THE JOYFUL REDUCTION OF UNCERTAINTY

Ketamine: An Update

In 2016, I wrote Ketamine Research In A New Light, which discussed the emerging consensus that, contra existing theory, ketamine’s rapid-acting antidepressant effects had nothing to do with NMDA at all. I discussed some experiments which suggested they might actually be due to a related receptor, AMPA.

The latest development is Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism, which finds that the opioid-blocker naltrexone prevents ketamine’s antidepressant effects. Naltrexone does not prevent dissociation or any of the other weird hallucinatory effects of ketamine, which are probably genuinely NMDA-related. This suggests it’s just a coincidence that NMDA antagonism and some secondary antidepressant effect exist in the same drug. If you can prevent an effect from working by blocking the opiate system, a natural assumption is that the effect works on the opiate system, and the authors suggest this is probably true.

(unexpected national news tie-in: Kavanaugh accuser Christine Blasey Ford is one of the authors of this paper)

In retrospect, there were warnings. The other study to have found an exciting rapid-acting antidepressant effect for an ordinary drug was Ultra-Low-Dose Buprenorphine As A Time-Limited Treatment For Severe Suicidal Ideation. It finds that buprenorphine (the active ingredient in suboxone), an opiate painkiller also used in treating addictions to other opiates, can quickly relieve the distress of acutely suicidal patients.

This didn’t make as big a splash as the ketamine results, for two reasons. First, everyone knows opiates feel good, and so maybe this got interpreted as just a natural extension of that truth (the Scientific American article on the discovery focused on an analogy where “mental pain” was the same as “physical pain” and so could be treated with painkillers). Second, we’re currently fighting a War On Opiates, and discovering new reasons to prescribe them seems kind of like giving aid and comfort to the enemy.

Ketamine is interesting because nobody can just reduce its mode of action to “opiates feel good”. Although it was long known to have some weak opiate effects, it doesn’t feel good; all the dissociation and hallucinations and stuff make sure of that. Whatever is going on is probably something more complicated.

The psychiatric establishment’s response, as published in the prestigious American Journal of Psychiatry, is basically “well, f@#k”. Here we were, excited about NMDA (or AMPA) giving us a whole new insight into the mechanisms of depression and the opportunity for a whole new class of treatment – and instead it looks like maybe it’s just pointing to The Forbidden Drugs That Nobody Is Supposed To Prescribe. The article concludes that ketamine should not be abandoned, but ketamine clinics under anaesthesiologists should be discouraged in favor of care monitored by psychiatrists. I will try not to be so cynical as to view this as the establishment seizing the opportunity for a power grab.

What happens now? A lot of this depends on addiction. One way we could go would be to say that although ketamine might have some opiate effects, it’s not addictive to the same degree as morphine, and it doesn’t seem to turn users into drug fiends, so we should stop worrying and press forward. We could even focus research on finding other opiates in a sweet spot where they’re still strong enough to fight depression but not strong enough to get people addicted. Maybe very-low-dose-buprenorphine is already in this sweet spot, I don’t know.

But all of this is going to be shaped by history. Remember that heroin was originally invented (and pushed) as a less-addictive, safer opiate that would solve the opiate crisis. Medicine has a really bad habit of seizing on hopes that we have found a less addictive version of an addictive thing, and only admitting error once half the country is addicted to it. And there are all sorts of weird edge cases – does ketamine cross-sensitize people to other opiates? Does it increase some sort of domain-general addiction-having-center in the brain? I know substance abuse doctors who believe all of this stuff.

Also, should we start thinking opiates have some sort of deep connection to depression? “Depression is related to the stuff that has the strongest effect on human happiness of any molecule class known” seems…actually pretty plausible now that I think about it. I don’t know how much work has been done on this before. I hope to see more.

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62 Responses to Ketamine: An Update

  1. Watchman says:

    Doesn’t the comment “Depression is related to the stuff that has the strongest effect on human happiness of any molecule class known” need a bit more nuance? For a start I’d suggest you need something in there to indicate depression is not the same thing as being unhappy, so in some cases an opiates effect is not simply going to be about cheering you up through chemical stimulation; it’s going to be a bit more complex (at least I hope so, or all the really helpful people who’ve told me to cheer up when I’ve been in a down phase were actually right…).

    More to the point though, isn’t some depression linked to addictive behaviours, perhaps due to the effects of these on the brain or because of the struggle with coping with the social implications of the condition (wish I could remember where I read that; might even have been here thoigh), and if so isn’t even a mild opioid hardly ideal for depression where addiction is in itself a factor?

  2. Robert L says:

    Does ketamine not feel good? Its numerous abusers presumably think it does.

    • Scott Alexander says:

      I honestly don’t know what they’re thinking.

      People abuse salvia, so I guess it takes all types to make a world.

      • Peter Gerdes says:

        Man I found Ketamine to be great fun. It’s like super super nitrous (as one might expect).

        Some people dislike opiates thought so to each their own.

        Salvia isn’t directly fun the way Ketamine is….indeed it’s overall weird and unpleasant but the intense experiences can be an interesting time.

        I always felt that Salvia feels just like one would imagine drugs should feel…like someone went into your CNS and scrambled the shit out of it.

        • Deiseach says:

          Luckily for you, we do have some knowledge of what it’s like to have the shit scrambled out of your CNS.

          Epilepsy! Polio! Encephalitis! Palsy! Parkinsons! Alzheimers! Multiple Sclerosis!

          Good luck with finding something to give you all the fun effects of these scramblers!

          (This is the point at which me and other fuddy-duddy no-fun old conservatives go about drugs legalisation because what can it possibly hurt “Fucking idiots“).

          • Adam Kadmon says:

            If there were safe, fully reversible drugs that temporarily mimicked these conditions then I would absolutely try a few for curiousity’s sake. My grandmother died after a particularly aggressive run of Alzheimer’s and I would very much like to have known what it was like for her, wandering around her memory palace as the lights winked out one by one. Maybe it would have granted some insight as to how she could have been comforted. In fact, I might encourage any doctors working on those diseases to do the same, so that they’d have some direct experience of what their patients endure.

            Also, your comment seems 1 or maybe 2 standard deviations more hostile than perhaps is necessary.

          • Mark Atwood says:

            Also, your comment seems 1 or maybe 2 standard deviations more hostile than perhaps is necessary.

            I disagree.

            Remember, Deiseach’s dayjob consists in significant part with dealing with the wake of shit, agony, and devastation left in the wake of an unending cohort of people who scrambled thier CNS “for fun”. They had the fun, and now everyone around them pays the cost without having had the fun.

          • Gerry Quinn says:

            Nobody scrambles their CNS for fun in a way analogous to those.

            Even if enough alcohol or something else can make you fall down, you are using it for temporary, more interesting effects.

          • Peter Gerdes says:

            I said it *felt* like one might *think* (naively and before trying) monkeying up the CNS via drugs might feelt.

            Yes, used frequently Ketamine can cause some degree of damage like many other dissociates but it’s still (used infrequently) not a bad risk reward trade off at all. I don’t believe we have any evidence of Salvia causing long term harms at all.

            Frankly, the overuse of these two drugs doesn’t seem as bad as that of alcohol where chronic abuse is both a real danger and leads to one of the most horrible conditions (the dementia resulting from failure of blood cleaning organs) caused by drug abuse anywhere.

            Besides if you want to talk about banning drugs what is it about drugs in particular as opposed to all the other potentially dangerous activities that people find appealing to do that warrant calling them out for special treatment. Indeed, the very fact that your response to a comment that merely described my personal feelings about the effects of said drugs but didn’t bring up policy at all was so emotional suggests that this dry risk/reward consideration is not your true objection.

          • Freddie deBoer says:

            Human beings take chemicals to change their consciousness. This has always happened and will always happen and any position that does not reflect those two facts are not adult positions.

      • emmag says:

        It makes it easier to think in contextless valenceless ways at lower doses.

      • naughtyhash says:

        As a casual recreational user of various drugs (mostly psychedelics, cannabis, and ketamine), I can safely say that the ketamine high is one of my favorites.

        Taken in a favorable set and setting (I prefer a dimly-lit room with great music and a couple of friends) and at the right dose (30-75mg insufflated), it induces fascinating visual effects, a philosophical mindset, physical pleasure and relaxation, and a general sense of being at ease.

        I find the antidepressant effects to be profound but sometimes inconsistent. The recreational effects, however, are quite predictable and enjoyable.

      • vaticidalprophet says:

        Wait until you hear about deliriants.

      • raj says:

        Experience doesn’t have to “feel good” to be worth pursuing. Novel mental states are inherently valuable for their own sake.

      • JRG says:

        Salvia divinorum has a compound that is a selective kappa-opioid agonist, which is probably why those people like it.

      • StataTheLeft says:

        In my experience, taking ketamine at the relatively low doses recommended for a sublingual anti-depressant effect, it just feels nice. Pleasant/slightly euphoric, relaxing. Makes me physically less coordinated (I can still type but not as well), a bit less coherent, and a bit goofier. To the extent that I have visual hallucinations, they’re very subtle: “the grass looks slightly prettier and more vivid than usual.”

        N=1 but for me at least the high is much closer to taking a benzo than what I think you’re imagining. Presumably the dissociation, hallucinations, etc kick in at a higher dose. Maybe they’re also more common if you don’t take it sublingually?

    • Winter Shaker says:

      Its numerous abusers presumably think it does

      And, presumably, also its numerous recreational users whose use is not causing sufficiently significant problems to themselves or others to count as ‘abuse’. Did you mean to exclude them from your analysis?

    • vaticidalprophet says:

      Dissociatives aren’t as purely euphoric as many drug classes, but they’re still frequently positive experiences to both the experiencing and remembering self (hallucinogens tend to give a lot more to the latter than most drugs).

    • Freddie deBoer says:

      It’s fun but not in any way like the fun of opiates. Different in both degree and kind.

  3. 27chaos says:

    I will try to be charitable and avoid viewing this as the establishment seizing the opportunity for a power grab.

    Very nitpicky: here, as well as on the subreddit, we’re seeing a gradual watering down of the concept of charity, which I think is unfortunate. I would have preferred you make this joke/point in a different way.

    • Mark Atwood says:

      I will try to be charitable and avoid viewing this as the establishment seizing the opportunity for a power grab.

      I will not so pretend, it is a power grab. However, it’s a very unwise and dangerous power grab. Your field of medical practice does not appear to generally have to deal with the problem of licensed practitioners diverting the drugs that they prescribe.

      Anaesthesiologists have to deal with this ALL THE TIME. The drugs they handle generally are used inside the actual care clinic, and they generally work shoulder to shoulder with other practitioners from other fields. And even so, that field has a standard process for dealing with the problem, that was slowly and painfully evolved over time in teeth-gritted barely-there cooperation with licensing and law enforcement authorities.

      Psychiatry should not want to Go There, even for the aboveboard reason of patient care.

      They should instead want to make the recommendation, and then have a different MD actually write the Rx, and then have an anaesthesiologist actually administer the ketamine, inside an existing secure clinic.

      • Janet says:

        THIS.

        A medical degree or license doesn’t magically protect a person from bad life choices, dishonesty, greed, or just naivety about their patients. Better by far to leave this particular treatment modality to people who have been dealing with this in all its gory details, for many decades. (Not to mention, anesthesiologists will also have vastly more experience with that drug, and more ability to recognize and deal with the inevitable issues– idiosyncratic reactions, cross-reactions with various other drugs, legal questions like “can I drive in CA after this?”, etc.)

        It simply staggers me that ANYBODY could just now be realizing that opioid abuse was due to self-medicating psychological pain, BTW. So, let me go ahead and say it here: if it becomes known that all you have to do is tell Dr. A. that you’re thinking of killing yourself and you get a free, clean, recreational high– you’re going to get one hell of a load of young people showing up at your office, repeating the magic phrase word-for-word. And not too long after that, you’re going to be in an MMA match for your license and livelihood.

        I’m 100% behind working out whether ketamine or buprenorphine is useful for depressed patients, and if so, for getting them reliable access to treatment. I don’t doubt for a minute that psychological pain is “real” pain. But this needs to be handled by specialists, for a lot of reasons.

      • JRG says:

        While I am sure it is not quite as bad as what anesthesiologists have to deal with wrt prescribing opioids and the many opportunities for malfeasance that presents, psychiatrists certainly do regularly prescribe some drugs that are strongly coveted substances of misuse, specifically benzos and stimulants. Every single practicing psychiatrist had had patients demanding these things and trying stratagems to obtain them in the absence of compelling reasons to believe they will be therapeutically useful. I would also say that all psychiatrists in a community of any size can tell you exactly who the local Candyman is, i.e., the colleague and ostensible peer who appears to be willing to give high doses of Adderall IR and Xanax to just about anyone (often to the same person concurrently). A good number of psychiatrists in this country also face legal sanctions/jail time for running benzo/stimulant mills, though again, the scope for malfeasance is probably less than it is for a shady pain clinic.

        Navigating this dilemma is something every psychiatric trainee is exposed to over the course of their residency.

  4. entobat says:

    Lots of “updates on drugs” posts in the past few days. Are you going through old posts and looking for ones where you can make interesting additions to your past conclusions? Are you looking into a bunch of drugs as part of your job and sharing what you learn here? Did I accidentally vote for you on the Writing Lots About Drugs board on Tuesday?

    • Deiseach says:

      Did I accidentally vote for you on the Writing Lots About Drugs board on Tuesday?

      Great, now you’ve got me thinking Scott is conducting a controlled clinical trial about the cumulative effect of drugs posts on his test subjects (us) 🙂

      “First subject to register a complaint appeared on Friday 9th November – unusual sensitivity to reading drugs posts or merely less tolerance than other subjects? Note to investigate further”.

    • Vivificient says:

      Hey, it’s not just drugs–there was also the one about preschool. It’s just the week of updates to previous opinions in general. Who knows what the next one could be?

      Personally, I’m hoping for “Cancer in Whales: An Update” or “Ars Longa, Vita Brevis: An Update”. I’ll also settle for “Horses Are Just Elongated Cows: I Was Wrong.”

      • Iknownothing says:

        Frequency of posts seems to have increased overall. This increase is probably related to his recent post about blog page view decline.

        I know he’s regained my views, which I’ll admit have declined in recent months.

      • Iguana says:

        This comment finally made me register an account after three years of lurking. I’m in the middle of an unpleasant task and started to despair of it, but after reading “elongated cows: I was wrong” I burst into laughing and regained some perspective. Whoever you are, thank you, you have created significant utilons.

  5. Password says:

    Since my personal experience seems unusually relevant to this post, here’s my anecdote.

    I’m in my early 30s and was diagnosed with atypical depression over a decade ago, but in hindsight exhibited symptoms starting in my teens. I spent years in therapy (both individual and group) and have tried over a dozen antidepressants, adjuncts, thyroid boosters, and assorted other treatments like Adderall and lithium with no effect. When those failed me I moved on to Transcranial Magnetic Stimulation and then a course of a dozen ECT treatments, also with no effect besides the typical ECT memory side effects. After all that I tried some ketamine treatments under the supervision of a doctor running an experimental trial.

    My first ketamine treatment was an infusion, followed by somewhere between 5-10 injections (as opposed to infusions) of increasing dosage occurring twice a week. I don’t recall the dosages involved, but the last few treatments were at the maximum dose he felt comfortable administering even without any negative effects on my part. All of the treatments got me high, with the initial infusion having the strongest effect. I would receive the ketamine treatment and then be left alone in a darkened room for about an hour, which I mainly spent lying back in a chair with my eyes closed (though I sometimes opened them and looked around me if the mood struck).

    I experienced strong imagery in the style of a music visualizer, with the most memorable instance being imagery of myself flying through a grid of Minecraft/voxel style cubes. I tended to let my mind drift in a dreamlike state, but I was always aware I had received the treatment and never hallucinated in the sense of confusing imagery with reality.

    While I was under the influence my mood would improve in the same way it does when I drink alcohol, but after an hour or so the effect dissipated and there was no lasting effect.

    After my last injection my doctor mentioned that my response was different from what he usually observed in a couple ways. First, I had told him that the infusion was stronger for me than the injections, while his other patients had apparently found the opposite to be true. Second, during each treatment he would peek in the room a couple times and ask me how I was doing, to which I basically answered “I’m fine”; apparently his other patients had a tendency to be highly emotive, talking about how they wanted to hug the tree outside the window or similarly “under the influence” behavior.

    With regards to addiction, I don’t know what the addiction profile of ketamine is like but I never felt the urge to seek any out after the trial.

  6. Peter Gerdes says:

    We could also give up the idea that opiate maintenance is the end of the world. People maintained on buprenorphine live perfectly fine and it’s certainly a less bad way to live than constant depression. I mean it’s not nothing to be stuck taking a drug with some significant withdrawal effects but it’s sure as hell a lot better than severe depression. However, I’m afraid this won’t be taken seriously because many people lump all kinds of depression together and of course we don’t want to treat mild depression this way.

    I should acknowledge a horse in this race as I’ve stayed on buprenorphine for the past 15 years exactly because going off it resulted in a return of serious depression even months after full elimination. Sadly, after moving finding treatment by people who even acknowledge such effects are possible and have read the literature is hard.

    Not to mention that I’ve had friends die because of severe treatment resistant depression so I believe strongly that severe suicidal inclinations persisting over years despite treatment attempts should inspire a search for extreme measures in just the same way that we would for treatment resistance cancer or a serious risk of a life threatening heart attack.

    • Deiseach says:

      I think part of the problem is drugs that have previously been abused then being trialled as medications. There’s going to be a lot of resistance to legalisation or even wide-spread testing because of the fears of potential abuse, the way that people abused the medical marijuana loophole (“oh doctor I have a pain in my elbow” “really, here’s your script for medical cannabis to be used for medical reasons of pain relief only and certainly not for getting high, you understand?” *nod and wink on both sides*).

      I don’t know what the answer is. I’ve had long-term suicidal ideation for years but it’s not severe enough that I’ve ever tried doing anything (though I have had occasional strong impulses to do so) and the attitude of my doctor and the failed attempt at accessing therapy seemed to be ‘so long as you’re not cutting yourself and don’t have a plan to off yourself and have not even tried offing yourself, it’s not a problem wanting to be dead all the time, so stop asking for anti-depressants, you don’t need them’. I don’t know. Good luck and if it works for you, I hope you do find someone to prescribe and monitor for you!

      • Peter Gerdes says:

        the attitude of your doctor here should be malpractice. The goal is to enable people to have enjoyable, worthwhile lives and depression is probably even more of a threat to this than physical ailments.

        There are plenty of people who live happy fulfilling lives despite serious untreated medical ailments that no doctor in the west would bat an eye at taking extreme measures to treat yet, by definition, being depressed stops you from living a happy fulfilling life.

        So no, I don’t think the primary problem is that they have been abused (though it is probably part of the issue). I mean we don’t have a problem giving even opiate addicts with cancer opiates for their pain. the problem is people acting like depression isn’t every bit as serious an affliction that warrants taking the same risks to treat as cancer, heart disease or other major physical malady.

        • cuke says:

          I agree with this. My work as a therapist with people who have severe, treatment-resistant depression is agony, and I would be thrilled to have really any halfway decent option for them, and then let them make an informed choice about the risks (as we do with cancer patients). Their lives are constantly at risk anyway. And these are folks whose suffering is unremittingly severe despite the fact that they work hard in therapy, eat right, sleep enough, all the lifestyle stuff, and take their antidepressants. This is a minority of people with depression, but wow, are they suffering with no help in sight.

          It feels pretty clear to me that if someone were in that kind of constant unremitting pain in a physical sense that doctors would be pulling out the stops to get their pain under control. This kind of mental suffering (which also often comes with all kinds of physical pain) is no less life-threatening and disabling. But instead, many of these folks are told by doctors, friends, and family that they just aren’t trying hard enough, that they need to “snap out of it,” “be more grateful for what they have,” and so on.

          Some of them find limited, occasional relief from benzos, for comorbid anxiety. And often keeping anxiety under control reduces the depression a bit. But of course, doctors are just as reluctant to prescribe benzos as opiates, even with people who have no substance abuse history. I get that this is a really complicated issue, but I also see the debates around dealing with the opioid crisis taking on cartoonish knee-jerk tones that are more likely to impede real solutions.

          The reluctance in the U.S. to promote medical management of opioid addiction feeds into this I believe. I’ve watched family members spend tens of thousands of dollars to put their kids through fancy abstinence rehab programs again and again but be unwilling to support medical management, which all the evidence tells us is more effective and allows people to function in their lives again, thus avoiding things like prison and homelessness. We have a very hard time being clear-eyed about this issue, preferring to shame people instead, whether they’re addicted or depressed.

          • cryptoshill says:

            There’s a moral component to this – we think that people are just supposed to be Strong Enough to never be addicted to opiates again.

            The reason why functional alcoholics exist is because alcohol is easily obtainable, everywhere – at reasonable prices that don’t involve you having to be friends with Local Shady Meth Guy and his Friends.

            It’s a lot harder to “just stay off the drugs” when your whole social circle is drug-involved.

    • Jliw says:

      Same here, my friend. I was horribly depressed, to the point of literally doing nothing except sitting and staring, for most of my life; I have been put on every possible drug you can think of. My ultimate psychiatrist was very open-minded and even gave me a chance with amphetamine and alprazolam… but nope, nuthin’.

      The miracle that saved my life was trying an opioid. Maintenance is just fine by me if I can actually have a life; it’s really not too bad.

      There are reasons to believe that problems with one’s endogenous opioid peptides can exist and manifest as treatment-resistent depression. I have personal reasons, as well — e.g., the other problems I suffered from (irritable gut, restless legs) were also instantly treated by opioids, and I’ve never suffered nausea or constipation from them.

      My money’s always been on “it’s the opioids, you fool!” re: treatment-resistent depression.

      • Peter Gerdes says:

        Out of curiosity are you maintained on a partial agonist/antagonist like buprenorphine or a full agonist? At least in my experience they have very different effects even long term with long term buprenorphine maintenance offering less sustained opiate like effects than maintenance on a full agonist like methadone.

        Also one wonders if some effects at other receptors like kappa have some role (you get a very intense experience of a change in kappa stimulation if you go from high dose methadone directly to bup without going into wd first….though you may not pay much attention to it given how miserable you will be at the time).

        Interestingly, I believe that (like many SSRIs are claimed to do) I’ve found maintenance on bup seems to make me a little bit less emotionally responsive to the environment (movies don’t quite make me cry or feel full of joy quite as much etc..). Maybe this is an illusion just because w/d does make me feel emotions more strongly and it’s been forever since I’ve been off but I think it’s real.

  7. Deiseach says:

    Although it was long known to have some weak opiate effects, it doesn’t feel good; all the dissociation and hallucinations and stuff make sure of that.

    Given that ketamine is an abused drug, I think that demonstrates plenty of people do think it feels good, all the weird stuff notwithstanding.

    As for the disassociation, “ketamine takes you out of your own head” sounds good to me in the throes of a bad episode of “why can’t I just turn off my fucking brain and get it to leave me alone?”

    Remember that heroin was originally invented (and pushed) as a less-addictive, safer opiate that would solve the opiate crisis.

    And cocaine in the late 19th century was seen as a wonder drug that could be used to treat morphine addicts with no side-effects whatsoever, and indeed we all know the history of Coca-Cola. People have long been chasing after “this makes you feel great, gets rid of what ails you, and has no downsides at all!”

  8. Peter Gerdes says:

    Also maybe we could try a bit harder to find a way to eliminate opiate tolerance effects (for awhile there were some interesting results about tolerance and NMDA receptors but I don’t think that fully panned out) or find other drugs that boost mood without the strong withdrawal effects. After all the fact that it’s pleasurable and people like using it is a *good* thing not a bad thing (it poses difficulties but one could give people implants or other long acting forms). The bad thing about opiates is that they produce tolerance and withdrawals not that they make people happy when the take them.

    While you’ve convinced me that depression is a unique disorder and in most cases isn’t just the result of having a low happiness set point or just getting stuck in a self-reinforcing spiral of bad events I still think that our best bet in treating it might be to give up the idea of producing a drug that makes depressed people better and leaves everyone else alone and instead look for a drug that boosts mood for everyone with minimal long term tolerance or withdrawal effects.

    I mean we’ll never totally get rid of tolerance but we may be able to minimize it so that long term treatment retains a significant effect.

  9. Manx says:

    Any thoughts on how likely the antidepressant effects of tianeptine – which you mentioned previously – are related to it’s weak opiate effects? Like ketamine it also has effects at AMPA and NMDA receptors, though without the hallucinations. There have been several studies that find the opiate agonist Buprenorphine helpful for depression. The important question in my mind is does the effect last? Can people experience continued improvement in their hedonic tone, or will they just adjust their baseline to whatever dose of opiates they are given? To me that needs further investigation. Given that at least some opiate addicts can be treated indefinitely with buprenorphine and maintain their hedonic tone, it seems possible that some people really just need an adjustment in their opiate system and this will just work. On the other hand, there are plenty of opiate addicts who relapse and don’t recover, so I don’t feel I can state this with confidence. And once you’ve fucked your opiate system – it seems to remain fucked. My preliminary assessment is that other antidepressant options should be exhausted first, but for treatment-resistant depression it might be worth a go since at that point the benefits outweigh the risks…

  10. ZachJacobi says:

    Scott, would I be reading too much into this if I updated towards anything that releases endorphins (exercise, spicy food, etc.) actually being a mechanistic treatment for some depressions? This would suggest that people who deal with depression by running might actually be on to something (although obviously there’s no guarantee it would work for everyone).

    It also feels like it would make the relationship between depression and self-harm make sense in the same way as the relationship between schizophrenia and smoking. There’s obviously a good narrative explanation, but having a supplementary mechanistic one would be very interesting.

    (N.B. for those who don’t know; endorphin = endogenous morphine)

    • Peter Gerdes says:

      Probably not. There is every difference in the world between maintaining a constant stimulation of a receptor and cycling it from on to off during the day. It could well be that maintaining someone on opiates treats depression but the ups and downs from endorphin rushes followed by down times makes it worse. Not suggesting it does but pointing out how different it is.

      • christianschwalbach says:

        I certainly have noticed that my running performance has dropped off the past year when I feel more Depressed (as with many people, each day is different), but I do also feel much happier and at peace after I run, so the effect, while blunted , is certainly still there. There is a community of both endurance and power athletes looking at Marijuana effects on athletic performance, and research has been done as to the effects of opioids on increasing endurance in a physiological, less than psychological manner. In a way the system, when activiated by MJ compounds, takes some of the brakes off of athletic processes, which is just like I feel when Depression lifts and I run. Much easier, less heavy leg feeling, more mental clarity, etc…

      • cuke says:

        I had thought there was lots of unequivocal evidence that exercise is one of the most effective treatments we have for mild-to-moderate depression (probably not severe).

  11. vV_Vv says:

    Also, should we start thinking opiates have some sort of deep connection to depression? “Depression is related to the stuff that has the strongest effect on human happiness of any molecule class known” seems…actually pretty plausible now that I think about it. I don’t know how much work has been done on this before. I hope to see more.

    So can we just replace the “serotonin hypothesis” of depression with the “endorphins hypothesis”? Actually it makes more sense.

  12. Doug S. says:

    Opiates were the drug treatment for depression before more modern drugs were invented. They do work, but usually the side effects make them undesirable these days…

  13. megavolt says:

    Interesting to hear about the opioid aspect of ketamine.

    Contra your article, there are certainly ketamine fiends and like cocaine and nitrous it a drug with a common use pattern of fiending.

    And unfortunately there are quite negative health effects on bladder and kidney. These people are in the bay and it’s an active concern for those of whose subculture has a lot ketamine use in it.

    The opioid connection makes me wonder how much the ketamine addictions I have observed are explained via the opioid aspect.

  14. Mark Atwood says:

    As you point out, it’s plausible when actually confronted. We’ve avoided thinking about this by dismissing opiates as “merely physical” “pleasure”, which makes zero sense when actually bothering to listen to what the people who use opiates “recreationally” actually say.

    As the quote goes, a heroin high feels like being in love.

    Right there, that should have caught everyone’s attention.

    • Gerry Quinn says:

      I heard a quote that it was just like being Jesus’s son, and you don’t really care any more about all the politicians making crazy sounds, and all the people putting everybody else down, and all the dead bodies piled up in mounds.

      But I guess he just didn’t know.

  15. JRG says:

    One of the truly novel antidepressants that was in the pipeline until very recently was a combination of buprenorphine and samidorphan (a potent mu-opioid antagonist and weak kappa-opioid agonist). The clinical data was a bit mixed (missed endpoints in two Phase III trials, beat placebo in a third Phase III trial) but an NDA was submitted earlier this year. The samidorphan was really in the mix to reduce abuse liability, as far as I understand, but it may also be preventing actual useful action.

    We will probably not be seeing this in clinic anytime soon, unfortunately, as the FDA Psychopharmacological Advisory Committee voted overwhelmingly against an MDD indication earlier this month. Final decision is due on January 31 of next year; still possible it will be approved, but rare for FDA to go against the Advisory Committee.

    https://en.wikipedia.org/wiki/Buprenorphine/samidorphan

    https://endpts.com/fda-experts-gun-down-alkermes-pitch-for-alks-5461-slamming-the-company-on-multiple-fronts/

    At least we’re getting esketamine and brexanolone next year (probably). One wonders based on the apparent importance of opioid system in ketamine’s anti-depressant effectiveness if rapastinel (which antagonizes NMDA) will ever see the light of day. Certainly we hear much less about it now…

    • Peter Gerdes says:

      Seems like even the bup/sam combo leaves a fair bit of net mu activation if this study of drug liking is anything to go on: http://sci-hub.tw/10.1002/jcph.1280

      I know from personal experience that the inclusion of nalaxone in the buprenorphine/nalaxone combo is pretty much pointless since buprenorphine binds to the mu receptors too tightly to be displaced by the nalaxone (it does make immediate effects less pleasant especially at lower dosages but even if you inject it there is no precipitated withdrawal and you get the buprenorphine effects fine).

      If the goal is pure kappa activation they should probably just find a more selective agonist but that is probably more expensive than trying to combine existing drugs already approved.

  16. legalmeezer says:

    Anecdotal experience which is consistent with the research: I have suffered from physical pain due to spinal stenosis for years. Opiates due very little to relieve the pain. One doctor suggested that I had a naturally high tolerance to opioids. I used to suffer from depression, and about two years ago started using ketamine to try to treat it. I first tried the self-help method (injecting or snorting stuff I’d ordered off the Internet), and then tried it clinically. It did not help at all. If the opiate aspect of ketamine is what’s responsible for the anti-depressive effects, it would make sense that someone with high opioid tolerance would not benefit much from ketamine.

  17. Doug says:

    Is it not just possible that depression is poly-causal? Maybe opiates have an effect, but so do NMDA. Co-administering naltoxtrene may just act as a “pro-depressant”. Maybe it negates ketamine not by blocking its anti-depressant mechanism, but just by working in the opposite direction on a different system.

    For example, I’m sure co-administering cocaine would “attenuate” alcohol’s impact on sleepiness. That doesn’t mean that alcohol’s hypnotic properties secretly work through the dopamine system. It just means that cocaine is a pretty effective stimulant on its own.

    The Blasey Ford experiment could have addressed this issue by including a third group which just received naltoxtrene alone, no ketamine. If that group wasn’t anymore significantly depressed than ketamine+naltoxtrene, then it would show that naltoxtrene is specifically interacting with ketamine. Rather than just pushing in the opposite direction.

    • christmansm says:

      It is beyond certain that “depression” is a dirty, poorly-characterized, polycausal thing, with the caveat that it’s not really just one thing. That said, we routinely give people naltrexone for opioid and alcohol abuse, and it’s surprisingly neutral and well-tolerated on its own. With overwhelming mu-opioid blockade, they don’t get more depressed or anhedonic or apathetic, they just don’t relapse quite as much.

  18. noahyetter says:

    Also, should we start thinking opiates have some sort of deep connection to depression? “Depression is related to the stuff that has the strongest effect on human happiness of any molecule class known” seems…actually pretty plausible now that I think about it.

    What of humans whose happiness is not affected by opiates? I’ve taken (prescribed!) oxycodone a number of times and it’s not “fun” or anything, it just relieves pain. I understand that this experience, while not typical, is also not rare.

    • The Nybbler says:

      Same here with percocet (oxycodone/acetaminophen). But it may be a matter of dosage and method and possibly particular opiate (though I thought oxy was one of the more euphoria-inducing ones); I’ve never heard of anyone who didn’t get high by shooting up heroin.

  19. algekalipso says:

    Yes! Opioids should be the focus of chemical mental health treatments. Not the dirty street opioids of the present, but non-tolerance-producing *future opioids*. I highly recommend David Pearce’s essay “Future Opioids” (conveniently found in opioids.com). My take is that physical pain is indeed very much implemented with the same underlying neurological principles as psychological pain, and pretending that it is not is a huge sleight of hand by the medical establishment that is delaying the discovery of breakthrough medications for depression and anxiety.

    Of course current opioids have all sorts of negative side effects that make them unusable for mental pain, but here is the thing: We already have proofs of concept that there are biochemical methods to reduce, prevent, and even reverse tolerance to opioids. Rather than putting the efforts of smart budding psychopharmacologists into “finding the next SSRI” we should instead focus their efforts into figuring out how to reverse tolerance.

    I recently wrote about this in my latest article: Anti-Tolerance Drugs. Some of the most promising leads to look into would be: Ibogaine, proglumide, ultra low dose naltrexone, and Ibudilast (AV-411).

    • Lambert says:

      Yeah, I hear Bayer is developing non-addicting opiates. Acetylising morphine looks like the best avenue at the moment.

      • The Nybbler says:

        Just because Bayer got it wrong with diacetylmorphine doesn’t mean it’s not possible, although the string of failures since then is cause for pessimism. It’s possible, even likely, that the mechanism by which opoids addict is the same as or inextricably linked to the mechanism by which they treat.

  20. Doug says:

    Along the lines of esoteric hallucinogens with strange connections to the opiate system… Has there been any investigation of ibogaine as a treatment for depression?

  21. CheshireCat says:

    I recently wrote a comment in the open thread on my experiences self-administering sublingual ketamine once weekly for depression, so I guess now is as good a time as any to have an impromptu AMA on my experiences. Sparknotes:

    – Enormous improvement in mood, anxiety, motivation and energy within 56 hours

    – Very inexpensive all things considered (4 months worth costs me about $26)

    – Treats a stubborn longterm depression that hasn’t responded to anything, and halts depressive episodes in their tracks

    – Anhedonia greatly improved, can enjoy everyday pleasures again

    – Wears off after about 6 days, depression returns in full force

    – Doses aren’t really “fun” and I experience no cravings or other addiction indicators

    – No discernible side effect profile, apart from the dose itself being psychoactive for a few hours

    All in all it has been an enormous success and completely enriched my life. I’m going through extremely high stress events right now and I would seriously be a wreck without it. My current plans are to a) add Wellbutrin to try to further improve anhedonia/emotional reactiveness, b) try a couple of well-supported supplements like SAM-e and L-Methylfolate as adjuncts, and c) use my improved motivation and energy to maintain a workout routine.

    Because at the end of the day, even though ketamine does so much for me, the return of my misery at the end of every week makes it clear that I’m still depressed underneath it all. It does a truly excellent job of treating symptoms and getting me in a position where I can implement lifestyle changes and improve my life in non-medical ways, but I still feel like it needs something more to be a complete depression treatment. That said, it’s still far and away the best depression treatment out there for my money. Putting a pause button on depression for 4-6 days is an enormous deal.

  22. StataTheLeft says:

    Has anybody seen any compelling research on the extent to which people taking anti-depressant level doses of ketamine build tolerance over time?

    • CheshireCat says:

      I haven’t, which is unfortunate because apparently ketamine tolerance is extremely stubborn and sometimes takes years to reset, if it resets at all. I did find one paper, Bonnet 2015, which is focused on tolerance to ketamine’s antidepressant effects. It doesn’t seem like much though.

      There is a wealth of anecdotal evidence from recreational drug users, however (un)reliable that kind of info might be. My general impression from reading those is that low doses once or twice a week probably wouldn’t lead to substantial tolerance. But I really can’t say.

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