence suggests..." You can just start with "Increasing evidence suggests..."

After the "First and foremost..." sentence, you go on to list five reasons why you don't prefer to prescribe ketamine. This is a lot to wade through. Bullet points instead? Or say it much shorter in one sentence -- concerns about cost, government oversight, addiction, etc? Or put it in positive terms -- "here are the situations in which I think prescribing ketamine makes good sense and here's why" -- and then move that paragraph way to the top of the piece. That much negative framing about why you don't like to prescribe to wrap up a piece that's sort of advocating for prescribing it (and advocating for your colleagues to prescribe it) comes across as a little confusing.

This paragraph is another example of a mouthful of a lead-in: "Some people without access to a KAP clinic, but with access to ketamine, try a version of this where they skip the part where they interact with the formal medical system." A bit clunky but also not far off, I get you're aiming for a tone here.

There are tons of other paragraphs that you start sharp and crisp, so this isn't everywhere by any means.

I love places where you give these sentences their own paragraph: "Currently this is very poorly understood" and "Good question, currently without a good answer." There's a wonderful authority to that, even though you're describing various kinds of uncertainty. I find that much preferable to any kind of hedging language.

I gather you're aiming here at two audiences -- potential patients and other psychiatrists. That's a hard needle to thread. It made me wonder if It would make sense to strip out a lot of the research and data references and put them in a separate section described something like "if you're interested in the state of research on ketamine" and then you can refer people to that section in several places to remind them there's more they can look into. I think most patients would be happy for you to give them your assessment of the research in narrative form.

I have a colleague who is a psychiatrist and specializes in ketamine treatment (spravato as well as therapy-assisted) and has just re-done her website if you're interested in looking at that, happy to send you the link. I don't want to post it here in case she'd rather it not show up here.

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I just had a ketamine infusion today from a ketamine clinic as part of assisted psychotherapy. I think your explanation of how it works is fine as far as it goes. But I think there should be room for saying. "Somehow people have insights into the nature of their depression that they wouldn't otherwise have." Things are preliminary, and I might relapse in the future based on the preponderance of the evidence, but I realized that a lot of the negativity I have toward myself is generated from a concern for others and the past ways I've dealt with people. I don't have to hurt myself to be good to others, and my goodness isn't superficial or banal. I don't know if that has something to do NMDA receptors, but it's different from the way I normally think FWIW.

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It was somewhat difficult to get proscribed Adderall for adult ADHD, and I suspect ketamine will be significantly harder given its novelty and awareness. Anyways I plan on trying by shotgunning messages via psychologytoday ("Hello I have treatment resistant depression. Would you consider prescribing off-label therapeutic ketamine after discussing other options?")

Sound like a reasonable idea?

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Long time reader, first time responder. Also a psychiatrist. I found this piece useful, well organized, and personally informative.

I've never prescribed ketamine myself. In my community the Spravato REMS--in which the med has to be administered in a healthcare setting and patient needs to be monitored for two hours after--has become the de facto standard of care for intranasal ketamine as well. Even if you get cheap ketamine from a compounding pharmacy, frequent two-hour appointments are cost-prohibitive. I was surprised you wrote about sending people home with ketamine, because no one here is doing that even though it's probably quite safe to do so especially after the first one or two test doses when you know how the patient will respond. Off-label prescribing is one thing, but not following the FDA's safety rules for an analogous drug is a bridge too far in terms of liability for most psychiatrists. If more of us did this, it would become the standard of care and thus the associated liability would be lower, but no one does it because it's not the standard of care so ketamine remains relatively inaccessible. How did the Bay Area get around this catch-22?

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founding

1. What is a "compounding pharmacy"? I feel like I'm a patient who has taken a lot of drugs and filled a lot of prescriptions and I have never encountered this term. Probably doctors know what this is, but it might not work that well in a patient-facing document?

2. I am a bit surprised you ended up recommending nasal ketamine in your dosing instructions. As a patient I have a fairly strong preference for pills over nasal sprays, and the previous parts of the document seemed to imply the route doesn't matter. It's possible that people might get turned off by this ("ketamine was sounding good, but then I kept reading and realized it would have to be sprayed up my nose!").

3. Somehow I got the impression from the intro that ketamine was more likely than SSRIs to "cure" depression without needing long-term treatment. Maybe it was the phrase "some people will find their depression comes back", which I took to mean "most people will find their depression doesn't come back"? But after reading the "How long does ketamine work for?" section and the conclusion where you say "the effects of ketamine wear off quickly unless you continue taking it indefinitely", I found myself confused. I think the intro could use a bit of tweaking to align with the rest of the piece in that regard.

4. One or two sentences comparing to SSRIs (or other depression treatments in general) would be nice to have in the intro section. Especially focused on when one might want ketamine vs. others, and the effectiveness and maintenance routines of ketamine vs. others.

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> Here I’m working off of The Effect Of Intravenous, Intranasal, And Oral Ketamine In Mood Disorders: A Meta-Analysis. Their data are hard to interpret, because different studies look at different time periods, and depending on what time period you choose, you can get different results. But in general, it shows about approximately equivalent efficacy for IV, IN, and PO ketamine (though they were hesitant to draw a firm conclusion about PO because of the small studies).

I had to look up what PO means. It means orally. Now that I know that, it's kind of obvious since IV, IN, PO is mapping to the title of that meta-analysis in the beginning of the paragraph, but in the moment I couldn't put it together.

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Leads with a discussion of risks. No focused discussion of benefits. Does say it's "effective," but doesn't explain what effective means. Doesn't answer the question, "WTF, you want me to take a horse tranquilizer?!?"

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> having no idea what to do when you need continued treatment.

Feels a bit ominous. Change "when" to "if"

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Scott: I don’t know if this is the message intended, but what I took away from this post is ‘ketamine doesn’t work.’ Maybe it makes you feel better for a couple of weeks, but then you relapse, so you need to take it lifelong. And taking up an expensive drug habit with no safety data on long term use to be continued indefinitely doesn’t seem like a great plan. Why should anyone take it? If the answer is no one should, then maybe this should be stated and not implied

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> This study supposedly is more pessimistic, but I’m unable to access full-text.

Does the author manuscript (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296748/) not count?

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> I’m less sure that there’s a standard dose of oral ketamine. The above sources say anything from 1 mg/kg body weight, to 50 mg, to as high as 150 mg or 300 mg.

this part is a bit confusing because you mix mg/kg and mg for a 70kg person (you wouldn't want to have someone misread and try to go for 300mg per kg)

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[Epistemic status: I've been using ketamine recreationally once or twice a month for years. I've witnessed a lot of people do ketamine for the first time. Amateur pharmacology enthusiast. I don't have depression.]

>In Acevedo-Diaz et al’s study of ketamine infusions, over 80% of participants felt “strange, >weird, or bizarre”; other popular adjectives included “spacey”, “woozy”, “loopy”, “floating”, and

>“numb”... Also, some studies find rates of these feelings are no different on ketamine compared >to placebo, maybe because people are pretty suggestible if you tell them they’re taking a drug >that might make them feel weird.

There is no way these effects are due to placebo. A dose >40mg insuffalated Ketamine will produce undeniable and unique psychoactive effects in ~99% of people; for IV I'd put the dose lower. In terms of [phenomenological change from sober base], Ketamine is closer to LSD than it is to alcohol or xanax. I can see how one wouldn't feel these effects from a low dose of oral/sublingual ketamine.

>There is no reason to think that esketamine is any better than regular ketamine.

I mostly agree with this, but figured I'd share my thoughts.

First of all, ketamine is chiral; its enantiomers are S-ketamine and R-ketamine. I think you can guess which one esketamine is. "Regular ketamine" is racemix ketamine, i.e. a 50/50 mix of S- and R-. S- and R- definitely give different subjective experiences. S- is more bizarre, trippy, dissociative, indescribable, just plain weird. R- is more mentally sedating and feels less trippy/bizarre. You feel more like 'yourself' on R-, which corroborates the literature's suggestion that S- has more NMDA activity.

>Do I have to take ketamine IV? What about nasal and oral ketamine?

I've only personally tried insuffulation. Trip reports suggest that IM (intramuscular, pretty much similar to IV) is more euphoric. Ketamine tastes *terrible* which is a point against oral/sublingual.

The more relevant factor here is that of duration: oral > sublingual > insuffalated > IV. My guess is that a shorter "trip" is more preferable. If money isn't a problem, I'd recommend IV and then insuffalated.

>What’s the right dose of ketamine?

Just noting that ~60mg is a standardish recreational dose, in which one can still move and talk. ~100mg is a recreational "k-hole" dose, where you forget that your body exists and you're pretty much unable to move. This applies to normal sized people without a tolerance insuffalating S-ketamine. YMMV.

> If you’re going to do this illegally, you might want to consider using an actually illegal substance, which could be more effective.

Ketamine is the first illegal substance I would suggest for medicating depression. (There are legal ones I'd suggest first!) What substances were you thinking of?

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Excellent ...more comments later but just as a first remark I'd love it if sometime you could cover more generally the research on opiate maintenance affecting depression.

Eg the doctor and former University hospital head of addiction med who prescribed me buprenorphine was convinced it also was helping with my depression but at the time there was only weak research supporting that conclusion. With all this evidence about ketamine which also seems to have activity at opiate receptors I'm curious if we now know more about depression and opiate maintenance.

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i don't know if there is much information on this outside of anecdote, but it's somewhat well-known among the hallucinogenic drug using community that ketamine has a tendency toward giving users delusions of grandeur. on an episode of the duncan trussell family hour, hamilton morris and duncan trussell talk about the nature of its "insights" into depression and the slippery slope into mania that they often present. and this is again anecdotal, but i have a very close friend whose bipolar was badly exacerbated by weekly ketamine infusions at a ketamine clinic until it developed into psychosis, even though friend was convinced they were making progress on gaining insight into their depression.

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General impressions. That's a very good summary, I think it does well at hitting the readable but authoritative middle ground.

I think the question which needs to be answered first or in the summary is "I know there's lots of different treatments for depression which work differently for different people. Is ketamine just better than all the other treatments? Or should I try ketamine if standard antidepressants don't work? Does it work for everyone or so you need to try it and see?" I think you can see the answers from what you already wrote, but if someone is depressed, they probably need that "is this what I should be doing step 1" up front

Likewise maybe make more explicit "people have tested ketamine in complicated IV settings but pills are probably as good -- how sure are we, is IV more certain if I can get it?"

And the list of sub headings is a great summary of questions people want answered but maybe it's a bit too much information, maybe it would be easier to read if a few sections were collapsed together?

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I have seen other comments on the effect sizes 2-3 times that of SSRIs and this struck me as being overly optimistic so I'd like to expand on it below.

To compare effect sizes between ketamine vs placebo and SSRI vs placebo, you would need to assume:

(i) comparable study design (I believe most ketamine studies are much shorter than SSRI studies and have substantially different study procedures, eg IV/sublingual dosing so this doesn't hold);

(ii) comparable study sample (I have a hunch that ketamine study participants would tend to be more educated/middle-class/white than typical SSRI study participants);

(iii) comparable placebo effect (placebo effect for ketamine likely to be reduced due to it becoming obvious you have placebo when you don't experience acute dissociative effects).

The above would inflate the effect size of ketamine in comparison to SSRIs.

Additionally, most new treatments in medicine start off with big effect sizes which gradually decrease as bigger and more rigorous studies are performed.

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A paragraph about trip-sitters would be good. Why do you need one, and what can happen without one? What qualifies a good trip-sitter? Could they face legal problems if something goes wrong, or be in trouble at all? Etc.

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What are the effects of ketamine on aboulia?

(IIRC) one commenter here or on SSC reported that they were able to complete restoration of a vintage car in record time after their first IV ketamine. The project had stopped due to lack of will for >1 year.

If this is backed up by similar observations it would be good to include this topic.

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A comprehensive and accessible review of ketamine for depression, both for practitioners and patients. This is a valuable resource!

It would be good to touch on what we know about ketamine's interactions with existing therapies, e.g. SSRIs. Are there known adverse reactions? Are there recommendations for stopping SSRIs before starting a ketamine course? I assume that the data are sparse, and even that would be helpful to signpost.

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> although I’m optimistic about ketamine, it’s new and poorly understood, and anything which is new and poorly understood has higher risk of having some side effect we don’t know about.

This felt like a sudden shift in the tone and recommendation of the article. I understand (/assume) that some part of this answer is just so you don't become "the doctor who prescribes ketamine easily", but if your genuine overall opinion is that ketamine should be a last resort drug for now, then big chunks of this answer should be much higher up in the page (so they're more likely to be read, and to provide mental context for the rest of the page). I'd recommend making the first (larger) paragraph of this answer into its own question, as the 2nd or 3rd question of the list, and then referencing that answer in this last question's answer.

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"For comparison, an average person who undergoes a course of ketamine infusion for depression receives about 8 doses of 35 mg each, for a total of about 3g of ketamine."

8 doses of 35 mg each is 280 mg or a bit less than a third of a gram, not 3 grams. Am I misunderstanding something?

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Hi, do you monitor your patients while they are on the ketamine, or do they just do it themselves? Have you spoken to your malpractice insurance company, and are you concerned about liability issues? Do you use any strategies or documentation techniques to avoid these?

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Section 6: "But in general, it shows about approximately equivalent efficacy for IV, IN, and PO ketamine (though they were hesitant to draw a firm conclusion about PO because of the small studies)."

"About approximately equivalent?" Seems a little redundant.

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Hey, I was tremendously helped by clinical ketamine, and have a few thoughts to share:

(a) You may be scaring people unnecessarily about the cost of IV treatments. I got infusions for $200-$250 in NJ, still a lot but much better than $800.

(b) In my experience, IV ketamine was more powerful and longer-acting vs. symptoms than oral, and created a much more trippy short-term subjective experience. I did switch to oral for cost, though.

(c) In my experience, you can actually get a short-term worsening of symptoms, especially from the first few treatments. I'm really glad I didn't give up too quickly.

(d) I now do the compounding pharmacy trick. I'd note that I don't think you necessarily need a local pharmacy, some of them are willing to ship, including out of state (I think). And I think trochees (lozenges) are better than pills for side effects.

(e) Probably BS but some people say that ECGC / green tea helped them with bladder symptoms. I never experienced side effects beyond nausea and transient hypertension.

(f) To get my psychiatrist comfortable with prescribing the trochees, I first bought a few sessions from Mindbloom, a group that does oral ketamine by mail and online therapy. We copied their dosing. (I generally had a good experience with them and would recommend them - a bit expensive still, but cheaper than IV and they will do the prescribing.)

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3. How can my doctor prescribe me ketamine?

This startup offers ketamine therapy: mindbloom.com. Disclosure: my friend is the founder. I’ve tried it and was impressed with his program.

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Scott, I am delighted that you have produced this smart, honest and sensible summary of ketamine info. What I’ve see on Reddit makes me think a write-up like yours is sorely needed. There’s an especially distressed and distressing sub call diytpk — Do It Yourself Therapeutic Ketamine — where broke, depressed people discuss ways to improvise and self-administer ketamine treatment. Somebody, for instance, had gotten hold of a powder that was probably street ketamine, and was seeking advice about how to make a nasal spray from it. There’s also a Therapeutic Ketamine subreddit where the users are getting ketamine via the usual medical route. Many there are sold on the idea that infusions are the gold standard, which I’m pretty sure is not true. Many also are sold on the idea that the way ketamine works is to induce an altered state which is sort of a portal into the psyche — with the portal open the user, often with the help of a therapist, is able to access and change damaged and damaging beliefs, feelings and patterns. It kind of creeps me out to see so many people turned into True Believers in the ketamine portal, but I’m not sure the idea is nonsense. Then again, I’m not sure it’s not. Maybe the mental status changes are side effects of ketamine, equivalent to the constipation and dry mouth tricyclic side effects (which nobody ever saw as portals . . .).

I am quite interested in ketamine myself, and have been trying to pass useful information to both subreddits, as well as corrections of misinformation. I have also learned a couple things on Reddit that will likely be of some interest to you, and I mention them in the course of my edits, below. Once you’ve edited the ketamine piece to your satisfaction I would love to put links to it on the appropriate subs, and anywhere else where it might find an audience who would benefit. Let’s get the word out about this stuff.

Overall, I did not think your piece needed heavy editing. It’s clear, it’s complete, the informal tone is mostly pleasant and fine, let’s not be picky. Most of my suggested changes have to do with making things clearer to layman, especially using real words instead of strings of capital letters that make sense only to professionals (PO, AMPA, NMDA . . .). There were a couple places where I think your informal style led to your coming across as flip about some serious matters (death was one such matter). And then I re-wrote your introductory paragraph, The Short Version, with the aim of making it clearer and more appealing — seems worth a little extra effort here to engage the reader and generally make a good first impression. (For instance, I made ketamine’s speedy & powerful action the first thing you mention, rather than the second . The AMPA/synaptic doodah stuff you led with, which I have now moved back to the second sentence, is gobbledegook for most layman anyhow, and would not be nearly as interesting to most people even if you edited to make it comprehensible to laymen, which you certainly should also do.)

OK, here’s edits:

[Rewritten Short Version:]

The short version: Ketamine is a new and exciting depression treatment, which takes effect within hours and works about 2-3x as well as traditional antidepressants. It probably works by [activating AMPA receptors and strengthening synaptic connections] [RESTATE BRACKETED PHRASE IN TERMS LAYMEN WILL UNDERSTAND]. Most people get it as esketamine, a heavily-regulated and expensive prescription nasal spray, or through even-more-expensive clinics that provide ketamine infusions, but evidence suggests that ketamine in the form of a lozenge or a pharmacy-made nasal spray, available by prescription through a compounding pharmacy, is equally effective. A single dose of ketamine lasts between a few days and a few weeks, after which some people will find their depression comes back; long-term repeated dosing with ketamine anecdotally seems to work great, but hasn’t been formally tested for safety. Some treaters offer ketamine-assisted psychotherapy, in the belief that the temporary ketamine-induced altered consciousness facilitates insight and productive change. This approach can have impressive long-term results, but is less explored.

Section 2: I ran across on Reddit one resource for affordable ketamine treatment that sounds quite good. He’s a California MD who offers a a truly minimalist online treatment package, and sounds quite smart and quite honest in his postings. Users on the Therapeutic Ketamine sub give him high praise, too. Seems like sort of the Robin Hood of ketamine. He will prescribe to users in any state where it’s legal to do so. Here’a a link to all his postings.

https://www.reddit.com/user/KetamineDrSmith

Who the hell is this guy? Unless you are able to spot something gravely wrong or deeply sleazy about this doc I think it might be worth including a link to him in your piece.

4. I think this section is too long and too prominent, especially given that your overall take is that ketamine is actually fairly safe when used at therapeutic doses. I recommend that you just have a section 4, without 5 subsections, and that in section 4 you make the point that the drug is fairly safe at therapeutic dosages, and that concerns about cognitive & urinary side effects, liver toxicity, etc, while not nonsense, are also not reason for great alarm. Explain in a sentence or 2 why each of these concerns is not a cause to panic, and then put the detailed info about why not to panic as clickable links for the reader who wants to know a shit-ton about, for instance, why they need not freak out about liver toxicity.

4.3.change “hepatotoxicity” to “liver toxicity” or even just “liver problems.”

4.4. “Addiction is a biopsychosocial process” is too fancy. Spell out what you mean, something like “people don’t get addicted to a drug only because of a drug’s pharmacologic properties. Some of what leads to addiction is stuff like the mystique the drug may have in the person’s peer group, and the patterns of use the person sees and adopts.”

4.4 Chart probably confusing to most laymen. Also, if the data on which this chart was based came from recreational users of ketamine it’s not particularly relevant to people who are going to be getting the drug in moderate doses by prescription. Note that in the chart ketamine is placed pretty high on the Physical Harm scale, and that contradicts the reassurance you’re giving about it’s relative safety at prescribed doses,

5. “Meta-analysis”: The first time you use this term, spell out what it is: Somebody looked at all the studies, chose the ones that were well-done and consolidated the results . . .

6 “IV, IM, PO . .” Translate these into words a layman will understand, at least the first time you use them, and probably for some later times you use them too.

6.1

“NMDA” Translate this into words, then explain briefly what those words mean

6.1

“No, take whichever” sounds too flip.

“What happened was” also sounds a bit too flip, and also is a vague sentence. How about “The reason esketamine came to be seen as the official depression-treatment form of the drug”?

“Your doctor might also prefer giving you esketamine if they haven’t researched this topic very clearly . . .” Strike off the “very clearly.” Or say “very thoroughly.”

7

Explain what “bioavailability” is the first time you use the word, before the table.

Explain what “racemic” means first time you use the word.

“Remember that recreational users are taking 3,000 mg a day or higher – this doesn’t exactly go well for them, but they also don’t die immediately.” Too flip, Scott. OK, you stopped short of saying “they didn’t croak straightaway,” but not short enough. It’s death, you know?, and your readers are depressed people, some of whom are probably scared of ketamine.

7.1

In the circles I’m familiar with lozenges are given for home use more often the nasal spray. How about giving instructions for a cautious dosage build-up using lozenges, too?

8. graph: To make it clearer for people who are not used to reading graphs like this, add arrows in a couple places, with explanatory notes: Maybe an arrow pointing at 7 days/ 11%, with note saying “after 7 days, only about 11% of subjects had relapsed.” Then at 27 days/70%, arrow and note saying “after 27 days, 70% had relapsed. While researchers followed subjects for a total of 83 days, no more relapsed after day 27.”

9 For thoughts and info about how the benefits of being in an unusually fluid mental state you send people to “Relaxed Beliefs Under Psychedelics And The Anarchic Brain or this review of it.” Thought you’d be interested to know about this study, too, which found that mystical experiences (but not general gorked-ness) on ketamine were associated in greater improvement in problem drinking in a group using ketamine experiences as part of a structured intervention.

https://files.websitebuilder.prositehosting.co.uk/11/5d/115d425e-5129-48c5-8c21-e1af10229ed5.pdf

Study used a placebo control and double blinding.

9.1 About ketamine payments: I have seen mention online of some people being able to get their insurance company to pay many of the charges from a ketamine-assisted therapy clinic. Clinic gave them a “super bill” to send to their insurance company.

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Ever since I read the Stanford trial in 2018 [https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.18020138] showing that the opioid antagonist naltrexone prevented the antidepressant effects of ketamine, I thought this was plausible. So I was surprised to see that Scott was skeptical of this [https://astralcodexten.substack.com/p/peer-review-request-ketamine], stating:

> Other theories include that ketamine is secretly an opioid and maybe opioids treat depression for some reason (based on this study [https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.18020138], but contradicted by this study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439824/], and I think no longer really plausible)

I decided to dig into the details a bit.

1. Pharmacologically, ketamine has significant opioid receptor activity. [for example, https://www.nature.com/articles/s41380-021-01167-1: "We are not surprised to see that out of nearly 100 screened receptors and enzymes, the authors found that ketamine interacts significantly with mu opioid receptors (MORs) and this interaction is comparable to ketamine’s interaction with NMDARs"]

2. If ketamine works as an antidepressant via NMDA receptor activity, it's probably a unique effect, because other NDMA receptors modulators have not been found to be effective antidepressants. [https://www.nature.com/articles/s41380-021-01167-1: "Despite considerable early enthusiasm for N-Methyl D-Aspartate receptor (NMDAR) antagonism as the primary antidepressant mechanism for ketamine, this explanation seems incomplete, considering that clinical trials of other NMDAR antagonists have failed to reproduce the rapid and sizeable antidepressant effect of ketamine"]

3. Many opioids are in fact very good depression treatments, acting rapidly (just like ketamine). For example here is a review on the antidepressant effects of buprenorphine. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121503: "Taken together, according to the included studies, [buprenorphine] has a rapid antidepressant and anti-suicidal action: in fact, this psychoactive compound seems to act in about a week after the first administration. This rapid response resembles the time course of sleep deprivation and electro-convulsive therapy (ECT); however, the antidepressant effects of [buprenorphine] might also suggest other mechanisms of action than that regarding current available antidepressants, for instance the activation of endorphin release in the central nervous system similarly to what occurred after electroconvulsive therapy (ECT)"]

4. Ketamine is a remarkably good pain reliever, similar to opioids. Study after study has shown this. Nobody seems to have a good explanation. Some (but not all) studies have suggested that blocking opiate receptors decreases the analgesic effect of ketamine. [ https://www.hindawi.com/journals/bmri/2015/749837/ - "The analgesic effects of ketamine do not end with NMDA receptors. It has been shown to interact with opioid receptors μ preferentially in rats [28]. Studies in guinea pig ileum pointed to possible activation of the κ-opioid receptor as the site of analgesia [29]. However, subsequent tests performed with naloxone failed to affect the analgesia attributed to the ketamine, and interaction with any opiate receptor was questioned [30]. Other studies showed the reduction in efficacy of ketamine as an anesthetic induction agent in the presence of naloxone, again implying an interaction with the opiate receptor [31]. A 2014 study by Pacheco et al. which used specific opioid receptor blocking agents suggests that interaction with μ- and δ-opioid receptors is responsible for the central antinociceptive effects of ketamine [32]"]

5. Both trials designed to directly test the hypothesis that ketamine works via opioid activity were tiny. But the one that found that ketamine's antidepressant effect is dependent on opioid receptors was larger (n = 14 vs n = 5), randomized, and just seems better designed in my opinion.

6. One might ask, "if ketamine worked by opioid agonism, wouldn't we know?" Not necessarily. There is a strong reference class that we have no idea how/why medicines work for a long period of time after they are in clinical use. Perhaps especially in psychiatry. Famous lore in the field is that benzodiazepines were thought to have minimal addictive potential long after they were introduced.

7. If this is true, what are the implications for clinical treatment? I have no idea and I'm not discussing that here. I'm not claiming that ketamine is still not a worthwhile antidepressant treatment. Perhaps opioid agonists like buprenorphine should also be considered more seriously as antidepressants.

In summary, my guess is that there's at least a 33% chance that by 15 years from now, opioid receptor activity will be considered a key part of the antidepressant effect of ketamine. I certainly do not think it is implausible.

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1. Typo: “This studies are very preliminary and I don’t think it’s worth taking them too seriously at this stage.” Should be “These”.

2. Typo: “This does have some disadvantages of this over regular ketamine therapy.” Grammar

3. Typo: “I sometimes prescribe patients ketamine, but I prefer not do to do this” Extra word

4. I’m curious how you decided to use scihub — isn’t this professionally risky?

5. Related, “If you’re going to do this illegally, you might want to consider using an actually illegal substance, which could be more effective” — isn’t this risky to say without one of them disclaimers about this not being medical advice?

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I haven't found many papers or studies comparing the difference in effects of the S and R isomers but here’s one interesting paper comparing the two stereoisomers which seems to indicate that R(–)ketamine not only has “longer lasting action” but also “It was found that R ketamine shows a greater potency and longer-lasting antidepressant effect than S ketamine. R ketamine also induces a more potent beneficial effect and decreased dendritic spine density, BDNF TrkB signaling and synaptogenesis in the prefrontal cortex, Cornus Ammonis Region 3 (CA3) and dentate gyrus.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/

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Personal experience, particularly regarding 9.2. After trying several different meds over several years with the same psychiatrist she finally had me try Ketamine. We eventually worked up to a dose of 350 mg once a week, I took it at home, orally as a lozenge. I'd hold it in my mouth, letting it dissolve, then swallow it all at once, it tasted like bug spay. I got it from a compounding pharmacy and I just had to pay my regular co-pay.

I didn't realize that 350mg was such a relatively high dosage, and my psychiatrist mentioned Ketamine assisted therapy, but as she described it it was just taking a small dose, then doing regular talk therapy. I tried it once, and my therapist liked that I was less inhibited in what I talked about, but otherwise it didn't seem to make a lot of difference.

I stumbled on the idea of "Forming an Intention" before taking the Ketamine on my own. I would take notes after most of my doses, and noticed that interesting things would happen when I was focused on a problem beforehand. I think this is where I saw most of the benefit of the Ketamine. I was able to work through a number of long standing issues thanks to the Ketamine sessions. Although I had a propensity for disassociation before I got started on the Ketamine, and it may have gotten worse during the treatment.

Unfortunately my psychiatrist moved out of state suddenly, without being able to refer me to another psychiatrist, so I went to one in the same office. He didn't feel comfortable with Ketamine, and pulled me off it, I've done some looking, but haven't found any other psychiatrists that say they will prescribe Ketamine, and I remember my psychiatrist saying that there was only one other psychiatrist in Salt Lake that was prescribing it, and I haven't been able to find him.

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I would rephrase 1. How can I get ketamine therapy?

"Ketamine therapy" sounds like "ketamine assisted psychotherapy". I'd rephrase to "1. How can I get ketamine?"

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>People definitely feel unusual (sometimes bad) while experiencing the acute effects of ketamine. In Acevedo-Diaz et al’s study of ketamine infusions, over 80% of participants felt “strange, weird, or bizarre”; other popular adjectives included “spacey”, “woozy”, “loopy”, “floating”, and “numb”. I don’t consider any of these to be unexpected side effects; this is just what happens when you take a dissociative drug. That having been said, some people who take very low doses of oral or intranasal ketamine will avoid all of this. Also, some studies find rates of these feelings are no different on ketamine compared to placebo, maybe because people are pretty suggestible if you tell them they’re taking a drug that might make them feel weird.

This is fine, I think, for an audience of psychiatrists, but I think a general-audiences article demands more of an explicit introduction to what a 'dissociative drug' actually is. Perhaps Something like "Ketamine produces what's called a 'dissociative state', causing temporary distortions in the perception of time and the temporary feeling of disconnection from one's thoughts, memories and surroundings, as well as auditory and visual distortions and seriously impaired motor skills."

Also, anecdotal-evidence time: an immediate family member has depression which is badly controlled without ketamine and barely controlled with, for whom both getting it from the pharmacy *and* supplementing that with occasional inpatient infusions has been necessary. The first three dozen or so infusions, over the course of more than half a decade, were strange/weird/bizarre/spacey/woozy/numb without further significant incident. Then, on a day on which they were sleep-deprived, in pain, anxious due to life events, was driven to the clinic by a family member who stressed them out to be around, and was unexpectedly treated by a different doctor new to the practice who she did not know and trust, they had a three-hour psychotic episode involving severe paranoia and extremely distressing delusions of identity.

On the strength of this, I think a brief discussion of the importance of set and setting might be warranted, more explicit than "Your first few tries will be tests to make sure you respond okay to the ketamine. Have a friend sit with you for these sessions.", though whether the value of putting it in that terms outweighs the risk of being seen as a Timothy Leary-style psychonaut is something I leave to you.

>Ketamine may come in the form of a nasal spray or a troche (tablet you place under your tongue and let dissolve).

The nasal powder I have presently been prescribed tastes so transcendently awful that, unless it's somehow a different chemical, I cannot imagine a troche would be a pleasant experience, and I would explicitly give a nasal spray/powder preference over a troche here. (These issues with the taste aren't because I'm trying to eat the powder I'm supposed to be inhaling nasally: I'm talking about what I can't avoid tasting *just from what drips down the back of the throat.* It is that bad.)

>[The risk of relapse] pretty bad. Are there ways to make sure you stay un-depressed after successfully using ketamine?

Though not *specifically* 'this works after ketamine', the strength of the evidence that physical exercise helps is strong enough that I think 'use the newfound energy you have to start an exercise program' might be advice useful enough to put in this section. See for instance 'Physical exercise intervention in depressive disorders: Meta-analysis and systematic review', Josefsson, Lindwall and Archer, Scandanavian Journal of Medicine & Science In Sports, 2014, or 'Physical Exercise and Clinically Depressed Patients: A Systematic Review and Meta-Analysis', Silveiera et al., Neuropsychobiology, 2014.

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I don't know Scott but I am a doctor and as a result have a bunch of smart doctor friends and this reads exactly like what I'd get if I emailed one of my smart doctor friends and asked what they thought about a new therapy.

I have no idea how it comes across to civilians but it definitely makes me feel properly informed and conforms to my previous belief that Scott is a smart doctor.

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My feedback is that ketamine saved my life, and that you're a hero for trying to publicize it more.

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Ok, I can afford the time to give this a more thorough going over.

First, I think that you might need your 1.) bullet point to be something like "why might I need ketamine" or "is ketamine right for me" or the like.

> A single dose of ketamine lasts between a few days and a few weeks, after which some people will find their depression comes back; long-term repeated dosing with ketamine anecdotally seems to work great, but hasn’t been formally tested for safety.

This is not my experience with ketamine at all.

I get on the order of 8 - 12 weeks of relief from the symptoms of my depression from a ketamine therapy session. I do start to experience more severe depressive ideation at the end of that period, or at least become less resistant to adversity, but prior to my most recent round, I had actually gone 20 weeks due to circumstances surrounding my current job (which takes me out of town for long periods) and the schedule for the clinic, and I was still fairly ok at the end. Certainly I wasn't as bad off as when I first started ketamine, most likely because a large chunk of why I was suicidal in the first place was because I had no hope of any relief, and now I know that ketamine exists.

Those sessions are IV, BTW. And they don't cost me anywhere *near* $800 each.

I've been undergoing repeated ketamine session therapy at roughly 10 week intervals since September of 2018. There do not appear to have been any negative long term effects.

> A typical course would be six treatments over three weeks[.]

Yes, I also read those protocols when I was researching ketamine prior to my first session. That's not how that went for me. Two sessions in one week (a Monday and Thursday) and that was enough to get me back "on keel" to a level of -- for lack of a better term -- "being myself again" that I hadn't experienced in at least 5 years, and quite possibly well over a decade. It possible that I didn't even need the second session, given how profound a difference the first session made for me, reference the story I referred elsethread.

> The standard dose of IV ketamine is 0.5 mg/kg (eg 35 mg for a 70 kg person). This is the dose used in most studies and recommended by UpToDate. If that doesn’t work, some people will try going up to 1 mg/kg.

The doctor administering my ketamine sessions has me on 2 mg/kg.

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I was expecting the long version to contain something like:

"0. What is ketamine?

Ketamine is a prescription pain medication and anaesthetic which is also used as a recreational drug. Recently there has also been interest in using it to treat depression."

The current draft mentions these facts but comes at them backwards, which might be taken as disingenuous, though I understand you don't mean it that way.

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>Realistically this whole procedure is overcautious. Again, a bunch of people at raves will randomly take 1000 mg + their first time, have some crazy hallucinations, and then feel fine.

In my experience, not even the most hardcore users would take 1000 mg at once. When discussing dosage, PsychonautWiki puts the start of the "heavy" range, their highest tier, at 150mg. I'd expect the number of people who take >200mg their first time to be vanishingly small, and even those first-timers who are "only" doing 150-200mg are probably having a really shitty time.

This must vary by regional drug culture, I wouldn't be that surprised to learn that e.g. in the UK there is a culture of giving heroic doses of ketamine to first-timers who then immediately pass out for several hours. But unless you have specific knowledge of such a subculture then I'd question your wording here.

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Ketamine saved my life. I had severe TRD. Can now live a normal life. It is absolutely heartbreaking how difficult it is for people to get it . Many countries' governments, including my own, New Zealand, are just plain ignorant. They won't allow it because pharmaceutical companies haven't said it is okay to use for depression. Well, we all know why that is. Ketamine took away my suicidal ideation and anhedonia straight away. I am sick of being treated like a junkie or someone who needs counselling. I didn't have any problems apart from the TRD. You'd be amazed how many people who work in the mental health arena have no empathy, are not up-to-date, and unwilling to prescribe something that actually helps many people. Yet, they are happy to prescribe all sorts of antidepressants that don't work for quite a few people. I just had bad side effects from those. In the USA, at least, it is widely available. However, it is very expensive to do IV and many people who have severe TRD haven't been able to work for a while. Best of luck to you. I do hope you can change things. xxx

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Regarding safety of long-term use: Here's a preprint I just heard about, reporting on approx 30 people who took ketamine daily, avg. 200 mg/day, for pain, many over a period of years. No evidence of its harming them or of tolerance and decreasing efficacy with time:

https://www.researchgate.net/publication/342966205_Long_Term_Safety_and_Efficacy_of_Sub-Lingual_Ketamine_Troches_Lozenges_in_Chronic_Non-Malignant_Pain_Management/link/5f0faf5292851c1eff15527a/download

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Typo: "You won’t have [to] get anything injected"

Thank you for writing this!

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I'm not sure what the rules are around here about commenting so much after the fact. Maybe this will get no visibility. But I thought I'd put forward my N of 1 results.

I have an interesting hippie pyschiatrist and he was pretty open to prescribing ketamine, had done it before. Since I'd had infusions a few times for nerve conditions he felt safer in doing it. For one or two hundred bucks I got 30 ketamine troches of 100 mgs each. That was the good part.

I grew up believing Mormon and have almost no experience with drugs. The infusions were something else. When I started the troches there were a few really nice experiences, but nowhere near as intense as the high dose infusions (as expected). But I had some good sensations and feelings and felt, a couple of times, like I was on the verge of figuring out some major breakthrough for my depression and my life. But I never got there.

Then I started having severe difficult with just how utterly nasty the troches were. I tried the original flavor of marshmallow cream, as well as a lemon flavor. I added jolly ranchers, life savers, etc. I read that maybe most of the effect is through the lining of the mouth, not swallowing, so I tried just swishing it around for 20 minutes. All of those helped, but for some reason it got worse and worse with every treatment. The last time I did a treatment I ended up violently throwing up with stomach cramps and spasms.

That's part of the reason I'm stopping the treatment. But also it just didn't seem to help my depression. Like I said, maybe if I could have been more regular and had a breakthrough or good experiences it would have helped, but it was spotty. When I moved to the "not swallowing" approach the results varied widely. Once it hit me like a ton of bricks but other times I felt nothing. I know this article said that it's not so much the experience as it is the changes in the brain, but I didn't notice anything helpful other than potential breakthroughs and positive feelings during treatment.

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